Abstract
Consumption of lactic acid bacteria (LAB) has been suggested to confer health-promoting effects on the host. However, effects of LABs have been reported to be species- and strain-specific and the mechanisms involved are subjects of discussion. Here, the possible mechanisms by which LABs induce antipathogenic, gut barrier enhancing and immune modulating effects in consumers are reviewed. Specific strains for which it has been proven that health is improved by these mechanisms are discussed. However, most strains probably act via several or combinations of mechanisms depending on which effector molecules they express. Current insight is that these effector molecules are either present on the cell wall of LAB or are excreted. These molecules are reviewed as well as the ligand binding receptors in the host. Also postbiotics are discussed. Finally, we provide an overview of the efficacy of LABs in combating infections caused by Helicobacter pylori, Salmonella, Escherichia coli, Streptococcus pneumoniae, and influenza virus, in controlling gut inflammatory diseases, in managing allergic disorders, and in alleviating cancer.
Introduction
Lactic acid bacteria (LAB) are a group of gram-positive microorganisms, which mainly produce lactic acid as end fermentation product during carbohydrate metabolism. They can be found in a wide range of foods such as vegetables, fruit, meat, and dairy products. In addition, many LAB species belong to indigenous microflora in various mucosal niches of both humans and animals (George et al. Citation2018). Certain LAB species and strains have been characterized as probiotics (George et al. Citation2018). Probiotics have been defined as living microorganisms, which when consumed in adequate amounts, can confer health benefits to the host (Hemarajata and Versalovic Citation2013). LAB is one of the most commonly applied sources of probiotics, and a variety of beneficial functions have been attributed to consumption of probiotic LAB strains (Bron, van Baarlen, and Kleerebezem Citation2012; Lebeer, Vanderleyden, and De Keersmaecker Citation2008). The majority of established probiotics come from the LAB species Lactobacillus, whereas certain LAB strains within the species Lactococcus and Streptococcus are also recognized for probiotic functionalities (Borchers et al. Citation2009).
Despite broad recognition as probiotic species, the mechanisms by which specific LAB strains contribute to health are still not completely understood (van Baarlen, Wells, and Kleerebezem Citation2013). The most proposed mechanisms include modulation of the composition and function of gut microbiome, improvement of intestinal barrier function, immune modulation, competitive adhesion for pathogens to mucosal sites, attenuation of virulent factors of pathogens, and production of bioactive compounds with anti-infectious or other functional properties. In the present review these potential mechanisms and the explicit modes of actions are discussed in detail. LAB may influence gut microbial communities via the provision of growth substrates for specific commensal microbes. LAB modulate gut mucus barrier via improving the production of mucus components, and enhance intestinal epithelial barrier via regulating tight junction (TJ) networks, lowering apoptosis, and supporting immune signaling in epithelial cells. The host immune function can be modified by LAB via modulating functional activities of different types of immune cells such as natural killer (NK) cells, phagocytes, dendritic cells (DCs), T cells, and B cells (). In these sections examples of specific strains are also included for which it has been proven that well-being is enhanced by one or combinations of these mechanisms.
Figure 1. Schematic representation illustrating key mechanisms through which LAB exert health-promoting effects. LAB can (A) modulate the composition and function of gut microbiota via (B) support of production of metabolites that can serve as growth substrates for specific commensal bacteria. LAB can combat pathogenic infections by (B) producing bioactive components with anti-infectious properties such as short chain fatty acids, bacteriocins, and biosurfactants, (C) inhibiting pathogen adhesion to the mucosal surface, and (D) attenuating the expression of virulent factors. Moreover, LAB can (E) modulate gut mucus barrier and (F) strengthen epithelial barrier. (G) Both innate and adaptive immunity can also be regulated by LAB.
However, most strains probably act via several or combinations of mechanisms depending on which effector molecules they express. Current insight is that these effector molecules are either present on the cell wall of LAB or are excreted. In this review, these molecules are reviewed as well as their associated ligand binding receptors in the host. Finally, examples of LABs are critically discussed for management of pathogenic bacterial and viral infections, gastrointestinal inflammatory disorders, allergy, and cancer.
Although the mechanisms and exact ligand on LABs for management of these diseases remain to be identified, the studies provide a proof of principle. With our review we hope to contribute to design of more systemical studies to create effective formulations of LABs for reproducibly inducing health benefits.
Mechanisms involved in probiotic actions of LAB
Regulation of gut microflora by LAB derived fermentation products
Gut microbiota plays a vital role in maintaining gut immune equilibrium (Derrien and van Hylckama Vlieg Citation2015). Modulatory effects of LAB consumption on gut microbiota have been demonstrated (Hemarajata and Versalovic Citation2013). LAB can influence intestinal microbial communities by providing growth substrates to other species by fermenting carbohydrates and amino acids and formation of secondary metabolites which leads to enhanced richness of specific commensal bacteria (Derrien and van Hylckama Vlieg Citation2015; Pessione Citation2012). An example for this reciprocal nutritional relationship is that LAB-derived lactic acid can be utilized and converted to butyrate by Eubacterium hallii, which is a specie of importance for a balanced microbial community (Engels et al. Citation2016). Moreover, exopolysaccharide synthesized by a wide array of LAB species was found to serve as energy source for symbiosis in microbial populations (Ryan et al. Citation2015).
By modulating gut microbiota, LABs might contribute to prevention of disease such as to reduce chances on pathogenic infection, intestinal inflammation, cancer, and allergy. There are a number of clear examples demonstrating this (Kepert et al. Citation2017; Liu et al. Citation2011; Rodríguez-Nogales et al. Citation2017; Zhang et al. Citation2018). Salmonellla translocation into liver could be attenuated by one-week pre-supplementation of a well-known probiotic strain Lactobacillus (L.) rhamnosus GG, which was partially attributed to the restoration of decreased gut microbial diversity (Zhang et al. Citation2018). Administration of a L. fermentum strain CECT5716 mitigated dextran sodium sulfate-induced colonic damage and suppressed colitis-associated aberrant changes in intestinal microbial composition (Rodríguez-Nogales et al. Citation2017). Liu et al. (Citation2011) reported that a strain mixture of lactobacilli and bifidobacteria mitigated post-surgery infection in colorectal cancer patients accompanied by improvement of intestinal microbial diversity. Moreover, lactobacilli-derived D-tryptophan was shown to beneficially regulate dysregulated gut microbiota, prevent allergic airway inflammation, and create a more balanced immune environment in the gut and lung of mice with experimental asthma (Kepert et al. Citation2017).
Production of bioactive or metabolic compounds with anti-pathogenic effects
LAB strains can produce molecules that reduce the possibility for pathogens to invade the host. The production of lactic acid and short chain fatty acids (SCFAs) such as acetate, propionate, and butyrate, is an example of that. These LAB derived acids create an unfavorable acidic environment for invading pathogens and inhibit their growth (Derrien and van Hylckama Vlieg Citation2015). The lactic acid produced by LABs can also have direct anti-pathogenic effects by disrupting the cell membrane of pathogenic bacteria such as Escherichia (E.) coli, Listeria monocytogenes, and Salmonella (Wang et al. Citation2015). It has suggested that via production of lactic acid, LAB protect against pathogens such as Helicobacter (H.) pylori, Salmonella, and E. coli (Choi et al. Citation2018; Zheng et al. Citation2016). SCFAs production by LAB was also considered as a mechanism responsible for the effects of LAB on cancer such as colorectal cancer due to the apoptosis-promoting properties of SCFAs on cancer cells (dos Reis et al. Citation2017).
Apart from the aforementioned molecules, some LABs synthesize other bactericidal agents such as bacteriocins, biosurfactant, and hydrogen peroxide (Lebeer, Vanderleyden, and De Keersmaecker Citation2008). Strong in vivo evidence that LAB derived bacteriocins are responsible for protective effects on pathogenic infections was provide by van Zyl, Deane, and Dicks (Citation2019), who observed that the mutant strain of L. plantarum 423 without ability to express bacteriocin plantaricin 423 could not confer protection against Listeria in mice. Also, for LAB derived biosurfactant and hydrogen peroxide proof was found for antipathogenic effects especially in the vagina. A vaginal biosurfactant-producing L. crispatus strain BC1 was demonstrated to antagonize urogenital pathogen Neisseria gonorrhoeae (Foschi et al. Citation2017). Stapleton et al. (Citation2011) showed that 10-week intravaginal administration of a hydrogen peroxide-producing L. crispatus strain CTV-05 was effective in diminishing the recurrence of urinary tract infection in women.
Spatial competition to prevent pathogen adhesion to mucosa
Another proposed anti-pathogenic mechanism of LAB is prevention of adhesion of pathogens to the mucosa surface by competition for mucosal adhesion sites (Lebeer, Vanderleyden, and De Keersmaecker Citation2008; van Baarlen, Wells, and Kleerebezem Citation2013). This has been proven to be a mechanism by which L. sobrius, L. acidophilus, and S. thermophilus prevent adherence of pathogenic E. coli on epithelium (Resta-Lenert and Barrett Citation2003; Roselli et al. Citation2007). Many surface components that might contribute to the adhesion of LAB to mucosal surfaces and prevent pathogen adhesion have been identified. These include molecules such as mucus-binding proteins, S-layer proteins, and exopolysaccharide (Ryan et al. Citation2015; Van Tassell and Miller Citation2011). Singh et al. (Citation2018) reported that Mubs5s6 protein, the last two domains of L. plantarum mucus-binding protein Lp_1643 effectively inhibited the adherence of enterotoxigenic E. coli to gut epithelium. L. johnsonii F0421-derived S-layer proteins were shown to dampen the adhesion of Shigella sonnei to human HT-29 gut epithelial cells (Zhang, Zhang, et al. Citation2012). Furthermore, it was demonstrated that exopolysaccharide molecules from L. reuteri DSM17938 and L. reuteri L26 prevented the attachment of E. coli to IPEC-1 porcine epithelial cell line (Kšonžeková et al. Citation2016).
Diminution of pathogenic virulence
In addition to production of bactericidal compounds and competition for adhesion sites, attenuation of expression of virulent factors has been proposed as another essential mechanism underlying the anti-pathogenic effects of LAB (Laughton et al. Citation2006; Li et al. Citation2011; Reid et al. Citation2011; Ryan et al. Citation2009). L. reuteri RC-14 can suppress the expression of staphylococcal exotoxin staphylococcal superantigen-like protein 11 and prevent its spreading in the host (Laughton et al. Citation2006). Li et al. (Citation2011) observed that this same L. reuteri RC-14 dampened the expression of staphylococcal exotoxin toxic shock syndrome toxin-1 in vitro. Probably this was caused by the L. reuteri RC-14 derived cyclic dipeptides (Li et al. Citation2011). L. salivarius strains were demonstrated to inhibit H. pylori-induced infection not only by acid production but also by interfering with expression and secretion of Cag pathogenicity island genes of H. pylori (Ryan et al. Citation2009). In addition to the cytotoxic virulent factor Cag, expression of H. pylori adhesin such as sabA can be decreased by L. gasseri Kx110 A1 and L. brevis ATCC14869, via which adhesion of H. pylori to gastric epithelium was suppressed (de Klerk et al. Citation2016).
Modulation of gut barrier function
Improving the intestinal mucus barrier
LAB have been reported to contribute to mucus barrier function (Dykstra et al. Citation2011; Mack et al. Citation2003; Otte and Podolsky Citation2004; van Beek et al. Citation2016; Wang et al. Citation2014). Mucus layers covering intestinal epithelium are of pivotal importance for gut homeostasis and gut barrier function (Deplancke and Gaskins Citation2001). The primary constituent of mucus are mucins, which are produced by secretory epithelium goblet cell and form the gel structure contributing to the defensive function of mucus (Kim and Ho Citation2010). Aside from mucins, other bioactive factors including goblet cell-synthesized molecules such as intestinal trefoil peptides and resistin-like molecule β, secretory antibodies such as sIgA, and Paneth cell-produced antimicrobial molecules such as defensins and lysozymes are crucial mucus components. These mucus-associated components are trapped in the mucus matrix and contribute to the rheological and defensive properties of mucus barrier (Kim and Ho Citation2010; McGuckin et al. Citation2011). In vitro studies demonstrate that lactobacilli or the probiotic strain mixture VSL#3 elevated the expression of mucins at mRNA and protein level (Mack et al. Citation2003; Otte and Podolsky Citation2004; Ren et al. Citation2018), which is suggested to be a possible mechanism underlying their conferred suppression of pathogenic E. coli adhesion to intestinal epithelium (He et al. Citation2017; Mack et al. Citation2003). Such an anti-pathogenic action of lactobacilli by up-regulation of mucin production can be achieved partly via fortifying mucus barrier, thereby diminishing the access of pathogen such as E. coli to Caco-2 intestinal epithelial cells (He et al. Citation2017). Also secretion of mucins such as MUC2 and MUC3 can lead to their binding with pathogens in the lumen of the gut and reduce pathogen invasion in the host (He et al. Citation2017; Mack et al. Citation2003). Furthermore, in vivo evidence suggest that L. rhamnosus GG restored declined MUC2 expression caused by Pseudomonas (P.) aeruginosa invasion, which might partially mediate L. rhamnosus GG-conferred protection of mice from P. aeruginosa-induced pneumonia (Khailova et al. Citation2017).
Not only direct interaction of LABs with intestinal cells but also LAB-derived molecules such as SCFA (Jung et al. Citation2015) and bioactive proteins (Wang et al. Citation2014) were shown to exert enhancing effects on mucin expression. L. rhamnosus GG-secreted p40 protein induced an epidermal growth factor receptor-dependent enhancement of mucin production both in vitro in LS174T human goblet cells and in vivo in mice, which might be the mechanism underlying the protective property of p40 on epithelial function (Wang et al. Citation2014). Moreover, LAB might also reinforce mucus barrier function via augmenting the production of other mucus elements such as defensins (Nocerino et al. Citation2017; Rizzo, Losacco, and Carratelli Citation2013) and sIgA (Nocerino et al. Citation2017; Zhang et al. Citation2010). L. paracasei CBA L74-fermented products potentiated the production of human defensins and sIgA, via which incidence of infection in children was declined (Nocerino et al. Citation2017). Promotion of human β-defensin 2 and 3 production was suggested to partly mediate L. crispatus ATCC33820-conferred protection on epithelial cells against urogenital pathogen Candida albicans-induced infection (Rizzo, Losacco, and Carratelli Citation2013). The mechanisms by which LABs contribute to mucus barrier function in the intestine are depicted in .
Figure 2. Schematic representation illustrating the effects of LAB on gut barrier. LAB can enhance gut mucus barrier via (A) increasing the production of mucins. In addition to mucins, LAB can also (B) augment the production of other mucus components such as defensins and sIgA. Moreover, LAB can contribute to intestinal epithelial barrier by (C) altering the expression and distribution of tight junctions (TJs)-associated proteins, (D) inhibiting epithelial cell apoptosis, and (E) modifying the immune signaling of intestinal epithelial cells.
Enhancing of gut epithelium function and gut epithelial barrier
A single layer of organized intestinal epithelial cells builds up a defensive barrier effectively separating the underlying immune system from luminal exogenous insults (Wells et al. Citation2011). Also, this part of the barrier function can be modulated by LAB via diverse mechanisms (). The epithelial barrier is a semipermeable cellular filter solely allowing the entry of water, electrolytes, and dietary nutrients from the lumen side, whilst excluding intrusion of luminal microbes and detrimental antigens (Groschwitz and Hogan Citation2009). Paracellular permeability, a pivotal regulator for epithelial barrier function, is regulated by interepithelial junctional complexes such as TJs, desmosomes, and adherens junctions (Groschwitz and Hogan Citation2009; Ohland and MacNaughton Citation2010). TJs are located at the apical site of the lateral membrane between two adjacent cells, and are composed of diverse transmembrane and adaptor proteins such as zonula occludens (ZOs), occludins, and claudins (Groschwitz and Hogan Citation2009; Ohland and MacNaughton Citation2010). LAB can enhance epithelial barrier via regulation of these TJ protein function (Anderson et al. Citation2010; Karczewski et al. Citation2010; Madsen Citation2012; Mennigen et al. Citation2009). L. plantarum strain WCFS1 has been shown to have such an effect in human. Administration of L. plantarum WCFS1 enhanced the expression of TJ proteins ZO-1 and occludin in the duodenal epithelial cells of healthy volunteers (Karczewski et al. Citation2010). Others have suggested that TJ protein enhancement might be one of the most important mechanisms for LAB induced protection of intestinal inflammation, pathogenic invasion, and colorectal cancer (dos Reis et al. Citation2017; Lépine et al. Citation2018; Liu et al. Citation2011; Mennigen et al. Citation2009). There is ample proof that this mechanism is involved in beneficial health effects of LABs. For example, the VSL#3 mixture was shown to reverse aberrant expression and redistribution of TJ proteins (i.e. claudin-1, -3, -4, and -5, occludin, and ZO-1) in mice with dextran sodium sulfate-induced colitis, which might contribute to the alleviation of gut inflammation (Mennigen et al. Citation2009). We previously found that L. acidophilus W37 protected intestinal epithelial cells against Salmonella invasion at least partially via up-regulating the expression of TJ-related proteins such as claudin-4, -15, and -16 (Lépine et al. Citation2018). Moreover, pre- and post-operative supplementation of L. plantarum CGMCC1258, L. acidophilus LA-11, and Bifidobacterium (B.) longum BL-88 in colorectal cancer patients effectively diminished the occurrence of post-operative infection in conjunction with enhanced gut barrier integrity and TJ protein expression (Liu et al. Citation2011).
Occludins, claudins, and ZOs are the most frequently measured TJ proteins in most studies on epithelial barrier function regulation. Of note, apart from those vital TJ formation proteins occludin, ZO-1, ZO-2, and cingulin, Anderson et al. (Citation2010) tested L. plantarum MB452-induced alterations in basal expression level of a range of crucial regulators involved in TJ-correlated signalings by using global gene-expression analysis. L. plantarum MB452 enhanced the expression of occludin, ZO-1, ZO-2, and cingulin, but down-regulated the expression of cytoskeleton protein tubulin and proteasomes (Anderson et al. Citation2010). Moreover, it was shown that LAB not only modulate the expression of the TJ-proteins but can also modulate epithelial barrier function through influencing phosphorylation of TJ proteins (e.g. ZO-1 and occludins) and cytoskeletal proteins (e.g. actin and actinin) (Resta-Lenert and Barrett Citation2003).
In addition to modulation of TJ function, LAB can preserve epithelial barrier function by inhibition of epithelial apoptosis (Dykstra et al. Citation2011; Mennigen et al. Citation2009; Yan et al. Citation2007). Yan et al. (Citation2007) characterized two bioactive proteins p40 and P75 from L. rhamnosus GG, and showed that these two proteins effectively dampened tumor necrosis factor-induced epithelial apoptosis in colon epithelial cell lines and murine colon explants via evoking the apoptosis-antagonizing Akt pathway. In addition, VSL#3 administration was shown to prevent epithelial apoptosis in a murine acute colitis model (Mennigen et al. Citation2009). In another study L. plantarum 299v was shown to stimulate both gene and protein expression of apoptosis-inhibiting HIAP2/cIAP1 in the jejunum of rats (Dykstra et al. Citation2011). Also, L. brevis SBC8803a and a soluble peptide from L. rhamnosus GG were shown to enhance the expression of cytoprotective molecules such as heat shock protein in intestinal epithelium, which is a pivotal mediator in extracellular stress defense of cells and avoider of cell-death (Tao et al. Citation2006; Ueno et al. Citation2011).
LABs can also change immune signaling of intestinal epithelial cells (Wan et al. Citation2016). Gut epithelial cells not only serve as elemental structural components of the gut epithelial barrier, but also initiate immune signals in response to extrinsic stimuli. It has been suggested that some LAB strain such as L. sobrius DSM 16698T or strain mixture such as VSL#3 can also modulate gut epithelial function by affecting epithelium-involved immune signals such as cytokines production (Lépine et al. Citation2018; Roselli et al. Citation2007; Wan et al. Citation2016). For example, the porcine L. sobrius strain DSM16698T potentiated IL-10 secretion in porcine IPEC-1 intestinal epithelial cells, which was demonstrated to fully mediate its protective actions against E. coli K88 invasion (Roselli et al. Citation2007). Enhancement of epithelial barrier by LAB was also suggested to mediate their beneficial properties on allergic disease. For instance, a gnotobiotic mouse model colonized with the mixture of L. casei LOCK0919, L. rhamnosus LOCK0900, and L. rhamnosus LOCK0908 displayed attenuated allergic sensitization, which was suggested to be partly induced by the fortification of gut epithelial barrier function (Kozakova et al. Citation2016).
Modulation of immune function by LABs
Effects on innate immunity
Regulation of host immunity by LAB through their crosstalk with the immune system has been acknowledged as a fundamental mode of probiotic actions (Bron, van Baarlen, and Kleerebezem Citation2012; Lebeer, Vanderleyden, and De Keersmaecker Citation2010; van Baarlen, Wells, and Kleerebezem Citation2013). A large body of research substantiate that both innate and adaptive immune responses can be modified by LAB supplementation (Borchers et al. Citation2009; Cangemi de Gutierrez, Santos, and Nader-MacÃAs Citation2001; de Moreno de LeBlanc, Castillo, and Perdigon Citation2010; Delcenserie et al. Citation2008; Gill et al. Citation2001; Harata et al. Citation2010; Izumo et al. Citation2010; Lin et al. Citation2007; Nagai et al. Citation2011; Nanno et al. Citation2011; Ogawa et al. Citation2006; Pelto et al. Citation1998; Racedo et al. Citation2006; Schiffrin et al. Citation1995; Shu and Gill Citation2002; Takeda et al. Citation2006; Villena et al. Citation2009; Villena et al. Citation2005; Yasui, Kiyoshima, and Hori Citation2004). NK cells and phagocytes such as macrophages, neutrophils, and monocytes as cardinal participants in innate immunity, serve as crucial immunological defense barrier against exogenous invaders, and their functions can be modified by LAB () (Cangemi de Gutierrez, Santos, and Nader-MacÃAs Citation2001; de Moreno de LeBlanc, Castillo, and Perdigon Citation2010; Gill et al. Citation2001; Harata et al. Citation2010; Izumo et al. Citation2010; Lin et al. Citation2007; Nagai et al. Citation2011; Nanno et al. Citation2011; Ogawa et al. Citation2006; Olivares et al. Citation2007; Pelto et al. Citation1998; Racedo et al. Citation2006; Schiffrin et al. Citation1995; Shu and Gill Citation2002; Takeda et al. Citation2006; Villena et al. Citation2009; Villena et al. Citation2005; Yasui, Kiyoshima, and Hori Citation2004). Animal studies on anti-pathogenic potentials of LAB confirm enhancement of phagocyte functions by LAB, causing enhanced clearance of various pathogens including Salmonella typhimurium, Streptococcus (S.) pneumoniae, and E. coli (Cangemi de Gutierrez, Santos, and Nader-MacÃAs Citation2001; de Moreno de LeBlanc, Castillo, and Perdigon Citation2010; Gill et al. Citation2001; Lin et al. Citation2007; Racedo et al. Citation2006; Shu and Gill Citation2002; Villena et al. Citation2009; Villena et al. Citation2005). Animal studies showed that orally or intranasally administration of alive or heat-killed lactobacilli of differential species such as L. acidophilus, L. casei, L. fermentum, and L. rhamnosus augmented phagocytes functions at both the intestinal and extraintestinal level as defined by up-regulated activation of lung macrophages (Cangemi de Gutierrez, Santos, and Nader-MacÃAs Citation2001; Racedo et al. Citation2006), increased numbers of leukocytes and neutrophils in blood and bronchoalveolar lavage (BAL) (Villena et al. Citation2005), enhanced phagocytic activity of phagocytes from Peyer’s patches, spleen, peritoneum, blood, and BAL (de Moreno de LeBlanc, Castillo, and Perdigon Citation2010; Gill et al. Citation2001; Lin et al. Citation2007; Shu and Gill Citation2002; Villena et al. Citation2009; Villena et al. Citation2005). A human trial in healthy subjects also demonstrated that intake of L. acidophilus La1 potentiated the phagocytic activity of blood leukocytes (Schiffrin et al. Citation1995). Intriguingly, L. rhamnosus GG was found to distinctively impact expression of phagocytosis receptors in peripheral neutrophils in healthy participants and individuals with allergies (Pelto et al. Citation1998). In healthy groups, the expression of phagocytosis receptors was elevated by L. rhamnosus GG, whereas in milk-hypersensitive individuals LAB administration attenuated allergen challenge-induced heightened expressions of phagocytosis receptors (Pelto et al. Citation1998).
Figure 3. Schematic representation illustrating the effects of LAB on host immune functions. LAB can influence host innate immunity via (A) enhancing the functions of phagocytes such as macrophages. LAB can (B) be recognized and captured by dendritic cells (DCs), thereby inducing the activation and maturation of DCs. Subsequently, LAB-primed DCs can (C) polarize naïve T cells and direct their differentiation into varying T cell subsets. Moreover, LAB can also (D) alter the production of antibodies such as IgA and IgG in B cells.
In addition to their influence on phagocyte activities, LAB were also suggested to augment NK cell function (Harata et al. Citation2010; Izumo et al. Citation2010; Nagai et al. Citation2011; Nanno et al. Citation2011; Ogawa et al. Citation2006; Olivares et al. Citation2007; Takeda et al. Citation2006; Yasui, Kiyoshima, and Hori Citation2004). L. casei Shirota was shown to enhance pulmonary NK activity and to heighten IL-12 secretion by mediastinal lymph node cells in an influenza infected infant mouse model (Yasui, Kiyoshima, and Hori Citation2004). Moreover, in other murine influenza virus infection models some other LABs such as L. rhamnosus GG, L. pentosus S-PT84, and L. delbrueckii ssp. bulgaricus OLL1073R-1 potentiated NK function in lung or spleen, which might account for LAB-elicited protective actions against influenza virus infection (Harata et al. Citation2010; Izumo et al. Citation2010; Nagai et al. Citation2011). In healthy volunteers, consumption of L. casei ssp. casei JCM1134T initiated an increased peripheral NK frequency (Ogawa et al. Citation2006). L. fermentum CECT5716 also enhanced peripheral NK proportion in healthy subjects and fortified the immune efficacy of influenza vaccination (Olivares et al. Citation2007). Both in vivo and ex vivo L. casei Shirota enhanced peripheral NK activity in healthy humans, which correlated with L. casei Shirota’s capability of elevating peripheral IL-12 production (Nanno et al. Citation2011; Takeda et al. Citation2006). Apart from healthy subjects, L. casei Shirota intake also boosted NK cell function in patients with bladder or colorectal cancer and thereby decreased the occurrence of relapse (Nanno et al. Citation2011).
Effects on adaptive immunity
Many LAB strains including the extensively studied VSL#3 mixtures influence adaptive immunity. This often starts with modulation of DCs (). DCs are a crucial cell type participating in both innate and adaptive immune signaling. Different LAB strains have been suggested to divergently regulate the maturation and activation of DCs, which is accompanied by increased expression of major histocompatibility complex molecules as well as co-stimulatory molecules such as CD40, CD80, CD83, and CD86, and by enhanced cytokine secretion (Borchers et al. Citation2009; Smelt, de Haan, Bron, van Swam, Meijerink, Wells, Faas, et al. Citation2013). In vitro studies on LAB-induced modulation of DC function applied multiple types of DCs from humans and rodents including peripheral blood monocyte-derived DCs (MDDCs), enteric lamina propria (LP)-derived DCs (LPDCs), mesenteric lymph node (MLN)-derived DCs (MLN DCs), and bone marrow-derived DCs (BMDCs) (Borchers et al. Citation2009; Hart et al. Citation2004). It was proposed that DCs of different sources might react differently to LAB strains (Borchers et al. Citation2009). Despite this, specific LAB-mediated similar effects on polarization of DCs of different sources were obtained (Borchers et al. Citation2009; Drakes, Blanchard, and Czinn Citation2004; Hart et al. Citation2004). For instance, stimulation of both human LPDCs and human MDDCs by VSL#3 resulted in elevated IL-10 production (Hart et al. Citation2004). Another study also reported augmented IL-10 production level induced by VSL#3 in BMDCs (Drakes, Blanchard, and Czinn Citation2004). Our own previous in vivo study also demonstrated the strain-dependent effects of LAB on DC distribution and function which were different in the small and large intestine (Smelt, de Haan, Bron, van Swam, Meijerink, Wells, Faas, et al. Citation2013). Of the three tested LAB strains, i.e., Lactococcus (Lc). lactis MG1363, L. plantarum WCFS1, and L. salivarius UCC118, only L. salivarius UCC118 potentiated the regulatory CD103+ DCs population in the small intestine Peyer’s patches of healthy mice (Smelt, de Haan, Bron, van Swam, Meijerink, Wells, Faas, et al. Citation2013). The intestinal site-dependent effects were illustrated by the observation that L. salivarius UCC118 increased the activated CD86+ DCs proportion in the small intestine Peyer’s patches but reduced the activated CD80+ DCs proportion in the small intestine LP (Smelt, de Haan, Bron, van Swam, Meijerink, Wells, Faas, et al. Citation2013).
LAB-primed DCs can polarize T lymphocytes and instruct the differentiation of naive T cells into divergent T cell subsets, subsequently priming distinctive immune responses () (Borchers et al. Citation2009). Of note, it was validated both in vitro and in vivo that LAB-polarized DCs can trigger the generation of regulatory T cells (Foligne et al. Citation2007; Lebeer, Vanderleyden, and De Keersmaecker Citation2008; Smelt et al. Citation2012; Smits et al. Citation2005). Similar to the aforementioned effects of LAB on DC responses, we also observed strain- and small and large intestinal dependent effects of LAB on T cell differentiations and responses in healthy mice (Smelt et al. Citation2012). Only one out of the tested LAB strains, i.e., L. plantarum WCFS1, specifically augmented regulatory T cell population in the spleen but not in the MLN (Smelt et al. Citation2012). For T helper (Th) cell subsets, we found that only L. salivarius UCC118 induced a decline in Th17 cell proportion in MLN but not in the spleen (Smelt et al. Citation2012). Those LAB strains with abilities of eliciting regulatory cell subsets are promising candidates for managing inflammatory disorders.
Aside from DC and T cells, B cells are another important lymphocyte subpopulation in adaptive immunity (Delcenserie et al. Citation2008). A large number of studies indicate that LABs alter IgA and IgG production by B-cells (). IgA, a major antibody isotype in the mucosal system, is a vital player in mucosal defense against noxious agents (Bron, van Baarlen, and Kleerebezem Citation2012). Animal experiments disclosed that LAB strains such as L. casei CRL431, L. pentosus b240, L. delbrueckii ssp. bulgaricus OLL1073R-1, and L. rhamnosus GG enhanced production of total or antigen-specific IgA at both intestinal and respiratory level, and/or at a systemic level such as on serum and plasma values, which might be a principal mechanism involved in LAB-exerted protection against pathogenic microorganisms such as Salmonella Typhimurium, influenza virus, S. pneumoniae, and E. coli (de Moreno de LeBlanc, Castillo, and Perdigon Citation2010; Kobayashi et al. Citation2011; Nagai et al. Citation2011; Racedo et al. Citation2006; Shu and Gill Citation2002; Villena et al. Citation2009; Villena et al. Citation2006; Villena et al. Citation2005; Zhang et al. Citation2010). Consumption of L. pentosus b240 prior to influenza virus infection in mice reduced the viral titers in the lung and up-regulated specific IgA responses in BAL (Kobayashi et al. Citation2011). Further, regulation of adaptive antibody responses by LAB is commonly concomitant with modification of innate immunity such as phagocytosis (de Moreno de LeBlanc, Castillo, and Perdigon Citation2010; Racedo et al. Citation2006; Shu and Gill Citation2002; Villena et al. Citation2009; Villena et al. Citation2006; Villena et al. Citation2005). However, the systemic and mucosal IgA production induced by LAB such as L. rhamnosus GG and L. fermentum CECT5716 is different in healthy and diseased individuals (Malin et al. Citation1996; Olivares et al. Citation2007). Besides IgA, also IgG can be altered by the administration of LAB strains such as by L. pentosus b240, L. rhamnosus GG, and L. casei CRL431, which might be an important mechanism mediating the anti-pathogenic effects of these LAB strains (Kobayashi et al. Citation2011; Nagai et al. Citation2011; Racedo et al. Citation2006; Villena et al. Citation2009; Villena et al. Citation2006). In the aforementioned study investigating the protective potentials of L. pentosus b240 for influenza virus infection in mice, specific IgG levels in BAL were also enhanced by L. pentosus b240 treatment (Kobayashi et al. Citation2011).
Molecular basis for gastrointestinal mucosa-LAB interaction
The previous sections review the different host cellular levels at which LABs might influence host health. LABs with specific cell-wall components interact with specialized receptor on host cells. The molecules on LABs that interact with gastrointestinal mucosal cells are often referred to as LAB-derived microbe associated molecular patterns (MAMPs) and the receptors on host cells are referred to as pattern recognition receptors (PRRs) (Lebeer, Vanderleyden, and De Keersmaecker Citation2010). Below we will review the current insight in the MAMPs on LABs responsible for PRR-signaling in the host. Such knowledge is essential in designing effective bacteria-based strategies to manage health and disease.
Toll-like receptor (TLR)–LAB interaction
TLR is the most widely studied PRR family and is regarded as a canonical player mediating LAB-initiated signaling responses in the host (Bron, van Baarlen, and Kleerebezem Citation2012; Lebeer, Vanderleyden, and De Keersmaecker Citation2010). TLRs are expressed on a wide range of cell lineages within the gut including on intestinal epithelium, subepithelial stromal cell, and subepithelial immune cell such as DC, macrophage, T cell, and B cell (Cario Citation2005; Wells et al. Citation2011). Distinctive expression levels, distribution patterns as well as signaling specificities of TLRs in various cell types of different gastrointestinal compartments are strategically designed to maintain mucosal homeostasis (Wells et al. Citation2011). The binding of ligands to TLR recruits particular adaptor molecules such as myeloid differentiation primary-response protein 88 (MyD88), and subsequently evokes downstream signaling cascades (Akira and Takeda Citation2004; Lebeer, Vanderleyden, and De Keersmaecker Citation2010). Adaptor protein MyD88 engages in all the TLRs signaling except TLR4-mediated type I IFNs induction and TLR3 pathway (Akira and Takeda Citation2004).
TLR2 is identified as one major TLR responsible for initiating LAB-induced signaling response via recognizing cell surface components of LAB such as peptidoglycan (PGN), wall teichoic acid (WTA), and lipoteichoic acid (LTA) (Bron, van Baarlen, and Kleerebezem Citation2012). For fully priming downstream signaling cascades, TLR2 forms heterodimers with different co-receptors such as TLR1 and TLR6 and thereby triggers differential immune responses (van Bergenhenegouwen et al. Citation2013). TLR2/TLR1 heterodimer recognizes triacyl lipopeptides (Akira and Takeda Citation2004), and was proposed to elicit pro-inflammatory responses (DePaolo et al. Citation2012; DePaolo et al. Citation2008). In contrast, TLR2/TLR6 heterodimer is responsible for ligating diacyl lipopeptides and LTA (Akira and Takeda Citation2004), and engages in mounting regulatory responses (DePaolo et al. Citation2012; DePaolo et al. Citation2008). Therefore, variations in the structural characteristics of LAB-derived TLR2 ligands may result in the activation of different TLR2 pathways. In our previous study, among a number of LAB strains of various species only 6 strains such as L. acidophilus CCFM137, S. thermophilus CCFM218, L. fermentum CCFM381, L. fermentum CCFM787, L. plantarum CCFM634, and L. plantarum CCFM734 were confirmed to activate TLR and to signal via TLR2/TLR6 pathway (Ren et al. Citation2016).
In addition to TLR2, it was shown that TLR5 transduced immune signals toward flagellin-producing LAB strains such as L. ruminis ATCC27782 via flagellin-TLR5 interaction (Neville et al. Citation2012). Moreover, TLR9 was defined to mediate the probiotic mixture VSL#3-elicited alleviation of colitis in mice via interaction with this mixture-derived unmethylated CpG DNA (Rachmilewitz et al. Citation2004). These finding suggest that LAB-derived flagellin or CPG DNA could independently interact with corresponding TLRs without the requirement of viable or intact bacterial cell context (Neville et al. Citation2012; Rachmilewitz et al. Citation2004).
Other PRRs–LAB interaction
Apart from TLRs, other PRRs such as intracellular nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) and C-type lectin receptors (CLRs) can also mediate certain LAB strains-initiated signaling responses. Well-defined NLRs such as NOD1 and NOD2 are differentially expressed in the gut. NOD1 is expressed in multiple cell types comprising intestinal epithelium and DC, whereas absence of expression of NOD2 in intestinal epithelial cells was reported (Wells et al. Citation2011). NOD1 is known to recognize PGN-derived structural motif γ‑d-glutamyl-mesodiaminopimelic acid of specific lactobacilli, while NOD2 senses PGN muramyl dipeptide in all microbes including on LABs (Bron, van Baarlen, and Kleerebezem Citation2012; Kozakova et al. Citation2016; Lebeer, Vanderleyden, and De Keersmaecker Citation2010). Notably, NOD2-PGN interplay was defined to be essential in immuno-stimulatory and anti-inflammatory functions of specific LAB strains (Fernandez et al. Citation2011; Foligne et al. Citation2007; Zeuthen, Fink, and Frøkiaer Citation2008). For example, TLR2 and NOD2 were suggested to act in synergism to prime regulatory DCs in response to a L. rhamnosus strain (Lr32), resulting in amelioration of inflammatory responses (Foligne et al. Citation2007). Further, L. casei LOCK0919, L. rhamnosus LOCK0908, and L. rhamnosus LOCK0900 were shown to stimulate both TLR2 and NOD2 pathways (Kozakova et al. Citation2016). These findings also correlate with the broadly accepted view that multiple rather than single PRR–MAMP interactions dictate the ultimate tune of immune responses toward specific LAB (Lebeer, Claes, and Vanderleyden Citation2012).
LAB were reported to signal through DC-SIGN to confer inflammation-inhibiting effects (Konstantinov et al. Citation2008; Smits et al. Citation2005). DC-SIGN, a receptor of CLR family, can respond to carbohydrate structures on microbial cells (Konstantinov et al. Citation2008). DC-SIGN is primarily expressed on DCs, and is a key mediator in DC responses to environmental stimuli (Konstantinov et al. Citation2008). LAB strains from the species L. reuteri and L. casei were verified to ligate DC-SIGN, thereby modulating DC function to promote regulatory T cell responses (Smits et al. Citation2005). Moreover, S layer protein A of probiotic L. acidophilus NCFM was reported to drive the development of tolerogenic DC subtype via binding to DC-SIGN (Konstantinov et al. Citation2008).
PRRs-LAB crosstalk and strain-dependency of LAB-mediated regulation
Species- and strain-specific functional properties of LAB have been described in many studies (Cruchet et al. Citation2003; Sgouras et al. Citation2005; Yang et al. Citation2015; Youn et al. Citation2012). From the perspective of molecular communication of LAB with host gut mucosa, this species- and strain-specificity of LAB may partially arise from the distinctions in MAMPs expression on LAB cells, which result in different actions of LAB on PRR signaling pathways (Lebeer, Claes, and Vanderleyden Citation2012; Lee et al. Citation2013). PGN and TA (especially LTA), have been characterized as pivotal determinants for disparate cellular responses elicited by different LAB strains (Lebeer, Claes, and Vanderleyden Citation2012; Lee et al. Citation2013). Despite shared conserved structural features, slight structural differences of PGN or TA among diverse LAB strains give rise to varying functional activities of LAB (Fernandez et al. Citation2011; Lee et al. Citation2013; Smelt, de Haan, Bron, van Swam, Meijerink, Wells, Kleerebezem, et al. Citation2013). Anti-inflammatory effects conferred by L. salivarius Ls33 but not L. acidophilus NCFM was due to the existence of additional muropeptides in PGN structure of strain Ls33 (Fernandez et al. Citation2011). Subtle structural mutations of LTA in LAB cells such as switch from D-Ala to D-glucose substitution, deletion of D-Ala substitution and D-alanine esters, and LTA deletion have been shown to reverse immunomodulatory performances of LAB strains (Claes et al. Citation2010; Grangette et al. Citation2005; Smelt, de Haan, Bron, van Swam, Meijerink, Wells, Kleerebezem, et al. Citation2013). Our previous study showed that D-Ala substitution is vital for both the pro- and anti-inflammatory properties of L. plantarum WCFS1 in mice (Smelt, de Haan, Bron, van Swam, Meijerink, Wells, Kleerebezem, et al. Citation2013).
Previous studies showed that specific structural components separated from LAB cells were able to activate PRR (particularly TLR) signaling pathways. Moreover, some of these “independent components” interact with TLRs differently from that when they are in the context of intact LAB cells (Kaji et al. Citation2010). This can be attributed to structural properties of LAB cells (i.e. spatial organization of cell surface components) that can influence the spatial accessibility of specific cell components to PRRs when they are in intact LAB cell context (Kaji et al. Citation2010). In addition, interactions between diverse PRRs triggered by different LAB ligands determine the final cellular host-response to LAB (Foligne et al. Citation2007; Kaji et al. Citation2010). This is also the reason why combinations of different LAB strains or their derived ligands may elicit different cytokine responses (Christensen, Frøkiaer, and Pestka Citation2002; Kaji et al. Citation2010). A better understanding of these molecular interactions is crucial for targeted modulation of host immune functions and defining effective mixtures of multiple strains or their derived bacterial ligands.
Aside from complexity in biochemical or conformational characteristics of LAB cell components, secreted metabolites or bioactive proteins from LAB strains can also mediate host-LAB interplay and contribute to strain-specific effects (Ren et al. Citation2020; Tao et al. Citation2006; Voltan et al. Citation2008; Wang et al. Citation2014; Yan et al. Citation2007). For instance, a L. crispatus strain-released hydrogen peroxide regulated PRR expression levels via activating peroxisome proliferator activated receptor-γ signaling (Voltan et al. Citation2008).
Do LABs have to be alive to confer beneficial effects
It has been shown that growth conditions and phase of harvesting, that is, log or stationary phase, of administered LAB affects the composition of the LAB cell surface and therewith the presence of MAMPs. As a consequence this impacts the final effects of LAB on the host (van Baarlen et al. Citation2009). Some strains such as L. gasseri TMC0356, L. brevis SBC8803, and L. casei CRL431 do not even have to be alive when administered when they carry the beneficial ligands on their cell wall (Kawase et al. Citation2010; Kawase et al. Citation2012; Ueno et al. Citation2011; Villena et al. Citation2009; Villena et al. Citation2005). However, for other strains such as L. johnsonii La1, L. plantarum 299v, and L. rhamnosus, gastrointestinal transit tolerance and viability in vivo can impact their specific regulatory activities (Cruchet et al. Citation2003; Dykstra et al. Citation2011; Youn et al. Citation2012). For those strains whose viability is a determining factor in their clinical effects, direct interactions of host cells with intact bacterial cells or/and their produced functional metabolites in vivo probably are prerequisites for their beneficial effects. For some strains whose intracellular molecules such as CPG DNA-evoked signaling responses are parts of mechanisms of their actions, bacterial viability can also influence their effects since their intracellular ligands can only be released following lysis of bacterial cells and subsequently become accessible to PRRs expressed on host cells. Taken together, the impact of LAB survival ability on their modulatory effects in the host needs to be addressed for individual LAB strains.
Postbiotics is a new, emerging term proposed to define beneficial effects of microbial fermentation products as well as enhanced generation of supporting microbial cell components following bacterial lysis (Wegh et al. Citation2019). Previous findings have suggested that apart from probiotic bacteria the formation of postbiotic compounds such as organic acids, enzymes, exopolysaccharides, and bacterial cell lysates may provide additional physiological benefits (Aguilar-Toalá et al., Citation2018; Ren et al. Citation2020; Verkhnyatskaya et al. Citation2019). Therefore, postbiotic compounds with bioactive properties may offer novel options for the development of nutraceutical products, dietary supplements, or functional foods. When compared to postbiotic products, traditional probiotic products require a more stringent control of manufacturing, transport, and storage to ensure optimal bacterial viability in products. Postbiotics probably suffer less from this and may also overcome the potential adverse effects of viable probiotic bacteria when applied in highly vulnerable populations such as premature babies and immunocompromised individuals, which endows postbiotics with a more favorable safety profile (Wegh et al. Citation2019). Nevertheless, considering the distinctive biochemical properties of different postbiotic compounds, the manufacturing process and storage methods of postbiotic products should be carefully optimized to achieve desirable functional efficacy.
Health promotion and disease control by LABs
Efficacy of LABs in pathogenic infections
In the previous sections, we have described the mechanisms by which LAB can contribute to reduction of pathogenic infections. Crucial mechanisms are regulation of gut microbiome, production of antibacterial metabolites or bactericides, inhibition of pathogen adhesion to gut mucosa, suppression of virulent factors, reinforcement of gut barrier function, and enhancement of host immunity. Proof of principle of administration of LABs to manage pathogenic disease have been shown for pathogenic bacteria such as H. pylori (Sgouras et al. Citation2004; Wang et al., Citation2004), Salmonella (Wu et al. Citation2018; Yang et al. Citation2017) and E. coli (Wang et al. Citation2018; Zhang et al. Citation2010), but also against viral infections such as influenza virus (Hori et al. Citation2001, Citation2002; Yasui, Kiyoshima, and Hori Citation2004) (). These studies will be reviewed below.
Table 1. Effects of LAB on pathogenic infection in experimental animals and humans.
Efficacy of LABs in reducing H. pylori gastric infection
Helicobacter pylori is a pathogen affecting the stomach, and has been linked with enhanced chances to develop chronic gastritis, peptic ulcer disease, and gastric cancer (Kabir et al. Citation1997; Wang et al., Citation2004). Different in vitro experiments and in vivo animal experiments have been performed to select LAB strains that effectively suppress or prevent H. pylori infection. An effective strain was L. salivarius WB1004 that showed inhibitory capability on the adhesion of H. pylori to both murine and human gastric epithelial cells as well as on IL-8 induction in vitro (Kabir et al. Citation1997). This L. salivarius strain weakened colonization of H. pylori in the stomach in a gnotobiotic mouse model and by that prevented but also expedited recovery from H. pylori infection (Kabir et al. Citation1997). Moreover, postinfection administration of L. gasseri OLL2716 in H. pylori-infected germ-free mice effectively dampened the colonization of clarithromycin-resistant H. pylori (Ushiyama et al. Citation2003). Probiotic L. casei Shirota was also reported to exert long–term beneficial effects against H. pylori colonization and attenuated the associated gastritis (Sgouras et al. Citation2004). A mechanistic study showed that L. johnsonii La1 ameliorated H. pylori-induced gastritis probably through dampening proinflammatory chemotactic responses and attenuating subsequent intramucosal infiltration of lymphocytes and neutrophils (Sgouras et al. Citation2005).
In addition to experimental animal studies, LABs have also been tested in the fight against H. pylori in clinical trials (Cruchet et al. Citation2003; Francavilla et al. Citation2008; Gotteland et al. Citation2008; Hauser et al. Citation2015; Wang et al., Citation2004) (). Six-week consumption of a commercial yoghurt containing L. acidophilus La5 and B. lactis Bb12 by patients with H. pylori infection significantly reduced H. pylori density (Wang et al., Citation2004). Cruchet et al. (Citation2003) showed that also L. johnsonii La1 has such an effect in children and demonstrated that it is important to administer this strain alive. Besides, probiotic LAB strains have been applied as an adjunct treatment to support the conventional antibiotics therapy against H. pylori infection and to ameliorate the side effects of antibiotic treatment (Francavilla et al. Citation2008; Hauser et al. Citation2015). Improvement of H. pylori eradication rate and alleviation of antibiotic therapy-associated adverse effects by a strain mixture of L. rhamnosus GG and B. lactis Bb12 were validated (Hauser et al. Citation2015). However, L. reuteri ATCC55730 intervention did not enhance the H. pylori eradication rate with antibiotic therapy in H. pylori-infected patients, but four-week treatment of this L. reuteri strain prior to antibiotic therapy decreased H. pylori density and alleviated H. pylori-induced gastrointestinal symptom (Francavilla et al. Citation2008). This illustrates species and strain dependent efficacy of LAB and the differences in preventing infection and contributing to enhanced clearance of the pathogens. As outlined in the preceding sections this is probably due to the different mechanism by which different LAB strains and species contribute to anti-pathogenic effects.
Efficacy of LABs in reducing enteric Salmonella infection
Another enteropathogen in which efficacy of LAB against infection and symptoms has been shown is Salmonella. Experimental animal studies examining the effects of LAB in fighting Salmonella infection exploited oral infection models, and mainly focused on Salmonella colonization in the gut (Abatemarco Júnior et al. Citation2018; He et al. Citation2019; Mian et al. Citation2016; Wu et al. Citation2018; Yang et al. Citation2017; Yu et al. Citation2017), Salmonella invasion into visceral organs (liver and spleen) (Abatemarco Júnior et al. Citation2018; He et al. Citation2019; Zhang et al. Citation2018), and local/systemic immunity against Salmonella (Abatemarco Júnior et al. Citation2018; Mian et al. Citation2016; Yang et al. Citation2017; Zhang et al. Citation2019) (). In many studies on efficacy of LABs against Salmonella infection administration of LAB prior to infection of animals was applied. Administration of L. rhamnosus strain GG before Salmonella challenge was shown to effectively reduce Salmonella colonization and translocation in weaned piglet models (Yang et al. Citation2017; Yu et al. Citation2017; Zhang et al. Citation2019; Zhang et al. Citation2018). Anti-Salmonella efficacy of this well-recognized probiotic strain may be ascribed to its role in inhibiting infection-induced gut microbial changes (Zhang et al. Citation2019; Zhang et al. Citation2018), in enhancing intestinal epithelial barrier function (Zhang et al. Citation2018), and in fortifying innate/adaptive immunity against Salmonella (Yang et al. Citation2017; Zhang et al. Citation2019). Moreover, other LAB strains such as L. johnsonii L531 and L. acidophilus ATCC4356 were shown to restore declined SCFA production and to suppress goblet cell depletion during Salmonella infection (He et al. Citation2019; Wu et al. Citation2018), which are other possible mechanisms involved in the anti-Salmonella actions of LABs. Prophylactic efficacy of LAB against Salmonella infection was also studied and confirmed in both conventional and germ-free mice by Abatemarco Júnior et al. (Citation2018).
Furthermore, the supportive effects of LAB on antibiotic therapy against Salmonella infection was also demonstrated (Truusalu et al. Citation2008). For example, supplementation of L. fermentum ME-3 with the antibiotic ofloxacin achieved complete Salmonella eradication in the liver, serum, and ileum of mice (Truusalu et al. Citation2008). Clinical efficacy of LAB against Salmonella infection was evaluated by Alm (Citation1983), who observed reduced Salmonella colonization in Salmonella carrying patients by consumption of a L. acidophilus strain. However, another strain L. plantarum 299 v was shown to be ineffective in combating infection in Salmonella-infected patients (Lönnermark et al. Citation2015).
Efficacy of LABs in reducing enteric E. coli infection
Multiple animal infection models were used to study potential beneficial effects of LAB in fighting E. coli infection in the gut (Shu and Gill Citation2002; Wang et al. Citation2018; Zhang et al. Citation2010) (). Shu and Gill found that both pre- and post-infection administration of probiotic L. rhamnosus HN001 (DR20™) effectively decreased E. coli-induced morbidity in mice and reduced E. coli invasion to blood, liver as well as to spleen (Shu and Gill Citation2002). These beneficial effects might be attributed to strengthened humoral and cellular immunity by LAB supplement, which initiated stronger enteric specific IgA responses and phagocytosis in blood leucocytes (Shu and Gill Citation2002). Another study evaluated anti-E. coli efficacy of L. reuteri HCM2 in mice and observed that E. coli colonization and infection-induced inflammation in jejunum were dampened by this strain (Wang et al. Citation2018). Maintaining gut microbiome stability was suggested as one possible mechanism that mediated the anti-E. coli effects of L. reuteri HCM2 (Wang et al. Citation2018). Moreover, in post-weaning piglets alleviation of E. coli infection was achieved by supplementation of L. rhamnosus GG and reuteran-producing L. reuteri TMW1.656 (Yang et al. Citation2015; Zhang et al. Citation2010). In addition, effectiveness of L. acidophilus strains against E. coli infection was confirmed in feedlot cattles (Peterson et al. Citation2007).
In human trials the clinical efficacy of LAB against E. coli invasion was also evaluated (Ten Bruggencate et al., Citation2014) but to the best of our knowledge was not successful up to now. In healthy subjects, a mixture of L. helveticus Rosell-52, L. rhamnosus Rosell-11, B. longum ssp. longum Rosell-175, and Saccharomyces cerevisiae var boulardii CNCM I-1079 was shown to be ineffective in reducing the colonization of enterotoxigenic E. coli in the intestine and attenuating E. coli challenge-induced increased fecal output (Ten Bruggencate et al., Citation2014). Moreover, in infants with colic L. reuteri DSM17938 did not inhibit gut E. coli colonization (Sung et al. Citation2014).
Efficacy of LABs in avoiding respiratory S. pneumoniae infection
Streptococcus pneumoniae is one of the most common respiratory pathogens and the major cause of pneumococcal infectious disease (Villena et al. Citation2011). Pneumococcal infections still have a high occurrence and mortality rate despite currently available prophylactic and therapeutic approaches (Villena et al. Citation2011). Because of this low efficacy of current therapeutic approaches there have been many efforts to reduce S. pneumoniae infection with LABs. There is substantial evidence from animal experiments that specific LAB stains are capable to stimulate host innate and adaptive immunity against S. pneumoniae infection (Agüero et al. Citation2006; Racedo et al. Citation2006; Villena et al. Citation2009; Villena et al. Citation2005) (). Protective capabilities of L. casei CRL431 have been systemically evaluated in various murine pneumococcal infection models with different supplementation schemes (Racedo et al. Citation2006). Different pretreatment durations (2, 5, and 7 days) of L. casei CRL431 against S. pneumoniae challenge were tested (Racedo et al. Citation2006). Interestingly, it was found that a short duration of 2 days of LAB intake prior to S. pneumoniae-infection conferred the most effective protection in mice. This was illustrated by a more declined pneumococcal density as well as enhanced phagocytosis in lung, and increased specific IgG and IgA antibodies titers in serum and BAL compared with 5 and 7 days administration of L. casei CRL431(Racedo et al. Citation2006).
The effectiveness of L. casei CRL431 in potentiating host immune defense against S. pneumoniae was also evaluated in malnutritioned mice (Agüero et al. Citation2006; Villena et al. Citation2009; Villena et al. Citation2005). These mice were subjected to protein-free diet for 21 days after weaning (Villena et al. Citation2005). After pneumococcal challenge, the mice were fed with live L. casei CRL431 and received protein containing diet again. The mice with a diet containing L. casei CRL431 had a faster recovery of impaired defense immunity caused by nutritional deficiency, a higher pathogen eradication rate, improved tissue damage in lung, and up-regulated phagocytosis of blood and BAL neutrophils (Villena et al. Citation2005). Similar beneficial effect on S. pneumoniae infection was obtained by intranasally administration of malnutritioned mice with either alive or heat-killed L. casei CRL431 (Villena et al. Citation2009). Since crosstalk between inflammation and coagulation processes play an important role in infection (Agüero et al. Citation2006), the influence of LAB treatment on inflammation and coagulation processes using the same L. casei CRL431 intervention strategy (Villena et al. Citation2005) was studied in a S. pneumoniae infection-caused pneumonia model without inducing sepsis (Agüero et al. Citation2006). It was observed that L. casei CRL431 supplementation normalized IL-4 production, heightened IL-10 levels in BAL, and improved blood coagulation (Agüero et al. Citation2006). Additionally, malnutritioned mice with dietary supplementation of yoghurt containing L. bulgaricus CRL423 and S. thermophilus CRL412 exhibited a quicker regaining of defective immune functions against pneumococcal infection (Villena et al. Citation2006). Furthermore, protective potentials of L. fermentum and L. pentosus were also demonstrated in S. pneumoniae-infected healthy mice (Cangemi de Gutierrez, Santos, and Nader-MacÃAs Citation2001; Tanaka et al. Citation2011).
The efficacy of LABs in reducing respiratory colonization of S. pneumoniae was tested in clinical trials (Franz et al. Citation2015; Glück and Gebbers Citation2003). Three-weeks of consumption of a probiotic drink containing L. acidophilus, L. rhamnosus GG, S. thermophilus, and Bifidobacterium sp diminished the incidence of S. pneumoniae in the nasal microbiota of healthy participants (Glück and Gebbers Citation2003). However, it was shown that supplementation of L. casei Shirota could not decrease the pharyngeal colonization of S. pneumoniae in healthy subjects with low NK cell functions (Franz et al. Citation2015).
Efficacy of LABs in reducing viral infections induced by influenza virus
Influenza virus-caused acute respiratory infection is characterized by high morbidity and fatality worldwide especially in susceptible subjects such as children and elderly (Kobayashi et al. Citation2011). Present anti-influenza treatments were not efficacious enough owing to rapid viral mutations, thus demanding novel generic treatment strategies (Nagai et al. Citation2011). LAB strains with recognized properties of strengthening host unspecific innate immunity gain extensive research interests for protecting hosts from influenza virus infection. Anti-influenza potential of probiotic L. casei Shirota has been explored in mice models of different ages (Hori et al. Citation2001, Citation2002; Yasui, Kiyoshima, and Hori Citation2004). Intranasal inoculation of adult mice with L. casei Shirota prior to influenza viral challenge reduced viral density in the respiratory tract and up-regulated survival rate of infected mice, which probably resulted from L. casei Shirota-induced Th1 cytokine responses (Hori et al. Citation2001). In both infant and elderly mice, prophylactic oral supplementation of L. casei Shirota was also shown to boost respiratory innate immunity and to protect mice against viral infection (Hori et al. Citation2002; Yasui, Kiyoshima, and Hori Citation2004). Mice administrated with probiotic L. rhamnosus GG via the intranasal route before influenza infection displayed improved general health during the influenza infection period (Harata et al. Citation2010). Moreover, L. gasseri TMC0356 was shown to confer beneficial effects against influenza (Kawase et al. Citation2010; Kawase et al. Citation2012). The importance of viability and inoculation route of L. rhamnosus for efficacy of influenza management was investigated by Youn et al. (Citation2012), who reported that intranasal administration of live L. rhamnosus provided the most protection. In a clinical trial the supportive potential of L. fermentum CECT5716 derived from human breast milk on anti-influenza vaccination was examined (Olivares et al. Citation2007). It was found that 2-week consumption of this L. fermentum strain before and after vaccination enhanced NK cell frequencies, augmented specific IgA responses, and decreased the occurrence of influenza-like illness during a 5-month post-vaccination period (Olivares et al. Citation2007).
Gastrointestinal inflammatory disorders
Inflammatory bowel disease (IBD) is a common and prevalent gut inflammatory disorder characterized by recurrent intestinal inflammatory symptoms. Crohn’s disease (CD) and ulcerative colitis are two primary clinical forms of IBD and have distinctly different symptoms. Inflammation in ulcerative colitis is generally limited to the large intestine, whereas CD affects the whole gastrointestinal tract (Celiberto et al. Citation2017). The pathogenesis of IBD is broadly regarded as a combination of genetic predisposition, aberrant gastrointestinal microbiota ecology, and defective host gastrointestinal immune-sensitivity to commensal flora or other luminal antigens (Celiberto et al. Citation2017). Because of the influence of microbiota ecology and immunity, probiotic LAB strains with defined beneficial properties have received interests in IBD management (Celiberto et al. Citation2017).
CD Management and LABs
IL-10-deficient mice were found to spontaneously develop human CD-like colitis under conventional conditions. Microbes are involved in development of this CD-like colitis in mice as colitis was not observed in germ-free IL-10-deficient mice (Madsen et al. Citation2001). Several studies evaluated preventative and therapeutic benefits of various LAB strains in this genetically predisposed CD mouse model (Madsen et al. Citation2001; Madsen et al. Citation1999; McCarthy et al. Citation2003; Schultz et al. Citation2002; Sheil et al. Citation2004) (). Administration of a single L. reuteri strain in IL-10 deficient mice boosted the colonization of intestinal lactobacilli and ameliorated colitis (Madsen et al. Citation1999). Subsequently, this research team examined therapeutic effect of VSL#3 in the IL-10-deficient murine model. It was observed that VSL#3 reversed colonic inflammatory responses in IL-10-deficient mice as well and possibly had such an effect through strengthening the intestinal epithelial barrier (Madsen et al. Citation2001). Also oral and subcutaneous administration of L. salivarius UCC118 were shown to mitigate colitis and to facilitate the establishment of an anti-inflammatory cytokine environment in an IL-10-deficient CD mouse model (McCarthy et al. Citation2003; Sheil et al. Citation2004). In addition, the prophylactic and curative efficacy of L. plantarum 299V was shown in IL-10 deficient mice with colitis (Schultz et al. Citation2002).
Table 2. Effects of LAB on gastrointestinal inflammatory disorders in experimental animals and humans.
Also, in some clinical trials the protective potentials of specific probiotic LAB strains such as that of L. rhamnosus GG, VSL#3, and L. johnsonii LA1 were tested (). However, although some efficacy was shown there were discrepancies between efficacy of LAB strains (Bousvaros et al. Citation2005; Fedorak et al. 2015; Gupta et al. Citation2000; Malin et al. Citation1996; Marteau et al. Citation2006; Prantera et al. Citation2002; Van Gossum et al. Citation2007). L. rhamnosus GG was reported to stimulate intestinal IgA responses (Malin et al. Citation1996) and to restore intestinal barrier function in children with CD (Gupta et al. Citation2000). This strain however was not capable to delay or to prevent the recurrence of CD symptoms in either children or adults with CD remission (Bousvaros et al. Citation2005; Prantera et al. Citation2002). Notably, VSL#3 administration during and after the surgical treatment resulted in lower recurrence rate and attenuated mucosal inflammatory response (Fedorak et al. 2015). Besides, L. johnsonii LA1 intake was not efficacious to prevent endoscopic relapse in CD patients after surgery (Marteau et al. Citation2006; Van Gossum et al. Citation2007).
Ulcerative colitis
VSL#3 was clinically demonstrated to be efficacious in managing ulcerative colitis (Bibiloni et al. Citation2005; Miele et al. Citation2009; Sood et al. Citation2009; Tursi et al. Citation2004; Venturi et al. Citation1999) (). It was shown that VSL#3 abrogated clinical symptoms in patients with active mild-to-moderate ulcerative colitis when either applied alone or in combination with anti-inflammatory drug balsalazide (Bibiloni et al. Citation2005; Sood et al. Citation2009; Tursi et al. Citation2004). VSL#3 in combination with balsalazide was shown to be more effective in inducing remission than treatment with balsalazide or mesalazine in ulcerative colitis patients (Tursi et al. Citation2004). Another promising clinical trial with VSL#3 was conducted by Miele et al. (Citation2009), who found that VSL#3 consumption in combination with regular medication significantly enhanced remission rate, declined recurrence rate, and was safe in children with ulcerative colitis within a one-year, placebo-controlled, double-blind clinical study. The probiotic strain L. rhamnosus GG however was not found to induce statistically significant effects in retaining ulcerative colitis remission when administrated alone or in combination with mesalazine in a 12-month clinical trial (Zocco et al. Citation2006).
In addition to oral consumption, rectal administration was also shown to be an effective route for probiotic application in ulcerative colitis patients (D’Incà et al. Citation2011; Oliva et al. Citation2012). L. reuteri ATCC55730 applied as rectal enema beneficially down-regulated rectal mucosal inflammatory responses in children with active mild to moderate ulcerative colitis (Oliva et al. Citation2012). In another study, rectal inoculation of L. casei DG together with oral consumption of 5-aminosalicylic acid favorably adjusted microbiota profile and mucosal cytokine signals in the colon, whereas oral supplementation of this strain combined with 5-aminosalicylic acid was ineffective (D’Incà et al. Citation2011). In the above two studies modulation of mucosal inflammatory signals by LAB strains might be one possible mechanism whereby LAB improving clinical status of ulcerative colitis patients. However not all trials were successful. A 52-week duration of treatment with a mixture of L. acidophilus La-5 and B. animalis BB-12 did not contribute to retaining remission in ulcerative colitis patients (Wildt et al. Citation2011).
Pouchitis
Pouchitis is a common IBD-related complication, which occurs in ulcerative colitis patients after ileal pouch-anal anastomosis (IPAA) surgery (Gionchetti et al. Citation2000). Clinical trials have proved the efficacy of probiotic LAB in managing pouchitis (Landy and Hart Citation2013) (). One-year supplementation of the probiotic mixture VSL#3 started straight away after IPAA in patients was suggested to effectively prevent the incidence of pouchitis (Gionchetti et al. Citation2003). Another study showed that daily VSL#3 consumption by patients who were at different stages after receiving IPAA weakened pouchitis clinical activities and enhanced mucosal regulatory T cell responses (Pronio et al. Citation2008). In addition, efficacy of VSL#3 intervention in inhibiting relapse of pouchitis was demonstrated in two clinical studies (Gionchetti et al. Citation2000; Mimura et al. Citation2004).
Probiotic L. rhamnosus GG was also reported to delay or prevent onset of pouchitis in patients with IPAA (Gosselink et al. Citation2004). However, this effect of L. rhamnosus GG was not confirmed in another clinical study (Kuisma et al. Citation2003). Eight-week consumption of a probiotic mixture of bifidobacteria, lactobacilli, and lactococci following antibiotic treatment strengthened gut barrier function in patients with severe pouchitis, which was suggested as one mechanism underlying the beneficial effects of LAB on pouchitis (Persborn et al. Citation2013).
Allergic diseases
The frequency and morbidity of allergic diseases have been rising over the past several decades especially in industrialized countries (Toh et al. Citation2012). A popular explanation for this is the “microbiota hypothesis,” previously referred to as the “hygiene hypothesis.” This theory explains the enhanced allergy frequency by aberrant microbial exposure during early childhood, which leads to an inappropriate intestinal microecology and primes aberrant immune maturation characterized by a Th2-biased immunity (Kuitunen Citation2013; Toh et al. Citation2012). This emphasizes the essential role of gut microbiome in the pathogenesis of allergic diseases (Kuitunen Citation2013). Accordingly, probiotic LAB-interventions that specially target intestinal microflora have been extensively studied. Clinical attempts which demonstrate the proof of principle of LAB administration to manage allergy have been mainly focused on eczema and specifically IgE-associated eczema (), a common type of allergy that develops during early life (Kuitunen Citation2013). Most prospective clinical evidence demonstrates that LABs can prevent rather than cure eczema, which is also acknowledged by the World Allergy Organization (Forsberg et al. Citation2016).
Table 3. Effects of LAB on allergic disease in humans.
Of note, some systematic reviews and meta-analyses revealed that prenatal together with early postnatal LAB supplementation seems to provide the most preventative benefits when compared with a solely prenatal or postnatal administration strategy (Boyle et al. Citation2011; Forsberg et al. Citation2016; Kuitunen Citation2013; Kuitunen et al. Citation2009; Kukkonen et al. Citation2007; Toh et al. Citation2012; Wickens et al. Citation2008). This indicates that timing is of great importance for the efficacy of LAB intervention in eczema (Toh et al. Citation2012). In a clinical trial conducted by Kukkonen et al. (Citation2007), a LAB mixture of 2 L. rhamnosus strains, 1 Bifidobacterium strain, and 1 Propionibacterium strain was given to a large cohort of pregnant women (n = 1223) 2–4 weeks prior to delivery. Their babies with high risk of allergic disorders also received this LAB mixture together with galacto-oligosaccharides as off birth until 6 months old. At the age of 2 years, it was shown that the LAB-supplementation prevented IgE-related allergy and specifically reduced the morbidity of eczema in infants (Kukkonen et al. Citation2007). However, overall frequency of allergy was not statistically lower compared to controls (Kukkonen et al. Citation2007). In the follow-up study at 5 years after birth, also no significant decrease in the occurrence of allergic disorders was observed but IgE-induced allergic disease was lower specifically in children delivered by cesarean section within LAB receiving group (Kuitunen et al. Citation2009). Efficacy of L. rhamnosus strains in modulating allergy was confirmed in another clinical trial (Wickens et al. Citation2008), in which pregnant mothers carrying high-allergy risk children consumed L. rhamnosus HN001, B. animalis subsp lactis HN019 or placebo after week 35 of gestation. Probiotic intake continued during breast-feeding. Also, the infants received the probiotics from birth to 2 years old. It was shown that L. rhamnosus but not B. animalis effectively reduced the cumulative incidence of eczema (Wickens et al. Citation2008). An even more promising finding was that during the 4th-year of follow-up, a significant decrease was found in the cumulative occurrence of eczema and in the incidence of rhinoconjunctivitis by L. rhamnosus HN001 administration (Wickens et al. Citation2012). However, another similar clinical study reported that consumption of L. rhamnosus GG by pregnant women with allergic disorders since the second trimester until 6 months after delivery or by their children without breast feeding from birth till 6 months old only alleviated atopic disorders in the mothers but not in the infants (Ou et al. Citation2012). This illustrates that the timing of administration and the strain applied are probably key in the clinical efficacy of the strain.
In general, to be effective LABs have to be given both pre- and postnatally as either prenatal or postnatal treatment alone elicited insufficient protection against allergy (Boyle et al. Citation2011). Only prenatal maternal intake of L. rhamnosus GG could not effectively inhibit eczema in infants during their first year after birth even though down-regulated levels of soluble CD14 and total IgA in breast milk was found by L. rhamnosus GG treatment (Boyle et al. Citation2011). Similarly, most clinical trials exploring only postnatal supplementation of LAB strains such as L. rhamnosus LPR and L. acidophilus LAVRI-A1 in high-risk individuals failed to confer adequate benefits against eczema based on both short-term (Soh et al. Citation2009; Taylor, Dunstan, and Prescott Citation2007) and longer-term follow-up periods (Jensen et al. Citation2012; Prescott et al. Citation2008). However, strain dependency of effects cannot be excluded in relation to pre- or post-natal administration of LABs. In clinical study by Morisset et al. (Citation2011), it was shown that postnatal administration of heat killed B. breve C50 and S. thermophilus 065 in infant formula fed babies during the first year after birth effectively lowered respiratory allergic adverse events at both 1 and 2 years of age, although no significant decline in the prevalence of cow’s milk allergy was found. It cannot be excluded that the longer treatment duration, for example, 1 year of LAB administration (Morisset et al. Citation2011) as compared with the intervention length of others, for example, first 6 months might have led to different results (Jensen et al. Citation2012; Prescott et al. Citation2008; Soh et al. Citation2009; Taylor, Dunstan, and Prescott Citation2007). It should be noted that also different results with respect to allergy-modulating efficacy of LAB might be obtained in clinical trials using different study populations. Consumption of L. paracasei F19 by nonselected infants during their weaning period, that is, 4–13-month old, induced reduced eczema morbidity accompanied by augmented Th1-type responses (West, Hammarström, and Hernell Citation2009).
Collectively, even though promising clinical benefits of LAB intervention have been reported hitherto, inconsistent results in different investigations make it difficult to draw definitive conclusions as to the effectiveness of probiotic LAB application in allergy management (Forsberg et al. Citation2016; Kuitunen Citation2013). Variations in experimental setups such as inclusion of either high-risk, healthy or nonselected populations, differences in LAB strains applied, maternal or infants administration of LABs, differences in timing, for example, pre- and/or post-natal treatment, variations in doses and duration of LAB administration, and application of varying food matrices, for example, capsules, prebiotic supplement, and infant formula, might contribute to inconsistencies in reported results (Forsberg et al. Citation2016; Kuitunen Citation2013; Nermes, Salminen, and Isolauri Citation2013). More stringently-designed, standardized protocols are required to further validate the protective functions of probiotic LAB strains in allergic disorders (Forsberg et al. Citation2016).
Cancer
Cancer is becoming a globally prevalent clinical health burden. High fatality among cancer patients is still observed in most countries despite improved cancer therapies such as radiotherapy and chemotherapy. The increasing morbidity of various cancers, particularly colorectal cancer has been linked to unhealthy diet and life style and is associates with intestinal microflora dysbiosis (Kahouli, Tomaro-Duchesneau, and Prakash Citation2013). Consequently, probiotic LAB strains with well-defined capabilities to adjust microbiota dysbiosis have been considered as potential beneficial dietary supplementations for cancer (dos Reis et al. Citation2017; Kahouli, Tomaro-Duchesneau, and Prakash Citation2013). The majority of in vitro studies on anti-cancer potentials of LAB strains of different species such as L. acidophilus, L. brevis, L. casei, L. fermentum, L. plantarum, L. reuteri, and Lc. Lactis focused on the effects of LAB on proliferation and apoptosis of cancer cell lines in vitro (So, Wan, and El-Nezami Citation2017). A kimchi-derived Lc. lactis strain KC24 was demonstrated to inhibit the proliferation of human HT-29 and LoVo colon carcinoma, AGS gastric carcinoma, MCF-7 breast carcinoma, and SK-MES-1 lung carcinoma cell lines (Lee et al. Citation2015). It was shown that L. casei ATCC393 significantly suppressed the proliferation and augmented the apoptosis of CT26 murine and HT29 human colon cancer cells (Tiptiri-Kourpeti et al. Citation2016). Such an in vitro cancer cell-inhibitory effect of L. casei ATCC393 was also confirmed in vivo in a colon carcinoma mouse model, in which inhibition of colonic tumor growth was observed (Tiptiri-Kourpeti et al. Citation2016). There are some other in vivo studies in animals exploring the direct tumor-inhibitory properties of LAB (Kahouli, Tomaro-Duchesneau, and Prakash Citation2013; Rafter Citation2004; So, Wan, and El-Nezami Citation2017). Administration of L. acidophilus NCFM before and after tumor initiation was shown to dampen colon cancer development in a murine colon carcinoma model (Chen et al. Citation2012). Notably, the anti-tumor effects of L. acidophilus ATCC314 were found to be more effective in the small than in the large intestine (Urbanska et al. Citation2016). In the APC (Min/+) mouse model of intestinal tumorigenesis, supplementation of L. acidophilus ATCC314 specifically reduced the number of tumors in the small intestine but did not alter the amount of polyps in the large intestine (Urbanska et al. Citation2016).
At present, several clinical studies substantiate beneficial potentials of probiotic LAB in cancer management (Kahouli, Tomaro-Duchesneau, and Prakash Citation2013; So, Wan, and El-Nezami Citation2017) (). For instance, a 12-year clinical survey involving 45241 volunteers in Italy showed that high yoghurt consumption containing L. delbrueckii subsp bulgaricus and S. thermophilus seemed to reduce the incidence of colorectal cancer (Pala et al. Citation2011). Also, the efficacy of the probiotic LAB strain L. casei Shirota and the probiotic strain mixture of lactobacilli, bifidobacteria, and enterococci were also investigated in cancer patients prior to or following resection surgery for their potential for reducing relapse (Nanno et al. Citation2011), for mitigating postoperative complications (Kotzampassi et al. Citation2015; Liu et al. Citation2011; Zhang, Du, et al. Citation2012), and for improving other physiological health functions (Liu et al. Citation2011; Zhang, Du, et al. Citation2012). Administration of L. casei Shirota following surgery was shown to significantly reduce the postoperative relapse in patients with bladder or colorectal cancer probably via enhancing NK cell activity (Nanno et al. Citation2011). Pre-operative administration of L. acidophilus mixed with other probiotic strains, that is, B. longum and Enterococcus faecalis, reduced the incidence of post-operative infections accompanied by reinforcement of gut barrier function, up-regulation of serum IgG and sIgA levels, increase in fecal Bifidobacteria, and decrease in Escherichia (Zhang, Du, et al. Citation2012). Moreover, protective properties of a mixture of L. rhamnosus LC705 and a probiotic strain Propionibacterium freudenreichii ssp shermanii JS against potential cancer were found in still healthy populations as reflected by reduced activities of carcinogenic enzyme beta-glucosidase after consumption of this strain mixture (Hatakka et al. Citation2008).
Table 4. Effects of LAB on intestinal cancer in experimental animals and humans.
As illustrated in the aforementioned clinical studies on the efficacy of LAB for cancer management, possible involved mechanisms include gut microflora modulation, reinforcement of host immunity, diminution of the activity of carcinogenic agents, production of anti-carcinogenic factors, and enhancement of gut barrier function (dos Reis et al. Citation2017; Kahouli, Tomaro-Duchesneau, and Prakash Citation2013). However, reproducible efficacious clinical protocols remain to be developed.
Concluding remarks
The well-established safety status and demonstrated health-promoting properties render LAB promising candidates to be applied as dietary supplements or medical interventions. The primary mechanisms underlying the functions of LAB include modulation of gut commensal microflora, production of bioactive or bactericidal molecules, preclusion of pathogen attachment, attenuation of virulent factors of pathogens, fortification of intestinal barrier function, and regulation of innate and adaptive immune function. The current available studies have confirmed the clinical efficacy of different LAB strains in reducing infections induced by H. pylori, Salmonella, and influenza virus, in managing gastrointestinal inflammatory disorders especially pouchitis, in controlling allergies specifically eczema, and in ameliorating the postoperative complications in cancer patients.
Despite these promising findings in the research field of LAB, only limited numbers of LAB strains have been approved to be applied as dietary supplements or medical interventions when considering the extensive LAB resources in nature. Lack of standard, highly efficient evaluation systems for screening suitable LAB strains for diverse intervention purposes is a major bottleneck that hampers the identification of proper strain candidates. Furthermore, inconsistent effects of specific strains or varied effects between different strains often exist. Mechanistic studies aiming at identification of effector factors and elucidating the relationship between specific LAB effector molecules and associated effects will undoubtedly contribute to our deeper understanding of strain specificity. This will also facilitate the establishment of more effective and targeted selection systems for LAB strains.
However, it should be noted that the observed modulatory effects of LAB intervention are most likely the combinations of responses elicited by various LAB effector molecules, which increases the complexity of LAB-host interaction. Another critical aspect is how particular LAB strains react to the in vivo environments. As discussed earlier, in vivo resistance or adaptivity of LAB strains to harsh gastrointestinal milieu determines final physiological responses evoked by LAB. Moreover, in vivo conditions were also suggested to specifically influence the expression profiles of specific genes in LAB, thus impacting LAB-conferred functions on the host (Bron, van Baarlen, and Kleerebezem Citation2012).
Besides these LAB-related factors, host-associated factors such as age, gender, genotype, life style factors, and dietary pattern play a vital part in shaping gut microbiota composition and immune status of the host, thereby affecting host responsiveness to specific LAB strains. Thus, establishing comprehensive repositories of well-defined characteristics for both individual strains and humans will contribute to more personalized LAB selection or consumption for targeted populations. Notably, factors in LAB intervention regimens including administration mode, dose, timing, and duration, and the parameters that measured should be more standardized in order to achieve a more consistent and comparable physiological efficacy of LAB consumption.
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References
- Abatemarco Júnior, M., S. H. C. Sandes, M. F. Ricci, R. M. E. Arantes, Á. C. Nunes, J. R. Nicoli, and E. Neumann. 2018. Protective effect of Lactobacillus diolivorans 1Z, isolated from Brazilian Kefir, against Salmonella enterica Serovar Typhimurium in experimental murine models. Frontiers in Microbiology 9:2856.
- Agüero, G., J. Villena, S. Racedo, C. Haro, and S. Alvarez. 2006. Beneficial immunomodulatory activity of Lactobacillus casei in malnourished mice pneumonia: Effect on inflammation and coagulation. Nutrition 22 (7–8):810–9. doi: 10.1016/j.nut.2006.03.013.
- Aguilar-Toalá, J. E., R. Garcia-Varela, H. S. Garcia, V. Mata-Haro, A. F. González-Córdova, B. Vallejo-Cordoba, and A. Hernández-Mendoza. 2018. Postbiotics: An evolving term within the functional foods field. Trends in Food Science & Technology 75:105–14. doi: 10.1016/j.tifs.2018.03.009.
- Akira, S., and K. Takeda. 2004. Toll-like receptor signalling. Nature Reviews Immunology 4 (7):499–511. doi: 10.1038/nri1391.
- Alm, L. 1983. The effect of Lactobacillus acidophilus administration upon the survival of Salmonella in randomly selected human carriers. Progress in Food & Nutrition Science 7 (3–4):13–7.
- Anderson, R. C., A. L. Cookson, W. C. McNabb, Z. Park, M. J. McCann, W. J. Kelly, and N. C. Roy. 2010. Lactobacillus plantarum MB452 enhances the function of the intestinal barrier by increasing the expression levels of genes involved in tight junction formation. BMC Microbiology 10 (1):316. doi: 10.1186/1471-2180-10-316.
- Bibiloni, R., R. N. Fedorak, G. W. Tannock, K. L. Madsen, P. Gionchetti, M. Campieri, C. D. Simone, and R. B. Sartor. 2005. VSL#3 probiotic-mixture induces remission in patients with active ulcerative colitis. The American Journal of Gastroenterology 100 (7):1539–46. doi: 10.1111/j.1572-0241.2005.41794.x.
- Borchers, A. T., C. Selmi, F. J. Meyers, C. L. Keen, and M. E. Gershwin. 2009. Probiotics and immunity. Journal of Gastroenterology 44 (1):26–46. doi: 10.1007/s00535-008-2296-0.
- Bousvaros, A., S. Guandalini, R. N. Baldassano, C. Botelho, J. Evans, G. D. Ferry, B. Goldin, L. Hartigan, S. Kugathasan, J. Levy, et al. 2005. A randomized, double-blind trial of lactobacillus GG versus placebo in addition to standard maintenance therapy for children with Crohn's disease. Inflammatory Bowel Diseases 11 (9):833–9. doi: 10.1097/01.mib.0000175905.00212.2c.
- Boyle, R. J., I. H. Ismail, S. Kivivuori, P. V. Licciardi, R. M. Robins-Browne, L. J. Mah, C. Axelrad, S. Moore, S. Donath, J. B. Carlin, et al. 2011. Lactobacillus GG treatment during pregnancy for the prevention of eczema: A randomized controlled trial. Allergy 66 (4):509–16. doi: 10.1111/j.1398-9995.2010.02507.x.
- Bron, P. A., P. van Baarlen, and M. Kleerebezem. 2012. Emerging molecular insights into the interaction between probiotics and the host intestinal mucosa. Nature Reviews Microbiology 10 (1):66–78. doi: 10.1038/nrmicro2690.
- Cangemi de Gutierrez, R., V. Santos, and MÃa E. Nader-MacÃAs. 2001. Protective effect of intranasally inoculated Lactobacillus fermentum against Streptococcus pneumoniae challenge on the mouse respiratory tract. FEMS Immunology & Medical Microbiology 31 (3):187–95. doi: 10.1111/j.1574-695X.2001.tb00519.x.
- Cario, E. 2005. Bacterial interactions with cells of the intestinal mucosa: Toll-like receptors and NOD2. Gut 54 (8):1182–93. doi: 10.1136/gut.2004.062794.
- Celiberto, L. S., R. Bedani, E. A. Rossi, and D. C. U. Cavallini. 2017. Probiotics: The scientific evidence in the context of inflammatory bowel disease. Critical Reviews in Food Science and Nutrition 57:1759–1768. doi: 10.1080/10408398.2014.941457.
- Chen, C.-C., W.-C. Lin, M.-S. Kong, H. N. Shi, W. A. Walker, C.-Y. Lin, C.-T. Huang, Y.-C. Lin, S.-M. Jung, and T.-Y. Lin. 2012. Oral inoculation of probiotics Lactobacillus acidophilus NCFM suppresses tumour growth both in segmental orthotopic colon cancer and extra-intestinal tissue. British Journal of Nutrition 107 (11):1623–34. doi: 10.1017/S0007114511004934.
- Choi, A.-R., J. K. Patra, W. J. Kim, and S.-S. Kang. 2018. Antagonistic activities and probiotic potential of lactic acid bacteria derived from a plant-based fermented food. Frontiers in Microbiology 9:1963. doi: 10.3389/fmicb.2018.01963.
- Christensen, H. R., H. Frøkiaer, and J. J. Pestka. 2002. Lactobacilli differentially modulate expression of cytokines and maturation surface markers in murine dendritic cells. The Journal of Immunology 168 (1):171–8. doi: 10.4049/jimmunol.168.1.171.
- Claes, I. J. J., S. Lebeer, C. Shen, T. L. A. Verhoeven, E. Dilissen, G. De Hertogh, D. M. A. Bullens, J. L. Ceuppens, G. Van Assche, S. Vermeire, et al. 2010. Impact of lipoteichoic acid modification on the performance of the probiotic Lactobacillus rhamnosus GG in experimental colitis. Clinical & Experimental Immunology 162 (2):306–14. doi: 10.1111/j.1365-2249.2010.04228.x.
- Cruchet, S., M. C. Obregon, G. Salazar, E. Diaz, and M. Gotteland. 2003. Effect of the ingestion of a dietary product containing Lactobacillus johnsonii La1 on Helicobacter pylori colonization in children. Nutrition 19 (9):716–21. doi: 10.1016/S0899-9007(03)00109-6.
- D’Incà, R., M. Barollo, M. Scarpa, A. R. Grillo, P. Brun, M. G. Vettorato, I. Castagliuolo, and G. C. Sturniolo. 2011. Rectal administration of Lactobacillus casei DG modifies flora composition and toll-like receptor expression in colonic mucosa of patients with mild ulcerative colitis. Digestive Diseases and Sciences 56 (4):1178–87. doi: 10.1007/s10620-010-1384-1.
- de Klerk, N., L. Maudsdotter, H. Gebreegziabher, S. D. Saroj, B. Eriksson, O. S. Eriksson, S. Roos, S. Lindén, H. Sjölinder, and A.-B. Jonsson. 2016. Lactobacilli reduce Helicobacter pylori attachment to host gastric epithelial cells by inhibiting adhesion gene expression. Infection and Immunity 84 (5):1526–35. doi: 10.1128/IAI.00163-16.
- de Moreno de LeBlanc, A., N. A. Castillo, and G. Perdigon. 2010. Anti-infective mechanisms induced by a probiotic Lactobacillus strain against Salmonella enterica serovar Typhimurium infection. International Journal of Food Microbiology 138 (3):223–31. doi: 10.1016/j.ijfoodmicro.2010.01.020.
- Delcenserie, V., D. Martel, M. Lamoureux, J. Amiot, Y. Boutin, and D. Roy. 2008. Immunomodulatory effects of probiotics in the intestinal tract. Current Issues in Molecular Biology 10 (1–2):37–54.
- DePaolo, R. W., F. Tang, I. Kim, M. Han, N. Levin, N. Ciletti, A. Lin, D. Anderson, O. Schneewind, and B. Jabri. 2008. Toll-like receptor 6 drives differentiation of tolerogenic dendritic cells and contributes to LcrV-mediated plague pathogenesis. Cell Host & Microbe 4 (4):350–61. doi: 10.1016/j.chom.2008.09.004.
- DePaolo, R. W., K. Kamdar, S. Khakpour, Y. Sugiura, W. Wang, and B. Jabri. 2012. A specific role for TLR1 in protective T(H)17 immunity during mucosal infection. The Journal of Experimental Medicine 209 (8):1437–44. doi: 10.1084/jem.20112339.
- Deplancke, B., and H. R. Gaskins. 2001. Microbial modulation of innate defense: Goblet cells and the intestinal mucus layer. The American Journal of Clinical Nutrition 73 (6):1131S–41S. doi: 10.1093/ajcn/73.6.1131S.
- Derrien, M., and J. E. T. van Hylckama Vlieg. 2015. Fate, activity, and impact of ingested bacteria within the human gut microbiota. Trends in Microbiology 23 (6):354–66. doi: 10.1016/j.tim.2015.03.002.
- dos Reis, S. A., L. L. da Conceição, N. P. Siqueira, D. D. Rosa, L. L. da Silva, and M. d C. G. Peluzio. 2017. Review of the mechanisms of probiotic actions in the prevention of colorectal cancer. Nutrition Research 37:1–19. doi: 10.1016/j.nutres.2016.11.009.
- Drakes, M., T. Blanchard, and S. Czinn. 2004. Bacterial probiotic modulation of dendritic cells. Infection and Immunity 72 (6):3299–309. doi: 10.1128/IAI.72.6.3299-3309.2004.
- Dykstra, N. S., L. Hyde, D. Adawi, D. Kulik, S. Ahrne, G. Molin, B. Jeppsson, A. MacKenzie, and D. R. Mack. 2011. Pulse probiotic administration induces repeated small intestinal Muc3 expression in rats. Pediatric Research 69 (3):206–11. doi: 10.1203/PDR.0b013e3182096ff0.
- Engels, C., H.-J. Ruscheweyh, N. Beerenwinkel, C. Lacroix, and C. Schwab. 2016. The common gut microbe Eubacterium hallii also contributes to intestinal propionate formation. Frontiers in Microbiology 7:713. doi: 10.3389/fmicb.2016.00713.
- Fedorak, R. N., B. G. Feagan, N. Hotte, D. Leddin, L. A. Dieleman, D. M. Petrunia, R. Enns, A. Bitton, N. Chiba, P. Paré, et al. 2008. The probiotic VSL#3 has anti-inflammatory effects and could reduce endoscopic recurrence after surgery for Crohn’s disease. Gastroenterology 134 (4):928–935.e922. doi: 10.1016/S0016-5085(08)61682-0.
- Fernandez, E. M., V. Valenti, C. Rockel, C. Hermann, B. Pot, I. G. Boneca, and C. Grangette. 2011. Anti-inflammatory capacity of selected lactobacilli in experimental colitis is driven by NOD2-mediated recognition of a specific peptidoglycan-derived muropeptide. Gut 60 (8):1050–9. doi: 10.1136/gut.2010.232918.
- Foligne, B., G. Zoumpopoulou, J. Dewulf, A. Ben Younes, F. Chareyre, J.-C. Sirard, B. Pot, and C. Grangette. 2007. A key role of dendritic cells in probiotic functionality. PLoS One. 2 (3):e313. doi: 10.1371/journal.pone.0000313.
- Forsberg, A., C. E. West, S. L. Prescott, and M. C. Jenmalm. 2016. Pre- and probiotics for allergy prevention: Time to revisit recommendations?. Clinical & Experimental Allergy 46 (12):1506–21. doi: 10.1111/cea.12838.
- Foschi, C., M. Salvo, R. Cevenini, C. Parolin, B. Vitali, and A. Marangoni. 2017. Vaginal lactobacilli reduce Neisseria gonorrhoeae viability through multiple strategies: An in vitro study. Frontiers in Cellular and Infection Microbiology 7:502. doi: 10.3389/fcimb.2017.00502.
- Francavilla, R., E. Lionetti, S. P. Castellaneta, A. M. Magistà, G. Maurogiovanni, N. Bucci, A. De Canio, F. Indrio, L. Cavallo, E. Ierardi, et al. 2008. Inhibition of Helicobacter pylori infection in humans by Lactobacillus reuteri ATCC 55730 and effect on eradication therapy: A pilot study. Helicobacter 13 (2):127–34. doi: 10.1111/j.1523-5378.2008.00593.x.
- Franz, C. M., M. Huch, S. Seifert, J. Kramlich, A. Bub, G. S. Cho, and B. Watzl. 2015. Influence of a probiotic Lactobacillus casei strain on the colonisation with potential pathogenic streptococci and Staphylococcus aureus in the nasopharyngeal space of healthy men with a low baseline NK cell activity. Medical Microbiology and Immunology 204 (4):527–38. doi: 10.1007/s00430-014-0366-x.
- George, F., C. Daniel, M. Thomas, E. Singer, A. Guilbaud, F. J. Tessier, A.-M. Revol-Junelles, F. Borges, and B. Foligné. 2018. Occurrence and dynamism of lactic acid bacteria in distinct ecological niches: A multifaceted functional health perspective. Frontiers in Microbiology 9:2899. doi: 10.3389/fmicb.2018.02899.
- Gill, H. S., Q. Shu, H. Lin, K. J. Rutherfurd, and M. L. Cross. 2001. Protection against translocating Salmonella typhimurium infection in mice by feeding the immuno-enhancing probiotic Lactobacillus rhamnosus strain HN001. Medical Microbiology and Immunology 190 (3):97–104. doi: 10.1007/s004300100095.
- Gionchetti, P., F. Rizzello, A. Venturi, P. Brigidi, D. Matteuzzi, G. Bazzocchi, G. Poggioli, M. Miglioli, and M. Campieri. 2000. Oral bacteriotherapy as maintenance treatment in patients with chronic pouchitis: A double-blind, placebo-controlled trial. Gastroenterology 119 (2):305–9. doi: 10.1053/gast.2000.9370.
- Gionchetti, P., F. Rizzello, U. Helwig, A. Venturi, K. M. Lammers, P. Brigidi, B. Vitali, G. Poggioli, M. Miglioli, and M. Campieri. 2003. Prophylaxis of pouchitis onset with probiotic therapy: A double-blind, placebo-controlled trial. Gastroenterology 124 (5):1202–9. doi: 10.1016/S0016-5085(03)00171-9.
- Glück, U., and J.-O. Gebbers. 2003. Ingested probiotics reduce nasal colonization with pathogenic bacteria (Staphylococcus aureus, Streptococcus pneumoniae, and β-hemolytic streptococci). The American Journal of Clinical Nutrition 77 (2):517–20. doi: 10.1093/ajcn/77.2.517.
- Gosselink, M. P., W. R. Schouten, L. M. C. van Lieshout, W. C. J. Hop, J. D. Laman, and J. G. H. Ruseler-van Embden. 2004. Delay of the first onset of pouchitis by oral intake of the probiotic strain Lactobacillus rhamnosus GG. Diseases of the Colon and Rectum 47 (6):876–84. doi: 10.1007/s10350-004-0525-z.
- Gotteland, M., M. Andrews, M. Toledo, L. Muñoz, P. Caceres, A. Anziani, E. Wittig, H. Speisky, and G. Salazar. 2008. Modulation of Helicobacter pylori colonization with cranberry juice and Lactobacillus johnsonii La1 in children. Nutrition 24 (5):421–6. doi: 10.1016/j.nut.2008.01.007.
- Grangette, C., S. Nutten, E. Palumbo, S. Morath, C. Hermann, J. Dewulf, B. Pot, T. Hartung, P. Hols, and A. Mercenier. 2005. Enhanced antiinflammatory capacity of a Lactobacillus plantarum mutant synthesizing modified teichoic acids. Proceedings of the National Academy of Sciences of the United States of America 102 (29):10321–6. doi: 10.1073/pnas.0504084102.
- Groschwitz, K. R., and S. P. Hogan. 2009. Intestinal barrier function: Molecular regulation and disease pathogenesis. Journal of Allergy and Clinical Immunology 124 (1):3–20. doi: 10.1016/j.jaci.2009.05.038.
- Gupta, P., H. Andrew, B. Kirschner, and S. Guandalini. 2000. Is Lactobacillus GG helpful in children with Crohn's disease? Results of a preliminary, open-label study. Journal of Pediatric Gastroenterology and Nutrition 31 (4):453–7. doi: 10.1097/00005176-200010000-00024.
- Harata, G., F. He, N. Hiruta, M. Kawase, A. Kubota, M. Hiramatsu, and H. Yausi. 2010. Intranasal administration of Lactobacillus rhamnosus GG protects mice from H1N1 influenza virus infection by regulating respiratory immune responses. Letters in Applied Microbiology 50 (6):597–602. doi: 10.1111/j.1472-765X.2010.02844.x.
- Hart, A. L., K. Lammers, P. Brigidi, B. Vitali, F. Rizzello, P. Gionchetti, M. Campieri, M. A. Kamm, S. C. Knight, and A. J. Stagg. 2004. Modulation of human dendritic cell phenotype and function by probiotic bacteria. Gut 53 (11):1602–9. doi: 10.1136/gut.2003.037325.
- Hatakka, K., R. Holma, H. El-Nezami, T. Suomalainen, M. Kuisma, M. Saxelin, T. Poussa, H. Mykkänen, and R. Korpela. 2008. The influence of Lactobacillus rhamnosus LC705 together with Propionibacterium freudenreichii ssp. shermanii JS on potentially carcinogenic bacterial activity in human colon. International Journal of Food Microbiology 128 (2):406–10. doi: 10.1016/j.ijfoodmicro.2008.09.010.
- Hauser, G., N. Salkic, K. Vukelic, A. JajacKnez, and D. Stimac. 2015. Probiotics for standard triple Helicobacter pylori eradication: A randomized, double-blind, placebo-controlled trial. Medicine 94 (17):e685. doi: 10.1097/MD.0000000000000685.
- He, T., Y.-H. Zhu, J. Yu, B. Xia, X. Liu, G.-Y. Yang, J.-H. Su, L. Guo, M.-L. Wang, and J.-F. Wang. 2019. Lactobacillus johnsonii L531 reduces pathogen load and helps maintain short-chain fatty acid levels in the intestines of pigs challenged with Salmonella enterica Infantis. Veterinary Microbiology 230:187–94. doi: 10.1016/j.vetmic.2019.02.003.
- He, X., Q. Zeng, S. Puthiyakunnon, Z. Zeng, W. Yang, J. Qiu, L. Du, S. Boddu, T. Wu, D. Cai, et al. 2017. Lactobacillus rhamnosus GG supernatant enhance neonatal resistance to systemic Escherichia coli K1 infection by accelerating development of intestinal defense. Scientific Reports 7 (1):43305. doi: 10.1038/srep43305.
- Hemarajata, P., and J. Versalovic. 2013. Effects of probiotics on gut microbiota: Mechanisms of intestinal immunomodulation and neuromodulation. Therapeutic Advances in Gastroenterology 6 (1):39–51. doi: 10.1177/1756283X12459294.
- Hori, T., J. Kiyoshima, K. Shida, and H. Yasui. 2001. Effect of intranasal administration of Lactobacillus casei Shirota on influenza virus infection of upper respiratory tract in mice. Clinical Diagnostic Laboratory Immunology 8 (3):593–7. doi: 10.1128/CDLI.8.3.593-597.2001.
- Hori, T., J. Kiyoshima, K. Shida, and H. Yasui. 2002. Augmentation of cellular immunity and reduction of influenza virus titer in aged mice fed Lactobacillus casei strain Shirota. Clinical and Vaccine Immunology 9 (1):105–8. doi: 10.1128/CDLI.9.1.105-108.2002.
- Izumo, T., T. Maekawa, M. Ida, A. Noguchi, Y. Kitagawa, H. Shibata, H. Yasui, and Y. Kiso. 2010. Effect of intranasal administration of Lactobacillus pentosus S-PT84 on influenza virus infection in mice. International Immunopharmacology 10 (9):1101–6. doi: 10.1016/j.intimp.2010.06.012.
- Jensen, M. P., S. Meldrum, A. L. Taylor, J. A. Dunstan, and S. L. Prescott. 2012. Early probiotic supplementation for allergy prevention: Long-term outcomes. Journal of Allergy and Clinical Immunology 130 (5):1209–11. doi: 10.1016/j.jaci.2012.07.018.
- Jung, T.-H., J. H. Park, W.-M. Jeon, and K.-S. Han. 2015. Butyrate modulates bacterial adherence on LS174T human colorectal cells by stimulating mucin secretion and MAPK signaling pathway. Nutrition Research and Practice 9 (4):343–9. doi: 10.4162/nrp.2015.9.4.343.
- Kabir, A. M., Y. Aiba, A. Takagi, S. Kamiya, T. Miwa, and Y. Koga. 1997. Prevention of Helicobacter pylori infection by lactobacilli in a gnotobiotic murine model. Gut 41 (1):49–55. doi: 10.1136/gut.41.1.49.
- Kahouli, I., C. Tomaro-Duchesneau, and S. Prakash. 2013. Probiotics in colorectal cancer (CRC) with emphasis on mechanisms of action and current perspectives. Journal of Medical Microbiology 62 (8):1107–23. doi: 10.1099/jmm.0.048975-0.
- Kaji, R., J. Kiyoshima-Shibata, M. Nagaoka, M. Nanno, and K. Shida. 2010. Bacterial teichoic acids reverse predominant IL-12 production induced by certain lactobacillus strains into predominant IL-10 production via TLR2-dependent ERK activation in macrophages. The Journal of Immunology 184 (7):3505–13. doi: 10.4049/jimmunol.0901569.
- Karczewski, J., F. J. Troost, I. Konings, J. Dekker, M. Kleerebezem, R.-J M. Brummer, and J. M. Wells. 2010. Regulation of human epithelial tight junction proteins by Lactobacillus plantarum in vivo and protective effects on the epithelial barrier. American Journal of Physiology-Gastrointestinal and Liver Physiology 298 (6):G851–G859. doi: 10.1152/ajpgi.00327.2009.
- Kawase, M., F. He, A. Kubota, G. Harata, and M. Hiramatsu. 2010. Oral administration of lactobacilli from human intestinal tract protects mice against influenza virus infection. Letters in Applied Microbiology 51:10. doi: 10.1111/j.1472-765X.2010.02849.x.
- Kawase, M., F. He, A. Kubota, K. Yoda, K. Miyazawa, and M. Hiramatsu. 2012. Heat-killed Lactobacillus gasseri TMC0356 protects mice against influenza virus infection by stimulating gut and respiratory immune responses. FEMS Immunology & Medical Microbiology 64 (2):280–8. doi: 10.1111/j.1574-695X.2011.00903.x.
- Kepert, I., J. Fonseca, C. Müller, K. Milger, K. Hochwind, M. Kostric, M. Fedoseeva, C. Ohnmacht, S. Dehmel, P. Nathan, et al. 2017. D-tryptophan from probiotic bacteria influences the gut microbiome and allergic airway disease. Journal of Allergy and Clinical Immunology 139 (5):1525–35. doi: 10.1016/j.jaci.2016.09.003.
- Khailova, L., C. H. Baird, A. A. Rush, C. Barnes, and P. E. Wischmeyer. 2017. Lactobacillus rhamnosus GG treatment improves intestinal permeability and modulates inflammatory response and homeostasis of spleen and colon in experimental model of Pseudomonas aeruginosa pneumonia. Clinical Nutrition 36 (6):1549–57. doi: 10.1016/j.clnu.2016.09.025.
- Kim, Y. S., and S. B. Ho. 2010. Intestinal goblet cells and mucins in health and disease: Recent insights and progress. Current Gastroenterology Reports 12 (5):319–30. doi: 10.1007/s11894-010-0131-2.
- Kobayashi, N., T. Saito, T. Uematsu, K. Kishi, M. Toba, N. Kohda, and T. Suzuki. 2011. Oral administration of heat-killed Lactobacillus pentosus strain b240 augments protection against influenza virus infection in mice. International Immunopharmacology 11 (2):199–203. doi: 10.1016/j.intimp.2010.11.019.
- Konstantinov, S. R., H. Smidt, W. M. de Vos, S. C. M. Bruijns, S. K. Singh, F. Valence, D. Molle, S. Lortal, E. Altermann, T. R. Klaenhammer, et al. 2008. S layer protein A of Lactobacillus acidophilus NCFM regulates immature dendritic cell and T cell functions. Proceedings of the National Academy of Sciences of the United States of America 105 (49):19474–9. doi: 10.1073/pnas.0810305105.
- Kotzampassi, K., G. Stavrou, G. Damoraki, M. Georgitsi, G. Basdanis, G. Tsaousi, and E. J. Giamarellos-Bourboulis. 2015. A four-probiotics regimen reduces postoperative complications after colorectal surgery: A randomized, double-blind, placebo-controlled study. World Journal of Surgery 39 (11):2776–83. doi: 10.1007/s00268-015-3071-z.
- Kozakova, H., M. Schwarzer, L. Tuckova, D. Srutkova, E. Czarnowska, I. Rosiak, T. Hudcovic, I. Schabussova, P. Hermanova, Z. Zakostelska, et al. 2016. Colonization of germ-free mice with a mixture of three lactobacillus strains enhances the integrity of gut mucosa and ameliorates allergic sensitization. Cellular & Molecular Immunology 13 (2):251–62. doi: 10.1038/cmi.2015.09.
- Kšonžeková, P., P. Bystrický, S. Vlčková, V. Pätoprstý, L. Pulzová, D. Mudroňová, T. Kubašková, T. Csank, and Ľ. Tkáčiková. 2016. Exopolysaccharides of Lactobacillus reuteri: Their influence on adherence of E. coli to epithelial cells and inflammatory response. Carbohydrate Polymers 141:10–9. doi: 10.1016/j.carbpol.2015.12.037.
- Kuisma, J., S. Mentula, H. Jarvinen, A. Kahri, M. Saxelin, and M. Farkkila. 2003. Effect of Lactobacillus rhamnosus GG on ileal pouch inflammation and microbial flora. Alimentary Pharmacology and Therapeutics 17 (4):509–15. doi: 10.1046/j.1365-2036.2003.01465.x.
- Kuitunen, M. 2013. Probiotics and prebiotics in preventing food allergy and eczema. Current Opinion in Allergy and Clinical Immunology 13 (3):280–6. doi: 10.1097/ACI.0b013e328360ed66.
- Kuitunen, M., K. Kukkonen, K. Juntunen-Backman, R. Korpela, T. Poussa, T. Tuure, T. Haahtela, and E. Savilahti. 2009. Probiotics prevent IgE-associated allergy until age 5 years in cesarean-delivered children but not in the total cohort. Journal of Allergy and Clinical Immunology 123 (2):335–41. doi: 10.1016/j.jaci.2008.11.019.
- Kukkonen, K., E. Savilahti, T. Haahtela, K. Juntunen-Backman, R. Korpela, T. Poussa, T. Tuure, and M. Kuitunen. 2007. Probiotics and prebiotic galacto-oligosaccharides in the prevention of allergic diseases: A randomized, double-blind, placebo-controlled trial. Journal of Allergy and Clinical Immunology 119 (1):192–8. doi: 10.1016/j.jaci.2006.09.009.
- Landy, J., and A. Hart. 2013. Commentary: The effects of probiotics on barrier function and mucosal pouch microbiota during maintenance treatment for severe pouchitis in patients with ulcerative colitis. Alimentary Pharmacology & Therapeutics 38 (11–12):1405–6. doi: 10.1111/apt.12517.
- Laughton, J. M., E. Devillard, D. E. Heinrichs, G. Reid, and J. K. McCormick. 2006. Inhibition of expression of a staphylococcal superantigen-like protein by a soluble factor from Lactobacillus reuteri. Microbiology 152 (4):1155–67. doi: 10.1099/mic.0.28654-0.
- Lebeer, S., I. J. J. Claes, and J. Vanderleyden. 2012. Anti-inflammatory potential of probiotics: Lipoteichoic acid makes a difference. Trends in Microbiology 20 (1):5–10. doi: 10.1016/j.tim.2011.09.004.
- Lebeer, S., J. Vanderleyden, and S. C. J. De Keersmaecker. 2008. Genes and molecules of lactobacilli supporting probiotic action. Microbiology and Molecular Biology Reviews 72 (4):728–64. doi: 10.1128/MMBR.00017-08.
- Lebeer, S., J. Vanderleyden, and S. C. J. De Keersmaecker. 2010. Host interactions of probiotic bacterial surface molecules: Comparison with commensals and pathogens. Nature Reviews Microbiology 8 (3):171–84. doi: 10.1038/nrmicro2297.
- Lee, I. C., S. Tomita, M. Kleerebezem, and P. A. Bron. 2013. The quest for probiotic effector molecules—Unraveling strain specificity at the molecular level. Pharmacological Research 69 (1):61–74. doi: 10.1016/j.phrs.2012.09.010.
- Lee, N.-K., K. J. Han, S.-H. Son, S. J. Eom, S.-K. Lee, and H.-D. Paik. 2015. Multifunctional effect of probiotic Lactococcus lactis KC24 isolated from kimchi. LWT - Food Science and Technology 64 (2):1036–41. doi: 10.1016/j.lwt.2015.07.019.
- Lépine, A. F. P., N. de Wit, E. Oosterink, H. Wichers, J. Mes, and P. de Vos. 2018. Lactobacillus acidophilus attenuates Salmonella-induced stress of epithelial cells by modulating tight-junction genes and cytokine responses. Frontiers in Microbiology 9:1439. doi: 10.3389/fmicb.2018.01439.
- Li, J., W. Wang, S. X. Xu, N. A. Magarvey, and J. K. McCormick. 2011. Lactobacillus reuteri-produced cyclic dipeptides quench agr-mediated expression of toxic shock syndrome toxin-1 in staphylococci. Proceedings of the National Academy of Sciences of the United States of America 108 (8):3360–5. doi: 10.1073/pnas.1017431108.
- Lin, W. H., B. Yu, C. K. Lin, W. Z. Hwang, and H. Y. Tsen. 2007. Immune effect of heat-killed multistrain of Lactobacillus acidophilus against Salmonella typhimurium invasion to mice. Journal of Applied Microbiology 102 (1):22–31. doi: 10.1111/j.1365-2672.2006.03073.x.
- Liu, Z., H. Qin, Z. Yang, Y. Xia, W. Liu, J. Yang, Y. Jiang, H. Zhang, Z. Yang, Y. Wang, et al. 2011. Randomised clinical trial: The effects of perioperative probiotic treatment on barrier function and post-operative infectious complications in colorectal cancer surgery – a double-blind study. Alimentary Pharmacology & Therapeutics 33 (1):50–63., doi: 10.1111/j.1365-2036.2010.04492.x.
- Lönnermark, E., G. Lappas, V. Friman, A. E. Wold, E. Backhaus, and I. Adlerberth. 2015. Effects of probiotic intake and gender on nontyphoid Salmonella infection. Journal of Clinical Gastroenterology 49 (2):116–23. doi: 10.1097/MCG.0000000000000120.
- Mack, D. R., S. Ahrne, L. Hyde, S. Wei, and M. A. Hollingsworth. 2003. Extracellular MUC3 mucin secretion follows adherence of Lactobacillus strains to intestinal epithelial cells in vitro. Gut 52 (6):827–33. doi: 10.1136/gut.52.6.827.
- Madsen, K. 2012. Enhancement of epithelial barrier function by probiotics. Journal of Epithelial Biology and Pharmacology 5:55–9.
- Madsen, K., A. Cornish, P. Soper, C. McKaigney, H. Jijon, C. Yachimec, J. Doyle, L. Jewell, and C. D. Simone. 2001. Probiotic bacteria enhance murine and human intestinal epithelial barrier function. Gastroenterology 121 (3):580–91. doi: 10.1053/gast.2001.27224.
- Madsen, K., J. Doyle, L. Jewell, M. Tavernini, and R. Fedorak. 1999. Lactobacillus species prevents colitis in interleukin 10 gene-deficient mice. Gastroenterology 116 (5):1107–14. doi: 10.1016/S0016-5085(99)70013-2.
- Malin, M., H. Suomalainen, M. Saxelin, and E. Isolauri. 1996. Promotion of IgA immune response in patients with Crohn’s disease by oral bacteriotherapy with Lactobacillus GG. Annals of Nutrition and Metabolism 40 (3):137–45. doi: 10.1159/000177907.
- Marteau, P., M. Lémann, P. Seksik, D. Laharie, J. F. Colombel, Y. Bouhnik, G. Cadiot, J. C. Soulé, A. Bourreille, E. Metman, et al. 2006. Ineffectiveness of Lactobacillus johnsonii LA1 for prophylaxis of postoperative recurrence in Crohn’s disease: A randomised, double blind, placebo controlled GETAID trial. Gut 55 (6):842–7. doi: 10.1136/gut.2005.076604.
- McCarthy, J., L. O’Mahony, L. O’Callaghan, B. Sheil, E. E. Vaughan, N. Fitzsimons, J. Fitzgibbon, G. C. O’Sullivan, B. Kiely, J. K. Collins, et al. 2003. Double blind, placebo controlled trial of two probiotic strains in interleukin 10 knockout mice and mechanistic link with cytokine balance. Gut 52 (7):975–80. doi: 10.1136/gut.52.7.975.
- McGuckin, M. A., S. K. Lindén, P. Sutton, and T. H. Florin. 2011. Mucin dynamics and enteric pathogens. Nature Reviews Microbiology 9 (4):265–78. doi: 10.1038/nrmicro2538.
- Mennigen, R., K. Nolte, E. Rijcken, M. Utech, B. Loeffler, N. Senninger, and M. Bruewer. 2009. Probiotic mixture VSL#3 protects the epithelial barrier by maintaining tight junction protein expression and preventing apoptosis in a murine model of colitis. American Journal of Physiology-Gastrointestinal and Liver Physiology 296 (5):G1140–G1149. doi: 10.1152/ajpgi.90534.2008.
- Mian, F., N. Kandiah, M. Chew, A. Ashkar, J. Bienenstock, P. Forsythe, and K. Karimi. 2016. A probiotic provides protection against acute salmonellosis in mice: Possible role of innate lymphid NKP46+ cells. Journal of Functional Foods 23:329–38. doi: 10.1016/j.jff.2016.02.020.
- Miele, E., F. Pascarella, E. Giannetti, L. Quaglietta, R. N. Baldassano, and A. Staiano. 2009. Effect of a probiotic preparation (VSL#3) on induction and maintenance of remission in children with ulcerative colitis. The American Journal of Gastroenterology 104 (2):437–43. doi: 10.1038/ajg.2008.118.
- Mimura, T., F. Rizzello, U. Helwig, G. Poggioli, S. Schreiber, I. C. Talbot, R. J. Nicholls, P. Gionchetti, M. Campieri, and M. A. Kamm. 2004. Once daily high dose probiotic therapy (VSL#3) for maintaining remission in recurrent or refractory pouchitis. Gut 53:108–14.
- Morisset, M.,. C. Aubert-Jacquin, P. Soulaines, D. A. Moneret-Vautrin, and C. Dupont. 2011. A non-hydrolyzed, fermented milk formula reduces digestive and respiratory events in infants at high risk of allergy. European Journal of Clinical Nutrition 65 (2):175–83. doi: 10.1038/ejcn.2010.250.
- Nagai, T., S. Makino, S. Ikegami, H. Itoh, and H. Yamada. 2011. Effects of oral administration of yogurt fermented with Lactobacillus delbrueckii ssp. bulgaricus OLL1073R-1 and its exopolysaccharides against influenza virus infection in mice. International Immunopharmacology 11 (12):2246–50. doi: 10.1016/j.intimp.2011.09.012.
- Nanno, M., I. Kato, T. Kobayashi, and K. Shida. 2011. Biological effects of probiotics: What impact does Lactobacillus casei shirota have on us?. International Journal of Immunopathology and Pharmacology 24 (1 Suppl):45S–50S.
- Nermes, M., S. Salminen, and E. Isolauri. 2013. Is there a role for probiotics in the prevention or treatment of food allergy?. Current Allergy and Asthma Reports 13 (6):622–30. doi: 10.1007/s11882-013-0381-9.
- Neville, B. A., B. M. Forde, M. J. Claesson, T. Darby, A. Coghlan, K. Nally, R. P. Ross, and P. W. O’Toole. 2012. Characterization of pro-Inflammatory flagellin proteins produced by Lactobacillus ruminis and related motile lactobacilli. PLoS One 7 (7):e40592. doi: 10.1371/journal.pone.0040592.
- Nocerino, R., L. Paparo, G. Terrin, V. Pezzella, A. Amoroso, L. Cosenza, G. Cecere, G. De Marco, M. Micillo, F. Albano, et al. 2017. Cow’s milk and rice fermented with Lactobacillus paracasei CBA L74 prevent infectious diseases in children: A randomized controlled trial. Clinical Nutrition 36 (1):118–25. doi: 10.1016/j.clnu.2015.12.004.
- Ogawa, T., Y. Asai, R. Tamai, Y. Makimura, H. Sakamoto, S. Hashikawa, and K. Yasuda. 2006. Natural killer cell activities of synbiotic Lactobacillus casei ssp. casei in conjunction with dextran. Clinical and Experimental Immunology 143 (1):103–9. doi: 10.1111/j.1365-2249.2005.02975.x.
- Ohland, C. L., and W. K. MacNaughton. 2010. Probiotic bacteria and intestinal epithelial barrier function. American Journal of Physiology-Gastrointestinal and Liver Physiology 298 (6):G807–G819. doi: 10.1152/ajpgi.00243.2009.
- Oliva, S., G. D. Nardo, F. Ferrari, S. Mallardo, P. Rossi, G. Patrizi, S. Cucchiara, and L. Stronati. 2012. Randomised clinical trial: The effectiveness of Lactobacillus reuteri ATCC 55730 rectal enema in children with active distal ulcerative colitis. Alimentary Pharmacology & Therapeutics 35 (3):327–34. doi: 10.1111/j.1365-2036.2011.04939.x.
- Olivares, M., M. P. Díaz-Ropero, S. Sierra, F. Lara-Villoslada, J. Fonollá, M. Navas, J. M. Rodríguez, and J. Xaus. 2007. Oral intake of Lactobacillus fermentum CECT5716 enhances the effects of influenza vaccination. Nutrition 23 (3):254–60. doi: 10.1016/j.nut.2007.01.004.
- Otte, J.-M., and D. K. Podolsky. 2004. Functional modulation of enterocytes by gram-positive and gram-negative microorganisms. American Journal of Physiology-Gastrointestinal and Liver Physiology 286 (4):G613–G626. doi: 10.1152/ajpgi.00341.2003.
- Ou, C. Y., H. C. Kuo, L. Wang, T. Y. Hsu, H. Chuang, C. A. Liu, J. C. Chang, H. R. Yu, and K. D. Yang. 2012. Prenatal and postnatal probiotics reduces maternal but not childhood allergic diseases: A randomized, double-blind, placebo-controlled trial. Clinical & Experimental Allergy 42 (9):1386–96. doi: 10.1111/j.1365-2222.2012.04037.x.
- Pala, V., S. Sieri, F. Berrino, P. Vineis, C. Sacerdote, D. Palli, G. Masala, S. Panico, A. Mattiello, R. Tumino, et al. 2011. Yogurt consumption and risk of colorectal cancer in the Italian European prospective investigation into cancer and nutrition cohort. International Journal of Cancer 129 (11):2712–9. doi: 10.1002/ijc.26193.
- Pelto, L., E. Isolauri, E. M. Lilius, J. Nuutila, and S. Salminen. 1998. Probiotic bacteria down-regulate the milk-induced inflammatory response in milk-hypersensitive subjects but have an immunostimulatory effect in healthy subjects. Clinical & Experimental Allergy 28:1474–9. doi: 10.1046/j.1365-2222.1998.00449.x.
- Persborn, M., J. Gerritsen, C. Wallon, A. Carlsson, L. M. A. Akkermans, and J. D. Söderholm. 2013. The effects of probiotics on barrier function and mucosal pouch microbiota during maintenance treatment for severe pouchitis in patients with ulcerative colitis. Alimentary Pharmacology & Therapeutics 38 (7):772–83. doi: 10.1111/apt.12451.
- Pessione, E. 2012. Lactic acid bacteria contribution to gut microbiota complexity: Lights and shadows. Frontiers in Cellular and Infection Microbiology 2:86. doi: 10.3389/fcimb.2012.00086.
- Peterson, R. E., T. J. Klopfenstein, G. E. Erickson, J. Folmer, S. Hinkley, R. A. Moxley, and D. R. Smith. 2007. Effect of Lactobacillus acidophilus strain NP51 on Escherichia coli O157:H7 fecal shedding and finishing performance in beef feedlot cattle. Journal of Food Protection 70 (2):287–91. doi: 10.4315/0362-028X-70.2.287.
- Prantera, C., M. L. Scribano, G. Falasco, A. Andreoli, and C. Luzi. 2002. Ineffectiveness of probiotics in preventing recurrence after curative resection for Crohn’s disease: A randomised controlled trial with Lactobacillus GG. Gut 51 (3):405–9. doi: 10.1136/gut.51.3.405.
- Prescott, S. L., J. Wiltschut, A. Taylor, L. Westcott, W. Jung, H. Currie, and J. A. Dunstan. 2008. Early markers of allergic disease in a primary prevention study using probiotics: 2.5-year follow-up phase. Allergy 63 (11):1481–90. doi: 10.1111/j.1398-9995.2008.01778.x.
- Pronio, A., C. Montesani, C. Butteroni, S. Vecchione, G. Mumolo, A. Vestri, D. Vitolo, and M. Boirivant. 2008. Probiotic administration in patients with ileal pouch-anal anastomosis for ulcerative colitis is associated with expansion of mucosal regulatory cells. Inflammatory Bowel Diseases 14 (5):662–8. doi: 10.1002/ibd.20369.
- Racedo, S., J. Villena, M. Medina, G. Agüero, V. Rodríguez, and S. Alvarez. 2006. Lactobacillus casei administration reduces lung injuries in a Streptococcus pneumoniae infection in mice. Microbes and Infection 8 (9-10):2359–66. doi: 10.1016/j.micinf.2006.04.022.
- Rachmilewitz, D., K. Katakura, F. Karmeli, T. Hayashi, C. Reinus, B. Rudensky, S. Akira, K. Takeda, J. Lee, K. Takabayashi, et al. 2004. Toll-like receptor 9 signaling mediates the anti-inflammatory effects of probiotics in murine experimental colitis. Gastroenterology 126 (2):520–8. doi: 10.1053/j.gastro.2003.11.019.
- Rafter, J. 2004. The effects of probiotics on colon cancer development. Nutrition Research Reviews 17 (2):277–84. doi: 10.1079/NRR200484.
- Reid, G., J. A. Younes, H. C. Van der Mei, G. B. Gloor, R. Knight, and H. J. Busscher. 2011. Microbiota restoration: Natural and supplemented recovery of human microbial communities. Nature Reviews Microbiology 9 (1):27–38. doi: 10.1038/nrmicro2473.
- Ren, C., J. Dokter-Fokkens, S. Figueroa Lozano, Q. Zhang, B. J. de Haan, H. Zhang, M. M. Faas, and P. de Vos. 2018. Lactic acid bacteria may impact intestinal barrier function by modulating goblet cells. Molecular Nutrition & Food Research 62 (6):e1700572. doi: 10.1002/mnfr.201700572.
- Ren, C., L. Cheng, Y. Sun, Q. Zhang, B. J. de Haan, H. Zhang, M. M. Faas, and P. de Vos. 2020. Lactic acid bacteria secrete toll like receptor 2 stimulating and macrophage immunomodulating bioactive factors. Journal of Functional Foods 66:103783. doi: 10.1016/j.jff.2020.103783.
- Ren, C., Q. Zhang, B. J. de Haan, H. Zhang, M. M. Faas, and P. de Vos. 2016. Identification of TLR2/TLR6 signalling lactic acid bacteria for supporting immune regulation. Scientific Reports 6 (1):34561. doi: 10.1038/srep34561.
- Resta-Lenert, S., and K. E. Barrett. 2003. Live probiotics protect intestinal epithelial cells from the effects of infection with enteroinvasive Escherichia coli (EIEC). Gut 52 (7):988–97. doi: 10.1136/gut.52.7.988.
- Rizzo, A., A. Losacco, and C. R. Carratelli. 2013. Lactobacillus crispatus modulates epithelial cell defense against Candida albicans through Toll-like receptors 2 and 4, interleukin 8 and human β-defensins 2 and 3. Immunology Letters 156 (1–2):102–9. doi: 10.1016/j.imlet.2013.08.013.
- Rodríguez-Nogales, A., F. Algieri, J. Garrido-Mesa, T. Vezza, M. P. Utrilla, N. Chueca, F. Garcia, M. Olivares, M. E. Rodríguez-Cabezas, and J. Gálvez. 2017. Differential intestinal anti-inflammatory effects of Lactobacillus fermentum and Lactobacillus salivarius in DSS mouse colitis: Impact on microRNAs expression and microbiota composition. Molecular Nutrition & Food Research 61 (11):1700144. doi: 10.1002/mnfr.201700144.
- Roselli, M., A. Finamore, M. S. Britti, S. R. Konstantinov, H. Smidt, W. M. de Vos, and E. Mengheri. 2007. The novel porcine Lactobacillus sobrius strain protects intestinal cells from enterotoxigenic Escherichia coli K88 infection and prevents membrane barrier damage. The Journal of Nutrition 137 (12):2709–16. doi: 10.1093/jn/137.12.2709.
- Ryan, K. A., A. M. O'Hara, J.-P. van Pijkeren, F. P. Douillard, and P. W. O'Toole. 2009. Lactobacillus salivarius modulates cytokine induction and virulence factor gene expression in Helicobacter pylori. Journal of Medical Microbiology 58 (8):996–1005. doi: 10.1099/jmm.0.009407-0.
- Ryan, P. M., R. P. Ross, G. F. Fitzgerald, N. M. Caplice, and C. Stanton. 2015. Sugar-coated: Exopolysaccharide producing lactic acid bacteria for food and human health applications. Food & Function 6 (3):679–93. doi: 10.1039/C4FO00529E.
- Schiffrin, E. J., F. Rochat, H. Link-Amster, J. M. Aeschlimann, and A. Donnet-Hughes. 1995. Immunomodulation of human blood cells following the ingestion of lactic acid bacteria. Journal of Dairy Science 78 (3):491–7. doi: 10.3168/jds.S0022-0302(95)76659-0.
- Schultz, M., C. Veltkamp, L. A. Dieleman, W. B. Grenther, P. B. Wyrick, S. L. Tonkonogy, and R. B. Sartor. 2002. Lactobacillus plantarum 299V in the treatment and prevention of spontaneous colitis in interleukin-10-deficient mice. Inflammatory Bowel Diseases 8 (2):71–80. doi: 10.1097/00054725-200203000-00001.
- Sgouras, D. N., E. G. Panayotopoulou, B. Martinez-Gonzalez, K. Petraki, S. Michopoulos, and Α. Mentis. 2005. Lactobacillus johnsonii La1 attenuates Helicobacter pylori-associated gastritis and reduces levels of proinflammatory chemokines in C57BL/6 mice. Clinical Diagnostic Laboratory Immunology 12 (12):1378–86. doi: 10.1128/CDLI.12.12.1378-1386.2005.
- Sgouras, D., P. Maragkoudakis, K. Petraki, B. Martinez-Gonzalez, E. Eriotou, S. Michopoulos, G. Kalantzopoulos, E. Tsakalidou, and Α. Mentis. 2004. In vitro and in vivo inhibition of Helicobacter pylori by Lactobacillus casei strain Shirota. Applied and Environmental Microbiology 70 (1):518–26. doi: 10.1128/AEM.70.1.518-526.2004.
- Sheil, B., J. McCarthy, L. O’Mahony, M. W. Bennett, P. Ryan, J. J. Fitzgibbon, B. Kiely, J. K. Collins, and F. Shanahan. 2004. Is the mucosal route of administration essential for probiotic function? Subcutaneous administration is associated with attenuation of murine colitis and arthritis. Gut 53 (5):694–700. doi: 10.1136/gut.2003.027789.
- Shu, Q., and H. S. Gill. 2002. Immune protection mediated by the probiotic Lactobacillus rhamnosus HN001 (DR20™) against Escherichia coli O157:H7 infection in mice. FEMS Immunology and Medical Microbiology 34 (1):59–64. doi: 10.1016/S0928-8244(02)00340-1.
- Singh, K. S., S. Kumar, A. K. Mohanty, S. Grover, and J. K. Kaushik. 2018. Mechanistic insights into the host-microbe interaction and pathogen exclusion mediated by the mucus-binding protein of Lactobacillus plantarum. Scientific Reports 8 (1):14198. doi: 10.1038/s41598-018-32417-y.
- Smelt, M. J., B. J. de Haan, P. A. Bron, I. van Swam, M. Meijerink, J. M. Wells, M. M. Faas, and P. de Vos. 2012. L. plantarum, L. salivarius, and L. lactis attenuate Th2 responses and increase Treg frequencies in healthy mice in a strain dependent manner. PLoS One 7 (10):e47244. doi: 10.1371/journal.pone.0047244.
- Smelt, M. J., B. J. de Haan, P. A. Bron, I. van Swam, M. Meijerink, J. M. Wells, M. M. Faas, and P. de Vos. 2013. Probiotics can generate FoxP3 T-cell responses in the small intestine and simultaneously inducing CD4 and CD8 T cell activation in the large intestine. PLoS One 8 (7):e68952. doi: 10.1371/journal.pone.0068952.
- Smelt, M. J., B. J. de Haan, P. A. Bron, I. van Swam, M. Meijerink, J. M. Wells, M. Kleerebezem, M. M. Faas, and P. de Vos. 2013. The impact of Lactobacillus plantarum WCFS1 teichoic acid D-alanylation on the generation of effector and regulatory T-cells in healthy mice. PLoS One 8 (4):e63099. doi: 10.1371/journal.pone.0063099.
- Smits, H. H., A. Engering, D. van der Kleij, E. C. de Jong, K. Schipper, T. M. M. van Capel, B. A. J. Zaat, M. Yazdanbakhsh, E. A. Wierenga, and Y. van Kooyk. 2005. Selective probiotic bacteria induce IL-10–producing regulatory T cells in vitro by modulating dendritic cell function through dendritic cell–specific intercellular adhesion molecule 3–grabbing nonintegrin. Journal of Allergy and Clinical Immunology 115 (6):1260–7. doi: 10.1016/j.jaci.2005.03.036.
- So, S. S. Y., M. L. Y. Wan, and H. El-Nezami. 2017. Probiotics-mediated suppression of cancer. Current Opinion in Oncology 29 (1):62–72. doi: 10.1097/CCO.0000000000000342.
- Soh, S. E., M. Aw, I. Gerez, Y. S. Chong, M. Rauff, Y. P. M. Ng, H. B. Wong, N. Pai, B. W. Lee, and L. P. C. Shek. 2009. Probiotic supplementation in the first 6 months of life in at risk Asian infants – effects on eczema and atopic sensitization at the age of 1 year. Clinical & Experimental Allergy 39 (4):571–8. doi: 10.1111/j.1365-2222.2008.03133.x.
- Sood, A., V. Midha, G. K. Makharia, V. Ahuja, D. Singal, P. Goswami, and R. K. Tandon. 2009. The probiotic preparation, VSL#3 induces remission in patients with mild-to-moderately active ulcerative colitis. Clinical Gastroenterology and Hepatology 7:1202–9.e1201
- Stapleton, A. E., M. Au-Yeung, T. M. Hooton, D. N. Fredricks, P. L. Roberts, C. A. Czaja, Y. Yarova-Yarovaya, T. Fiedler, M. Cox, and W. E. Stamm. 2011. Randomized, placebo-controlled phase 2 trial of a Lactobacillus crispatus probiotic given intravaginally for prevention of recurrent urinary tract infection. Clinical Infectious Diseases 52 (10):1212–7. doi: 10.1093/cid/cir183.
- Sung, V., H. Hiscock, M. L. K. Tang, F. K. Mensah, M. L. Nation, C. Satzke, R. G. Heine, A. Stock, R. G. Barr, and M. Wake. 2014. Treating infant colic with the probiotic Lactobacillus reuteri: Double blind, placebo controlled randomised trial. BMJ 348 (apr01 2):g2107–g2107. doi: 10.1136/bmj.g2107.
- Takeda, K., T. Suzuki, S. I. Shimada, K. Shida, M. Nanno, and K. Okumura. 2006. Interleukin-12 is involved in the enhancement of human natural killer cell activity by Lactobacillus casei Shirota. Clinical and Experimental Immunology 146 (1):109–15. doi: 10.1111/j.1365-2249.2006.03165.x.
- Tanaka, A., M. Seki, S. Yamahira, H. Noguchi, K. Kosai, M. Toba, Y. Morinaga, T. Miyazaki, K. Izumikawa, H. Kakeya, et al. 2011. Lactobacillus pentosus strain b240 suppresses pneumonia induced by Streptococcus pneumoniae in mice. Letters in Applied Microbiology 53 (1):35–43. doi: 10.1111/j.1472-765X.2011.03079.x.
- Tao, Y., K. A. Drabik, T. S. Waypa, M. W. Musch, J. C. Alverdy, O. Schneewind, E. B. Chang, and E. O. Petrof. 2006. Soluble factors from Lactobacillus GG activate MAPKs and induce cytoprotective heat shock proteins in intestinal epithelial cells. American Journal of Physiology-Cell Physiology 290 (4):C1018–C1030. doi: 10.1152/ajpcell.00131.2005.
- Taylor, A. L., J. A. Dunstan, and S. L. Prescott. 2007. Probiotic supplementation for the first 6 months of life fails to reduce the risk of atopic dermatitis and increases the risk of allergen sensitization in high-risk children: A randomized controlled trial. Journal of Allergy and Clinical Immunology 119 (1):184–91. doi: 10.1016/j.jaci.2006.08.036.
- Ten Bruggencate, S. J. M., S. A. Girard, E. G. M. Floris-Vollenbroek, R. Bhardwaj, and T. A. Tompkins. 2014. The effect of a multi-strain probiotic on the resistance toward Escherichia coli challenge in a randomized, placebo-controlled, double-blind intervention study. European Journal of Clinical Nutrition 69 (3):385–91. doi: 10.1038/ejcn.2014.238.
- Tiptiri-Kourpeti, A., K. Spyridopoulou, V. Santarmaki, G. Aindelis, E. Tompoulidou, E. E. Lamprianidou, G. Saxami, P. Ypsilantis, E. S. Lampri, C. Simopoulos, et al. 2016. Lactobacillus casei exerts anti-proliferative effects accompanied by apoptotic cell death and up-regulation of TRAIL in colon carcinoma cells. PLoS One 11 (2):e0147960. doi: 10.1371/journal.pone.0147960.
- Toh, Z. Q., A. Anzela, M. Tang, and P. Licciardi. 2012. Probiotic therapy as a novel approach for allergic disease. Frontiers in Pharmacology 3:171. doi: 10.3389/fphar.2012.00171.
- Truusalu, K., R.-H. Mikelsaar, P. Naaber, T. Karki, T. Kullisaar, M. Zilmer, and M. Mikelsaar. 2008. Eradication of Salmonella Typhimurium infection in a murine model of typhoid fever with the combination of probiotic Lactobacillus fermentum ME-3 and ofloxacin. BMC Microbiology 8 (1):132. doi: 10.1186/1471-2180-8-132.
- Tursi, A., G. Brandimarte, G. Giorgetti, G. Forti, M. Modeo, and A. Gigliobianco. 2004. Low-dose balsalazide plus a high-potency probiotic preparation is more effective than balsalazide alone or mesalazine in the treatment of acute mild-to-moderate ulcerative colitis. Medical Science Monitor 10:PI126–131.
- Ueno, N., M. Fujiya, S. Segawa, T. Nata, K. Moriichi, H. Tanabe, Y. Mizukami, N. Kobayashi, K. Ito, and Y. Kohgo. 2011. Heat‐killed body of Lactobacillus brevis SBC8803 ameliorates intestinal injury in a murine model of colitis by enhancing the intestinal barrier function. Inflammatory Bowel Diseases 17:2235–50.
- Urbanska, A. M., J. Bhathena, S. Cherif, and S. Prakash. 2016. Orally delivered microencapsulated probiotic formulation favorably impacts polyp formation in APC (Min/+) model of intestinal carcinogenesis. Artificial Cells, Nanomedicine, and Biotechnology 44 (1):1–11. doi: 10.3109/21691401.2014.898647.
- Ushiyama, A., K. Tanaka, Y. Aiba, T. Shiba, A. Takagi, T. Mine, and Y. Koga. 2003. Lactobacillus gasseri OLL2716 as a probiotic in clarithromycin-resistant Helicobacter pylori infection. Journal of Gastroenterology and Hepatology 18 (8):986–91. doi: 10.1046/j.1440-1746.2003.03102.x.
- van Baarlen, P., F. J. Troost, S. van Hemert, C. van der Meer, W. M. de Vos, P. J. de Groot, G. J. Hooiveld, R. J. Brummer, and M. Kleerebezem. 2009. Differential NF-kappaB pathways induction by Lactobacillus plantarum in the duodenum of healthy humans correlating with immune tolerance. Proceedings of the National Academy of Sciences of of the United States of America 106 (7):2371–6. doi: 10.1073/pnas.0809919106.
- van Baarlen, P., J. M. Wells, and M. Kleerebezem. 2013. Regulation of intestinal homeostasis and immunity with probiotic lactobacilli. Trends in Immunology 34 (5):208–15. doi: 10.1016/j.it.2013.01.005.
- van Beek, A. A., B. Sovran, F. Hugenholtz, B. Meijer, J. A. Hoogerland, V. Mihailova, C. van der Ploeg, C. Belzer, M. V. Boekschoten, J. H. J. Hoeijmakers, et al. 2016. Supplementation with Lactobacillus plantarum WCFS1 prevents decline of mucus barrier in colon of accelerated aging Ercc1−/Δ7 mice. Frontiers in Immunology 7:408. doi: 10.3389/fimmu.2016.00408.
- van Bergenhenegouwen, J., T. S. Plantinga, L. A. B. Joosten, M. G. Netea, G. Folkerts, A. D. Kraneveld, J. Garssen, and A. P. Vos. 2013. TLR2 & Co: A critical analysis of the complex interactions between TLR2 and coreceptors. Journal of Leukocyte Biology 94 (5):885–902. doi: 10.1189/jlb.0113003.
- Van Gossum, A., O. Dewit, E. Louis, G. de Hertogh, F. Baert, F. Fontaine, M. De Vos, M. Enslen, M. Paintin, and D. Franchimont. 2007. Multicenter randomized-controlled clinical trial of probiotics (Lactobacillus johnsonii, LA1) on early endoscopic recurrence of Crohn's disease after lleo-caecal resection. Inflammatory Bowel Diseases 13 (2):135–42. doi: 10.1002/ibd.20063.
- Van Tassell, M. L., and M. J. Miller. 2011. Lactobacillus adhesion to mucus. Nutrients 3 (5):613–36. doi: 10.3390/nu3050613.
- van Zyl, W. F., S. M. Deane, and L. M. T. Dicks. 2019. Bacteriocin production and adhesion properties as mechanisms for the anti-listerial activity of Lactobacillus plantarum 423 and Enterococcus mundtii ST4SA. Beneficial Microbes 10 (3):329–49. doi: 10.3920/BM2018.0141.
- Venturi, A., P. Gionchetti, F. Rizzello, R. Johansson, E. Zucconi, P. Brigidi, D. Matteuzzi, and M. Campieri. 1999. Impact on the composition of the faecal flora by a new probiotic preparation: Preliminary data on maintenance treatment of patients with ulcerative colitis. Alimentary Pharmacology & Therapeutics 13:1103–8. doi: 10.1046/j.1365-2036.1999.00560.x.
- Verkhnyatskaya, S., M. Ferrari, P. de Vos, and M. T. C. Walvoort. 2019. Shaping the infant microbiome with non-digestible carbohydrates. Frontiers in Microbiology 10:343. doi: 10.3389/fmicb.2019.00343.
- Villena, J., M. L. S. Oliveira, P. C. D. Ferreira, S. Salva, and S. Alvarez. 2011. Lactic acid bacteria in the prevention of pneumococcal respiratory infection: Future opportunities and challenges. International Immunopharmacology 11 (11):1633–45. doi: 10.1016/j.intimp.2011.06.004.
- Villena, J., N. Barbieri, S. Salva, M. Herrera, and S. Alvarez. 2009. Enhanced immune response to pneumococcal infection in malnourished mice nasally treated with heat-killed Lactobacillus casei. Microbiology and Immunology 53 (11):636–46. doi: 10.1111/j.1348-0421.2009.00171.x.
- Villena, J., S. Racedo, G. Agüero, and S. Alvarez. 2006. Yoghurt accelerates the recovery of defence mechanisms against Streptococcus pneumoniae in protein-malnourished mice. British Journal of Nutrition 95 (3):591–602. doi: 10.1079/BJN20051663.
- Villena, J., S. Racedo, G. AgüEro, E. Bru, M. Medina, and S. Alvarez. 2005. Lactobacillus casei improves resistance to pneumococcal respiratory infection in malnourished mice. The Journal of Nutrition 135 (6):1462–9. doi: 10.1093/jn/135.6.1462.
- Voltan, S., D. Martines, M. Elli, P. Brun, S. Longo, A. Porzionato, V. Macchi, R. D'Incà, M. Scarpa, G. Palù, et al. 2008. Lactobacillus crispatus M247-derived H2O2 acts as a signal transducing molecule activating peroxisome proliferator activated receptor-gamma in the intestinal mucosa. Gastroenterology 135 (4):1216–27., doi: 10.1053/j.gastro.2008.07.007.
- Wan, L. Y. M., Z. J. Chen, N. P. Shah, and H. El-Nezami. 2016. Modulation of intestinal epithelial defense responses by probiotic bacteria. Critical Reviews in Food Science and Nutrition 56 (16):2628–41. doi: 10.1080/10408398.2014.905450.
- Wang, C., T. Chang, H. Yang, and M. Cui. 2015. Antibacterial mechanism of lactic acid on physiological and morphological properties of Salmonella Enteritidis, Escherichia coli and Listeria monocytogenes. Food Control 47:231–6. doi: 10.1016/j.foodcont.2014.06.034.
- Wang, K.-Y., S.-N. Li, C.-S. Liu, D.-S. Perng, Y.-C. Su, D.-C. Wu, C.-M. Jan, C.-H. Lai, T.-N. Wang, and W.-M. Wang. 2004. Effects of ingesting Lactobacillus- and Bifidobacterium-containing yogurt in subjects with colonized Helicobacter pylori. The American Journal of Clinical Nutrition 83 (4):864–741. doi: 10.1093/ajcn/83.4.864.
- Wang, L., H. Cao, L. Liu, B. Wang, W. A. Walker, S. A. Acra, and F. Yan. 2014. Activation of epidermal growth factor receptor mediates mucin production stimulated by p40, a Lactobacillus rhamnosus GG-derived protein. Journal of Biological Chemistry 289 (29):20234–44. doi: 10.1074/jbc.M114.553800.
- Wang, T., K. Teng, G. Liu, Y. Liu, J. Zhang, X. Zhang, M. Zhang, Y. Tao, and J. Zhong. 2018. Lactobacillus reuteri HCM2 protects mice against Enterotoxigenic Escherichia coli through modulation of gut microbiota. Scientific Reports 8 (1):17485. doi: 10.1038/s41598-018-35702-y.
- Wegh, C. A. M., S. Y. Geerlings, J. Knol, G. Roeselers, and C. Belzer. 2019. Postbiotics and their potential applications in early life nutrition and beyond. International Journal of Molecular Sciences 20:4673. doi: 10.3390/ijms20194673.
- Wells, J. M., O. Rossi, M. Meijerink, and P. van Baarlen. 2011. Epithelial crosstalk at the microbiota–mucosal interface. Proceedings of the National Academy of Sciences of the United States of America 108 (Supplement_1):4607–14. doi: 10.1073/pnas.1000092107.
- West, C. E., M.-L. Hammarström, and O. Hernell. 2009. Probiotics during weaning reduce the incidence of eczema. Pediatric Allergy and Immunology 20 (5):430–7. doi: 10.1111/j.1399-3038.2009.00745.x.
- Wickens, K., P. Black, T. V. Stanley, E. Mitchell, C. Barthow, P. Fitzharris, G. Purdie, and J. Crane. 2012. A protective effect of Lactobacillus rhamnosus HN001 against eczema in the first 2 years of life persists to age 4 years. Clinical & Experimental Allergy 42 (7):1071–9. doi: 10.1111/j.1365-2222.2012.03975.x.
- Wickens, K., P. N. Black, T. V. Stanley, E. Mitchell, P. Fitzharris, G. W. Tannock, G. Purdie, and J. Crane. 2008. A differential effect of 2 probiotics in the prevention of eczema and atopy: A double-blind, randomized, placebo-controlled trial. Journal of Allergy and Clinical Immunology 122 (4):788–94.
- Wildt, S., I. Nordgaard, U. Hansen, E. Brockmann, and J. J. Rumessen. 2011. A randomised double-blind placebo-controlled trial with Lactobacillus acidophilus La-5 and Bifidobacterium animalis subsp. lactis BB-12 for maintenance of remission in ulcerative colitis. Journal of Crohn's and Colitis 5 (2):115–21. doi: 10.1016/j.crohns.2010.11.004.
- Wu, H., L. Ye, X. Lu, S. Xie, Q. Yang, and Q. Yu. 2018. Lactobacillus acidophilus alleviated Salmonella-induced goblet cells loss and colitis by Notch pathway. Molecular Nutrition & Food Research 62 (22):1800552. doi: 10.1002/mnfr.201800552.
- Yan, F., H. Cao, T. L. Cover, R. Whitehead, M. K. Washington, and D. B. Polk. 2007. Soluble proteins produced by probiotic bacteria regulate intestinal epithelial cell survival and growth. Gastroenterology 132 (2):562–75. doi: 10.1053/j.gastro.2006.11.022.
- Yang, G.-Y., J. Yu, J.-H. Su, L.-G. Jiao, X. Liu, and Y.-H. Zhu. 2017. Oral administration of Lactobacillus rhamnosus GG ameliorates Salmonella infantis-induced inflammation in a pig model via activation of the IL-22BP/IL-22/STAT3 pathway. Frontiers in Cellular and Infection Microbiology 7:323. doi: 10.3389/fcimb.2017.00323.
- Yang, Y.,. S. Galle, M. H. A. Le, R. T. Zijlstra, and M. G. Gänzle. 2015. Feed fermentation with reuteran- and levan-producing Lactobacillus reuteri reduces colonization of weanling pigs by enterotoxigenic Escherichia coli. Applied and Environmental Microbiology 81 (17):5743–5752. doi: 10.1128/AEM.01525-15.
- Yasui, H., J. Kiyoshima, and T. Hori. 2004. Reduction of influenza virus titer and protection against influenza virus infection in infant mice fed Lactobacillus casei Shirota. Clinical Diagnostic Laboratory Immunology 11 (4):675–679. doi: 10.1128/CDLI.11.4.675-679.2004.
- Youn, H.-N., D.-H. Lee, Y.-N. Lee, J.-K. Park, S.-S. Yuk, S.-Y. Yang, H.-J. Lee, S.-H. Woo, H.-M. Kim, J.-B. Lee, et al. 2012. Intranasal administration of live Lactobacillus species facilitates protection against influenza virus infection in mice. Antiviral Research 93 (1):138–143. doi: 10.1016/j.antiviral.2011.11.004.
- Yu, J., Y.-H. Zhu, G.-Y. Yang, W. Zhang, D. Zhou, J.-H. Su, and J.-F. Wang. 2017. Anti-inflammatory capacity of Lactobacillus rhamnosus GG in monophasic variant Salmonella infected piglets is correlated with impeding NLRP6-mediated host inflammatory responses. Veterinary Microbiology 210:91–100. doi: 10.1016/j.vetmic.2017.08.008.
- Zeuthen, L. H., L. N. Fink, and H. Frøkiaer. 2008. Toll-like receptor 2 and nucleotide-binding oligomerization domain-2 play divergent roles in the recognition of gut-derived lactobacilli and bifidobacteria in dendritic cells. Immunology 124 (4):489–502. doi: 10.1111/j.1365-2567.2007.02800.x.
- Zhang, J.-W., P. Du, B.-R. Yang, J. Gao, W.-J. Fang, and C.-M. Ying. 2012. Preoperative probiotics decrease postoperative infectious complications of colorectal cancer. The American Journal of the Medical Sciences 343 (3):199–205. doi: 10.1097/MAJ.0b013e31823aace6.
- Zhang, L., Y.-Q. Xu, H.-Y. Liu, T. Lai, J.-L. Ma, J.-F. Wang, and Y.-H. Zhu. 2010. Evaluation of Lactobacillus rhamnosus GG using an Escherichia coli K88 model of piglet diarrhoea: Effects on diarrhoea incidence, faecal microflora and immune responses. Veterinary Microbiology 141 (1-2):142–148.
- Zhang, W., Q. Wu, Y. Zhu, G. Yang, J. Yu, J. Wang, and H. Ji. 2019. Probiotic Lactobacillus rhamnosus GG induces alterations in ileal microbiota with associated CD3-CD19-T-bet+IFNγ+/- cell subset homeostasis in pigs challenged with Salmonella enterica Serovar 4,[5],12: I. Frontiers in Microbiology 10:977. doi: 10.3389/fmicb.2019.00977.
- Zhang, W., Y.-H. Zhu, G.-Y. Yang, X. Liu, B. Xia, X. Hu, J.-H. Su, and J.-F. Wang. 2018. Lactobacillus rhamnosus GG affects microbiota and suppresses autophagy in the intestines of pigs challenged with Salmonella infantis. Frontiers in Microbiology 8:2705. doi: 10.3389/fmicb.2017.02705.
- Zhang, Y.-C., L.-W. Zhang, W. Ma, H.-X. Yi, X. Yang, M. Du, Y.-J. Shan, X. Han, and L.-L. Zhang. 2012. Screening of probiotic lactobacilli for inhibition of Shigella sonnei and the macromolecules involved in inhibition. Anaerobe 18 (5):498–503. doi: 10.1016/j.anaerobe.2012.08.007.
- Zheng, P.-X., H.-Y. Fang, H.-B. Yang, N.-Y. Tien, M.-C. Wang, and J.-J. Wu. 2016. Lactobacillus pentosus strain LPS16 produces lactic acid, inhibiting multidrug-resistant Helicobacter pylori. Journal of Microbiology, Immunology and Infection 49 (2):168–174. doi: 10.1016/j.jmii.2014.04.014.
- Zocco, M. A., L. Z. Dal Verme, F. Cremonini, A. C. Piscaglia, E. C. Nista, M. Candelli, M. Novi, D. Rigante, I. A. Cazzato, V. Ojetti, et al. 2006. Efficacy of Lactobacillus GG in maintaining remission of ulcerative colitis. Alimentary Pharmacology and Therapeutics 23 (11):1567–1574. doi: 10.1111/j.1365-2036.2006.02927.x.