Elsevier

Metabolism

Volume 69, April 2017, Pages 76-86
Metabolism

Basic Science
Gut microbiota interactions with the immunomodulatory role of vitamin D in normal individuals

https://doi.org/10.1016/j.metabol.2017.01.007 Get rights and content

Abstract

Background

Due to immunomodulatory properties, vitamin D status has been implicated in several diseases beyond the skeletal disorders. There is evidence that its deficiency deteriorates the gut barrier favoring translocation of endotoxins into the circulation and systemic inflammation. Few studies investigated whether the relationship between vitamin D status and metabolic disorders would be mediated by the gut microbiota composition.

Objective

We examined the association between vitamin D intake and circulating levels of 25(OH)D with gut microbiota composition, inflammatory markers and biochemical profile in healthy individuals.

Methods

In this cross-sectional analysis, 150 young healthy adults were stratified into tertiles of intake and concentrations of vitamin D and their clinical and inflammatory profiles were compared. The DESeq2 was used for comparisons of microbiota composition and the log2 fold changes (log2FC) represented the comparison against the reference level. The association between 25(OH)D and fecal microbiota (16S rRNA sequencing, V4 region) was tested by multiple linear regression.

Results

Vitamin D intake was associated with its concentration (r = 0.220, p = 0.008). There were no significant differences in clinical and inflammatory variables across tertiles of intake. However, lipopolysaccharides increased with the reduction of 25(OH)D (p-trend < 0.05). Prevotella was more abundant (log2FC 1.67, p < 0.01), while Haemophilus and Veillonella were less abundant (log2FC − 2.92 and − 1.46, p < 0.01, respectively) in the subset with the highest vitamin D intake (reference) than that observed in the other subset (first plus second tertiles). PCR (r =  0.170, p = 0.039), E-selectin (r =  0.220, p = 0.007) and abundances of Coprococcus (r =  0.215, p = 0.008) and Bifdobacterium (r =  0.269, p = 0.001) were inversely correlated with 25(OH)D. After adjusting for age, sex, season and BMI, 25(OH)D maintained inversely associated with Coprococcus (β =  9.414, p = 0.045) and Bifdobacterium (β =  1.881, p = 0.051), but significance disappeared following the addition of inflammatory markers in the regression models.

Conclusion

The role of vitamin D in the maintenance of immune homeostasis seems to occur in part by interacting with the gut microbiota. The attenuation of association of bacterial genera by inflammatory markers suggests that inflammation participate in part in the relationship between the gut microbiota and vitamin D concentration. Studies with appropriate design are necessary to address hypothesis raised in the current study.

Introduction

The primary source of vitamin D depends on the skin exposure to sunlight, and up to 20% come from dietary intake. It is still controversial whether the consumption of vitamin D-containing foods has a direct impact in determining its circulating levels [1], [2], [3], [4], [5], [6]. Vitamin D2 (ergocalciferol) is found in yeast, mushrooms and some vegetables, while vitamin D3 (cholecalciferol) in animal-based foods. The latter is the one synthesized in the skin through the ultraviolet B radiation [7]. To be biologically active, vitamin D undergoes hydroxylations in the liver mediated by the 25-hydroxylase, and in the kidney by 1α-hydroxylase. The 1,25(OH)2D is recognized by its specific receptors (VDR) in various cells, mainly in the intestine to enhance calcium absorption, and in the bone to regulate skeletal homeostasis. Deranged absorptive or altered metabolic patterns result in disorders of calcium and phosphorus metabolism but, beyond these well-known roles, vitamin D disturbances have been involved in some other diseases.

Vitamin D plays important roles in innate and adaptive immune responses, cell cycle and metabolic processes, evidenced by the reported relationship between its deficiency and the prevalence of immune-mediated disorders, cancer and cardiometabolic diseases [5], [7], [8], [9], [10]. An inverse correlation between its concentrations and the prevalence of obesity and type 2 diabetes mellitus was described [11], [12]. The findings of VDR in β cells, endothelium, cardiac myocytes and renin-producing cells suggest a role for vitamin D in these diseases [13], [14], [15]. Also, there is evidence that inadequate vitamin D status increases inflammatory cytokines and reduces insulin sensitivity, which were described as pathophysiological links among the cardiometabolic diseases [16], [17].

More recently, the gut microbiota-induced metabolic endotoxemia has been associated with increased cardiometabolic risk [18]. As vitamin D plays a significant role in modulating the immune system at the intestine, it is possible that its deficiency could deteriorate the gut barrier function favoring the translocation of endotoxins such as lipopolysaccharides (LPSs) into the circulation. LPSs are known to promote low-grade inflammation, which predisposes to insulin resistance [19], [20]. Numerous circulating biomarkers have been used to assess inflammation for clinical [21] and research purposes [22], [23].

Certain compositions of the gut microbiota have been associated with systemic inflammation and metabolic disturbances. Particularly, gram-negative bacteria, containing LPS in their outer layer, were shown to stimulate immune response and to provoke metabolic endotoxemia, while other genera, such as Bifidobacteria, to reduce endotoxemia [18]. Despite being gram-negative, Akkermansia was found to improve intestinal barrier function and to induce beneficial metabolic effects [24].

Vitamin D deficiency and the lack of VDR have been associated with intestinal dysbiosis and increased susceptibility to intestinal diseases [25], [26], [27]. Few studies investigated whether the status of vitamin D would be contributing to disturbances of glucose metabolism by modulating the composition of the gut microbiota [28], [29], [30]. Deepening the comprehension of underlying mechanisms of cardiometabolic diseases is desirable considering their impact on the mortality rates of populations.

The Nutritionists' Health Study (NutriHS) was designed to assess novel biomarkers and predictors of cardiometabolic outcomes [31]. This Web-based observational cohort study of undergraduates and graduates from Brazilian nutrition colleges collected a variety of retrospective and prospective data. The NutriHS represents a unique opportunity to investigate relationships between nutrients and cardiometabolic outcomes, whose pathophysiology involves low-grade inflammation. A high-quality data collection should support these associations.

Facing the importance of the intestinal immune system to respond to microbial stimuli, and the immune modulatory role of vitamin D, we hypothesized that vitamin D status is associated with gut microbiota via low-grade inflammation. We examined the association between vitamin D intake and 25-hydroxyvitamin D concentration with fecal microbiota composition, inflammatory markers and biochemical profile in young adults, participants of the NutriHS.

Section snippets

Methods

Details on the objectives, population, and protocol of the NutriHS [31]. Briefly, to be included in the NutriHS, individuals should be 18 years and older, undergraduate or graduate from Nutrition colleges; pregnancy was an exclusion criterion. For the current cross-sectional analysis, data from a convenience sample of the first 150 participants aged from 18 to 40 years, who had complete data on the variables of interest, were eligible. Exclusion criteria were antibiotics, probiotics, prebiotics

Results

The sample was composed of 90.7% of women with a mean age of 24.9 ± 5.8 years and mean BMI of 23.6 ± 4.7 kg/m2. Overweight or obesity was present in 28.5%; all participants denied hypertension or diabetes mellitus but four participants exhibited plasma glucose ≥ 100 mg/dL.

Eighty-one percent of the entire sample had low intake of vitamin D and its major sources were milk, dairy products and eggs. Mean 25(OH)D concentration was 23.9 ± 9.7 ng/mL; 24.0% were sufficient of vitamin D (≥ 30 ng/mL), 39.3% were

Discussion

We found that both vitamin D intake and 25(OH)D concentration are associated with the abundance of certain commensal genera in gut microbiota of the NutriHS participants. Our findings of a distinct proportion of genera according to vitamin D status may raise the hypothesis that its modulatory effect in intestinal immune cells could influence bacterial composition. A reduced immune response in vitamin D deficiency could augment competitive advantage of Haemophilus and Veillonella, found to be

Author Contributions

Study design: SRGF. Study conduct, data collection: RVL, LGF, SRGF. Data analysis and interpretation: RVL, GRF, ACFM, LGF, SRGF. Drafting manuscript and revising manuscript content: RVL, GRF, ACFM, LGF, SRGF. Approving final version of manuscript: RVL, GRF, ACFM, LGF, SRGF.

Funding

This work was supported by a FAPESP—São Paulo Foundation for Research Support (Grant No. 2015/10045-7).

Conflicts of Interest

The authors declare no conflicts of interest.

Acknowledgments

The authors thank the NutriHS researchers and participants and to Capes and FAPESP for financial support.

References (60)

  • J.H. Ooi et al.

    Vitamin D regulates the gut microbiome and protects mice from dextran sodium sulfate-induced colitis

    J Nutr

    (2013)
  • N.P. Ly et al.

    Gut microbiota, probiotics, and vitamin D: interrelated exposures influencing allergy, asthma, and obesity?

    J Allergy Clin Immunol

    (2011)
  • I. Ciubotaru et al.

    Significant differences in fecal microbiota are associated with various stages of glucose tolerance in African American male veterans

    Transl Res

    (2015)
  • L. Mellenthin et al.

    Association between serum vitamin D concentrations and inflammatory markers in the general adult population

    Metab Clin Exp

    (2014)
  • M.C. Collado et al.

    Distinct composition of gut microbiota during pregnancy in overweight and normal-weight women

    Am J Clin Nutr

    (2008)
  • T.J. Wang et al.

    Vitamin D deficiency and risk of cardiovascular disease

    Circulation

    (2008)
  • A. Salehpour et al.

    Vitamin D 3 and the risk of CVD in overweight and obese women: a randomized controlled trial

    Br J Nutr

    (2012)
  • E.D. Michos et al.

    Vitamin D and cardiovascular disease risk

    Curr Opin Clin Nutr Metab Care

    (2008)
  • N.J. Schuch et al.

    Vitamin D and endocrine diseases

    Arq Bras Endocrinol Metab

    (2009)
  • P.E. Norman et al.

    Vitamin D and cardiovascular disease

    Circ Res

    (2014)
  • M. Herrmann et al.

    Serum 25-Hydroxy vitamin D: a predictor of macrovascular and microvascular complications in patients with type 2 diabetes

    Diabetes Care

    (2014)
  • K.E. Wellen et al.

    Inflammation, stress, and diabetes

    J Clin Invest

    (2005)
  • P.D. Cani et al.

    Gut microflora as a target for energy and metabolic homeostasis

    Curr Opin Clin Nutr Metab Care

    (2007)
  • A.M. Caricilli et al.

    Gut microbiota is a key modulator of insulin resistance in TLR 2 knockout mice

    PLoS Biol

    (2011)
  • A.C.F. Moraes et al.

    Microbiota intestinal e risco cardiometabólico: mecanismos e modulação dietética

    Arq Bras Endocrinol Metab

    (2014)
  • P.M. Ridker et al.

    Prospective study of C-reactive protein and the risk of future cardiovascular events among apparently healthy women

    Circulation

    (1998)
  • P.C. Calder et al.

    A consideration of biomarkers to be used for evaluation of inflammation in human nutritional studies

    Br J Nutr

    (2013)
  • B. Almeida-Pititto et al.

    Usefulness of circulating E-selectin to early detection of the atherosclerotic process in the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil)

    Diabetol Metab Syndr

    (2016)
  • A. Everard et al.

    Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity

    PNAS

    (2013)
  • J. Kong et al.

    Novel role of the vitamin D receptor in maintaining the integrity of the intestinal mucosal barrier

    Am J Physiol Gastrointest Liver Physiol

    (2008)
  • Cited by (126)

    • Vitamin D and colorectal cancer

      2023, Feldman and Pike's Vitamin D: Volume Two: Disease and Therapeutics
    View all citing articles on Scopus
    View full text