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