International Immunopharmacology: Sciencedirect

International Immunopharmacology 79 (2020) 106112
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International Immunopharmacology
journal homepage: www.elsevier.com/locate/intimp
Vitamin D and microbiota: Two sides of the same coin in the T

immunomodulatory aspects
Lucia Malaguarnera
Department of Biomedical and Biotechnological Sciences, University of Catania, Via Santa Sofia, 97, Catania, Italy
A R T I C LE I N FO A B S T R A C T
Keywords: The gut microbiota is crucial for host immune response, vitamin synthesis, short chain fatty acids (SCFAs)
Vitamin D3 production, intestinal permeability, nutrient digestion energy metabolism and protection from pathogens.
Microbiota Therefore, gut microbiota guarantees the host’s predisposition to gastrointestinal diseases. Intestinal microbiota
Immunoregulation may be damaged by environmental components with negative health conditions. Dysbiosis consisting in al-
teration in the gut microbiota has been involved in several disorders including inflammation, allergic reactions,
autoimmune diseases, heart diseases, obesity, and metabolic syndrome and even in the state of malignant car-
cinogenesis existing in humans. Several epidemiological studies have shown that inadequate solar exposure
results in vitamin D insufficiency/deficiency which has a strong impact on different immune responses and the
occurrence of a wide range of pathological conditions. Additionally, new evidence indicates that the vitamin D
pathway plays a key role in gut homeostasis. Due to the strong connection between vitamin D and microbiota,
herein we focus on the new findings about intestinal bacteria–immune crosstalk and the impact of vitamin D in
gut microbiota regulation, in order to offer new clarifications on their interaction. Understanding the mechanism
by which vitamin D can affect the gut microbiota composition and its dynamic activities, as well as the innate
and adaptive state of the immune system, is not only a fundamental research but also an opportunity to improve
health status.
1. Introduction microbiota embraces almost 100 times more genes than the human
genome [1]. The intestinal microbiota is one of the main environmental
The gastrointestinal (GI) tract covers a large area and interacts with elements influencing the disease’s onset. Gut microbiota achieves dif-
many foodborne and microbial antigens. The microbiota embraces an ferent structural and histological functions, inducing essential meta-
enormous number of commensal microorganisms that colonize the GI. bolic processes able to preserve health, including the digestion of
The microbiota residing in the human intestinal tract includes a po- complex carbohydrates and fats, amino-acid synthesis, the uptake of
pulation of about 100 trillion active and different microorganisms (in- vitamins, and withdrawals of supplementary energy [e.g., short chain
cluding 500 and 1,000 different species) [1]. As a whole, the gut fatty acids) from non-digestible dietary substrates [2]. This
Abbreviations: AJs, adherens junctions; AMPs, antimicrobial peptides; AP-1, activator protein-1; APCs, antigen-presenting cells; ASC, apoptosis-associated speck-like
protein; Bregs, regulatory B cells; CAMP, cathelicidin antimicrobial peptide; CCL, C–C motif chemokine ligand; CSGG, cell surface β-glucan/galactan; CD206,
mannose receptor; CTLA-4 or CD152, cytotoxic T lymphocyte antigen; Cyp24, 25-hydroxyvitamin D 24-hydroxylase; CYPR1, cytochrome P450; CYP27B1, cyto-
chrome P450 family 27 subfamily B member; 1, 25(OH)2D3, 1,25-dihydroxyvitamin D3; DCs, dendritic cells; DEFB4, defensin beta 4 gene; DSS, dextran sulfate
sodium; FGF23, fibroblast-like growth factor-23; GI, gastrointestinal; HBD-2, defensin ??2; hCAP18, cathelicidin; HDAC, histone deacetylase; IgA, immunoglobulin A;
IL, interleukin; ILCs, innate lymphoid cells; INF-γ, interferon gamma; IBD, irritable bowel disease; IEC, intestinal epithelial cells; IRAK 4, IL-1 receptor-associated
kinase 4; JAM-A, junctional adhesion molecule; KO, knockout; LL-37, Cathelicidin leucin-leucin-37; LPS, lipopolysaccharide; LP, lamina propria; M1, classically
activated macrophages; M2, alternatively activated macrophages; MAMPs, Microbe-Associated Molecular Patterns; MDP, muramyl dipeptide; MLCK, myosin light
chain kinase; MLNs, mesenteric lymph nodes; MyD88, Myeloid differentiation factor 88; NFAT, nuclear factor for activated T cells; NF-κB, nuclear factor kappa light
chain enhancer of B cells; Nod2, nucleotide binding oligomerization domain 2; NLRs, NOD-like receptors; PAMPs, pathogen-associated molecular patterns; PRRs,
pattern recognition receptors; sIgA, secretory IgA; SCFA, short chain fatty acids; PTH, parathyroid hormone; RORγT, retinoid-related orphan nuclear receptor; SFB,
segmented filamentous bacteria; TER, transepithelial resistance; TGF-β, transforming growth factor beta; T, helper 1; Th2, T helper 2; Th17, T helper 17; TJs, tight
junctions; TLR, toll-like receptor; TNBS, 2,4,6-trinitrobenzene sulfuric acid; TNF-α, tumor necrosis factor alpha; Treg, regulatory T cell; VDBP, vitamin D binding
protein; VDR, vitamin D receptor; VDREs, vitamin D responsive elements; D3, 1,25(OH)2D3; ZO-1, zonulin occluden-1; ZO-2, zonulin occluden-2
E-mail address: [email protected].
https://doi.org/10.1016/j.intimp.2019.106112
Received 21 October 2019; Received in revised form 2 December 2019; Accepted 2 December 2019
Available online 24 December 2019
1567-5769/ © 2019 Elsevier B.V. All rights reserved.
L. Malaguarnera International Immunopharmacology 79 (2020) 106112
Fig. 1. The most frequent effects of both Vitamin D 3 deficiency and gut microbiota modification are systemic and chronic inflammation. The alteration of the
mucosal immune system enhances the susceptibility to infectious diseases and increases the risk of various pathogenic conditions, including metabolic, autoimmune
and degenerative disorders and neoplastic process.
sophisticated bionetwork determines the host’s susceptibility to GI in- microbes and controls the inflammatory processes [10,11]. On the
fections, avoids inflammatory responses, recovers metabolism and contrary, the inflammation in the GI causes an alteration in the mi-
protecting against entero-pathogens guarantees resistance to infection crobiota, as a result more pathogenic organisms, named Proteobacteria,
[3]. A healthy gut microbiota, being indispensable for host immune compete with commensals microorganisms initiating alterations in the
function safeguards from autoimmune disease [4,5] (Fig. 1). The gut microbiota, namely dysbiosis. Therefore, the variation in the com-
composition of the intestinal microbiota constitutes a dynamic element position of the bacterial microbiota is an intensified reaction of the host
that in each person is predisposed by route of delivery [6] breast- to injury. A large number of dietary elements interact with enzymes,
feeding, age, sex, genetic background, environmental factors, lifestyle, transcription factors, and nuclear receptors of human cells stimulating
nutrients, hygiene, antioxidants, medications and antibiotics intake the selection of microbial populations and affecting the shift from eu-
[6,7]. Alteration of the microbial colonization in the GI tract since biosis to dysbiosis [12]. The most frequent effect of dysbiosis are sys-
birth, at the time of dynamic changes in the newborn gut, may have temic inflammation and chronic inflammatory diseases, the modifica-
long-term effects on health status [7]. The majority of the microbial tion of the mucosal immune system and the risk of various diseases,
populations, in the adult subject, belong to the phyla Actinobacteria and including metabolic, autoimmune and degenerative disorders, and even
Proteobacteria, and approximately 90% to the Bacteroidetes and Firmi- cancer [13] (Fig. 1). The relevance of microbiota homeostasis in the
cutes phyla [8]. These phyla are differentially disseminated throughout etiology of diseases underscores the need to recognize regulating factors
the gut and regulate the microbial ecosystems [9]. Among Firmicutes able to influence the intestinal bacterial composition. Vitamin D defi-
phylum, the Clostridium coccoides family is the principal residents in the ciency or insufficiency mainly due to insufficient sunlight exposure,
gut microbiota. The sophistication of the human gut microbiota is de- altered dietary composition, air pollution, and indoor lifestyles are
monstrated by the spatial distribution and alternation of microorgan- prevalent in the world and is often associated with various diseases
isms all through the GI tract. Diverse bacteria populate distinct seg- such as autoimmune diseases, hepatitis, and cancer [14–16] (Fig. 1).
ments of the intestine and the different layers of the gut [9]. Therefore, Vitamin D3 acts as immune modulator able to prevent inflammation
the diversity of the microbial population in each intestinal niche would and infections [14] and consequently may be important in affecting the
be the most suitable to protect local tissue homeostasis [10]. Since, the early gut microbiota. In this review, we will provide an insight of the
autochthonous microbiota has been modified to adapt to new func- interactions between Vitamin D3 and microbiota and their impact in
tional specializations, the various environmental factors and dietary the immune responses in order to disclose the potential association
variations influence, progressively over time, the human colonic mi- between vitamin D deficiency and dysbiosis.
crobiota conferring countless health benefits to the host [11]. So, gut
microbiota offers beneficial functions to the host, in return, the host
2. Vitamin D metabolism
offers an environment rich in nutrient that promotes grow of microbiota
and helps the host homeostasis [10]. This symbiotic synergism between
Vitamin D is predominantly synthesized in the skin via a photolysis
the intestinal microbiota with the host, named eubiosis, affects sig-
reaction. The nutrients are insufficient to provide adequate levels of
nificantly both the immune and neuroimmune system development
vitamin D3. Vitamin D3 produced in the skin by sunlight exposure or by
and, in that way, defends the host from colonization of pathogenic
nutrients is inactive. The metabolic processes that transform the
2
biologically inactive form of vitamin D3 into active metabolites initiates TJ protein expression and allocation. Furthermore, the intensification
when vitamin D3 is photosynthesized in the skin or once is ingested. In of the apoptotic process results in an intensified impairment, which
the course of photosynthesis in the skin, the 7-dehyrocholesterol is makes the host vulnerable to luminal pathogens and dietary antigens
transformed into pre-vitamin D3, which is then isomerized into chole- that can generate mucosal inflammation [29]. Recognition of pathogen-
calciferol or D3 [17]. The vitamin D3 synthesis is influenced by skin associated molecular patterns (PAMPs) by pathogen recognition re-
pigmentation, air pollution, sunscreen use, latitude, season, and time of ceptors (PRRs) of epithelial cells is essential for this balance. Through a
the day [17]. Once vitamin D3 binds Vitamin D-binding protein (VDBP) mechanism mediated by PRR the gut microbiota by its metabolites is
pours into the vessels where it is transported from the bloodstream to able to induce AMPs production by Paneth cells [30] (Table 1). Inter-
the liver [17]. Alternatively, vitamin D2 or ergocalciferol deriving from estingly, Myeloid differentiation factor 88 (MyD88) is a PRR located at
nutrient crosses the small intestines and binding to chylomicrons, the crossing point of the interaction between microorganisms and the
reaches the lymphatic system, and then in the bloodstream where they host and is the major adaptor molecule for the majority of the Toll-like
are poured into the liver. In the liver, both vitamin D2 and vitamin D3, receptors (TLRs) [31] (Fig. 2). In the intestinal epithelial cells, it acts as
are hydroxylated by the enzyme cytochrome P450 (CYP R1) to 25-hy- a sensor affecting the gut microbiota structure, energy metabolism and
droxyvitamin D3 [25(OH) D3]. The 25(OH)D3 is then transformed to the development of obesity and connected diseases [31].
1α,25-dihydroxyvitamin D3 [1α,25(OH)2D3] by the 1-α-hydroxylase
enzyme cytochrome P450 family 27 subfamily B member 1 (CYP27B1) 4. Vitamin D 3 and intestinal barrier function
mainly in the kidneys [17]. The active metabolite 1α,25(OH)2D3 (or
calcitriol), is a powerful steroid hormone [17]. Feedback mechanisms Vitamin D3 exerts extraordinary regulatory role in protecting the GI
control the synthesis of 1,25(OH)2D in the kidneys via serum levels of epithelium and mucosal barrier homeostasis. Several studies have un-
parathyroid hormone (PTH), fibroblast-like growth factor-23 (FGF23) derscored the relevance of vitamin D for intestinal mucosal immunity,
calcium, and phosphate [17]. Additionally, 1α,25(OH)2D3 is synthe- for preserving TJ and function of colonic epithelium. In contrast, vi-
tized in numerous tissues (e.g., blood vessels, macrophages, colon, tamin D deficiency induces enhanced gut permeability, colon mucosa
pancreas, etc.) by enzymatic processes [17]. 1,25(OH)2D3 binds to the bacterial infiltration, and translocation of intestinal pathogens in the
vitamin D receptor (VDR), which can be found in around 30 different gut of the host causing subclinical inflammation and metabolic en-
tissues [17] and is able to regulate the expression of more than 1000 dotoxemia [32]. Vitamin D considerably reduces the TJ injury-related
genes in the genome [18]. The VDR is member of the nuclear receptor increase in intestinal mucosa barrier permeability. Additionally, 25
family of ligand-regulated transcription factors. The complex1,25(OH) (OH)2D3 treatments significantly decrease MyD88 expression and zo-
2D bound to VDR facilitates the transcription of DNA binding to the nulin release levels [33], controls intestinal barrier by the up-regulation
DNA responsive elements of the controlled gene acting with another of TJ proteins including occludin, ZO1, claudin 2 and E-cadherin [34]
nuclear receptor, retinoid X receptor. These elements are located not (Table 2A) preserving in this manner the adhesive phenotype of in-
only in the promotor region, but are disseminated over the gene DNA. testinal epithelial cells. Several studies in VDR gene–knockout (KO)
The gene expression embraces several nuclear transcription factors mice with experimental colitis induced using dextran sulfate sodium
which interact with the responsive elements [19]. (DSS) showed serious incidence of colitis [35] demonstrating the de-
leterious consequences of vitamin D deficiency on inflammatory disease
3. Intestinal microbiota and intestinal barrier function severity. The VDR KO mice displayed an amplified vulnerability to li-
popolysaccharides (LPS), expressed significant levels of inflammatory
The GI tract is a selective barrier allowing liquids and nutrients cytokines such as IL-1α, IL-1β, TNF-α, IL-10, IL-21, and IFN-γ, and were
passage while act as the first line of defense against external insults predisposed to weight loss, bleeding, ulceration, septic shock, and death
[20]. The intestinal epithelial cells are bound each other by apical compared to wild-type mice [36] (Table 2B). Increased production of
junctional complexes including tight junctions (TJs), adherens junc- inflammatory cytokines such as TNF-α contributed to the failure of GI
tions (AJs), desmosomes and gap junctions, which along with mucus, barrier integrity in vitamin D deficient and VDR KO mice [36]. Also,
antimicrobial proteins, and immunoglobulin A (IgA) control para- 1α,25(OH)2D3 rises transepithelial resistance (TER) in cultured cells
cellular permeability and form an obstacle against toxins and enteric [35], while the absence of VDR significantly decreases TER in experi-
pathogens [21]. AJs are mostly constituted by cadherins linked to the mental colitis mouse models [36], supporting that vitamin D is essential
actin cytoskeleton through a member of catenins, while TJs are the in preserving mucosal epithelial barrier integrity [36]. The perme-
product of interactions of occludin, claudin and junctional adhesion ability of the gut enhanced along with the injury of TJ proteins both in
molecule (JAM)-A, connected to the actin cytoskeleton via zonula oc- VDR KO mice and vitamin D deficient mice [37] (Table 2B). In vitro
cludens proteins (ZO-1, ZO-2) and α-catenin [22]. Epithelial cells create studies confirmed that vitamin D protects the integrity of intercellular
a physical obstacle, inhibiting the passage of the luminal contents of the TJ against DSS-induced disruption [35] through the regulation of co-
internal tissues. Myosin phosphorylation and contraction of the ac- lonic antimicrobial activity [37]. Additionally, it was shown that in GI
tin–myosin complex control the absorbency of the epithelial barrier epithelial cells 1,25D alone or in combination with calcium stimulates
[23]. The intestinal epithelium is essential for the absorption of nu- the E-cadherin transcription as a result could reduce the risk for col-
trients, and ensures crosstalk with the external surface of the body as orectal neoplasms [38]. Interestingly, an experimental study executed
well as among gut microbes. Microbiota induces TJ protein expressions in Vitamin D-deficient mice challenged with C. rodentium showed co-
and support the host reduction paracellular permeability [24,25]. lonic epithelial crypt hyperplasia, enhanced intestinal paracellular
Variation in the structure of the intestinal microbiota causes epithelial permeability, synthesis of proinflammatory cytokines and weight loss,
barrier dysfunction [26] (Table 1), which consents the translocation of compared to vitamin D–sufficient animals [39]. Both vitamin D-defi-
endoluminal molecules into the deeper layers which, in turn, deterio- cient study groups without and with infection exhibited an altered
rates the intercellular connexion initiating inflammatory processes, composition of the fecal microbiome [39]. C. rodentium infection leads
generating colitis and bacterial infection of the intestinal tissue [27]. to TJ impairment and augmented colonic permeability to macro-
The activation of the inflammatory response induces the synthesis of molecules [40]. TNF-α regulates TJs and subsequently controls in-
proinflammatory cytokines, such as interferon gamma (IFN-γ) and tu- testinal epithelial barrier. It enhances the permeability of human colon
mour necrosis factor alpha (TNF-α), which both regulate the expression carcinoma cell monolayers by triggering the long isoform of myosin
of several TJ proteins, such as ZO-1, JAM-A, occludin, claudin-1 and light chain kinase (MLCK) and myosin II regulatory light chain phos-
claudin-4 [28]. The compromised intestinal barrier function triggered phorylation. 1α,25(OH)2D3 counteract the damage of the intestinal
by mucosal ulceration decreases the number of TJ strands and modifies barrier induced by TNF-α by inhibiting the MLCK pathway in cultured
3
Table 1A
Mechanisms of microbiota action on GI mucosal immuno-system.
Subjects Action /effect Ref.
Human enterocyte cell line HCT-8 and BALB/c mice Induces TJ expression [24,25]
Biopsies from Crohn's disease and ulcerative colitis Preserves mucosal epithelial barrier integrity [26]
Host tissues Induces AMPs production by its metabolites [30]
Intestinal epithelial cells Influences Nod2 receptors [70]
T cells: Affects differentiation of T cell subsets [74]
Induces CD4 to produces IL-10 and inhibits IL-17 [112]
Th17 Controls Th17 cells development and function [107,108,110,114]
Tregs Enhances Foxp3+ Treg cells number [135]
Induces the transcription factor RORγt in Treg cells via an MyD88-dependent mechanism [140]
Regulate Th17 /Tregs equilibrium [144]
Bregs Supports IL-10 producing B-cell differentiation [155]
Monocytes/macrophages: Induces AMPs production by its metabolites [146,147]
M2 subset Contributes to the M2 differentiation [171]
Promotes the anti-inflammatory properties of M2 [176]
Dendritic cells Supports the development of both tolerogenic and inflammatory moDC [188]
Induces tolerogenic state [187,189]
Fig. 2. Vitamin D3, Microbiota and Intestinal Barrier Function. 1,25(OH)2D3 reduces the TJ injury-related increase in intestinal mucosa barrier permeability and
decreasing MyD88 expression controls intestinal barrier. Vitamin D deficiency enhances IL-1α, IL-1β, TNF-α, IL-10, IL-21, and IFN-γ. TNF-α induces the loss of GI
barrier integrity and colonic inflammation. 1,25(OH)2D3 protects against TNF-α induced injury of the intestinal barrier by suppressing the myosin light chain kinase
(MLCK) by inhibiting nuclear factor kappa B (NF-κB) binding to the promoter of the MLCK gene. 1,25(OH)2D3 enhances alkaline phosphatase and maltase expression
which increases the formation of microvilli. VDR plays part in butyrate-mediated inhibition of inducible NFκB activation and regulates the expression of the TJ
proteins ZO-1, ZO-2. MyD88 influences the role of microbiota-induced pathways that may regulate expression and function of intestinal epithelial TLR adaptors and
thus impact on the expression of bacteria sensing TLRs.
HCT116, Caco-2 and SW480 cells [41]. This process is induced by the short-chain fatty acid butyrate increases VDR expression and the pro-
suppression of nuclear factor kappa B (NF-κB) binding to the promoter differentiative effect of 1α,25(OH)2D3 [46]. Moreover, VDR partici-
of the MLCK gene and is restored by 1α,25(OH)2D3 in a mouse model of pates in butyrate-mediated inhibition of inducible NFκB activation in
colitis [41]. Moreover, 1α,25(OH)2D3 repairs TJ upon injury elicited by human HT-29 colon carcinoma cells and prevents inflammation in a
bacterial lipopolysaccharide in Caco-2 cells [42]. 1α,25(OH)2D3 colitis model [47]. Also, VDRs safeguards intestinal barrier function by
maintains mucosal barrier integrity preventing intestinal cell apoptosis circumventing the enhanced intestinal permeability, dysbiosis, in-
triggered by TNF-α-NFκB-PUMA during the inflammatory process [43]. flammation, and a deficiency of immune response in the gut [48]. In-
1α,25(OH)2D3 increases the expression and activity of alkaline phos- terestingly, VDR regulates the expression of the TJ proteins ZO-1, ZO-2
phatase and maltase which improving the formation of microvilli act as through the up-regulation of claudin 2 and 12 and downregulation of
brush border enzymes and are employed as differentiation markers in cadherin-17 in the GI [46] (Fig. 2). As compared with wild-type mice,
the small intestine [44] (Fig. 1). The action on alkaline phosphatase is VDR mice treated with DSS exhibit a significant decrease expression of
facilitated by the transcription factor activator protein-1 (AP-1) [44]. In E-cadherin, claudin-1, ZO-1, and occluding proteins [37] (Table 2A).
CRC cells 1α,25(OH)2D3 rises the expression of a plasma membrane All these proteins are indispensable for maintaining intestinal barrier
calcium ATPase isoform connected with differentiation [45], while the function and consequently immune homeostasis and preserve from
4
Table 2A
Mechanisms of Vitamin D3 action on GI mucosal immuno-system.
Prediabetes and type 2 diabetes mellitus; Intestinal epithelial cells; VDR KO mice; Preserves TJ intestinal barrier integrity and function [32,34,36,42]
Caco-2 cell lines
Caco-2 cell lines and gluten-sensitized mouse model Decreases MyD88 expression [33]
Colorectal adenoma patients Stimulates E-cadherin transcription [38]
Human macrophages; VA10 Cell lines Induces antimicrobial peptides [52-54,147]
HEK293 cell lines Induces Nod2 expression [56,69]
T cell subsets:
Th17 Suppresses inflammation and Th17-mediated autoimmunity. [117]
Alleviates autoimmune diseases by reducing IL-17 production. [118,119]
Inhibits the expression of RORγt/IL-17 and NF-kB. [120]
Modulates the Th17/iTreg axis [122]
Downregulates IL-17 and IL-23 production [123]
Tregs Enhances Foxp3+ Treg cells number [132-134]
Stimulates IL-10 production [131,135]
Bregs Regulates Breg cells and stimulates IL-10 production [162,163]
Monocytes/macrophages Promotes the antimicrobial activities [15,172]
Prevents the expression of TLR-2, TLR-4, and TLR9. Modifies the TLR9- [173]
dependent production of IL-6
M2 subset Increases M2 number [174,175]
Inducing IL-10 prevent M1 subset differentiation [176]
Dendritic cells Inhibits DC differentiation and IL-12 secretion [183]
Induces tolerogenic state [185]
Table 2B transcription of anti-microbial peptides (AMPs) in several cell types,

VDR action on GI mucosal immuno-system. including colonic cells [51] (Fig. 3) (Table 2B). AMPs including, ca-
thelicidin (hCAP18) and defensin ??2 (HBD-2) exert numerous func-
tions such as chemotaxis of inflammatory immune cells [6] and mi-
VDR KO mice Failure of GI barrier integrity [36] crobicidal action [14]. In vitro studies, in human macrophages, revealed
Decreased transepithelial resistance TER [36] that toll-like receptor (TLR) activation elicits cathelicidin antimicrobial
Enhanced injury of TJ proteins [37]
In human HT-29 colon Participates in butyrate-mediated [47]
peptide (CAMP) expression via a vitamin D-dependent pathway [52].
cancer cells inhibition of inducible NFκB activation The induction of CAMP vitamin D-mediated intensifies antimicrobial
Reduces intestinal permeability [39,43] activity against pathogens specifically by direct killing cathelicidin
Caco-2 and epithelial cells VDR/RXR complex activates the [51,59] leucin-leucin-37 (LL-37) and increasing phagosome formation [53]. In
transcription AMPs
human primary monocytes 1α,25(OH)2D3 elicits the maturation of
Colonic cells Increases IL-22-producing innate [84]
lymphoid cells triggering dysbiosis autophagosomes and autophagolysosomes by means a hCAP18/LL-37-
VDR KO mice Absence of iTregs induction [138] mediated pathway [54]. In addition, in monocytes TLR activation of
T cells differentiate in Th17 [132] generates expression of the defensin beta 4 gene (DEFB4) through the
synergistic action of IL-1β and VDR pathways [55]. The stimulation of
intracellular pattern recognition receptor nucleotide-binding oligo-
autoimmune diseases such as irritable bowel disease (IBD). Moreover, merization domain protein 2 (NOD2) by its ligand muramyl dipeptide
VDR expression enhances trans-epithelial electrical resistance between (MDP), a lysosomal breakdown product of peptidoglycan from both
the TJs and reduced LPS levels in Caco-2 cells both treated or not with gram-negative and gram-positive bacteria, triggers the expression of the
DSS inducing less intestinal permeability [43]. Likewise, VDR avoids HBD-2 gene [56]. 1α,25(OH)2D3 powerfully induces NOD2/CARD15/
the decline in transepithelial electrical resistance by the pathogenic IBD1 in primary human monocytic and epithelial cells [57]. In parti-
Escherichia coli O157:H7 which, consequently, reduces intestinal per- cular pre-treatment with 1α,25(OH)2D3 followed by MDP causes a
meability in epithelial cells [39] (Table 2B). vigorous, synergistic expression of the HBD-2 gene [56]. Therefore,
AMPs effect the composition of the intestinal microbiota. Interestingly,
5. Vitamin D, gut microbiota and the immune system AMPs in association with IgA protect mucus layers outside of epithelial
cells [58]. In epithelial cells of the luminal lining of the digestive tract
In the last decades, one of the most extraordinary discoveries has AMP expression is also modulated by the bio-products of gut metabo-
been that 1α,25(OH)2D3 influences significantly the innate and adap- lism, thus creating a mucosal barrier and inhibiting the interaction of
tive immune response [14]. It modulates the immune response through microbes and pathogens with the intestinal epithelium [59] (Fig. 3). As
VDR which is expressed in immune cells, including activated or naïve evidenced by the observation that the short-chain fatty acids such as
CD4+ and CD8+ T cells, B cells, neutrophils and antigen-presenting sodium butyrate, which results from the fermentation process of in-
cells (APCs) such as monocytes, macrophages and dendritic cells [14] digestible polysaccharides (fibres) from microbes in the colon, could
(Fig. 3). Therefore, a viable immune response is significantly influenced stimulate cathelicidin expression [60]. The vitamin D pathway is in-
by the vitamin D endocrine system which balances inflammation versus volved in this stimulation [56], in fact, the synthesis of secondary bile
anti-inflammation [49]. When CD4+ T cells differentiate into various acids by microbes modulates cathelicidin expression in the colon
subsets exert both pro- and anti-inflammatory properties. Several T through VDR action [59] (Table 2B).
cells subsets and their cytokines are essential for the physiological
function and the pathological change of intestinal mucosa regulating 6. Microbiota and immune system
continuously the gut homeostasis and inflammation [50]. VDR func-
tions are crucial in immune response and gut homeostasis [34]. The Continuous cross talk happens among intestinal epithelial cells, gut
1,25/VDR/RXR complex increases in the innate immune cells chemo- microbiota, and the gut-associated lymphoid tissue, which is pre-
tactic and phagocytic capabilities and meanwhile activates the dominantly composed of Peyer’s patches, lymphoid nodules surrounded
5
Fig. 3. Vitamin 3 and Immune-regulation of T and B Cell Subsets:1α,25(OH)2D3 regulates the immune system via the VDR present in activated or naïve CD4+
and CD8+ T cells, B cells, neutrophils, macrophages and dendritic cells. The 1,25/VDR/RXR complex increases in the innate immune cells chemotactic and pha-
gocytic capabilities and activates the transcription of anti-microbial peptides (AMPs). AMP expression is modulated by sodium butyrate. 1α,25(OH)2D3 and VDR
regulate T cells function promoting Tregs development, prevents inflammation turning off the Th1 and Th17 cells function. 1α,25(OH)2D3 and VDR regulate of the
Th17/iTreg axis. 1α,25(OH)2D3 downregulates IL-17 and IL-23 production. 1α,25(OH)2D3 directly influences Treg cell growth and promotes IL-10 production.
1α,25(OH)2D3 regulates Breg cells. 1,25(OH)2D3 induces higher levels of IL-10 in human B cells. Microbiota and Immune-regulation of T and B Cell Subsets:
Microbiota stimulates the maturation and differentiation of T and B cells. IL-1, IL-6, IL-12, IL-18, and IL-23 regulate the Th17/ Tregs balance toward Th17 cells.
Microbiota affects the differentiation of T cell populations into different types of Th. TGF-β, IL-4, IL-10, IL-5, and IL-6 stimulate IgA production. IL-10 and TGF-β
sustain the mucosal tolerance. Microbiota regulates Th17/iTreg axis stimulating Tregs. Butyrate downregulate the production of nitric oxide and of IL-6, IL-12. The
gut microbiota promotes IL-10-producing B-cells.
in the submucosa of the small intestine, and lymphocytes disseminated muramic acid, and unmethylated bacterial DNA CpG motifs, poly-
through the lamina propria (LP) [61] (Fig. 3). Therefore, the gut mi- saccharides LPS and peptidoglycan components [64]. TLRs trigger a
crobiota is fundamental for the maturation and differentiation of im- sophisticated cascade of signals, producing the release of NF-κ light-
mune cells, for a suitable host immune response and plays a crucial role chain-enhancer of activated B cells, which in turn, stimulates a large
in the development of the host’s tolerance against foreign antigens quantity of genes coding effectors of the humoral immune response
[62,63]. The mucosal immune system is extremely specialized and acts such as acute phase proteins, cytokines, chemokines and antibacterial
autonomously than the systemic immune system [9,63], preserving and products [65]. Additionally, TLRs activation by antigens of the normal
activating immune tolerance within the intestine. The major mod- intestinal microbiota prevents inflammatory response, crucial to pre-
ifications of the mucosal immune system occur after bacterial coloni- serve intestinal homeostasis [66]. TLRs activity declines in the course of
zation of the intestinal tract [63]. It removes pathogens preventing the first weeks of life, enabling the development of a definitive gut
pathologies onset. Following the colonization of the mucosal entrance bacterial community. Further, NOD-like receptors (NLRs) discriminate
sites of pathogens, microbiota not only eludes the attack by external numerous microbial specific molecules and activate the inflammasomes
microbes by rivalling pathogenic bacteria in the gut for nutrients and assembly, which are cytoplasmic multi-protein complexes constituted
adhesion factors, but also by producing toxic molecules to neutralise by one of NLR proteins, such as NLRP1, NLRP3, and NLRC4, that act as
colonization of pathogens, a process named colonization resistance. sensors of exogenous or endogenous stress or damage-associated mo-
Epithelial cells, macrophages inside the LP and dendritic cells (DCs) lecular patterns [67]. Following the detection of proper signal, they
sited in Peyer’s patches present PRRs such as TLRs and Nod2 receptors, collect together with the adaptor protein, apoptosis-associated speck-
which control the different immune responses to avoid dysbiosis [64]. like protein (ASC), into a multi-protein complex that manages caspase-1
TLRs of the membrane of the epithelial and lymphoid cells of the small activation and successive cleavage of effector pro-inflammatory cyto-
intestine are engaged in this identification and coordinate the regular kines including IL-1, IL-6, IL-12, IL-18, and IL-23, which then regulate
development of the intestinal mucosal immune system. They prevent the Th17/ regulatory T cells (Tregs) balance toward Th17 cells [68]
inflammation and stimulate immunological tolerance of normal mi- (Fig. 2). It has been demonstrated that NLPRP6 deficiency is connected
crobiota constituents. TLRs stimulate the innate intestinal immunity with reduced levels of IL-18, altered immune response, dysbiosis, and
identifying a wide spectrum of Microbe-Associated Molecular Patterns intestinal hyperplasia [68]. It has been proved that Vitamin D is an
(MAMPs), encompassing various bacterial antigens such as flagellin, inducer of NOD2 gene expression and exerts different effects on the
6
expression of NOD2 and TLRinduced cytokines in Crohn‘s disease [69]. lymphoid cells triggering resistance to colonization by Citrobacter ro-
Intestinal microbiota and its metabolites act on both Nod1 and Nod2 dentium and dysbiosis [84]. Vdr /- mice show inflammation, decreased
receptors. Their defective signaling lead to inflammatory bowel disease expression of IkBα, increased basal and bacteria-induced NF-κB ac-
(IBD) onset [70] (Table 1). High-fat feeding enhances plasma LPS- tivity, along with scarcer Paneth cells in the ileum and higher bacterial
containing microbiota at a dose sufficient to increase inflammation [9]. load in the intestinal mucosa [84] (Table 2B). Immune modifications
LPS inhibits IL-1 receptor-associated kinase 4 (IRAK 4), a modulator of caused by Vdr deficiency in mice result in IBD-like inflammation in
IRAK1 required for NF-κB activation [71]. Supplementation with Vi- response to usually non-pathogenic bacteria and intensified suscept-
tamin D prevents inflammatory cytokine synthesis in LPS-induced acute ibility to Salmonella-induced colitis [85]. Several studies showed that
lung injury [72] and reduces LPS-induced renal oxidative stress by certain pathogenic bacteria and microorganisms downregulate Vdr
modulating oxidant and antioxidant enzyme genes [73]. GI tract mi- expression [85]. Nevertheless, pathogenic bacteria can also cause in-
crobiota affects both neutrophil migration and function and the dif- creased expression and relocation of Vdr in the colon [85]. Ad-
ferentiation of T cell populations into various types of helper cells (Th), ditionally, probiotic treatment with Lactobacillus Plantarum and Lacto-
such as Th1, Th2, and Th17 or into Tregs [74] (Table 1). Moreover, the bacillus Rhamnosus strain GG enhances the levels of VDR protein and the
colonic surroundings arouse de novo differentiation and development of expression of target genes in human and mouse intestinal epithelial
peripherally derived Tregs from naïve CD4+ T cells, their dysfunction cells, and prevent Salmonella-induced colitis in wild-type mice but not
induces autoimmune disorders [75]. Consequently, initiated by bac- in Vdr /- mice [86]. There are still few experimental evidences in hu-
terial recognition, the differentiation of effector Th1, Th2 and Th17 mans. In a multicentric study, double-blind, placebo-controlled, ran-
cells, the development of Tregs and the synthesis of secretory IgA (sIgA) domized, parallel-arm, oral supplementation with probiotic Lactoba-
occurs (Fig. 2). sIgA production specific to different mucosal antigens cillus reuteri NCIMB 30,242 improved circulating 25(OH)D levels
arises as a result of their capture by Peyer’s patches M cells, transfor- relative to placebo [87]. Remarkably, in an investigation on dietary
mation by primary dendritic cells (DCs), activation of T cells, and B cell variation and microbial composition of the intestinal tract between 52
class switch recombination in mesenteric lymph nodes (MLNs) and gut- African Americans and 46 Caucasian Americans were observed con-
associated lymphoid tissue. Specifically, a set of cytokines, including tradictory data on vitamin D supplementation and variances between
transforming growth factor beta (TGF-β), IL-4, IL-10, IL-5, and IL-6 the counts of Bacteroidetes in the fecal samples among the two groups
stimulates IgA synthesis (Fig. 3). Some of these cytokines, particularly [88]. In subjects with higher 25(OH)D concentration it was observed a
IL-10 and TGF-β are critical in sustaining the mucosal tolerance, thus reduction in the relative amount of Blautia, Roseburia, Ruminococcus and
demonstrating the link among sIgA synthesis, immunity, and intestinal Dorea (Firmicutes phylum, Clostridia class) [89]. Oral vitamin D3 sup-
homeostasis [76]. plementation in healthy volunteers decreased the relative amount of
Gammaproteobacteria including Escherichia/Shigella, spp., Helico-
7. Vitamin D and microbiota bacter spp. and Pseudomonas spp. [90]. These data confirmed the
finding that in CYP27B1 KO mice a calcitriol supplementation effica-
Studies assessing the effect of vitamin D deficiency on the micro- ciously reduced Helicobacteriaceae levels [37]. The important role of
biota are still few. Vitamin D not only controls the immune response of vitamin D3 in Helicobacter pylori infections is also confirmed by the
the microbiota but also influences the gut microbiota leading to dys- finding that Helicobacter pylori itself enhances VDR expression [90].
biosis [77]. It has been demonstrated that in new-born mice vitamin D A large scale observational study showed a correlation between
deficiency causes a reduction of colonic Bacteroides and Prevotella later prenatal vitamin D supplementation and the abundance of some key
in life. Treatment with 1α,25(OH)2D3 increases Citrobacter rodentium bacterial taxa in the infant intestinal microbiota. The prenatal vitamin
load in the colon of mice through impairment of the Th17 response D exposure measured in mothers supplemented with vitamin D, or
[78]. Instead, after infection with bacteria, vitamin D-deficiency ex- 25(OH)D quintiles, showed a statistically significant negative linear
acerbates barrier dysfunction, inflammation and dysbiosis [77]. In a trend with the abundance of Bifidobacterium spp. [91]. Whereas, a
mouse model of induced colitis, vitamin D deficient mice show reduced positive linear trend was observed with the amounts of B. fragilis and
colonic antimicrobial activity of angiogenin-4 protein (Ang4), bacterial 25(OH)D quintiles. Minor abundance of C. difficile was detected in
infiltration and increased expression of 16S rDNA in colonic tissue breastfed newborns whose mothers were more incline to follow dif-
compared to vitamin D sufficient mice [79]. Moreover, there is an ac- ferent dietary habits [91]. Hence, the different effects of vitamin D
tive interaction between bacteria and VDR expression in the gut. In fact, supplementation on the child varied according to maternal dietary
the absence of Vdr in mice generates dysbiosis, with reduction of Lac- habits indicate that lifestyle modulated the association between vitamin
tobacillus and augmentation of Clostridium and Bacteroides in the faecal D and the intestinal bacterial taxa [91]. Additionally, a genome-wide
matter and decrease of Alistipes and Odoribacter and enhancement of association analysis using two cohorts of 1812 individuals recognized
Eggerthella in the cecal section, also induces alterations in crucial the VDR gene as a host element affecting the gut microbiota [92]. Bi-
pathways of the intestinal microbiota. Overall these manifestations af- fidobacterium bifidum is a robust inducer of forkhead box P3 (Foxp3) +
fect detoxification, infection, cancer and other diseases [80]. In parti- Treg cells with different T cell receptor specificity to dietary antigens,
cular, the reduction of bacteria producing lactic acid in the fecal mi- commensal bacteria, and B. bifidum itself. In fact, cell surface β-glucan/
crobiota in Vdr–/– mice may influence the intestinal homeostasis galactan (CSGG) polysaccharides of B. bifidum have been recognized as
altering pH, unbalancing microflora predisposing to inflammation and an important component accountable for Treg stimulation. Treg cells
colon cancer [81]. The increment of Clostridium species may increase induced by B. bifidum or purified CSGG exhibit a robust suppressive
the risk for gut disorders such as colitis, enteritis and food poisoning action against experimental colitis. Moreover, it was observed that
[82]. The Eggerthella enrichment seems to be correlated with an en- CSGG stimulated regulatory dendritic cells through a moderately TLR
hanced risk for IBD, bacteraemia and abdominal sepsis. These findings 2-mediated mechanism and was able to amplify the activity of whole
implied that the faecal microbiota is more deeply influenced by VDR bacteria [93]. Overall, these studies indicate that vitamin D plays an
status than the cecal microbiota at the taxonomic level. Other studies important role in influencing the intestinal microbiota.
showed that mice lacking Vdr show depletion of bacteria from the
Firmicutes phylum and enhancement of bacteria from the Bacteroides 7.1. Relationship of calcium induced intestinal inflammation and its
and the Proteobacteria phyla in the faecal matter [37]. Modifications in regulation through vitamin-D
numerous bacterial genus members including Eubacterium, Bacteroides
and Salmonella have been detected between Vdr /- and wild-type mice It is hard to dissociate vitamin D and calcium roles, as 1,25(OH)2D3
[83]. Further, the absence of Vdr increased IL-22-producing innate maintains normal calcium homeostasis for cellular processes and
7
stimulates intestinal absorption calcium, for suitable skeleton miner- [108]. It has been observed that a high percentage of Th17 cells in the
alization [94]. Impaired intestinal calcium absorption predispose to gut express TCRs specific for SFB antigens. The specificities of these
osteoporosis, inflammation state and Crohn’s disease (CD) [95,96]. The TCRs are capable to induce Th17 polarization [109]. Th17 differ-
1,25 (OH)2D/VDR binding in the enterocytes causes in the intestine the entiation arises on epithelial cells nearness to SFB colonization [110]
increased expression of the calcium transporter proteins, such as cal- (Table 1). Th17 cells are important promoters of inflammatory re-
bindin 9 K, NCX1, PMCA1, and TRPV6, which elicit gut calcium ab- sponses in gut mucosal surfaces. Th17 by recruiting neutrophils and
sorption [97]. Interestingly, TRPV6 belongs to Transient receptor po- macrophages to infected tissues and by their production of IL-17A and
tential (TRP) ion channel superfamily which are widely expressed in IL-17F protect effectively the host against infection to extracellular
several tissues throughout the mammalian organism. TRP channels pathogens. Nevertheless, their expression alters mucosal healing and
preserve intracellular calcium homeostasis ensuring in the cells the leads to mucosal destruction. A further cytokine produced by Th17 is
regulation of different functions such as production and release of in- IL23, which regulates survival and preservation of the Th17 phenotype
flammatory mediators, cell migration and phagocytosis. It has been and is responsible for the crosstalk between innate and adaptive im-
shown that functional extra-neuronal TRP channel expression in immunity in the gut [111]. Often, abnormal expression and activity of the
mune and epithelial cells plays important effects for mucosal im- IL-17/IL-23 axis plays an important role in the pathogenesis of in-
munology [98]. Several evidences suggest that vitamin D supple- flammatory bowel diseases [112] (Table 1). Additionally, Th17 cells
mentation promotes calcium absorption by increasing gut calcium synthetizes IL-22 which is responsible in host defense at the mucosal
transporter proteins, decreasing mucosal inflammation and removing layer as well as in tissue repair [113]. Similarly, to IL-17, IL-22 is
intestinal resistance to vitamin D. In many diseases calcium absorption helpful to the host in numerous infectious and inflammatory diseases.
can be impaired by vitamin D deficiency [99]. Experimental studies in Nevertheless, synergistically with IL-17, it becomes pathological on
animal models suggest that high-calcium diets have a beneficial impact account of its proinflammatory properties [103]. Th17 cells are potent
in gut microbiota composition, favoring the growth of lactobacilli stimulators of chronic inflammatory responses in pathological condi-
[100]. In dietary obese mice calcium supplementation regulates gut tions of the gut. The presence of microbiota controls Th17 cells devel-
microbiota, enhancing the levels of Bifidobacterium spp. and Bacteroides/ opment and increases their function [114]. Th17 cells are absent in the
Prevotella and decreasing the levels of Clostridium coccoides and Clos- gut of germ-free mice [115]. Particularly, segmented filamentous bac-
tridiumleptum [101]. Moreover, in mice supplementation of calcium in teria are essential for inducing Th17 cells [108]. Interestingly, the ad-
drinking water allows the modification of gut microbiota composition ministration of capsular polysaccharide from the commensal bacterium
and specific bacterial abundance in feces [102]. Therefore, also dietary B. fragilis induces TCD4+ lymphocytes to synthesize IL-10 and inhibits
calcium might interfere with gut microbiota. However, at the moment the synthesis of IL-17 and preserves the colonic mucosa against in-
the influence of calcium on human gut microbiota need further inflammatory responses triggered by bacterial antigens [112]. The strain
vestigations. of Clostridium butyricum prevent DSS-induced acute colitis in mice in-
ducing IL-10-producing macrophage [116], instead segmented fila-
8. Immune-regulatory cell subsets, vitamin D and microbiota mentous bacteria increase the Th17 response to preserve the gut from
infection (e.g., Citrobacter rodentium) in mice [111]. Likewise,
Many immune-regulatory cell subsets, specialized with exclusive 1α,25(OH)2D3 addition prevents IL-17 production, suppresses in-
suppressive functions including T cells, B cell, dendritic cells (DCs) and flammation and Th17-mediated autoimmunity [117] (Fig. 3).
macrophage especially M2 phenotype are crucial to achieving constant 1α,25(OH)2D3 could inhibit and partially reverse experimental auto-
immune tolerance in the gut microenvironment inhibiting innate and immune uveitis by reducing IL-17 production [118]. Additionally, it
adaptive immune responses [103]. CD4 T cells producing IL-17 or IL-10 was proved that 1α,25(OH)2D3 suppress IL-17A induction in mouse
are common in the gut, where their balance is essential to retain tol- models of 2,4,6-trinitrobenzene sulfuric acid (TNBS) colitis and early
erance and immunity to the resident microbiota all together [104]. rheumatoid arthritis [118,119]. An effect that could be due to the re-
Vitamin D and VDR regulate T cells function promoting regulatory T pression of IL-17A at the transcriptional level by VDR through me-
cell development, turning off the Th1 and Th17 cells function and thus chanisms including nuclear factor for activated T cells (NFAT) inhibi-
controlling inflammatory response in the gut. CD4+ T cells possess dual tion, histone deacetylase (HDAC) recruitment, capture of Runx1 and
opposite roles in immune responses, acting either as Thelper/effector or direct induction of Foxp3 [120]. VDR cooperates with P105/P50,
Tregs. Particularly Th1, Th2, and Th17 cells cause mucosal inflamma- P100/P52 and P65 NF-κB family proteins. Th17 cells differentiate in the
tion and tissue injury, while Tregs, which are important intermediaries presence of TGF-β1 and IL-6 by preventing Foxp3 induction and up-
of immune tolerance, play anti-inflammatory functions and mitigate regulating two other Th17 transcription factors retinoid-related orphan
mucosal inflammation and stimulate tissue repair. receptor (ROR) γt and RORα [121]. In the spleen tissues of VDR-defi-
cient mice 1,25(OH)2D3 suppressed the inflammatory infiltrates and
8.1. T helper 17 cells vitamin D and microbiota inhibits the expression of RORγt/IL-17 by avoiding p65 transcription
factor translocating to the nucleus [120]. An investigation in VDR KO
Th 17 cells are a CD4 + T subset, their growth is influenced by mice supported that Vitamin D and the VDR are crucial modulators of
signals mediated by IL-6 and TGF-β, IL-21, and IL-23 and by stimulation the Th17/iTreg axis. VDR is important for iTreg activation and Th17
of the lineage-specifying transcription factor, retinoic acid- related or- cells inhibition. The absence of the VDR causes Th17 cells over-
phan nuclear receptor (RORγT). Th17, which secrete cytokines such as production at the detriment of iTregs. In VDR KO the expression of anti-
IL-22, IL-17A, and IL-17F, are essential in the gut immune homeostasis bacterial peptides, regulated by vitamin D and the VDR, disturb the
and inflammation [105] (Fig. 3). Unlike Th1 and Th2 cells, which after composition of the microbiota, compared to WT mice, causing the
differentiation are secretory cells, Th17 cells retain the ability to pro- presence of a greater number of Th17 cells [122]. Moreover, VDR is
duce different cytokine expression and function following their com- crucial for the increase of tolerogenic DCs that in turn influence the
mitment to Th17 [106]. This feature is related to the maintenance of amount of Th17 cells. Since microbial flora indirectly regulates Th17/
their stem cell–like properties, which consents them to keep on for a iTreg axis, this finding suggested that a connection of pathways results
long time while retaining the capacity to originate functionally dif- in higher amounts of Th17 cells, fewer iTregs and more serious symp-
ferent descendants when stimulated by antigen [106]. Th17 cells are toms of IBD in the absence of the VDR [122]. Furthermore, it has been
more abundant in the LP of the colon. Segmented filamentous bacteria described that maxacalcitol an analogue of vitamin D3 was able to
(SFB) richness in the gut positively regulates Th17 cell expansion [107]. downregulate IL-17 and IL-23 production [123] (Table 2A). Previously
SFB injection in germ-free mice was able to induce Th17 cells in LP it was proved that microbiota-specific Th17 protects the intestinal
8
mucosa from microbiota and pathogens by its capability to counter- IBD is more severe [132] (Table 2B). Likewise, the increased differ-
attack infection and stimulate the production of IgA through IL-17- entiation of VDR KO T cells into Th17 cells arises under Treg-inducing
dependent intestinal polymeric Ig receptor expression, IL-21-dependent conditions. Treating mice with 1,25 dihydroxyvitamin D3, suppresses
IgA+ cell differentiation and IgA class switch recombination. IgA se- IBD [139]. In addition, microbial flora regulates indirectly the Th17/
cretion limits microbiota adherence to the intestinal epithelial surface iTreg axis (Fig. 3). Various mechanisms are implicated in microbiota
[124]. regulation of Treg differentiation and function. Intestinal microbiota
plays an important role in the induction of Tregs [135] (Table 2A). For
8.2. Regulatory T Cells, vitamin D and microbiota example, Bacteroides fragilis and Clostridia species avoid the in-
flammatory responses in the intestine by stimulating Tregs. It has been
In the gut, Tregs are the principal mediator in preserving the im- reported that members of the Clostridiales and Bacteroidales induce the
mune homeostasis. A small percentage of Treg cells reside within transcription factor RORγt in nascent Treg cells via an upstream
lymphoid organs and peripheral tissues, they suppress immune re- MyD88-dependent mechanism to promote tolerance to dietary anti-
sponses. Tregs operate by inducing apoptosis of effector cells [125]. gens. Activation of this axis is damaged by the dysbiosis, and can be
Tregs, encompass many subtypes including Tregs produced in the restored by treatment with therapeutic microbiota [140] (Table 1).
thymus via IL-2 signaling and CD8+CD25High+FOXP3+ T cell, which Polysaccharide A of B. fragilis support the suppressive activity of in-
mostly express FoxP3 the master-switch lineage-specific the main reg- ducible Foxp3+ Tregs via Toll-like receptor 2 signaling and preserve the
ulatory gene for the development and function of Tregs subset and TNBS (2,4,6-trinitrobenzenesulfonic acid)-induced colitis in mice
coordinates the transcriptional process [126]. Instead, [141]. IL-6, IL-21, IL-23, and IL-27 avoid Treg differentiation, but
Foxp3−CD25−CD4+ cells develop from in peripheral organs/tissues support the induction of proinflammatory Th1/Th17 cells [142,143]
following induction with TGF-β and all-trans retinoic acid and are re- (Fig. 3). Various bacterial species control the cytokine milieu affecting
cognised as peripherally derived Tregs [127]. FoxP3+ Tregs are im- T-cell differentiation and activation. Essentially, the same commensal
portant modulators of immune tolerance by regulating innate and bacteria in diverse circumstances could induce different immune re-
adaptive immune responses against self and non-self-antigens [128]. sponses. In normal conditions of the intestine B. fragilis, unstable Clos-
Their contribution to immune tolerance is so significant that defi- tridia flora and transformed Schaedler flora species are capable to fulfil a
ciencies in Treg cells function cause severe immune disorders. In in- suppressive function by activating Tregs, while they increase Th1/Th17
testinal LP, Tregs safeguard homeostasis and by negative regulation of cell development in lack of Tregs [108]. Recently, it has been reported
effector T cells are essential in avoiding intestinal inflammation syn- that Lactobacillus acidophilus rises intestinal inflammation in an acute
thesising IL-10 or TGF-β and expressing cytotoxic T lymphocyte antigen colitis mouse model by regulation of Th17 and Treg cell equilibrium
(CTLA-4 or CD152) [129]. In Tregs, Foxp3 protein expression is crucial [144] (Table 1). Several investigations indicated that also the bacterial
for their inhibitory function. The absence of Foxp3 gene enhance re- metabolites regulate the gut immune response. In fact, butyrate
sponses to pathogens, induces tumours and autoimmune diseases, such downregulates the synthesis of nitric oxide and of proinflammatory
as enteropathy, polyendocrinopathy, and X-linked autoimmunity al- mediators of LM macrophages such as IL-6, IL-12, by preventing histone
lergic dysregulation syndrome [130]. Treg cells express vitamin D re- deacetylases [145]. Additionally, butyrate and its end products up-
ceptors and are more susceptible to the suppressive action of regulate cathelicidin in human colon epithelial cells [146] and sy-
1α,25(OH)2D3 than conventional T cells [131] (Fig. 2). Both in vitro nergistically with 1α,25(OH)2D3 induces human CAMP mRNA levels in
and in vivo evidence indicate that 1,25D3 supplementation enhance the lung epithelial and myeloid cells [147] (Table 1). Butyrate induces the
numbers of Foxp3+ Treg cells [132]. Studies in animal models and ex development of Tregs in the colonic LP (Fig. 3) and improves T cell-
vivo data demonstrate that vitamin D influences positively the amount dependent experimental colitis in mice [148]. Furthermore, it has been
of CD4+ Foxp3+ Treg cells [133]. Different concentrations of shown that butyrate through activation of Gpr109a signalling provides
1,25(OH)2D3 have the capacity to stimulate Foxp3+ Treg cells de- anti-inflammatory properties on colonic macrophages and DCs inducing
pending on the cytokine milieu. It has been suggested that the cytokines differentiation of Tregs and IL-10-producing T cells [149]. An im-
IL-2 and TGF-β cooperate in enhancing the differentiation of 1α,25(OH) balance of Tregs and Th17 occurs in IBD. But also the altered cytokine
2D3 -induced Foxp3+ Treg cells [134]. TGF-β is crucial for the gen- milieus of the intestine contribute to the impairment of differentiation
eration of Foxp3+ Treg cells from naive CD4+ T cells, and IL-2 is an and function of Tregs in IBD. CD25+ regulatory T cells from IBD pa-
important component in TGF-β-mediated induction of Foxp3+ Treg tients exert a compromised suppressive function, compared with
cells. 1,25(OH)2D3 directly influences Treg cell growth and stimulate healthy controls, that is connected with the co-expression of RORγt and
IL-10 (Fig. 3) production without deteriorating of the activation status Foxp3 inIL-17+Foxp3+ T cells. Therefore, the regulation of in-
and suppressive phenotype [131]. In vivo studies indicate a strong po- flammation in the gut depend on the equilibrium between the Th17
sitive correlation among vitamin D sufficiency and Foxp3+ Treg cell cells and inducible regulatory T (iTreg) cells [150]. CD4 cells treated
amounts and proliferation [131]. 1α,25(OH)2D3 is involved in several with TGF-β1 express Foxp3 and produce IL-10 [146] (Table 1). Hence,
stages of the evolution of these T-cell responses. Others findings de- Th17 and iTreg differentiate in response to TGF-β1. In vivo, a pro-
monstrating the importance of the cytokine milieu displayed that IL-10 liferation of Th17 cells in the gut is related with a mutual reduction in
exerts a negative impact on the differentiation of 1α,25(OH)2D3 -in- Treg cells and vice versa [151], so they could operate in part by direct
duced Foxp3+ Treg cells enhancing IL-10+ Treg cells [135] (Table 1). repression of each other [150]. It can be conceivable that Treg and
VDR is an important regulator of the Th17/iTreg axis (Fig. 3). The Th17 cells could represent alternative cell subtypes of the same pre-
FoxP3 promoter is controlled by numerous transcription factors in- cursor.
cluding NFAT, cRel, Creb and STAT5 to FoxP3 promoter [136]. Without
interactivity with the VDR, FoxP3 stimulation results ineffective. 8.3. Regulatory B cells vitamin D and microbiota
Moreover, FoxP3 expression is unbalanced and is influenced by the
environment. VDR cooperates with NFAT and cRel to regulate tran- B cells retain the peculiarity to synthetize antibodies. Additionally,
scription [137]. Several findings indicate that the absence of the VDR they produce cytokines and act as secondary APCs. B cells differentiate
leads a lack in the induction of iTregs by TGF-β1. Vitamin D-deficient or in different subpopulations fulfilling both regulatory and pathogenic
VDR KO mice are predisposed to IBD [138]. The absence of VDR causes functions. A lesser amount of B cell (about 10% of total B-cells in cir-
the inability of CD4 T cells to home the GI tract, to express CD8αα, and culation) are represented by Regulatory B cells (Bregs). They exert
produce IL-10. Then, in absence of the VDR, T cells preferentially dif- regulatory/suppressor functions and are necessary for the peripheral
ferentiate into Th17 cells to the detriment of iTreg and experimental tolerance mechanisms. Their regulatory action is usually achieved by
9
Fig. 4. Vitamin D3 and Microbiota Immune-regulation of Macrophage Subsets. Colonic macrophages show an anti-inflammatory M2-like phenotype, they
produce IL-10, promote Tregs proliferation and induce epithelial cell regeneration and proliferation. M2 generate from the interactions with intestinal epithelial cells
(IECs) and the gut microflora, and a combination of TLR and IL10 signaling. IL-10 contributes to the development of an anti-inflammatory phenotype in colonic
macrophages. 1α,25(OH)2D3 promotes the antimicrobial activities inhibiting TLR-2 and TLR-4 expression in monocytes. M2 regulates intestinal inflammation.
1α,25(OH)2D3 influences macrophage polarization towards M2 phenotype, through the inhibition of IFN-γ. M2 macrophages produce IL-10 which inhibits the
differentiation of M1 macrophages. M2 interacts with Butyrate, which is secreted mainly by Bacteroidetes and Firmicutes phyla bacteria and downregulate IL-6, IL-
12, and NOS2.
IL-10 production. Less than 20% of these cells are IL-10 producers after systemic lupus erythematosus and multiple sclerosis. In these diseases
stimulation [152]. Inflammation leads vigorous Bregs development and Bregs regulate the autoimmune responses [157]. Studies in chronic
differentiation. A variety of molecules including TLRs, CD40, the B cell intestinal inflammation demonstrated that the percentage of
receptor, CD80, CD86, and cytokines are necessary to activate Bregs CD19highCD1dhigh IL-10-producing B cells decreased in patients with
[152]. Based on the activation pathways three different types for Breg Crohn's disease and that this subset of B cells alleviated intestinal in-
cells have been characterized: innate Breg cells requiring signalling via flammation in colitis in a Treg-independent manner [158]. Therefore,
innate receptors, such as Toll-like receptors; immature Breg cells re- Bregs or plasma cells have been suggested as an innovative therapy for
quiring CD40 stimulation; antigen-specific Breg cells requiring both B- IBD [159]. CD19+CD5+ Foxp3+ B cells, a recently identified type of
cell receptor and CD40 signalling. Bregs hamper inflammation in- Bregs, also express Foxp3, but their immunologic function still remains
hibiting Th1 cells activation, Th17 differentiation and preservation of unknown [160]. Notably, CD138+ plasma cells, another subset of ac-
the Treg cell population [153]. It has been reported that IL-33 induces a tivated B cells, produce IL-35 and could avoid intestinal inflammation
subset of IL-10-producing B cells (BregIL-33) in mice, and adoptive after salmonella infection [161]. Whether or not Breg cells, are re-
transfer of these BregIL-33 into IL-10−/− mice efficiently reduced mu- sponsive to 1α,25(OH)2D3 has not yet been well established. It has been
cosal inflammatory responses in the gut [154]. Interestingly, the gut observed that Vitamin D could regulate Breg cells [162] (Fig. 3).
microbiota could support IL-10-producing B-cell differentiation in the Human B cells cultured and stimulated with BCR cross-linking, anti-
spleen and in mesenteric lymph nodes enhancing IL-1β and IL-6 CD40 and IL-4 for 2 days, in the absence or presence of 1α,25(OH)2D3
synthesis in mice [155] (Table 1). IL-10-producing B cells in mesenteric secreted higher levels of IL-10. Furthermore, higher percentage of IL-
lymph nodes prevent the progression of chronic colitis of TCRα KO 10+ Breg cells, as well as higher mean fluorescence intensities for IL-10
mice downregulating directly inflammatory cascades connected with meaning more IL-10 production per cell, were found in presence of
IL-1β synthesis and signal transducer and activator of transcription 3 1,25(OH)2D3 [163] (Table 2A).
activation [156]. In addition, Bregs play a regulatory role in some au-
toimmune disorders. In humans, Bregs have been investigated largely in
10
8.4. Monocytes/ macrophages subsets, vitamin D and microbiota towards M2 phenotype [174] (Fig. 3). As supported by a study showing
that Vitamin D sufficiency enhances the percentage of M2 macrophages
Among the immune cells present in the colon, the macrophages are and ameliorates IBD [174,175] (Table 2A). M2 macrophages are the
the most abundant [164]. Macrophages are well-known for their phe- greatest producers of IL-10 which prevent the differentiation of M1
notypic heterogeneity and for the wide range of biological activities macrophages [176] (Table 1). The modification in macrophage phe-
that they exert depending on signals received from the different cyto- notype occurs through the inhibition of IFN-γ by 1α,25(OH)2D3 and the
kines and from the tissue microenvironment stimulation [164]. Some of failure of M1 macrophage differentiation caused by IL10. In addition,
these functions seem to be opposing: immunogenic versus tolerogenic the anti-inflammatory properties of colonic macrophages (M2) could be
activities, anti- versus proinflammatory response, tissue-repair versus caused by the interaction with bacterial products. For example, buty-
tissue destruction [164]. Macrophages can be classically activated rate, which is produced mostly by Bacteroidetes and Firmicutes phyla
(M1), by IFN-γ and LPS induction, whereas by IL-4 and IL-13 or in- bacteria, is present at high concentrations in the colon and down-
directly through Th2 cells induction differentiate in alternatively acti- regulate the proinflammatory factors including IL-6, IL-12, and NOS2
vated macrophages (M2). Macrophage polarization strongly modifies produced by colonic macrophage in vitro and in vivo [176] (Fig. 4)
their immune asset. For instance, M1 macrophages exert potent anti- (Table 2A).
microbial properties, whereas M2 macrophages show marked tissue
repair properties [165]. The M1 macrophages are activated by proin- 8.5. Dendritic cell subsets, vitamin D and microbiota
flammatory cytokines and PAMPs that result in stimulation of PRRs
including the family of TLRs. The M1 macrophages stimulate in- Dendritic cells (DCs) are antigen-presenting cells (APCs) and have
flammation and/or type 1/Th1/Th17 immune responses and produce a been regarded as the most efficient APCs initiating innate immune re-
plethora of proinflammatory cytokines such as IL-1β, IL-6, IL-8, and sponses and as a bridge connecting innate and adaptive immunity. Once
TNF-α, and various cytotoxic molecules that stimulate the acquired DCs meet pathogens they present antigens to T cells activating them
immune response and promote the clearance of invading pathogens and inducing the immune response. Recently, studies on DC function
[166]. During the inflammation, M1 macrophages express the cell have recognized the important role of DCs in triggering inflammatory
surface CCR7 important for their own activation and the exodus of T responses against pathogens and tolerance to commensal microflora in
lymphocytes from blood to inflamed tissues. CCR7 mediated signals the gut [177]. Notably, DCs promote the differentiation of Tregs in the
promotes the polarization and activation of uncommitted T cells to Th1 gut from naive T cells. Depending on the expression of the surface
cells [167]. M2 macrophages exhibit a strong scavenging activity in the marker CD103 have been recognised numerous DC subpopulations in
form of increased mannosylated-BSA degradation and express an array the intestinal mucosa playing important roles in the preservation of the
of cell surface receptors such as CD163, CD206, MRC1, DECTIN-1, gut homeostasis. Accordingly, DCs have been divided into two principal
chemokines (CCL16, CCL17, CCL18, CCL22, CCL24), and chemokine subsets: CD11chighCD103+ and CD11chigh CD103− DCs [177].
receptors (CCR2, CXCR1, CXCR2). Activated M2 macrophages sig- CD11chighCD103− DCs have the capability to stimulate Th1 and Th17
nificantly express mannose receptor (CD206) [168]. CD206 expression cell development [177]. Whereas, CD11chighCD103+ DCs derived from
is induced by IL-10, which recruiting more M2 macrophages decreases the LP of the small intestine aid the differentiation of Tregs in a retinoic
the inflammatory response [167,168]. M2 macrophages inhibit in- acid- and TGF-β-dependent manner [178]. The intestinal DCs popula-
flammation and/or elicit type 2/Th2 immune responses. Colonic mac- tion CX3CRhighCD11b+CD11c+ prevent the proliferation of CD4+ T
rophages crowding the GI arise from circulating monocytes [169]. cells avoiding intestinal inflammation [179]. CD11b+ DCs produce IL-
Human colonic macrophages include CD68+CD14+HLA- 23 and are crucial for ILC3 activation. Moreover, by producing IL-22
+ + + +
DR CD64 CD45 CD163 [170]. In the steady state, colonic macro- and inhibiting commensal bacteria-specific CD4+ T-cell proliferation
phages display an anti-inflammatory M2-like phenotype expressing via MHC II-mediated antigen presentation they act as immune reg-
CD206 and CD163, exerting an anti-inflammatory activity under LPS ulatory cells [180]. An additional subpopulation of DCs has been phe-
stimulation, producing IL-10, promoting Tregs proliferation and induce notyped, termed Tr1-like cells, which secreting IL-10 show suppressive
epithelial cell regeneration and proliferation [169] (Fig. 4). The exact action [181]. Therefore, DCs induce T cell differentiation into an ef-
mechanism inducing colonic macrophages to achieve the M2/anti-in- fector cell with both pro- or anti inflammatory functions. Therefore,
flammatory phenotype is not yet fully known. Likely they generate from regulation of APCs is essential in starting and preserving adaptive im-
the interactions with both gut microbiota and intestinal epithelial cells, mune response and self-tolerance [182]. 1α,25(OH)2D3 is a potent in-
and a combination of TLR-signaling regulation and of IL-10 signaling. hibitor of DC differentiation and IL-12 secretion [183]. The inhibition
Along with IL-10-producing T cells, IECs supply IL-10 in the human of IL-12 expression is accomplished by a direct interaction between DCs
colon, thus contributing to the improvement of an anti-inflammatory and 1α,25(OH)2D3 bound to the VDR, which blocks NF-κB-induced
phenotype in colonic macrophages. In fact, it has been demonstrated transcription of IL-12 [184]. Since IL-12 is an important cytokine in-
that in co-cultures of human secondary colonic IECs (SW840, Caco-2 ducing Th1 development this is a significant immune-regulatory ac-
cell lines) with mouse peritoneal macrophages TLR-4 mediate the in- tivity. Dendritic cells cultured with VDR agonists maintain the mono-
creased IEC secretion of IL-10 [171] (Table 1). An important anti- cyte marker CD14 but are unable to upregulate CD1a and fail to express
microbial pathway in monocytes and macrophages includes the acti- their MHC and co-stimulatory molecules including CD40, CD80, CD86.
vation of TLRs. The regulation of TLRs appears to be a therapeutic tool This results in IL-12 and IFN-γ downregulation, IL-10 and TGF β up-
to activate the immune responses [52]. Previously it was showed that in regulation with the total consequence of the inhibition of T cell acti-
human macrophages, 1α,25(OH)2D3 triggers innate immunity inducing vation [183] (Fig. 5). Dendritic cells treated with 1α,25(OH)2D3
the synthesis of antimicrobial peptides in response to TLR-2/1 activa- showed a “tolerogenic state” characterized by reduction of in-
tion [14]. 1α,25(OH)2D3 promotes the antimicrobial activities also inflammatory cytokines, such as IL-12 and TNF-α, and enhanced ex-
hibiting TLR-2 and TLR-4 expression in monocytes and promoting a pression of the anti-inflammatory IL-10. These DCs promote apoptosis
state of hypo-responsiveness to PAMPs [172]. The expression of the coin the autoreactive T cells and the differentiation of Treg cells [185]
receptor of TLR-4, CD14, is up- regulated by 1α,25(OH)2D3 in human (Fig. 5) (Table 2A). DCs interacting with additional factors mutually
cells [14]. Furthermore, 1α,25(OH)2D3 prevents the expression of the retain gut homeostasis [186]. Once DCs interact with microbiota, they
innate-immunity receptors TLR-2, TLR-4, and TLR9 and modifies the increase their immune regulatory functions. Interestingly, MUC2, the
TLR9-dependent production of IL-6 in human monocyte [173]. Accu- building block of gut mucus secreted by goblet cells, imprint DCs with
mulating evidence reported that M2 could regulate intestinal in- anti-inflammatory DCs indicating that intestinal mucosa not only con-
flammation [166]. Vitamin D influences macrophage polarization stitutes a physical barrier but also limits the immunogenicity of gut
11
Fig. 5. Vitamin D and immune-regulation in DCs:1α,25(OH)2D3 bound to the VDR inhibits DC differentiation and downregulates IL-12 and IFN-γ, and upregulates
IL-10 and TGF-β. Dendritic cells treated with 1α,25(OH)2D3 achieve “tolerogenic state”. TDCs induce the differentiation of Treg cells and provoke apoptosis in the
autoreactive T cells. Microbiota and immune-regulation in DCs: DCs interacting with commensal flora amplify their immune regulatory functions. MUC2, secreted
by goblet cells, imprint DCs as anti-inflammatory cells limiting the immunogenicity of gut antigens by delivering tolerogenic signals. Commensal microbiota, tissue-
resident mononuclear phagocytes, and ILCs form an axis which regulate intestinal homeostasis. Macrophages secrete IL-1β to stimulate RORγt+ ILC3 to produce
colony-stimulating factor 2 that further promotes DCs to maintain Tregs.
antigens by supplying tolerogenic signals [179] (Fig. 5). Furthermore, VDR-RXR heterodimer. Bile acids act as both key VDR ligands and
the interaction between DCs and subsets of innate lymphoid cells (ILCs) regulators of VDR expression [191]. Genetic variation in VDR sig-
is essential in intestinal homeostasis regulation. In the steady state of nificantly influences GI mucosal immune-system (Table 2B) and mi-
the GI, after recognising and up taking microbiota or their products, crobial co-metabolism. Wang et al. found that VDR affects individual
macrophages produce IL-1β to stimulate RORγt+ ILC3 to synthetize bacterial taxa such as Parabacteroides [192]. These bacteria contain
colony-stimulating factor 2 that in turn induces DCs to support Tregs pathways involved in secondary bile acid metabolism [192]. It is con-
[187] (Fig. 5). Selected commensal bacterial strains are able to drive ceivable that VDR genetic polymorphisms, including BsmI, ApaI, TaqI,
strong effector immune responses by moDCs, while in the presence of and FokI which have been associated with susceptibility to autoimmune
ATRA, they support the development of both tolerogenic and in- diseases, obesity, metabolic disturbances and cancer [193–195], influ-
flammatory moDC in a RARα-dependent manner [188] (Table 1). encing the intestinal microbiota could be predisposing factor for these
Moreover, bacterial metabolites including short-chain fatty acids, pro- pathogenetic manifestations. Future research in this area, with genome-
duced by bacteria after digestion of dietary fibers are able to enhance wide association studies may provide further knowledge on the asso-
dendritic cell regulatory activity, leading to the induction of Treg cells ciation between vitamin D deficiency, dysbiosis and diseases.
and IL-10-secreting T cells [189] (Table 1). Therefore, microbiota,
tissue-resident macrophages and ILCs constitute a network which reg-
ulates intestinal homeostasis. 10. Conclusion
The gut is one of the most important target organs of vitamin D, as

9. Gut microbiota and VDR polymorphisms demonstrated by the local synthesis of 1α,25(OH)2D3 and of VDR ex-
pression in most cell types of GI tract. An optimal 1α,25(OH)2D3 status
In view of the above, VDR influences both microbiota and immune plays an important role in maintaining the gut homeostasis via many
system. VDR expression protects the host from invasive pathogens and regulatory activities such as calcium and phosphate absorption, pro-
maintains intestinal homeostasis also enteric bacteria activate VDR tection against infection, preservation of the epithelial barrier function,
signaling [190]. VDR is a ligand-activated transcription factor which anti-inflammatory action and modulation of the gut microbiota. On the
through heterodimerization with the RXR exerts a wide range of bio- other hand, a number of data have demonstrated a complex connection
logical effects. Both vitamin D and microbial metabolites act through of the gut microbiota with host metabolism, neuroendocrine and
12
immune homeostasis, and the potential impairments or disorders of the org/10.1126/science.1104816.

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Contents lists available at ScienceDirect

Vitamin D and microbiota: Two sides of the same coin in the T

Table 2B transcription of anti-microbial peptides (AMPs) in several cell types,

The gut is one of the most important target organs of vitamin D, as

immune homeostasis, and the potential impairments or disorders of the org/10.1126/science.1104816.

2012. S. Wang, Eﬀects of calcium chloride supplementation in drinking water on fat

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