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Vitamin D Signaling in Gastro-Rheumatology
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Vitamin D has been recently pointed out, and abnormalities of the vitamin D axis have been described in both in vitro and in vivo models of inflammatory bowel diseases (IBD) and arthritis.

osteoimmunology inflammatory bowel diseases spondyloarthritis microbiota
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    1. Introduction

    Bone metabolism is a complex and dynamic process that tightly regulates the composition of the skeleton of human body. Besides their structural function, the bones play a fundamental role for hosting, in the bone marrow, hematopoietic cells (HSCs), myeloid and lymphoid progenitors, and mature cell of the immune system. Those cells share the same milieu of the cells regulating the bone metabolism (e.g., osteoblasts, osteoclasts, and osteocytes) and are closely connected by reciprocal interactions mediated by multiple molecular mediators, such as cytokines, chemokines, transcription factors, and signaling molecules [1]. The potential relation between osteogenesis and immune system has been highlighted since the 1970s in studies regarding periodontitis [2]. In 2000, the term “osteoimmunology” was coined to define the complex interwoven link between these two systems, particularly evident in T-cells mediated regulation of osteoclastogenesis observed in autoimmune arthritis [3]. Multiple molecular mediators have shown a potential role in the osteoimmune network [4]. Osteoblasts progenitors produce stem cell factors and CXC-chemokine ligand 12 (CXCL12) that are crucial for HSC maintenance and differentiation, and mature osteoblasts produce interleukin-7 (IL-7) that has an important role in the regulation of the lymphoid lineage. Osteoclasts produce proteolytic enzymes, such as matrix-metallopeptidase 9 and cathepsin K, that contribute to the HSC mobilization. Moreover, the bone reabsorption process is essential for the bone marrow cavity formation as well as for the increase in calcium level and the release of some factors, e.g., transforming growth factor (TGF)-β), that have a role in HSC regulation. Osteocytes regulate lymphoid and myeloid differentiation through the production of sclerostin and granulocyte colony-stimulating factor (G-CSF). Conversely, the activated immune system and the aberrant inflammation may affect osteosynthesis through the production of IL-17 by Th17 cells and the induction of the receptor activator of nuclear factor-κB ligand (RANKL) further amplified by the pro-inflammatory cytokines IL-1, IL-6, and tumor necrosis factor (TNF), which promote osteoclastogenesis. In line with this vision, the bone alterations observed in several immune diseases are no longer considered related merely to malnutrition or steroids use, and the common osteoimmune molecular pathway has been proposed as a novel potential target for therapeutic strategies.

    2. Vitamin D and Intestinal Permeability

    Vitamin D is a dietary nutrient with demonstrated anti-inflammatory and immunomodulating functions. Recent data suggest that the intestinal mucosal barrier is a possible trait d’union between vitamin D, immune system, and gut microbiota. The intestinal mucosa is both an absorption site that allows entry of food-derived metabolites and a physical barrier that blocks pathogens translocation, thus protecting against infection with enteropathogenic microorganisms and intestinal inflammation. The intestinal epithelium is composed by enterocytes and specialized epithelial cells, such as Goblet and Paneth cells. Goblet cells produce mucus that forms a layer between the epithelium and the luminal contents, whereas Paneth cells release antibacterial molecules (e.g., α- and β-defensins, cathelicidin) [5]. Sub-mucosal cells of the innate immunity, such as macrophages and dendritic cells (DCs), clear microorganisms and luminal particles that penetrate the first line of defense of the epithelial/mucus layer, thus containing the immune inflammatory reaction. The presence of different structures between adjacent epithelial cells, such as tight junctions (occludin, proteins of the zonula occludens, and claudins), adherens junctions (E-cadherin, catenins, nectin), and desmosomes, is also essential in maintaining the resistance of the intestinal mucosa [6].

    In view of the above, it is not surprising that dysregulation in these components, such as defective expression of defensins, upregulation of claudin-2, or increased apoptosis of epithelial cells, can contribute to the disruption of the mucosal barrier, as reported in IBD and SpA patients [7][8][9][10][11]. In particular, it has been hypothesized that, in SpA patients, the increased intestinal permeability, probably induced by genetic factors (HLA-B27), could induce a disruption of the basal membrane, hyperplasia of goblet cells, and activation of Paneth cells producing high levels of anti-microbial peptides (AMPs) and IL-23, leading to exaggerated antigenic stimulation and activation of effector T-cells of the intestinal mucosa [12][13][14][15][16][17].

    Vitamin D/VDR signaling can modulate the number and the functionality of tight junction proteins in both in vitro and in vivo studies on transgenic mice. VDR knockout and vitamin D-deficient mice displayed epithelial barrier dysfunction with hyperfunction of claudin-2, decreased transepithelial resistance, and increased susceptibility to invasive bacteria colonization and colitis [18][19][20][21]. Conversely, transgenic mice overexpressing VDR in the gut epithelium have resistance to colitis with decreased mucosal inflammation and apoptosis of epithelial cells [22]. In addition, vitamin D supplementation has been shown to ameliorate the clinical symptoms and the histologic findings in Dextran sulphate sodium (DSS) treated mice by preserving the expression of E-cadherin, claudin, and zonula occludens in Caco-2 cells [23].

    3. Vitamin D and Gut Microbiota Homeostasis

    The gut microbiota is a complex ecosystem of archaea, bacteria, fungi, and viruses that is essential for digestion of complex carbohydrates as well as absorption and supply of vitamins, but it exerts also immunomodulatory, metabolic, and anti-infective functions. Any imbalance in the gut microbiota resulting in a loss or overgrowth of a species and/or reduction in microbial diversity is defined as dysbiosis. In the last two decades, dysbiosis of the gut microbiota has been described in different pathologies such as depression, IBD, RA, and SpA [24][25][26].

    The impact of diet and nutrients on the gut microbiota is suggested by the differences in its composition/variety between geographically and life-style distant populations [27]. It is known, indeed, that a western diet rich in animal proteins, simple sugars, and saturated fats is characterized by a reduction in the variety of microbiomes and is associated with the Bacteroides enterotype, whereas a diet habit rich in fruits and vegetables leads to a prevalence of Prevotella [28]. Dietary intervention can also impact the gut microbiota composition and richness. Foods rich in fibers, such as those present in the Mediterranean diet (MD), indeed, are degraded by Firmicutes and Bacteroidetes into SCFA, such as butyrate [29][30], which can have a protective role on the gut barrier by reducing its permeability. We have recently found that RA patients with high adherence to MD have a lower disease activity joined to a healthier gut microbiota composition with a significant decrease in Lactobacillaceae and an almost complete absence of Prevotella copri in comparison with the low/moderate adherence patients [31].

    It has been also shown that vitamin D can also influence the composition of the gut microbiome in animal models [32][33]. VDR KO mice with defective autophagy have consequent gut dysbiosis with depletion of Lactobacillus and Bacteroides. Moreover, administration of butyrate can increase intestinal VDR expression and suppress inflammation in an experimental colitis model [34].

    Results on human studies have been recently summarized in a systematic review by Waterhouse et al. [35]. Most of the fourteen analyzed studies evaluated both microbiota diversity and composition and reported significant association between vitamin D and specific changes in gut microbiota. However, there was scarce consistency in the taxa affected and the direction of effect. Indeed, results are hard to compare due to several variables, in particular the heterogeneity in study designs (e.g., cross-sectional vs. prospective, randomized trials vs. observational study), the differences in the assessment of vitamin D (e.g., self-reported dietary, nutritional supplement vitamin D i6ntake, serum 25(OH)D administration), and in the population setting (e.g., healthy people, IBD, cystic fibrosis, multiple sclerosis, infants, pregnant women). Moreover, most of the studies were conducted on very limited samples, and only some of them adjusted for confounding factors such as body mass index, smoking, physical activity, comorbidity, and therapy. Three studies evaluated the effect of vitamin D on the gut microbiota in UC and CD patients. Administration of vitamin D demonstrated a positive effect in modulating the intestinal bacterial composition in both CD and UC patients, leading to a reduced intestinal inflammation in patients with active UC, with a concomitant increase in Enterobacteriaceae without changes in microbial diversity [36][37][38]. An additional study published in 2020 was in contrast with these results. In fact, the authors found that reduced levels of vitamin D observed in winter/spring were associated with more balanced microbiome composition both in UC and CD. In particular, they identified lower level of Escherichia/Shigella in stool of UC patients and increased level of Bacteroidetes in the stool of CD patients accompanied by lower proportion of Clostridium spp. and higher proportion of Firmicutes in the mucosa [39]. Another study that evaluated samples of the intestinal mucosa found a decrease in gammaproteobacteria and increased Bacteroidetes in the microbiome of the upper gastrointestinal tract of patients receiving vitamin D supplementation without significant effects on terminal ileum, ascending colon, sigmoid colon, and stools [40]. Of note, the only GWAS study demonstrated that the VDR gene variation correlated with beta diversity in both humans and mice [41].

    Assuming that microbiota and vitamin D have a bidirectional and possible feedback interaction, few studies have evaluated the role of bacteria in modulating vitamin D levels. In fact, it is known that both commensal and pathogenic bacteria can regulate VDR expression and location in mice [42]; some bacteria have enzymes involved in the hydroxylation of steroids and can process and activate vitamin D [43]. Butyrate produced by some gut microorganisms such as Firmicutes and Bacteroidetes can increase VDR expression in the epithelial cells of mice models [21]. In addition, the microbiota can influence vitamin D metabolism through the fibroblast growth factor (FGF)-23 (the protein that regulates the 1,25(OH)2D3 hydroxylating enzyme, CYP27B1). Germ free mice, indeed, have low levels of vitamin D and high FGF-23, and their colonization with bacteria leads to normalization of vitamin D levels and reduced FGF-23 [44].


    1. Tsukasaki, M.; Takayanagi, H. Osteoimmunology: Evolving concepts in bone-immune interactions in health and disease. Nat. Rev. Immunol. 2019, 19, 626–642.
    2. Horton, J.E.; Raisz, L.G.; Simmons, H.A.; Oppenheim, J.J.; Mergenhagen, S.E. Bone resorbing activity in supernatant fluid from cultured human peripheral blood leukocytes. Science 1972, 177, 793–795.
    3. Arron, J.R.; Choi, Y. Bone versus immune system. Nature 2000, 408, 535–536.
    4. Takayanagi, H. Osteoimmunology: Shared mechanisms and crosstalk between the immune and bone systems. Nat. Rev. Immunol. 2007, 7, 292–304.
    5. Chelakkot, C.; Ghim, J.; Ryu, S.H. Mechanisms regulating intestinal barrier integrity and its pathological implications. Exp. Mol. Med. 2018, 50, 103.
    6. Zhang, Y.G.; Wu, S.; Sun, J. Vitamin D, Vitamin D Receptor, and Tissue Barriers. Tissue Barriers 2013, 1.
    7. Kellermann, L.; Jensen, K.B.; Bergenheim, F.; Gubatan, J.; Chou, N.D.; Moss, A.; Nielsen, O.H. Mucosal vitamin D signaling in inflammatory bowel disease. Autoimmun. Rev. 2020, 19, 102672.
    8. Blander, J.M. On cell death in the intestinal epithelium and its impact on gut homeostasis. Curr. Opin. Gastroenterol. 2018, 34, 413–419.
    9. Hagiwara, C.; Tanaka, M.; Kudo, H. Increase in colorectal epithelial apoptotic cells in patients with ulcerative colitis ultimately requiring surgery. J. Gastroenterol. Hepatol. 2002, 17, 758–764.
    10. Delgado, M.E.; Grabinger, T.; Brunner, T. Cell death at the intestinal epithelial front line. FEBS J. 2016, 283, 2701–2719.
    11. Zhang, C.; Yan, J.; Xiao, Y.; Shen, Y.; Wang, J.; Ge, W.; Chen, Y. Inhibition of Autophagic Degradation Process Contributes to Claudin-2 Expression Increase and Epithelial Tight Junction Dysfunction in TNF-alpha Treated Cell Monolayers. Int. J. Mol. Sci. 2017, 18, 157.
    12. Ciccia, F.; Bombardieri, M.; Principato, A.; Giardina, A.; Tripodo, C.; Porcasi, R.; Peralta, S.; Franco, V.; Giardina, E.; Craxi, A.; et al. Overexpression of interleukin-23, but not interleukin-17, as an immunologic signature of subclinical intestinal inflammation in ankylosing spondylitis. Arthritis Rheum. 2009, 60, 955–965.
    13. Picchianti-Diamanti, A.; Rosado, M.M.; D’Amelio, R. Infectious Agents and Inflammation: The Role of Microbiota in Autoimmune Arthritis. Front. Microbiol. 2017, 8, 2696.
    14. Rosenbaum, J.T.; Davey, M.P. Time for a gut check: Evidence for the hypothesis that HLA-B27 predisposes to ankylosing spondylitis by altering the microbiome. Arthritis Rheum. 2011, 63, 3195–3198.
    15. Lin, P.; Bach, M.; Asquith, M.; Lee, A.Y.; Akileswaran, L.; Stauffer, P.; Davin, S.; Pan, Y.; Cambronne, E.D.; Dorris, M.; et al. HLA-B27 and human beta2-microglobulin affect the gut microbiota of transgenic rats. PLoS ONE 2014, 9, e105684.
    16. Bowness, P. Hla-B27. Annu. Rev. Immunol. 2015, 33, 29–48.
    17. Ciccia, F.; Accardo-Palumbo, A.; Alessandro, R.; Rizzo, A.; Principe, S.; Peralta, S.; Raiata, F.; Giardina, A.; De Leo, G.; Triolo, G. Interleukin-22 and interleukin-22-producing NKp44+ natural killer cells in subclinical gut inflammation in ankylosing spondylitis. Arthritis Rheum. 2012, 64, 1869–1878.
    18. Zhang, Y.G.; Lu, R.; Xia, Y.; Zhou, D.; Petrof, E.; Claud, E.C.; Sun, J. Lack of Vitamin D Receptor Leads to Hyperfunction of Claudin-2 in Intestinal Inflammatory Responses. Inflamm. Bowel Dis. 2019, 25, 97–110.
    19. Chen, S.W.; Wang, P.Y.; Zhu, J.; Chen, G.W.; Zhang, J.L.; Chen, Z.Y.; Zuo, S.; Liu, Y.C.; Pan, Y.S. Protective effect of 1,25-dihydroxyvitamin d3 on lipopolysaccharide-induced intestinal epithelial tight junction injury in caco-2 cell monolayers. Inflammation 2015, 38, 375–383.
    20. Assa, A.; Vong, L.; Pinnell, L.J.; Rautava, J.; Avitzur, N.; Johnson-Henry, K.C.; Sherman, P.M. Vitamin D deficiency predisposes to adherent-invasive Escherichia coli-induced barrier dysfunction and experimental colonic injury. Inflamm. Bowel Dis. 2015, 21, 297–306.
    21. Wu, S.; Zhang, Y.G.; Lu, R.; Xia, Y.; Zhou, D.; Petrof, E.O.; Claud, E.C.; Chen, D.; Chang, E.B.; Carmeliet, G.; et al. Intestinal epithelial vitamin D receptor deletion leads to defective autophagy in colitis. Gut 2015, 64, 1082–1094.
    22. Liu, W.; Chen, Y.; Golan, M.A.; Annunziata, M.L.; Du, J.; Dougherty, U.; Kong, J.; Musch, M.; Huang, Y.; Pekow, J.; et al. Intestinal epithelial vitamin D receptor signaling inhibits experimental colitis. J. Clin. Investig. 2013, 123, 3983–3996.
    23. Zhao, H.; Zhang, H.; Wu, H.; Li, H.; Liu, L.; Guo, J.; Li, C.; Shih, D.Q.; Zhang, X. Protective role of 1,25(OH)2 vitamin D3 in the mucosal injury and epithelial barrier disruption in DSS-induced acute colitis in mice. BMC Gastroenterol. 2012, 12, 57.
    24. Lach, G.; Schellekens, H.; Dinan, T.G.; Cryan, J.F. Anxiety, Depression, and the Microbiome: A Role for Gut Peptides. Neurother. J. Am. Soc. Exp. Neurother. 2018, 15, 36–59.
    25. Picchianti-Diamanti, A.; Panebianco, C.; Salemi, S.; Sorgi, M.L.; Di Rosa, R.; Tropea, A.; Sgrulletti, M.; Salerno, G.; Terracciano, F.; D’Amelio, R.; et al. Analysis of Gut Microbiota in Rheumatoid Arthritis Patients: Disease-Related Dysbiosis and Modifications Induced by Etanercept. Int. J. Mol. Sci. 2018, 19, 2938.
    26. Manichanh, C.; Borruel, N.; Casellas, F.; Guarner, F. The gut microbiota in IBD. Nat. Rev. Gastroenterol. Hepatol. 2012, 9, 599–608.
    27. Diamanti, A.P.; Rosado, M.M.; Laganà, B.; D’Amelio, R. Microbiota and chronic inflammatory arthritis: An interwoven link. J. Transl. Med. 2016, 14, 1–12.
    28. Salonen, A.; de Vos, W.M. Impact of diet on human intestinal microbiota and health. Ann. Rev. Food Sci. Technol. 2014, 5, 239–262.
    29. Mitsou, E.K.; Kakali, A.; Antonopoulou, S.; Mountzouris, K.C.; Yannakoulia, M.; Panagiotakos, D.B.; Kyriacou, A. Adherence to the Mediterranean diet is associated with the gut microbiota pattern and gastrointestinal characteristics in an adult population. Br. J. Nutr. 2017, 117, 1645–1655.
    30. Lerner, A.; Patricia, J.; Matthias, T. Nutrients, bugs and us: The short-chain fatty acids story in celiac disease. Int. J. Celiac Dis. 2016, 4, 92–94.
    31. Picchianti Diamanti, A.; Panebianco, C.; Salerno, G.; Di Rosa, R.; Salemi, S.; Sorgi, M.L.; Meneguzzi, G.; Mariani, M.B.; Rai, A.; Iacono, D.; et al. Impact of Mediterranean Diet on Disease Activity and Gut Microbiota Composition of Rheumatoid Arthritis Patients. Microorganisms 2020, 8, 1989.
    32. Luthold, R.V.; Fernandes, G.R.; Franco-de-Moraes, A.C.; Folchetti, L.G.; Ferreira, S.R. Gut microbiota interactions with the immunomodulatory role of vitamin D in normal individuals. Metab. Clin. Exp. 2017, 69, 76–86.
    33. Ooi, J.H.; Li, Y.; Rogers, C.J.; Cantorna, M.T. Vitamin D regulates the gut microbiome and protects mice from dextran sodium sulfate-induced colitis. J. Nutr. 2013, 143, 1679–1686.
    34. Wang, T.T.; Dabbas, B.; Laperriere, D.; Bitton, A.J.; Soualhine, H.; Tavera-Mendoza, L.E.; Dionne, S.; Servant, M.J.; Bitton, A.; Seidman, E.G.; et al. Direct and indirect induction by 1,25-dihydroxyvitamin D3 of the NOD2/CARD15-defensin beta2 innate immune pathway defective in Crohn disease. J. Biol. Chem. 2010, 285, 2227–2231.
    35. Waterhouse, M.; Hope, B.; Krause, L.; Morrison, M.; Protani, M.M.; Zakrzewski, M.; Neale, R.E. Vitamin D and the gut microbiome: A systematic review of in vivo studies. Eur. J. Nutr. 2019, 58, 2895–2910.
    36. Garg, M.; Hendy, P.; Ding, J.N.; Shaw, S.; Hold, G.; Hart, A. The Effect of Vitamin D on Intestinal Inflammation and Faecal Microbiota in Patients with Ulcerative Colitis. J. Crohn’s Colitis 2018, 12, 963–972.
    37. Schaffler, H.; Herlemann, D.P.; Klinitzke, P.; Berlin, P.; Kreikemeyer, B.; Jaster, R.; Lamprecht, G. Vitamin D administration leads to a shift of the intestinal bacterial composition in Crohn’s disease patients, but not in healthy controls. J. Dig. Dis. 2018, 19, 225–234.
    38. Jorgensen, S.P.; Agnholt, J.; Glerup, H.; Lyhne, S.; Villadsen, G.E.; Hvas, C.L.; Bartels, L.E.; Kelsen, J.; Christensen, L.A.; Dahlerup, J.F. Clinical trial: Vitamin D3 treatment in Crohn’s disease—A randomized double-blind placebo-controlled study. Aliment. Pharmacol. Ther. 2010, 32, 377–383.
    39. Soltys, K.; Stuchlikova, M.; Hlavaty, T.; Gaalova, B.; Budis, J.; Gazdarica, J.; Krajcovicova, A.; Zelinkova, Z.; Szemes, T.; Kuba, D.; et al. Seasonal changes of circulating 25-hydroxyvitamin D correlate with the lower gut microbiome composition in inflammatory bowel disease patients. Sci. Rep. 2020, 10, 6024.
    40. Bashir, M.; Prietl, B.; Tauschmann, M.; Mautner, S.I.; Kump, P.K.; Treiber, G.; Wurm, P.; Gorkiewicz, G.; Hogenauer, C.; Pieber, T.R. Effects of high doses of vitamin D3 on mucosa-associated gut microbiome vary between regions of the human gastrointestinal tract. Eur. J. Nutr. 2016, 55, 1479–1489.
    41. Wang, J.; Thingholm, L.B.; Skieceviciene, J.; Rausch, P.; Kummen, M.; Hov, J.R.; Degenhardt, F.; Heinsen, F.A.; Ruhlemann, M.C.; Szymczak, S.; et al. Genome-wide association analysis identifies variation in vitamin D receptor and other host factors influencing the gut microbiota. Nat. Genet. 2016, 48, 1396–1406.
    42. Wu, S.; Liao, A.P.; Xia, Y.; Li, Y.C.; Li, J.D.; Sartor, R.B.; Sun, J. Vitamin D receptor negatively regulates bacterial-stimulated NF-kappaB activity in intestine. Am. J. Pathol. 2010, 177, 686–697.
    43. Szaleniec, M.; Wojtkiewicz, A.M.; Bernhardt, R.; Borowski, T.; Donova, M. Bacterial steroid hydroxylases: Enzyme classes, their functions and comparison of their catalytic mechanisms. Appl. Microbiol. Biotechnol. 2018, 102, 8153–8171.
    44. Bora, S.A.; Kennett, M.J.; Smith, P.B.; Patterson, A.D.; Cantorna, M.T. The Gut Microbiota Regulates Endocrine Vitamin D Metabolism through Fibroblast Growth Factor 23. Front. Immunol. 2018, 9, 408.
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    Update Time: 29 Apr 2021
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      Picchianti-Diamanti, A. Vitamin D Signaling in Gastro-Rheumatology. Encyclopedia. Available online: (accessed on 01 December 2022).
      Picchianti-Diamanti A. Vitamin D Signaling in Gastro-Rheumatology. Encyclopedia. Available at: Accessed December 01, 2022.
      Picchianti-Diamanti, Andrea. "Vitamin D Signaling in Gastro-Rheumatology," Encyclopedia, (accessed December 01, 2022).
      Picchianti-Diamanti, A. (2021, April 28). Vitamin D Signaling in Gastro-Rheumatology. In Encyclopedia.
      Picchianti-Diamanti, Andrea. ''Vitamin D Signaling in Gastro-Rheumatology.'' Encyclopedia. Web. 28 April, 2021.