Vitamin D Signaling in Gastro-Rheumatology: From Immuno-Modulation to Potential Clinical Applications

Abstract

In the last decades, the comprehension of the pathophysiology of bone metabolism and its interconnections with multiple homeostatic processes has been consistently expanded. The branch of osteoimmunology specifically investigating the link between bone and immune system has been developed. Among molecular mediators potentially relevant in this field, 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. Furthermore, vitamin D deficiency has been reported in patients affected by IBD and chronic inflammatory arthritis, thus suggesting the intriguing possibility of impacting the disease activity by the administration vitamin D supplements. In the present review, the complex interwoven link between vitamin D signaling, gut barrier integrity, microbiota composition, and the immune system was examined. Potential clinical application exploiting vitamin D pathway in the context of IBD and arthritis is presented and critically discussed. A more detailed comprehension of the vitamin D effects and interactions at molecular level would allow one to achieve a novel therapeutic approach in gastro-rheumatologic inflammatory diseases through the design of specific trials and the optimization of treatment protocols.

Keywords: immunomodulation; inflammatory bowel diseases; intestinal mucosal barrier; microbiota; osteoimmunology; spondyloarthritis; vitamin D; vitamin D receptor.

Figure 1

Metabolism of vitamin D. Vitamin D from dietary sources or endogenously synthetized reaches blood circulation. After a double phosphorylation process in the liver and in the kidney (or in some epithelial and immune cells), the active form 1,25 (OH)₂ D reached many target organs to exert pleiotropic actions, including calcium absorption regulation, bone metabolism, intestinal mucosal homeostasis regulation, and immunomodulation.

Figure 2

Potential effect of vitamin D towards the gut–joint inflammatory axis. Abnormalities in vitamin D axis could contribute at multiple levels to the dynamic vicious circle, potentially leading to the onset/maintenance of inflammatory bowel diseases (IBD) and spondyloarthritis (SpA). Reduced function of anti-bacterial molecules, decreased expression of tight junctions proteins and autophagy, can lead to impaired intestinal barrier function and increased permeability with a downstream effect on the gut microbiota composition. The unbalance of the Th17/Treg axis toward the former can lead to increased release of proinflammatory cytokines. Reduction of host defense, increased mucosal inflammation, translocation of bacterial products across the mucosal barrier, and interactions with the host immune system would result in the induction of chronic inflammation and autoimmunity.