The renin-angiotensin system and vitamin D in inflammatory bowel disease

Background The renin-angiotensin system (RAS) is well-recognised in cardiovascular and renal homeostasis, but may regulate inflammation, fibrosis and angiogenesis in multiple other organs, including the gastrointestinal tract. Similarly, the vitamin D axis is increasingly recognised for potential immunoregulatory and other functions beyond musculoskeletal health and calcium homeostasis. This study aimed to characterise both systems in the circulating and intestinal compartments, examine their relationship to inflammation, and to define the effects of their modulation, retrospectively or prospectively, in patients with inflammatory bowel disease (IBD). Methods Circulating components of both systems were measured in patients with Crohn’s disease (CD), ulcerative colitis (UC) and non-IBD controls, and associations with markers of disease activity evaluated. Terminal ileal, ascending colon and sigmoid colon from patients undergoing intestinal resection and colonoscopy were surveyed for mRNA expression and immunohistochemical localisation and semi-quantification of these components. A retrospective study evaluating the effect of angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) in patients with IBD taking these medications for traditional indications was performed. A prospective pilot study evaluating a targeted dosing regimen for vitamin D supplementation for immunomodulatory effect in patients with IBD was performed. Results Circulating renin, ACE2:ACE ratio and angiotensin (Ang) (1-7) were higher, aldosterone:renin ratio lower, and ACE and Ang II similar in participants with IBD compared with controls. All of the components required for intra-organ production of RAS were identified by qRT-PCR and immunohistochemistry in healthy and diseased bowel, with significantly higher expression of ACE and ACE2 in the terminal ileum than colon. Angiotensinogen mRNA expression was higher in inflamed colonic biopsies from patients with IBD than non-inflamed biopsies and biopsies from non-IBD controls. Immunohistochemical staining intensity for ACE2 was higher but Ang (1-7) lower in patients with IBD than non-IBD controls. The use of ACE inhibitors and ARBs was associated with lower disease activity and requirement for surgery or hospitalisation, but these effects were likely due to the older age of these patients. Despite similar levels to non-IBD controls, serum total, free and bioavailable 25-hydroxyvitamin D (25(OH)D) inversely correlated with faecal calprotectin amongst patients with IBD. A 25(OH)D level of ≥100 nmol/L was associated with a faecal calprotectin of <100 µg/g. A targeted vitamin D dosing regimen increased 25(OH)D to ≥100 nmol/L in most patients with IBD, improved symptoms, but did not reduce faecal calprotectin. Vitamin D receptor (VDR) protein was present in all layers of the intestinal wall. VDR mRNA expression and staining intensity was lower in patients with IBD. VDR mRNA inversely correlated with faecal calprotectin in the terminal ileum of patients with CD, and in the sigmoid colon in patients with UC. Mucosal VDR did not correlate with serum 25(OH)D levels. Conclusions Circulating and mucosal components of the alternative RAS axis are upregulated in patients with IBD, but mucosal Ang (1-7) is reduced. Circulating 25(OH)D inversely correlates with intestinal inflammation, and intestinal VDR is deficient in patients with IBD. Therapies which increase mucosal Ang (1-7), or which deliver VDR agonists targeted to the intestine, potentially have roles in IBD.