The impact of inflammation on determinants of mucosal disease in Inflammatory Bowel Disease

Inflammatory Bowel Disease (IBD) is characterised by a dysregulated mucosal immune response, resulting in loss of the protective gut mucosal barrier with unopposed mucosal inflammation. Inflammation is associated with activation of regulatory pathways, including the Hypoxia Inducible Factor (HIF) pathway which aims to promote cell survival under hypoxic conditions, and the Angiotensin Converting Enzyme (ACE2) pathway which counteracts the inflammation and fibrosis associated with classical Renin Angiotensin System (RAS) activation. Manipulation of the HIF pathway in experimental models via hydroxylase inhibition attenuates colitis through upregulation of genes promoting barrier function and the inhibition of epithelial cell apoptosis. ACE2 knockout mice develop severe colitis after intestinal injury with evidence to suggest that restoration of ACE2 reduces inflammation. We hypothesised that mucosal inflammation in IBD leads to alterations in the local tissue expression of components of the HIF and ACE2 pathways, and that pharmacological targets in these pathways can impact disease determinants such as mucosal barrier function and response to medical therapies in addition to covid susceptibility. We demonstrated differential expression of the HIF hydroxylases in the gut mucosa of patients with IBD, with PHD1 demonstrating a clear mucosal expression pattern. Additionally, we identified significant alterations in the expression of barrier protective components such as IL33, CD73 and Occludin as well as inflammatory cytokines known to be under transcriptional regulation of the HIF pathway and identified a reduction in CD55 expression following incubation with pan-hydroxylase and PHD1 specific inhibitors. ACE2 tissue expression was found to be consistently elevated in inflamed colon and consistently reduced in inflamed ileum in patients with IBD and serum soluble ACE2 was altered in patients with IBD with the highest levels in Ulcerative Colitis (UC) and significantly lower levels in patients on corticosteroid therapy. Our findings demonstrate inflammation-associated alterations in tissue and serum ACE2 and in HIF-associated barrier components in patients with IBD. Further exploration of these pathways has the potential to advance therapeutic avenues in IBD.