Interplay of processed diet, gut microbiota, and interferon-linked mucosal immunity in the onset and prevalence of inflammatory bowel disease

PROJECT SUMMARY/ABSTRACT Environmental factors including diet and gut microbiota profoundly impact the host resistance and susceptibility towards intestinal inflammation. A high intake of ultra-processed foods enriched with refined starch, sugar, protein, and hydrogenated fat and low in whole grain contents increases the risk of inflammatory bowel disease (IBD). Despite such robust epidemiological data that ultra-processed food is associated with a higher risk of IBD, the underlying mechanisms by which ultra-processed foods escalate IBD susceptibility remains sparse. This proposal aims to elucidate such mechanisms with a goal to devise a dietary-based intervention(s) to reduce IBD onset and occurrence. Interferon gamma (IFNγ)-inducible immunity-related GTPases (IRGs) family M, named IRGM in humans and Irgm1 in mice, is a disease susceptibility risk allele for Crohn’s disease in humans. Irgm1 orchestrates autophagy-mediated immunity against bacteria and impedes NLRP3 inflammasome activation. Our preliminary observation demonstrated that ultra-processed ingredient diet (PID) reduced colonic expression of IFN-γ inducible genes, which protect against invading microbes. PID-fed mice also exhibited increased encroachment of colonic bacteria into the mucus layer and NLRP3 inflammasome activation. Notably, these mice developed severe experimental acute (induced by dextran sulfate sodium, DSS) and chronic (induced by IL-10 receptor neutralization) colitis. Based on our preliminary data, we hypothesize that heightened microbial encroachment due to impaired host resistance against microbes and persistent activation of NLRP3 inflammasome escalates susceptibility to IBD in PID-fed mice. This hypothesis will be tested by pursuing three specific aims: Aim 1 : Assess the role of IFNγ-inducible GTPases in escalating PID-induced predisposition to IBD. Aim 2 : Assess the role of gut microbiota and their metabolites in the regulation of IFNγ-inducible GTPases and PID-induced IBD susceptibility. Aim 3 : Assess the role of NLR inflammasomes and IFNγ-inducible GTPase axis in PID-induced IBD susceptibility. This proposal has potential implications for public health, given that the prevalence of IBD has risen in parallel with the increase in the intake of ultra-processed foods. Completion of the aims of this proposal will identify the mechanism(s) by which a processed diet increases the risk of IBD. A mechanistic understanding of how ultra-processed diet increases susceptibility to IBD will lead the way toward defining a dietary strategy to reduce the incidence of IBD in humans. 1