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

项目总结/摘要 包括饮食和肠道微生物群在内的环境因素深刻地影响着宿主的抵抗力， 易患肠道炎症。大量摄入富含精制淀粉的超加工食品， 糖、蛋白质和氢化脂肪以及全谷物含量低会增加肠道炎症的风险 疾病（IBD）。尽管有如此强大的流行病学数据表明，超加工食品与更高的 IBD的风险，超加工食品升级IBD易感性的潜在机制仍然存在 稀疏。本提案旨在阐明这些机制，目的是设计基于饮食的干预措施。 减少IBD的发作和发生。 干扰素γ（IFNγ）诱导的免疫相关GTP酶（IRGs）M家族，在人体中称为IRGM 和Irgm 1，是人类克罗恩病的疾病易感性风险等位基因。Irgm 1管弦乐队 自噬介导的针对细菌的免疫，并阻碍NLRP 3炎性体活化。我们的初步 观察表明，超加工成分饮食（PID）降低了IFN-γ的结肠表达 可诱导基因，保护免受入侵的微生物。PID喂养的小鼠也表现出增加的侵犯 结肠细菌进入粘液层和NLRP 3炎性体激活。值得注意的是，这些老鼠 严重的实验性急性（由葡聚糖硫酸钠（DSS）诱导）和慢性（由IL-10受体诱导 中和）结肠炎。根据我们的初步数据，我们假设微生物入侵的加剧 由于宿主对微生物的抗性受损和NLRP 3炎性体的持续活化， 在PID喂养的小鼠中对IBD的易感性。将通过追求三个具体目标来检验这一假设： 要求1 评估IFNγ诱导的GTP酶在PID诱导的IBD易感性升级中的作用。 目的2 ：评估肠道微生物群及其代谢产物在IFNγ诱导型GTP酶调节中的作用， PID诱导的IBD易感性。 目标3 评估NLR炎性小体和IFNγ诱导的GT3轴在PID诱导的IBD中的作用 易感性 鉴于IBD的患病率在2009年上升，该建议对公共卫生具有潜在影响。 与超加工食品摄入量的增加平行。完成本提案的目标将 确定加工饮食增加IBD风险的机制。机械地理解 超加工饮食如何增加对IBD的易感性将引导我们制定饮食策略， 降低人类IBD的发病率。 1

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