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

加工饮食、肠道微生物群和干扰素相关粘膜免疫在炎症性肠病发病和患病率中的相互作用

• 批准号: 10658741
• 负责人: Vishal Singh
• 金额: $ 44.37万
• 依托单位: PENNSYLVANIA STATE UNIVERSITY, THE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10658741
• 关键词: Acute; Address; American diet; Attenuated; Autophagocytosis; Bacteria; Bile Acids; Binding Proteins; Cells; Chronic; Colitis; Colon; Country; Crohn' s disease; Data; Development; Diet; Dietary Fiber; Disease susceptibility; Environmental Risk Factor; Exhibits; Family; Fatty acid glycerol esters; Fiber; Food; Fortified Food; Genes; Genetic Transcription; Goals; Grain; Guanosine; Health; High Prevalence; Homeostasis; Host Defense; Host resistance; Human; Hydrogenation; Immune; Immune system; Immunity; Impairment; Incidence; Individual; Infectious colitis; Inflammasome; Inflammatory Bowel Diseases; Intake; Interferon Type II; Interferons; Intervention; Intestines; Invaded; Link; Mediating; Metabolic; Microbe; Modeling; Mucosal Immune Responses; Mucosal Immunity; Mucous Membrane; Mucous body substance; Mus; Names; Onset of illness; Organoids; Pathway interactions; Play; Predisposition; Prevalence; Process; Proteins; Public Health; Recombinant Interferon; Reducing diet; Regulation; Reporting; Repression; Resistance; Risk; Role; Severities; Sodium Dextran Sulfate; Starch; System; Testing; United States; colon bacteria; deoxycholate; dextran sulfate sodium induced colitis; dietary; enteric pathogen; epidemiologic data; feeding; genome wide association study; guanylate; gut inflammation; gut microbiota; high risk; interleukin-10 receptor; microbial; microorganism; non-genetic; novel; pathogen; pathogenic bacteria; prevent; receptor; risk variant; sugar

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

项目摘要/摘要 饮食和肠道菌群在内 对肠道炎症的敏感性。高摄入富含精制淀粉的超级加工食品， 糖，蛋白质和氢化脂肪和全谷物含量低的脂肪会增加炎症性肠的风险 疾病（IBD）。尽管如此强大的流行病学数据，超处是较高的食物 IBD的风险，超级加工食品升级的基本机制仍然存在IBD易感性 疏。该建议旨在以设计基于饮食的干预措施的目标来阐明此类机制。 减少IBD发作和发生。 干扰素伽玛（IFNγ） - 可诱导的免疫相关GTPases（IRGS）家族，称为人类IRGM 小鼠中的IRGM1是人类克罗恩病的疾病敏感性风险等位基因。 IRGM1编排 自噬介导的针对细菌的免疫支持并阻碍NLRP3炎性体激活。我们的初步 观察结果表明，超处理的成分饮食（PID）降低了IFN-γ的结肠表达 诱导基因，可防止入侵微生物。 PID喂养的小鼠还暴露了增加的侵占 结肠细菌进入粘液层和NLRP3炎性体激活。值得注意的是，这些小鼠发展了 严重的实验急性（由硫酸葡萄糖钠，DSS诱导）和慢性（由IL-10接收器诱导 中和）结肠炎。根据我们的初步数据，我们假设微生物加密增强 由于宿主对微生物的阻力受损，NLRP3炎性体的持续激活升级 PID喂养的小鼠对IBD的敏感性。该假设将通过追求三个具体目标来检验： 目标1 ：评估IFNγ诱导的GTP酶在不断增加的PID诱导的IBD易感性中的作用。 目标2 ：评估肠道菌群及其代谢产物在IFNγ诱导GTPase和 PID引起的IBD敏感性。 目标3 ：评估NLR炎症体和IFNγ诱导的GTPase轴在PID诱导的IBD中的作用 敏感性。 鉴于IBD的普遍性已经上升，该提议对公共卫生具有潜在的影响 与超处加工食品的摄入量的增加并行。完成本提案的目标将 确定加工饮食增加IBD风险的机制。机械理解 超处理的饮食如何增加对IBD的敏感性将导致定义饮食策略的方向 减少人类IBD的发生率。 1