Host-Microbiota-Diet Interactions in Metabolic Syndrome and IBD

人类越来越多地受到慢性炎症性疾病的折磨，包括炎症性肠病 (IBD)和代谢综合征（MetSyn），统称为代谢问题的星座 与肥胖有关。本申请寻求更新的资助发展了我们的假设，即IBD和 Met Syn具有疾病病理生理学的共同点，即肠道微生物群管理不善 在驱动炎症方面起着关键作用，而炎症是两种疾病状态的核心。的核心特征 在IBD和Met Syn中观察到的微生物群生态失调是一种更具“侵略性”的微生物群， 这可能与其促进炎症密切相关。诱导的一种方法 微生物群侵入及其炎症后果是通过食用缺乏可发酵的食物， 光纤我们发现，这种低纤维饮食诱导的侵蚀涉及微生物介导的 先天性淋巴样细胞（ILC）IL-22的产生，通常用于强化上皮。因此，委员会认为， 用可发酵的纤维菊粉而不是不溶性/不可发酵的纤维纤维素来富集这种饮食， 恢复IL-22的产生，减少微生物群的侵入，改善轻度炎症，并且 保护小鼠免受饮食诱导的Met Syn。然而，我们也观察到， 一些可发酵纤维还诱导一些IL-22非依赖性的负面后果，包括加重 实验诱导的结肠炎和促进肝癌，因此强调，目前，我们缺乏 安全设计促进健康食品的知识。因此，我们的中心总体假设是， 对膳食纤维如何影响宿主-微生物群关系的机械理解将为以下努力提供信息： 设计饮食和/或更安全有效地设计食物，促进有益的肠道微生物群 因此改善肠道炎症及其相关疾病状态，包括IBD和Met Syn。 我们将通过3个具体目标来研究这一假设：目标1：确定营养微生物群 结果ILC介导的IL-22产生。目标2：确定欧车前能力的潜在机制， 预防代谢综合征和结肠炎。目的3：开发结肠靶向递送IL-22的方法 并研究其恢复肠道健康和改善炎症性疾病的能力。

Humanity is increasingly afflicted by chronic inflammatory diseases, including inflammatory bowel disease (IBD) and metabolic syndrome (Met Syn), which collectively refers to the constellation of metabolic problems associated with obesity. The grant this application seeks to renew has developed our hypothesis that IBD and Met Syn share commonalities of disease pathophysiology, namely that poor management of gut microbiota plays a key role in driving inflammation that is central to both disease states. A central feature of the microbiota dysbiosis observed in both IBD and Met Syn is a more “aggressive” microbiota that encroaches upon the gut epithelium, which is likely germane to its promotion of inflammation. One means of inducing microbiota encroachment and its inflammatory consequences is via consumption of a diet lacking fermentable fiber. We found that such low fiber diet-induced encroachment involves ablation of microbiota-mediated innate lymphoid cell (ILC) IL-22 production that normally serves to fortify the epithelium. Consequently, enriching such diets with the fermentable fiber inulin, but not the insoluble/non-fermentable fiber cellulose, restored IL-22 production, reduced microbiota encroachment, ameliorated low-grade inflammation, and protected mice from diet-induced Met Syn. However, we’ve also observed that enriching refined diets with some fermentable fibers also induced some IL-22-independent negative consequences, including exacerbating experimentally-induced colitis and promoting liver cancer thus highlighting that, at present, we lack the knowledge to safely engineer health-promoting foods. Hence, our central overall hypothesis is that better mechanistic understanding of how dietary fiber impacts the host-microbiota relationship will inform efforts to design diets and/or more safely and effectively engineer foods that promote beneficial intestine-microbiota interactions, thus ameliorating gut inflammation and its associated disease states, including IBD and Met Syn. We will investigate this hypothesis via 3 specific aims: Aim 1: Identify means by which nourishing microbiota with fiber results in ILC-mediated IL-22 production. Aim 2: Define mechanism underlying psyllium’s ability to protect against metabolic syndrome and colitis. Aim 3: Develop a means of targeted delivery of colonic IL-22 and investigate its ability to restore gut health and ameliorate inflammatory diseases.