Effect of an Anti-Inflammatory Diet on Gut Homeostasis in Active and Experimental Crohn's Disease

项目摘要 炎症性肠病(IBD)亚型克罗恩病(CD)是一种慢性复发性炎症性疾病 胃肠道的紊乱。尽管IBD的确切病因尚不清楚，但有证据表明 环境因素，包括饮食，有助于其发病。1-3具体地说，饮食中的氨基酸是 细胞和微生物代谢途径中的关键调节因素及其代谢障碍，3 AS CD患者也观察到氨基酸浓度(血液/粪便/尿液)的变化。 已被证明对CD有促炎作用，但对抗炎饮食知之甚少 (例如，大豆)。5、6通过饮食调节肠道微生物是治疗CD的必要策略； 然而，目前还没有针对CD患者的具体建议。此外，研究表明，特定于人的 饮食干预引起的宿主免疫/代谢功能的变化反映了独特的微生物区系 签名。这项提案将侧重于饮食大豆和个别氨基酸对微生物区系的影响。 活动期CD患者的酸补充量与健康对照组比较。这一点的中心假设是 有观点认为，大豆饮食可以诱导CD患者体内的抗炎微生物区系，而且这种“反应水平” 可以通过代谢和微生物组生物标记物来预测每个个体。我们将检验这一假设 直接在人体内具有活性的镉和机械性地关注饮食中大豆对‘促炎’的影响 CD患者肠道微生物区系的潜力。在实验中，我们将使用我们经过验证的人类肠道微生物群 SAMP1/YitFC；SAMP(hGM-SAMP)小鼠CD-回肠炎模型的定量和力学验证 人粪便对环状回肠炎严重程度的影响作为一个主要的 目的：我们将确定以大豆为基础的饮食在多大程度上可以引起粪便/血液炎症的变化。 活动期CD患者的生物标志物。以下目标是我们继续努力理解 微生物区系介导的饮食对肠道炎症的影响。目标1：将描述饮食大豆的影响 对患有活动性CD的人进行快速筛查，并量化他们肠道微生物群的炎症潜力 HGM-SAMP DSS-结肠炎模型。通过对炎性微生物组/血液标志物进行分层，我们将确定 可以预测饮食“有反应”或“无反应”的生物标记物。我们希望生成一份新陈代谢的清单 以及微生物组临床生物标志物，可用于监测CD患者对饮食的反应。目标2：意志 确定日粮中添加大豆相关氨基酸对微生物组、代谢组的影响 HGM-SAMP、SPF SAMP和AKR对照组小鼠自发性CD样回肠炎的免疫学研究。我们会 确定与饮食反应的小鼠CD-回肠炎严重程度相关的功能代谢机制。 这一建议是基于对以大豆为基础的饮食治疗和治疗的IBD小鼠模型的强有力的初步数据。 预防严重的肠道炎症。将这一信息翻译成人类CD代表着一种非常 这是这一研究领域的重要研究领域，并最终将为今后的研究指明方向。

Project Summary The inflammatory bowel disease (IBD) subtype, Crohn’s disease (CD) is a chronic and relapsing inflammatory disorder of the gastrointestinal tract. Although the precise etiology of IBD is not known, evidence suggests that environmental factors, including diet, contribute to its pathogenesis.1-3 Specifically, dietary amino acids serve as key regulatory factors in cellular and microbial metabolic pathways, and disturbances in their metabolism,3 as well as altered presence of amino acid concentrations (blood/feces/urine), are observed in CD patients.4 Diet has been shown to have a pro-inflammatory effect in CD, but not much is known about anti-inflammatory diets (e.g., soy).5, 6 Gut microbial modulation via diet is a needed strategy for the therapeutic management of CD; however, no specific recommendations exist for CD patients. Moreover, studies show that the person-specific changes elicited by a dietary intervention on host immune/metabolic function reflect unique microbiota signatures. This proposal will focus on the microbiota-mediated effects of dietary soy and individual amino acid supplementation in patients with active CD compared to healthy controls. The central hypothesis of this proposal is that a soy diet induces anti-inflammatory microbiota in CD patients and that the ‘level of response’ for each individual can be predicted by metabolic and microbiome biomarkers. We will test this hypothesis directly in humans with active CD and mechanistically focus on the effect of dietary soy on the ‘pro-inflammatory potential’ of gut microbiota in CD patients. Experimentally, we will use our validated human gut microbiota SAMP1/YitFC; SAMP (hGM-SAMP) mouse model of CD-ileitis to quantify and mechanistically validate the functional effect of human feces on the severity of CD-ileitis after transplantation into GF SAMP. As a main objective, we will determine to what extent a soy-based diet could induce changes in fecal/blood inflammatory biomarkers in patients with active CD. The following aims are a continuation of our efforts to understand the microbiota-mediated effects of diet on intestinal inflammation. AIM 1: will characterize the effect of dietary soy in humans with active CD and quantify the inflammatory potential of their gut microbiome using a ‘rapid screening’ hGM-SAMP DSS-colitis model. By stratifying inflammatory microbiome/blood markers, we will identify biomarkers that could predict ‘responders’/‘non-responders’ to diet. We expect to generate a list of metabolic and microbiome clinical biomarkers that could be used to monitor response to diet in CD patients. AIM 2: will determine the impact of soy-associated amino acid dietary supplementation on the microbiome, metabolome and immunology of a spontaneous CD-like ileitis in hGM-SAMP and SPF SAMP, and AKR control mice. We will identify functional metabolic mechanisms associated with the severity of mouse CD-ileitis in response to diet. This proposal is based on strong preliminary data in mouse models of IBD that a soy-based diet treats and prevents the severity of intestinal inflammation. To translate this information to human CD represents a very significant area of investigation in this field of research and will ultimately inform the direction of future studies.