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

抗炎饮食对活动性和实验性克罗恩病肠道稳态的影响

• 批准号: 10320962
• 负责人: Abigail Raffner
• 金额: $ 12.18万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10320962
• 关键词: Affect; American; Amino Acids; Animals; Anti-Inflammatory Agents; Antiinflammatory Effect; Area; Bioinformatics; Biological Markers; Blood; Chronic; Clinical Medicine; Complex; Crohn' s disease; Data; Diet; Dietary Factors; Dietary Intervention; Dietary Supplementation; Dietitian; Digestive System Disorders; Disease; Disease remission; Doctor of Philosophy; Eating; Environmental Risk Factor; Etiology; Feces; Functional disorder; Future; Germ-Free; Glycine; Goals; Grant; Health; Human; Ileitis; Immune; Immune response; Immunologics; Immunology; Individual; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Intervention Studies; Investigation; Isoleucine; Leucine; Mass Spectrum Analysis; Mediating; Metabolic; Metabolic Pathway; Metabolism; Methionine; Modeling; Modification; Monitor; Mus; National Health and Nutrition Examination Survey; Nutrient; Pathogenesis; Patients; Persons; Phenotype; Plasma; Prevention; Probiotics; Proteins; Randomized; Rapid screening; Recommendation; Relapse; Reporting; Reproducibility; Research; Rodent; Severities; Supplementation; Surveys; Symptoms; Testing; Therapeutic; Threonine; Time; Translating; Transplantation; Urine; Valine; Virulence; Work; base; career; clinical biomarkers; dextran sulfate sodium induced colitis; dietary; disorder control; disorder subtype; dysbiosis; fecal transplantation; germ free condition; gut bacteria; gut homeostasis; gut inflammation; gut microbiome; gut microbiota; improved; metabolic profile; metabolome; metatranscriptome; microbial; microbiome; microbiota; microbiota profiles; mouse model; novel therapeutic intervention; open label; oral supplementation; prevent; responders and non-responders; response; soy; stool sample; transcriptomics; treatment strategy

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.

项目摘要 炎症性肠病（IBD）亚型，克罗恩病（CD）是一种慢性和复发性炎症性肠病， 胃肠道疾病。虽然IBD的确切病因尚不清楚，但有证据表明， 环境因素，包括饮食，有助于其发病机制。1 -3具体而言，饮食中的氨基酸作为 细胞和微生物代谢途径中的关键调节因子，以及它们代谢中的干扰， 以及氨基酸浓度（血液/粪便/尿液）的改变。4饮食 已被证明对CD有促炎作用，但对抗炎饮食知之甚少 (e.g.,大豆）。5，6通过饮食调节肠道微生物是CD治疗管理所需的策略; 然而，对于CD患者没有具体的建议。此外，研究表明， 饮食干预对宿主免疫/代谢功能引起的变化反映了独特的微生物群 签名.这项建议将集中在微生物群介导的影响，饮食大豆和个人的氨基 与健康对照组相比，活动性CD患者的酸补充。这个问题的核心假设是 一个建议是，大豆饮食诱导CD患者的抗炎微生物群， 可以通过代谢和微生物组生物标志物来预测。我们将检验这一假设 直接在患有活动性CD的人中进行，并在机制上关注饮食大豆对“促炎” CD患者肠道菌群的潜力。在实验上，我们将使用经过验证的人类肠道微生物群 SAMP 1/YitFC; SAMP（hGM-SAMP）CD-回肠炎小鼠模型，以定量和机械验证 移植入GF SAMP后，人粪便对CD-回肠炎严重程度的功能作用。作为主要 目的，我们将确定在何种程度上大豆为基础的饮食可以诱导粪便/血液炎症的变化， 活动性CD患者的生物标志物。以下目标是我们继续努力了解 微生物群介导的饮食对肠道炎症的影响。目的1：将描述饮食大豆的影响 在患有活动性CD的人中，并使用“快速筛查”来量化其肠道微生物组的炎症潜力 hGM-SAMP DSS-结肠炎模型。通过对炎症微生物组/血液标志物进行分层，我们将识别 可以预测饮食的“反应者”/“无反应者”的生物标志物。我们希望能得到一份代谢物清单 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：将 确定大豆相关氨基酸膳食补充剂对微生物组、代谢组 hGM-SAMP和SPF SAMP以及AKR对照小鼠中自发性CD样回肠炎的免疫学。我们将 确定与小鼠CD-回肠炎严重程度相关的功能性代谢机制。 这一建议是基于强有力的初步数据，在小鼠模型的IBD，大豆为基础的饮食治疗和 预防严重的肠道炎症。将这些信息翻译成人类CD代表了一个非常 这是该研究领域的重要研究领域，并将最终为未来的研究方向提供信息。