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: 10539262
• 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/10539262
• 关键词: Affect; American; Amino Acids; Animals; Anti-Inflammatory Agents; Antiinflammatory Effect; Area; Bioinformatics; Biological Markers; Blood; Chronic; Clinical Medicine; Colitis; 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; biomarker identification; career; clinical biomarkers; 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; 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.

项目总结