Identification and Functional Characterization of Bioactive Microbial Metabolites of Beta-Glucan Degradation

β-葡聚糖降解的生物活性微生物代谢物的鉴定和功能表征

基本信息

批准号：
10651978
负责人：
CHENTHAMARAKSHAN VASU
金额：
$ 69.61万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-15 至 2028-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10651978
关键词：
Administrative Supplement Adolescent Age Algae Anti-Inflammatory Agents Autoimmune Autoimmune Diseases Autoimmunity B-Lymphocytes Biological Assay Carbohydrates Cell physiology Cells Clinical Colitis Complex Consult Consumption Dendritic Cells Development Diet Dietary Polysaccharide Disease Disease Outcome Disease Progression Distal Energy-Generating Resources Event Fermentation Functional disorder Genetic Predisposition to Disease Glucans Gnotobiotic Goals Gut Mucosa Human Immune In Vitro Inflammatory Inflammatory Bowel Diseases Insulin-Dependent Diabetes Mellitus Intestines Link Mediating Medicine Metabolic Metabolic Diseases Methods Microbe Modeling Mucins Mus National Institute of Allergy and Infectious Disease National Institute of Diabetes and Digestive and Kidney Diseases Nature Nutraceutical Onset of illness Oral Outcome Pathogenesis Patients Persons Process Production Property Reporting Series Severities Shapes Structure Systemic Lupus Erythematosus T-Lymphocyte Therapeutic Therapeutic Effect United States National Institutes of Health Volatile Fatty Acids Work Yeasts beneficial microorganism beta-Glucans comparison control data sharing dietary supplements dysbiosis fecal microbiota gastrointestinal epithelium gut dysbiosis gut inflammation gut microbes gut microbiota immune function immunoregulation in vivo insulin dependent diabetes mellitus onset intestinal epithelium knowledgebase meetings microbial microbial signature microbiota novel prebiotics precision nutrition prevent progenitor response signature molecule small molecule symposium

项目摘要

PROJECT DESCRIPTION / ABSTRACT Unhealthy changes in the gut microbiota might trigger the pathogenesis of many diseases. We have reported that priming the gut by -glucan-shaped microbiota, prior to clinical disease onset, can profoundly suppress autoimmune and colitis severity. Accumulating evidence suggests that microbes and their metabolites critically modulate the pathophysiology of various diseases. However, vast majority of microbial metabolites including those resulting from microbiota-diet interaction remain unknown and/or uncharacterized. Non-digestible, microbiota-accessible carbohydrates (MACs) including -glucans are thought to have major impact on microbiota composition and function. Our findings show that high-pure -glucans (BGs) from yeast (yeast -1,3/1,6-glucan; YBG) and microalgae (algal -1,3-glucan; paramylon, PM): a) have prebiotic properties, b) can increase the intestinal production of SCFA, c) can enhance gut integrity, and d) can suppress autoimmune progression and gut inflammation. However, to fully explain the mechanisms associated with the host-benefits of BG-shaped microbiota and to develop nutraceutical approaches, it is important to identify metabolites generated from BG- like CDP degradation and characterize their functional impacts. In this regard, our observations from in vitro and in vivo studies suggest that “BG-degradation” by gut microbes produces a distinct metabolite profile that includes the higher abundance of immune regulatory SCFAs. Therefore, we hypothesize that “identification and functional characterization of unique microbial metabolites of BG-degradation could lead to the development of precision- nutrition and -medicine approaches to enhance gut and systemic immune regulation”. Here, in response to PAR-21-253, we have proposed to, first identify BG degradation- and autoimmunity- associated novel microbial metabolites. Our studies will focus on i) determining if BG degradation, by human fecal microbiota, produces a distinct metabolite profile and ii) identifying the novel microbial metabolites of this process. We will also examine if fecal microbes from autoimmune type 1 diabetes and systemic lupus erythematosus patients produce pro-inflammatory metabolites and determine if BG-degradation process skews this pro-inflammatory metabolite profile to immune regulatory type. The pro- and anti- inflammatory properties of BG degradation- and autoimmunity-associated microbial metabolites will be studied in a series of in vitro and in vivo studies. The functional impacts of candidate metabolites on T-, B- and dendritic- cell responses will also be studied. We will then examine if in vivo immune function and autoimmune disease outcomes can be modulated by select microbial metabolites. Overall, these studies will demonstrate if fermentation of BG-like MACs generates microbial metabolites with therapeutic value, in terms of preventing and/or treating immune mediated disorders. We will work closely with the Knowledgebase Management Center (KMC) for different aspects of the project and share data and experimental details freely with KMC and other grantees.

项目描述/摘要我们已经报道过，肠道微生物群的不健康变化可能引发许多疾病的发病机制。在临床疾病发作之前，通过 -葡聚糖形状的微生物群启动肠道，可以深刻地抑制越来越多的证据表明微生物及其代谢物对自身免疫和结肠炎的严重程度至关重要。然而，绝大多数微生物代谢物包括调节各种疾病的病理生理学。由微生物群与饮食相互作用产生的那些仍然未知和/或无法消化，包括 β-葡聚糖在内的微生物可接触碳水化合物 (MAC) 被认为对微生物群具有重大影响我们的研究结果表明，来自酵母的高纯度 β-葡聚糖 (BG)（酵母 β-1,3/1,6-葡聚糖； YBG）和微藻（藻类 -1,3-葡聚糖；裸藻淀粉，PM）：a) 具有益生元特性，b) 可以增加肠道产生 SCFA，c) 可以增强肠道完整性，d) 可以抑制自身免疫进展，然而，要充分解释与 BG 形状的宿主益处相关的机制。微生物群和开发营养保健方法，识别 BG- 产生的代谢物非常重要例如 CDP 降解并描述其功能影响。在这方面，我们从体外和体外观察到的结果。体内研究表明，肠道微生物的“BG 降解”会产生独特的代谢物特征，其中包括免疫调节 SCFA 的丰度更高，因此，我们认为“鉴定和功能”。 BG 降解的独特微生物代谢物的表征可能会导致精确的开发增强肠道和全身免疫调节的营养和药物方法”。在此，针对 PAR-21-253，我们建议首先确定 BG 降解和自身免疫—— 我们的研究将集中于 i) 确定 BG 是否被人类降解。粪便微生物群产生独特的代谢物特征，并且 ii) 鉴定该物质的新微生物代谢物我们还将检查粪便微生物是否来自自身免疫 1 型糖尿病和系统性狼疮。红斑狼疮患者产生促炎代谢物并确定 BG 降解过程是否存在偏差这种促炎代谢特征为免疫调节型。 BG 降解和自身免疫相关的微生物代谢物将在一系列体外和体内研究候选代谢物对 T、B 和树突状细胞反应的功能影响也将进行体内研究。然后我们将研究是否可以调节体内免疫功能和自身免疫性疾病的结果。总的来说，这些研究将证明 BG 样 MAC 的发酵是否有效。在预防和/或治疗免疫介导方面产生具有治疗价值的微生物代谢物我们将与知识库管理中心（KMC）在不同方面密切合作。项目并与 KMC 和其他受资助者自由共享数据和实验细节。