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

项目描述/摘要 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。我们已经报道 在临床疾病发作之前，通过β-葡聚糖形状的微生物群启动肠道， 自身免疫和结肠炎严重程度。越来越多的证据表明，微生物及其代谢产物 调节各种疾病的病理生理学。然而，绝大多数微生物代谢产物，包括 由微生物群-饮食相互作用产生的那些仍然是未知的和/或未表征的。不易消化， 包括β-葡聚糖在内的微生物群可接近的碳水化合物（MAC）被认为对微生物群有重大影响 组成和功能。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β-1，3-葡聚糖;副淀粉，PM）：a）具有益生元性质，B）可以增加微藻的生物活性， 肠产生SCFA，c）可增强肠完整性，和d）可抑制自身免疫进展， 肠道炎症然而，为了充分解释与BG形的宿主益处相关的机制， 微生物和开发营养方法，重要的是要确定从BG产生的代谢物。 如CDP降解，并描述其功能影响。在这方面，我们从体外和 体内研究表明，肠道微生物的“BG-降解”产生不同的代谢物谱，包括 免疫调节SCFAs的丰度越高。因此，我们假设“识别和功能 BG降解的独特微生物代谢产物的表征可能导致精密度的发展， 加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降解和自身免疫性， 相关的新型微生物代谢物。我们的研究将集中在i）确定BG降解， 粪便微生物群，产生不同的代谢物谱，和ii）鉴定这种代谢物的新的微生物代谢物， 过程我们还将检查自身免疫性1型糖尿病和系统性狼疮的粪便微生物 红斑狼疮患者产生促炎代谢产物并确定BG降解过程是否发生偏差 这种促炎代谢物的特征转化为免疫调节型。的促炎和抗炎特性 BG降解和自身免疫相关的微生物代谢产物将在一系列体外和体内研究。 体内研究。候选代谢物对T细胞、B细胞和树突状细胞应答的功能影响也将在 研究了然后，我们将研究体内免疫功能和自身免疫性疾病的结果是否可以调节 通过选择微生物代谢物。总之，这些研究将证明BG样MAC的发酵是否 产生具有治疗价值的微生物代谢物， 紊乱我们将与知识库管理中心（KMC）密切合作， 项目和共享数据和实验细节自由与KMC和其他受助人。

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.