Elucidating the consequences of dietary sugar consumption on the gut microbiota

阐明膳食糖消耗对肠道微生物群的影响

• 批准号: 10658136
• 负责人: Guy Edmund Townsend
• 金额: $ 59.1万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10658136
• 关键词: Autoimmune Diseases; Bacteroides; Bacteroides thetaiotaomicron; Bacteroidetes; Binding; Carbohydrates; Colitis; Colorectal Cancer; Consumption; Development; Diet; Dietary Sugars; Disease; Disease susceptibility; Distal; Exhibits; Fructose; Fucose; Gene Expression; Genes; Genetic Transcription; Glucose; Growth; Health; Homologous Gene; Human; Immune system; In Vitro; Individual; Industrialization; Inflammatory Bowel Diseases; Insulinase; Intestines; Ligands; Mammals; Mediating; Metabolic; Metabolism; Modernization; Molecular; Molecular Target; Mus; Pathogenesis; Pathway interactions; Peptide Hydrolases; Physiology; Polysaccharides; Population; Predisposition; Process; Proteins; Reducing diet; Regulatory T-Lymphocyte; Reporter; Rodent Model; Role; Signal Pathway; Signal Transduction; T cell differentiation; Thinness; Work; absorption; commensal bacteria; dietary; fitness; gut bacteria; gut colonization; gut inflammation; gut microbes; gut microbiota; host microbiota; host-microbe interactions; human disease; immunoregulation; in vivo; metabolomics; microbial; microbial products; mutant; non-alcoholic fatty liver disease; novel; response; sugar; transcription factor; transcriptomics

Project Summary The gut microbiota is a critical determinant of human health and development. Diets rich in the refined sugars glucose and fructose can modulate gut microbial abundance and metabolism thereby increasing disease susceptibility. However, the mechanisms governing microbial responses to dietary sugar in the gut remain poorly understood. We have demonstrated that host dietary sugar consumption silences expression of a colonization factor called Roc in Bacteroides thetaiotaomicron, an abundant gut bacterium associated with lean, healthy individuals. We determined that a conserved transcription factor is necessary to synthesize Roc and regulates additional bacterial factors that mediate critical host-microbial interactions, including an immunomodulatory protein and fucose utilization genes. We hypothesize that the activity of this transcription factor is governed by a putative intracellular metabolite that is differentially synthesized according to host diet composition and dramatically reduced upon sugar-rich diet consumption. We have identified critical molecular players governing the activity of this transcription factor and propose to 1.) elucidate the mechanisms governing its activation, 2.) determine how dietary sugar consumption silences its activity, and 3.) characterize the consequences of host sugar-rich diet consumption on microbial product synthesis in vivo. We believe that this work will reveal a conserved pathway that is disrupted by host sugar consumption resulting in aberrant gut microbial activities. Furthermore, this work has uncovered a molecular target for modulation of microbial abundance and metabolism in the host and can be exploited for rational manipulation of the gut microbiota to treat diseases.

项目摘要 肠道微生物群是人类健康和发展的关键决定因素。富含精制糖的饮食 葡萄糖和果糖可以调节肠道微生物的丰度和代谢，从而增加疾病 易感性然而，控制肠道中微生物对膳食糖的反应的机制仍然很差 明白我们已经证明，宿主饮食中的糖消耗沉默了一种定殖的表达， 多形拟杆菌中一种名为Roc的因子，这是一种与瘦、健康 个体我们确定了一个保守的转录因子是合成Roc所必需的，并调节Roc的表达。 介导关键宿主-微生物相互作用的其他细菌因子，包括免疫调节因子， 蛋白质和岩藻糖利用基因。我们假设，这种转录因子的活性是由 根据宿主饮食组成差异合成的推定细胞内代谢物， 显著减少高糖饮食的摄入。我们已经确定了关键的分子参与者， 该转录因子活性，并提出1.）阐明其激活的机制，2.） 确定饮食中的糖消耗如何抑制其活性，以及3.）描述宿主的后果 高糖饮食对体内微生物产物合成影响。我们相信，这项工作将揭示一个 被宿主糖消耗破坏的保守途径，导致异常的肠道微生物活性。 此外，这项工作还揭示了调节微生物丰度和代谢的分子靶点 并且可以用于合理操纵肠道微生物群以治疗疾病。