Is Obesity an Infectious Disease?: Gut bacterial and fungal translocation as an underappreciated driver of visceral adipose expansion.

肥胖是一种传染病吗？：肠道细菌和真菌易位是内脏脂肪扩张的一个未被充分认识的驱动因素。

• 批准号: 10326683
• 负责人: Suzanne Devkota
• 金额: $ 81.83万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10326683
• 关键词: Abate; Adipose tissue; Adult; Age; Antibiotics; Bacteria; Bacteriophages; Behavior; Body Weight decreased; Body part; Cell Communication; Cells; Central obesity; Child; Childhood; Chronic; Communicable Diseases; Crohn' s disease; Epidemic; Fatty acid glycerol esters; Gastric Bypass; Gnotobiotic; Goals; Health; Human; Immune response; Inflammation; Lead; Life Style; Life Style Modification; Lipids; Literature; Love; Mediating; Mesentery; Metabolic; Metabolic dysfunction; Microbe; Mus; Obesity; Organism; Organoids; Overweight; Patients; Play; Population; Reporting; Risk; Testing; Tissue Expansion; Tissues; Visceral; Weight Gain; abdominal fat; bariatric surgery; base; catalyst; comorbidity; diet and exercise; driving behavior; fungus; gut bacteria; gut microbiome; high risk; induced pluripotent stem cell; innovation; microbial; microorganism interaction; novel strategies; obese patients; prevent; prospective

PROJECT SUMMARY/ABSTRACT Currently, over 70% of the U.S. adult population is overweight or obese, and this number is only increasing. Even more alarming is that 1 in 6 children is now overweight or obese, a number that has been rising even more rapidly than the adult population. While lifestyle modifications and gastric bypass surgeries are proven approaches to reducing adiposity and metabolic dysfunction, there is still no sign that obesity and its co- morbidities are abating. Safe, new strategies to mitigate weight gain, in combination with lifestyle choices, may prove more effective than any one strategy alone. Our long-term goal for this Catalyst project is to develop an obesity-mitigating strategy that leverages the activities of the gut microbiome to selectively target visceral adipose depots. Our rationale for this is based on recent findings from my lab while studying Crohn’s disease. We reported that certain lipid-loving bacteria and fungi in the gut, can translocate from the gut to mesenteric visceral adipose tissue in Crohn’s disease patients. The interaction of these microorganisms in the adipose tissue, promoted tissue expansion and the phenomenon known as ‘creeping fat’ (Ha et al., Cell 2020). Many features of Crohn’s creeping fat appear similar to obese visceral adipose. Therefore, if microbes may be a potent driver of creeping fat, perhaps they are a potent driver of visceral adiposity in obesity. Our approach to this question will involve the use of human gastric bypass tissues to first characterize the microbial presence in these tissues, and then test these organisms prospectively in gnotobiotic mice. We will in parallel create iPSC-derived organoids from obese patients to test specific host-microbe cellular interactions. This contribution is innovative because it poses a radically new, fringe concept that gut bacteria are directly interacting with adipose tissue to influence its behavior. If so, we may be able to target these specific organisms in the gut before they translocate, which we propose could be achieved through phage-mediated killing rather than antibiotics. It is high-risk because there is no established body of literature to support the notion that bacteria are directly driving the behavior of adipose through cell-cell interactions, but if it proves to be true, will necessitate a paradigm shift in how we think about obesity. Finally, the contribution is significant, because it may open entirely new avenues for maintaining metabolic health in the population, and particularly in our most vulnerable, pediatric population.

项目概要/摘要 目前，超过 70% 的美国成年人超重或肥胖，而且这个数字还在不断增加。 更令人担忧的是，现在有六分之一的儿童超重或肥胖，而且这一数字还在不断上升 生活方式的改变和胃绕道手术已被证明。 减少肥胖和代谢功能障碍的方法，仍然没有迹象表明肥胖及其并发症 减轻体重增加的安全新策略与生活方式的选择相结合可能会减少。 事实证明，这比任何单一策略都更有效。我们这个 Catalyst 项目的长期目标是开发一种策略。 利用肠道微生物群的活动选择性地针对内脏的减轻肥胖的策略 我们的理由是基于我的实验室在研究克罗恩病时的最新发现。 我们报道肠道中某些嗜脂细菌和真菌可以从肠道转移到肠系膜 克罗恩病患者的内脏脂肪组织这些微生物在脂肪中的相互作用。 组织、组织扩张以及被称为“蠕动脂肪”的现象（Ha et al., Cell 2020）。 克罗恩氏蠕动脂肪的特征与肥胖内脏脂肪相似，因此，如果微生物可能是一种有效的方法。 蠕动脂肪的驱动因素，也许它们是肥胖中内脏肥胖的潜在驱动因素。 问题将涉及使用人类胃绕道组织来首先表征这些组织中的微生物存在 组织，然后在无菌小鼠中前瞻性地测试这些生物体，我们将同时创建 iPSC 衍生的。 来自肥胖患者的类器官来测试特定的宿主-微生物细胞相互作用，这一贡献是创新的。 因为它提出了一个全新的边缘概念，即肠道细菌直接与脂肪组织相互作用 如果是这样，我们也许能够在肠道中的这些特定生物体移位之前将其定位， 我们建议可以通过噬菌体介导的杀灭而不是抗生素来实现它是高风险的。 因为没有既定的文献支持细菌直接驱动这一观点 脂肪通过细胞与细胞相互作用的行为，但如果它被证明是正确的，将有必要进行范式转变 最后，这一贡献是重大的，因为它可能为肥胖问题开辟全新的途径。 维持人群的代谢健康，特别是我们最脆弱的儿科人群。