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

项目摘要/摘要 目前，超过70%的美国成年人口超重或肥胖，而且这个数字还在不断增加。连 更令人担忧的是，现在每6个孩子中就有一个超重或肥胖，这个数字还在不断上升 比成年人口要快。虽然生活方式的改变和胃旁路手术得到了证实 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共同的 病态正在减少。安全的减轻体重增加的新策略，结合生活方式的选择，可能会 事实证明，这比任何一种策略都更有效。我们这个Catalyst项目的长期目标是开发一个 利用肠道微生物群的活动选择性地针对内脏的减肥策略 脂肪库。我们这样做的理由是基于我的实验室在研究克罗恩病时的最新发现。 我们报告了肠道中的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，促进组织扩张和被称为“蠕动脂肪”的现象(Ha等人，Cell 2020)。许多 克罗恩爬行脂肪的特征与肥胖的内脏脂肪相似。因此，如果微生物可能是一种强大的 令人毛骨悚然的脂肪的驱动者，也许它们是肥胖中内脏肥胖的有力驱动力。我们对此采取的方法 问题将涉及使用人类胃旁路组织来首先表征这些组织中的微生物存在 组织，然后在诺生菌小鼠身上前瞻性地测试这些微生物。我们将并行创建IPSC派生的 来自肥胖患者的有机化合物，以测试特定的宿主-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 影响它的行为。如果是这样的话，我们也许能够在这些特定的微生物移位之前将它们定位在肠道中， 我们认为这可以通过噬菌体介导的杀灭而不是抗生素来实现。这是高风险的 因为没有确凿的文献来支持细菌直接驱动 脂肪通过细胞-细胞相互作用的行为，但如果证明是真的，将需要在 我们是如何看待肥胖的。最后，这一贡献是巨大的，因为它可能为 在人群中保持代谢健康，特别是在我们最脆弱的儿科人群中。

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.