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

项目总结/摘要 目前，超过70%的美国成年人超重或肥胖，而且这个数字还在增加。甚至 更令人担忧的是，现在每6个儿童中就有1个超重或肥胖，这个数字一直在上升 比成年人更快。虽然生活方式的改变和胃旁路手术被证明 尽管有很多方法可以减少肥胖和代谢功能障碍，但仍然没有迹象表明肥胖及其共同作用 发病率正在下降。安全，新的策略，以减轻体重增加，结合生活方式的选择，可能 比单独使用任何一种策略都要有效。我们这个Catalyst项目的长期目标是开发一个 减轻肥胖的策略，利用肠道微生物组的活动，选择性地靶向内脏 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。 我们报道了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，促进组织扩张和称为“蠕动脂肪”的现象（Ha等人，Cell 2020）。许多 克罗恩氏蠕动脂肪的特征似乎与肥胖内脏脂肪相似。因此，如果微生物可能是一种有效的 他们是爬行脂肪的驱动者，也许他们是肥胖症内脏肥胖的有力驱动者。我们的做法是 问题将涉及使用人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gnotobiotic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 肥胖患者的类器官，以测试特定的宿主-微生物细胞相互作用。这种贡献是创新的 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， 影响其行为。如果是这样的话，我们也许能够在肠道中的这些特定生物体移位之前将其作为目标， 我们建议可以通过噬菌体介导的杀伤而不是抗生素来实现。这是高风险的 因为没有建立的文献支持细菌直接驱动细菌的概念， 脂肪的行为通过细胞间的相互作用，但如果它被证明是真的，将需要一个范式转变， 我们对肥胖的看法。最后，这一贡献是重大的，因为它可能为以下方面开辟全新的途径： 维持人群的代谢健康，特别是我们最脆弱的儿科人群。

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.