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

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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.