Commensal resilience mechanisms in the inflamed intestine

点击翻译按钮获取中文摘要

PROJECT SUMMARY The human gut microbiota is increasingly recognized as having essential functions in human health. However, the microbiota is constantly subjected to challenges such as intestinal inflammation, which drives the microbiota into a perturbed state that can exacerbate diseases. Therefore, microbial resilience, which maintains the structural and functional stabilities of the gut microbiome in the face of perturbations, is critical to host health. The overarching goal of our research program is to elucidate the molecular mechanisms that govern commensal resilience in the inflamed intestine. During intestinal inflammation, host processes known as nutritional immunity starve gut microbes from essential micronutrients such as iron. In contrast to the well-studied strategies that pathogens employ to overcome host nutritional immunity, little is known about how gut commensals survive iron starvation in the inflamed gut. The primary goal of our research program for the next five years is to define the resilience mechanisms that maintain commensal iron homeostasis during gut inflammation. Enteric pathogens overcome nutritional immunity by producing iron-chelating molecules termed siderophores. Here, we show that the model gut commensal Bacteroides thetaiotaomicron (B. theta) acquires iron in the inflamed gut by pirating siderophores from an enteric pathogen that causes intestinal iron limitation. Notably, B. theta captures siderophores using a unique system absent in other Gram-negative bacteria. However, such a capture mechanism can be exploited by enteric pathogens to “re-pirate” siderophores from gut commensals to evade nutritional immunity. In addition to increasing iron uptake, we show that B. theta employs small, non-coding RNAs to orchestrate iron conservation and maintain intracellular iron homeostasis in the inflamed intestine. With this MIRA award, we will define commensal resilience mechanisms by addressing two related but independent questions in fundamental bacterial physiology: 1) How does xenosiderophore acquisition mediate B. theta resilience during gut inflammation? 2) How does B. theta manage intracellular iron homeostasis in the inflamed intestine? We will approach these questions using an interdisciplinary pipeline consisting of cutting-edge omics experiments, bacterial & host genetics, and a mechanistic understanding of bacterial physiology in vivo. The completion of these research projects will reveal the mechanisms by which gut commensals adapt to iron limitation in the inflamed gut and how such adaptation shapes the structural and functional stability of the gut microbiome. The proposed work is innovative because it adds commensal iron metabolism as a previously unappreciated dimension to the intricate interactions between pathogen and nutritional immunity. This work is impactful because it will provide much-needed insights into how interphylum iron metabolism contributes to gut microbiota resilience in the inflamed gut.