Wasting syndrome is a dysregulated metabolic state in which there is a profound depletion of muscle and fat tissue accompanied by weight loss. Wasting is an important sequela of infectious and inflammatory conditions that accounts for significant morbidity and mortality. A current paradigm is that inflammation drives wasting, however current efforts to antagonize wasting by inhibiting the inflammatory response have met with little success. The studies presented demonstrate that specific constituents of the mammalian intestinal microbiota can antagonize wasting pathology triggered by intestinal injury and the intestinal pathogen Salmonella Typhimurium. This protection cannot be attributed to limiting the canonical inflammatory mediators that contribute to wasting pathogenesis or by heightening the host immune response, suggesting that the microbiota can promote host tolerance defenses by limiting wasting pathology. The central hypothesis of this proposal is that the intestinal commensal, E. coli O21:H+, directly manipulates host physiologies to promote tolerance by antagonizing infection/inflammation induced wasting without impacting the canonical inflammatory mediators of wasting. The proposed studies will address: 1) Determine the mechanism of protection from skeletal muscle wasting by the intestinal microbiota. Preliminary results show that the commensal, E. coli O21:H+ limits skeletal muscle wasting induced by intestinal injury and infection via manipulation of the IGF-1 signaling pathway, which is a critical regulator of skeletal muscle size. 2) Determine how the intestinal microbiota impacts adipose tissue physiology during wasting. Preliminary data demonstrates that intestinal colonization with E. coli O21:H+ is sufficient to prevent wasting of white adipose tissue (WAT). Furthermore, preliminary studies suggest that E. coli O21:H+ prevents the physiological changes in WAT that are associated with brown fat - a process called WAT browning. These studies will determine how this commensal limits WAT atrophy and browning by focusing on known mechanisms that contribute to these processes - signaling via the sympathetic nervous system and the innate immune system. 3) What are the cellular and genetic factors required for microbiota protection from intestinal infection and injury induced wasting? Bacterial mutants will be used to determine the microbial factors that are necessary to confer protection from wasting. Mouse mutants will be used to determine the cells and tissues that sense E. coli O21:H+ to mediate the protective effects conferred by this microbe. These studies will be focused on a key orchestrator of the innate immune system called the inflammasome. The discovery that tolerance defenses mediate host-microbiota interactions, that a microbe has evolved mechanisms to promote tolerance, and the identification of commensals that antagonize wasting represent fundamental new insights into host-microbiota interactions, and form the basis for this proposal.
In this project, we will investigate a role for the intestinal microbiota in promoting tolerance defenses of the host by focusing on a common pathology associated with infections and inflammation called wasting syndrome - the depletion of energy stores that causes significant morbidity and mortality. We have identified an intestinal commensal that antagonizes wasting triggered by intestinal injury and infections and we will delineate the mechanisms by which this intestinal commensal prevents wasting of skeletal muscle and alterations in white adipose tissue physiology by focusing on signaling of the endocrine system and the innate immune system. This work will open the possibility of treating wasting associated with inflammatory and infectious diseases via manipulation of the intestinal microbiota.
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