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Woongjae Yoo,1,2,8 Nicolas G. Shealy,1,8 Jacob K. Zieba,1 Teresa P. Torres,1 Madi Baltagulov,1 Julia D. Thomas,1 Catherine D. Shelton,1 Anna G. McGovern,1 Nora J. Foegeding,1 Erin E. Olsan,3 and Mariana X. Byndloss 1,4,5,6,7,9,*
1Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
2Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang 37673, Republic of Korea
3Department of Biological Sciences, California State University, Sacramento, CA 95819, USA
4Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, TN 37232, USA
5Vanderbilt Digestive Disease Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA
6Vanderbilt Microbiome Innovation Center, Vanderbilt University, Nashville, TN 37235, USA
7Howard Hughes Medical Institute, Vanderbilt University Medical Center, Nashville, TN 37232, USA
8These authors contributed equally
9Lead contact
*Corresponding author: correspondence to Mariana X. Byndloss
Abstract
Inflammation boosts the availability of electron acceptors in the intestinal lumen, creating a favorable niche for pathogenic Enterobacteriaceae. However, the mechanisms linking intestinal inflammation-mediated changes in luminal metabolites and pathogen expansion remain unclear. Here, we show that mucosal inflammation induced by Salmonella enterica serovar Typhimurium (S. Tm) infection increases intestinal levels of the amino acid aspartate. S. Tm used aspartate-ammonia lyase (aspA)-dependent fumarate respiration for growth in the murine gut only during inflammation. AspA-dependent growth advantage was abolished in the gut of germ-free mice and restored in gnotobiotic mice colonized with members of the classes Bacteroidia and Clostridia. Reactive oxygen species (ROS) produced during the host response caused lysis of commensal microbes, resulting in the release of microbiota-derived aspartate that was used by S. Tm, in concert with nitrate-dependent anaerobic respiration, to outcompete commensal Enterobacteriaceae. Our findings demonstrate the role of microbiota-derived amino acids in driving respiration-dependent S. Tm expansion during colitis.
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