Dysbiosis-Associated Change in Host Metabolism Generates Lactate to Support Salmonella Growth

Caroline C. Gillis, Elizabeth R. Hughes, Luisella Spiga, Maria G. Winter, Wenhan Zhu, Tatiane Furtado de Carvalho, Rachael B. Chanin, Cassie L. Behrendt, Lora V. Hooper, Renato L. Santos, Sebastian E. Winter

Research output: Contribution to journalArticle

34 Scopus citations

Abstract

During Salmonella-induced gastroenteritis, mucosal inflammation creates a niche that favors the expansion of the pathogen population over the microbiota. Here, we show that Salmonella Typhimurium infection was accompanied by dysbiosis, decreased butyrate levels, and substantially elevated lactate levels in the gut lumen. Administration of a lactate dehydrogenase inhibitor blunted lactate production in germ-free mice, suggesting that lactate was predominantly of host origin. Depletion of butyrate-producing Clostridia, either through oral antibiotic treatment or as part of the pathogen-induced dysbiosis, triggered a switch in host cells from oxidative metabolism to lactate fermentation, increasing both lactate levels and Salmonella lactate utilization. Administration of tributyrin or a PPARγ agonist diminished host lactate production and abrogated the fitness advantage conferred on Salmonella by lactate utilization. We conclude that alterations of the gut microbiota, specifically a depletion of Clostridia, reprogram host metabolism to perform lactate fermentation, thus supporting Salmonella infection. Intestinal infection with Salmonella Typhimurium results in inflammation-induced dysbiosis. Gillis et al. demonstrate that depletion of commensal Clostridia reduces butyrate availability and subsequently alters host metabolism to produce lactate. Lactate oxidation by Salmonella enhances fitness in the gut and allows the pathogen to outcompete the microbiota.

Original languageEnglish (US)
JournalCell Host and Microbe
DOIs
StateAccepted/In press - Jan 1 2017

Keywords

  • Gut microbiota
  • Host metabolism during infection
  • Host-microbe interaction
  • Microbial metabolism
  • Salmonella

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Virology

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    Gillis, C. C., Hughes, E. R., Spiga, L., Winter, M. G., Zhu, W., Furtado de Carvalho, T., Chanin, R. B., Behrendt, C. L., Hooper, L. V., Santos, R. L., & Winter, S. E. (Accepted/In press). Dysbiosis-Associated Change in Host Metabolism Generates Lactate to Support Salmonella Growth. Cell Host and Microbe. https://doi.org/10.1016/j.chom.2017.11.006