A Gut Commensal-Produced Metabolite Mediates Colonization Resistance to Salmonella Infection

Cell Host Microbe. 2018 Aug 8;24(2):296-307.e7. doi: 10.1016/j.chom.2018.07.002. Epub 2018 Jul 26.

Abstract

The intestinal microbiota provides colonization resistance against pathogens, limiting pathogen expansion and transmission. These microbiota-mediated mechanisms were previously identified by observing loss of colonization resistance after antibiotic treatment or dietary changes, which severely disrupt microbiota communities. We identify a microbiota-mediated mechanism of colonization resistance against Salmonella enterica serovar Typhimurium (S. Typhimurium) by comparing high-complexity commensal communities with different levels of colonization resistance. Using inbred mouse strains with different infection dynamics and S. Typhimurium intestinal burdens, we demonstrate that Bacteroides species mediate colonization resistance against S. Typhimurium by producing the short-chain fatty acid propionate. Propionate directly inhibits pathogen growth in vitro by disrupting intracellular pH homeostasis, and chemically increasing intestinal propionate levels protects mice from S. Typhimurium. In addition, administering susceptible mice Bacteroides, but not a propionate-production mutant, confers resistance to S. Typhimurium. This work provides mechanistic understanding into the role of individualized microbial communities in host-to-host variability of pathogen transmission.

Keywords: Bacteroides; Salmonella; colonization resistance; intestine; intracellular pH; metabolism; microbiota; pathogen shedding; propionate; short-chain fatty acids.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Bacterial Shedding / physiology
  • Bacteroides / physiology
  • Cation Transport Proteins / genetics
  • Cation Transport Proteins / metabolism
  • Fatty Acids, Volatile / metabolism
  • Fecal Microbiota Transplantation
  • Feces / microbiology
  • Female
  • Gastrointestinal Microbiome / physiology*
  • Host-Pathogen Interactions / physiology*
  • Intestinal Diseases / microbiology
  • Male
  • Mice, Inbred C57BL
  • Propionates / metabolism*
  • Salmonella Infections / etiology*
  • Salmonella typhimurium / pathogenicity*

Substances

  • Cation Transport Proteins
  • Fatty Acids, Volatile
  • Propionates
  • natural resistance-associated macrophage protein 1