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

Amanda Jacobson; Lilian Lam; Manohary Rajendram; Fiona Tamburini; Jared Honeycutt; Trung Pham; Will Van Treuren; Kali Pruss; Stephen Russell Stabler; Kyler Lugo; Donna M Bouley; Jose G Vilches-Moure; Mark Smith; Justin L Sonnenburg; Ami S Bhatt; Kerwyn Casey Huang; Denise Monack

doi:10.1016/j.chom.2018.07.002

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.

Authors

Amanda Jacobson¹, Lilian Lam¹, Manohary Rajendram², Fiona Tamburini³, Jared Honeycutt¹, Trung Pham¹, Will Van Treuren¹, Kali Pruss¹, Stephen Russell Stabler⁴, Kyler Lugo¹, Donna M Bouley⁵, Jose G Vilches-Moure⁵, Mark Smith⁴, Justin L Sonnenburg⁶, Ami S Bhatt⁷, Kerwyn Casey Huang⁸, Denise Monack⁹

Affiliations

¹ Department of Microbiology and Immunology, Stanford University, Stanford, CA 94305, USA.
² Department of Bioengineering, Stanford University, Stanford, CA 94305, USA.
³ Department of Genetics, Stanford University, Stanford, CA 94305, USA.
⁴ Department of CHEM-H, Stanford University, Stanford, CA 94305, USA.
⁵ Department of Comparative Medicine, Stanford University, Stanford, CA 94305, USA.
⁶ Department of Microbiology and Immunology, Stanford University, Stanford, CA 94305, USA; Chan Zuckerberg Biohub, San Francisco, CA 94158 USA.
⁷ Department of Genetics, Stanford University, Stanford, CA 94305, USA; Department of Medicine, Stanford University, Stanford, CA 94305 USA.
⁸ Department of Microbiology and Immunology, Stanford University, Stanford, CA 94305, USA; Department of Bioengineering, Stanford University, Stanford, CA 94305, USA; Chan Zuckerberg Biohub, San Francisco, CA 94158 USA.
⁹ Department of Microbiology and Immunology, Stanford University, Stanford, CA 94305, USA. Electronic address: dmonack@stanford.edu.

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

Abstract

Publication types

MeSH terms

Substances

Grants and funding