The microbiota metabolite indole inhibits Salmonella virulence: Involvement of the PhoPQ two-component system

• Published in: PloS one Vol. 13; no. 1; p. e0190613
• Main Authors: Kohli, Nandita, Crisp, Zeni, Riordan, Rebekah, Li, Michael, Alaniz, Robert C, Jayaraman, Arul
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.01.2018; Public Library of Science (PLoS)
• Subjects: Antibiotics; Bacteria; Biofilms; Biology and Life Sciences; Cell survival; Chemical engineering; Colonization; Drug dosages; E coli; Epithelial cells; Escherichia coli; Fatty acids; Gastrointestinal tract; Gene expression; Immunology; Indoles; Infections; Intestine; Macrophages; Medicine and Health Sciences; Metabolites; Microbiota; Microorganisms; Motility; Organs; Pathogenesis; Pathogenicity; Pathogens; Physical Sciences; Salmonella; Salmonella enterica; Solvents; Tryptophan; Virulence
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0190613

The microbial community present in the gastrointestinal tract is an important component of the host defense against pathogen infections. We previously demonstrated that indole, a microbial metabolite of tryptophan, reduces enterohemorrhagic Escherichia coli O157:H7 attachment to intestinal epithelial cells and biofilm formation, suggesting that indole may be an effector/attenuator of colonization for a number of enteric pathogens. Here, we report that indole attenuates Salmonella Typhimurium (Salmonella) virulence and invasion as well as increases resistance to colonization in host cells. Indole-exposed Salmonella colonized mice less effectively compared to solvent-treated controls, as evident by competitive index values less than 1 in multiple organs. Indole-exposed Salmonella demonstrated 160-fold less invasion of HeLa epithelial cells and 2-fold less invasion of J774A.1 macrophages compared to solvent-treated controls. However, indole did not affect Salmonella intracellular survival in J774A.1 macrophages suggesting that indole primarily affects Salmonella invasion. The decrease in invasion was corroborated by a decrease in expression of multiple Salmonella Pathogenicity Island-1 (SPI-1) genes. We also identified that the effect of indole was mediated by both PhoPQ-dependent and independent mechanisms. Indole also synergistically enhanced the inhibitory effect of a short chain fatty acid cocktail on SPI-1 gene expression. Lastly, indole-treated HeLa cells were 70% more resistant to Salmonella invasion suggesting that indole also increases resistance of epithelial cells to colonization. Our results demonstrate that indole is an important microbiota metabolite that has direct anti-infective effects on Salmonella and host cells, revealing novel mechanisms of pathogen colonization resistance.