Acetate uptake alleviates propionate-mediated growth restriction in Yersinia enterocolitica.

The gut microbiota impedes infection by enteric pathogens, a process termed colonization resistance. Microbial production of short-chain fatty acids (SCFAs), such as acetate, propionate, and butyrate, contributes to colonization resistance. Yersinia enterocolitica encounters short-chain fatty acids at several stages during intestinal infection. However, our understanding of how Y. enterocolitica copes with SCFA stress is limited. Here, we found that acetate, propionate, and butyrate restrict Y. enterocolitica growth in vitro. Propionate exerted the most potent toxicity by both pH-dependent and pH-independent mechanisms. pH-dependent propionate growth restriction was worsened in a mutant lacking ornithine decarboxylase, suggesting that this enzyme is involved in counteracting cytoplasmic acidification by propionate under acidic environmental conditions. pH-independent propionate toxicity required phosphate acetyltransferase (phosphotransacetylase) and acetate kinase, pointing to conversion of intracellular propionate to toxic propionyl-CoA by promiscuous phosphotransacetylase and acetate kinase activities as a mechanism of propionate toxicity. We also found that pH-independent propionate toxicity was alleviated by exogenous acetate, taken up via the acetate/succinate transporter SatP. This work advances our understanding of how short-chain fatty acids restrict pathogen growth and highlights strategies used by bona fide pathogens to overcome short-chain fatty acid-mediated colonization resistance.