Intestinal commensal microorganisms mediate colonization resistance against bacterial pathogens through various mechanisms, including activation of the host immune system and production of antagonistic molecules. Microbial-derived short-chain fatty acids (SCFAs) were reported to inhibit pathogen growth, an effect that was not well understood. Jacobson et al. used a mouse model of oral Salmonella enterica subsp. enterica serovar Typhimurium infection in which mice were not pre-treated with an antibiotic to study colonization resistance. They showed that commensal Bacteroides spp. produce the SCFA propionate, which disrupts intracellular pH homeostasis in S. Typhimurium, leading to slow and reduced pathogen growth. In sum, this study uncovers how the unperturbed, resident microbiota directly protects the host from enteric infection.