Salmonella enterica serotype Typhimurium (S. Typhimurium) causes acute gut inflammation by invading the intestinal epithelium and surviving in mucosal macrophages. The inflammatory response enhances the pathogen's transmission by promoting its growth in the gut lumen. This study shows that reactive oxygen species generated during inflammation react with endogenous sulfur compounds (thiosulfate) to form tetrathionate, a new respiratory electron acceptor. The genes enabling tetrathionate respiration give S. Typhimurium a growth advantage over competing microbes in the inflamed gut. This suggests that S. Typhimurium uses host-driven production of tetrathionate to compete with fermenting gut microbes, highlighting the importance of intestinal inflammation in its pathogenicity. Inflammation leads to the production of tetrathionate through the oxidation of thiosulfate by reactive oxygen species. This process is supported by the presence of neutrophils and nitric oxide radicals during inflammation. In vivo experiments using a mouse colitis model confirmed that tetrathionate respiration promotes the growth of S. Typhimurium in the gut lumen. The ttr genes, which enable tetrathionate respiration, are crucial for this advantage, as their absence reduces the pathogen's ability to outcompete other microbes. Tetrathionate respiration provides a significant selective advantage for S. Typhimurium in anaerobic conditions, such as those found in the intestinal mucus layer. This advantage is most pronounced in close proximity to the inflamed mucosal surface. In the absence of inflammation, tetrathionate respiration does not confer a growth benefit, indicating that inflammation is necessary for the formation of tetrathionate. Oxygen radicals, particularly those produced by NADPH oxidase, are essential for tetrathionate respiration in vivo. The study also shows that tetrathionate respiration enhances the abundance of S. Typhimurium in the intestinal lumen, contributing to its transmission via the fecal-oral route. These findings highlight the role of host responses in enabling S. Typhimurium to outgrow the intestinal microbiota and establish infection. The ability to utilize tetrathionate respiration is a key factor in the pathogen's success, as it allows the use of respiratory pathways to compete with fermenting microbes. This mechanism is also present in other enteric pathogens like Yersinia enterocolitica, suggesting a broader role in bacterial pathogenesis.Salmonella enterica serotype Typhimurium (S. Typhimurium) causes acute gut inflammation by invading the intestinal epithelium and surviving in mucosal macrophages. The inflammatory response enhances the pathogen's transmission by promoting its growth in the gut lumen. This study shows that reactive oxygen species generated during inflammation react with endogenous sulfur compounds (thiosulfate) to form tetrathionate, a new respiratory electron acceptor. The genes enabling tetrathionate respiration give S. Typhimurium a growth advantage over competing microbes in the inflamed gut. This suggests that S. Typhimurium uses host-driven production of tetrathionate to compete with fermenting gut microbes, highlighting the importance of intestinal inflammation in its pathogenicity. Inflammation leads to the production of tetrathionate through the oxidation of thiosulfate by reactive oxygen species. This process is supported by the presence of neutrophils and nitric oxide radicals during inflammation. In vivo experiments using a mouse colitis model confirmed that tetrathionate respiration promotes the growth of S. Typhimurium in the gut lumen. The ttr genes, which enable tetrathionate respiration, are crucial for this advantage, as their absence reduces the pathogen's ability to outcompete other microbes. Tetrathionate respiration provides a significant selective advantage for S. Typhimurium in anaerobic conditions, such as those found in the intestinal mucus layer. This advantage is most pronounced in close proximity to the inflamed mucosal surface. In the absence of inflammation, tetrathionate respiration does not confer a growth benefit, indicating that inflammation is necessary for the formation of tetrathionate. Oxygen radicals, particularly those produced by NADPH oxidase, are essential for tetrathionate respiration in vivo. The study also shows that tetrathionate respiration enhances the abundance of S. Typhimurium in the intestinal lumen, contributing to its transmission via the fecal-oral route. These findings highlight the role of host responses in enabling S. Typhimurium to outgrow the intestinal microbiota and establish infection. The ability to utilize tetrathionate respiration is a key factor in the pathogen's success, as it allows the use of respiratory pathways to compete with fermenting microbes. This mechanism is also present in other enteric pathogens like Yersinia enterocolitica, suggesting a broader role in bacterial pathogenesis.