Very long O-antigen chains enhance fitness during Salmonella-induced colitis by increasing bile resistance

Intestinal inflammation changes the luminal habitat for microbes through mechanisms that have not been fully resolved. We noticed that the FepE regulator of very long O-antigen chain assembly in the enteric pathogen Salmonella enterica serotype Typhimurium (S. Typhimurium) conferred a luminal fitness advantage in the mouse colitis model. However, a fepE mutant was not defective for survival in tissue, resistance to complement or resistance to polymyxin B. We performed metabolite profiling to identify changes in the luminal habitat that accompany S. Typhimurium-induced colitis. This analysis suggested that S. Typhimurium-induced colitis increased the luminal concentrations of total bile acids. A mutation in fepE significantly reduced the minimal inhibitory concentration (MIC) of S. Typhimurium for bile acids in vitro. Oral administration of the bile acid sequestrant cholestyramine resin lowered the concentrations of total bile acids in colon contents during S. Typhimurium infection and significantly reduced the luminal fitness advantage conferred by the fepE gene in the mouse colitis model. Collectively, these data suggested that very long O-antigen chains function in bile acid resistance of S. Typhimurium, a property conferring a fitness advantage during luminal growth in the inflamed intestine.
Author Summary Microbial communities inhabiting the intestinal tract have been characterized using high-throughput sequencing approaches, but little is known about factors that change their luminal habitat. Using metabolite profiling we discovered that luminal concentrations of total bile acids become significantly elevated during Salmonella-induced colitis. Very long O-antigen chains of Salmonella enterica serotype Typhimurium (S. Typhimurium) were required for luminal growth in the presence of such elevated bile concentrations during colitis. In contrast, very long O-antigen chains were dispensable for luminal growth in the presence of normal concentrations of bile acids or for growth in organs of mice. Thus, elevated bile concentrations during Salmonella-induced colitis change the luminal habitat and microbial growth in this environment requires increased bile resistance, which in case of S. Typhimurium is conferred by very long O-antigen chains.