Salmonella enterica Serovar Typhimurium Exploits Inflammation to Compete with the Intestinal Microbiota

Abstract

Most mucosal surfaces of the mammalian body are colonized by microbial communities (“microbiota”). A high density of commensal microbiota inhabits the intestine and shields from infection (“colonization resistance”). The virulence strategies allowing enteropathogenic bacteria to successfully compete with the microbiota and overcome colonization resistance are poorly understood. Here, we investigated manipulation of the intestinal microbiota by the enteropathogenic bacterium Salmonella enterica subspecies 1 serovar Typhimurium (S. Tm) in a mouse colitis model: we found that inflammatory host responses induced by S. Tm changed microbiota composition and suppressed its growth. In contrast to wild-type S. Tm, an avirulent invGsseD mutant failing to trigger colitis was outcompeted by the microbiota. This competitive defect was reverted if inflammation was provided concomitantly by mixed infection with wild-type S. Tm or in mice (IL10^−/−, VILLIN-HA^CL4-CD8) with inflammatory bowel disease. Thus, inflammation is necessary and sufficient for overcoming colonization resistance. This reveals a new concept in infectious disease: in contrast to current thinking, inflammation is not always detrimental for the pathogen. Triggering the host's immune defence can shift the balance between the protective microbiota and the pathogen in favour of the pathogen. A dense microbial community colonizes the intestinal tract of mammals, contributing to health and nutrition and conferring efficient protection against most pathogenic intruders. Intestinal pathogens can overcome this colonization resistance and cause disease; however, the mechanisms used to do this are still elusive. In this study we analyzed intestinal infection by the model pathogen Salmonella enterica subspecies 1 serovar Typhimurium (S. Tm). We show that the virulent wild-type pathogen overcomes colonization resistance by inducing the host's inflammatory immune response and exploiting it for its purpose. In contrast, an avirulent Salmonella mutant defective in triggering inflammation was unable to overcome colonization resistance by itself. Colonization by this mutant was restored if inflammation was provided concomitantly, in mice with inflammatory bowel disease (genetic and inducible) or by co-infection with wild-type S. Tm. These findings reveal a previously unrecognized strategy by which pathogenic bacteria overcome colonization resistance: abusing the host's inflammatory immune response to gain an edge against the normal microbial community of the gut. This represents a first step towards unravelling the molecular mechanisms underlying this three-way interaction of host, microbiota, and pathogens.