Microbiota outgrowth by Salmonella

ABSTRACT
Our intestine is host to a complex microbial community, the gut microbiota, which is dominated
by obligate anaerobic bacteria belonging to the classes Clostridia and Bacteroidia. This
community provides benefit to the host by contributing to nutrition, immune education and niche
protection against enteric pathogens (colonization resistance). However, Salmonella enterica
serovar (S.) Typhimurium can use its virulence factors to overcome colonization resistance by
triggering intestinal inflammation. The host inflammatory response remodels the intestinal
environment, which fuels growth of the pathogen, but also causes an imbalance in the microbiota
(dysbiosis). The question of how intestinal inflammation drives changes in the microbiota
composition and how these changes affect host physiology and pathogen expansion represents
a high-impact topic that will be addressed in this application. The objectives of this application are
to study the mechanisms that enable the pathogen to gain an edge over competing
Enterobacterales during intestinal inflammation. Our central hypothesis is that S. Typhimurium
virulence factors trigger host responses that remodel the intestinal environment to generate
resources that fuel pathogen growth while at the same time enabling it to edge out competing
Enterobacterales. To test this hypothesis, we will determine in Specific Aim 1 whether S.
Typhimurium benefits from intestinal inflammation because this host response increases the
availability of polyols. In Specific Aim 2 we will determine whether S. Typhimurium depletes a
neurotransmitter to compete with Enterobacterales for iron. Finally, our third specific aim will
determine whether sulfide production by S. Typhimurium provides a benefit during competition
with endogenous Enterobacterales. It is our expectation that successful completion of the
proposed experiments will usher in important conceptual advances in understanding the
mechanisms underlying pathogen expansion during S. Typhimurium-induced gastroenteritis.

Grant Number: 5R01AI096528-15
NIH Institute/Center: NIH
Principal Investigator: Andreas Baumler