UC Davis

The gut microbiota is comprised of trillions of diverse and densely populated microbial species. Recent understanding has linked the maintenance of microbial homeostasis to regulation of other organ system to subsequently impact the overall health of the host. The coexistence of these microbial species requires many different nutrient niches to support microbial diversity and limit overgrowth of any particular species. However, foodborne pathogens, like Salmonella enterica serovar Typhimurium, overcome this competitive environment by triggering sweeping physiological changes to establish new niches for outgrowth. Here, we present novel evidence that nutrient-niches in the gut are subdivided into discrete host cell-derived microhabitats. We use Salmonella and E. coli, to show how 1. different bacteria exhibit biogeographical localization to these distinct luminal nutrient-niches and 2. pathogens modulate the host to promote pro-inflammatory landscapes and outcompete commensal microbial members.

In chapter 1, we introduce the host factors that shape the competitive environment of the gut microbiota, known as habitat filters. The pressures exerted by the host are driving forces for commensal microbial members to evolve better protective strategies by occupying existing niches. Thus, habitat filters maintain the longitudinal and cross-sectional heterogeneity of the microbiota to promote microbial diversity and gut homeostasis.In chapter 2, we show that critical resources in the large intestine, such as nitrate, aren’t defined by only global availability, but separated by different host cells into distinct biogeographical microhabitats for gut microbes. We show that commensal Escherichia coli and pathogenic Salmonella enterica serovar Typhimurium both utilized nitrate for intestinal growth, but each accessed this resource in a distinct biogeographical niche. Commensal E. coli utilized epithelial-derived nitrate, whereas nitrate in the niche occupied by S. Typhimurium was derived from phagocytes recruited by its virulence factors. Surprisingly, avirulent S. Typhimurium was unable to utilize epithelial-derived nitrate, because the chemotaxis receptors McpB and McpC excluded the pathogen from the niche occupied by E. coli. In contrast, E. coli invaded the niche constructed by S. Typhimurium virulence factors and conferred colonization resistance by competing for nitrate. Thus, nutrient-niches are not defined solely by critical resources but can be further subdivided by the host biogeographically into distinct microhabitats, thereby driving the effects of habitat filters and generating new niche opportunities for distinct bacterial species. In chapter 3, we show Salmonella changes the intestinal landscape to introduce a nutrient-niche that benefits the pathogen while suppressing commensal microbiota . While Salmonella benefits from gut inflammation, commensal members of the microbiota often cannot survive this robust immune response. However, the specifics of this reduction of commensal microbial members are not well understood. We show that phagocyte infiltration during Salmonella outgrowth is correlated to the depletion of Clostridia, a commensal microbe that is known to inhibit Salmonella. Chemical inhibition of reactive species and depletion of phagocytes during Salmonella infection both mitigate Clostridia depletion. We also show replicate this phenomenon in a non-infectious piroxicam-accelerated IL10-/- model for colitis. These findings demonstrate phagocyte-derived reactive species reduce Clostridia numbers during gut inflammation and suggest new therapeutic directions for mitigating both infectious and non-infectious gut colitis. Overall, we provide evidence that the host limits access to valuable host-derived nutrients by subdividing availability of these critical resources into discrete biogeographical niches. This heterogeneity of nutrient-niches maintains homeostasis in the large intestine and supports gut commensals ability to prevent infection and drives enteric pathogens to evolve new strategies to overcome colonization resistance and habitat filters.