The gastrointestinal tract is host to a dense microbial community, known as the gut microbiota, which is dominated by obligate anaerobic bacteria belonging to the phyla Bacteroidetes (class Bacteroidia) and Firmicutes (class Clostridia). This microbial community offers benefit by conferring niche protection against facultative anaerobic Enterobacteriaceae (e.g. Escherichia coli or Salmonella enterica), a property known as colonization resistance. Perturbation of the gut microbiota by antibiotic treatment can disrupt colonization resistance, which can permit pathogen expansion. Furthermore, surgery or repeated courses of antibiotics are often followed by irritable bowel syndrome (IBS), a condition characterized by low-level intestinal inflammation, diarrhea and a microbiota imbalance (dysbiosis). However, the precise mechanisms by which the gut microbiota confers colonization resistance remain obscure. Our central hypothesis is that obligate anaerobic Clostridia mediate colonization resistance against Enterobacteriaceae by activating proliferator-activated receptor gamma (PPAR-?), which helps maintain a respiratory energy metabolism of colonic epithelial cells (colonocytes). Disruption of these microbe-host interactions by antibiotic treatment drives colonocytes to obtain energy through fermentation, which is accompanied by increased oxygen levels in the epithelium and elevated expression of inducible nitric oxide synthase (iNOS), thereby promoting luminal growth of Enterobacteriaceae by respiration.
In Aim 1 we will determine whether post-antibiotic butyrate depletion increases the availability of electron acceptors for Enterobacteriaceae in the intestinal lumen.
In Aim 2 we will determine the mechanism by which butyrate controls colonocyte metabolism.
In Aim 3 we will determine the consequences of reduced epithelial PPAR-? signaling for the composition of gut- associated microbial communities. The rationale for the proposed research is that a better understanding of the factors responsible for disruption of gut homeostasis after antibiotic treatment will provide insights into mechanisms of post-antibiotic pathogen expansion and the pathogenesis of IBS. This information will aid in the design of therapies to alleviate these unwanted side effects of antibiotic therapy.

Public Health Relevance

Over 90% of the cells in the human body are microbes, the majority of which reside in the large intestine, where they provide benefit to the host by educating the immune system and by providing niche protection against colonization with potentially harmful bacteria, a property known as colonization resistance. Antibiotic therapy is accompanied by a microbial imbalance that leads to a loss of colonization resistance. Here we will study the mechanism underlying colonization resistance and develop a potential treatment strategy for restoring it, which will usher in important conceptual advances that have a strong potential to exert a high impact on this field of science.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Host Interactions with Bacterial Pathogens Study Section (HIBP)
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Mills, Melody
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University of California Davis
Schools of Medicine
United States
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