The intestinal microbiome is increasingly recognized as an important part of our immune system. Specific members of this consortium are thought to inhibit enteric disease, yet current in vivo models have confounded investigation of bacterial interactions in the intestine due to the complex interdependence between host and microbiota. C. elegans lacks many of these complicating factors and provides a tractable model for the mechanistic exploration of specific bacterial interactions in the intestine. We have identified Enterococcus faecium, a commensal member of the human intestinal microbiota, as an in vivo inhibitor of Salmonella virulence in C. elegans. We hypothesize that E. faecium is acting via a conserved mechanism in worms and mammals to attenuate Salmonella pathogenesis.
We aim to identify and characterize the E. faecium factor(s) required for this effect in C. elegans, then analyze the role of these factor(s) in the mouse. Thus, our C. elegans model system provides a bridge between in vitro studies and complex mouse models to investigate the mechanism of a conserved commensal-pathogen interaction. Due to the diverse and considerable influence the intestinal microbiota exerts on host health, the development of probiotic approaches for preventing disease may provide an alternative to antibiotics. Although antibiotics are a mainstay of modern medicine, antibiotic use has fallen under scrutiny in recent years due to the spread of antibiotic resistance in bacterial populations. In addition, antibiotic use has been shown to cause dysbiosis, increasing host vulnerability to gut inflammation and enteric infection. Many members of our intestinal microbiota have been observed to improve host health in various ways. Further development of probiotic therapies, however, will require understanding the roles of individual bacterial species in the complex intestinal environment. The development of C. elegans as a general model for studying intestinal commensal-pathogen interactions could be an important step towards characterizing these interactions, providing an efficient in vivo model system to identify genetic components of commensalism that can then be analyzed in higher animal models.
The intestinal microbiota regulates host metabolism and immunity and is associated with various human diseases. While the gut microbiota is known to confer host resistance to invading pathogens, the mechanisms by which specific commensal bacteria confer protection against enteric pathogens have been difficult to elucidate due to the complex interactions between the host and its microbiota. This proposal describes the utilization of a Caenorhabditis elegans model system to investigate how specific commensal intestinal bacteria, such as Enterococcus faecium, can confer protection against gut pathogens such as Salmonella enterica. E. faecium is a normal member of the human intestinal microflora. Some strains are used as probiotics, but the specific mechanisms that enable to E. faecium colonize and protect various animals from infection are unknown. We demonstrate that E. faecium inhibition of Salmonella pathogenesis can be recapitulated in the C. elegans model. We will use this robust and efficient system to identify E. faecium factors that are required for protection of C. elegans from infection by employing candidate-based mutation analysis and unbiased genetic screening approaches. Imaging of bacterial distribution and dynamics during host colonization, along with complementary biochemical and genetic approached, will allow the characterization of identified E. faecium mutants. The E. faecium mutants characterized from these C. elegans studies will then be evaluated in mouse models of inflammation and bacterial infection to identify conserved mechanisms of host colonization and protection. These studies will reveal important mechanisms of commensal bacteria interactions with animal hosts and should guide the development of improved and tailored probiotics for the treatment of human diseases.
| Rangan, Kavita J; Hang, Howard C (2017) Biochemical Mechanisms of Pathogen Restriction by Intestinal Bacteria. Trends Biochem Sci 42:887-898 |
| Rangan, Kavita J; Pedicord, Virginia A; Wang, Yen-Chih et al. (2016) A secreted bacterial peptidoglycan hydrolase enhances tolerance to enteric pathogens. Science 353:1434-1437 |
| Pedicord, Virginia A; Lockhart, Ainsley A K; Rangan, Kavita J et al. (2016) Exploiting a host-commensal interaction to promote intestinal barrier function and enteric pathogen tolerance. Sci Immunol 1: |
