Microbiology & Immunology

The intestinal microbiota is a complex and primarily bacterial ecosystem that lives in a symbiotic relationship with its host. When maintained in a homeostatic relationship with the host, the microbiota carries out numerous critical functions for the host, related to nutrition, metabolism, immune maturation and host protection, and in this context becomes part of the host barrier to infection. The host immune system interacts with the intestinal microbiota, ultimately establishing and maintaining a homeostatic relationship with this vast ecosystem. Disruptions in either the host barrier or the microbial ecosystem can lead to homeostatic collapse and the development of intestinal inflammation in both animal models and in human disease.

Our laboratory is engaged in both basic and translational studies to investigate the innate mucosal immunology of the GI tract, with a focus on host-microbiome interactions and innate barriers to bacterial infection. Antimicrobial peptides (AMPs) are essential components of the host barrier. These are peptides with broad-spectrum antibiotic activity against bacteria, fungi, and viruses, but have been shown to have diverse additional roles both related and unrelated to host defense. Epithelial cells and circulating immune cells endogenously produce these peptides, as do bacteria. One of our primary interests is to understand the multifaceted in vivo roles of intestinal AMPs. Our work has focused primarily on enteric alpha-defensins, produced in Paneth cells localized to the small intestinal crypts. Previous work in our lab demonstrated that Paneth cell defensins have an important role in protecting the mammalian host from enteric bacterial pathogen infection. Recent work from our laboratory has shown that Paneth cell defensins are essential regulators of the composition of the intestinal microbiota, and can modulate mucosal immune responsiveness through their regulation of the microbiota.

Recently, we have translated our findings to the study of Paneth cell antimicrobial peptides (AMPs) in pediatric Crohn’s disease (CD). CD, one of the subtypes of inflammatory bowel diseases manifests with chronic intestinal inflammation and is associated with abnormal bacterial growth at mucosal surfaces (dysbiosis). Several genetic mutations that have been associated with increased risk for the development of CD have also been associated with Paneth cell dysfunction. As part of the Crohn’s and Colitis Foundation of America (CCFA) Microbiome Consortium, we are investigating the relationship between Paneth cell dysfunction and dysbiosis in pediatric CD patients.

A second translational study focuses on the role of the microbiome in the development and progression of pediatric non-alcoholic fatty liver disease (NAFLD). NAFLD is associated with obesity and metabolic syndrome and its prevalence has increased in parallel to the prevalence of obesity and type-2 diabetes. The development of NAFLD, its different phenotypes, and the heterogeneity of disease progression are not completely understood. Recent evidence suggests that there is an association between intestinal microbial colonization (the intestinal microbiome) and obesity in humans and in animal models. In addition, there is evidence of abnormalities of bacterial colonization, and intestinal bacterial product induced inflammation associated with NAFLD and progression to NASH. This study investigates the composition of the intestinal microbiome in pediatric patients with obesity and obesity plus NAFLD, to determine the relationship between alterations in the intestinal microbiome, immune activation, and the development of NAFLD.

We have recently begun to investigate the basic mechanisms of bacterial colonization of the GI tract, using Enterococcus faecalis as a model organism. E. faecalis is a common commensal of the mammalian gut, but also an opportunistic pathogen, which is currently an important cause of infection in hospitalized patients. We have developed a novel system to colonize mice with marked laboratory strains of E. faecalis and are using this system to explore both bacterial-host and bacterial-microbiome interactions in the native mouse GI tract, to understand the important host and bacterial determinants essential for colonization and permissive/protective for systemic infection.