The largest microbial biomass in the human body resides in the distal portion of the gastrointestinal (GI) tract, and there is overwhelming evidence that this complex microbial community (or ‘microbiome’) is a critical determinant of gut health and disease. Our research approach to study the microbiome is unique in that it combines a strong basic research component with animal models, and leverages database tools for integrating and mining large collections of data. The result is a ‘one health’ perspective of the microbiome. This is possible due to great collaborations with veterinarians and human clinians.
The microbiome in inflammatory bowel disease (IBD) and remission
Dogs provide a unique model for IBD-microbiome research. Client-owned dogs frequently develop IBD that shares many characteristics with human IBD, including spontaneous onset, relapsing/remitting course of disease, similar symptoms, and responsiveness to some of the same therapies. One really fascinating aspect of IBD in veterinary medicine is that treatment with prescription diets is routine and highly effective at inducing durable remission. Interestingly, diet is also first-line therapy for treating pediatric Crohn’s disease. We use this system to explore diet-microbiome-disease interactions, and recently carried out a canine clinical trial in which we tracked changes in the microbiome in dogs being treated for IBD. Our work in this area led to the identification of key taxa associated with diet-induced remission, which were capable of ameliorating disease in mouse models as well. In the future, we hope to dissect the mechanisms by which commensals can limit inflammation and restrict the growth of pathobionts.
Parasite infections and the microbiome
Infectious diseases are important factors in disrupting otherwise stable microbial communities, and we are interested in understanding the specific causes and consequences of these perturbations during parasite infections. We recently used a combination of animal models and database methods to show that parasites, and Giardia in particular, are potent disruptors of microbiome structure in naturally infected humans and animals. To understand the cause and consequences of parasite-induced microbiome perturbations, we studied intestinal dysbiosis in following infection with Toxoplasma gondii – a natural parasite of mice and humans. Our work in this area showed that immune effector mechanisms that are critical to controlling parasite replication, can also lead to severe disruption of the microbiome. Using a combination of targeted KO mice and in vivo bacterial competition assays, we identified macrophage-derived iNOS as a critical factor that is both required for early control of parasite replication, but which also provides a substrate for anaerobic respiration by facultative anaerobes, particularly E. coli. Many other exciting questions remain to be answered. Do microbiome perturbations contibute to the clinical aspects of these infections? What are the full range of mechanisms by which pathobionts hijack host immunity to thrive in harsh inflammatory environments?
In vitro systems for microbiome research
We are interested in utilizing in vitro systems for testing hypotheses of microbe-microbe and host-microbe interactions that emerge from our animal and database studies. Using the 3D gut epithelial cultures shown in the image at the top of this page, and with support from the Institute of Translational Medicine and Therapeutics’ Program in Comparative Animal Biology (ITMAT-PICAB), we are preparing to work togther with Sara Cherry to study the interaction of attaching/effacing (A/E) bacteria with these gut-like structures using high-throughput screening methods. Our goal is to identify specific cellular responses and gut metabolites that regulate inflammatory signaling triggered by A/E pathogens.