IGI Seminar Series: Gut microbial adaptations to diverse selection pressures in Crohn’s Disease

Summary

Crohn’s disease (CD) is a complex, relapsing and remitting disease of unclear etiology. Multiple “hits” are required to trigger disease onset including some combination of host genetics, immune reactivity, diet/environment, and gut microbiome structure and function. CD can also mysteriously manifest extra-intestinally as chronic joint inflammation, skin lesions, and uncontrolled mesenteric adipose growth called “creeping fat”, the latter of which our lab has particular interest due to its strong association with fibrotic complications. Here we discovered a consistently translocating gut bacterium, Clostridium innocuum, in the mesenteric adipose exclusively in CD patients with fibrosis, and not ulcerative colitis or healthy tissue controls. Comparative analysis of 36 hybrid assembled C. innocuum genomes recovered from our CD patients and over 100 publicly available genomes reveal a strain variation, reflecting likely adaptations to a specific host niche and local selection pressures that may be unique to CD. Taking a multi-omic and experimental approach integrating sequencing, single-cell and spatial approaches in human tissue, ex-vivo tissue models, and gnotobiotic mice, our findings suggest translocation may precede the development of creeping fat and fibrosis and serve as a potential disease-modulating target.
 

Speaker

Suzanne Devkota, PhD, is an Associate Professor in the Cedars-Sinai Division of Gastroenterology and Director of the Cedars Human microbiome Research Institute. Her lab studies the role of the gut microbiome in inflammatory and metabolic diseases originating in the GI tract. Her research into dietary impacts on host-microbe interactions has led to some of the first mechanistic insights into why diseases such as IBD, diabetes, and food allergies have rapidly increased over the last 50-100 years. Her ongoing research focuses on the role of pathobionts- symbiotic microbes that turn pathogenic under certain selective pressures- on host immune responses, and counteractive nutritional therapies. More recently her lab has been studying the microbial ecology of gut bacterial translocation in the human body, and the host response, particularly of adipose tissue. Devkota teams with Cedars-Sinai physicians to combine clinical and basic research utilizing patient samples, in vivo conventional and gnotobiotic animal models, and sequencing- and culture-based microbial methodologies to investigate the molecular mechanisms underlying clinical phenomena. Her goal is to add a powerful new dimension to diagnosis and treatment through a better understanding of gut microbial contributions to disease.