Inflammatory Bowel Diseases
The inflammatory bowel diseases (IBD) - comprised of Crohn's disease and ulcerative colitis - are chronic inflammatory diseases with growing prevalence in the Western world. It is believed to arise from a combination of genetic susceptibility and environmental factors that trigger an inappropriate mucosal inflammatory response. A role for the microbiome in the pathogenesis of IBD has been suggested by studies demonstrating alterations in the composition and function of the intestinal microbiome in IBD patients compared to healthy controls. This is consistent with the results of genome-wide association studies, which have found that many IBD-associated genes are involved in mucosal host-microbe interactions, and animal studies demonstrating resistance to colitis in many experimental models in the absence of a microbiome.
The Jacobs Laboratory is investigating the role of dysbiosis - i.e. altered composition and function of the intestinal microbiome - in the development of IBD. Ongoing research projects include:
- Pre-disease microbiome changes in those at risk for IBD: Dr. Jacobs has shown that healthy siblings and children of IBD patients can have a gut microbiome profile resembling that seen in IBD. This dysbiosis was associated with alterations in bioactive intestinal metabolites that affect immune activity and epithelial function. He is now investigating the use of microbial biomarkers to predict future risk for IBD in a long-term study of families with a history of IBD. His lab is also performing experiments using germ-free mice colonized with human microbiota to determine whether dysbiosis in healthy relatives of IBD patients confers increased susceptibility to experimental IBD. This research offers the prospect of preventing IBD by identifying those at risk and changing their microbiome before IBD develops.
- Characterization of genes that promote IBD by altering the intestinal microbiome: Dysbiosis in individuals at risk for IBD may arise due to genetic variants that disrupt regulation of the microbiome by the mucosal immune system. This possibility is being studied with a combination of human studies to identify genetic variants associated with microbial composition and knockout/transgenic mice to validate a causal relationship between candidate IBD-associated genes and microbial composition. The Jacobs Laboratory is currently focusing on three genes implicated in IBD to determine whether they regulate the intestinal microbiome and, if so, whether these changes in the microbiome affect IBD susceptibility.
- Prediction of IBD disease course with microbial biomarkers: The Jacobs Laboratory is performing microbiome analysis of intestinal samples biobanked from IBD patients undergoing colonoscopy five or more years ago who have continued to receive care through UCLA. These data are being used to identify novel biomarkers for future disease progression - including need for surgery and loss of response to medications - which could provide valuable prognostic information for IBD physicians.
- The microbiome-gut-brain axis in stress-induced IBD flares: The Jacobs Laboratory is collaborating with Dr. Jenny Sauk in the UCLA IBD Center and Dr. Emeran Mayer in the UCLA Oppenheimer Center for Neurobiology of Stress and Resilience to identify markers of vulnerability to stress-induced IBD flares. This study uses a unique combination of longitudinal clinical monitoring, psychological measurements, brain imaging, blood/saliva tests, and gut microbiome analysis to define brain-gut pathways involved in IBD flares. This research could serve as the foundation to develop novel strategies to prevent flares and improve quality of life for IBD patients.
- Effect of air pollution on the intestinal microbiome and IBD risk: Dr. Jacobs and his collaborators have found that exposure to a type of air pollution, ultrafine particles, alters the gut microbiome and incites intestinal inflammation. In ongoing experiments, the Jacobs Laboratory is investigating how chronic inhalation of ultrafine particles promotes IBD in animal models through the microbiome. This research will provide insight into why the incidence of IBD has been rapidly rising in industrializing nations around the world.