Gut Dysbiosis and Cardiac Remodeling in IBD

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PROJECT SUMMARY/ABSTRACT Inflammatory bowel disease (IBD) is a debilitating and difficult to manage chronic inflammation in the digestive tract, causing gastrointestinal symptoms such as diarrhea. It is associated with lifelong morbidity, greater medical attention, and diminished quality of life. About 3 million Americans suffer from IBD and its huge financial burden. Extraintestinal manifestations (EIM) of IBD are common, especially in children, and even overshadow the intestinal symptoms. Accumulating evidence suggests that IBD is associated with an increased incidence of cardiovascular events. However, the molecular mechanisms by which IBD predisposes patients to cardiovascular diseases (CVD) remain elusive. In addition to chronic inflammation, a signature of IBD is dysbiosis of the gut microbiota marked by a significant reduction of obligate anaerobes and a sharp increase in facultative anaerobes. While inflammation could be well controlled by drug therapy or surgery, gut microbial dysbiosis persists and may play a key role in IBD-associated CVD. We confirmed this phenomenon in murine models of colitis, which recapitulate some common EIM of human IBD. Our preliminary findings suggest that dysbiotic gut microbiota contributes to cardiac dysfunction by up-regulating miR-155 and down-regulating brain- derived neurotrophic factor (BDNF), both identified as crucial players in cardiac system. We hypothesize that colitis-induced microbiota dysbiosis triggers molecular remodeling in the adult heart through epigenetic mechanisms. We will test the hypothesis by pursuing three specific aims. Aim 1 will establish dysbiosis as a key player in colitis-induced heart dysfunction by transplanting dysbiotic fecal microbiota from patients with IBD and mice with colitis to bacteria-depleted mice. We will also determine whether the disease signal can be ablated by transplantation of normal fecal microbiota and/or probiotics. Aim 2 will focus on characterizing exosomal miR- 155 as a key player in IBD-induced molecular remodeling. We foresee that exosomal miR-155 derived specifically from the intestinal epithelial cells (IEC) functions as a major mediator of the crosstalk between gut microbiota and the heart. Using novel IEC-specific miR-155-knockout (Mir155ΔIEC) and Mir155ΔIEC/IL10-/- mice, we aim to show that exosomal miR-155 of gut origin epigenetically down-regulates cardiac BDNF in the presence of chronic colitis. We will also determine if miR-155 inhibitors mitigate IBD-induced heart diseases. In Aim 3, epigenetic mechanisms of BDNF reduction in cardiomyocytes will be elucidated using in vivo, in vitro, and proteomics approaches. We will characterize the functional and phenotypic roles of BDNF in the adult heart using a novel tamoxifen-inducible, cardiac-specific BDNF knockout mouse model. We will also explore the preventive and therapeutic potential of BDNF for IBD-associated CVD. Our results should help establish a novel paradigm that colitis induces cardiac remodeling through microbiota dysbiosis→exosomal miR-155→BDNF signaling axis, resulting in heart dysfunction.