Project Grant R41DK138693

AIM PROTEIN-BASED ANTI-INFLAMMATORY THERAPEUTIC FOR THE TREATMENT OF IBD - INFLAMMATORY BOWEL DISEASE (IBD), WHICH IS SUBDIVIDED INTO ULCERATIVE COLITIS (UC) AND CROHN'S DISEASE (CD), CONSTITUTES A PREVALENT AND GROWING CLINICAL HEALTH PROBLEM WORLDWIDE. THESE DISEASES ARE CHARACTERIZED BY DEBILITATING SYMPTOMS INCLUDING DIARRHEA, ABDOMINAL PAIN, AND FATIGUE, AND INCREASED RISK OF GASTROINTESTINAL CANCERS. IN ADDITION, IBD PATIENTS HAVE PERTURBED INTESTINAL MICROBIOMES, REFERRED TO AS DYSBIOSIS. THE ETIOLOGY OF IBD INVOLVES COMPLICATED INTERACTIONS BETWEEN IMMUNOLOGICAL GENETIC VARIANTS, ENVIRONMENTAL FACTORS, AND THE INTESTINAL MICROBIOME. CURRENT THERAPIES FOR IBD INCLUDE CORTICOSTEROIDS AND BIOLOGICS, WHICH CAN AMELIORATE OVERPRODUCTION OF PRO-INFLAMMATORY CYTOKINES, AND OTHER INFLAMMATORY MEDIATORS, BUT WHICH DO NOT TREAT THE MICROBIOME DYSBIOSIS THAT OFTEN TRIGGERS OR PROPAGATES INFLAMMATION. IN ADDITION, LONG TERM USE OF CORTICOSTEROIDS AND BIOLOGICS HAS SERIOUS SIDE EFFECTS, INCLUDING OSTEOPOROSIS, PEPTIC ULCERS, PANCREATITIS, AND IMPAIRED WOUND HEALING. THEREFORE, AN URGENT NEED EXISTS FOR MORE EFFECTIVE THERAPIES FOR IBD THAT TREAT BOTH INFLAMMATION AND MICROBIOME DYSBIOSIS. A FEATURE OF THE IBD SUBTYPE UC IS THE ACCUMULATION OF HIGH LEVELS OF NEUTROPHILS IN INFLAMED COLONIC TISSUES AND AN EXCESSIVE NEUTROPHILIC RESPONSE TO RESIDENT COLONIC MICROBES. OUR RESEARCH TEAM AT THE UNIVERSITY OF OREGON, LED BY THE FOUNDERS OF KEYBIOME, HAS IDENTIFIED A NOVEL ANTI-INFLAMMATORY PROTEIN SECRETED BY A ZEBRAFISH GUT SYMBIONT, AEROMONAS, WHICH WE NAMED AEROMONAS IMMUNE MODULATOR (AIMA). WE HAVE SHOWN THAT AIMA HAS POTENT ANTI-INFLAMMATORY PROPERTIES, INDICATED BY A REDUCTION IN INTESTINAL NEUTROPHILS. MOREOVER, WE HAVE EVIDENCE THAT AIMA HAS MICROBIOME- MODULATING ACTIVITIES THAT INCLUDE GROWTH INHIBITION OF PRO-INFLAMMATORY BACTERIAL SPECIES. THEREFORE, AIMA PRESENTS AN OPPORTUNITY TO DEVELOP A THERAPEUTIC FOR IBD, UNIQUE IN ITS ABILITY TO BOTH TARGET A PRIMARY MEDIATOR OF INFLAMMATION, NEUTROPHILS, AND FACILITATE RESTORATION OF MICROBIOME DYSBIOSIS. IN THIS PROJECT WE WILL ESTABLISH PROOF OF CONCEPT DATA FOR AIMA'S THERAPEUTIC EFFICACY AND MICROBIOME-MODULATING ACTIVITY IN A MOUSE MODEL OF IBD. THIS WILL MOTIVATE FUTURE DEVELOPMENT OF AIMA INTO A NOVEL HUMAN THERAPEUTIC TO OFFER PATIENTS SUFFERING FROM IBD A MORE EFFECTIVE AND SAFER ALTERNATIVE TO CURRENT THERAPIES.