Mycophenolate mofetil (MMF) is an important immunosuppressive drug widely used post- transplantation, but whose use is often limited by gastrointestinal (GI) side effects including diarrhea, weight loss and colitis. The etiology of this GI toxicity has not been fully explained although we have shown in the mouse that an intact microbiome is required. This thesis developed and tested a potential mechanism, hypothesizing that bacterial conversion of the MMF metabolite mycophenolic acid glucuronide (MPAG) to mycophenolic acid (MPA) in the colon is responsible for the GI toxicity caused by MMF. Vancomycin both prevented and reversed MMF- induced GI toxicity and we characterized its effect on the intestinal microbiota in MMF-treated mice. Vancomycin eliminated many β-glucuronidase-producing bacteria, resulting in decreased hydrolysis of MPAG to MPA that was also associated with decreased weight loss and reduced colonic inflammation and injury. These findings outline a mechanism permitting interventions to improve MMF tolerance.