Alterations in the intestinal microbiota contribute to the gastrointestinal toxicity of the anti‐rejection drug mycophenolate mofetil

Abstract

Transplantation is curative for end‐stage organ failure but requires potent immunosuppressive medications to prevent rejection including the immunosuppressant mycophenolate mofetil (MMF). While MMF is effective as maintenance therapy, it is commonly associated with gastrointestinal (GI) side effects (e.g. diarrhea, rapid weight loss, colitis) which can necessitate its discontinuation, increasing the chances of graft failure and rejection. While the mechanism(s) contributing to MMF‐related GI toxicity are not understood, we recently reported a clinical case where MMF complications were associated with shifts in the composition of the intestinal microbiota. Thus, in the current study, we hypothesized that the GI toxicity associated with MMF was dependent on the intestinal microbiota. To test this, we fed C57BL/6 mice chow containing MMF and assessed a variety of outcomes. Mice consuming MMF exhibited significant weight loss (>20% after 9 days), which reflected a loss of body fat and lean muscle mass. This was accompanied by marked inflammation of the colon. MMF treatment also promoted changes in gut microbial composition, demonstrated by a loss of overall diversity, expansion of Proteobacteria and loss of beneficial bacterial genera. PICRUSt predicted gene counts identified several components of LPS biosynthesis that were significantly upregulated following MMF treatment. This was associated with an increase in fecal and serum levels of LPS in MMF‐treated mice. Treatment with broad‐spectrum antibiotics prevented and reversed MMFinduced weight loss and colonic inflammation. Importantly, MMF did not induce intestinal toxicity in germ free mice. Our results reveal that MMF triggers GI toxicity by altering the intestinal microbiota and highlights the microbiota as an important driver of the side‐effects associated with immunosuppressive anti‐rejection therapies.Support or Funding InformationAlberta Innovates, Canadian Institutes of Health Research, Canadian Foundation for Innovation, Dr. Lloyd Sutherland Fund in IBD/GI Research, Cumming School of MedicineThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.