An intact microbiota is required for the gastrointestinal toxicity of the immunosuppressant mycophenolate mofetil. Flannigan Kyle L,Taylor Michael R,Pereira Sheldon K,Rodriguez-Arguello Jimena,Moffat Andrew W,Alston Laurie,Wang Xuemei,Poon Karen K,Beck Paul L,Rioux Kevin P,Jonnalagadda Mahesh,Chelikani Prasanth K,Galipeau Heather J,Lewis Ian A,Workentine Matthew L,Greenway Steven C,Hirota Simon A The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation BACKGROUND:Mycophenolate mofetil (MMF) is commonly prescribed after transplantation and has major advantages over other immunosuppressive drugs, but frequent gastrointestinal (GI) side-effects limit its use. The mechanism(s) underlying MMF-related GI toxicity have yet to be elucidated. METHODS:To investigate MMF-related GI toxicity, experimental mice were fed chow containing MMF (0.563%) and multiple indices of toxicity, including weight loss and colonic inflammation, were measured. Changes in intestinal microbial composition were detected using 16S rRNA Illumina sequencing, and downstream PICRUSt analysis was used to predict metagenomic pathways involved. Germ-free (GF) mice and mice treated with orally administered broad-spectrum antibiotics (ABX) were utilized to interrogate the importance of the microbiota in MMF-induced GI toxicity. RESULTS:Mice treated with MMF exhibited significant weight loss, related to loss of body fat and muscle, and marked colonic inflammation. MMF exposure was associated with changes in gut microbial composition, as demonstrated by a loss of overall diversity, expansion of Proteobacteria (specifically Escherichia/Shigella), and enrichment of genes involved in lipopolysaccharide (LPS) biosynthesis, which paralleled increased levels of LPS in the feces and serum. MMF-related GI toxicity was dependent on the intestinal microbiota, as MMF did not induce weight loss or colonic inflammation in GF mice. Furthermore, ABX prevented and reversed MMF-induced weight loss and colonic inflammation. CONCLUSIONS:An intact intestinal microbiota is required to initiate and sustain the GI toxicity of MMF. MMF treatment causes dynamic changes in the composition of the intestinal microbiota that may be a targetable driver of the GI side-effects of MMF. 10.1016/j.healun.2018.05.002

Vancomycin relieves mycophenolate mofetil-induced gastrointestinal toxicity by eliminating gut bacterial β-glucuronidase activity. Taylor Michael R,Flannigan Kyle L,Rahim Hannah,Mohamud Amina,Lewis Ian A,Hirota Simon A,Greenway Steven C Science advances Mycophenolate mofetil (MMF) is commonly prescribed and has proven advantages over other immunosuppressive drugs. However, frequent gastrointestinal side effects through an unknown mechanism limit its use. We have found that consumption of MMF alters the composition of the gut microbiota, selecting for bacteria expressing the enzyme β-glucuronidase (GUS) and leading to an up-regulation of GUS activity in the gut of mice and symptomatic humans. In the mouse, vancomycin eliminated GUS-expressing bacteria and prevented MMF-induced weight loss and colonic inflammation. Our work provides a mechanism for the toxicity associated with MMF and a future direction for the development of therapeutics. 10.1126/sciadv.aax2358