Kyle L Flannigan1, Michael R Taylor2, Sheldon K Pereira3, Jimena Rodriguez-Arguello2, Andrew W Moffat2, Laurie Alston4, Xuemei Wang5, Karen K Poon6, Paul L Beck7, Kevin P Rioux8, Mahesh Jonnalagadda9, Prasanth K Chelikani10, Heather J Galipeau11, Ian A Lewis12, Matthew L Workentine13, Steven C Greenway14, Simon A Hirota15. 1. Department of Physiology and Pharmacology, Cumming School of Medicine; Snyder Institute for Chronic Diseases. Electronic address: Steven.Greenway@albertahealthservices.ca. 2. Department of Paediatrics and Alberta Children's Hospital Research Institute, Cumming School of Medicine. 3. Snyder Institute for Chronic Diseases; Department of Paediatrics and Alberta Children's Hospital Research Institute, Cumming School of Medicine. 4. Department of Physiology and Pharmacology, Cumming School of Medicine; Snyder Institute for Chronic Diseases. 5. Department of Paediatrics and Alberta Children's Hospital Research Institute, Cumming School of Medicine; Department of Cardiac Sciences and the Libin Cardiovascular Institute of Alberta, Cumming School of Medicine. 6. Snyder Institute for Chronic Diseases; Department of Microbiology, Immunology and Infectious Diseases, Cumming School of Medicine. 7. Department of Physiology and Pharmacology, Cumming School of Medicine; Snyder Institute for Chronic Diseases; Division of Gastroenterology and Hepatology, Department of Medicine, University of Calgary, Calgary, Alberta, Canada. 8. Snyder Institute for Chronic Diseases; Department of Microbiology, Immunology and Infectious Diseases, Cumming School of Medicine; Division of Gastroenterology and Hepatology, Department of Medicine, University of Calgary, Calgary, Alberta, Canada. 9. Laboratory of Animal Medical Services, University of Cincinnati, Cincinnati, Ohio, USA. 10. Department of Production, Animal Health, Faculty of Veterinary Medicine, University of Calgary, Calgary, Alberta, Canada. 11. Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada. 12. Department of Biological Sciences. 13. Faculty of Veterinary Medicine. 14. Department of Paediatrics and Alberta Children's Hospital Research Institute, Cumming School of Medicine; Department of Cardiac Sciences and the Libin Cardiovascular Institute of Alberta, Cumming School of Medicine; Department of Biochemistry & Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada. 15. Department of Physiology and Pharmacology, Cumming School of Medicine; Snyder Institute for Chronic Diseases; Department of Microbiology, Immunology and Infectious Diseases, Cumming School of Medicine.
Abstract
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.
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.
Authors: Michael R Taylor; Kyle L Flannigan; Hannah Rahim; Amina Mohamud; Ian A Lewis; Simon A Hirota; Steven C Greenway Journal: Sci Adv Date: 2019-08-07 Impact factor: 14.136
Authors: Melana Yuzefpolskaya; Bruno Bohn; Paolo C Colombo; Ryan T Demmer; Azka Javaid; Giulio M Mondellini; Lorenzo Braghieri; Alberto Pinsino; Duygu Onat; Barbara Cagliostro; Andrea Kim; Koji Takeda; Yoshifumi Naka; Maryjane Farr; Gabriel T Sayer; Nir Uriel; Renu Nandakumar; Sumit Mohan Journal: Circ Heart Fail Date: 2021-06-15 Impact factor: 10.447