An intact microbiota is required for the gastrointestinal toxicity of the immunosuppressant mycophenolate mofetil
| Autor: | Michael R. Taylor, Laurie Alston, Xuemei Wang, Jimena Rodriguez-Arguello, Heather J. Galipeau, Karen K. Poon, Steven C. Greenway, Mahesh Jonnalagadda, Matthew L. Workentine, Paul L. Beck, Kyle L. Flannigan, Andrew Moffat, Kevin P. Rioux, Prasanth K. Chelikani, Sheldon K. Pereira, Simon A. Hirota, Ian A. Lewis |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Pulmonary and Respiratory Medicine Male Lipopolysaccharide medicine.drug_class Colon medicine.medical_treatment Antibiotics Inflammation Mice Inbred Strains Pharmacology Mycophenolate 03 medical and health sciences chemistry.chemical_compound Mice 0302 clinical medicine Weight loss RNA Ribosomal 16S Proteobacteria Weight Loss medicine Animals Germ-Free Life Humans Transplantation business.industry Sequence Analysis RNA Microbiota High-Throughput Nucleotide Sequencing Immunosuppression Mycophenolic Acid Gastrointestinal Tract Disease Models Animal 030104 developmental biology chemistry Toxicity 030211 gastroenterology & hepatology Surgery medicine.symptom Cardiology and Cardiovascular Medicine business Immunosuppressive Agents |
| Zdroj: | The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation. 37(9) |
| ISSN: | 1557-3117 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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