Gut Microbiota and Effect on Immune Suppressants in Transplantation

Myocphenolate mofetil (MMF) and tacrolimus are the main immune suppressants used in over 90% of kidney transplants (tx). Several studies have shown an association between low mycophenolic acid (MPA, active metabolite of MMF) exposure as measured by 12-hour area-under-the-curve (AUC) and acute allograft rejection. However, significant inter-individual variation in the pharmacokinetics (PK) of MMF exists with as much as a 10-fold variation in AUC with the same dose. Elevated MPA concentrations have been associated in some studies with toxicities such as diarrhea, leukopenia and anemia. PK studies show a second peak of MPA 6-8 hours after oral MMF from enterohepatic recycling (EHR) of MPA due to biliary excretion of its phenolic glucuronide (MPAG, major inactive metabolite of MPA). EHR occurs by hydrolysis of the glucuronide by ?-glucuronidases produced by gut bacteria and reabsorption of MPA. Extensive EHR greatly increases systemic exposure to MPA and likely enhances immunosuppression and toxicity. ?-glucuronidases are produced by the gut microbes Streptococcus agalactiae, Clostridium perfringens, and E. coli and are known to influence drug substrates and potentially the extent of EHR. In a pilot study of stool from tx patients, Bacteroides, Ruminococcus, Coprococcus, and Dorea were significantly lower in tx patients with diarrhea. The specific hypothesis is that certain patterns of stool microbiota lead to increased EHR, greater MPA systemic exposure and toxicities.