Pharmacomicrobiomics: Immunosuppressive Drugs and Microbiome Interactions in Transplantation

Abstract

The human microbiome is associated with human health and disease. Exogenous compounds, including pharmaceutical products, are also known to be affected by the microbiome, and this discovery has led to the field of pharmacomicobiomics. The microbiome can also alter drug pharmacokinetics and pharmacodynamics, possibly resulting in side effects, toxicities, and unanticipated disease response. Microbiome-mediated effects are referred to as drug-microbiome interactions (DMI). Rapid advances in the field of pharmacomicrobiomics have been driven by the availability of efficient bacterial genome sequencing methods and new computational and bioinformatics tools. The success of fecal microbiota transplantation for recurrent Clostridioides difficile has fueled enthusiasm and research in the field. This review focuses on the pharmacomicrobiome in transplantation. Alterations in the microbiome in transplant recipients are well documented, largely because of prophylactic antibiotic use, and the potential for DMI is high. There is evidence that the gut microbiome may alter the pharmacokinetic disposition of tacrolimus and result in microbiome-specific tacrolimus metabolites. The gut microbiome also impacts the enterohepatic recirculation of mycophenolate, resulting in substantial changes in pharmacokinetic disposition and systemic exposure. The mechanisms of these DMI and the specific bacteria or communities of bacteria are under investigation. There are little or no human DMI data for cyclosporine A, corticosteroids, and sirolimus. The available evidence in transplantation is limited and driven by small studies of heterogeneous designs. Larger clinical studies are needed, but the potential for future clinical application of the pharmacomicrobiome in avoiding poor outcomes is high.

Figure 1.. Tacrolimus sites of metabolism by human enzymes and bacteria.

① Oral TAC in the intestinal lumen is absorbed into the enterocytes where it is metabolized by intestinal CYP3A4/5 enzymes forming several TAC human metabolites including 13-O-desmethyl-TAC (DMT), 15-DMT and 31-DMT metabolites. ② In the intestinal lumen, TAC is also metabolized by gut microbiota which form a bacterial specific C-9 keto reduction and possibly other TAC metabolites. ③ TAC metabolites and remaining parent TAC enters the liver through the portal circulation where it enters the hepatocytes to be metabolized by hepatic CYP3A4/5 enzymes to human TAC metabolites including 13-DMT, 15-DMT and 31-DMT metabolites and their glucuronides. Created with BioRender.com.

Figure 2.. Mycophenolate mofetil metabolism and enterohepatic recirculation.

① Mycophenolate mofetil (MMF) is hydrolyzed to the active moiety, mycophenolic acid (MPA) by carboxylesterase (CES) enzymes in the intestine. ② MPA is absorbed into the enterocytes where it enters the portal vein and travels to the liver. ③ In the liver, MPA undergoes glucuronidation by UDP-glucuronosyltransferases (UGTs) producing mycophenolic acid glucuronide (MPAG, major inactive metabolite) and acylMPAG (minor active metabolite). ④ A portion of the MPAG is excreted into the bile via the MRP2 transporter where it is stored in the gallbladder while the majority is renally eliminated. ⑤ Upon gallbladder contraction, MPAG is transferred to the small intestine where it undergoes deglucuronidation ⑥ by microbiome-produced β-glucuronidase enzymes. MPA is reformed and reabsorbed to the circulation in a process referred to as enterohepatic recirculation (EHR). Created with BioRender.com.