ESPN 53rd Annual Meeting

ESPN 2021


 
Identifying interpersonal differences in gut microbiota metabolism of transplantation and chronic kidney disease drugs
MARAL BAGHAI ARASSI 1 NICOLAI KARCHER 2 BURKHARD TOENSHOFF 1 GEORG ZELLER 2 MICHAEL ZIMMERMANN 2

1- DEPARTMENT OF PAEDIATRICS I, UNIVERSITY CHILDRENS HOSPITAL HEIDELBERG, HEIDELBERG, GERMANY
2- STRUCTURAL AND COMPUTATIONAL BIOLOGY UNIT, EUROPEAN MOLECULAR BIOLOGY LABORATORY, HEIDELBERG, GERMANY
 
Introduction:

The outcome of kidney transplantation (KTx) and chronic kidney disease (CKD) depends on multiple therapeutic factors. We investigated how interpersonal differences in gut microbiome composition may impact interpersonal variability in drug metabolism and the activation of prodrugs. We specifically focused on immunosuppressants, including tacrolimus and mycophenolate mofetil, which are challenging to dose due to their narrow therapeutic index and large interpersonal variability in drug response. 

Material and methods:

We constructed an in vitro system mimicking the intestinal environment and tested 10 human bacterial communities for the metabolism of 27 drugs, comprising four different classes of immunosuppressants and relevant non-immunosuppressive drugs. To link the metabolic activity of complex microbial communities to their composition, we additionally screened our drug panel against 44 highly abundant and prevalent gut bacterial strains. 

Results:

Our analysis revealed donor and compound-specific differences in bacterial drug metabolism. While more than 75% of the immunosuppressants were metabolized by at least one bacterial community, less than 30% of the non-immunosuppressive drugs were metabolized. Strikingly, bacterial communities differed in compound spectrum and velocity of drug metabolism, indicating pronounced donor-specific differences. Further, we observed marked differences in metabolism between individual bacterial species and strains. Over 90% of the drug community metabolism was reproduced with single species, indicating a causal link between microbiome composition and metabolic activity. 

Conclusions:

We identified large interpersonal variability in gut bacterial metabolism of common immunosuppressive and non-immunosuppressive drugs used in KTx and CKD. Donor and drug-specific differences were particularly pronounced for immunosuppressants. Given the challenges associated with the dosage of immunosuppressants, we suggest that further studies should focus on how bacterial metabolism impacts immunosuppressive drug response in kidney disease patients. This may open new opportunities to establish microbial biomarkers for personalised drug selection and dosing.