Alterations in the Gut Microbiome in Liver Recipients with Post-Transplant Diabetes Mellitus

Abstract

Post-transplant diabetes mellitus (PTDM) increases the risk of graft failure and death in liver transplant (LT) recipients. Experimental studies have indicated that enteric dysbiosis mediated by immunosuppressive tacrolimus (TAC) could contribute to glucose disorders, but no data on human recipients with PTDM have been reported. Here, by combining high-throughput shotgun metagenomics sequencing and metabolomics profiling, we characterized the intestinal microbiome (IM) in LT recipient cohort with or without PTDM and deciphered the potential relationship among IM, TAC dosage, and diabetes. By comparing with both non-PTDM and classical type 2 diabetes mellitus (T2DM), we identified microbial signatures of PTDM, which was characterized by the enriched Proteobacteria and decreased Bacteroidetes. Additionally, the altered microbes, as well as the microbial metabolomics, correlated with the dosage of TAC. Specifically, the levels of beneficial microbes associated with PTDM were lowered in recipients with the high TAC trough concentrations (> 5 ng∙mL–1) than those with low ones (< 5 ng∙mL–1), which was accompanied by reduced faecal metabolites involved in the biosynthesis of α-linolenic acid and arachidonic acid-lowering factors of developing T2DM. Moreover, these microbial signatures linked with the extent of glucose disorders in LT recipients. In summary, the faecal microbiome and metabolome differed between PTDM and non-PTDM patients, which were linked with TAC dosage. This study was the first to explore taxonomic alterations and bacterial gene functions to better understand the contribution of the IM to PTDM.

Keywords

• Post-transplant diabetes mellitus
• Tacrolimus
• Metagenomics
• Metabolomics