Vancomycin relieves tacrolimus-induced hyperglycemia by eliminating gut bacterial beta-glucuronidase enzyme activity

ABSTRACT

Up to 40% of transplant recipients treated long-term with tacrolimus (TAC) develop post-transplant diabetes mellitus (PTDM). TAC is an important risk factor for PTDM, but is also essential for immunosuppression after transplantation. Long-term TAC treatment alters the gut microbiome, but the mechanisms of TAC-induced gut microbiota in the pathogenesis of PTDM are poorly characterized. Here, we showed that vancomycin, an inhibitor of bacterial beta-glucuronidase (GUS), prevents TAC-induced glucose disorder and insulin resistance in mice. Metagenomics shows that GUS-producing bacteria are predominant and flourish in the TAC-induced hyperglycemia mouse model, with upregulation of intestinal GUS activity. Targeted metabolomics analysis revealed that in the presence of high GUS activity, the hydrolysis of bile acid (BAs)-glucuronic conjugates is increased and most BAs are overproduced in the serum and liver, which, in turn, activates the ileal farnesoid X receptor (FXR) and suppresses GLP-1 secretion by L-cells. The GUS inhibitor vancomycin significantly eliminated GUS-producing bacteria and inhibited bacterial GUS activity and BAs levels, thereby enhancing L-cell GLP-1 secretion and preventing hyperglycemia. Our results propose a novel clinical strategy for inhibiting the bacterial GUS enzyme to prevent hyperglycemia without requiring withdrawal of TAC treatment. This strategy exerted its effect through the ileal bile acid-FXR-GLP-1 pathway.

KEYWORDS:

• Post-transplant diabetes mellitus
• tacrolimus
• beta-glucuronidase
• gut microbiota
• bile acids

Disclosure statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as potential conflicts of interest.

Author contributions

Shaojun Shi, and Yani Liu conceptualized the study and designed the research. Peixia Li and Rui Zhang organized all in vivo and in vitro studies and critically discussed of the results. Peixia Li and Rui Zhang performed the experiments and the overall analysis. Jingping Zhou and Pengpeng Guo contributed to the animal experiments. Peixia Li and Shaojun Shi wrote and revised the manuscript with the input of other coauthors.

Data availability statement

The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.

Materials & correspondence

Correspondence and requests for materials should be addressed to Yani Liu or Shaojun Shi.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/19490976.2024.2310277

Additional information

Funding

This study was supported by the National Natural Science Foundation of China (82173902, 82104274 and 81874326); General project of Wuhan Health Research Fund (WX21D55); Project of Beijing Medical Award Foundation (YXJL-2018-0095-00685).