Effects of tacrolimus treatment on the gut microbiota and metabolites in liver transplant recipients.

Increasing duration of tacrolimus use was associated with increased gut microbiota diversity and altered bacterial abundance.

• The study included 36 patients who received tacrolimus treatment after liver transplantation.
• As the duration of tacrolimus use increased, the diversity of the gut microbiota also increased.
• The abundance of Escherichia coli_D and Bacteroides stercoris rose with longer treatment duration.
• Patients were stratified into subgroups according to tacrolimus treatment duration, whole-blood tacrolimus concentration, and tacrolimus concentration-to-dose (C/D) ratio.
• Gut metagenome was detected using the Illumina HiSeq X platform.

Longer tacrolimus treatment duration was associated with decreased abundance of specific bacteriophage genera and reduced gene functions related to chemical carcinogenesis and bacterial invasion.

• The abundance of Brunovirus and Uetakevirus tended to decrease with longer tacrolimus treatment duration.
• The abundance of gene functions related to chemical carcinogenesis and bacterial invasion of epithelial cells significantly decreased with longer treatment duration.
• Fecal samples and whole-blood specimens were collected from all 36 participants for analysis.

Tacrolimus treatment duration was associated with significant changes in gut microbiota metabolites, with 16 substances increasing and 108 substances decreasing.

• 16 substances including Astragaloside A and Acetyl-L-carnitine significantly increased with longer tacrolimus use.
• 108 substances including Capsaicin and TLK significantly decreased with longer tacrolimus use.
• Metabolites were detected using liquid chromatography-tandem mass spectrometry (LC-MS/MS) technology.

Within a certain range, increasing whole-blood tacrolimus concentration was associated with increased gut microbiota diversity and altered microbial abundance, but excessively high concentrations had the opposite effect.

• Within a certain range, as the concentration of tacrolimus in whole blood increased, the diversity of the gut microbiota increased.
• The abundance of Phocaeicola and Klebsiella increased with higher tacrolimus concentrations within a certain range.
• The abundance of Peduovirus among viruses also rose with increasing tacrolimus concentration within range.
• Excessively high concentrations may lead to a decrease in the diversity of the gut microbiota and a decrease in the abundance of Phocaeicola.

Higher tacrolimus concentration-to-dose (C/D) ratio was associated with significant changes in fecal metabolite levels.

• Increased C/D ratios were linked to significantly higher levels of 57 fecal metabolites, including PC 34:2 and 5-Methyl-2'-deoxycytidine.
• 13 metabolites, including FAHFA 2:0/16:0, showed substantial declines with increased C/D ratio.
• The C/D ratio was used as one of three key stratification variables alongside treatment duration and whole-blood concentration.