Identification of Gut Microbial Lysine and Histidine Degradation and CYP-Dependent Metabolites as Biomarkers of Fatty Liver Disease

Abstract

Numerous studies have described specific metabolites as biomarkers of severe liver diseases, but very few have measured gut microbiota (GM)-produced metabolites in fatty liver disease. We aimed at finding GM signatures and metabolite markers in plasma and feces related to high liver fat content. Based on imaging, we divided study participants into low (<5%, LF, n = 25) and high (>5%, HF, n = 39) liver fat groups. Fecal (LF n = 14, HF n = 25) and plasma (LF n = 11, HF n = 7) metabolomes of subsets of participants were studied using liquid chromatography/high resolution mass spectrometry. The GM were analyzed using 16S rRNA gene sequencing. Additionally, blood clinical variables and diet were studied. Dyslipidemia, higher liver enzymes and insulin resistance characterized the HF group. No major differences in diet were found between the groups. In the GM, the HF group had lower abundance of Bacteroides and Prevotellaceae NK3B31 group than the LF group after adjusting for metformin use or obesity. In feces, the HF group had higher levels of lysine and histidine degradation products, while 6-hydroxybetatestosterone (metabolized by CYP3A4) was low. Higher plasma levels of caffeine and its metabolites in the HF group indicate that the activity of hepatic CYP1A2 was lower than in the LF group. Our results suggest, that low fecal Prevotellaceae NK3B31 and Bacteroides abundance, and increased lysine and histidine degradation may serve as GM biomarkers of high liver fat. Altered plasma caffeine metabolites and lowered testosterone metabolism may specify decreased CYP activities, and their potential utility, as biomarkers of fatty liver disease.