Gut-Microbial and -Metabolomic Signatures in the Prevention of Non-Alcoholic Fatty Liver Disease by Lactobacillus Lactis and Pediococcus Pentosaceus

Abstract

Background: Despite a recent preventive evidence of Lactobacillus and Pediococcus on non-alcoholic fatty liver disease (NAFLD) progression, the underlying mechanistic is less understood. We explored the causality of L. lactis and P. pentosaceus on the gut-metabolomic modulation in the prevention of NAFLD progression in mouse model and subsequently discovered metabolic biomarkers based on NAFLD patients.Results: Six-week-old male C57BL/6J mice were divided into 4 groups (control, Western diet [WD], and 2 WD with strains [L. lactis and P. pentosaceus]). Given completely reproduced data (liver/body ratio, pathology, and metagenomic profiles), comorbid etiologies including inflammation and diabetes were significantly amended by 2 strains. The comprehensive metabolomic profiles of the mouse cecum revealed unique compositional characteristic according to the groups. L. lactis and P. pentosaceus supplementation restored the dysregulation in short chain fatty acids (SCFAs), bile acids, and tryptophan metabolites. Indole derivatives (indole-3-acetic acid, indole-3-propionic acid, and indole-3-acrylic acid) showed anti-inflammatory activities by suppressing pro-inflammation cytokines. Human data (healthy control [n=30] and NAFLD patients [n=74]) were analyzed for clinical association and biomarker. The Fermicutes/Bacteroidetes ratio of NAFLD (4.3) was significantly higher compared with control (0.6)(p<0.05), accompanied by the dysregulation in the key metabolic signatures identified in mouse model. Metabolic panel with 5 stool metabolites (indole, bile acids, and SCFAs) revealed 0.868 (area under the curve; 95% CI 0.773-0.933) in the diagnosis of NAFLD.Conclusion: L. lactis and P. pentosaceus ameliorate NAFLD by modulating gut metabolic environment, particularly the indole pathway, of the gut-liver axis. NAFLD progression was associated with metabolic deterioration in the SCFAs, bile acid, and indole pathways. ClinicalTrials.gov: NCT04339725