Modulation of Microbial Bile Acid Metabolism by DT-109 Ameliorates Nonalcoholic Steatohepatitis in Nonhuman Primates
The prevalence of nonalcoholic steatohepatitis (NASH) is rising at an alarming rate with no pharmacotherapy approved. A major hurdle in developing drugs for NASH is the poor translatability of preclinical studies to clinical trials, and recent failures highlight a need to identify new targetable pathways. Dysregulated glycine metabolism has emerged as a causative factor and therapeutic target in NASH, and we identified DT-109, a tripeptide (Gly-Gly-Leu), that lowers steatohepatitis and fibrosis in a dose-response manner in mice. We developed a nonhuman primate model that histologically and transcriptionally mimics human NASH to study DT-109’s efficacy. A multi-omics approach combining transcriptomics, proteomics, metabolomics, and metagenomics revealed that DT-109 reverses hepatic steatosis and prevents fibrosis progression in monkeys, not only by stimulating fatty acid degradation and glutathione formation, as found in mice, but also by modulating microbial bile acid metabolism. Thus, the therapeutic potential of DT-109 in NASH warrants clinical evaluation.