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.

非酒精性脂肪性肝炎（nonalcoholic steatohepatitis, NASH）的患病率正以惊人速度攀升，目前尚无获批的药物治疗方案。开发NASH治疗药物的核心障碍之一，是临床前研究向临床试验的转化可行性不足，近期的研发失败更凸显了识别全新可靶向通路的迫切需求。甘氨酸代谢失调已被证实为NASH的致病因素与治疗靶点，我们团队鉴定出DT-109——一种三肽（Gly-Gly-Leu，甘氨酸-甘氨酸-亮氨酸），其可在小鼠模型中以剂量依赖的方式减轻脂肪性肝炎并缓解纤维化。我们构建了在组织学与转录组学层面模拟人类NASH的非人灵长类动物模型，用于评估DT-109的药效。通过整合转录组学、蛋白质组学、代谢组学与宏基因组学的多组学分析方法，研究发现DT-109可逆转非人灵长类的肝脂肪变性并阻断纤维化进展：其不仅如在小鼠模型中观察到的那样，可促进脂肪酸降解与谷胱甘肽合成，还能调控微生物胆汁酸代谢。因此，DT-109在NASH治疗中的应用潜力值得开展临床评估。