Richards-Corke Khyle C, Jiang Yindi, Yeliseyev Vladimir, Zhang Yancong, Franzosa Eric A, Wang Zhipeng A, Yapa Abeywardana Maheeshi, Cole Phillip A, Huttenhower Curtis, Bry Lynn, Balskus Emily P
Harvard University, Department of Chemistry and Chemical Biology, Cambridge, Massachusetts 02138, United States.
Brigham and Women's Hospital, Massachusetts Host-Microbiome Center, Department of Pathology, Boston, Massachusetts 02115, United States.
ACS Chem Biol. 2025 Jan 17;20(1):48-55. doi: 10.1021/acschembio.3c00556. Epub 2025 Jan 8.
Hyperammonemia is characterized by the accumulation of ammonia within the bloodstream upon liver injury. Left untreated, hyperammonemia contributes to conditions such as hepatic encephalopathy that have high rates of patient morbidity and mortality. Previous studies have identified gut bacterial urease, an enzyme that converts urea into ammonia, as a major contributor to systemic ammonia levels. Here, we demonstrate use of benurestat, a clinical candidate used against ureolytic organisms in encrusted uropathy, to inhibit urease activity in gut bacteria. Benurestat inhibits ammonia production by urease-encoding gut bacteria and is effective against individual microbes and complex gut microbiota. When administered to conventional mice with liver injury induced by thioacetamide exposure, benurestat reduced gut and serum ammonia levels and rescued 100% of mice from lethal acute liver injury. Overall, this study provides an important proof-of-concept for modulating host ammonia levels and microbiota-driven risks for hyperammonemia with gut microbiota-targeted small-molecule inhibitors.
高氨血症的特征是肝脏损伤时血液中氨的积累。若不加以治疗，高氨血症会导致诸如肝性脑病等疾病，这些疾病的患者发病率和死亡率都很高。先前的研究已确定肠道细菌脲酶（一种将尿素转化为氨的酶）是全身氨水平的主要促成因素。在此，我们展示了贝奴司他（一种用于治疗结痂性尿路感染中尿素分解菌的临床候选药物）可抑制肠道细菌中的脲酶活性。贝奴司他可抑制编码脲酶的肠道细菌产生氨，并且对单个微生物和复杂的肠道微生物群均有效。当给予硫代乙酰胺暴露诱导肝损伤的常规小鼠时，贝奴司他可降低肠道和血清中的氨水平，并使100%的小鼠免于致命的急性肝损伤。总体而言，本研究为用靶向肠道微生物群的小分子抑制剂调节宿主氨水平以及微生物群驱动的高氨血症风险提供了重要的概念验证。
