Fu Haoshuang, Zhao Shuang, Song Shuying, Xie Qing
Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Department of Critical Liver Diseases, Liver Research Center, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Diseases, Beijing, China.
Front Microbiol. 2024 Jul 18;15:1432049. doi: 10.3389/fmicb.2024.1432049. eCollection 2024.
The gut microbiota and plasma metabolites play important roles in the progression of drug-induced liver injury (DILI). We investigated the causal associations between the gut microbiota, plasma metabolome, and DILI.
The summary data for gut microbiota ( = 18,340), plasma metabolome ( = 8,299), and DILI ( = 366,838) were obtained from the large genome-wide association studies. A two-sample Mendelian randomization was performed to explore the associations between the gut microbiota, plasma metabolome, and DILI. Additionally, a two-step Mendelian randomization was performed to explore the potential metabolites.
Five taxa were causally associated with DILI, including [odds ratio (OR) = 2.257, 95% confidence interval (CI) = 1.110-4.590], (OR = 2.311, 95% CI = 1.010-5.288), (OR = 2.869, 95% CI = 1.429-5.761), (OR = 1.995, 95% CI = 1.024-3.890), and (OR = 1.549, 95% CI = 1.065-2.253). Moreover, 53 metabolites were causally associated with DILI. After mediation analysis, four taxa were found to affect DILI through five mediation metabolites. N6-carbamoylthreonyladenosine mediated the effect of on DILI. Acetylcarnitine mediated the effect of on DILI. In addition, 4-cholesten-3-one mediated the effect of on DILI. Furthermore, 5,6-dihydrothymine levels and the salicylate-to-citrate ratio mediated the effect of on DILI.
We found that the gut microbiota could affect DILI through plasma metabolites, which could serve as potential biomarkers for risk stratification and elucidate underlying mechanisms for further investigation of DILI.
肠道微生物群和血浆代谢物在药物性肝损伤（DILI）的进展中起重要作用。我们研究了肠道微生物群、血浆代谢组与DILI之间的因果关系。
从大型全基因组关联研究中获得肠道微生物群（n = 18,340）、血浆代谢组（n = 8,299）和DILI（n = 366,838）的汇总数据。进行两样本孟德尔随机化以探索肠道微生物群、血浆代谢组与DILI之间的关联。此外，进行两步孟德尔随机化以探索潜在的代谢物。
5个分类群与DILI存在因果关系，包括[比值比（OR）= 2.257，95%置信区间（CI）= 1.110 - 4.590]，（OR = 2.311，95% CI = 1.010 - 5.288），（OR = 2.869，95% CI = 1.429 - 5.761），（OR = 1.995，95% CI = 1.024 - 3.890），以及（OR = 1.549，95% CI = 1.065 - 2.253）。此外，53种代谢物与DILI存在因果关系。经过中介分析，发现4个分类群通过5种中介代谢物影响DILI。N6 - 氨基甲酰苏氨酰腺苷介导了对DILI的影响。乙酰肉碱介导了对DILI的影响。此外，4 - 胆甾烯 - 3 - 酮介导了对DILI的影响。此外，5,6 - 二氢胸腺嘧啶水平和水杨酸与柠檬酸盐的比值介导了对DILI的影响。
我们发现肠道微生物群可通过血浆代谢物影响DILI，这些代谢物可作为风险分层的潜在生物标志物，并阐明DILI进一步研究的潜在机制。
