AUTHOR=Fu Haoshuang , Zhao Shuang , Song Shuying , Xie Qing 

TITLE=Gut microbiota causally affects drug-induced liver injury via plasma metabolites: a Mendelian randomization study

JOURNAL=Frontiers in Microbiology

VOLUME=15

YEAR=2024

URL=https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2024.1432049

DOI=10.3389/fmicb.2024.1432049

ISSN=1664-302X

ABSTRACT=<sec><title>Background</title><p>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.</p></sec><sec><title>Methods</title><p>The summary data for gut microbiota (<italic>n</italic> = 18,340), plasma metabolome (<italic>n</italic> = 8,299), and DILI (<italic>n</italic> = 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.</p></sec><sec><title>Results</title><p>Five taxa were causally associated with DILI, including <italic>Oscillospira</italic> [odds ratio (OR) = 2.257, 95% confidence interval (CI) = 1.110–4.590], <italic>Blautia</italic> (OR = 2.311, 95% CI = 1.010–5.288), <italic>Roseburia</italic> (OR = 2.869, 95% CI = 1.429–5.761), <italic>Fusicatenibacter</italic> (OR = 1.995, 95% CI = 1.024–3.890), and <italic>Prevotella 7</italic> (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 <italic>Blautia</italic> on DILI. Acetylcarnitine mediated the effect of <italic>Fusicatenibacter</italic> on DILI. In addition, 4-cholesten-3-one mediated the effect of <italic>Prevotella 7</italic> on DILI. Furthermore, 5,6-dihydrothymine levels and the salicylate-to-citrate ratio mediated the effect of <italic>Oscillospira</italic> on DILI.</p></sec><sec><title>Conclusion</title><p>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.</p></sec>