AUTHOR=He Yining , Han Chao , Li Chengjuan , Yin Xiaofan , Wang Jiawen , Gu Lina , Yan Ruxue , Liu Buhui , Zhou Xuan , He Weiming 

TITLE=Role of N-acetylkynurenine in mediating the effect of gut microbiota on urinary tract infection: a Mendelian randomization study

JOURNAL=Frontiers in Microbiology

VOLUME=15

YEAR=2024

URL=https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2024.1384095

DOI=10.3389/fmicb.2024.1384095

ISSN=1664-302X

ABSTRACT=<sec><title>Introduction</title><p>This study explored the causal connections between gut microbiota (GM), urinary tract infection (UTI), and potential metabolite mediators using Mendelian randomization (MR).</p></sec><sec><title>Methods</title><p>We utilized summary statistics from the most comprehensive and extensive genome-wide association studies (GWAS) available to date, including 196 bacterial traits for GM, 1,091 blood metabolites, 309 metabolite ratios, alongside UTI data from ukb-b-8814 and ebi-a-GCST90013890. Bidirectional MR analyses were conducted to investigate the causal links between GM and UTI. Subsequently, two MR analyses were performed to identify the potential mediating metabolites, followed by a two-step MR analysis to quantify the mediation proportion.</p></sec><sec><title>Results</title><p>Our findings revealed that out of the total 15 bacterial traits, significant associations with UTI risk were observed across both datasets. Particularly, taxon <italic>g_Ruminococcaceae UCG010</italic> displayed a causal link with a diminished UTI risk in both datasets (ukb-b-8814: odds ratio [OR] = 0.9964, 95% confidence interval [CI] = 0.9930–0.9997, <italic>P</italic> = 0.036; GCST90013890: OR = 0.8252, 95% CI = 0.7217–0.9436, <italic>P</italic> = 0.005). However, no substantial changes in <italic>g_Ruminococcaceae UCG010</italic> due to UTI were noted (ukb-b-8814: β = 0.51, <italic>P</italic> = 0.87; ebi-a-GCST90013890: β = −0.02, <italic>P</italic> = 0.77). Additionally, variations in 56 specific metabolites were induced by <italic>g_Ruminococcaceae UCG010</italic>, with N-acetylkynurenine (NAK) exhibiting a causal correlation with UTI. A negative association was found between <italic>g_Ruminococcaceae UCG010</italic> and NAK (OR: 0.8128, 95% CI: 0.6647–0.9941, <italic>P</italic> = 0.044), while NAK was positively associated with UTI risk (OR: 1.0009; 95% CI: 1.0002–1.0016; <italic>P</italic> = 0.0173). Mediation analysis revealed that the association between <italic>g_Ruminococcaceae UCG010</italic> and UTI was mediated by NAK with a mediation proportion of 5.07%.</p></sec><sec><title>Discussion</title><p>This MR study provides compelling evidence supporting the existence of causal relationships between specific GM taxa and UTI, along with potential mediating metabolites.</p></sec>