Background: The interaction between intestinal microbiota and infertility is less researched. This study was performed to investigate the causal association between gut microbiota and infertility. Methods: In this two-sample Mendelian randomization (MR) study, genetic variants of intestinal microbiota were obtained from the MiBioGen consortium, which included 18,340 individuals. Inverse variance weighting (IVW), MR-Egger, weighted median, maximum likelihood, MR Robust adjusted profile score, MR Pleiotropy residual sum, and outlier (MR-PRESSO) methods were used to explore the causal links between intestinal microbiota and infertility. The MR-Egger intercept term and the global test from the MR-PRESSO estimator were used to assess the horizontal pleiotropy. The Cochran Q test was applied to evaluate the heterogeneity of instrumental variables (IVs). Results: As indicated by the IVW estimator, significantly protective effects of the Family XIII AD3011 group (OR = 0.87) and Ruminococcaceae NK4A214 group (OR = 0.85) were identified for female fertility, while Betaproteobacteria (OR = 1.18), Burkholderiales (OR = 1.18), Candidatus Soleaferrea (OR = 1.12), and Lentisphaerae (OR = 1.11) showed adverse effects on female fertility. Meanwhile, Bacteroidaceae (OR = 0.57), Bacteroides (OR = 0.57), and Ruminococcaceae NK4A214 group (OR = 0.61) revealed protective effects on male fertility, and a causal association between Anaerotruncus (OR = 1.81) and male infertility was detected. The effect sizes and directions remained consistent in the other five methods except for Candidatus Soleaferrea. No heterogeneity or pleiotropy were identified by Cochran’s Q test, MR-Egger, and global test (all p > 0.05). Conclusions: This two-sample MR study revealed that genetically proxied intestinal microbiota had potentially causal effects on infertility. In all, the Ruminococcaceae NK4A214 group displayed protective effects against both male and female infertility. Further investigations are needed to establish the biological mechanisms linking gut microbiota and infertility.

Acute kidney injury (AKI) is a critical clinical syndrome characterized by a rapid decline in renal function, frequently resulting from ischemia, nephrotoxicity, or sepsis. It represents a major global health burden due to its high morbidity and mortality and its strong association with progression to chronic kidney disease. In this study, we identified a novel small-molecule TLR4 inhibitor, DB03476, via structure-based virtual screening targeting the intracellular TIR domain of murine Tlr4. Molecular dynamics simulations confirmed that DB03476 stabilizes Tlr4 without altering its global conformation. In a murine ischemia–reperfusion-induced AKI model, DB03476 administration significantly attenuated renal inflammation, macrophage infiltration, and apoptosis and suppressed the TLR4/MyD88/NF-κB pathway. Moreover, DB03476 exhibited cross-species efficacy by binding conserved residues in human TLR4 with high affinity. Functional validation using human kidney organoids confirmed its protective effects against inflammatory challenge. These results demonstrate DB03476 as a promising therapeutic agent for AKI through selective inhibition of TLR4-mediated inflammatory responses.