Uncovering novel therapeutic targets for premature ejaculation from gut microbiota: A prospective high‐throughput sequencing study

Abstract Background Despite being the only approved oral therapy for premature ejaculation (PE), dapoxetine faces high discontinuation rates because of its suboptimal efficacy. Given that the role of gut microbiota in PE treatment has remained unexplored, we aim to investigate gut microbiota that may reflect the efficacy of dapoxetine. Methods Clinical data and fecal samples were collected from patients with lifelong PE before treatment. Gut microbiota was profiled via 16S rDNA sequencing, and differential microbiota between effective and ineffective groups were identified with the LEfSe method. To explore potential links between gut dysbiosis and efficacy, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway functional predictions were performed with the PICRUSt2 method. Efficacy was assessed using the Clinical Global Impression of Change (CGIC) scale, with scores ≥1 defined as the effective group. Results In the effective group, Erysipelotrichaceae_UCG_003, Parabacteroides_distasonis , and Prevotella_7_unclassified were significantly more prevalent, while Collinsella aerofaciens was less abundant. Their abundance was significantly correlated with CGIC scores, with correlation coefficients of 0.331, 0.250, 0.288, and ‒0.345, respectively. The discriminatory abilities of the four differential microbiota were 0.654, 0.669, 0.701, and 0.615, respectively. Incorporating them significantly improved the accuracy of the model predicting efficacy (0.796 vs. 0.738), which further suggests that modulating microbiota could be a novel strategy for PE treatment. The predicted gene abundance in the arachidonic acid metabolism pathway was significantly elevated in the effective group, indicating that dapoxetine's mechanism may also involve modulating this pathway. Conclusions This study identified gut microbiota associated with the efficacy of dapoxetine for the first time. Targeted modulation of specific gut microbiota may provide a novel strategy for PE treatment.