Oral versus vaginal Lactobacillus supplementation for endometrial dysbiosis: A paired pre and post–endometrial microbiome study

Infertility is a global health challenge, and impaired endometrial receptivity remains an important contributor to treatment failure. Endometrial dysbiosis, characterized by a low proportion of Lactobacillus in the endometrial microbiota, has been proposed as a potentially modifiable factor that may affect endometrial receptivity and fertility, and treatment with Lactobacillus-containing probiotics is emerging as a promising therapeutic approach. However, the optimal route of Lactobacillus supplementation remains unclear. We compared oral versus vaginal supplementation using the same Lactobacillus-containing formulation as an adjunct to standardized doxycycline/metronidazole therapy and continued oral lactoferrin in patients with baseline endometrial Lactobacillus <10%, based on paired microbiome profiling of endometrial samples (aspirated intrauterine fluid and endometrial tissue). In this single-center retrospective cohort study, thirty-two patients underwent paired endometrial microbiome testing before and after 30 days of supplementation (oral, n = 18; vaginal, n = 14). In the vaginal group, the median endometrial Lactobacillus proportion increased from 0.05% [0.00-0.20] to 99.15% [70.45-100.00] (p = 0.001), whereas in the oral group it increased from 0.00% [0.00-0.18] to 0.30% [0.03-66.33] (p = 0.005). The median change was greater with vaginal versus oral supplementation (+98.90% [70.45-99.80] vs + 0.25% [0.03-66.33], p < 0.001). Post-treatment Lactobacillus ≥80%, used as an exploratory marker of marked microbiota improvement, was observed in 9/14 patients (64%) in the vaginal group and 3/18 (17%) in the oral group (p = 0.010). Exploratory reproductive outcomes were limited by the small sample size and did not define a reliable clinical threshold. These findings suggest that, within this combined treatment regimen, vaginal Lactobacillus supplementation may provide a greater route-associated additional improvement in endometrial microbiota profiles than oral administration.