Vaginal Lactobacillus Supplementation Outperforms Oral Route in Restoring Endometrial Microbiota

Women undergoing fertility treatment whose uterine lining is dominated by bacteria other than Lactobacillus may respond very differently to probiotic supplementation depending on how the microbes are delivered, according to a paired pre- and post-treatment microbiome study. In patients whose endometrial Lactobacillus proportion was below 10 percent at baseline, vaginal supplementation with a Lactobacillus-containing formulation raised the median endometrial Lactobacillus share from 0.05 percent to 99.15 percent over 30 days, while oral supplementation of the same formulation produced only a modest median increase from 0.00 percent to 0.30 percent.

The study, conducted at a single center as a retrospective cohort analysis, enrolled 32 patients who underwent paired endometrial microbiome testing before and after one month of supplementation. Eighteen patients received the probiotic orally and 14 received it vaginally. Both routes were used as an adjunct to a standardized antibiotic regimen of doxycycline and metronidazole, together with continued oral lactoferrin. The researchers profiled the endometrial microbiota using samples of aspirated intrauterine fluid and endometrial tissue, allowing each patient to serve as her own before-and-after comparison.

The difference between routes was statistically pronounced. The median change in endometrial Lactobacillus proportion was plus 98.90 percent in the vaginal group versus plus 0.25 percent in the oral group, a contrast that remained highly significant with a p value below 0.001. When the researchers applied an exploratory threshold of at least 80 percent Lactobacillus after treatment as a marker of marked microbiota improvement, 9 of 14 patients, or 64 percent, in the vaginal group reached it, compared with 3 of 18 patients, or 17 percent, in the oral group, a difference with a p value of 0.010.

Endometrial dysbiosis, defined by a low proportion of Lactobacillus in the endometrial microbiota, has been proposed as a potentially modifiable factor that may influence endometrial receptivity, the capacity of the uterine lining to support embryo implantation. Impaired receptivity remains an important contributor to treatment failure in infertility care, which is a global health challenge, and Lactobacillus-containing probiotics have emerged as a promising therapeutic approach. What remained unclear was whether the route of administration matters, which prompted the researchers to compare oral and vaginal delivery of the same formulation within an otherwise standardized treatment regimen.

The authors caution that the findings are route-associated observations within a combined treatment regimen rather than proof of a superior therapy, and that the exploratory reproductive outcomes were limited by the small sample size and did not define a reliable clinical threshold. As a retrospective single-center cohort, the study also cannot exclude selection effects between the two groups. Even so, the paired microbiome data suggest that, when added to standardized doxycycline and metronidazole therapy with oral lactoferrin, vaginal Lactobacillus supplementation may provide a greater additional improvement in endometrial microbiota profiles than oral administration in patients with baseline endometrial dysbiosis.

Subject of Research: Comparing oral and vaginal Lactobacillus supplementation for endometrial dysbiosis in infertility patients

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

Article References: Hiratsuka, D., Iki, A., Kinoshita, M., Doi, Y., Kato, O., Oshima, K., Hiraoka, T., Matsuo, M., Ichinose, M., Makabe, T., Izumi, G., Harada, M., Hirota, Y., & Nabeta, M. (2026). Oral versus vaginal Lactobacillus supplementation for endometrial dysbiosis: A paired pre and post–endometrial microbiome study. PLOS One, 21(10), e0360619. https://doi.org/10.1371/journal.pone.0360619

Image Credits: AI Generated

DOI: 10.1371/journal.pone.0360619

Keywords: endometrial microbiome, Lactobacillus, probiotics, infertility, endometrial receptivity, dysbiosis, reproductive medicine, vaginal supplementation, oral supplementation, doxycycline, metronidazole, lactoferrin