Alfonso Manzi

Background: Recurrent implantation failure (RIF) remains one of the most challenging conditions in reproductive medicine. Although increasing evidence implicates chronic endometritis (CE) and alterations of the endometrial microbiota in impaired implantation, the potential contribution of gastrointestinal dysfunction and intestinal dysbiosis remains poorly characterized. We hypothesized that, in a subgroup of women with pure RIF, reproductive failure may be associated with a broader mucosal phenotype involving both intestinal and endometrial compartments. Objective: To characterize the coexistence of gastrointestinal disorders, intestinal dysbiosis, CE, and endometrial microbial alterations in women diagnosed with pure RIF, and to descriptively report reproductive outcomes observed during subsequent multidisciplinary clinical management. Methods: This retrospective, single-centre, observational, hypothesis-generating study included women who met the strict ESHRE criteria for pure RIF, and were assessed at the “Federico II” IVF Centre, Naples, Italy. Patients underwent multidisciplinary assessment combining reproductive medicine, outpatient hysteroscopy, gastroenterological evaluation according to Rome IV criteria, conventional microbiological investigation and paired intestinal and endometrial microbiome characterization by 16S rRNA sequencing. Following clinical assessment, individualized gastroenterological management was undertaken according to routine practice. Reproductive outcomes were descriptively recorded during follow-up. Results: 19 women were analysed, all of whom met the Rome IV guidelines, and showed hysteroscopic and histologic signs of CE. Gut dysbiosis was identified in 94.7% (18/19) of patients, whereas endometrial microbial alterations were observed in 78.9% (15/19). In 84.2% (16/19) of the cohort, microbial profiles characterized by an abundance of Enterobacteriaceae in the intestinal and/or endometrial compartments were detected. Conventional microbiological positivity was present in less than half of patients, highlighting the distinction between microbiological infection and ecological microbial imbalance. During the follow-up period following completion of the personalized multidisciplinary treatment program, which included the administration of a well-characterized probiotic strain, Escherichia coli Nissle 1917, 11 women (57.9%) achieved a clinical pregnancy. Dysbiosis of the intestine was reported in 94.7% (18 out of 19) of participants, whereas endometrial microbiota disturbances were present in 78.9% (15 out of 19) of subjects. The Enterobacteriaceae-enriched microbiota profiles affecting the intestine and/or endometrium were seen in 84.2% (16 out of 19) of subjects. Out of 19 patients, 11 (57.9%) conceived during the follow-up period after gut-targeted treatment comprising Escherichia coli Nissle 1917. Conclusions: Women who meet strict criteria for pure RIF may represent a clinically identifiable subgroup characterized by the coexistence of gastrointestinal disorders, intestinal dysbiosis, CE, and endometrial microbial alterations. Rather than demonstrating therapeutic efficacy, the present study provides a translational and hypothesis-generating framework supporting the need for prospective validation of this integrated biological phenotype in women with pure RIF before evaluating personalized multidisciplinary management. Prospective controlled studies are warranted to evaluate whether gut-directed interventions may influence reproductive outcomes in this population.

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