Interaction between Cervical Microbiota and Host Gene Regulation in Caesarean Section Scar Diverticulum

Cesarean section scar diverticulum (CSD) has become a formidable obstacle preventing women receiving CS from reproducing. However, the pathogenesis of CSD remains unexplored. In this study, we characterized the cervical microbiota, metabolome, and endometrial transcriptome of women with CSD. Based on the 16s rRNA results of cervical microbes, the microbial diversity in the CSD group was higher than that in the control group. Lactobacillus were significantly decreased in the CSD group and were mutually exclusive with potentially harmful species (Sphingomonas, Sediminbacterium, and Ralstonia) abnormally elevated in CSD. The microbiota in the CSD group exhibited low activity in carbohydrate metabolism and high activity in fatty acid metabolism, as confirmed by the metabolomic data. The metabolomic characterization identified 6,130 metabolites, of which 34 were significantly different between the two groups. In the CSD group, N-(3-hydroxy-eicosanoid)-homoserine lactone and Ternatin were significantly increased, in addition to the marked decrease in fatty acids due to high consumption. N-(3-hydroxy-eicosanoyl)-homoserine lactone is a regulator that promotes abnormal apoptosis in a variety of cells, including epithelial cells and vascular endothelial cells. This abnormal apoptosis of endometrial epithelial cells and neovascularization was also reflected in the transcriptome of the endometrium surrounding the CSD. In the endometrial transcriptome data, the upregulated genes in the CSD group were active in negatively regulating the proliferation of blood vessel endothelial cells, endothelial cells, and epithelial cells. This alteration in the host's endometrium is most likely influenced by the abnormal microbiota, which appears to be confirmed in the results by integrating host transcriptome and microbiome data. For the first time, this study described the abnormal activity characteristics of microbiota and the mechanism of host-microbiota interaction in CSD. IMPORTANCE Cesarean section scar diverticulum (CSD) has become a formidable obstacle preventing women receiving CS from reproducing. In this study, we revealed that potentially harmful microbes do have adverse effects on the host endometrium. The mechanism of these adverse effects includes the inhibition of the activity of beneficial bacteria such as lactobacilli, consumption of protective metabolites of the endometrium, and also the production of harmful metabolites. In the present study, we elucidated the mechanism from the perspectives of microbial, metabolic, and host responses, providing an important rationale to design preventive and therapeutic strategies for CSD.