Connecting gut microbiome composition to symptom severity and host genetics in endometriosis

Background: Endometriosis (EM) is a multifactorial, estrogen-dependent inflammatory disease characterized by high clinical variability. Growing evidence is highlighting the role of gut microbiome dysbiosis in EM pathophysiology; however, associations between microbiome, symptom severity, and host genetics remain poorly characterized. Extra-oral taste receptor genes (TGs), expressed in both the gastrointestinal and female reproductive systems, may represent novel mediators of gut-reproductive tract axis crosstalk.Methods: A total of 50 women with surgically confirmed EM were deeply clinically characterized, including the evaluation of EM-symptoms and their severity. Microbiome profiles were obtained by 16S rRNA gene sequencing of rectal swabs. Genetic variants within four TGs (TAS2R3, TAS2R4, TAS2R5, and TAS2R14) were assessed using SNP-array genotyping. Microbiome composition was investigated through the evaluation of alpha and beta diversity, as well as enterotype classification analyses. Associations between EM-related features, bacterial taxa and TG-SNPs were investigated using regression models.Results: Three distinct gut microbiome community types were identified, dominated by Bacteroides, Prevotella, and Escherichia–Shigella. While microbiome composition did not differ significantly across EM stages, beta diversity was associated with dysmenorrhea (R2 = 0.13) and disease stage (R2 = 0.12). Regarding TGs, SNPs within TAS2R14 gene showed significant associations with alpha and beta diversity indices. Reduced abundance of short-chain fatty acid–producing taxa, including members of the Lachnospiraceae and Ruminococcaceae families, was associated with dysmenorrhea, whereas increased abundance of Prevotella and Mobiluncus with dysuria and infertility, respectively. Finally, an increased premenstrual pain severity was associated with a reduced relative abundance of taxa within the order Burkholderiales (β = −2.265) and the family Sutterellaceae (β = −1.563); high postmenstrual pain severity was associated with a lower abundance of Bifidobacteriales (β = −4.932) and Bifidobacteriaceae (β = −4.134).Conclusion: This case-only study elucidated the complex relationship between gut microbiome composition, EM-related symptoms, and host genetic variation. In particular, extra-oral taste receptor genes emerged as novel risk factors to host–microbiome interactions, supporting their potential role in the microbiota-endometriosis axis and opening new perspectives on EM pathogenesis.