Identification of distinct stool metabolites in women with endometriosis for non-invasive diagnosis and potential for microbiota-based therapies

Context and significanceClinical management of endometriosis, a gynecological disease that is a leading cause of infertility in women, remains a challenge with no known cure. Scientists from Baylor College of Medicine combined the gut metabolomic and microbiota signatures in the stool samples from women with endometriosis to identify a gut-bacteria-derived therapeutic intervention candidate, 4-hydroxyindole. They demonstrate that 4-hydroxyindole prevents the formation of endometriotic lesions, augments their regression, and reduces disease-associated pain. Their work also identified altered bacteria-derived distinct metabolites that could potentially be used for non-invasive diagnosis of the disease.Highlights•Women with endometriosis have a distinct stool metabolome for non-invasive diagnosis•Bacteria-derived metabolites in endometriosis are associated with those in IBD•Bacteria-derived 4-hydroxyindole level is lower in stool from women with endometriosis•4-Hydroxyindole inhibits the onset and progression of endometriosisSummaryBackgroundEndometriosis, a poorly studied gynecological condition, is characterized by the presence of ectopic endometrial lesions resulting in pelvic pain, inflammation, and infertility. These associated symptoms contribute to a significant burden, often exacerbated by delayed diagnosis. Current diagnostic methods involve invasive procedures, and existing treatments provide no cure.MethodsMicrobiome-metabolome signatures in stool samples from individuals with and without endometriosis were determined using unbiased metabolomics and 16S bacteria sequencing. Functional studies for selected microbiota-derived metabolites were conducted in vitro using patient-derived cells and in vivo by employing murine and human xenograft pre-clinical disease models.FindingsWe discovered a unique bacteria-derived metabolite signature intricately linked to endometriosis. The altered fecal metabolite profile exhibits a strong correlation with that observed in inflammatory bowel disease (IBD), revealing intriguing connections between these two conditions. Notably, we validated 4-hydroxyindole, a gut-bacteria-derived metabolite that is lower in stool samples of endometriosis. Extensive in vivo studies found that 4-hydroxyindole suppressed the initiation and progression of endometriosis-associated inflammation and hyperalgesia in heterologous mouse and in pre-clinical models of the disease.ConclusionsOur findings are the first to provide a distinct stool metabolite signature in women with endometriosis, which could serve as stool-based non-invasive diagnostics. Further, the gut-microbiota-derived 4-hydroxyindole poses as a therapeutic candidate for ameliorating endometriosis.FundingThis work was funded by the NIH/NICHD grants (R01HD102680, R01HD104813) and a Research Scholar Grant from the American Cancer Society to R.K.Graphical abstract