Distinct stool metabolite signatures in women with endometriosis may lead to non-invasive diagnostic tests and potential microbiota-based therapies, according to a study published in Med.
Women with endometriosis have altered gut microbiota profiles and metabolites compared to healthy controls. Notably, the bacteria-derived metabolite 4-hydroxyindole (4HI) is significantly reduced in stool samples from endometriosis patients.
In mouse models, oral administration of 4HI inhibited the initiation and progression of endometriotic lesions and reduced associated inflammation and pain. The compound also demonstrated efficacy in regressing established lesions in both mouse and human xenograft models of the disease.
The researchers analyzed stool samples from 18 women with confirmed endometriosis and 31 healthy controls using untargeted metabolomics and 16S rRNA gene sequencing. They identified 371 distinct metabolites, with 61 significantly altered in endometriosis patients compared to controls. Twelve metabolites showed potential as non-invasive diagnostic biomarkers including linoleic acid, 2'-deoxyadenosine, N-formyl-L-methionine, adenine, cytosine, and adenosine. Purine metabolism was notably impacted in endometriosis, similar to inflammatory bowel disease (IBD).
A reduction in alpha diversity, decreased populations of Ruminococcus, Faecalibacterium, Alistipes, and Roseburia, and increased populations of Erysipelatoclostridium, Streptococcus, Lacticaseibacillus, Actinomyces, and Tyzzerella was found in endometriosis patients. 4HI levels were significantly lower in endometriosis stool samples, showing strong positive correlations with Faecalibacterium and Lachnospiraceae, and a negative correlation with Dorea formicigenerans.
The mouse models showed significantly reduced lesion mass and volume at 14 days post-induction. Additionally, 4HI-treated lesions showed thinner epithelia, fewer glands, and reduced proliferation, reduced infiltration of both M1-like and M2-like macrophages in peritoneal lavage, and 4HI treatment alleviated endometriosis-associated hyperalgesia, with treated mice withdrawing their hind paws similarly to sham mice by day 14.
In the human xenograft model, the 4HI treatment for 14 days regressed established lesions, and the treated lesions showed reduced proliferation and macrophage infiltration. The 4HI treatment also resulted in significantly smaller lesions compared to vehicle-treated groups.
High-throughput, unbiased metabolomics was used to analyze stool samples. Statistical filtering revealed 61 metabolites that differentiated endometriosis patients from controls. Reduced alpha diversity and altered beta diversity in endometriosis patients were observed.
Multiple mouse models were used to evaluate 4HI’s effects, demonstrating its potential to suppress lesion initiation and progression and to regress established lesions. Although further human studies are needed, the findings suggest a promising avenue for non-invasive diagnosis and microbiota-targeted therapies for endometriosis.
The researchers noted limitations, including the need for larger cohort sizes to account for individual variability in microbiota profiles, and suggested simultaneous comparisons with IBD patients could further elucidate overlaps between the two conditions.
Conflict of interest statements can be found in the study.
