Evidence suggests that the microbiome is altered in women with endometriosis. Now, in a study “Gut microbiota and microbiota-derived metabolites promotes endometriosis,” published in Cell Death Discovery, researchers at the Baylor College of Medicine demonstrate that an altered gut microbiome plays a pivotal role in endometriosis disease progression in a mouse model.

“To investigate the role of the microbiome in endometriosis we first implemented a novel mouse model of the condition in which we eliminated the microbiome using antibiotics,” said lead author Rama Kommagani, PhD, associate professor in the departments of pathology and immunology and molecular virology and microbiology.

The scientists found that mice lacking a gut microbiome had smaller endometriotic lesions than mice with a microbiome. Furthermore, when gut microbiome-free mice received gut microbiota from mice with endometriosis, the lesions grew as large as those in mice retaining their microbiome.

This work suggests that altered gut bacteria drive disease progression. On the other hand, the uterine microbiome did not seem to affect disease progression.

Estimates of endometriosis indicate that it affects ten percent of women between the age 15 and 49 in the U.S and about 196 million women worldwide [Carol Yepes/Getty Images].
“Endometriosis is a pathological condition of the female reproductive tract characterized by the existence of endometrium-like tissue at ectopic sites, affecting 10% of women between the age 15 and 49 in the USA [and about 196 million women worldwide]. However, currently there is no reliable non-invasive method to detect the presence of endometriosis without surgery and many women find hormonal therapy and surgery as ineffective in avoiding the recurrences. There is a lack of knowledge on the etiology and the factors that contribute to the development of endometriosis,” write the investigators.

“A growing body of recent evidence suggests an association between gut microbiota and endometriosis pathophysiology. However, the direct impact of microbiota and microbiota-derived metabolites on the endometriosis disease progression is largely unknown. To understand the causal role of gut microbiota and endometriosis, we have implemented a novel model using antibiotic-induced microbiota-depleted (MD) mice to investigate the endometriosis disease progression. Interestingly, we found that MD mice showed reduced endometriotic lesion growth and, the transplantation of gut microbiota by oral gavage of feces from mice with endometriosis rescued the endometriotic lesion growth. “Additionally, using germ-free donor mice, we indicated that the uterine microbiota is dispensable for endometriotic lesion growth in mice.

Microbiota modulates immune cell populations

“Furthermore, we showed that gut microbiota modulates immune cell populations in the peritoneum of lesions-bearing mice. Finally, we found a novel signature of microbiota-derived metabolites that were significantly altered in feces of mice with endometriosis. Finally, we found one the altered metabolite, quinic acid promoted the survival of endometriotic epithelial cells in vitro and lesion growth in vivo, suggesting the disease-promoting potential of microbiota-derived metabolites.

“In summary, these data suggest that gut microbiota and microbiota-derived metabolome contribute to lesion growth in mice, possibly through immune cell adaptations. Of translational significance, these findings will aid in designing non-invasive diagnostics using stool metabolites for endometriosis.

As the study points out, certain microbiome communities and/or their metabolites can contribute to endometriosis progression and that modifying the composition of these communities could help control the condition in human patients. “We are currently investigating this possibility,” noted Kommagani.

The study also indicates that examining microbiome metabolites in human stool samples could be used as a diagnostic tool.

“Endometriosis is typically diagnosed with ultrasound, and an invasive procedure is necessary to characterize the lesion well,” explained Kommagani. “We are investigating whether microbiome metabolites in human stool samples could be a useful diagnostic tool and also whether some of these metabolites could be used as a treatment strategy.”

Regarding translating gut microbiome research in mice into human studies, a review article in Disease Models and Mechanisms had this to say: “The pioneering studies cited…on new animal models for gut microbiota research have greatly demonstrated their potential. However, despite the limitations of mouse models outlined in this review, their advantages are numerous and, furthermore, the amount of research and knowledge on mouse gastroenterology, genetics and immunology far surpasses any other model.

“Murine mouse models provide a range of customizable genotypes and phenotypes far superior to any other model organism. They have thus played a very important role in the emerging gut microbiota research field.”