Gut microbiota-derived short-chain fatty acids protect against the progression of endometriosis.

Sangappa B Chadchan,Nagireddy Putluri,Serdar E Bulun,Scott W Biest,Pooja Popli,Ramakrishna Kommagani,Sang Jun Han,Chandrasekhar R Ambati,Eric Tycksen

doi:10.26508/lsa.202101224

Abstract

Worldwide, ∼196 million are afflicted with endometriosis, a painful disease in which endometrial tissue implants and proliferates on abdominal peritoneal surfaces. Theories on the origin of endometriosis remained inconclusive. Whereas up to 90% of women experience retrograde menstruation, only 10% develop endometriosis, suggesting that factors that alter peritoneal environment might contribute to endometriosis. Herein, we report that whereas some gut bacteria promote endometriosis, others protect against endometriosis by fermenting fiber to produce short-chain fatty acids. Specifically, we found that altered gut microbiota drives endometriotic lesion growth and feces from mice with endometriosis contained less of short-chain fatty acid and n-butyrate than feces from mice without endometriosis. Treatment with n-butyrate reduced growth of both mouse endometriotic lesions and human endometriotic lesions in a pre-clinical mouse model. Mechanistic studies revealed that n-butyrate inhibited human endometriotic cell survival and lesion growth through G-protein-coupled receptors, histone deacetylases, and a GTPase activating protein, RAP1GAP. Our findings will enable future studies aimed at developing diagnostic tests, gut bacteria metabolites and treatment strategies, dietary supplements, n-butyrate analogs, or probiotics for endometriosis.

Highlights

Endometriosis, in which endometrial tissue exits the uterus and implants and proliferates on peritoneal surfaces in the abdomen, afflicts ~196 million women globally, or 1 in 10 females between 12 and 52 yr of age
We report that mice with endometriosis have less fecal n-butyrate than those without endometriosis and that n-butyrate administration can reduce endometriotic lesion growth
To determine whether gut bacteria promote endometriotic lesion growth in a mouse injection model of endometriosis, we considered two possible models: germ-free or microbiota-depleted mice

Summary

Introduction

Endometriosis, in which endometrial tissue exits the uterus and implants and proliferates on peritoneal surfaces in the abdomen, afflicts ~196 million women globally, or 1 in 10 females between 12 and 52 yr of age. Half of these women experience chronic pelvic pain [1], and many experience excessive bleeding, infertility, and pain with menstruation, intercourse, bowel movements, or urination. If this process fails, the endometrial cells establish lesions, which can spread in response to inflammation and macrophage-released pro-inflammatory cytokines and growth factors [2, 3]. To develop new approaches to treat this painful disease and improve women’s fertility, we need a more detailed understanding of the underlying mechanisms of and improve the women’s fertility rate and health affected by this disease

Methods

Results

Conclusion