TY - JOUR
T1 - Gut microbiota and microbiota-derived metabolites promotes endometriosis
AU - Chadchan, Sangappa B.
AU - Naik, Sumanta K.
AU - Popli, Pooja
AU - Talwar, Chandni
AU - Putluri, Satwikreddy
AU - Ambati, Chandrasekhar R.
AU - Lint, Michael A.
AU - Kau, Andrew L.
AU - Stallings, Christina L.
AU - Kommagani, Ramakrishna
N1 - Funding Information:
We thank Dr. Deborah J. Frank (Department of Obstetrics and Gynecology, Washington University) for assistance with manuscript editing, Alma Jackson (Department of Obstetrics and Gynecology, Washington University) for technical expertise. We also thank the Gnotobiotic core facility, Washington University, School of Medicine Saint Louis, MO, USA for housing the germ-Free mice. This work was funded, in part, by National Institutes of Health/National Institute of Child Health and Human Development grants R01HD102680, R01HD065435, and R00HD080742 to RK. SKN received Stephen I. Morse Fellowship and CLS awarded Burroughs Wellcome Fund Investigators in the Pathogenesis of Infectious Disease. The metabolomics core was supported by the CPRIT Core Facility Support Award RP210227 “Proteomic and Metabolomic Core Facility,” NCI Cancer Center Support Grant P30CA125123, NIH/NCI R01CA220297, NIH/NCI R01CA216426 intramural funds from the Dan L. Duncan Cancer Center.
Funding Information:
We thank Dr. Deborah J. Frank (Department of Obstetrics and Gynecology, Washington University) for assistance with manuscript editing, Alma Jackson (Department of Obstetrics and Gynecology, Washington University) for technical expertise. We also thank the Gnotobiotic core facility, Washington University, School of Medicine Saint Louis, MO, USA for housing the germ-Free mice. This work was funded, in part, by National Institutes of Health/National Institute of Child Health and Human Development grants R01HD102680, R01HD065435, and R00HD080742 to RK. SKN received Stephen I. Morse Fellowship and CLS awarded Burroughs Wellcome Fund Investigators in the Pathogenesis of Infectious Disease. The metabolomics core was supported by the CPRIT Core Facility Support Award RP210227 “Proteomic and Metabolomic Core Facility,” NCI Cancer Center Support Grant P30CA125123, NIH/NCI R01CA220297, NIH/NCI R01CA216426 intramural funds from the Dan L. Duncan Cancer Center.
Publisher Copyright:
© 2023, The Author(s).
PY - 2023/12
Y1 - 2023/12
N2 - 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. 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. 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. 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.
AB - 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. 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. 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. 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.
UR - http://www.scopus.com/inward/record.url?scp=85146893549&partnerID=8YFLogxK
U2 - 10.1038/s41420-023-01309-0
DO - 10.1038/s41420-023-01309-0
M3 - Article
C2 - 36693853
AN - SCOPUS:85146893549
SN - 2058-7716
VL - 9
JO - Cell Death Discovery
JF - Cell Death Discovery
IS - 1
M1 - 28
ER -