A research group has discovered that using an antibiotic to target Fusobacterium, a common bacterium that causes inflammation, improved the symptoms of the gynaecological condition of endometriosis, and could provide an alternative treatment.
The team, from the Graduate School of Medicine and iGCORE at Nagoya University in Japan, found the antibiotic reduced the formation of lesions associated with endometriosis, which is characterised by endometrial tissue – usually found inside the uterus – being found outside it.
The study was published in Science Translational Medicine.
Endometriosis affects one in 10 women between 15 and 49, and can cause lifelong health problems, including pelvic pain and infertility. Although it can be treated using hormone therapy and surgical resection, these procedures sometimes lead to side effects, recurrence, and a significant impact on pregnancy.
The group led by Professor Yutaka Kondo and Assistant Professor Ayako Muraoka from the Nagoya University Graduate School of Medicine, in collaboration with the National Cancer Centre, found that the uterus of mice infected with Fusobacterium had more and heavier lesions. However, those that had been given an antibiotic saw improved lesion formation.
The findings strongly suggest that targeting Fusobacterium is an effective non-hormonal antibiotic treatment for endometriosis.
This study also shows the benefit of looking at upstream events to determine causative agents.
The initial finding was that a protein called transgelin (TAGLN) was often upregulated in patients with endometriosis. This was unsurprising because the protein is associated with processes that are important in the development of endometriosis.
However, this finding led them to determine that transforming growth factor beta (TGF-β) seemed to cause the upregulation of TAGLN. Since TGF-β is released by macrophages, the natural anti-inflammatory response and immune regulation cells of the body, they concluded that these macrophages were being activated in response to Fusobacterium.
“In this study, we demonstrated that the Fusobacterium-TAGLN-endometriosis axis is frequently dysregulated in endometriosis,” said Kondo. “Our data provide a strong and novel rationale for targeting Fusobacterium as a non-hormonal antibiotic-based treatment for endometriosis.”
Clinical trials of antibiotic treatment for human patients are ongoing at the Department of Obstetrics and Gynaecology at Nagoya University Hospital.
Study details
Fusobacterium infection facilitates the development of endometriosis through the phenotypic transition of endometrial fibroblasts
Ayako Muraoka, Miho Suzuki, Tomonari Hamaguchi, Shinya Watanabe, Kenta Iijima, Yoshiteru Murofushi, Keiko Shinjo, Satoko Osuka, Yumi Hariyama, Mikako Ito, Kinji Ohno, Tohru Kiyono, Satoru Kyo, Akira Iwase, Fumitaka Kikkawa, Hiroaki Kajiyama, Yutaka Kondo.
Published in Science Translational Medicine on 14 June 2023
Abstract
Retrograde menstruation is a widely accepted cause of endometriosis. However, not all women who experience retrograde menstruation develop endometriosis, and the mechanisms underlying these observations are not yet understood. Here, we demonstrated a pathogenic role of Fusobacterium in the formation of ovarian endometriosis. In a cohort of women, 64% of patients with endometriosis but <10% of controls were found to have Fusobacterium infiltration in the endometrium. Immunohistochemical and biochemical analyses revealed that activated transforming growth factor–β (TGF-β) signaling resulting from Fusobacterium infection of endometrial cells led to the transition from quiescent fibroblasts to transgelin (TAGLN)–positive myofibroblasts, which gained the ability to proliferate, adhere, and migrate in vitro. Fusobacterium inoculation in a syngeneic mouse model of endometriosis resulted in a marked increase in TAGLN-positive myofibroblasts and increased number and weight of endometriotic lesions. Furthermore, antibiotic treatment largely prevented establishment of endometriosis and reduced the number and weight of established endometriotic lesions in the mouse model. Our data support a mechanism for the pathogenesis of endometriosis via Fusobacterium infection and suggest that eradication of this bacterium could be an approach to treat endometriosis.
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