A translational study published month has suggested that Fusobacterium infection of the endometrium might contribute to the pathogenesis of endometriosis, the first to suggest a link between infection and endometriosis, writes Priya Venkatesan in The Lancet Microbe, and suggesting further research is urgently needed regarding treatment for the condition.
Endometriosis is a chronic, painful disease that affects around 10% of women of reproductive age worldwide. Characterised by endometrial-like tissue growing outside the uterus, the disease leads to systemic inflammation, scar tissue, and lesions forming in the pelvis and other areas, causing multiple symptoms including chronic pelvic pain, heavy bleeding during or in between menstruations, infertility, fatigue and depression.
Treatment options are few and only manage the symptoms.
Part of the problem of finding treatment options is that the cause of endometriosis is not fully known. Although retrograde menstruation is generally accepted as a cause of endometriosis, most women experience retrograde menstruation yet only 10% develop endometriosis, suggesting that other factors might contribute to its development.
Dominique de Ziegler (Department of Obstetrics and Gynaecology and Reproductive Medicine, Hopital Foch-Université de Paris Ouest UVSQ, Paris,) commented: “There has been mounting evidence that the primary mechanism in some or all cases of endometriosis resides in alterations of the endometrium stemming from inflammation.”
Stromal fibroblast proliferation and migration are key contributors to the progression of endometriosis, and inflammation has been shown to trigger the transition of quiescent fibroblasts to activated myofibroblasts in other chronic conditions such as fibrosis.
Additionally, as the incidence of endometritis (i.e, a bacterial infection of the endometrium causing inflammation) is markedly increased in women with endometriosis, an infectious aetiology of endometriosis is conceivable.
Five bacterial genera are thought to be significantly increased in the endometria of patients with endometriosis compared with individuals without endometriosis, including Erysipelothrix and Fusobacterium.
Ayako Muraoka (Division of Cancer Biology, Nagoya University Graduate School of Medicine, Japan) and colleagues did a study using uterine tissue samples from 79 patients in two Japanese hospitals to investigate whether the types of endometrial fibroblasts differed between people with and without endometriosis, and whether fibroblasts from individuals with endometriosis were associated with the presence of bacteria.
qPCR analysis showed that Erysipelothrix was not abundant in the endometrial tissue from study participants. However, Fusobacterium infiltration, mostly Fusobacterium nucleatum, was significantly more frequent in endometrial and endometriotic tissues from patients with endometriosis (27 [64·3%] of 42) than from the controls (three [7·1%] of 42; p<0·01).
Muraoka and colleagues found that the protein transgelin (TAGLN), linked to increased cell motility and migration, was up-regulated in fibroblasts from patients with endometriosis and that TAGLN was specifically expressed by these fibroblasts.
Immuno-histochemical analyses showed that Fusobacterium infection of endometrial cells activated transforming growth factor–β signalling (known to play a major role in endometriosis), leading to quiescent fibroblasts transitioning to TAGLN-positive myofibroblasts, with the ability to proliferate, adhere and migrate in vitro.
In subsequent in-vivo experiments in a mouse model, Muraoka and colleagues showed that inoculation of tissue from F nucleatum-infected uteri from donor mice caused the formation of multiple endometriotic lesions in recipient mice, whereas tissue from uninfected uteri did not cause endometriosis.
Infection with Lactobacillus iners, a major bacterium in the vaginal microbiota of reproductive-age women, did not cause the development of endometriotic lesions.
And mice receiving endometrial tissue from donor mice infected with F nucleatum that had been treated with metronidazole and chloramphenicol developed fewer endometriotic lesions than mice receiving tissue from infected mice that were not treated with antibiotics (p<0·01).
Muraoka and colleagues’ study is the first to suggest a link between infection and endometriosis; although a previous study had shown that treatment with metronidazole reduced the growth and progression of endometriotic lesions in a mouse model, any relevance to human endometriosis was unclear.
Co-author Yutaka Kondo (Division of Cancer Biology, Nagoya University Graduate School of Medicine) said: “Our findings suggest that Fusobacterium infection may contribute to the pathogenesis of endometriosis and that antibiotic treatment to eradicate endometrial infection should be further studied. Therefore, the next important requirement is clinical trials of antibiotic treatment for endometriosis patients in a big cohort.”
De Ziegler said: “The primary mechanism causing the inflammatory alterations identified in the eutopic endometrium and prone to causing endometriosis are unknown. The study by Muraoka et al is of prime importance; the identification of Fusobacterium infection is clearly a plausible path that needs to be further investigated.
“At this stage, studies are urgently needed for treating endometriosis.”
The Lancet Microbe article – Bacterial infection linked to endometriosis (Creative Commons Licence)
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