Fusobacterium infection facilitates the development of endometriosis through the phenotypic transition of endometrial fibroblasts 2023 Muraoka et al

[Andy]

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.

Paywall, https://www.science.org/doi/10.1126/scitranslmed.add1531

 

[Andy]

Could endometriosis be caused by bacteria? Study offers fresh clues

"Infection by a particular group of bacteria could be linked to endometriosis, a painful condition that affects up to 10% of women and girls of reproductive age.

In a study of 155 women in Japan, members of the bacterial genus Fusobacterium were found in the uteruses of around 64% of those with endometriosis, and 7% of those who do not have the condition1. Follow-up experiments in mice infected with Fusobacterium showed that treatment with an antibiotic could reduce the size and frequency of the lesions, which are associated with endometriosis.

Researchers will need to do more work before the findings, published on 14 June in Science Translational Medicine, can be used to develop treatments for endometriosis, says Elise Courtois, a genomicist who studies the disease at the Jackson Laboratory in Farmington, Connecticut.

But the results highlight growing interest in the potential role of microbes in endometriosis, which has limited treatment options and whose origins are poorly understood. “There are definitely things that make us suspect the microbiome is implicated in endometriosis,” says Courtois. “Genetics doesn’t explain everything.”"

https://www.nature.com/articles/d41586-023-01956-4

 

[Arnie Pye]

In a study of 155 women in Japan, members of the bacterial genus Fusobacterium were found in the uteruses of around 64% of those with endometriosis, and 7% of those who do not have the condition

Very interesting. I wonder if they consider bacteria outside the uterus, anywhere in the pelvic cavity. If they don't I could imagine a scenario where a woman's uterus is free of the bacteria in question, but it exists elsewhere in the body.

And where does the bacterium originate? Is it passed down from parent to child over generations? If this turns out to be true it would suggest that women contemplating getting pregnant need a test to see if they have this bacterium so they can be treated for it before getting pregnant. One could also test when babies are at a certain age - long before puberty and long before intercourse is likely to take place.

 

[Hutan]

From a different paper,
Fusobacterium nucleatum: a commensal-turned pathogen, 2015, Han
"Fusobacterium nucleatum is an anaerobic oral commensal and a periodontal pathogen associated with a wide spectrum of human diseases. This article reviews its implication in adverse pregnancy outcomes (chorioamnionitis, preterm birth, stillbirth, neonatal sepsis, preeclampsia), GI disorders (colorectal cancer, inflammatory bowel disease, appendicitis), cardiovascular disease, rheumatoid arthritis, respiratory tract infections, Lemierre’s syndrom and Alzheimer’s disease. The virulence mechanisms involved in the diseases are discussed, with a particular emphasis on its colonization, systemic dissemination, and induction of host inflammatory and tumorigenic responses. The FadA adhesin/invasin conserved in F. nucleatum is a key virulence factor and a potential diagnostic marker for F. nucleatum-associated diseases."

 

[Hutan]

More info from the 2015 Han paper:

F. nucleatum elicits a variety of host responses [82]. It induces human b-defensin 2 from oral epithelial cells via FAD-I [103], stimulates factors predisposing to atherosclerosis by GroEL [65], and activates lymphocyte apoptosis by Fap2 and RadD [94]. F. nucleatum is a potent stimulator of inflammatory cytokines, IL-6, IL-8, and TNFα [96,104]. Binding of F. nucleatum to NK cells activates inflammatory responses involved in periodontal disease [31]. It is reported that F. nucleatum activates the immune responses through retinoic acid-inducible gene I (RIG-I) [105].

During periodontal health, the pro- and anti-inflammatory factors are maintained under homeostasis. Once disseminated outside the oral cavity and under dysbiosys, F. nucleatum induces exacerbated inflammation thus turning into a pathogen. For example, F. nucleatum stimulates TLR4-mediated inflammatory responses in the placentas of pregnant mice, causing fetal demise [51,52]. Suppression of inflammation protects the fetuses, even in the presence of bacterial colonization [52]. In colorectal cancer cells, F. nucleatum activates not only inflammatory responses, but also oncogenes and Wnt gene expressions, all of which are hallmarks of tumorigenesis [68]. F. nucleatum modulates the tumor-immune microenvironment and selectively expands myeloid cells in Apcmin/+ mice [66].

As a fastidious anaerobe, cultivation of F. nucleatum has been difficult. Hence, although cultivable, F. nucleatum is frequently missed in routine culture employed by hospital laboratories. The recent discovery of this opportunistic commensal in a wide spectrum of human disease is due largely to the employment of culture-independent methods. In addition, not all subtypes of F. nucleatum are equally prevalent in diseases. Thus, it is crucial to update microbial detection technologies in clinical practice for accurate diagnosis of disease and for identification of individuals at risk. The involvement of F. nucleatum in some of the diseases discussed above is still at the stage of association, with no established causal roles.

 

[Arnie Pye]

This sounds like a nasty thing to say, but I hope it turns out that fusobacterium is found to be a factor in the development of prostate cancer. If it is it will be taken much more seriously, and will be looked into far more quickly.

 

[rvallee]

This sounds like a nasty thing to say, but I hope it turns out that fusobacterium is found to be a factor in the development of prostate cancer. If it is it will be taken much more seriously, and will be looked into far more quickly.

Sounds very pragmatic to me.

One thing has been made clear with COVID, and it's that when threat levels vary between people, so does the overall response, to the point where those facing the worst risk are openly left to die if the majority doesn't oppose it. It's only when everyone faces the same threat that sufficient resources are put together.

And of course the vast majority of people making those decisions finding this personally very relevant to themselves is probably the main factor in the end. Nothing beats having stakes in the outcome, and conversely very little happens when those making the decisions have none.

 

[SNT Gatchaman]

I hope it turns out that fusobacterium is found to be a factor in the development of prostate cancer

Presence of Specific Periodontal Pathogens in Prostate Gland Diagnosed With Chronic Inflammation and Adenocarcinoma (2021, Cureus) —

Fusobacterium nucleatum is identified in the prostates that harbor cancer, chronic inflammation, and BPH.

The bacterial load is identified in BPH, inflammation, and cancer areas of the prostate gland diagnosed with malignancy. Moreover, it was determined the presence of Fusobacterium nucleatum subsp. fusiform strain ATCC 51190 in BPH, inflammation, and cancer areas. This study identifies the periodontal pathogen F. nucleatum in prostate glands diagnosed with adenocarcinoma. However, other periodontal pathogens investigated were not identified.

See also Microbiomes of Urine and the Prostate Are Linked to Human Prostate Cancer Risk Groups (2022, Eur Urology Oncology)