The cause of "dysmenorrhea" was found: bacterial infection caused endometriosis

Dysmenorrhea is widely existed among the female groups, but 10%-15%of childcare women will feel severe pain during menstruation because of endometriosis ("EMS").As a common gynecological disease, the cause of EMS is still unsolvable.At present, several assumptions have been proposed to explain the cause of endometriosis, including the existence of menstrual retrograde, body cavity, and remnants of Miaole tube.Menstrual retrograde (menstrual blood does not flow out of the vagina, but flows back to the fallopian tube, and enters the pelvic cavity) is a recognized cause of EMS.However, most of the childcare women have experienced menstruation retrograde, but only 10%-15%of women suffer from EMS, which indicates that there are other mechanisms to promote EMS development.

EMS refers to the endometrial tissue that exists in the uterus, but grows elsewhere outside the uterus. It is most common in pelvic peritoneum, fallopian tube and ovarian. The main symptoms are pelvic pain and infertility.70%of the pain occur during menstruation, and pain during sexual intercourse is also very common. 50%of patients have infertility. A few patients have symptoms of urination or intestinal part. About 25%of patients do not have no patients.Any symptoms.

For a long time, clinically believed that the uterine cavity was almost sterile, but there was a significant relationship between EMS and endometriosis, and inflammation and bacteria were inseparable.As a pathway connecting the uterus, most of the bacteria in the vagina are lactobacillus, but when the vaginal ecology is disordered, other bacteria can also be detected, such as nucleus.It is known that the species of the genus Rouctal is a common member of the oral and gastrointestinal microorganisms, and it has been considered opportunistic pathogens for a long time.However, recent studies have shown that some clutch species (such as nucleus) have not only played an important role in periodontitis, but also play an important role in carcinogenic effects by inducing various inflammatory cytokines such as TGF-β.

The growth of EMS is benign, but a large number of connected tissue proliferation matrix has clinical problems in the clinic, and the growth factor secreted by its secretion will promote the strong proliferation and migration of fibroblasts.These matrix into fibroblasts is a key decisive factor in EMS progress.Activated muscle forming fibroblast contains cytoplasm microfil-related proteins, such as transport protein (TAGLN), waveform protein (VIM) and α-smooth muscle moving protein (αSMA).The transformation from the static fibroblast to the activated muscle into fibroblasts is caused by chronic inflammation, and chronic inflammation involves the production of multiple cytokines.For example, in the process of wound healing and chronic inflammation (such as fibrosis and cancer), static fibrous cells can be activated and differentiated into muscle fibroblasts.So, is EMS related to the inflammatory cytokines brought by vagina?

On June 14, the research team of Nagoya University in Japan published in the Science Translational Medicine entitled "Fusobacterium Infection Facilities The Development of Endometriosis Throuspic Tran. The research results of the size of Endometric Fibroblasts ".This study determines the potential pathogenic factor of endometriosis: Peris infection.

Figure 1 Research results (Figure Source: [1])

Researchers have designed a series of studies to determine the mechanism of TGF-β-induced endometrium fibroblast phenotype transformation that causes EMS to occur, and verify the assumptions of the transformation of the phenotype transformation of the endometriosis infection.First of all, a observation study is designed among humans to determine the genetic expression of the endometrium in the endometrium of EMS patients with a fibroblast -specific expression; then, a study of function research on the endometrium formation fibroblasts that strongly express the tagln are designed; After that, continue to study the upstream target to determine whether the transformation of the phenotype is caused by the system and local inflammation reactions after the TGF-β and Peris infection.The development of mice EMS also explores the effectiveness of antibiotics as an EMS non -comprehensive therapy.

turn out:

01EMS patients with muscle formation of fibroblast Tagln gene expression upward increase to promote proliferation

Tagln works as a calcium protein family’s muscle -proof protein, and is a symbol for muscle fibroblasts.The results of gene expression spectrum show that compared to the normal endometrium tissue, 10 genes in EMS samples are raised and 3 genes are lowered.Among these 13 genes, only Tagln’s expression increased significantly.Excessive expression of the proliferation, migration and attachment of Tagln muscle into fibroblasts.

Figure 2 Tagln from EMS patients raised (Figure Source: [1])

02Tagln promotes endometrial cell proliferation through IL-6

Muscle fibroblasts produce and secrete multiple cytokines during contraction.By checking Tagln’s expression related cytokines, it is found that IL-6 is the most prominent among 30 cytokines and growth factors tested on the protein array.Adding IL-6 to promote EMS-related cell proliferation.In clinical samples, the expression of IL-6 sample samples of EMS patients has increased significantly, and the protein expression of Tagln is positively related to the IL-6 in these tissues.

03TGF-β1-induced Tagln expression

TGF-β1 is a key growth factor in the main role in EMS. TGF-β1 induces muscle-related genes, including TAGLN by SMA and MAD-related (SMAD)), combined with its promoter.Compared to normal endometrium, the abundance of TGF-β1 and TGF-β-β-βr1 (TGF-βR1) in the tissue of EMS patients in the tissue of EMS has increased.The in vitrory implementation shows the expression of Tagln in TGF-β1 regulation, while SB431542 can eliminate this upstream.SB431542 is a specific inhibitor of SMAD2/3 -mediated signal transition.These discoveries show that epigenetic regulation participates in the transformation of the TGF-β signal from static to fibroblasts into muscle into fibroblasts.

Figure 3 TGF-β1’s expression of Tagln in vitro (source: [1])

04 Pyrthylococcus infection affects the endometrium micro -environment

The abundance of TGF-β in the endometrium may be related to bacterial infections.Compared with healthy patients, the five bacteria have increased significantly in the endometrium of EMS patients.Among these bacteria, the lower -ranking ERYSIPELOTHRIX does not exist in the endometrium tissue of individuals with orientation or endometriosis.In the tissue of EMS patients, the second -ranked tissue is significantly higher than that of the control group, and the bacteria that infiltrate the endometrium of the uterine of EMS are mainly nucleus.

Cobacteria can induce congenital immune response through its membrane fat polysaccharides. The increased CD163-positive m2 macrophage can produce TGF-β1, and macrophages are the most abundant immune cells in the endometriosis.Compared with the control group, the number of macrophages and TGF-β1 in the endometrial tissue of the endometrial tissue significantly increased significantly.In vitro tests, even the hot and lively nucleus can promote the formation of M2 macrophages and stimulate TGF-β1.These data indicate that the nucleus in the endometrium may affect the abundance of Tagln in the fiber cell by raising the TGF-β1 signal.

Figure 4 Actinobacteria infection affects the micro -environment of the endometrium (Figure source: [1])

05 in infection of nucleus infection promotes EMS, antibiotic treatment can be relieved

Through the body experiments of the vaginal infection of the mouse vaginal infection, the expression of Tagln protein in the endometriosis after nucleus infection.Two different types of antibiotic metronidazole (MZ) and chloramphenicillin (CP) are sensitive to nucleus. After the infection of the supply mouse infected, the vagina doses the vagina every day for 5 days.After a week of antibiotic treatment, nuclearbacter bacteria infiltration no longer exists, and the M2 macrophage infiltration, TGF-β1 and TAGLN expression in the endometrium and receptor mouse endometrium endometrium endometriosis are reducedEssenceMZ or CP antibiotic treatment may help treat endometriosis.

Figure 5 Antibiotics with nuclearioxidae can reduce the weight of the endometriosis lesion of the mouse (source: [1])

This study proves that the endometrium infection may lead to disease, which further understands the pathogenesis of EMS: Terobacteria infection activates the TGF-β signal, induces Tagln expression, and promote the proliferation of endometrial cells.The cause of the endometrium in the priority infection of Permatology is not clear.Studies have shown that in the mouth of the oral cavity, the hemogenesis of nucleus can be infected in the palace.This kind of communication mainly occurs during pregnancy, and the blood flow flowing to the placenta at this time generally increases.Because EMS patients are usually not born, they can also consider spreading through vagina.

At present, the treatment of EMS is hormone therapy, such as long -term ovulation suppression, which not only has side effects, but also makes women unable to get pregnant during treatment.Stubborn pelvic pain usually requires surgical treatment, but after surgical removal of endometriosis, a high recurrence rate is a high probability problem.This study reveals the potential pathogenic mechanism of EMS and uses MZ or CP to eradicate, which may be a choice to improve this disease treatment.Therefore, combining antibiotics and other therapies such as hormone therapy may be another effective way, and it is expected to be tested in future clinical trials.

This study has some limitations.First of all, the research lacks direct evidence to support the presence of the existence of Peris in the endometrium to promote the hypothesis of EMS after menstruation.Many studies have recorded the mechanism of EMS, so further accurate research is needed; secondly, clinical research needs to be performed to determine whether antibiotic therapy for Peris is really effective for EMS patients.

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School Division | Wenzuchuan



[1] Ayako Muraoka, Miho Suzuki, Tomonart Hamaguchi, et al., Fusobacterium Infection Facilities the Development of Endometrios Through the Phenotypic Transition of Endometric Fibroblasts.sci. Transl. Med.15, Eadd1531 (2023) .doi: 10.1126/scitranslmed.ADD1531 This article is an original biological exploration, and individuals are welcome to repost and share.If any other media or websites need to be reproduced, it must indicate the source biological exploration in front of the text.

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