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Microbes & Immunity A disruptive solution for endometriosis

1. Introduction steroid hormones, pro-inflammatory cytokines, and
hypoxic stress. 11,12 Remarkably, the gut microbiota is a
Endometriosis, a very common but complex chronic major regulator of circulating estrogens (through the
1
disorder affecting young women worldwide, is classically estrobolome, the collection of genes of the gut microbiota
13
defined as the presence of endometrial-like glands and responsible for estrogen metabolism, in particular,
stroma outside the uterine cavity, leading to chronic pelvic the β-glucuronidase gene coding for an enzyme that
pain and infertility. With the advent of a validated non- deconjugates estrogens into their active forms), immune
14
invasive saliva-based diagnostic microRNA signature, response 15,16 and stress (including hypoxic stress) as well.
2-4
17
18
histopathological confirmation may not soon remain Therefore, gut microbiota dysbiosis, acting as a catalyst of
essential for the diagnosis of endometriosis. Thus, an earlier the main epigenetic cues, appears as the most interesting
diagnosis is likely to open new avenues to improve the therapeutic target to focus on in endometriosis.
prognosis and the quality of life of the patients, provided
an etiological and equally non-invasive treatment can be After reviewing the detrimental consequences of
rapidly initiated. microbiome dysbiosis on endometriosis pathogenesis,
we will underscore brain dysfunctions underpinning
At the beginning of 2024, a group of international endometriosis pathophysiology before focusing on vagus
experts called for a full revision of the pathogenesis and nerve dysfunction, a pivotal, yet underappreciated, target
pathophysiology of endometriosis. This reassessment for endometriosis progression. Consequently, non-
5
is a rare opportunity to question an upstream unifying invasive VNS appears as an innovative therapy, naturally
rationale underpinning this seemingly heterogeneous connecting the central and peripheral nervous systems
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chronic disease. This review aims to pave the way for an and gathering the necessary conditions to provide a safe,
innovative, scientifically proven therapeutic option: Non- global, and long-lasting maintenance of homeostasis
invasive vagus nerve stimulation (VNS).
regarding endometriosis.
Having a family member with endometriosis
noticeably increases a woman’s chances of developing it 2. Targeting microbiota dysbiosis as a
as well. A 2023 meta-analysis, including 60,674 cases potential strategy to prevent endometriosis
7
6
and 701,926 controls, identified 42 genome-wide During homeostasis, a balance between the microbiota
significant loci comprising 49 distinct association signals and the immune system maintains immune quiescence.
with endometriosis. A significant genetic correlation Dysbiosis is defined as the perturbances to microbiota
between endometriosis and 11 pain conditions (including resulting from alterations in the bacteria, immune system,
migraine), as well as inflammatory conditions was shown or local environment.
in this meta-analysis. Moreover, multitrait genetic analyses
identified substantial sharing of variants associated with The issue of the involvement of microbiota dysbiosis and
endometriosis and migraine. Nevertheless, the identified the estrobolome in endometriosis has been reviewed lately,
genetic signals only explained up to 5.01% of endometriosis confirming their importance in the physiopathology of the
variance and regulated not only expression but also disease. Altered microbiota have been reported in the
20
methylation (hence epigenetic mechanisms) of genes in genital tract of infertile patients with chronic endometritis
21
endometrium and blood. Besides, three programmed or endometrial polyps and in women with histology-
7
cell death-related genes have recently been identified proven stage 3/4 endometriosis. A complete absence
22
as key biomarkers of endometriosis, through machine of Atopobium in the vaginal and cervical microbiota
learning and Mendelian randomization. Actually, the of the case group, as well as an increase of Gardnerella,
8
results revealed marked upregulation of the expression of Streptococcus, Escherichia, Shigella, and Ureaplasma, in
TNFSF12 and PDK2 in endometriotic samples, coupled the cervical microbiota of the endometriosis group were
with a significant downregulation of the expression of found. Besides, an enrichment of Shigella/Escherichia
AP3M1, emphasizing, once more, the importance of the was found in the stool microbiome of the endometriosis
epigenetic mechanisms in this disease. group. Peritoneal microbiota is also modified in
22
Thus, the main determinants of endometriosis (and endometriosis, 23,24 and this dysbiosis probably accounts for
25
main therapeutic targets to focus on) are likely to be local inflammation and pelvic pain.
epigenetic ones, resulting in altered expression of genetic Noteworthily, a growing body of recent evidence also
material, independent of the modification of the genetic suggests the existence of gut dysbiosis (notably gut dysbiosis-
sequence itself. 9-11 Three driving microenvironmental cues derived β-glucuronidase, i.e., the estrobolome), promoting
modulating the expression of genes for the development the development of endometriosis, 26-29 underscoring a
of endometriosis have been identified: Locally produced potential similar role of microbiota in endometriosis and

Volume 1 Issue 2 (2024) 47 doi: 10.36922/mi.4389