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Microbes & Immunity A disruptive solution for endometriosis

irritable bowel syndrome (IBS) conditions and even intestine. According to Harada et al. lipopolysaccharide
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inflammatory bowel disease (IBD). IBS is a common can activate the macrophage TLR4 in innate immunity,
functional bowel disorder (abdominal pain and distension leading to the production of significant levels of tumor
with an altered bowel movement), whereas IBD refers to necrosis factor alpha and interleukin 8 and the development
inflammation in the gastrointestinal tract, traditionally of an inflammatory environment. Otherwise, VIP is a
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categorized into ulcerative colitis and Crohn’s disease. non-cholinergic non-adrenergic neurotransmitter mainly
Actually, IBD, more than IBS (because of the absence expressed in the nerve terminals of the digestive tract, the
of histologic lesions), shares a similar pathophysiology genitourinary tract, the adrenal glands, and the central
with endometriosis. A positive association between nervous system, playing a key role in controlling the
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endometriosis and IBD has been confirmed in a systematic balance of pro- and anti-inflammatory cytokines and in
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review. Unfortunately, a meta-analysis on this topic is angiogenesis, notably through alternative splicing. VIP
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currently not possible due to the heterogeneity of the expression is upregulated in women with endometriosis and
groups and because information on the temporal sequence chronic pelvic pain, concomitantly with inflammation,
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of endometriosis and IBD is not available in several and the increase in nerve fiber density within ectopic
studies. A large-scale genome-wide association study endometrial tissue. Moreover, dysfunction of VIP signaling
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has confirmed an increased risk of developing IBD after could be involved in genital barrier disruption, allowing
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endometriosis, but not vice versa. 32 endometriotic cell migration, as well as impacting gut 50,51
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Finally, two Mendelian randomization studies (assessed and brain barrier permeability, supporting the recent
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by two different teams) using huge consortium databases insight that endometriosis is “no longer a pelvic disease.”
on gut microbiota (MibioGen, including 18,340 cases 3. Brain and vagus nerve dysfunction in
from 24 cohorts, mainly from Europe) and endometriosis endometriosis
(FinnGen, including data from 77,257 European
participants) supported the causal relationship between gut In addition to peripheral alterations provoked by
microbiota and endometriosis without bidirectional causal endometriosis, such as peritoneal inflammation and
effects. 33,34 More precisely, some families (Prevotellaceae, angiogenesis, central repercussions, such as stress, pain,
genus Anaerotruncus, genus Olsenella, genus Oscillospira) anxiety, depression, and even bipolar and panic disorder
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and order Bacillales were identified as risk factors for have been described, supported by experimental studies.
endometriosis, while others (Melainabacteria and genus Alteration in gene expression and electrophysiology in
Eubacterium ruminantium group) were protective factors. distinct brain regions, upregulation of the expression of
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Therefore, it seems that gut microbiota modification can glial markers (GFAP and IBA-1) as well as morphological
trigger the onset of endometriosis, but any gut microbiota changes in glial cells in the spinal cord, 57,58 the hippocampus
dysbiosis cannot promote endometriosis. Subsequently, and the hypothalamus were found in mice with
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gut microbiota dysbiosis that favors endometriosis is likely endometriosis. Moreover, in a murine model, endometriosis
to also favor IBD, depending on the concomitance of other lesions were shown to develop in the central nervous system,
risk factors. Indeed, similarly, gut microbiota dysbiosis, as endometriosis-derived cells were able to migrate and
especially a decrease in the abundance and diversity of engraft to the brain. Several teams have suggested chronic
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specific genera (reduction in Faecalibacterium prausnitzii; stress as a central, top-down mechanism exacerbating
Alistipes, Collinsella, and Ruminococcaceae), has been endometriosis by triggering the dysregulation of the
suggested as a trigger for IBD-initiating events. Similarly, hypothalamic-pituitary-adrenal axis, ending up with a release
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the onset of IBD is likely to be more strongly influenced by of inflammatory mediators in the circulatory system. 61,62
environmental factors, especially gut microbiota, than by Endometriosis-linked central stress could also influence
genetic factors. 36 the desynchronization of both the Hypothalamic-pituitary-
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Besides, gut dysbiosis triggers inflammation through gonadal axis and the circadian system, underpinning the
recruitment and/or activation of immune cells, as well occurrence of several comorbidities. Indeed, night shift
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as through modulation of the vasoactive intestinal peptide work has been significantly associated with an increased risk
(VIP) signalling. 38,39 Because of the altered composition of of endometriosis as well as an increased risk of estrogen-
the intestinal microbiota, a significant number of Gram- influence diseases (namely breast cancer and adverse
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negative bacteria translocate and infiltrate outside the coronary events) and menstrual disruption.
intestinal cavity, resulting in the destruction of intestinal Whether endometriosis results from a top-down
tight junctions and the reduction of tight junction protein neuroinflammation or a bottom-up activation of
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2 (ZO-2) expression, leading to the infiltration of a microglia by peripheral inflammatory mediators remains
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significant amount of Gram-negative bacteria outside the an elusive question. Regarding the current validated level
Volume 1 Issue 2 (2024) 48 doi: 10.36922/mi.4389