Inflammation, Innate Immunity, MIcrobiota and Inovative Treatments in ENDOmetriosis

Endometriosis is a chronic inflammatory, polygenic, and multifactorial disease affecting approximately 10% of women of reproductive age, corresponding to over one million women in France. Endometriosis profoundly impairs the health and quality of life of affected individuals and carries a significant socio-economic burden, making it a major public health concern. To date, the pathogenesis and prognostic factors of disease progression remain poorly understood. Despite current treatment options, which are based on hormonal therapy or surgery, resistance and recurrence are frequent, underscoring the urgent need for innovative therapeutic strategies.

The hypothesis of retrograde menstruation of endometrial cells, among other proposed theories, appears insufficient to fully explain the development of the disease. Immunological factors may be implicated. Endometriosis is characterized by the presence of endometriotic tissue outside the uterine cavity- within the peritoneal cavity or at distant sites-forming lesions that, like eutopic endometrium, contain infiltrating immune cells, with varying compositions across menstrual cycle phases. Although data remain scarce, the literature points to several key mechanisms:

Inflammation and innate immunity with the dendritic cells, that initiate and orchestrate immune responses, appear to be present in different proportions and exhibit altered phenotypes in endometriotic tissue compared to healthy tissue. Macrophages, essential for phagocytosis, tissue repair, and the resolution of inflammation, also show functional and phenotypic modulation. In particular, efferocytosis-their ability to clear apoptotic cells-is impaired, and an imbalance in M1/M2 polarization has been described, potentially facilitating menstrual cell escape. The local microenvironment is characterized by altered cytokine and chemokine profiles. Natural Killer cells exhibit disrupted expression patterns of activating and degranulation capacity.

Microbiota: Many studies suggest a potential role for the intestinal microbiota in the initiation and/or promotion of endometriosis. Patients frequently exhibit gut dysbiosis, marked by reduced microbial diversity.

Resolution of Inflammation: Endometriosis may be associated with defective resolution of inflammation. Resolutive pharmacology involves the use of pro-resolving factors to exert a therapeutic effect by accelerating or stimulating the resolution of inflammation.

The interplay between local inflammation, the gut microbiota, and disease progression remains incompletely elucidated. A comprehensive phenotypic and functional characterization of immune cells-particularly innate immune cells (dendritic cells, macrophages, Natural Killer cells) - in parallel with microbiome profiling and clinical outcome data, may yield novel insights into disease mechanisms and support the development of pro-resolutive therapeutic strategies that may be of interest in endometriosis.

Study Design This will be a monocentric (at Grenoble University Hospital), open-label, prospective experimental study with a control arm.

The primary objective is to identify immune biomarkers associated with endometriosis.

Secondary objectives include:

1. Identification of immune biomarkers associated with clinical outcomes in endometriosis.
2. Characterization of the immunogenetic KIR/HLA (Killer Immunoglobulin-like Receptors / Human Leukocyte Antigen) system in both study groups.
3. Analysis of stromal cells, apoptosis, macrophage efferocytosis, and their responsiveness to pro-resolutive factors in both groups.
4. Identification of a characteristic bacterial gut microbiota profile at diagnosis in women with endometriosis versus controls, and/or profiles associated with one-year clinical outcomes (favorable vs unfavorable), as well as temporal microbiota trajectories over one year in relation to clinical response.

Study Population:

The study will include women undergoing surgery for endometriosis versus control women undergoing benign gynecological surgery with no known history or intraoperative evidence of endometriosis, aged 18 to 42.

Study Procedures:

Women in the endometriosis group will undergo collection of endometriotic lesions, adjacent tissue, eutopic endometrium, and peritoneal lavage during surgery. Controls will provide biopsies of eutopic endometrium, unaffected peritoneum, and peritoneal lavage. For both groups, peripheral blood samples will be collected during routine care and stool samples obtained at baseline (Day 0). For the endometriosis group, a second stool sample will be collected at 12 months (M12).

A clinical evaluation will be performed at inclusion for all participants and repeated at one year for the endometriosis group. Participation for control group subjects is limited to the day of surgery, whereas endometriosis group subjects will be followed for 12 months.