Endometrial macrophages, endometriosis, and microbiota: time to unravel the complexity of the relationship
2019; Elsevier BV; Volume: 112; Issue: 6 Linguagem: Inglês
10.1016/j.fertnstert.2019.09.021
ISSN1556-5653
Autores Tópico(s)Uterine Myomas and Treatments
ResumoTraditionally the endometrial cavity was considered sterile. However, this concept is fundamentally changing slowly but steadily. Maintaining an ideal uterine environment is vital for embryo implantation, placentation, pregnancy development, and healthy childbirth at term. This requires integrity of the anatomic and histologic structure, hormonal milieu, signaling pathways, endometrial immune niche, and may be hospitable genital tract microbiome. This will be even more important for conditions known to have a significant impact on fertility and quality of life such as endometriosis. There is lack of understanding of the relationship between endometriosis—a disease with known inflammatory and immunologic changes—and possible infectious etiology. In addition, the precise role of specific immune cells and their products in the pathophysiology of endometriosis remains uncertain. A study by Vallvé-Juanico and colleagues (1Vallvé-Juanico J. Santamariab X. Vo K. Houshdaran S. Giudice L.C. Macrophages display pro-inflammatory phenotypes in eutopic endometrium of women with endometriosis with relevance to an infectious etiology of the disease.Fertil Steril. 2019; 112: 1118-1128Abstract Full Text Full Text PDF Scopus (35) Google Scholar) characterized the phenotypic state(s) of macrophages isolated from the eutopic endometrium of women with confirmed endometriosis and control subjects. Their primary finding is that the phenotypic identity of macrophages acquired from patients with endometriosis is more proinflammatory than cells isolated from control tissue donors. This study validates the findings from other groups and provides novel observations that can facilitate future large-scale studies to further develop this aspect of reproductive medicine. In my opinion the most significant contribution of that article (1Vallvé-Juanico J. Santamariab X. Vo K. Houshdaran S. Giudice L.C. Macrophages display pro-inflammatory phenotypes in eutopic endometrium of women with endometriosis with relevance to an infectious etiology of the disease.Fertil Steril. 2019; 112: 1118-1128Abstract Full Text Full Text PDF Scopus (35) Google Scholar) is the development and successful use of probes that allowed the characterization of the primary innate immune cells residing within the endometrium, including macrophages (type 1 and 2), uterine natural killer cells and regulatory T cells. This unique panel of 10 conjugated antibodies will likely be of use by other investigators interested in these immune cell types and their phenotypes despite the relatively small number of endometrial samples tested. If reproducible, this will be a valuable resource for precise identification and evaluation of the immune cells, not only reproductive disorders but other systems as well. Another novel observation is that the known anti-inflammatory type 2 macrophages exhibit an enhanced proinflammatory phenotype in the patient with endometriosis compared with controls. Despite the on-going controversy about the macrophage subpopulations in the immunology literature, this could have potentially important therapeutic implications for endometriosis. The investigators did not perform specific or metagenomics microbial assays, despite their postulation that the microbiome in the eutopic endometrium of patients with endometriosis could be implicated in this proinflammatory macrophage phenotype. It is well-known that ascension of pathogenic bacteria from the vagina to the uterus, Fallopian tubes, and ovaries can be asymptomatic (occult) or lead to pelvic inflammatory disease (PID). There is no agreement on what physiologic microbiota exists in the upper reproductive tract of most women who are not infected or pregnant, and the exact role—if any—of bacteria that colonize the upper reproductive tract in gynecologic diseases including endometriosis and possible implications on pregnancy outcomes. With the recent accumulation of data indicating disturbances of the female reproductive tract microbiota and inflammatory processes that influence the development of PID and endometriosis, a recent study used data from the National Health Insurance Research Database that assessed the association between PID and endometriosis (2Tai F.W. Chang C.Y. Chiang J.H. Lin W.C. Wan L. Association of pelvic inflammatory disease with risk of endometriosis: a nationwide cohort study involving 141,460 individuals.J Clin Med. 2018; 7Crossref Scopus (37) Google Scholar). Interestingly, in this nationwide retrospective cohort, involving a total of 141,460 patients, Tai et al. (2Tai F.W. Chang C.Y. Chiang J.H. Lin W.C. Wan L. Association of pelvic inflammatory disease with risk of endometriosis: a nationwide cohort study involving 141,460 individuals.J Clin Med. 2018; 7Crossref Scopus (37) Google Scholar) found that patients with PID had a threefold increase in the risk of developing endometriosis (hazard ratio, 3.02; 95% confidence interval [CI], 2.85–3.2). These findings add relevance to a possible infectious etiology in endometriosis. In addition, during the past decade evidence is accumulating to denote poor obstetrics outcome in patients with endometriosis. It would be very interesting to evaluate bacteria present in the endometrium of women with endometriosis and study correlations with reproductive outcomes. Perhaps this could provide an explanation and a possible intervention to improve obstetric outcomes in these women. Recently, Farland et al. (3Farland L.V. Prescott J. Sasamoto N. Tobias D.K. Gaskins A.J. Stuart J.J. et al.Endometriosis and risk of adverse pregnancy outcomes.Obstet Gynecol. 2019; 134: 527-536Crossref PubMed Scopus (50) Google Scholar) looked at the reproductive outcome in 116,429 women in the Nurses' Health Study II. These investigators found that women with laparoscopically confirmed endometriosis were associated with a greater risk of pregnancy loss (spontaneous abortion: risk ratio [RR] 1.40; 95% CI 1.31–1.49; ectopic pregnancy: RR 1.46, 95% CI 1.19–1.80). In addition, endometriosis was associated with a greater risk of gestational diabetes mellitus (RR 1.35, 95% CI 1.11–1.63) and hypertensive disorders of pregnancy (RR 1.30, 95% CI 1.16–1.45). In the largest metanalysis published at present, women with endometriosis have a statistically significantly higher risk of preterm birth, miscarriage, placenta previa, small for gestational age infants, and cesarean delivery (4Zullo F. Spagnolo E. Saccone G. Acunzo M. Xodo S. Ceccaroni M. et al.Endometriosis and obstetrics complications: a systematic review and meta-analysis.Fertil Steril. 2017; 108: 667-672Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar). With all of these observations in mind, the relationship of the endometrial immune niche and possibly the microbiome to obstetric outcomes in patients with confirmed endometriosis deserves further evaluation. Although this study (1Vallvé-Juanico J. Santamariab X. Vo K. Houshdaran S. Giudice L.C. Macrophages display pro-inflammatory phenotypes in eutopic endometrium of women with endometriosis with relevance to an infectious etiology of the disease.Fertil Steril. 2019; 112: 1118-1128Abstract Full Text Full Text PDF Scopus (35) Google Scholar) used innovative methods and reported novel findings, it is necessary to take in consideration the complex nature of endometriosis, multiple confounding factors, such as occult infections, small sample size, which may skew the results. In addition, macrophages phenotypes are known to be plastic and respond to various infectious agents and may migrate rapidly to sites of infection. Macrophages are also not strictly M1 or M2, but often exhibit multiple variations. Despite published studies including the one by Vallvé-Juanico et al. (1Vallvé-Juanico J. Santamariab X. Vo K. Houshdaran S. Giudice L.C. Macrophages display pro-inflammatory phenotypes in eutopic endometrium of women with endometriosis with relevance to an infectious etiology of the disease.Fertil Steril. 2019; 112: 1118-1128Abstract Full Text Full Text PDF Scopus (35) Google Scholar) and advances in uterine immune niche characterization, microbiome sequencing, our knowledge base could significantly improve with further fine tuning of study design, sampling method, sequencing methods, downstream analysis, and functional assays. It is time to further investigate the uterine immune niche and microbiome to increase our understanding of reproductive disorders, including endometriosis, and to develop more personalized reproductive therapies. Macrophages display proinflammatory phenotypes in the eutopic endometrium of women with endometriosis with relevance to an infectious etiology of the diseaseFertility and SterilityVol. 112Issue 6PreviewTo phenotype transcriptomically M1 macrophages (Mϕ1) and M2 macrophages (Mϕ2) in the endometrium of women with endometriosis. Full-Text PDF
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