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Metabolite profiles in the peritoneal cavity of endometriosis patients and mouse models

      Highlights

      • Endometriosis was associated with aberrant metabolism in the peritoneal cavity.
      • Lysophosphatidylcholine and phosphoethanolamine expression was upregulated in both humans and mice.
      • Human and mouse samples shared most of the metabolite sets.

      Abstract

      Research question

      Which metabolites are altered in the peritoneal cavity of women with endometriosis? Could the mouse endometriosis model simulate these alterations?

      Design

      Thirteen women with endometriosis and seven women with other benign gynaecological diseases, who underwent laparoscopic surgery, were included in this study. None had received hormonal therapy for 3 months before surgery. For the animal experiments, six and five mice were included in the endometriosis and control groups, respectively. Peritoneal fluid from the patients and peritoneal lavage fluid from the mice was collected and analysed. Non-targeted metabolomics via liquid chromatography with tandem mass spectrometry was used to identify the altered metabolites in the peritoneal fluid of endometriosis patients and mouse models. MetaboAnalyst 4.0 was used to visualize the data.

      Results

      Several metabolites in the peritoneal cavity were significantly altered in both humans and mice with endometriosis. Concentrations of lysophosphatidylcholine (LysopC) (P=0.017 in patients and P=0.041 in the mouse model) and derivatives of phosphoethanolamine (1-arachidonoyl-sn-glycero-3-phosphoethanolamine in patients, P=0.027; 1-oleoyl-sn-glycero-3-phosphoethanolamine in patients, P=0.0086; and phosphorylethanolamine in the mouse model, P=0.0027) were significantly up-regulated in both, whereas concentrations of acylcarnitines (l-palmitoylcarnitine, P=0.047; and stearoylcarnitine, P=0.029) and kynurenine (P=0.045) were significantly increased only in humans. The human and mouse samples shared three altered enriched metabolite sets.

      Conclusions

      Women with endometriosis show an altered metabolic state in the abdominal cavity. The endometriosis mouse model shared half of the significantly altered metabolite sets found in the abdominal cavity of humans.

      Key words

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      References

        • Adams S.H.
        • Hoppel C.L.
        • Lok K.H.
        • Zhao L.
        • Wong S.W.
        • Minkler P.E.
        • Hwang D.H.
        • Newman J.W.
        • Garvey W.T.
        Plasma acylcarnitine profiles suggest incomplete long-chain fatty acid β-oxidation and altered tricarboxylic acid cycle activity in type 2 diabetic African-American women.
        J. Nutr. 2009; 139 (https://doi.org/): 1073-1081https://doi.org/10.3945/jn.108.103754
        • Bacci M.
        • Capobianco A.
        • Monno A.
        • Cottone L.
        • Di Puppo F.
        • Camisa B.
        • Mariani M.
        • Brignole C.
        • Ponzoni M.
        • Ferrari S.
        • Panina-Bordignon P.
        • Manfredi A.A.
        • Rovere-Querini P.
        Macrophages are alternatively activated in patients with endometriosis and required for growth and vascularization of lesions in a mouse model of disease.
        Am. J. Pathol. 2009; 175 (https://doi.org/): 547-556https://doi.org/10.2353/ajpath.2009.081011
        • Balmer M.L.
        • Ma E.H.
        • Thompson A.J.
        • Epple R.
        • Unterstab G.
        • Lötscher J.
        • Dehio P.
        • Schürch C.M.
        • Warncke J.D.
        • Perrin G.
        • Woischnig A.K.
        • Grählert J.
        • Löliger J.
        • Assmann N.
        • Bantug G.R.
        • Schären O.P.
        • Khanna N.
        • Egli A.
        • Bubendorf L.
        • Rentsch K.
        • Hapfelmeier S.
        • Jones R.G.
        • Hess C.
        Memory CD8+ T Cells Balance Pro- and Anti-inflammatory Activity by Reprogramming Cellular Acetate Handling at Sites of Infection.
        Cell Metab. 2020; 32 (e5https://doi.org/): 457-467https://doi.org/10.1016/j.cmet.2020.07.004
        • Campbell B.M.
        • Charych E.
        • Lee A.W.
        • Möller T.
        Kynurenines in CNS disease: Regulation by inflammatory cytokines.
        Front. Neurosci. 2014; 8 (https://doi.org/): 1-22https://doi.org/10.3389/fnins.2014.00012
        • Campesato L.F.
        • Budhu S.
        • Tchaicha J.
        • Weng C.H.
        • Gigoux M.
        • Cohen I.J.
        • Redmond D.
        • Mangarin L.
        • Pourpe S.
        • Liu C.
        • Zappasodi R.
        • Zamarin D.
        • Cavanaugh J.
        • Castro A.C.
        • Manfredi M.G.
        • McGovern K.
        • Merghoub T.
        • Wolchok J.D.
        Blockade of the AHR restricts a Treg-macrophage suppressive axis induced by L-Kynurenine.
        Nat. Commun. 2020; 11 (https://doi.org/): 1-11https://doi.org/10.1038/s41467-020-17750-z
        • Carvalho L.F.P.
        • Samadder A.N.
        • Agarwal A.
        • Fernandes L.F.C.
        • Abrão M.S.
        Oxidative stress biomarkers in patients with endometriosis: Systematic review.
        Arch. Gynecol. Obstet. 2012; 286 (https://doi.org/): 1033-1040https://doi.org/10.1007/s00404-012-2439-7
        • Chen B.
        • Gao A.
        • Tu B.
        • Wang Yonghui
        • Yu X.
        • Wang Yingshu
        • Xiu Y.
        • Wang B.
        • Wan Y.
        • Huang Y.
        Metabolic modulation via mTOR pathway and anti-angiogenesis remodels tumor microenvironment using PD-L1-targeting codelivery.
        Biomaterials. 2020; 255 (https://doi.org/)120187https://doi.org/10.1016/j.biomaterials.2020.120187
        • Chen L.
        • Sun M.
        • Wu W.
        • Yang W.
        • Huang X.
        • Xiao Y.
        • Ma C.
        • Xu L.
        • Yao S.
        • Liu Z.
        • Cong Y.
        Microbiota Metabolite Butyrate Differentially Regulates Th1 and Th17 Cells’ Differentiation and Function in Induction of Colitis.
        Inflamm. Bowel Dis. 2019; 25 (https://doi.org/): 1450-1461https://doi.org/10.1093/ibd/izz046
        • Cronin S.J.F.
        • Seehus C.
        • Weidinger A.
        • Talbot S.
        • Reissig S.
        • Seifert M.
        • Pierson Y.
        • McNeill E.
        • Longhi M.S.
        • Turnes B.L.
        • Kreslavsky T.
        • Kogler M.
        • Hoffmann D.
        • Ticevic M.
        • da Luz Scheffer D.
        • Tortola L.
        • Cikes D.
        • Jais A.
        • Rangachari M.
        • Rao S.
        • Paolino M.
        • Novatchkova M.
        • Aichinger M.
        • Barrett L.
        • Latremoliere A.
        • Wirnsberger G.
        • Lametschwandtner G.
        • Busslinger M.
        • Zicha S.
        • Latini A.
        • Robson S.C.
        • Waisman A.
        • Andrews N.
        • Costigan M.
        • Channon K.M.
        • Weiss G.
        • Kozlov A.V.
        • Tebbe M.
        • Johnsson K.
        • Woolf C.J.
        • Penninger J.M.
        The metabolite BH4 controls T cell proliferation in autoimmunity and cancer.
        Nature. 2018; 563 (https://doi.org/): 564-568https://doi.org/10.1038/s41586-018-0701-2
        • Davies L.C.
        • Ridnour L.A.
        • Wink D.A.
        • McVicar D.W.
        • Ileva L.
        • Karwan M.
        • Ozaki M.K.
        • Annunziata C.M.
        • Weiss J.M.
        • Cheng R.Y.S.
        Itaconic acid mediates crosstalk between macrophage metabolism and peritoneal tumors.
        J. Clin. Invest. 2018; 128 (https://doi.org/)https://doi.org/10.1172/jci99169
        • Dionyssopoulou E.
        • Vassiliadis S.
        • Evangeliou A.
        • Koumantakis E.E.
        • Athanassakis I.
        Constitutive or induced elevated levels of L-carnitine correlate with the cytokine and cellular profile of endometriosis.
        J. Reprod. Immunol. 2005; 65 (https://doi.org/): 159-170https://doi.org/10.1016/j.jri.2004.12.002
        • Dolynchuk K.N.
        Inhibition of tissue transglutaminase and e (γ-glutamyl) lysine cross-linking in human hypertrophic scar.
        Wound Repair Regen. 1996; 4 (https://doi.org/): 16-20https://doi.org/10.1046/j.1524-475X.1996.40105.x
        • Dunselman G.A.J.
        • Vermeulen N.
        • Becker C.
        • Calhaz-Jorge C.
        • D'Hooghe T.
        • De Bie B.
        • Heikinheimo O.
        • Horne A.W.
        • Kiesel L.
        • Nap A.
        • Prentice A.
        • Saridogan E.
        • Soriano D.
        • Nelen W.
        ESHRE guideline: Management of women with endometriosis.
        Hum. Reprod. 2014; 29 (https://doi.org/): 400-412https://doi.org/10.1093/humrep/det457
        • Dutta M.
        • Anitha M.
        • Smith P.B.
        • Chiaro C.R.
        • Maan M.
        • Chaudhury K.
        • Patterson A.D.
        Metabolomics reveals altered lipid metabolism in a mouse model of endometriosis.
        J. Proteome Res. 2016; 15 (https://doi.org/): 2626-2633https://doi.org/10.1021/acs.jproteome.6b00197
        • Flores I.
        • Rivera E.
        • Ruiz L.A.
        • Santiago O.I.
        • Vernon M.W.
        • Appleyard C.B.
        Molecular profiling of experimental endometriosis identified gene expression patterns in common with human disease.
        Fertil. Steril. 2007; 87 (https://doi.org/): 1180-1199https://doi.org/10.1016/j.fertnstert.2006.07.1550
        • Greaves E.
        • Cousins F.L.
        • Murray A.
        • Esnal-Zufiaurre A.
        • Fassbender A.
        • Horne A.W.
        • Saunders P.T.K.
        A novel mouse model of endometriosis mimics human phenotype and reveals insights into the inflammatory contribution of shed endometrium.
        Am. J. Pathol. 2014; 184 (https://doi.org/): 1930-1939https://doi.org/10.1016/j.ajpath.2014.03.011
      1. Herrmann, J., Mannheim, D., Wohlert, C., Versari, D., Lerman, L.O., Meyer, F.B., Mcconnell, J.P., Go, M., Lerman, A., 2009. Expression of lipoprotein-associated phospholipase A 2 in carotid artery plaques predicts long-term cardiac outcome 2930–2938. https://doi.org/ 10.1093/eurheartj/ehp309

        • Krina T.
        • Zondervan D.Phil.
        • Becker Christian M.
        • Missmer Stacey A.
        Endometriosis, Review Article.
        N. Engl. J. Med. 2020; 382 (M.D.) (https://doi.org/): 56https://doi.org/10.1056/NEJMra1810764
        • Lee H.J.
        • Ko H.J.
        • Song D.K.
        • Jung Y.J.
        Lysophosphatidylcholine promotes phagosome maturation and regulates inflammatory mediator production through the protein kinase a-phosphatidylinositol 3 kinase-p38 mitogen-activated protein kinase signaling pathway during mycobacterium tuberculosis infect.
        Front. Immunol. 2018; (https://doi.org/)https://doi.org/10.3389/fimmu.2018.00920
        • Letsiou S.
        • Peterse D.P.
        • Fassbender A.
        • Hendriks M.M.
        • van den Broek N.J.
        • Berger R.
        • Dorien O.F.
        • Vanhie A.
        • Vodolazkaia A.
        • Van Langendonckt A.
        • Donnez J.
        • Harms A.C.
        • Vreeken R.J.
        • Groothuis P.G.
        • Dolmans M.M.
        • Brenkman A.B.
        • D'Hooghe T.M.
        Endometriosis is associated with aberrant metabolite profiles in plasma.
        Fertil. Steril. 2017; 107 (e6https://doi.org/): 699-706https://doi.org/10.1016/j.fertnstert.2016.12.032
        • Li M.Q.
        • Hou X.F.
        • Lv S.J.
        • Meng Y.H.
        • Wang X.Q.
        • Tang C.L.
        • Li D.J.
        CD82 gene suppression in endometrial stromal cells leads to increase of the cell invasiveness in the endometriotic milieu.
        J. Mol. Endocrinol. 2011; 47 (https://doi.org/): 195-208https://doi.org/10.1530/JME-10-0165
        • Liu N.
        • Wang G.
        • Yang X.
        • Liu N.
        • Luo J.
        • Kuang D.
        • Xu S.
        • Duan Y.
        • Xia Y.
        • Wei Z.
        • Xie X.
        • Yin B.
        • Chen F.
        • Luo S.
        • Liu H.
        • Wang J.
        • Jiang K.
        • Gong F.
        • Tang Z.
        • Cheng X.
        • Li H.
        • Li Z.
        Lactate inhibits ATP6V0d2 expression in tumor- associated macrophages to promote HIF-2 a – mediated tumor progression.
        J. Clin. Invest. 2019; 129: 631-646
        • Maignien C.
        • Santulli P.
        • Kateb F.
        • Caradeuc C.
        • Marcellin L.
        • Pocate-Cheriet K.
        • Bourdon M.
        • Chouzenoux S.
        • Batteux F.
        • Bertho G.
        • Chapron C.
        Endometriosis phenotypes are associated with specific serum metabolic profiles determined by proton-nuclear magnetic resonance.
        Reprod. Biomed. Online. 2020; 41 (https://doi.org/): 640-652https://doi.org/10.1016/j.rbmo.2020.06.019
        • Mariuzzi L.
        • Domenis R.
        • Orsaria M.
        • Marzinotto S.
        • Londero A.P.
        • Bulfoni M.
        • Candotti V.
        • Zanello A.
        • Ballico M.
        • Mimmi M.C.
        • Calcagno A.
        • Marchesoni D.
        • Di Loreto C.
        • Beltrami A.P.
        • Cesselli D.
        • Gri G.
        Functional expression of aryl hydrocarbon receptor on mast cells populating human endometriotic tissues.
        Lab. Investig. 2016; (https://doi.org/)https://doi.org/10.1038/labinvest.2016.74
        • McCoin C.S.
        • Knotts T.A.
        • Adams S.H.
        Acylcarnitines-old actors auditioning for new roles in metabolic physiology.
        Nat. Rev. Endocrinol. 2015; 11 (https://doi.org/): 617-625https://doi.org/10.1038/nrendo.2015.129
        • Mehla K.
        • Singh P.K.
        Metabolic Regulation of Macrophage Polarization in Cancer.
        Trends in Cancer. 2019; 5 (https://doi.org/): 822-834https://doi.org/10.1016/j.trecan.2019.10.007
        • Beste Michael T.
        • Pfäffle-Doyle Nicole
        • Prentice Emily A.
        • Morris Stephanie N.
        • Lauffenburger Douglas A.
        • Isaacson Keith B.
        Molecular Network Analysis of Endometriosis Reveals a Novel Role for c-Jun Regulated Macrophage Activation.
        Sci. Transl. Med. 2014; 6 (https://doi.org/): 1-27https://doi.org/10.1126/scitranslmed.3007988.Molecular
        • Murgia F.
        • Angioni S.
        • D'Alterio M.N.
        • Pirarba S.
        • Noto A.
        • Santoru M.L.
        • Tronci L.
        • Fanos V.
        • Atzori L.
        • Congiu F.
        Metabolic Profile of Patients with Severe Endometriosis: a Prospective Experimental Study.
        Reprod. Sci. 2020; (https://doi.org/)https://doi.org/10.1007/s43032-020-00370-9
        • Osawa T.
        • Shimamura T.
        • Saito K.
        • Hasegawa Y.
        • Ishii N.
        • Nishida M.
        • Ando R.
        • Kondo A.
        • Anwar M.
        • Tsuchida R.
        • Hino S.
        • Sakamoto A.
        • Igarashi K.
        • Saitoh K.
        • Kato K.
        • Endo K.
        • Yamano S.
        • Kanki Y.
        • Matsumura Y.
        • Minami T.
        • Tanaka T.
        • Anai M.
        • Wada Y.
        • Wanibuchi H.
        • Hayashi M.
        • Hamada A.
        • Yoshida M.
        • Yachida S.
        • Nakao M.
        • Sakai J.
        • Aburatani H.
        • Shibuya M.
        • Hanada K.
        • Miyano S.
        • Soga T.
        • Kodama T.
        Phosphoethanolamine Accumulation Protects Cancer Cells under Glutamine Starvation through Downregulation of PCYT2.
        Cell Rep. 2019; 29 (e7https://doi.org/): 89-103https://doi.org/10.1016/j.celrep.2019.08.087
        • Shang W.
        • Xu R.
        • Xu T.
        • Wu M.
        • Xu J.
        • Wang F.
        Ovarian Cancer Cells Promote Glycolysis Metabolism and TLR8-Mediated Metabolic Control of Human CD4+ T Cells.
        Front. Oncol. 2020; 10 (https://doi.org/): 1-13https://doi.org/10.3389/fonc.2020.570899
      2. Shi, Y., Zhang, P., Zhang, L., Osman, H., Mohler, E.R., Macphee, C., Zalewski, A., Postle, A., Wilensky, R.L., 2007. Role of lipoprotein-associated phospholipase A 2 in leukocyte activation and inflammatory responses 191, 54–62. https://doi.org/ 10.1016/j.atherosclerosis.2006.05.001

        • Simoens S.
        • Dunselman G.
        • Dirksen C.
        • Hummelshoj L.
        • Bokor A.
        • Brandes I.
        • Brodszky V.
        • Canis M.
        • Colombo G.L.
        • Deleire T.
        • Falcone T.
        • Graham B.
        • Halis G.
        • Horne A.
        • Kanj O.
        • Kjer J.J.
        • Kristensen J.
        • Lebovic D.
        • Mueller M.
        • Vigano P.
        • Wullschleger M.
        • Dhooghe T.
        The burden of endometriosis: Costs and quality of life of women with endometriosis and treated in referral centres.
        Hum. Reprod. 2012; 27 (https://doi.org/): 1292-1299https://doi.org/10.1093/humrep/des073
        • Snaebjornsson M.T.
        • Janaki-raman S.
        • Schulze A.
        Review Greasing the Wheels of the Cancer Machine : The Role of Lipid Metabolism in Cancer.
        Cell Metab. 2020; (https://doi.org/): 1-15https://doi.org/10.1016/j.cmet.2019.11.010
        • Vallvé-Juanico J.
        • Houshdaran S.
        • Giudice L.C.
        The endometrial immune environment of women with endometriosis.
        Hum. Reprod. Update. 2019; 25 (https://doi.org/): 565-592https://doi.org/10.1093/humupd/dmz018
        • Vallvé-Juanico J.
        • Santamaria X.
        • Vo K.C.
        • Houshdaran S.
        • Giudice L.C.
        Macrophages display proinflammatory phenotypes in the eutopic endometrium of women with endometriosis with relevance to an infectious etiology of the disease.
        Fertil. Steril. 2019; (https://doi.org/)https://doi.org/10.1016/j.fertnstert.2019.08.060
        • Vouk K.
        • Ribič-Pucelj M.
        • Adamski J.
        • Rižner T.L.
        Altered levels of acylcarnitines, phosphatidylcholines, and sphingomyelins in peritoneal fluid from ovarian endometriosis patients.
        J. Steroid Biochem. Mol. Biol. 2016; 159 (https://doi.org/): 60-69https://doi.org/10.1016/j.jsbmb.2016.02.023
        • Wu M.H.
        • Hsiao K.Y.
        • Tsai S.J.
        Hypoxia: The force of endometriosis.
        J. Obstet. Gynaecol. Res. 2019; 45 (https://doi.org/): 532-541https://doi.org/10.1111/jog.13900
        • Yang L.V.
        • Radu C.G.
        • Wang L.
        • Riedinger M.
        • Witte O.N.
        Gi-independent macrophage chemotaxis to lysophosphatidylcholine via the immunoregulatory GPCR G2A.
        Blood. 2005; (https://doi.org/)https://doi.org/10.1182/blood-2004-05-1916
        • Young V.J.
        • Ahmad S.F.
        • Brown J.K.
        • Duncan W.C.
        • Horne A.W.
        ID2 mediates the transforming growth factor-β1-induced Warburg-like effect seen in the peritoneum of women with endometriosis.
        Mol. Hum. Reprod. 2016; (https://doi.org/)https://doi.org/10.1093/molehr/gaw045
        • Young V.J.
        • Brown J.K.
        • Maybin J.
        • Saunders P.T.K.
        • Duncan W.C.
        • Horne A.W.
        Transforming growth factor-β induced warburg-like metabolic reprogramming may underpin the development of peritoneal endometriosis.
        J. Clin. Endocrinol. Metab. 2014; 99 (https://doi.org/): 3450-3459https://doi.org/10.1210/jc.2014-1026
        • Yuan M.
        • Li D.
        • An M.
        • Li Q.
        • Zhang L.
        • Wang G.
        Rediscovering peritoneal macrophages in a murine endometriosis model.
        Hum. Reprod. 2017; 32 (https://doi.org/): 94-102https://doi.org/10.1093/humrep/dew274
        • Yuan M.
        • Li D.
        • Zhang Z.
        • Sun H.
        • An M.
        • Wang G.
        Endometriosis induces gut microbiota alterations in mice.
        Hum. Reprod. 2018; 33 (https://doi.org/): 607-616https://doi.org/10.1093/humrep/dex372
        • Zhu W.
        • Stevens A.P.
        • Dettmer K.
        • Gottfried E.
        • Hoves S.
        • Kreutz M.
        • Holler E.
        • Canelas A.B.
        • Kema I.
        • Oefner P.J.
        Quantitative profiling of tryptophan metabolites in serum, urine, and cell culture supernatants by liquid chromatography-tandem mass spectrometry.
        Anal. Bioanal. Chem. 2011; 401 (https://doi.org/): 3249-3261https://doi.org/10.1007/s00216-011-5436-y
        • Zondervan K.T.
        • Becker C.M.
        • Koga K.
        • Missmer S.A.
        • Taylor R.N.
        • Viganò P.
        Endometriosis.
        Nat. Rev. Dis. Prim. 2018; (https://doi.org/)https://doi.org/10.1038/s41572-018-0008-5

      Biography

      Guoyun Wang is certified as a Chief Physician of Obstetrics and Gynecology by Qilu Hospital and as a PhD tutor by Shandong University, China. She is committed to clinical and basic research into endometriosis and adenomyosis.
      Key message
      Patients with endometriosis have an altered metabolic state in the abdominal cavity. The endometriosis mouse model generated herein may reflect metabolic changes in humans. This study adds to current knowledge of metabolomic alterations in the peritoneal fluid of women with endometriosis and in the mouse model.