SESSO ORMONI MICROBIOTA E IMMUNITA’

20 Settembre 2021

Microbiota Intestinale

Negli ultimi anni la nozione di asse intestino-cervello è stata estesa al microbioma, definito “asse microbiota-intestino-cervello” (180). Il tratto gastrointestinale ospita trilioni di batteri che inviano attraverso l’asse intestino-cervello molte interazioni diverse tra cui il rilascio di serotonina (181, 182). Il microbiota intestinale svolge un ruolo importante nella salute dell’ospite e le alterazioni nella composizione e nella funzione potrebbero contribuire alla patogenesi dell’IBS e all’efficacia terapeutica (183).

Diana YEDID 

Senior Scientific and Managing Director 

DyD Medicina Integrativa®  

Nonostante la mancanza di consenso su differenze microbiche distinte nell’IBS, le caratteristiche del microbioma intestinale, come la ricchezza della sua comunità batterica, viene individuata come correlazione nella gravità dei sintomi dell’IBS (184, 185), ma questi risultati sono il più delle volte generalizzabili. Non solo il microbiotainfluenza lo sviluppo e la funzione dell’intestino, ma può anche esercitare un impatto sui sintomi extra-intestinali tra cui la depressione (186). È importante sottolineare come sia altamente probabile che la composizione del microbiota intestinale sia influenzata dai sintomi dell’IBS, in particolare dal movimento intestinale che influenza sia il tempo sia i prodotti metabolici che derivano dall’interazione tra il microbiota intestinale, l’ospite e i componenti dietetici.

La composizione del microbiota intestinale è strettamente associata ai livelli di steroidi sessuali in modo reciproco. Nell’uomo, l’estradiolo sistemico e il testosterone sono correlati con la diversità e il profilo microbico intestinale nei maschi e nelle femmine (187, 188). Il microbiota intestinale svolge un ruolo fondamentale nella regolazione del metabolismo degli steroidi, contenenti enzimi come solfatasi e glucuronidasi che deconidiscono gli steroidi per il riassorbimento nell’intestino (189). I topi privi di germi hanno alti livelli di steroidi coniugati fecali (190), che si osserva anche dopo l’uso di antibiotici nell’uomo, ad esempio l’uso di ampicillina durante la gravidanza (191). Inoltre, il microbiota intestinale degrada gli steroidi in altri prodotti metabolici. Alcuni batteri influenzano la potenza degli estrogeni convertendo l’estrone in una forma più potente di estradiolo e viceversa (192) (193). Batteri specifici, ad esempio Steroidobacter denitrificans e Comamonas testosteroni trasformano e utilizzano steroidi sessuali (194, 195).

Oltre alla modulazione del metabolismo degli steroidi da parte dei microbi, gli steroidi sessuali possono anche regolare la struttura e la funzione della comunità del microbiota intestinale. Maschi e femmine presentano diversi profili microbici negli animali e nell’uomo (196, 197). Ad esempio, Akkermansia è segnalato per essere più abbondante nelle femmine che nei maschi (198, 199). Perturbazioni degli ormoni sessuali dopo ovariectomia o somministrazione di steroidi sessuali agli animali sposta i loro profili microbioco intestinale (200, 201). Gli steroidi possono anche svolgere un ruolo nel cambiamento dei profili del microbioco durante la gravidanza e dopo la menopausa (202, 203), anche se molti altri fattori influenzano senza dubbio queste comunità del microbiota.

Gli steroidi sessuali influenzano il microbiota intestinale alterando le risposte immunitarie adattative e la funzione batterica. Ad esempio, gli estrogeni aumentano il livello di immunoglobulina A secretoria (IgA) che si lega e controlla la crescita batterica (204). Gli estrogeni coniugati e il bazedoxifene riducono l’attività enzimatica fecale β-glucuronidasi (GUS), che è coinvolta nella deconjugazione microbica degli steroidi (205).

In considerazione dell’interazione tra steroidi sessuali e microbiota intestinale, i batteri potrebbero svolgere un ruolo importante nel mediare gli effetti degli steroidi e contribuire al dimorfismo sessuale nell’IBS. Questa possibilità è supportata dall’esempio del diabete di tipo 1. Come riportato da uno studio sui roditori, l’incidenza femminile predominante del diabete di tipo 1 dipende dal microbiota (206). Il testosterone sierico è più alto nei topi femmina privi di germi rispetto alle femmine SPF, mentre il contrario è evidente nei maschi. La transfaunazione del contenuto cecale maschile in svezzamenti femminili non solo altera il microbioma dei riceventi, ma aumenta anche il loro livello di testosterone e li protegge dal diabete di tipo 1 e dalle malattie autoimmuni. Un altro studio sui topi ha dimostrato che il microbiota è strettamente associato al pregiudizio sessuale nel diabete di tipo 1 (196). Oltre al diabete di tipo 1, la modulazione dei profili del microbiota intestinale da parte degli steroidi sessuali media anche il loro impatto sulla sindrome metabolica (207). “Questi studi forniscono informazioni per studi futuri per valutare l’associazione tra steroidi sessuali e microbiota intestinale nella fisiopatologia IBS.”

MODULAZIONE EPIGENETICA DELL’ASSE MICROBIOTA-INTESTINO-CERVELLO NELL’IBS

L’IBS è un disturbo complesso e multifattoriale dell’asse intestino-cervello e si ritiene che l’epigenetica sia uno dei meccanismi chiave che collega i fattori ambientali alla genetica nell’IBS. L’epigenetica è lo studio dei cambiamenti ereditari dell’espressione genica che sono reversibili e non alterano la sequenza del DNA. I cambiamenti spesso coinvolgono meccanismi tra cui la metilazione del DNA, la modificazione post-traduzionale degli istoni e l’RNA non codificante. In un modello epigenetico di IBS (208), si propone che i primi eventi avversi della vita si traducano in cambiamenti epigenetici dell’asse HPA che successivamente alterano le risposte al fattore di stress ambientale e aumentano la produzione di cortisolo. Le risposte alterate delle citochine e le vie di segnalazione 5-HT sono influenzate e potrebbero contribuire alla manifestazione dei sintomi dell’IBS.

Nell’uomo, il profilo di metilazione del DNA a livello di genoma delle cellule mononucleate del sangue periferico dei pazienti con IBS ha identificato vari geni con stato alterato di metilazione del DNA (209). Nei modelli di IBS indotti dallo stress animale, sono stati identificati geni differenzialmente metilati o espressi, dimostrando l’influenza dello stress sull’epigenoma (210). Inoltre, l’alterazione dell’epigenetica da parte dell’inibitore dell’istone deacetilasi ha ridotto la sensibilità viscerale negli animali stressati (211). In recenti studi, si è dimostrato come la disfunzione della barriera intestinale è associata a segnali epigenetici, ai fattori di stress della prima infanzia.  Questi meccanismi potrebbero essere collegati all’infiammazione intestinale e al dolore addominale (212, 213).

I cambiamenti epigenetici sono evidenti in risposta a vari fattori tra cui l’assunzione dietetica, l’attività fisica e i farmaci. Questi fattori sono anche strettamente associati al microbioma intestinale, mentre i metaboliti microbici influenzano l’epigenetica e guidano l’interazione ospite-microbico. Il microbioma intestinale media gli effetti di diversi fattori ambientali sulla neurotrasmissione enterica attraverso la regolazione epigenetica (214). Dieta a basso contenuto di FODMAP, una dieta a basso contenuto di carboidrati fermentabili che migliora i sintomi dell’IBS, modula la composizione del microbiota intestinale e riduce gli SCFA che sono riconosciuti come inibitori dell’istone deacetilasi e influenzano i processi epigenetici. In uno studio sui topi, il microbiota intestinale ha regolato l’acetilazione e la metilazione globale degli istoni, mentre l’effetto è disturbato dal consumo di dieta occidentale ed è ricapitolato dalla supplementazione di SCFA (215). In un altro studio, il butirrato SCFA contribuisce all’effetto epigenetico sulla differenziazione delle cellule T regolatorie del colon (216). Altri studi hanno anche dimostrato gli effetti scfa sulla modificazione degli istoni nel colon e nel cervello nei roditori (217, 218). Questi rapporti dimostrano che gli SCFA sono prodotti microbici in grado di modulare i segnali epigenetici nell’IBS, possibilmente attraverso la segnalazione alterata dell’asse microbiota-intestino-cervello.

Gli steroidi sessuali sono anche importanti modulatori epigenetici. La diafonia tra l’epigenoma, gli steroidi sessuali e i loro recettori è proposta come meccanismo per il dimorfismo sessuale del sistema nervoso e la funzione immunitaria. Gli estrogeni e l’ER fungono da modulatori epigenetici attraverso diversi meccanismi, tra cui l’alterazione della metilazione del DNA (219) e le modificazioni degli istoni (220). Questi segnali possono influenzare vari fenotipi dipendenti dal sesso, tra cui l’espressione enzimatica, la cognizione e la funzione riproduttiva (221). Allo stesso tempo, gli effetti epigenetici sull’ER provocano cambiamenti nella sua espressione genica e nella risposta agli estrogeni (222), così come il fenotipo dell’ospite compresa la resistenza endocrina nel cancro al seno (223). Simile agli estrogeni, gli androgeni e l’AR possiedono anche effetti di modulazione epigenetica. Questi segnali sono segnalati per essere critici nella sindrome dell’ovaio policistico, in cui l’iperandrogenismo è la caratteristica primaria (224, 225). Inoltre, la regolazione epigenetica dell’AR mediante metilazione del DNA e acetilazione degli istoni è stata suggerita associata a disturbi endocrini e cancro alla prostata (226, 227).

Diversi studi si sono concentrati sull’associazione dell’esposizione precoce agli androgeni e dell’epigenoma durante le fasi dello sviluppo neuronale. Il testosterone perinatale modula l’acetilazione degli istoni durante lo sviluppo del cervello nei topi (228). L’interruzione della modulazione epigenetica altera l’effetto mascolinizzante del testosterone sullo sviluppo della struttura cerebrale sessualmente dimorfica nei topi (229). Presi insieme, gli steroidi sessuali e il microbiota intestinale modulano il fenotipo dell’ospite e l’asse intestino-cervello attraverso meccanismi epigenetici. Sono necessari studi futuri che studino come l’epigenetica è coinvolta nell’interazione tra microbiota e steroidi sessuali nell’IBS.

LA COMUNITÀ MICROBICA COMMENSALE ALTERA I LIVELLI DI ORMONI SESSUALI E REGOLA IL DESTINO DELLE MALATTIE AUTOIMMUNI.

Le esposizioni microbiche e gli ormoni sessuali esercitano potenti effetti sulle malattie autoimmuni, molte delle quali sono più diffuse nelle donne. Dimostriamo che le esposizioni microbiche precoci determinano i livelli di ormoni sessuali e modificano la progressione verso l’autoimmunità nel modello murino diabetico non obeso (NOD) di diabete di tipo 1 (T1D). La colonizzazione da parte di microbi commensali ha aumentato il testosterone sierico e ha protetto i maschi NOD dal T1D. Il trasferimento del microbiota intestinale da maschi adulti a femmine immature ha alterato il microbiota del ricevente, con conseguente aumento del testosterone e cambiamenti metabolomici, riduzione dell’infiammazione delle isole e della produzione di autoanticorpi e robusta protezione dal T1D. Questi effetti dipendevano dall’attività del recettore degli androgeni. Pertanto, la comunità microbica commensale altera i livelli di ormoni sessuali e regola il destino delle malattie autoimmuni in individui ad alto rischio genetico.

 

CONCLUSIONE E PROSPETTIVE FUTURE

Gli steroidi sessuali sono strettamente associati all’insorgenza di IBS e sintomi in molteplici aspetti. Tuttavia, i risultati riguardanti il loro ruolo esatto nell’IBS e nei meccanismi sottostanti sono stati incoerenti. Al momento, non è chiaro se un aumento degli steroidi sessuali è benefico o causale in IBS. Ciò è in parte spiegato dalla natura complicata della chimica degli steroidi e dal loro meccanismo d’azione. Le incongruenze si riflettono anche nella progettazione clinica della coorte e nei modelli animali utilizzati per l’interpretazione dello studio, sottolineando la necessità di stratificare il design dello studio per sesso e standardizzare la dose di trattamento quando si studiano gli steroidi sessuali. Inoltre, se il microbiota intestinale può mediare gli effetti degli steroidi sessuali sull’IBS non è ancora chiaro e merita ulteriori indagini in quanto un precedente è già stato stabilito in altre malattie. Ci sono anche poche informazioni su come gli androgeni surrenali e i prodotti metabolici degli steroidi sessuali sono associati all’IBS e alla segnalazione dell’asse intestino-cervello. Questi ultimi studi  forniscono una base per continuare l’esplorazione della complessa interazione tra steroidi sessuali e metaboliti, i loro recettori e l’asse microbiota-intestino-cervello nella fisiopatologia dell’IBS e delle malattie autoimmuni.

Fonti

Bibliografia

  1. J Neurogastroenterol Motil(2017) 23:151–63. doi: 10.5056/jnm16214

  2. Oka P, Parr H, Barberio B, Black C, Savarino E, Ford A. Global Prevalence of Irritable Bowel Syndrome According to Rome III or IV Criteria: A Systematic Review and Meta-Analysis. Lancet Gastroenterol Hepatol(2020) 5:908–17. doi: 10.1016/S2468-1253(20)30217-X

  3. Fond G, Loundou A, Hamdani N, Boukouaci W, Dargel A, Oliveira J, et al. Anxiety and Depression Comorbidities in Irritable Bowel Syndrome (IBS): A Systematic Review and Meta-Analysis. Eur Arch Psychiatry Clin Neurosci(2014) 264:651–60. doi: 10.1007/s00406-014-0502-z

  4. Han CJ, Yang GS. Fatigue in Irritable Bowel Syndrome: A Systematic Review and Meta-analysis of Pooled Frequency and Severity of Fatigue. Asian Nurs Res (Korean Soc Nurs Sci)(2016) 10:1–10. doi: 10.1016/j.anr.2016.01.003

  5. Aziz I, Törnblom H, Palsson OS, Whitehead WE, Simrén M. How the Change in IBS Criteria From Rome III to Rome Iv Impacts on Clinical Characteristics and Key Pathophysiological Factors. Am J Gastroenterol(2018) 113:1017–25. doi: 10.1038/s41395-018-0074-z

  6. Narayanan SP, Anderson B, Bharucha AE. Sex- and Gender-Related Differences in Common Functional Gastroenterologic Disorders. Mayo Clin Proc(2021) 96:1071–89. doi: 10.1016/j.mayocp.2020.10.004

  7. Camilleri M. Sex as a Biological Variable in Irritable Bowel Syndrome. Neurogastroenterol Motil Off J Eur Gastrointest Motil Soc(2020) 32:e13802. doi: 10.1111/nmo.13802

  8. Kim YS, Kim N. Sex-Gender Differences in Irritable Bowel Syndrome. J Neurogastroenterol Motil(2018) 24:544–58. doi: 10.5056/jnm18082

  9. Bharadwaj S, Barber MD, Graff LA, Shen B. Symptomatology of Irritable Bowel Syndrome and Inflammatory Bowel Disease During the Menstrual Cycle. Gastroenterol Rep(2015) 3:185–93. doi: 10.1093/gastro/gov010

  10. Saito YA. The Role of Genetics in IBS. Gastroenterol Clin North Am(2011) 40:45–67. doi: 10.1016/j.gtc.2010.12.011

  11. Lovell R, Ford A. Effect of Gender on Prevalence of Irritable Bowel Syndrome in the Community: Systematic Review and Meta-Analysis. Am J Gastroenterol(2012) 107:991–1000. doi: 10.1038/ajg.2012.131

  12. Rajindrajith S, Devanarayana NM. Subtypes and Symptomatology of Irritable Bowel Syndrome in Children and Adolescents: A School-Based Survey Using Rome Iii Criteria. J Neurogastroenterol Motil(2012) 18:298–304. doi: 10.5056/jnm.2012.18.3.298

  13. Zhu X, Chen W, Zhu X, Shen Y. A Cross-Sectional Study of Risk Factors for Irritable Bowel Syndrome in Children 8-13 Years of Age in Suzhou, China. Gastroenterol Res Pract(2014) 2014:198461. doi: 10.1155/2014/198461

  14. García Rodríguez LA, Wallander M-A, Johansson S, Olbe AR L. Detection of Colorectal Tumor and Inflammatory Bowel Disease During Follow-up of Patients With Initial Diagnosis of Irritable Bowel Syndrome. Scand J Gastroenterol(2000) 35:306–11. doi: 10.1080/003655200750024191

  15. Triadafilopoulos G, Finlayson M, Grellet C. Bowel Dysfunction in Postmenopausal Women. Women Health(1998) 27:55–66. doi: 10.1300/J013v27n04_04

  16. Olafsdottir LB, Gudjonsson H, Jonsdottir HH, Björnsson E, Thjodleifsson B. Natural History of Irritable Bowel Syndrome in Women and Dysmenorrhea: A 10-Year Follow-Up Study. Gastroenterol Res Pract(2012) 2012:534204. doi: 10.1155/2012/534204

  17. Herman J, Pokkunuri V, Braham L, Pimentel M. Gender Distribution in Irritable Bowel Syndrome is Proportional to the Severity of Constipation Relative to Diarrhea. Gend Med(2010) 7:240–6. doi: 10.1016/j.genm.2010.06.007

  18. 1Ghoshal UC, Abraham P, Bhatt C, Choudhuri G, Bhatia SJ, Shenoy KT, et al. Epidemiological and Clinical Profile of Irritable Bowel Syndrome in India: Report of the Indian Society of Gastroenterology Task Force. Indian J Gastroenterol Off J Indian Soc Gastroenterol(2008) 27:22–8.

  19. Cui J, Shen Y, Li R. Estrogen Synthesis and Signaling Pathways During Aging: From Periphery to Brain. Trends Mol Med(2013) 19:197–209. doi: 10.1016/j.molmed.2012.12.007

  20. Levin ER, Hammes SR. Nuclear Receptors Outside the Nucleus: Extranuclear Signalling by Steroid Receptors. Nat Rev Mol Cell Biol(2016) 17:783–97. doi: 10.1038/nrm.2016.122

  21. Kalyvianaki K, Panagiotopoulos AA, Malamos P, Moustou E, Tzardi M, Stathopoulos EN, et al. Membrane Androgen Receptors (OXER1, GPRC6A and ZIP9) in Prostate and Breast Cancer: A Comparative Study of Their Expression. Steroids(2019) 142:100–8. doi: 10.1016/j.steroids.2019.01.006

  22. Turcu A, Smith JM, Auchus R, Rainey WE. Adrenal Androgens and Androgen Precursors-Definition, Synthesis, Regulation and Physiologic Actions. Compr Physiol(2014) 4:1369–81. doi: 10.1002/cphy.c140006

  23. Storbeck K-H, Bloem LM, Africander D, Schloms L, Swart P, Swart AC. 11β-Hydroxydihydrotestosterone and 11-Ketodihydrotestosterone, Novel C19 Steroids With Androgenic Activity: A Putative Role in Castration Resistant Prostate Cancer? Mol Cell Endocrinol(2013) 377:135–46. doi: 10.1016/j.mce.2013.07.006

  24. Rege J, Turcu AF, Kasa-Vubu JZ, Lerario AM, Auchus GC, Auchus RJ, et al. 11-Ketotestosterone Is the Dominant Circulating Bioactive Androgen During Normal and Premature Adrenarche. J Clin Endocrinol Metab(2018) 103:4589–98. doi: 10.1210/jc.2018-00736

  25. Rege J, Nakamura Y, Satoh F, Morimoto R, Kennedy MR, Layman LC, et al. Liquid Chromatography–Tandem Mass Spectrometry Analysis of Human Adrenal Vein 19-Carbon Steroids Before and After Acth Stimulation. J Clin Endocrinol Metab(2013) 98:1182–8. doi: 10.1210/jc.2012-2912

  26. Tajar A, Forti G, O’Neill TW, Lee DM, Silman AJ, Finn JD, et al. Characteristics of Secondary, Primary, and Compensated Hypogonadism in Aging Men: Evidence From the European Male Ageing Study. J Clin Endocrinol Metab(2010) 95:1810–8. doi: 10.1210/jc.2009-1796

  27. Stanikova D, Zsido RG, Luck T, Pabst A, Enzenbach C, Bae YJ, et al. Testosterone Imbalance may Link Depression and Increased Body Weight in Premenopausal Women. Transl Psychiatry(2019) 9:160. doi: 10.1038/s41398-019-0487-5

  28. Majewska MD, Demirgo¨ren S, Spivak CE, London ED. The Neurosteroid Dehydroepiandrosterone Sulfate is an Allosteric Antagonist of the GABAA Receptor. Brain Res(1990) 526:143–6. doi: 10.1016/0006-8993(90)90261-9

  29. Weaver KR, Boulineaux CM, Robinson JM, Butler K, Heitkemper MM, Henderson WA. Sex Hormones, Bdnf, Leptin, and TGF-β1 in Females With Ibs: A Pilot Investigation. Biol Res Nurs(2020) 23:231–7. doi: 10.1177/1099800420948589

  30. Miller V, Whitaker K, Morris JA, Whorwell PJ. Gender and Irritable Bowel Syndrome: The Male Connection. J Clin Gastroenterol(2004) 38:558–60. doi: 10.1097/00004836-200408000-00004

  31. Kim BJ, Rhee P-L, Park JH, Chang DK, Kim Y-H, Son HJ, et al. Male Sex Hormones May Influence the Symptoms of Irritable Bowel Syndrome in Young Men. Digestion(2008) 78:88–92. doi: 10.1159/000166600

  32. Mathur R, Ko A, Hwang LJ, Low K, Azziz R, Pimentel M. Polycystic Ovary Syndrome Is Associated With an Increased Prevalence of Irritable Bowel Syndrome. Dig Dis Sci(2010) 55:1085–9. doi: 10.1007/s10620-009-0890-5

  33. Adeyemo MA, Spiegel BMR, Chang L. Meta-Analysis: do Irritable Bowel Syndrome Symptoms Vary Between Men and Women? Aliment Pharmacol Ther(2010) 32:738–55. doi: 10.1111/j.1365-2036.2010.04409.x

  34. Chang L, Mayer EA, Labus JS, Schmulson M, Lee OY, Olivas TI, et al. Effect of Sex on Perception of Rectosigmoid Stimuli in Irritable Bowel Syndrome. Am J Physiol Regul Integr Comp Physiol(2006) 291:R277–84. doi: 10.1152/ajpregu.00729.2005

  35. Naliboff BD, Berman S, Chang L, Derbyshire SWG, Suyenobu B, Vogt BA, et al. Sex-Related Differences in IBS Patients: Central Processing of Visceral Stimuli. Gastroenterology(2003) 124:1738–47. doi: 10.1016/s0016-5085(03)00400-1

  36. Icenhour A, Labrenz F, Roderigo T, Siebert C, Elsenbruch S, Benson S. Are There Sex Differences in Visceral Sensitivity in Young Healthy Men and Women? Neurogastroenterol Motil(2019) 31:e13664. doi: 10.1111/nmo.13664

  37. Hubbard CS, Karpowicz JM, Furman AJ, da Silva JT, Seminowicz DA, Traub RJ. Estrogen-Dependent Visceral Hypersensitivity Following Stress in Rats: An fMRI Study. Mol Pain(2016) 12:1744806916654145. doi: 10.1177/1744806916654145

  38. Ji Y, Hu B, Li J, Traub RJ. Opposing Roles of Estradiol and Testosterone on Stress-Induced Visceral Hypersensitivity in Rats. J Pain(2018) 19:764–76. doi: 10.1016/j.jpain.2018.02.007

  39. Lu C-L, Hsieh J-C, Tsaur M-L, Huang Y-H, Wang PS, Wu L-L, et al. Estrogen Rapidly Modulates Mustard Oil-Induced Visceral Hypersensitivity in Conscious Female Rats: A Role of CREB Phosphorylation in Spinal Dorsal Horn Neurons. Am J Physiol Liver Physiol(2007) 292:G438–46. doi: 10.1152/ajpgi.00210.2006

  40. Aloisi AM, Affaitati G, Ceccarelli I, Fiorenzani P, Lerza R, Rossi C, et al. Estradiol and Testosterone Differently Affect Visceral Pain-Related Behavioural Responses in Male and Female Rats. Eur J Pain(2010) 14:602–7. doi: 10.1016/j.ejpain.2009.10.016

  41. Qin B, Dong L, Guo X, Jiang J, He Y, Wang X, et al. Expression of G Protein-Coupled Estrogen Receptor in Irritable Bowel Syndrome and its Clinical Significance. Int J Clin Exp Pathol(2014) 7:2238–46.

  42. Amandusson A, Hallbeck M, Hallbeck AL, Hermanson O, Blomqvist A. Estrogen-Induced Alterations of Spinal Cord Enkephalin Gene Expression. Pain(1999) 83:243–8. doi: 10.1016/s0304-3959(99)00109-8

  43. Taleghany N, Sarajari S, DonCarlos LL, Gollapudi L, Oblinger MM. Differential Expression of Estrogen Receptor Alpha and Beta in Rat Dorsal Root Ganglion Neurons. J Neurosci Res(1999) 57:603–15. doi: 10.1002/(SICI)1097-4547(19990901)57:5<603::AID-JNR3>3.0.CO;2-R

  44. Shughrue PJ, Lane MV, Merchenthaler I. Comparative Distribution of Estrogen Receptor-Alpha and -Beta mRNA in the Rat Central Nervous System. J Comp Neurol(1997) 388:507–25. doi: 10.1002/(sici)1096-9861(19971201)388:4<507::aid-cne1>3.0.co;2-6

  45. Sun L-H, Zhang W-X, Xu Q, Wu H, Jiao C-C, Chen X-Z. Estrogen Modulation of Visceral Pain. J Zhejiang Univ Sci B(2019) 20:628–36. doi: 10.1631/jzus.B1800582

  46. Akbar A, Yiangou Y, Facer P, Walters JRF, Anand P, Ghosh S. Increased Capsaicin Receptor TRPV1-expressing Sensory Fibres in Irritable Bowel Syndrome and Their Correlation With Abdominal Pain. Gut(2008) 57:923–9. doi: 10.1136/gut.2007.138982

  47. Du Q, Liao Q, Chen C, Yang X, Xie R, Xu J. The Role of Transient Receptor Potential Vanilloid 1 in Common Diseases of the Digestive Tract and the Cardiovascular and Respiratory System. Front Physiol(2019) 10:1064. doi: 10.3389/fphys.2019.01064

  48. Payrits M, Sághy É, Csekő K, Pohóczky K, Bölcskei K, Ernszt D, et al. Estradiol Sensitizes the Transient Receptor Potential Vanilloid 1 Receptor in Pain Responses. Endocrinology(2017) 158:3249–58. doi: 10.1210/en.2017-00101

  49. Yamagata K, Sugimura M, Yoshida M, Sekine S, Kawano A, Oyamaguchi A, et al. Estrogens Exacerbate Nociceptive Pain Via Up-Regulation of TRPV1 and ANO1 in Trigeminal Primary Neurons of Female Rats. Endocrinology(2016) 157:4309–17. doi: 10.1210/en.2016-1218

  50. Greaves E, Grieve K, Horne AW, Saunders PTK. Elevated Peritoneal Expression and Estrogen Regulation of Nociceptive Ion Channels in Endometriosis. J Clin Endocrinol Metab(2014) 99:E1738–43. doi: 10.1210/jc.2014-2282

  51. Méndez-Reséndiz KA, Enciso-Pablo Ó, González-Ramírez R, Juárez-Contreras R, Rosenbaum T, Morales-Lázaro SL. Steroids and TRP Channels: A Close Relationship. Int J Mol Sci(2020) 21:3819. doi: 10.3390/ijms21113819

  52. Smith YR, Stohler CS, Nichols TE, Bueller JA, Koeppe RA, Zubieta J-K. Pronociceptive and Antinociceptive Effects of Estradiol Through Endogenous Opioid Neurotransmission in Women. J Neurosci(2006) 26:5777–85. doi: 10.1523/JNEUROSCI.5223-05.2006

  53. Houghton LA, Jackson NA, Whorwell PJ, Morris J. Do Male Sex Hormones Protect From Irritable Bowel Syndrome? Am J Gastroenterol(2000) 95:2296–300. doi: 10.1016/S0002-9270(00)01106-0

  54. Asuthkar S, Velpula KK, Elustondo PA, Demirkhanyan L, Zakharian E. TRPM8 Channel as a Novel Molecular Target in Androgen-Regulated Prostate Cancer Cells. Oncotarget(2015) 6:17221–36. doi: 10.18632/oncotarget.3948

  55. Asuthkar S, Elustondo PA, Demirkhanyan L, Sun X, Baskaran P, Velpula KK, et al. The TRPM8 Protein is a Testosterone Receptor: I. Biochemical Evidence for Direct TRPM8-testosterone Interactions. J Biol Chem(2015) 290:2659–69. doi: 10.1074/jbc.M114.610824

  56. Bidaux G, Roudbaraki M, Merle C, Crépin A, Delcourt P, Slomianny C, et al. Evidence for Specific TRPM8 Expression in Human Prostate Secretory Epithelial Cells: Functional Androgen Receptor Requirement. Endocr Relat Cancer(2005) 12:367–82. doi: 10.1677/erc.1.00969

  57. Henström M, Hadizadeh F, Beyder A, Bonfiglio F, Zheng T, Assadi G, et al. TRPM8 Polymorphisms Associated With Increased Risk of IBS-C and IBS-M. Gut(2017) 66:1725–7. doi: 10.1136/gutjnl-2016-313346

  58. Harrington AM, Hughes PA, Martin CM, Yang J, Castro J, Isaacs NJ, et al. A Novel Role for TRPM8 in Visceral Afferent Function. PAIN®(2011) 152:1459–68. doi: 10.1016/j.pain.2011.01.027

  59. Cappello G, Spezzaferro M, Grossi L, Manzoli L, Marzio L. Peppermint Oil (Mintoil®) in the Treatment of Irritable Bowel Syndrome: A Prospective Double Blind Placebo-Controlled Randomized Trial. Dig Liver Dis(2007) 39:530–6. doi: 10.1016/j.dld.2007.02.006

  60. Ford AC, Talley NJ, Spiegel BMR, Foxx-Orenstein AE, Schiller L, Quigley EMM, et al. Effect of Fibre, Antispasmodics, and Peppermint Oil in the Treatment of Irritable Bowel Syndrome: Systematic Review and Meta-Analysis. BMJ(2008) 337:a2313. doi: 10.1136/bmj.a2313

  61. Degen LP, Phillips SF. Variability of Gastrointestinal Transit in Healthy Women and Men. Gut(1996) 39:299–305. doi: 10.1136/gut.39.2.299

  62. Fischer M, Fadda HM. The Effect of Sex and Age on Small Intestinal Transit Times in Humans. J Pharm Sci(2016) 105:682–6. doi: 10.1002/jps.24619

  63. Sadik R, Abrahamsson H, Stotzer P-O. Gender Differences in Gut Transit Shown With a Newly Developed Radiological Procedure. Scand J Gastroenterol(2003) 38:36–42. doi: 10.1080/00365520310000410

  64. Jung H-K, Kim D-Y, Moon I-H. Effects of Gender and Menstrual Cycle on Colonic Transit Time in Healthy Subjects. Korean J Intern Med(2003) 18:181–6. doi: 10.3904/kjim.2003.18.3.181

  65. Al−Shboul AO, Nazzal SM, Mustafa GA, Al−Dwairi NA, Alqudah AM, Abu Omar A, et al. Estrogen Relaxes Gastric Muscle Cells Via a Nitric Oxide− and Cyclic Guanosine Monophosphate−Dependent Mechanism: A Sex−Associated Differential Effect. Exp Ther Med(2018) 16:1685–92. doi: 10.3892/etm.2018.6406

  66. Li Y, Xu J, Jiang F, Jiang Z, Liu C, Li L, et al. G Protein-Coupled Estrogen Receptor is Involved in Modulating Colonic Motor Function Via Nitric Oxide Release in C57BL/6 Female Mice. Neurogastroenterol Motil(2016) 28:432–42. doi: 10.1111/nmo.12743

  67. Zielińska M, Fichna J, Bashashati M, Habibi S, Sibaev A, Timmermans J-P, et al. G Protein-Coupled Estrogen Receptor and Estrogen Receptor Ligands Regulate Colonic Motility and Visceral Pain. Neurogastroenterol Motil(2017) 29:e13025. doi: 10.1111/nmo.13025

  68. Jacenik D, Cygankiewicz AI, Fichna J, Mokrowiecka A, Małecka-Panas E, Krajewska WM. Estrogen Signaling Deregulation Related With Local Immune Response Modulation in Irritable Bowel Syndrome. Mol Cell Endocrinol(2018) 471:89–96. doi: 10.1016/j.mce.2017.07.036

  69. De Schepper HU, De Man JG, Ruyssers NE, Deiteren A, Van Nassauw L, Timmermans J-P, et al. TRPV1 Receptor Signaling Mediates Afferent Nerve Sensitization During Colitis-Induced Motility Disorders in Rats. Am J Physiol Liver Physiol(2008) 294:G245–53. doi: 10.1152/ajpgi.00351.2007

  70. De Man JG, Boeckx S, Anguille S, De Winter BY, De Schepper HU, Herman AG, et al. Functional Study on TRPV1-mediated Signalling in the Mouse Small Intestine: Involvement of Tachykinin Receptors. Neurogastroenterol Motil(2008) 20:546–56. doi: 10.1111/j.1365-2982.2007.01064.x

  71. Rahmati R. The Transient Receptor Potential Vanilloid Receptor 1, TRPV1 (VR1) Inhibits Peristalsis in the Mouse Jejunum. Arch Iran Med(2012) 15:433–8.

  72. Szymaszkiewicz A, Włodarczyk J, Wasilewski A, Di Marzo V, Storr M, Fichna J, et al. Desensitization of Transient Receptor Potential Vanilloid Type-1 (TRPV1) Channel as Promising Therapy of Irritable Bowel Syndrome: Characterization of the Action of Palvanil in the Mouse Gastrointestinal Tract. Naunyn Schmiedebergs Arch Pharmacol(2020) 393:1357–64. doi: 10.1007/s00210-020-01829-x

  73. Chen TS, Doong ML, Chang FY, Lee SD, Wang PS. Effects of Sex Steroid Hormones on Gastric Emptying and Gastrointestinal Transit in Rats. Am J Physiol Liver Physiol(1995) 268:G171–6. doi: 10.1152/ajpgi.1995.268.1.G171

  74. González-Montelongo MC, Marín R, Gómez T, Marrero-Alonso J, Díaz M. Androgens Induce Nongenomic Stimulation of Colonic Contractile Activity Through Induction of Calcium Sensitization and Phosphorylation of LC20 and CPI-17. Mol Endocrinol(2010) 24:1007–23. doi: 10.1210/me.2009-0472

  75. González-Montelongo M del C, Marin R, Gómez T, Diaz M. Androgens Differentially Potentiate Mouse Intestinal Smooth Muscle by Nongenomic Activation of Polyamine Synthesis and Rho Kinase Activation. Endocrinology(2007) 147:5715–29. doi: 10.1210/en.2006-0780

  76. Blanchard EB, Keefer L, Galovski TE, Taylor AE, Turner SM. Gender Differences in Psychological Distress Among Patients With Irritable Bowel Syndrome. J Psychosom Res(2001) 50:271–5. doi: 10.1016/S0022-3999(01)00207-0

  77. Tang Y, Yang W, Wang Y-L, Lin L. Sex Differences in the Symptoms and Psychological Factors That Influence Quality of Life in Patients With Irritable Bowel Syndrome. Eur J Gastroenterol Hepatol(2012) 24:702–7. doi: 10.1097/MEG.0b013e328351b2c2

  78. Simrén M, Abrahamsson H, Svedlund J, Björnsson ES. Quality of Life in Patients With Irritable Bowel Syndrome Seen in Referral Centers Versus Primary Care: The Impact of Gender and Predominant Bowel Pattern. Scand J Gastroenterol(2001) 36:545–52. doi: 10.1080/003655201750153476

  79. Kvrgic S, Harhaji S, Mijatovic Jovanovic V, Ac Nikolic E, Radic I, Cankovic S, et al. Gender Differences in Mental Health Among Adult Population in Vojvodina, Serbia. Iran J Public Health(2013) 42:833–41.

  80. Matud MP, Bethencourt JM, Ibáñez I. Gender Differences in Psychological Distress in Spain. Int J Soc Psychiatry(2015) 61:560–8. doi: 10.1177/0020764014564801

  81. Van Droogenbroeck F, Spruyt B, Keppens G. Gender Differences in Mental Health Problems Among Adolescents and the Role of Social Support: Results From the Belgian Health Interview Surveys 2008 and 2013. BMC Psychiatry(2018) 18:6. doi: 10.1186/s12888-018-1591-4

  82. Hantsoo L, Epperson CN. Premenstrual Dysphoric Disorder: Epidemiology and Treatment. Curr Psychiatry Rep(2015) 17:87. doi: 10.1007/s11920-015-0628-3

  83. Borrow AP, Handa RJ. Estrogen Receptors Modulation of Anxiety-Like Behavior. Vitam Horm(2017) 103:27–52. doi: 10.1016/bs.vh.2016.08.004

  84. Chen CV, Brummet JL, Lonstein JS, Jordan CL, Breedlove SM. New Knockout Model Confirms a Role for Androgen Receptors in Regulating Anxiety-Like Behaviors and HPA Response in Mice. Horm Behav(2014) 65:211–8. doi: 10.1016/j.yhbeh.2014.01.001

  85. Walther A, Breidenstein J, Miller R. Association of Testosterone Treatment With Alleviation of Depressive Symptoms in Men: A Systematic Review and Meta-Analysis. JAMA Psychiatry(2019) 76:31–40. doi: 10.1001/jamapsychiatry.2018.2734

  86. Wong SYS, Leung JC, Kwok T, Ohlsson C, Vandenput L, Leung PC, et al. Low DHEAS Levels are Associated With Depressive Symptoms in Elderly Chinese Men: Results From a Large Study. Asian J Androl(2011) 13:898–902. doi: 10.1038/aja.2011.116

  87. Morsink LFJ, Vogelzangs N, Nicklas BJ, Beekman ATF, Satterfield S, Rubin SM, et al. Associations Between Sex Steroid Hormone Levels and Depressive Symptoms in Elderly Men and Women: Results From the Health ABC Study. Psychoneuroendocrinology(2007) 32:874–83. doi: 10.1016/j.psyneuen.2007.06.009

  88. Wald A, Van Thiel DH, Hoechstetter L, Gavaler JS, Egler KM, Verm R, et al. Gastrointestinal Transit: The Effect of the Menstrual Cycle. Gastroenterol (New York NY 1943)(1981) 80:1497–500. doi: 10.1016/0016-5085(81)90263-8

  89. Heitkemper MM, Chang L. Do Fluctuations in Ovarian Hormones Affect Gastrointestinal Symptoms in Women With Irritable Bowel Syndrome? Gend Med(2009) 6 Suppl 2:152–67. doi: 10.1016/j.genm.2009.03.004

  90. Lee OY, Mayer EA, Schmulson M, Chang L, Naliboff B. Gender-Related Differences in IBS Symptoms. Am J Gastroenterol(2001) 96:2184–93. doi: 10.1016/S0002-9270(01)02524-2

  91. Houghton LA, Lea R, Jackson N, Whorwell PJ. The Menstrual Cycle Affects Rectal Sensitivity in Patients With Irritable Bowel Syndrome But Not Healthy Volunteers. Gut(2002) 50:471–4. doi: 10.1136/gut.50.4.471

  92. Hutson WR, Roehrkasse RL, Wald A. Influence of Gender and Menopause on Gastric Emptying and Motility. Gastroenterology(1989) 96:11–7. doi: 10.1016/0016-5085(89)90758-0

  93. Chiloiro M, Darconza G, Piccioli E, De Carne M, Clemente C, Riezzo G. Gastric Emptying and Orocecal Transit Time in Pregnancy. J Gastroenterol(2001) 36:538–43. doi: 10.1007/s005350170056

  94. Iwasaki H, Collins JG, Saito Y, Kerman-Hinds A. Naloxone-Sensitive, Pregnancy-Induced Changes in Behavioral Responses to Colorectal Distention: Pregnancy-Induced Analgesia to Visceral Stimulation. Anesthesiol J Am Soc Anesthesiol Inc(1991) 74:927–33. doi: 10.1097/00000542-199105000-00019

  95. van Kessel L, Teunissen D, Lagro-Janssen T. Sex-Gender Differences in the Effectiveness of Treatment of Irritable Bowel Syndrome: A Systematic Review. Int J Gen Med(2021) 14:867–84. doi: 10.2147/IJGM.S291964

  96. Camilleri M, Mayer EA, Drossman DA, Heath A, Dukes GE, McSorley D, et al. Improvement in Pain and Bowel Function in Female Irritable Bowel Patients With Alosetron, a 5-HT3 Receptor Antagonist. Aliment Pharmacol Ther(1999) 13:1149–59. doi: 10.1046/j.1365-2036.1999.00610.x

  97. Koch KM, Palmer JL, Noordin N, Tomlinson JJ, Baidoo C. Sex and Age Differences in the Pharmacokinetics of Alosetron. Br J Clin Pharmacol(2002) 53:238–42. doi: 10.1046/j.0306-5251.2001.01565.x

  98. Cash BD, Epstein MS, Shah SM. A Novel Delivery System of Peppermint Oil Is an Effective Therapy for Irritable Bowel Syndrome Symptoms. Dig Dis Sci(2016) 61:560–71. doi: 10.1007/s10620-015-3858-7

  99. Labus JS, Dinov ID, Jiang Z, Ashe-McNalley C, Zamanyan A, Shi Y, et al. Irritable Bowel Syndrome in Female Patients is Associated With Alterations in Structural Brain Networks. Pain(2014) 155:137–49. doi: 10.1016/j.pain.2013.09.020

  100. Blankstein U, Chen J, Diamant NE, Davis KD. Altered Brain Structure in Irritable Bowel Syndrome: Potential Contributions of Pre-Existing and Disease-Driven Factors. Gastroenterology(2010) 138:1783–9. doi: 10.1053/j.gastro.2009.12.043

  101. Alzahrani MA, Alshamrani AS, Ahmasani IM, Alahmari FS, Asiri AH, Alshehri AM, et al. Coronavirus Disease 2019 Pandemic Stress and its Effects on Irritable Bowel Syndrome Patients in Saudi Arabia. Med (Baltimore)(2020) 99(51):e23711. doi: 10.1097/MD.0000000000023711

  102. Drossman DA, Leserman J, Nachman G, Li ZM, Gluck H, Toomey TC, et al. Sexual and Physical Abuse in Women With Functional or Organic Gastrointestinal Disorders. Ann Intern Med(1990) 113:828–33. doi: 10.7326/0003-4819-113-11-828

  103. Walker EA, Katon WJ, Roy-Byrne PP, Jemelka RP, Russo J. Histories of Sexual Victimization in Patients With Irritable Bowel Syndrome or Inflammatory Bowel Disease. Am J Psychiatry(1993) 150:1502–6. doi: 10.1176/ajp.150.10.1502

  104. Bradford K, Shih W, Videlock EJ, Presson AP, Naliboff BD, Mayer EA, et al. Association Between Early Adverse Life Events and Irritable Bowel Syndrome. Clin Gastroenterol Hepatol(2012) 10:385–90.e903. doi: 10.1016/j.cgh.2011.12.018

  105. Kanuri N, Cassell B, Bruce SE, White KS, Gott BM, Gyawali CP, et al. The Impact of Abuse and Mood on Bowel Symptoms and Health-Related Quality of Life in Irritable Bowel Syndrome (IBS). Neurogastroenterol Motil(2016) 28:1508–17. doi: 10.1111/nmo.12848

  106. Heitkemper MM, Cain KC, Burr RL, Jun S-E, Jarrett ME. Is Childhood Abuse or Neglect Associated With Symptom Reports and Physiological Measures in Women With Irritable Bowel Syndrome? Biol Res Nurs(2011) 13:399–408. doi: 10.1177/1099800410393274

  107. Smith SM, Vale WW. The Role of the Hypothalamic-Pituitary-Adrenal Axis in Neuroendocrine Responses to Stress. Dialogues Clin Neurosci(2006) 8:383–95. doi: 10.31887/DCNS.2006.8.4/ssmith

  108. Chang L, Sundaresh S, Elliott J, Anton PA, Baldi P, Licudine A, et al. Dysregulation of the Hypothalamic-Pituitary-Adrenal (HPA) Axis in Irritable Bowel Syndrome. Neurogastroenterol Motil(2009) 21:149–59. doi: 10.1111/j.1365-2982.2008.01171.x

  109. Fukudo S, Nomura T, Hongo M. Impact of Corticotropin-Releasing Hormone on Gastrointestinal Motility and Adrenocorticotropic Hormone in Normal Controls and Patients With Irritable Bowel Syndrome. Gut(1998) 42:845–9. doi: 10.1136/gut.42.6.845

  110. Dinan TG, Quigley EMM, Ahmed SMM, Scully P, O’Brien S, O’Mahony L, et al. Hypothalamic-Pituitary-Gut Axis Dysregulation in Irritable Bowel Syndrome: Plasma Cytokines as a Potential Biomarker? Gastroenterology(2006) 130:304–11. doi: 10.1053/j.gastro.2005.11.033

  111. Kano M, Muratsubaki T, Van Oudenhove L, Morishita J, Yoshizawa M, Kohno K, et al. Altered Brain and Gut Responses to Corticotropin-Releasing Hormone (CRH) in Patients With Irritable Bowel Syndrome. Sci Rep(2017) 7:12425. doi: 10.1038/s41598-017-09635-x

  112. Böhmelt AH, Nater UM, Franke S, Hellhammer DH, Ehlert U. Basal and Stimulated Hypothalamic-Pituitary-Adrenal Axis Activity in Patients With Functional Gastrointestinal Disorders and Healthy Controls. Psychosom Med(2005) 67:288–94. doi: 10.1097/01.psy.0000157064.72831.ba

  113. Videlock EJ, Shih W, Adeyemo M, Mahurkar-Joshi S, Presson AP, Polytarchou C, et al. The Effect of Sex and Irritable Bowel Syndrome on HPA Axis Response and Peripheral Glucocorticoid Receptor Expression. Psychoneuroendocrinology(2016) 69:67–76. doi: 10.1016/j.psyneuen.2016.03.016

  114. Kirschbaum C, Kudielka BM, Gaab J, Schommer NC, Hellhammer DH. Impact of Gender, Menstrual Cycle Phase, and Oral Contraceptives on the Activity of the Hypothalamus-Pituitary-Adrenal Axis. Psychosom Med(1999) 61:154–62. doi: 10.1097/00006842-199903000-00006

  115. Seale JV, Wood SA, Atkinson HC, Harbuz MS, Lightman SL. Gonadal Steroid Replacement Reverses Gonadectomy-Induced Changes in the Corticosterone Pulse Profile and Stress-Induced Hypothalamic-Pituitary-Adrenal Axis Activity of Male and Female Rats. J Neuroendocrinol(2004) 16:989–98. doi: 10.1111/j.1365-2826.2004.01258.x

  116. Figueiredo HF, Ulrich-Lai YM, Choi DC, Herman JP. Estrogen Potentiates Adrenocortical Responses to Stress in Female Rats. Am J Physiol Metab(2007) 292:E1173–82. doi: 10.1152/ajpendo.00102.2006

  117. Lund TD, Hinds LR, Handa RJ. The Androgen 5alpha-Dihydrotestosterone and its Metabolite 5alpha-androstan-3beta, 17beta-Diol Inhibit the Hypothalamo-Pituitary-Adrenal Response to Stress by Acting Through Estrogen Receptor Beta-Expressing Neurons in the Hypothalamus. J Neurosci(2006) 26:1448–56. doi: 10.1523/JNEUROSCI.3777-05.2006

  118. Seale JV, Wood SA, Atkinson HC, Bate E, Lightman SL, Ingram CD, et al. Gonadectomy Reverses the Sexually Diergic Patterns of Circadian and Stress-Induced Hypothalamic-Pituitary-Adrenal Axis Activity In Male and Female Rats. J Neuroendocrinol(2004) 16:516–24. doi: 10.1111/j.1365-2826.2004.01195.x

  119. Ochedalski T, Subburaju S, Wynn PC, Aguilera G. Interaction Between Oestrogen and Oxytocin on Hypothalamic-Pituitary-Adrenal Axis Activity. J Neuroendocrinol(2007) 19:189–97. doi: 10.1111/j.1365-2826.2006.01525.x

  120. Young EA, Altemus M, Parkison V, Shastry S. Effects of Estrogen Antagonists and Agonists on the ACTH Response to Restraint Stress in Female Rats. Neuropsychopharmacology(2001) 25:881–91. doi: 10.1016/S0893-133X(01)00301-3

  121. Handa RJ, Weiser MJ. Gonadal Steroid Hormones and the Hypothalamo-Pituitary-Adrenal Axis. Front Neuroendocrinol(2014) 35:197–220. doi: 10.1016/j.yfrne.2013.11.001

  122. Kirschbaum C, Schommer N, Federenko I, Gaab J, Neumann O, Oellers M, et al. Short-Term Estradiol Treatment Enhances Pituitary-Adrenal Axis and Sympathetic Responses to Psychosocial Stress in Healthy Young Men. J Clin Endocrinol Metab(1996) 81:3639–43. doi: 10.1210/jcem.81.10.8855815

  123. Kudielka BM, Schmidt-Reinwald AK, Hellhammer DH, Kirschbaum C. Psychological and Endocrine Responses to Psychosocial Stress and Dexamethasone/ Corticotropin-Releasing Hormone in Healthy Postmenopausal Women and Young Controls: The Impact of Age and a Two-Week Estradiol Treatment. Neuroendocrinology(1999) 70:422–30. doi: 10.1159/000054504

  124. Liu J, Bisschop PH, Eggels L, Foppen E, Fliers E, Zhou JN, et al. Intrahypothalamic Estradiol Modulates Hypothalamus-Pituitary-Adrenal-Axis Activity in Female Rats. Endocrinology(2012) 153:3337–44. doi: 10.1210/en.2011-2176

  125. Viau V, Meaney MJ. Testosterone-Dependent Variations in Plasma and Intrapituitary Corticosteroid Binding Globulin and Stress Hypothalamic-Pituitary-Adrenal Activity in the Male Rat. J Endocrinol(2004) 181:223–31. doi: 10.1677/joe.0.1810223

  126. Toufexis DJ, Wilson ME. Dihydrotestosterone Differentially Modulates the Cortisol Response of the Hypothalamic-Pituitary-Adrenal Axis in Male and Female Rhesus Macaques, and Restores Circadian Secretion of Cortisol in Females. Brain Res(2012) 1429:43–51. doi: 10.1016/j.brainres.2011.10.024

  127. Rubinow DR, Roca CA, Schmidt PJ, Danaceau MA, Putnam K, Cizza G, et al. Testosterone Suppression of CRH-stimulated Cortisol in Men. Neuropsychopharmacology(2005) 30:1906–12. doi: 10.1038/sj.npp.1300742

  128. Zuloaga DG, Poort JE, Jordan CL, Breedlove SM. Male Rats With the Testicular Feminization Mutation of the Androgen Receptor Display Elevated Anxiety-Related Behavior and Corticosterone Response to Mild Stress. Horm Behav(2011) 60:380–8. doi: 10.1016/j.yhbeh.2011.07.008

  129. Zuloaga DG, Morris JA, Jordan CL, Breedlove SM. Mice With the Testicular Feminization Mutation Demonstrate a Role for Androgen Receptors in the Regulation of Anxiety-Related Behaviors and the Hypothalamic–Pituitary–Adrenal Axis. Horm Behav(2008) 54:758–66. doi: 10.1016/j.yhbeh.2008.08.004

  130. Tillisch K, Mayer EA, Labus JS, Stains J, Chang L, Naliboff BD. Sex Specific Alterations in Autonomic Function Among Patients With Irritable Bowel Syndrome. Gut(2005) 54:1396–401. doi: 10.1136/gut.2004.058685

  131. Waring WS, Chui M, Japp A, Nicol EF, Ford MJ. Autonomic Cardiovascular Responses Are Impaired in Women With Irritable Bowel Syndrome. J Clin Gastroenterol(2004) 38:658–63. doi: 10.1097/01.mcg.0000135362.35665.49

  132. Burr RL, Heitkemper M, Jarrett M, Cain KC. Comparison of Autonomic Nervous System Indices Based on Abdominal Pain Reports in Women With Irritable Bowel Syndrome. Biol Res Nurs(2000) 2:97–106. doi: 10.1177/109980040000200203

  133. Yildirir A, Kabakci G, Akgul E, Tokgozoglu L, Oto A. Effects of Menstrual Cycle on Cardiac Autonomic Innervation as Assessed by Heart Rate Variability. Ann Noninvasive Electrocardiol(2002) 7:60–3. doi: 10.1111/j.1542-474x.2001.tb00140.x

  134. Mercuro G, Podda A, Pitzalis L, Zoncu S, Mascia M, Melis GB, et al. Evidence of a Role of Endogenous Estrogen in the Modulation of Autonomic Nervous System. Am J Cardiol(2000) 85:787–9. doi: 10.1016/S0002-9149(99)00865-6

  135. Carnethon MR, Anthony MS, Cascio WE, Folsom AR, Rautaharju PM, Liao D, et al. Prospective Association Between Hormone Replacement Therapy, Heart Rate, and Heart Rate Variability: The Atherosclerosis Risk in Communities Study. J Clin Epidemiol(2003) 56:565–71. doi: 10.1016/S0895-4356(03)00008-8

  136. Virtanen I, Polo-Kantola P, Erkkola R, Polo O, Ekholm E. Climacteric Vasomotor Symptoms do Not Imply Autonomic Dysfunction. BJOG Int J Obstet Gynaecol(1999) 106:155–64. doi: 10.1111/j.1471-0528.1999.tb08216.x

  137. Liu CC, Kuo TBJ, Yang CCH. Effects of Estrogen on Gender-Related Autonomic Differences in Humans. Am J Physiol Circ Physiol(2003) 285:H2188–93. doi: 10.1152/ajpheart.00256.2003

  138. Rosano GMC, Patrizi R, Leonardo F, Ponikowski P, Collins P, Sarrel PM, et al. Effect of Estrogen Replacement Therapy on Heart Rate Variability and Heart Rate in HealthyPostmenopausal Women. Am J Cardiol(1997) 80:815–7. doi: 10.1016/S0002-9149(97)00528-6

  139. Rosa Brito-Zurita O, Posadas-Romero C, Hermosillo AG, Zamora-González J, Hernández-Ono A, Cardoso-Saldaña G, et al. Estrogen Effect on Heart Rate Variability in Hypertensive Postmenopausal Women. Maturitas(2003) 44:39–48. doi: 10.1016/S0378-5122(02)00294-3

  140. Liang Y, Yao S. Potential Role of Estrogen in Maintaining the Imbalanced Sympathetic and Sensory Innervation in Endometriosis. Mol Cell Endocrinol(2016) 424:42–9. doi: 10.1016/j.mce.2016.01.012

  141. Doğru MT, Başar MM, Yuvanç E, Şimşek V, Şahin Ö. The Relationship Between Serum Sex Steroid Levels and Heart Rate Variability Parameters in Males and the Effect of Age. Arch Turkish Soc Cardiol(2010) 38:459–65.

  142. Yildirir A, Aybar F, Kabakci G, Yarali H, Oto A. Heart Rate Variability in Young Women With Polycystic Ovary Syndrome. Ann Noninvasive Electrocardiol(2006) 11:306–12. doi: 10.1111/j.1542-474X.2006.00122.x

  143. Nohara K, Waraich RS, Liu S, Ferron M, Waget A, Meyers MS, et al. Developmental Androgen Excess Programs Sympathetic Tone and Adipose Tissue Dysfunction and Predisposes to a Cardiometabolic Syndrome in Female Mice. Am J Physiol Endocrinol Metab(2013) 304:E1321–30. doi: 10.1152/ajpendo.00620.2012

  144. Wranicz JK, Rosiak M, Cygankiewicz I, Kula P, Kula K, Zareba W. Sex Steroids and Heart Rate Variability in Patients After Myocardial Infarction. Ann Noninvasive Electrocardiol(2004) 9:156–61. doi: 10.1111/j.1542-474X.2004.92539.x

  145. Ramesh S, Wilton SB, Holroyd-Leduc JM, Turin TC, Sola DY, Ahmed SB. Testosterone is Associated With the Cardiovascular Autonomic Response to a Stressor in Healthy Men. Clin Exp Hypertens(2015) 37:184–91. doi: 10.3109/10641963.2014.933966

  146. Niesler B, Kuerten S, Demir IE, Schäfer K-H. Disorders of the Enteric Nervous System — a Holistic View. Nat Rev Gastroenterol Hepatol(2021). doi: 10.1038/s41575-020-00385-2

  147. Li S, Fei G, Fang X, Yang X, Sun X, Qian J, et al. Changes in Enteric Neurons of Small Intestine in a Rat Model of Irritable Bowel Syndrome With Diarrhea. J Neurogastroenterol Motil(2016) 22:310–20. doi: 10.5056/jnm15082

  148. Medland JE, Pohl CS, Edwards LL, Frandsen S, Bagley K, Li Y, et al. Early Life Adversity in Piglets Induces Long-Term Upregulation of the Enteric Cholinergic Nervous System and Heightened, Sex-Specific Secretomotor Neuron Responses. Neurogastroenterol Motil(2016) 28:1317–29. doi: 10.1111/nmo.12828

  149. Makowska K, Gonkowski S. Age and Sex-Dependent Differences in the Neurochemical Characterization of Calcitonin Gene-Related Peptide-Like Immunoreactive (Cgrp-Li) Nervous Structures in the Porcine Descending Colon. Int J Mol Sci(2019) 20:1024. doi: 10.3390/ijms20051024

  150. Crowell MD. Role of Serotonin in the Pathophysiology of the Irritable Bowel Syndrome. Br J Pharmacol(2004) 141:1285–93. doi: 10.1038/sj.bjp.0705762

  151. Mawe GM, Hoffman JM. Serotonin Signalling in the Gut–Functions, Dysfunctions and Therapeutic Targets. Nat Rev Gastroenterol Hepatol(2013) 10:473–86. doi: 10.1038/nrgastro.2013.105

  152. Nishizawa S, Benkelfat C, Young SN, Leyton M, Mzengeza S, de Montigny C, et al. Differences Between Males and Females in Rates of Serotonin Synthesis in Human Brain. Proc Natl Acad Sci U S A(1997) 94:5308–13. doi: 10.1073/pnas.94.10.5308

  153. Nakai A, Kumakura Y, Boivin M, Rosa P, Diksic M, D’Souza D, et al. Sex Differences of Brain Serotonin Synthesis in Patient With Irritable Bowel Syndrome Using α-[11c]methyl-L-tryptophan, Positron Emission Tomogrpahy and Statistical Parametric Mapping. Can J Gastroenterol(2003) 17:191–6. doi: 10.1155/2003/572127

  154. Pecins-Thompson M, Brown NA, Kohama SG, Bethea CL. Ovarian Steroid Regulation of Tryptophan Hydroxylase Mrna Expression in Rhesus Macaques. J Neurosci(1996) 16:7021–9. doi: 10.1523/JNEUROSCI.16-21-07021.1996

  155. Bethea CL, Smith AW, Centeno ML, Reddy AP. Long-Term Ovariectomy Decreases Serotonin Neuron Number and Gene Expression in Free Ranging Macaques. Neuroscience(2011) 192:675–88. doi: 10.1016/j.neuroscience.2011.06.003

  156. Shors TJ, Leuner B. Estrogen-Mediated Effects on Depression and Memory Formation in Females. J Affect Disord(2003) 74:85–96. doi: 10.1016/s0165-0327(02)00428-7

  157. Pecins-Thompson M A, Brown N, Bethea CL. Regulation of Serotonin Re-Uptake Transporter mRNA Expression by Ovarian Steroids in Rhesus Macaques. Mol Brain Res(1998) 53:120–9. doi: 10.1016/S0169-328X(97)00286-6

  158. Smith LJ, Henderson JA, Abell CW, Bethea CL. Effects of Ovarian Steroids and Raloxifene on Proteins That Synthesize, Transport, and Degrade Serotonin in the Raphe Region of Macaques. Neuropsychopharmacology(2004) 29:2035–45. doi: 10.1038/sj.npp.1300510

  159. Kugaya A, Epperson CN, Zoghbi S, van Dyck CH, Hou Y, Fujita M, et al. Increase in Prefrontal Cortex Serotonin2A Receptors Following Estrogen Treatment in Postmenopausal Women. Am J Psychiatry(2003) 160:1522–4. doi: 10.1176/appi.ajp.160.8.1522

  160. Moses-Kolko EL, Berga SL, Greer PJ, Smith G, Cidis Meltzer C, Drevets WC. Widespread Increases of Cortical Serotonin Type 2A Receptor Availability After Hormone Therapy in Euthymic Postmenopausal Women. Fertil Steril(2003) 80:554–9. doi: 10.1016/S0015-0282(03)00973-7

  161. Fiorica-Howells E, Hen R, Gingrich J, Li Z, Gershon MD. 5-HT2A Receptors: Location and Functional Analysis in Intestines of Wild-Type and 5-HT2A Knockout Mice. Am J Physiol Liver Physiol(2002) 282:G877–93. doi: 10.1152/ajpgi.00435.2001

  162. Markoutsaki T, Karantanos T, Gazouli M, Anagnou NP, Karamanolis DG. 5-Ht2a Receptor Gene Polymorphisms and Irritable Bowel Syndrome. J Clin Gastroenterol(2011) 45:514–7. doi: 10.1097/MCG.0b013e318205e13b

  163. Perfalk E, da Cunha-Bang S, Holst KK, Keller S, Svarer C, Knudsen GM, et al. Testosterone Levels in Healthy Men Correlate Negatively With Serotonin 4 Receptor Binding. Psychoneuroendocrinology(2017) 81:22–8. doi: 10.1016/j.psyneuen.2017.03.018

  164. Kranz GS, Wadsak W, Kaufmann U, Savli M, Baldinger P, Gryglewski G, et al. High-Dose Testosterone Treatment Increases Serotonin Transporter Binding in Transgender People. Biol Psychiatry(2015) 78:525–33. doi: 10.1016/j.biopsych.2014.09.010

  165. Bethea CL, Coleman K, Phu K, Reddy AP, Phu A. Relationships Between Androgens, Serotonin Gene Expression and Innervation in Male Macaques. Neuroscience(2014) 274:341–56. doi: 10.1016/j.neuroscience.2014.05.056

  166. Carvalho-Dias E, Miranda A, Martinho O, Mota P, Costa Â, Nogueira-Silva C, et al. Serotonin Regulates Prostate Growth Through Androgen Receptor Modulation. Sci Rep(2017) 7:15428. doi: 10.1038/s41598-017-15832-5

  167. Barbara G, Stanghellini V, De Giorgio R, Cremon C, Cottrell GS, Santini D, et al. Activated Mast Cells in Proximity to Colonic Nerves Correlate With Abdominal Pain in Irritable Bowel Syndrome. Gastroenterology(2004) 126:693–702. doi: 10.1053/j.gastro.2003.11.055

  168. Cremon C, Gargano L, Morselli-Labate AM, Santini D, Cogliandro RF, De Giorgio R, et al. Mucosal Immune Activation in Irritable Bowel Syndrome: Gender-Dependence and Association With Digestive Symptoms. Am J Gastroenterol(2009) 104:392–400. doi: 10.1038/ajg.2008.94

  169. Piche T, Saint-Paul MC, Dainese R, Marine-Barjoan E, Iannelli A, Montoya ML, et al. Mast Cells and Cellularity of the Colonic Mucosa Correlated With Fatigue and Depression in Irritable Bowel Syndrome. Gut(2008) 57:468–73. doi: 10.1136/gut.2007.127068

  170. Muñoz-Cruz S, Mendoza-Rodríguez Y, Nava-Castro KE, Yepez-Mulia L, Morales-Montor J. Gender-Related Effects of Sex Steroids on Histamine Release and Fcϵri Expression in Rat Peritoneal Mast Cells. J Immunol Res(2015) 2015:351829. doi: 10.1155/2015/351829

  171. Mackey E, Ayyadurai S, Pohl CS, D’Costa S, Li Y, Moeser AJ. Sexual Dimorphism in the Mast Cell Transcriptome and the Pathophysiological Responses to Immunological and Psychological Stress. Biol Sex Differ(2016) 7:60. doi: 10.1186/s13293-016-0113-7

  172. Zaitsu M, Narita S-I, Lambert KC, Grady JJ, Estes DM, Curran EM, et al. Estradiol Activates Mast Cells Via a non-Genomic Estrogen Receptor-Alpha and Calcium Influx. Mol Immunol(2007) 44:1977–85. doi: 10.1016/j.molimm.2006.09.030

  173. Jing H, Wang Z, Chen Y. Effect of Oestradiol on Mast Cell Number and Histamine Level in the Mammary Glands of Rat. Anat Histol Embryol(2012) 41:170–6. doi: 10.1111/j.1439-0264.2011.01120.x

  174. Narita S, Goldblum RM, Watson CS, Brooks EG, Estes DM, Curran EM, et al. Environmental Estrogens Induce Mast Cell Degranulation and Enhance IgE-mediated Release of Allergic Mediators. Environ Health Perspect(2007) 115:48–52. doi: 10.1289/ehp.9378

  175. Vliagoftis H, Dimitriadou V, Boucher W, Rozniecki JJ, Correia I, Raam S, et al. Estradiol Augments While Tamoxifen Inhibits Rat Mast Cell Secretion. Int Arch Allergy Immunol(1992) 98:398–409. doi: 10.1159/000236217

  176. Di Matteo L, Chieffi Baccari G, Chieffi P, Minucci S. The Effects of Testosterone and Estradiol on Mast Cell Number in the Harderian Gland of the Frog, Rana Esculenta. Zoolog Sci(1995) 12:457–66. doi: 10.2108/zsj.12.457

  177. Mackey E, Thelen KM, Bali V, Fardisi M, Trowbridge M, Jordan CL, et al. Perinatal Androgens Organize Sex Differences in Mast Cells and Attenuate Anaphylaxis Severity Into Adulthood. Proc Natl Acad Sci(2020) 117:23751–61. doi: 10.1073/pnas.1915075117

  178. Guhl S, Artuc M, Zuberbier T, Babina M. Testosterone Exerts Selective Anti-Inflammatory Effects on Human Skin Mast Cells in a Cell Subset Dependent Manner. Exp Dermatol(2012) 21:878–80. doi: 10.1111/exd.12006

  179. Mayer EA, Savidge T, Shulman RJ. Brain-Gut Microbiome Interactions and Functional Bowel Disorders. Gastroenterology(2014) 146:1500–12. doi: 10.1053/j.gastro.2014.02.037

  180. Cryan JF, O’Riordan KJ, Cowan CSM, Sandhu KV, Bastiaanssen TFS, Boehme M, et al. The Microbiota-Gut-Brain Axis. Physiol Rev(2019) 99:1877–2013. doi: 10.1152/physrev.00018.2018

  181. Foong JPP, Hung LY, Poon S, Savidge TC, Bornstein JC. Early Life Interaction Between the Microbiota and the Enteric Nervous System. Am J Physiol Gastrointest liver Physiol(2020) 319:G541–8. doi: 10.1152/ajpgi.00288.2020

  182. Chumpitazi BP, Hollister EB, Oezguen N, Tsai CM, McMeans AR, Luna RA, et al. Gut Microbiota Influences Low Fermentable Substrate Diet Efficacy in Children With Irritable Bowel Syndrome. Gut Microbes(2014) 5:165–75. doi: 10.4161/gmic.27923

  183. Tap J, Derrien M, Törnblom H, Brazeilles R, Cools-Portier S, Doré J, et al. Identification of an Intestinal Microbiota Signature Associated With Severity of Irritable Bowel Syndrome. Gastroenterology(2017) 152:111–23.e8. doi: 10.1053/j.gastro.2016.09.049

  184. Labus JS, Hollister EB, Jacobs J, Kirbach K, Oezguen N, Gupta A, et al. Differences in Gut Microbial Composition Correlate With Regional Brain Volumes in Irritable Bowel Syndrome. Microbiome(2017) 5:49. doi: 10.1186/s40168-017-0260-z

  185. Valles-Colomer M, Falony G, Darzi Y, Tigchelaar EF, Wang J, Tito RY, et al. The Neuroactive Potential of the Human Gut Microbiota in Quality of Life and Depression. Nat Microbiol(2019) 4:623–32. doi: 10.1038/s41564-018-0337-x

  186. Shin J-H, Park Y-H, Sim M, Kim S-A, Joung H, Shin D-M. Serum Level of Sex Steroid Hormone is Associated With Diversity and Profiles of Human Gut Microbiome. Res Microbiol(2019) 170:192–201. doi: 10.1016/j.resmic.2019.03.003

  187. Flores R, Shi J, Fuhrman B, Xu X, Veenstra TD, Gail MH, et al. Fecal Microbial Determinants of Fecal and Systemic Estrogens and Estrogen Metabolites: A Cross-Sectional Study. J Transl Med(2012) 10:253. doi: 10.1186/1479-5876-10-253

  188. Pace F, Watnick PI. The Interplay of Sex Steroids, the Immune Response, and the Intestinal Microbiota. Trends Microbiol(2020). doi: 10.1016/j.tim.2020.11.001

  189. Colldén H, Landin A, Wallenius V, Elebring E, Fändriks L, Nilsson ME, et al. The Gut Microbiota is a Major Regulator of Androgen Metabolism in Intestinal Contents. Am J Physiol Metab(2019) 317:E1182–92. doi: 10.1152/ajpendo.00338.2019

  190. Martin F, Peltonen J, Laatikainen T, Pulkkinen M, Adlercreutz H. Excretion of Progesteone Metabolites and Estriol in Faeces From Pregnant Women During Ampicillin Administration. J Steroid Biochem(1975) 6:1339–46. doi: 10.1016/0022-4731(75)90363-5

  191. Järvenpää P, Kosunen T, Fotsis T, Adlercreutz H. In Vitro Metabolism of Estrogens by Isolated Intestinal Micro-Organisms and by Human Faecal Microflora. J Steroid Biochem(1980) 13:345–9. doi: 10.1016/0022-4731(80)90014-X

  192. Tamura M, Hori S, Nakagawa H. Intestinal Bacterium Tm-30: An S-equol-producing Bacterium Isolated From Human Feces is Involved in Estrogen Metabolism In Vitro. Food Sci Technol Res(2014) 20:309–16. doi: 10.3136/fstr.20.309

  193. Wang P-H, Leu Y-L, Ismail W, Tang S-L, Tsai C-Y, Chen H-J, et al. Anaerobic and Aerobic Cleavage of the Steroid Core Ring Structure by Steroidobacter Denitrificans[s]. J Lipid Res(2013) 54:1493–504. doi: 10.1194/jlr.M034223

  194. Zhang H, Ji Y, Wang Y, Zhang X, Yu Y. Cloning and Characterization of a Novel β-ketoacyl-ACP Reductase From Comamonas Testosteroni. Chem Biol Interact(2015) 234:213–20. doi: 10.1016/j.cbi.2015.01.003

  195. Yurkovetskiy L, Burrows M, Khan AA, Graham L, Volchkov P, Becker L, et al. Gender Bias in Autoimmunity is Influenced by Microbiota. Immunity(2013) 39:400–12. doi: 10.1016/j.immuni.2013.08.013

  196. Mueller S, Saunier K, Hanisch C, Norin E, Alm L, Midtvedt T, et al. Differences in Fecal Microbiota in Different European Study Populations in Relation to Age, Gender, and Country: A Cross-Sectional Study. Appl Environ Microbiol(2006) 72:1027–33. doi: 10.1128/AEM.72.2.1027-1033.2006

  197. Sinha T, Vich Vila A, Garmaeva S, Jankipersadsing SA, Imhann F, Collij V, et al. Analysis of 1135 Gut Metagenomes Identifies Sex-Specific Resistome Profiles. Gut Microbes(2019) 10:358–66. doi: 10.1080/19490976.2018.1528822

  198. Takagi T, Naito Y, Inoue R, Kashiwagi S, Uchiyama K, Mizushima K, et al. Differences in Gut Microbiota Associated With Age, Sex, and Stool Consistency in Healthy Japanese Subjects. J Gastroenterol(2019) 54:53–63. doi: 10.1007/s00535-018-1488-5

  199. Moreno-Indias I, Sánchez-Alcoholado L, Sánchez-Garrido MÁ, Martín-Núñez GM, Pérez-Jiménez F, Tena-Sempere M, et al. Neonatal Androgen Exposure Causes Persistent Gut Microbiota Dysbiosis Related to Metabolic Disease in Adult Female Rats. Endocrinology(2016) 157:4888–98. doi: 10.1210/en.2016-1317

  200. Song C-H, Kim N, Nam RH, Choi SI, Lee H-N, Surh Y-J. 17β-Estradiol Supplementation Changes Gut Microbiota Diversity in Intact and Colorectal Cancer-Induced ICR Male Mice. Sci Rep(2020) 10:12283. doi: 10.1038/s41598-020-69112-w

  201. Koren O, Goodrich JK, Cullender TC, Spor A, Laitinen K, Bäckhed HK, et al. Host Remodeling of the Gut Microbiome and Metabolic Changes During Pregnancy. Cell(2012) 150:470–80. doi: 10.1016/j.cell.2012.07.008

  202. Zhao H, Chen J, Li X, Sun Q, Qin P, Wang Q. Compositional and Functional Features of the Female Premenopausal and Postmenopausal Gut Microbiota. FEBS Lett(2019) 593:2655–64. doi: 10.1002/1873-3468.13527

  203. Diebel ME, Diebel LN, Liberati DM. Gender Dimorphism in the Gut: Mucosal Protection by Estrogen Stimulation of IgA Transcytosis. J Trauma(2011) 71:474–9. doi: 10.1097/ta.0b013e318228239d

  204. Chen KLA, Liu X, Zhao YC, Hieronymi K, Rossi G, Auvil LS, et al. Long-Term Administration of Conjugated Estrogen and Bazedoxifene Decreased Murine Fecal β-Glucuronidase Activity Without Impacting Overall Microbiome Community. Sci Rep(2018) 8:8166. doi: 10.1038/s41598-018-26506-1

  205. Markle JGM, Frank DN, Mortin-Toth S, Robertson CE, Feazel LM, Rolle-Kampczyk U, et al. Sex Differences in the Gut Microbiome Drive Hormone-Dependent Regulation of Autoimmunity. Sci (80- )(2013) 339:1084–8. doi: 10.1126/science.1233521

  206. Kaliannan K, Robertson RC, Murphy K, Stanton C, Kang C, Wang B, et al. Estrogen-Mediated Gut Microbiome Alterations Influence Sexual Dimorphism in Metabolic Syndrome in Mice. Microbiome(2018) 6:205. doi: 10.1186/s40168-018-0587-0

  207. Dinan TG, Cryan J, Shanahan F, Keeling PWN, Quigley EMM. IBS: An Epigenetic Perspective. Nat Rev Gastroenterol Hepatol(2010) 7:465–71. doi: 10.1038/nrgastro.2010.99

  208. Mahurkar S, Polytarchou C, Iliopoulos D, Pothoulakis C, Mayer EA, Chang L. Genome-Wide DNA Methylation Profiling of Peripheral Blood Mononuclear Cells in Irritable Bowel Syndrome. Neurogastroenterol Motil(2016) 28:410–22. doi: 10.1111/nmo.12741

  209. Zhu S, Min L, Guo Q, Li H, Yu Y, Zong Y, et al. Transcriptome and Methylome Profiling in a Rat Model of Irritable Bowel Syndrome Induced by Stress. Int J Mol Med(2018) 42:2641–9. doi: 10.3892/ijmm.2018.3823

  210. Tran L, Chaloner A, Sawalha AH, Greenwood Van-Meerveld B. Importance of Epigenetic Mechanisms in Visceral Pain Induced by Chronic Water Avoidance Stress. Psychoneuroendocrinology(2013) 38:898–906. doi: 10.1016/j.psyneuen.2012.09.016

  211. Kline KT, Lian H, Zhong XS, Luo X, Winston JH, Cong Y, et al. Neonatal Injury Increases Gut Permeability by Epigenetically Suppressing E-Cadherin in Adulthood. J Immunol(2020) 204:980–9. doi: 10.4049/jimmunol.1900639

  212. Zhong XS, Winston JH, Luo X, Kline KT, Nayeem SZ, Cong Y, et al. Neonatal Colonic Inflammation Epigenetically Aggravates Epithelial Inflammatory Responses to Injury in Adult Life. Cell Mol Gastroenterol Hepatol(2018) 6:65–78. doi: 10.1016/j.jcmgh.2018.02.014

  213. Savidge TC. Epigenetic Regulation of Enteric Neurotransmission by Gut Bacteria. Front Cell Neurosci(2016) 9:503. doi: 10.3389/fncel.2015.00503

  214. Krautkramer KA, Kreznar JH, Romano KA, Vivas EI, Barrett-Wilt GA, Rabaglia ME, et al. Diet-Microbiota Interactions Mediate Global Epigenetic Programming in Multiple Host Tissues. Mol Cell(2016) 64:982–92. doi: 10.1016/j.molcel.2016.10.025

  215. Furusawa Y, Obata Y, Fukuda S, Endo TA, Nakato G, Takahashi D, et al. Commensal Microbe-Derived Butyrate Induces the Differentiation of Colonic Regulatory T Cells. Nature(2013) 504:446–50. doi: 10.1038/nature12721

  216. Fellows R, Denizot J, Stellato C, Cuomo A, Jain P, Stoyanova E, et al. Microbiota Derived Short Chain Fatty Acids Promote Histone Crotonylation in the Colon Through Histone Deacetylases. Nat Commun(2018) 9:105. doi: 10.1038/s41467-017-02651-5

  217. Soliman ML, Rosenberger TA. Acetate Supplementation Increases Brain Histone Acetylation and Inhibits Histone Deacetylase Activity and Expression. Mol Cell Biochem(2011) 352:173–80. doi: 10.1007/s11010-011-0751-3

  218. Yang Y-M, Sun D, Kandhi S, Froogh G, Zhuge J, Huang W, et al. Estrogen-Dependent Epigenetic Regulation of Soluble Epoxide Hydrolase Via DNA Methylation. Proc Natl Acad Sci U S A(2018) 115:613–8. doi: 10.1073/pnas.1716016115

  219. Dumasia K, Kumar A, Deshpande S, Balasinor NH. Estrogen, Through Estrogen Receptor 1, Regulates Histone Modifications and Chromatin Remodeling During Spermatogenesis in Adult Rats. Epigenetics(2017) 12:953–63. doi: 10.1080/15592294.2017.1382786

  220. Fortress AM, Kim J, Poole RL, Gould TJ, Frick KM. 17β-Estradiol Regulates Histone Alterations Associated With Memory Consolidation and Increases Bdnf Promoter Acetylation in Middle-Aged Female Mice. Learn Mem(2014) 21:457–67. doi: 10.1101/lm.034033.113

  221. Zhang X, Tanaka K, Yan J, Li J, Peng D, Jiang Y, et al. Regulation of Estrogen Receptor α by Histone Methyltransferase SMYD2-mediated Protein Methylation. Proc Natl Acad Sci(2013) 110:17284–9. doi: 10.1073/pnas.1307959110

  222. Achinger-Kawecka J, Valdes-Mora F, Luu P-L, Giles KA, Caldon CE, Qu W, et al. Epigenetic Reprogramming At Estrogen-Receptor Binding Sites Alters 3D Chromatin Landscape in Endocrine-Resistant Breast Cancer. Nat Commun(2020) 11:320. doi: 10.1038/s41467-019-14098-x

  223. Kokosar M, Benrick A, Perfilyev A, Fornes R, Nilsson E, Maliqueo M, et al. Epigenetic and Transcriptional Alterations in Human Adipose Tissue of Polycystic Ovary Syndrome. Sci Rep(2016) 6:22883. doi: 10.1038/srep22883

  224. Sinha N, Roy S, Huang B, Wang J, Padmanabhan V, Sen A. Developmental Programming: Prenatal Testosterone-Induced Epigenetic Modulation and its Effect on Gene Expression in Sheep Ovary†. Biol Reprod(2020) 102:1045–54. doi: 10.1093/biolre/ioaa007

  225. Nakayama T, Watanabe M, Suzuki H, Toyota M, Sekita N, Hirokawa Y, et al. Epigenetic Regulation of Androgen Receptor Gene Expression in Human Prostate Cancers. Lab Investig(2000) 80:1789–96. doi: 10.1038/labinvest.3780190

  226. Hornig NC, Rodens P, Dörr H, Hubner NC, Kulle AE, Schweikert H-U, et al. Epigenetic Repression of Androgen Receptor Transcription in Mutation-Negative Androgen Insensitivity Syndrome (Ais Type Ii). J Clin Endocrinol Metab(2018) 103:4617–27. doi: 10.1210/jc.2018-00052

  227. Tsai H-W, Grant PA, Rissman EF. Sex Differences in Histone Modifications in the Neonatal Mouse Brain. Epigenetics(2009) 4:47–53. doi: 10.4161/epi.4.1.7288

  228. Murray EK, Hien A, de Vries GJ, Forger NG. Epigenetic Control of Sexual Differentiation of the Bed Nucleus of the Stria Terminalis. Endocrinology(2009) 150:4241–7. doi: 10.1210/en.2009-0458

  229. Scobie H. M., et al., Anthrax toxin receptor 2-dependent lethal toxin killing in vivo. PLoS Pathog.2, e111 (2006).

  230. Whitacre C. C., Sex differences in autoimmune disease.  Immunol.2, 777 (2001).

  231. Ober C., Loisel D. A., Gilad Y., Sex-specific genetic architecture of human disease.  Rev. Genet.9, 911 (2008).

  232. Bach J. F., The effect of infections on susceptibility to autoimmune and allergic diseases.  Engl. J. Med.347, 911 (2002).

  233. Makino S., et al., Breeding of a non-obese, diabetic strain of mice. Jikken Dobutsu29, 1 (1980).

  234. Leiter, M. Atkinson, NOD Mice and Related Strains: Research Applications in Diabetes, AIDS, Cancer and Other Diseases(Landes, Austin, TX, 1998), vol. 2.

  235. Serreze D. V., Leiter E. H., Genes and cellular requirements for autoimmune diabetes susceptibility in nonobese diabetic mice.  Dir. Autoimmun.4, 31 (2001).

  236. Miao D., Yu L., Eisenbarth G. S., Role of autoantibodies in type 1 diabetes.  Biosci.12, 1889 (2007).

  237. Anderson M. S., Bluestone J. A., The NOD mouse: A model of immune dysregulation.  Rev. Immunol.23, 447 (2005).

  238. Ghosh S., et al., Polygenic control of autoimmune diabetes in nonobese diabetic mice.  Genet.4, 404 (1993).

  239. Pozzilli P., Signore A., Williams A. J., Beales P. E., NOD mouse colonies around the world—recent facts and figures.  Today14, 193 (1993).

  240. Makino S., Kunimoto K., Muraoka Y., Katagiri K., Effect of castration on the appearance of diabetes in NOD mouse. Jikken Dobutsu30, 137 (1981).

  241. Fox H. S., Androgen treatment prevents diabetes in nonobese diabetic mice.  Exp. Med.175, 1409 (1992).

  242. Harada M., Kishimoto Y., Makino S., Prevention of overt diabetes and insulitis in NOD mice by a single BCG vaccination. Diabetes Res. Clin. Pract.8, 85 (1990).

  243. Qin H. Y., Sadelain M. W., Hitchon C., Lauzon J., Singh B., Complete Freund’s adjuvant-induced T cells prevent the development and adoptive transfer of diabetes in nonobese diabetic mice.  Immunol.150, 2072 (1993).

  244. Ivakine E. A., et al., The idd4 locus displays sex-specific epistatic effects on type 1 diabetes susceptibility in nonobese diabetic mice. Diabetes55, 3611 (2006).

  245. Ivakine E. A., et al., Sex-specific effect of insulin-dependent diabetes 4 on regulation of diabetes pathogenesis in the nonobese diabetic mouse.  Immunol.174, 7129 (2005).

  246. Nicholson J. K., et al., Host-gut microbiota metabolic interactions. Science336, 1262 (2012)

  247. Koal T., Deigner H. P., Challenges in mass spectrometry based targeted metabolomics.  Mol. Med.10, 216 (2010).

  248. Oberbach A., et al., Combined proteomic and metabolomic profiling of serum reveals association of the complement system with obesity and identifies novel markers of body fat mass changes.  Proteome Res.10, 4769 (2011).

  249. Sadelain M. W., Qin H. Y., Lauzon J., Singh B., Prevention of type I diabetes in NOD mice by adjuvant immunotherapy. Diabetes39, 583 (1990).

  250. Slack E., et al., Innate and adaptive immunity cooperate flexibly to maintain host-microbiota mutualism. Science325, 617 (2009).

  251. Mittelstrass K., et al., Discovery of sexual dimorphisms in metabolic and genetic biomarkers. PLoS Genet.7, e1002215 (2011).

  252. Chai J. G., James E., Dewchand H., Simpson E., Scott D., Transplantation tolerance induced by intranasal administration of HY peptides. Blood103, 3951 (2004).

  253. Koren O., et al., Host remodeling of the gut microbiome and metabolic changes during pregnancy. Cell150, 470 (2012).

  254. Yatsunenko T., et al., Human gut microbiome viewed across age and geography. Nature486, 222 (2012).

  255. Doran M. F., Pond G. R., Crowson C. S., O’Fallon W. M., Gabriel S. E., Trends in incidence and mortality in rheumatoid arthritis in Rochester, Minnesota, over a forty-year period. Arthritis Rheum.46, 625 (2002)

  256. Weinshenker B. G., Natural history of multiple sclerosis.  Neurol.36 (suppl.), S6 (1994).

  257. Burton P. R., et al.Wellcome Trust Case Control Consortium, Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature447, 661 (2007)

  258. Patterson C. C., Dahlquist G. G., Gyürüs E., Green A., Soltész G.EURODIAB Study Group, Incidence trends for childhood type 1 diabetes in Europe during 1989-2003 and predicted new cases 2005-20: A multicentre prospective registration study. Lancet373, 2027 (2009).

  259. Brown C. T., et al., Gut microbiome metagenomics analysis suggests a functional model for the development of autoimmunity for type 1 diabetes. PLoS ONE6, e25792 (2011).

  260. Frank D. N., Zhu W., Sartor R. B., Li E., Investigating the biological and clinical significance of human dysbioses. Trends Microbiol.19, 427 (2011).

  261. Berer K., et al., Commensal microbiota and myelin autoantigen cooperate to trigger autoimmune demyelination. Nature479, 538 (2011).

  262. Wagner B. D., Robertson C. E., Harris J. K., Application of two-part statistics for comparison of sequence variant counts. PLoS ONE6, e20296 (2011).

  263. Smith K., McCoy K. D., Macpherson A. J., Use of axenic animals in studying the adaptation of mammals to their commensal intestinal microbiota.  Immunol.19, 59 (2007).

  264. Dewhirst F. E., et al., Phylogeny of the defined murine microbiota: Altered Schaedler flora.  Environ. Microbiol.65, 3287 (1999).

  265. Frank D. N., BARCRAWL and BARTAB: Software tools for the design and implementation of barcoded primers for highly multiplexed DNA sequencing. BMC Bioinformatics10, 362 (2009).

  266. Frank J. A., et al., Critical evaluation of two primers commonly used for amplification of bacterial 16S rRNA genes.  Environ. Microbiol.74, 2461 (2008).

  267. J. Lane, in Nucleic Acid Techniques in Bacterial Systematics, E. Stackebrandt, M. Goodfellow, Eds. (Wiley, New York, 1991), pp. 115–175.

  268. Caporaso J. G., et al., Global patterns of 16S rRNA diversity at a depth of millions of sequences per sample.  Natl. Acad. Sci. U.S.A.108 (suppl. 1), 4516 (2011).

  269. Frank D. N., et al., The human nasal microbiota and Staphylococcus aureusPLoS ONE 5, e10598 (2010).

  270. Nawrocki E. P., Kolbe D. L., Eddy S. R., Infernal 1.0: Inference of RNA alignments. Bioinformatics25, 1335 (2009).

  271. Haas B. J., et al.Human Microbiome Consortium, Chimeric 16S rRNA sequence formation and detection in Sanger and 454-pyrosequenced PCR amplicons. Genome Res.21, 494 (2011)

  272. Li E., et al., Inflammatory bowel diseases phenotype,  difficileand NOD2 genotype are associated with shifts in human ileum associated microbial composition. PLoS ONE 7, e26284 (2012).

  273. Ludwig W., et al., ARB: A software environment for sequence data. Nucleic Acids Res.32, 1363 (2004).

  274. Pruesse E., Peplies J., Glöckner F. O., SINA: Accurate high-throughput multiple sequence alignment of ribosomal RNA genes. Bioinformatics28, 1823 (2012).

  275. Pruesse E., et al., SILVA: A comprehensive online resource for quality checked and aligned ribosomal RNA sequence data compatible with ARB. Nucleic Acids Res.35, 7188 (2007).49

  276. Magurran, Measuring Biological Diversity(Blackwell, Malden, MA, 2004).

  277. Ewing B., Green P., Base-calling of automated sequencer traces using phred. II. Error probabilities. Genome Res.8, 186 (1998).

  278. Ewing B., Hillier L., Wendl M. C., Green P., Base-calling of automated sequencer traces using phred. I. Accuracy assessment. Genome Res.8, 175 (1998).

  279. Gordon D., Abajian C., Green P., Consed: A graphical tool for sequence finishing. Genome Res.8, 195 (1998).

  280. Edgar R. C., Haas B. J., Clemente J. C., Quince C., Knight R., UCHIME improves sensitivity and speed of chimera detection. Bioinformatics27, 2194 (2011).

  281. Schloss P. D., Gevers D., Westcott S. L., Reducing the effects of PCR amplification and sequencing artifacts on 16S rRNA-based studies. PLoS ONE6, e27310 (2011).

  282. Gaboriau-Routhiau V., et al., The key role of segmented filamentous bacteria in the coordinated maturation of gut helper T cell responses. Immunity31, 677 (2009).

  283. Atarashi K., et al., Induction of colonic regulatory T cells by indigenous ClostridiumScience 331, 337 (2011).

  284. Fox C. J., Paterson A. D., Mortin-Toth S. M., Danska J. S., Two genetic loci regulate T cell-dependent islet inflammation and drive autoimmune diabetes pathogenesis.  J. Hum. Genet.67, 67 (2000).

  285. Yu L., et al., Early expression of antiinsulin autoantibodies of humans and the NOD mouse: Evidence for early determination of subsequent diabetes.  Natl. Acad. Sci. U.S.A.97, 1701 (2000).

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