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The microgenderome revealed: sex differences in bidirectional interactions between the microbiota, hormones, immunity and disease susceptibility

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Abstract

Sex differences in immunity are well described in the literature and thought to be mainly driven by sex hormones and sex-linked immune response genes. The gastrointestinal tract (GIT) is one of the largest immune organs in the body and contains multiple immune cells in the GIT-associated lymphoid tissue, Peyer’s patches and elsewhere, which together have profound effects on local and systemic inflammation. The GIT is colonised with microbial communities composed of bacteria, fungi and viruses, collectively known as the GIT microbiota. The GIT microbiota drives multiple interactions locally with immune cells that regulate the homeostatic environment and systemically in diverse tissues. It is becoming evident that the microbiota differs between the sexes, both in animal models and in humans, and these sex differences often lead to sex-dependent changes in local GIT inflammation, systemic immunity and susceptibility to a range of inflammatory diseases. The sexually dimorphic microbiome has been termed the ‘microgenderome’. Herein, we review the evidence for the microgenderome and contemplate the role it plays in driving sex differences in immunity and disease susceptibility. We further consider the impact that biological sex might play in the response to treatments aimed at manipulating the GIT microbiota, such as prebiotics, live biotherapeutics, (probiotics, synbiotics and bacteriotherapies) and faecal microbial transplant. These alternative therapies hold potential in the treatment of both psychological (e.g., anxiety, depression) and physiological (e.g., irritable bowel disease) disorders differentially affecting males and females.

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Abbreviations

DC:

dendritic cell

MØ:

macrophage

IECs:

intestinal epithelial cells

References

  1. Tran J, Wilson K, Plebanski M, Flanagan KL (2017) Manipulating the microbiota to improve human health throughout life. Trans R Soc Trop Med Hyg 111:379–381

    Article  CAS  PubMed  Google Scholar 

  2. Weng M, Walker WA (2013) The role of gut microbiota in programming the immune phenotype. J Dev Orig Health Dis 4:203–214

    Article  CAS  PubMed  Google Scholar 

  3. Fawkner-Corbett D, Simmons A, Parikh K (2017) Microbiome, pattern recognition receptor function in health and inflammation. Best Pract Res Clin Gastroenterol 31:683–691

    Article  PubMed  Google Scholar 

  4. Jandhyala SM, Talukdar R, Subramanyam C, Vuyyuru H, Sasikala M, Nageshwar Reddy D (2015) Role of the normal gut microbiota. World J Gastroenterol 21:8787–8803

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Swiatczak B, Rescigno M (2012) How the interplay between antigen presenting cells and microbiota tunes host immune responses in the gut. Semin Immunol 24:43–49

    Article  CAS  PubMed  Google Scholar 

  6. Rakoff-Nahoum S, Paglino J, Eslami-Varzaneh F, Edberg S, Medzhitov R (2004) Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis. Cell 118:229–241

    Article  CAS  PubMed  Google Scholar 

  7. Sjogren YM, Tomicic S, Lundberg A, Bottcher MF, Bjorksten B, Sverremark-Ekstrom E, Jenmalm MC (2009) Influence of early gut microbiota on the maturation of childhood mucosal and systemic immune responses. Clin Exp Allergy 39:1842–1851

    Article  CAS  PubMed  Google Scholar 

  8. Zeuthen LH, Fink LN, Frokiaer H (2008) Epithelial cells prime the immune response to an array of gut-derived commensals towards a tolerogenic phenotype through distinct actions of thymic stromal lymphopoietin and transforming growth factor-beta. Immunology 123:197–208

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Ghorpade DS, Kaveri SV, Bayry J, Balaji KN (2011) Cooperative regulation of NOTCH1 protein-phosphatidylinositol 3-kinase (PI3K) signaling by NOD1, NOD2, and TLR2 receptors renders enhanced refractoriness to transforming growth factor-beta (TGF-beta)- or cytotoxic T-lymphocyte antigen 4 (CTLA-4)-mediated impairment of human dendritic cell maturation. J Biol Chem 286:31347–31360

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Mao K, Baptista AP, Tamoutounour S, Zhuang L, Bouladoux N, Martins AJ, Huang Y, Gerner MY, Belkaid Y, Germain RN (2018) Innate and adaptive lymphocytes sequentially shape the gut microbiota and lipid metabolism. Nature 554:255–259

    Article  CAS  PubMed  Google Scholar 

  11. Shen S, Prame Kumar K, Stanley D, Moore RJ, Van TTH, Wen SW, Hickey MJ, Wong CHY (2018) Invariant natural killer T cells shape the gut microbiota and regulate neutrophil recruitment and function during intestinal inflammation. Front Immunol 9:999

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Hiippala K, Jouhten H, Ronkainen A, Hartikainen A, Kainulainen V, Jalanka J, Satokari R (2018) The potential of gut commensals in reinforcing intestinal barrier function and alleviating inflammation. Nutrients 10(8)

  13. Round JL, Lee SM, Li J, Tran G, Jabri B, Chatila TA, Mazmanian SK (2011) The toll-like receptor 2 pathway establishes colonization by a commensal of the human microbiota. Science 332:974–977

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Sankaran-Walters S, Macal M, Grishina I, Nagy L, Goulart L, Coolidge K, Li J, Fenton A, Williams T, Miller MK, Flamm J, Prindiville T, George M, Dandekar S (2013) Sex differences matter in the gut: effect on mucosal immune activation and inflammation. Biol Sex Differ 4:10

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Gaboriau-Routhiau V, Rakotobe S, Lecuyer E, Mulder I, Lan A, Bridonneau C, Rochet V, Pisi A, De Paepe M, Brandi G, Eberl G, Snel J, Kelly D, Cerf-Bensussan N (2009) The key role of segmented filamentous bacteria in the coordinated maturation of gut helper T cell responses. Immunity 31:677–689

    Article  CAS  PubMed  Google Scholar 

  16. Ivanov II, Atarashi K, Manel N, Brodie EL, Shima T, Karaoz U, Wei D, Goldfarb KC, Santee CA, Lynch SV, Tanoue T, Imaoka A, Itoh K, Takeda K, Umesaki Y, Honda K, Littman DR (2009) Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell 139:485–498

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Atarashi K, Tanoue T, Shima T, Imaoka A, Kuwahara T, Momose Y, Cheng G, Yamasaki S, Saito T, Ohba Y, Taniguchi T, Takeda K, Hori S, Ivanov II, Umesaki Y, Itoh K, Honda K (2011) Induction of colonic regulatory T cells by indigenous Clostridium species. Science 331:337–341

    Article  CAS  PubMed  Google Scholar 

  18. Lathrop SK, Bloom SM, Rao SM, Nutsch K, Lio CW, Santacruz N, Peterson DA, Stappenbeck TS, Hsieh CS (2011) Peripheral education of the immune system by colonic commensal microbiota. Nature 478:250–254

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Cebula A, Seweryn M, Rempala GA, Pabla SS, McIndoe RA, Denning TL, Bry L, Kraj P, Kisielow P, Ignatowicz L (2013) Thymus-derived regulatory T cells contribute to tolerance to commensal microbiota. Nature 497:258–262

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Sefik E, Geva-Zatorsky N, Oh S, Konnikova L, Zemmour D, McGuire AM, Burzyn D, Ortiz-Lopez A, Lobera M, Yang J, Ghosh S, Earl A, Snapper SB, Jupp R, Kasper D, Mathis D, Benoist C (2015) MUCOSAL IMMUNOLOGY. Individual intestinal symbionts induce a distinct population of RORgamma(+) regulatory T cells. Science 349:993–997

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Arpaia N, Campbell C, Fan X, Dikiy S, van der Veeken J, deRoos P, H L CJR, Pfeffer K, Coffer PJ, Rudensky AY (2013) Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature 504:451–455

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Furusawa Y, Obata Y, Fukuda S, Endo TA, Nakato G, Takahashi D, Nakanishi Y, Uetake C, Kato K, Kato T, Takahashi M, Fukuda NN, Murakami S, Miyauchi E, Hino S, Atarashi K, Onawa S, Fujimura Y, Lockett T, Clarke JM, Topping DL, Tomita M, Hori S, Ohara O, Morita T, Koseki H, Kikuchi J, Honda K, Hase K, Ohno H (2013) Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature 504:446–450

    Article  CAS  PubMed  Google Scholar 

  23. Smith PM, Howitt MR, Panikov N, Michaud M, Gallini CA, Bohlooly YM, Glickman JN, Garrett WS (2013) The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science 341:569–573

    Article  CAS  PubMed  Google Scholar 

  24. Singh N, Gurav A, Sivaprakasam S, Brady E, Padia R, Shi H, Thangaraju M, Prasad PD, Manicassamy S, Munn DH, Lee JR, Offermanns S, Ganapathy V (2014) Activation of Gpr109a, receptor for niacin and the commensal metabolite butyrate, suppresses colonic inflammation and carcinogenesis. Immunity 40:128–139

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Suzuki K, Ha SA, Tsuji M, Fagarasan S (2007) Intestinal IgA synthesis: a primitive form of adaptive immunity that regulates microbial communities in the gut. Semin Immunol 19:127–135

    Article  CAS  PubMed  Google Scholar 

  26. Smith K, McCoy KD, Macpherson AJ (2007) Use of axenic animals in studying the adaptation of mammals to their commensal intestinal microbiota. Semin Immunol 19:59–69

    Article  CAS  PubMed  Google Scholar 

  27. Ibnou-Zekri N, Blum S, Schiffrin EJ, von der Weid T (2003) Divergent patterns of colonization and immune response elicited from two intestinal Lactobacillus strains that display similar properties in vitro. Infect Immun 71:428–436

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Gronlund MMAH, Kero P, Lehtonen OP, Isolauri E (2000) Importance of intestinal colonisation in the maturation of humoral immunity in early infancy: a prospective follow up study of healthy infants aged 0–6 months. Arch Dis Child Fetal Neonatal Ed 83:186–192

    Article  Google Scholar 

  29. Ochoa-Repáraz J, Mielcarz DW, Haque-Begum S, Kasper LH (2010) Induction of a regulatory B cell population in experimental allergic encephalomyelitis by alteration of the gut commensal microflora. Gut Microbes 1:103–108

    Article  PubMed  PubMed Central  Google Scholar 

  30. Nash MJ, Frank DN, Friedman JE (2017) Early microbes modify immune system development and metabolic homeostasis—the “restaurant” hypothesis revisited. Front Endocrinol (Lausanne) 8:349

    Article  Google Scholar 

  31. Valdes AM, Walter J, Segal E, Spector TD (2018) Role of the gut microbiota in nutrition and health. Brit Med J 361:k2179

    Article  PubMed  PubMed Central  Google Scholar 

  32. Ley RE, Turnbaugh PJ, Klein S, Gordon JI (2006) Microbial ecology: human gut microbes associated with obesity. Nature 444:1022–1023

    Article  CAS  PubMed  Google Scholar 

  33. Browne HP, Forster SC, Anonye BO, Kumar N, Neville BA, Stares MD, Goulding D, Lawley TD (2016) Culturing of ‘unculturable’ human microbiota reveals novel taxa and extensive sporulation. Nature 533(7604):543–546

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Scholtens PA, Oozeer R, Martin R, Amor KB, Knol J (2012) The early settlers: intestinal microbiology in early life. Annu Rev Food Sci Technol 3:425–447

    Article  CAS  PubMed  Google Scholar 

  35. Condliffe SB, Doolan CM, Harvey BJ (2001) 17beta-oestradiol acutely regulates Cl- secretion in rat distal colonic epithelium. J Physiol 530(Pt 1):47–54

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Sylvia KE, Jewell CP, Rendon NM, St John EA, Demas GE (2017) Sex-specific modulation of the gut microbiome and behavior in Siberian hamsters. Brain Behav Immun 60:51–62

    Article  PubMed  Google Scholar 

  37. Steegenga WT, Mischke M, Lute C, Boekschoten MV, Pruis MG, Lendvai A, Verkade HJ, Boekhorst J, Timmerman HM, Plösch T, Müller M (2014) Sexually dimorphic characteristics of the small intestine and colon of prepubescent C57BL/6 mice. Biol Sex Differ 5:11

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Xiao L, Feng Q, Liang S, Sonne SB, Xia Z, Qiu X, Li X, Long H, Zhang J, Zhang D, Liu C, Fang Z, Chou J, Glanville J, Hao Q, Kotowska D, Colding C, Licht TR, Wu D, Yu J, Sung JJ, Liang Q, Li J, Jia H, Lan Z, Tremaroli V, Dworzynski P, Nielsen HB, Backhed F, Dore J, Le Chatelier E, Ehrlich SD, Lin JC, Arumugam M, Wang J, Madsen L, Kristiansen K (2015) A catalog of the mouse gut metagenome. Nat Biotechnol 33:1103–1108

    Article  CAS  PubMed  Google Scholar 

  39. Miyoshi J, Leone V, Nobutani K, Musch MW, Martinez-Guryn K, Wang Y, Miyoshi S, Bobe AM, Eren AM, Chang EB (2018) Minimizing confounders and increasing data quality in murine models for studies of the gut microbiome. Peer J 6:e5166

    Article  PubMed  PubMed Central  Google Scholar 

  40. Martino DJ, Currie H, Taylor A, Conway P, Prescott SL (2008) Relationship between early intestinal colonization, mucosal immunoglobulin A production and systemic immune development. Clin Exp Allergy 38:69–78

    CAS  PubMed  Google Scholar 

  41. Weiss G, Forster S, Irving A, Tate M, Ferrero RL, Hertzog P, Frokiaer H, Kaparakis-Liaskos M (2013) Helicobacter pylori VacA suppresses Lactobacillus acidophilus-induced interferon beta signaling in macrophages via alterations in the endocytic pathway. MBio 4:e00609–e00612

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Shin NR, Whon TW, Bae JW (2015) Proteobacteria: microbial signature of dysbiosis in gut microbiota. Trends Biotechnol 33:496–503

    Article  CAS  PubMed  Google Scholar 

  43. Fransen F, van Beek AA, Borghuis T, Meijer B, Hugenholtz F, van der Gaast-de Jongh C, Savelkoul HF, de Jonge MI, Faas MM, Boekschoten MV, Smidt H, El Aidy S, de Vos P (2017) The impact of gut microbiota on gender-specific differences in immunity. Front Immunol 8:754

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Elderman M, Hugenholtz F, Belzer C, Boekschoten M, van Beek A, de Haan B, Savelkoul H, de Vos P, Faas M (2018) Sex and strain dependent differences in mucosal immunology and microbiota composition in mice. Biol Sex Differ 9:26

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Maurice CF, Knowles SC, Ladau J, Pollard KS, Fenton A, Pedersen AB, Turnbaugh PJ (2015) Marked seasonal variation in the wild mouse gut microbiota. ISME J 9:2423–2434

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Zhang H, Wang Z, Li Y, Han J, Cui C, Lu C, Zhou J, Cheong L, Li Y, Sun T, Zhang D, Su X (2018) Sex-based differences in gut microbiota composition in response to tuna oil and algae oil supplementation in a D-galactose-induced aging mouse model. Front Aging Neurosci 10:187

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Kosiewicz MM, Dryden GW, Chhabra A, Alard P (2014) Relationship between gut microbiota and development of T cell associated disease. FEBS Lett 588:4195–4206

    Article  CAS  PubMed  Google Scholar 

  48. Ohnmacht C, Park J-H, Cording S, Wing JB, Atarashi K, Obata Y, Gaboriau-Routhiau V, Marques R, Dulauroy S, Fedoseeva M, Busslinger M, Cerf-Bensussan N, Boneca IG, Voehringer D, Hase K, Honda K, Sakaguchi S, Eberl G (2015) Mucosal immunology. The microbiota regulates type 2 immunity through RORγt+ T cells. Science 349:989–993

    Article  CAS  PubMed  Google Scholar 

  49. Neufeld KM, Kang N, Bienenstock J, Foster JA (2011) Reduced anxiety-like behavior and central neurochemical change in germ-free mice. Neurogastroenterol Motil 23(255–64):e119

    Google Scholar 

  50. Desbonnet L, Clarke G, Shanahan F, Dinan TG, Cryan JF (2014) Microbiota is essential for social development in the mouse. Mol Psychiatry 19:146–148

    Article  CAS  PubMed  Google Scholar 

  51. Klein SL, Flanagan KL (2016) Sex differences in immune responses. Nat Rev Immunol 16:626–638

    Article  CAS  PubMed  Google Scholar 

  52. Flores R, Shi J, Fuhrman B, Xu X, Veenstra TD, Gail MH, Gajer P, Ravel J, Goedert JJ (2012) Fecal microbial determinants of fecal and systemic estrogens and estrogen metabolites: a cross-sectional study. J Transl Med 10:253

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Kawano N, Koji T, Hishikawa Y, Murase K, Murata I, Kohno S (2004) Identification and localization of estrogen receptor alpha- and beta-positive cells in adult male and female mouse intestine at various estrogen levels. Histochem Cell Biol 121:399–405

    Article  CAS  PubMed  Google Scholar 

  54. Hogan AM, Collins D, Baird AW, Winter DC (2009) Estrogen and its role in gastrointestinal health and disease. Int J Color Dis 24:1367–1375

    Article  Google Scholar 

  55. Bábíčková J, Tóthová Ľ, Lengyelová E, Bartoňová A, Hodosy J, Gardlík R, Celec P (2015) Sex differences in experimentally induced colitis in mice: a role for estrogens. Inflammation 38:1996–2006

    Article  CAS  PubMed  Google Scholar 

  56. Verdú EF, Deng Y, Bercik P, Collins SM (2002) Modulatory effects of estrogen in two murine models of experimental colitis. Am J Physiol Gastrointest Liver Physiol 283:G27–G36

    Article  PubMed  Google Scholar 

  57. Markle JGM, Frank DN, Mortin-Toth S, Robertson CE, Feazel LM, Rolle-Kampczyk U, von Bergen M, McCoy KD, Macpherson AJ, Danska JS (2013) Sex differences in the gut microbiome drive hormone-dependent regulation of autoimmunity. Science 339:1084–1088

    Article  CAS  PubMed  Google Scholar 

  58. Yurkovetskiy L, Burrows M, Khan AA, Graham L, Volchkov P, Becker L, Antonopoulos D, Umesaki Y, Chervonsky AV (2013) Gender bias in autoimmunity is influenced by microbiota. Immunity 39:400–412

    Article  CAS  PubMed  Google Scholar 

  59. Mueller S, Saunier K, Hanisch C, Norin E, Alm L, Midtvedt T, Cresci A, Silvi S, Orpianesi C, Verdenelli MC, Clavel T, Koebnick C, Zunft HJ, Dore J, Blaut M (2006) Differences in fecal microbiota in different European study populations in relation to age, gender, and country: a cross-sectional study. Appl Environ Microbiol 72:1027–1033

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Dominianni C, Sinha R, Goedert JJ, Pei Z, Yang L, Hayes RB, Ahn J (2015) Sex, body mass index, and dietary fiber intake influence the human gut microbiome. PLoS One 10:e0124599

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Takagi T, Naito Y, Inoue R, Kashiwagi S, Uchiyama K, Mizushima K, Tsuchiya S, Dohi O, Yoshida N, Kamada K, Ishikawa T, Handa O, Konishi H, Okuda K, Tsujimoto Y, Ohnogi H, Itoh Y (2018) Differences in gut microbiota associated with age, sex, and stool consistency in healthy Japanese subjects. J Gastroenterol Epub ahead of print

  62. Suzuki TA, Worobey M (2014) Geographical variation of human gut microbial composition. Biol Lett 10:20131037

    Article  PubMed  PubMed Central  Google Scholar 

  63. Haro C, Rangel-Zúñiga O, Alcalá-Díaz J, Gómez-Delgado F, Pérez-Martínez P, Delgado-Lista J, Quintana-Navarro GM, Landa BB, Navas-Cortés JA, Tena-Sempere M, Clemente JC, López-Miranda J, Pérez-Jiménez F, Camargo A (2016) Intestinal microbiota is influenced by gender and body mass index. PLoS One 11:e0154090

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Singh P, Manning SD (2016) Impact of age and sex on the composition and abundance of the intestinal microbiota in individuals with and without enteric infections. Ann Epidemiol 26:380–385

    Article  PubMed  Google Scholar 

  65. Koren O, Goodrich JK, Cullender TC, Spor A, Laitinen K, Bäckhed HK, Gonzalez A, Werner JJ, Angenent LT, Knight R, Bäckhed F, Isolauri E, Salminen S, Ley RE (2012) Host remodeling of the gut microbiome and metabolic changes during pregnancy. Cell 150:470–480

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Mukhopadhya I, Hansen R, El-Omar EM, Hold GL (2012) IBD—what role do Proteobacteria play? Nat Rev Gastroenterol Hepatol 9:219–230

    Article  CAS  PubMed  Google Scholar 

  67. Yatsunenko T, Rey FE, Manary MJ, Trehan I, Dominguez-Bello MG, Contreras M, Magris M, Hidalgo G, Baldassano RN, Anokhin AP, Heath AC, Warner B, Reeder J, Kuczynski J, Caporaso JG, Lozupone CA, Lauber C, Clemente JC, Knights D, Knight R, Gordon JI (2012) Human gut microbiome viewed across age and geography. Nature 486:222–227

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Jakobsdottir G, Bjerregaard JH, Skovbjerg H, Nyman M (2013) Fasting serum concentration of short-chain fatty acids in subjects with microscopic colitis and celiac disease: no difference compared with controls, but between genders. Scand J Gastroenterol 48:696–701

    Article  CAS  PubMed  Google Scholar 

  69. Mulle JG, Sharp WG, Cubells JF (2013) The gut microbiome: a new frontier in autism research. Curr Psychiatry Rep 15:337

    Article  PubMed  PubMed Central  Google Scholar 

  70. Wallis A, Butt H, Ball M, Lewis DP, Bruck D (2016) Support for the microgenderome: associations in a human clinical population. Sci Rep 6

  71. Pigrau M, Rodino-Janeiro BK, Casado-Bedmar M, Lobo B, Vicario M, Santos J, Alonso-Cotoner C (2016) The joint power of sex and stress to modulate brain-gut-microbiota axis and intestinal barrier homeostasis: implications for irritable bowel syndrome. Neurogastroenterol Motil 28:463–486

    Article  CAS  PubMed  Google Scholar 

  72. Bolnick DI, Snowberg LK, Hirsch PE, Lauber CL, Org E, Parks B, Lusis AJ, Knight R, Caporaso JG, Svanback R (2014) Individual diet has sex-dependent effects on vertebrate gut microbiota. Nat Commun 5:4500

    Article  CAS  PubMed  Google Scholar 

  73. Gaskins AJ, Mumford SL, Zhang C, Wactawski-Wende J, Hovey KM, Whitcomb BW, Howards PP, Perkins NJ, Yeung E, Schisterman EF, BioCycle Study G (2009) Effect of daily fiber intake on reproductive function: the BioCycle study. Am J Clin Nutr 90:1061–1069

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Bulun SE, Chen D, Moy I, Brooks DC, Zhao H (2012) Aromatase, breast cancer and obesity: a complex interaction. Trends Endocrinol Metab 23:83–89

    Article  CAS  PubMed  Google Scholar 

  75. Turnbaugh PJ, Hamady M, Yatsunenko T, Cantarel BL, Duncan A, Ley RE, Sogin ML, Jones WJ, Roe BA, Affourtit JP, Egholm M, Henrissat B, Heath AC, Knight R, Gordon JI (2009) A core gut microbiome in obese and lean twins. Nature 457:480–484

    Article  CAS  PubMed  Google Scholar 

  76. Lampe JW, Fredstrom SB, Slavin JL, Potter JD (1993) Sex differences in colonic function: a randomised trial. Gut 34:531–536

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Degen LP, Phillips SF (1996) Variability of gastrointestinal transit in healthy women and men. Gut 39:299–305

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Stepankova R, Powrie F, Kofronova O, Kozakova H, Hudcovic T, Hrncir T, Uhlig H, Read S, Rehakova Z, Benada O, Heczko P, Strus M, Bland P, Tlaskalova-Hogenova H (2007) Segmented filamentous bacteria in a defined bacterial cocktail induce intestinal inflammation in SCID mice reconstituted with CD45RBhigh CD4+ T cells. Inflamm Bowel Dis 13:1202–1211

    Article  PubMed  Google Scholar 

  79. Wu HJ, Ivanov II, Darce J, Hattori K, Shima T, Umesaki Y, Littman DR, Benoist C, Mathis D (2010) Gut-residing segmented filamentous bacteria drive autoimmune arthritis via T helper 17 cells. Immunity 32:815–827

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Kriegel MA, Sefik E, Hill JA, Wu HJ, Benoist C, Mathis D (2011) Naturally transmitted segmented filamentous bacteria segregate with diabetes protection in nonobese diabetic mice. Proc Natl Acad Sci U S A 108:11548–11553

    Article  PubMed  PubMed Central  Google Scholar 

  81. Hevia A, Milani C, Lopez P, Cuervo A, Arboleya S, Duranti S, Turroni F, González S, Suárez A, Gueimonde M, Ventura M, Sánchez B, Margolles A (2014) Intestinal dysbiosis associated with systemic lupus erythematosus. MBio 5:e01548–e01514

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Mu Q, Zhang H, Liao X, Lin K, Liu H, Edwards MR, Ahmed SA, Yuan R, Li L, Cecere TE, Branson DB (2017) Control of lupus nephritis by changes of gut microbiota. Microbiome 5:73

    Article  PubMed  PubMed Central  Google Scholar 

  83. Gomez A, Luckey D, Taneja V (2015) The gut microbiome in autoimmunity: sex matters. Clin Immunol 159:154–162

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Li YN, Huang F, Liu L, Qiao HM, Li Y, Cheng HJ (2012) Effect of oral feeding with Clostridium leptum on regulatory T-cell responses and allergic airway inflammation in mice. Ann Allergy Asthma Immunol 109:201–207

    Article  CAS  PubMed  Google Scholar 

  85. Huang R, Li T, Ni J, Bai X, Gao Y, Li Y, Zhang P, Gong Y (2018) Different sex-based responses of gut microbiota during the development of hepatocellular carcinoma in liver-specific Tsc1-knockout mice. Front Microbiol 9:1008

    Article  PubMed  PubMed Central  Google Scholar 

  86. Cross TL, Kasahara K, Rey FE (2018) Sexual dimorphism of cardiometabolic dysfunction: gut microbiome in the play? Mol Metab 5:e01548–e01514

    Google Scholar 

  87. Ohlsson C, Engdahl C, Fåk F, Andersson A, Windahl SH, Farman HH, Movérare-Skrtic S, Islander U, Sjögren K (2014) Probiotics protect mice from ovariectomy-induced cortical bone loss. PLoS One 9:e92368

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Britton RA, Irwin R, Quach D, Schaefer L, Zhang J, Lee T, Parameswaran N, McCabe LR (2014) Probiotic L. reuteri treatment prevents bone loss in a menopausal ovariectomized mouse model. J Cell Physiol 229:1822–1830

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Poutahidis T, Springer A, Levkovich T, Qi P, Varian BJ, Lakritz JR, Ibrahim YM, Chatzigiagkos A, Alm EJ, Erdman SE (2014) Probiotic microbes sustain youthful serum testosterone levels and testicular size in aging mice. PLoS One 9:e84877

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Shastri P, McCarville J, Kalmokoff M, Brooks SP, Green-Johnson JM (2015) Sex differences in gut fermentation and immune parameters in rats fed an oligofructose-supplemented diet. Biol Sex Differ 6:13

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Karunasena E, McMahon KW, Chang D, Brashears MM (2014) Host responses to the pathogen Mycobacterium avium subsp. paratuberculosis and beneficial microbes exhibit host sex specificity. Appl Environ Microbiol 80:4481–4490

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Bakker GJ, Nieuwdorp M (2017) Fecal microbiota transplantation: therapeutic potential for a multitude of diseases beyond Clostridium difficile. Microbiol Spectr 5

  93. de Groot PF, Frissen MN, de Clercq NC, Nieuwdorp M (2017) Fecal microbiota transplantation in metabolic syndrome: history, present and future. Gut Microbes 8:253–267

    Article  PubMed  PubMed Central  Google Scholar 

  94. Singh B, Qin N, Reid G (2015) Microbiome regulation of autoimmune, gut and liver associated diseases. Inflamm Allergy Drug Targets 14:84–93

    Article  CAS  PubMed  Google Scholar 

  95. Kurokawa S, Kishimoto T, Mizuno S, Masaoka T, Naganuma M, Liang KC, Kitazawa M, Nakashima M, Shindo C, Suda W, Hattori M, Kanai T, Mimura M (2018) The effect of fecal microbiota transplantation on psychiatric symptoms among patients with irritable bowel syndrome, functional diarrhea and functional constipation: an open-label observational study. J Affect Disord 235:506–512

    Article  PubMed  Google Scholar 

  96. Wang JJ, Wang J, Pang XY, Zhao LP, Tian L, Wang XP (2016) Sex differences in colonization of gut microbiota from a man with short-term vegetarian and inulin-supplemented diet in germ-free mice. Sci Rep 6:36137

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Cui M, Xiao H, Li Y, Zhou L, Zhao S, Luo D, Zheng Q, Dong J, Zhao Y, Zhang X, Zhang J (2017) Faecal microbiota transplantation protects against radiation-induced toxicity. EMBO Mol Med 9:448–461

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Duarte-Chavez R, Wojda TR, Zanders TB, Geme B, Fioravanti G, Stawicki SP (2018) Early results of fecal microbial transplantation protocol implementation at a community-based university hospital. J Glob Infect Dis 10:47–57

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Flak MB, Neves JF, Blumberg RS (2013) Welcome to the microgenderome. Science 339:1044–1045

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Neville BA, Forster SC, Lawley TD (2018) Commensal Koch’s postulates: establishing causation in human microbiota research. Curr Opin Microbiol 42:47–52

    Article  PubMed  Google Scholar 

  101. Forster SC, Browne HP, Kumar N, Hunt M, Denise H, Mitchell A, Finn RD, Lawley TD (2016) HPMCD: the database of human microbial communities from metagenomic datasets and microbial reference genomes. Nucleic Acids Res 44:D604–D609

    Article  CAS  PubMed  Google Scholar 

  102. Mitchell AL, Scheremetjew M, Denise H, Potter S, Tarkowska A, Qureshi M, Salazar GA, Pesseat S, Boland MA, Hunter FMI, Ten Hoopen P, Alako B, Amid C, Wilkinson DJ, Curtis TP, Cochrane G, Finn RD (2018) EBI metagenomics in 2017: enriching the analysis of microbial communities, from sequence reads to assemblies. Nucleic Acids Res 46:D726–DD35

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We would like to acknowledge Claudio Rosa for designing the figure.

Funding

KES was supported by the NIH/NIAID Center of Excellence in Influenza Research and Surveillance contracts HHS N272201400007C; SCF is supported by NHMRC CJ Martin Fellowship (1091097) and the Victorian Government’s Operational Infrastructure Support Program; MP is supported by a NHMRC Senior Research Fellowship. RE and KLF are recipients of a grant from the Clifford Craig Foundation for microbiota research.

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Authors and Affiliations

  1. School of Health Sciences, College of Health and Medicine, University of Tasmania, Hobart, Tasmania, Australia

    Ravichandra Vemuri, Magdalena Plebanski, Raj Eri & Katie L. Flanagan

  2. The W. Harry Feinstone Department of Molecular Microbiology and Immunology, The Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA

    Kristyn E. Sylvia & Sabra L. Klein

  3. Microbiota and Systems Biology Laboratory, Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Melbourne, Victoria, Australia

    Samuel C. Forster

  4. Department of Molecular and Translational Sciences, Monash University, Melbourne, Victoria, Australia

    Samuel C. Forster

  5. School of Health and Biomedical Science, RMIT University, Melbourne, Victoria, Australia

    Magdalena Plebanski & Katie L. Flanagan

  6. Department of Immunology and Pathology, Monash University, Melbourne, Victoria, Australia

    Katie L. Flanagan

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  1. Ravichandra Vemuri
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  2. Kristyn E. Sylvia
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  3. Sabra L. Klein
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  7. Katie L. Flanagan
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Correspondence to Katie L. Flanagan.

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Additional information

This article is a contribution to the special issue on Sex differences in immunity – Guest Editors: Hanna Lotter and Marcus Altfeld

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Vemuri, R., Sylvia, K.E., Klein, S.L. et al. The microgenderome revealed: sex differences in bidirectional interactions between the microbiota, hormones, immunity and disease susceptibility. Semin Immunopathol 41, 265–275 (2019). https://doi.org/10.1007/s00281-018-0716-7

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  • DOI: https://doi.org/10.1007/s00281-018-0716-7

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