title: Sex differences in the gut microbiome-brain axis across the lifespan.
abstract: In recent years, the bidirectional communication between the gut microbiome and the brain has emerged as a factor that influences immunity, metabolism, neurodevelopment and behaviour. Cross-talk between the gut and brain begins early in life immediately following the transition from a sterile in utero environment to one that is exposed to a changing and complex microbial milieu over a lifetime. Once established, communication between the gut and brain integrates information from the autonomic and enteric nervous systems, neuroendocrine and neuroimmune signals, and peripheral immune and metabolic signals. Importantly, the composition and functional potential of the gut microbiome undergoes many transitions that parallel dynamic periods of brain development and maturation for which distinct sex differences have been identified. Here, we discuss the sexually dimorphic development, maturation and maintenance of the gut microbiome-brain axis, and the sex differences therein important in disease risk and resilience throughout the lifespan.
authors.affiliation: Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA eldin@vet.upenn.edu.
authors.forename: Eldin
authors.initials: E
authors.lastname: Jašarević
authors.affiliation: Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Kathleen E
authors.initials: KE
authors.lastname: Morrison
authors.affiliation: Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Tracy L
authors.initials: TL
authors.lastname: Bale
mesh_terms: D000375:Aging; D000818:Animals; D001921:Brain / Q000502:physiology*; D005260:Female; D041981:Gastrointestinal Tract / Q000382:microbiology*; D008297:Male; D008322:Mammals / Q000382:microbiology* / Q000502:physiology*; D012737:Sex Factors
keywords: development; lifespan; microbiome; sex differences
references.citation: Clin Immunol. 2015 Aug;159(2):154-62
references.pmid: 25956531
references.citation: Microbiome. 2015 Aug 26;3:36
references.pmid: 26306392
references.citation: Brain Res Rev. 2008 Mar;57(2):571-85
references.pmid: 18164765
references.citation: Science. 2010 Apr 9;328(5975):228-31
references.pmid: 20203013
references.citation: Brain Behav Immun. 2014 Mar;37:197-206
references.pmid: 24333160
references.citation: Proc Natl Acad Sci U S A. 2011 Sep 20;108(38):16050-5
references.pmid: 21876150
references.citation: Antonie Van Leeuwenhoek. 1996 Oct;70(2-4):187-221
references.pmid: 8879407
references.citation: Nature. 2013 Dec 5;504(7478):158-62
references.pmid: 24196717
references.citation: Nature. 2012 Jun 13;486(7402):207-14
references.pmid: 22699609
references.citation: Endocrinology. 2015 Sep;156(9):3265-76
references.pmid: 26079804
references.citation: Curr Opin Microbiol. 2013 Jun;16(3):240-5
references.pmid: 23845749
references.citation: World Psychiatry. 2007 Oct;6(3):168-76
references.pmid: 18188442
references.citation: Sci Transl Med. 2014 Nov 19;6(263):263ra158
references.pmid: 25411471
references.citation: Mol Psychiatry. 2014 Feb;19(2):146-8
references.pmid: 23689536
references.citation: Nature. 2006 Dec 21;444(7122):1027-31
references.pmid: 17183312
references.citation: Nat Rev Neurosci. 2013 Feb;14(2):97-111
references.pmid: 23324667
references.citation: Nat Rev Microbiol. 2011 Apr;9(4):279-90
references.pmid: 21407244
references.citation: Gut. 2010 Dec;59(12):1635-42
references.pmid: 20926643
references.citation: J Autism Dev Disord. 2005 Aug;35(4):471-8
references.pmid: 16134032
references.citation: Gut Microbes. 2014 Jan-Feb;5(1):28-39
references.pmid: 24637807
references.citation: Front Cell Infect Microbiol. 2014 Oct 29;4:147
references.pmid: 25401092
references.citation: Psychoneuroendocrinology. 2015 Mar;53:233-45
references.pmid: 25638481
references.citation: Pediatr Res. 2015 Jan;77(1-2):189-95
references.pmid: 25310759
references.citation: J Endocrinol. 2013 Apr 15;217(2):161-73
references.pmid: 23428582
references.citation: J Neuroimmunol. 2006 Feb;171(1-2):29-37
references.pmid: 16253348
references.citation: Ageing Res Rev. 2010 Apr;9(2):107-16
references.pmid: 19874918
references.citation: Nat Med. 2014 May;20(5):524-30
references.pmid: 24747744
references.citation: Am J Phys Anthropol. 2014 Dec;155(4):652-64
references.pmid: 25252073
references.citation: Proc Natl Acad Sci U S A. 2013 Mar 26;110(13):5169-74
references.pmid: 23487789
references.citation: Brain Behav Immun. 2007 Aug;21(6):727-35
references.pmid: 17604598
references.citation: Nat Neurosci. 2004 Oct;7(10):1040-7
references.pmid: 15452575
references.citation: J Steroid Biochem. 1978 Aug;9(8):795-801
references.pmid: 713557
references.citation: Neuroscience. 2017 Feb 7;342:37-54
references.pmid: 26432952
references.citation: BMC Microbiol. 2014 Jul 15;14:189
references.pmid: 25028050
references.citation: J Steroid Biochem Mol Biol. 2012 Mar;129(1-2):31-46
references.pmid: 21884790
references.citation: Psychoneuroendocrinology. 2015 Oct;60:58-74
references.pmid: 26135201
references.citation: Genes Brain Behav. 2014 Jan;13(1):69-86
references.pmid: 24286462
references.citation: Physiol Behav. 2009 Aug 4;98(1-2):94-102
references.pmid: 19394351
references.citation: J Neurosci. 2009 Oct 14;29(41):12815-23
references.pmid: 19828794
references.citation: J Clin Invest. 2015 Mar 2;125(3):926-38
references.pmid: 25689247
references.citation: Proc Natl Acad Sci U S A. 2008 Dec 2;105(48):18964-9
references.pmid: 19033196
references.citation: PLoS Biol. 2007 Jul;5(7):e177
references.pmid: 17594176
references.citation: Psychoneuroendocrinology. 2012 Sep;37(9):1369-78
references.pmid: 22483040
references.citation: Neurobiol Stress. 2015 Jan 1;1:81-88
references.pmid: 25530984
references.citation: Science. 2012 Jun 8;336(6086):1262-7
references.pmid: 22674330
references.citation: Physiol Behav. 2006 Jul 30;88(4-5):605-14
references.pmid: 16828814
references.citation: Proc Natl Acad Sci U S A. 2010 Jun 29;107(26):11971-5
references.pmid: 20566857
references.citation: Nat Rev Neurosci. 2012 Oct;13(10):701-12
references.pmid: 22968153
references.citation: Nat Rev Genet. 2008 Dec;9(12):911-22
references.pmid: 19002143
references.citation: Nature. 2010 Mar 4;464(7285):59-65
references.pmid: 20203603
references.citation: PLoS Biol. 2008 Nov 18;6(11):e280
references.pmid: 19018661
references.citation: Best Pract Res Clin Gastroenterol. 2007;21(5):807-18
references.pmid: 17889809
references.citation: Cell Host Microbe. 2015 May 13;17(5):565-76
references.pmid: 25974299
references.citation: Behav Brain Res. 2009 Jan 30;197(1):144-9
references.pmid: 18786572
references.citation: Nature. 2012 May 09;486(7402):222-7
references.pmid: 22699611
references.citation: Pain. 2013 Oct;154(10):2088-2099
references.pmid: 23791896
references.citation: Mol Psychiatry. 2013 Jun;18(6):666-73
references.pmid: 22688187
references.citation: World J Gastroenterol. 2014 Jun 14;20(22):6725-43
references.pmid: 24944465
references.citation: Crit Rev Neurobiol. 1996;10(2):189-203
references.pmid: 8971129
references.citation: Arch Gen Psychiatry. 2008 Feb;65(2):146-52
references.pmid: 18250252
references.citation: Nature. 2014 Jan 23;505(7484):559-63
references.pmid: 24336217
references.citation: Behav Neurosci. 2012 Feb;126(1):123-7
references.pmid: 22004260
references.citation: J Clin Microbiol. 1983 May;17(5):830-3
references.pmid: 6863502
references.citation: Clin Investig. 1994 Oct;72(10):742-8
references.pmid: 7865976
references.citation: Behav Brain Res. 2015 Jan 15;277:32-48
references.pmid: 25078296
references.citation: Adv Exp Med Biol. 2014;817:3-24
references.pmid: 24997027
references.citation: J Neurosci. 1992 Jul;12(7):2549-54
references.pmid: 1613547
references.citation: Neuropsychopharmacology. 2016 Jan;41(1):207-18
references.pmid: 26250599
references.citation: Dev Psychobiol. 1999 Sep;35(2):146-55
references.pmid: 10461128
references.citation: Science. 2013 Mar 1;339(6123):1084-8
references.pmid: 23328391
references.citation: Behav Neurosci. 2012 Feb;126(1):4-16
references.pmid: 22289042
references.citation: Science. 2011 Oct 7;334(6052):105-8
references.pmid: 21885731
references.citation: Nat Commun. 2014 Apr 15;5:3654
references.pmid: 24736369
references.citation: Br J Psychiatry. 1998 Apr;172:324-6
references.pmid: 9715334
references.citation: Proc Natl Acad Sci U S A. 2014 Feb 25;111(8):3074-9
references.pmid: 24569806
references.citation: Brain Behav Immun. 2011 Mar;25(3):397-407
references.pmid: 21040780
references.citation: PLoS One. 2014 Jan 22;9(1):e87072
references.pmid: 24466331
references.citation: Paediatr Perinat Epidemiol. 2007 Mar;21(2):98-113
references.pmid: 17302638
references.citation: J Pediatr Gastroenterol Nutr. 2004 Apr;38(4):414-21
references.pmid: 15085020
references.citation: Adv Appl Microbiol. 2015;91:1-62
references.pmid: 25911232
references.citation: Infect Immun. 2013 Sep;81(9):3253-63
references.pmid: 23798531
references.citation: Gut. 2004 Sep;53(9):1388-9
references.pmid: 15306608
references.citation: Nat Neurosci. 2015 Jul;18(7):965-77
references.pmid: 26030851
references.citation: Physiol Behav. 2007 May 16;91(1):55-65
references.pmid: 17367828
references.citation: J Neurosci. 2008 Sep 3;28(36):9055-65
references.pmid: 18768700
references.citation: Immunity. 2013 Aug 22;39(2):400-12
references.pmid: 23973225
references.citation: Lancet. 1995 May 6;345(8958):1186-7
references.pmid: 7723579
references.citation: Biol Psychiatry. 2007 Oct 15;62(8):847-55
references.pmid: 17544382
references.citation: Arch Gen Psychiatry. 2005 Jun;62(6):593-602
references.pmid: 15939837
references.citation: J Neurosci. 1990 Dec;10(12):4035-9
references.pmid: 2269895
references.citation: Cell Host Microbe. 2015 Jun 10;17(6):852
references.pmid: 26308884
references.citation: Menopause. 2006 May-Jun;13(3):411-22
references.pmid: 16735938
references.citation: Proc Natl Acad Sci U S A. 2010 Nov 2;107(44):18933-8
references.pmid: 20937875
references.citation: Eur J Neurosci. 2002 Aug;16(3):377-9
references.pmid: 12193177
references.citation: Neuroscience. 2014 Sep 26;277:885-901
references.pmid: 25088912
references.citation: Brain Res Brain Res Rev. 1990 Jan-Apr;15(1):41-70
references.pmid: 2163714
references.citation: Nat Commun. 2014 Jul 29;5:4500
references.pmid: 25072318
references.citation: Gastroenterology. 2011 May;140(6):1713-9
references.pmid: 21530737
references.citation: Biol Psychiatry. 2010 Aug 15;68(4):314-9
references.pmid: 20674602
references.citation: J Clin Microbiol. 2011 Mar;49(3):858-65
references.pmid: 21177896
references.citation: Trends Mol Med. 2014 Sep;20(9):509-18
references.pmid: 24956966
references.citation: Q Rev Biol. 2015 Sep;90(3):251-68
references.pmid: 26591850
references.citation: Nature. 2012 Aug 9;488(7410):178-84
references.pmid: 22797518
references.citation: Neurogastroenterol Motil. 2015 Jan;27(1):105-13
references.pmid: 25443141
references.citation: Science. 2012 Jun 8;336(6086):1268-73
references.pmid: 22674334
references.citation: World J Gastroenterol. 2014 Mar 14;20(10):2433-48
references.pmid: 24627581
references.citation: Proc Nutr Soc. 2014 Nov;73(4):441-51
references.pmid: 24824449
references.citation: Exp Gerontol. 1994 May-Aug;29(3-4):431-6
references.pmid: 7925761
references.citation: Gerontologist. 2006 Dec;46(6):726-34
references.pmid: 17169928
references.citation: Infect Immun. 2010 Apr;78(4):1509-19
references.pmid: 20145094
references.citation: ANS Adv Nurs Sci. 2005 Oct-Dec;28(4):364-75
references.pmid: 16292022
references.citation: Gastroenterology. 2011 Aug;141(2):599-609, 609.e1-3
references.pmid: 21683077
references.citation: Thorax. 2009 Feb;64(2):107-13
references.pmid: 19052046
references.citation: Proc Natl Acad Sci U S A. 2002 Oct 29;99(22):14422-7
references.pmid: 12381787
references.citation: Cell. 2015 Apr 9;161(2):264-76
references.pmid: 25860609
references.citation: Clin Exp Allergy. 2005 Nov;35(11):1466-72
references.pmid: 16297144
references.citation: ISME J. 2016 Jan;10(1):170-82
references.pmid: 26090993
references.citation: CNS Neurosci Ther. 2016 Feb;22(2):102-17
references.pmid: 26662472
references.citation: Nat Rev Microbiol. 2011 May;9(5):356-68
references.pmid: 21423246
references.citation: PLoS Pathog. 2013;9(11):e1003726
references.pmid: 24244158
references.citation: Science. 2015 Jun 26;348(6242):1427-8
references.pmid: 26113704
references.citation: Science. 2009 Dec 18;326(5960):1694-7
references.pmid: 19892944
references.citation: Physiol Rev. 2008 Jan;88(1):91-124
references.pmid: 18195084
references.citation: Microbiome. 2014 Jul 21;2:25
references.pmid: 25061514
references.citation: Gastroenterology. 2014 May;146(6):1470-6
references.pmid: 24631493
references.citation: Behav Brain Res. 2011 Feb 2;217(1):47-54
references.pmid: 20937326
references.citation: Trends Mol Med. 2015 Feb;21(2):109-17
references.pmid: 25578246
references.citation: Neurogastroenterol Motil. 2011 Mar;23(3):187-92
references.pmid: 21303428
references.citation: Gastroenterol Pol. 2010;17(2):89-97
references.pmid: 25435761
references.citation: Bioessays. 2013 Aug;35(8):717-24
references.pmid: 23733656
references.citation: Aging (Albany NY). 2013 Dec;5(12):902-12
references.pmid: 24334635
references.citation: Endocrinology. 2014 Jul;155(7):2635-46
references.pmid: 24797632
references.citation: ISME J. 2013 Jun;7(6):1112-5
references.pmid: 23535917
references.citation: Neurosci Biobehav Rev. 2003 Jan-Mar;27(1-2):119-27
references.pmid: 12732228
references.citation: NIDA Res Monogr. 1993;133:185-205
references.pmid: 8232513
references.citation: Bioessays. 2014 Oct;36(10):940-9
references.pmid: 25103109
references.citation: Biol Psychol. 2010 May;84(2):272-8
references.pmid: 20193731
references.citation: Sci Aging Knowledge Environ. 2005 Jun 08;2005(23):pe17
references.pmid: 15944465
references.citation: J Autism Dev Disord. 2016 Feb;46(2):603-14
references.pmid: 26412364
references.citation: Cell. 2012 Aug 3;150(3):470-80
references.pmid: 22863002
references.citation: Front Behav Neurosci. 2009 Aug 24;3:14
references.pmid: 19738918
references.citation: Nat Rev Gastroenterol Hepatol. 2009 May;6(5):306-14
references.pmid: 19404271
references.citation: J Endocrinol. 2015 May;225(2):R21-34
references.pmid: 25792117
references.citation: Stress. 2001 Sep;4(3):157-67
references.pmid: 22432137
references.citation: Neuroscience. 2014 May 16;267:252-62
references.pmid: 24513388
references.citation: Placenta. 2010 Feb;31(2):126-33
references.pmid: 20022372
references.citation: Neurogastroenterol Motil. 2011 Mar;23(3):255-64, e119
references.pmid: 21054680
references.citation: Brain Behav Immun. 2015 Nov;50:166-177
references.pmid: 26144888
references.citation: Microb Ecol Health Dis. 2012 Aug 24;23:
references.pmid: 23990817
references.citation: J Clin Invest. 2015 Mar 2;125(3):956-64
references.pmid: 25729852
references.citation: Proc Natl Acad Sci U S A. 2013 Feb 26;110(9):3229-36
references.pmid: 23391737
references.citation: Infect Immun. 1974 Mar;9(3):591-8
references.pmid: 4593471
references.citation: Front Neuroendocrinol. 2015 Oct;39:28-37
references.pmid: 26368654
references.citation: Trends Neurosci. 2015 Jan;38(1):13-25
references.pmid: 25705750
references.citation: Nat Rev Gastroenterol Hepatol. 2013 Dec;10(12):729-40
references.pmid: 24061204
references.citation: Horm Behav. 2015 Nov;76:3-10
references.pmid: 25917865
references.citation: Cell. 2005 Jul 15;122(1):107-18
references.pmid: 16009137
references.citation: Biol Psychiatry. 2013 Nov 15;74(10):720-6
references.pmid: 23759244
references.citation: J Child Psychol Psychiatry. 2015 May;56(5):500-8
references.pmid: 25348074
references.citation: PLoS One. 2012;7(4):e36095
references.pmid: 22553482
references.citation: Int J Obes (Lond). 2013 Jul;37(7):900-6
references.pmid: 23670220
references.citation: FEMS Microbiol Rev. 2015 Jul;39(4):509-21
references.pmid: 25701044
references.citation: Proc Natl Acad Sci U S A. 2011 Feb 15;108(7):3047-52
references.pmid: 21282636
references.citation: Evol Med Public Health. 2015 Apr 02;2015(1):106-21
references.pmid: 25835022
references.citation: Appl Environ Microbiol. 2006 Feb;72(2):1027-33
references.pmid: 16461645
references.citation: Proc Natl Acad Sci U S A. 2000 Sep 26;97(20):11032-7
references.pmid: 11005874
references.citation: CMAJ. 2013 Mar 19;185(5):373-4
references.pmid: 23401408
references.citation: J Nutr. 1997 Aug;127(8):1489-95
references.pmid: 9237942
references.citation: Proc Natl Acad Sci U S A. 2011 Mar 15;108 Suppl 1:4586-91
references.pmid: 20571116
references.citation: Biol Psychiatry. 2009 Feb 1;65(3):263-7
references.pmid: 18723164