1. Lynch SV, Pedersen O. The human intestinal microbiome in health and disease. N Engl J Med. 2016;375:2369–79.

2. Fung TC, Olson CA, Hsiao EY. Interactions between the microbiota, immune and nervous systems in health and disease. Nat Neurosci. 2017;20:145–55.

3. Miquel S, Champ C, Day J, Aarts E, Bahr BA, Bakker M, et al. Poor cognitive ageing: vulnerabilities, mechanisms and the impact of nutritional interventions. Ageing Res Rev. 2018;42:40–55.

4. Sandhu KV, Sherwin E, Schellekens H, Stanton C, Dinan TG, Cryan JF. Feeding the microbiota–gut–brain axis: diet, microbiome, and neuropsychiatry. Transl Res. 2017;179:223–44.

5. David LA, Maurice CF, Carmody RN, Gootenberg DB, Button JE, Wolfe BE, et al. Diet rapidly and reproducibly alters the human gut microbiome. Nature. 2014;505:559–63.

6. Donovan SM. Introduction to the special focus issue on the impact of diet on gut microbiota composition and function and future opportunities for nutritional modulation of the gut microbiome to improve human health. Gut Microbes. 2017;8:75–81.

7. Ennaceur A, Michalikova S, van Rensburg R, Chazot PL. Detailed analysis of the behavior and memory performance of middle-aged male and female CD-1 mice in a 3D maze. Behav Brain Res. 2008;187:312–26.

8. Bensalem J, Servant L, Alfos S, Gaudout D, Laye S, Pallet V, et al. Dietary polyphenol supplementation prevents alterations of spatial navigation in middle-aged mice. Front Behav Neurosci. 2016;10:9.

9. Duarte JM, Do KQ, Gruetter R. Longitudinal neurochemical modifications in the aging mouse brain measured in vivo by 1H magnetic resonance spectroscopy. Neurobiol Aging. 2014;35:1660–8.

10. Francia N, Cirulli F, Chiarotti F, Antonelli A, Aloe L, Alleva E. Spatial memory deficits in middle-aged mice correlate with lower exploratory activity and a subordinate status: role of hippocampal neurotrophins. Eur J Neurosci. 2006;23:711–28.

11. Shoji H, Takao K, Hattori S, Miyakawa T. Age-related changes in behavior in C57BL/6J mice from young adulthood to middle age. Mol Brain. 2016;9:11.

12. Prenderville JA, Kennedy PJ, Dinan TG, Cryan JF. Adding fuel to the fire: the impact of stress on the ageing brain. Trends Neurosci. 2015;38:13–25.

13. Sparkman NL, Johnson RW. Neuroinflammation associated with aging sensitizes the brain to the effects of infection or stress. Neuroimmunomodulation. 2008;15:323–30.

14. Franceschi C, Salvioli S, Garagnani P, de Eguileor M, Monti D, Capri M. Immunobiography and the heterogeneity of immune responses in the elderly: a focus on inflammaging and trained immunity. Front Immunol. 2017;8:982.

15. Norden DM, Godbout JP. Review: microglia of the aged brain: primed to be activated and resistant to regulation. Neuropathol Appl Neurobiol. 2013;39:19–34.

16. Hickman S, Izzy S, Sen P, Morsett L, El Khoury J. Microglia in neurodegeneration. Nat Neurosci. 2018;21:1359–69.

17. Tay TL, Savage JC, Hui CW, Bisht K, Tremblay ME. Microglia across the lifespan: from origin to function in brain development, plasticity and cognition. J Physiol. 2017;595:1929–45.

18. Perry VH, Newman TA, Cunningham C. The impact of systemic infection on the progression of neurodegenerative disease. Nat Rev Neurosci. 2003;4:103–12.

19. Streit WJ, Sammons NW, Kuhns AJ, Sparks DL. Dystrophic microglia in the aging human brain. Glia. 2004;45:208–12.

20. Nimmerjahn A, Kirchhoff F, Helmchen F. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science. 2005;308:1314–8.

21. Hickman SE, Kingery ND, Ohsumi TK, Borowsky ML, Wang LC, Means TK, et al. The microglial sensome revealed by direct RNA sequencing. Nat Neurosci. 2013;16:1896–905.

22. Scott KA, Ida M, Peterson VL, Prenderville JA, Moloney GM, Izumo T, et al. Revisiting Metchnikoff: age-related alterations in microbiota–gut–brain axis in the mouse. Brain Behav Immunity. 2017;65:20–32.

23. van der Lugt B, Rusli F, Lute C, Lamprakis A, Salazar E, Boekschoten MV, et al. Integrative analysis of gut microbiota composition, host colonic gene expression and intraluminal metabolites in aging C57BL/6J mice. Aging (Albany NY). 2018;10:930–50.

24. Biagi E, Franceschi C, Rampelli S, Severgnini M, Ostan R, Turroni S, et al. Gut microbiota and extreme longevity. Curr Biol. 2016;26:1480–5.

25. Biagi E, Nylund L, Candela M, Ostan R, Bucci L, Pini E, et al. Through ageing, and beyond: gut microbiota and inflammatory status in seniors and centenarians. PLoS ONE. 2010;5:e10667.

26. Fransen F, van Beek AA, Borghuis T, Aidy SE, Hugenholtz F, van der Gaast-de Jongh C, et al. Aged gut microbiota contributes to systemical inflammaging after transfer to germ-free mice. Front Immunol. 2017;8:1385.

27. Thevaranjan N, Puchta A, Schulz C, Naidoo A, Szamosi JC, Verschoor CP, et al. Age-associated microbial dysbiosis promotes intestinal permeability, systemic inflammation, and macrophage dysfunction. Cell Host Microbe. 2017;21:455–66 e4.

28. Smith P, Willemsen D, Popkes M, Metge F, Gandiwa E, Reichard M, et al. Regulation of life span by the gut microbiota in the short-lived African turquoise killifish. Elife. 2017;6:e27014.

29. Gibson GR, Hutkins R, Sanders ME, Prescott SL, Reimer RA, Salminen SJ, et al. Expert consensus document: The International Scientific Association for Probiotics and Prebiotics (ISAPP) consensus statement on the definition and scope of prebiotics. Nat Rev Gastroenterol Hepatol. 2017;14:491.

30. Vulevic J, Drakoularakou A, Yaqoob P, Tzortzis G, Gibson GR. Modulation of the fecal microflora profile and immune function by a novel trans-galactooligosaccharide mixture (B-GOS) in healthy elderly volunteers. Am J Clin Nutr. 2008;88:1438–46.

31. Schiffrin EJ, Thomas DR, Kumar VB, Brown C, Hager C, Van’t Hof MA, et al. Systemic inflammatory markers in older persons: the effect of oral nutritional supplementation with prebiotics. J Nutr Health Aging. 2007;11:475–9.

32. Burokas A, Arboleya S, Moloney RD, Peterson VL, Murphy K, Clarke G, et al. Targeting the microbiota–gut–brain axis: prebiotics have anxiolytic and antidepressant-like effects and reverse the impact of chronic stress in mice. Biol Psychiatry. 2017;82:472–87.

33. Matt SM, Allen JM, Lawson MA, Mailing LJ, Woods JA, Johnson RW. Butyrate and dietary soluble fiber improve neuroinflammation associated with aging in mice. Front Immunol. 2018;9:1832.

34. Faul F, Erdfelder E, Lang AG, Buchner A. G*Power 3: a flexible statistical power analysis program for the social, behavioral, and biomedical sciences. Behav Res Methods. 2007;39:175–91.

35. van de Wouw M, Boehme M, Lyte JM, Wiley N, Strain C, O’Sullivan O, et al. Short-chain fatty acids: microbial metabolites that alleviate stress-induced brain-gut axis alterations. J Physiol. 2018;596:4923–44.

36. Messaoudi M, Rozan P, Nejdi A, Hidalgo S, Desor D. Behavioural and cognitive effects of oligofructose-enriched inulin in rats. Br J Nutr. 2005;93 Suppl 1:S27–30.

37. Rozan P, Nejdi A, Hidalgo S, Bisson JF, Desor D, Messaoudi M. Effects of lifelong intervention with an oligofructose-enriched inulin in rats on general health and lifespan. Br J Nutr. 2008;100:1192–9.

38. Rault-Nania MH, Gueux E, Demougeot C, Demigne C, Rock E, Mazur A. Inulin attenuates atherosclerosis in apolipoprotein E-deficient mice. Br J Nutr. 2006;96:840–4.

39. Savignac HM, Tramullas M, Kiely B, Dinan TG, Cryan JF. Bifidobacteria modulate cognitive processes in an anxious mouse strain. Behav Brain Res. 2015;287:59–72.

40. Vorhees CV, Williams MT. Morris water maze: procedures for assessing spatial and related forms of learning and memory. Nat Protocols. 2006;1:848–58.

41. Izquierdo A, Wellman CL, Holmes A. Brief uncontrollable stress causes dendritic retraction in infralimbic cortex and resistance to fear extinction in mice. J Neurosci. 2006;26:5733–8.

42. Desbonnet L, O’Tuathaigh C, Clarke G, O’Leary C, Petit E, Clarke N, et al. Phenotypic effects of repeated psychosocial stress during adolescence in mice mutant for the schizophrenia risk gene neuregulin-1: a putative model of gene x environment interaction. Brain Behav Immunity. 2012;26:660–71.

43. Porsolt RD, Bertin A, Jalfre M. Behavioral despair in mice: a primary screening test for antidepressants. Arch Int Pharmacodyn Ther. 1977;229:327–36.

44. Cryan JF, Mombereau C. In search of a depressed mouse: utility of models for studying depression-related behavior in genetically modified mice. Mol Psychiatry. 2004;9:326–57.

45. Schellekens H, Clarke G, Jeffery IB, Dinan TG, Cryan JF. Dynamic 5-HT2C receptor editing in a mouse model of obesity. PLoS ONE. 2012;7:e32266.

46. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) Method. Methods (San Diego, CA). 2001;25:402–8.

47. Edgar RC. Search and clustering orders of magnitude faster than BLAST. Bioinformatics. 2010;26:2460–1.

48. Caporaso JG, Kuczynski J, Stombaugh J, Bittinger K, Bushman FD, Costello EK, et al. QIIME allows analysis of high-throughput community sequencing data. Nat Methods. 2010;7:335–6.

49. Smart KF, Aggio RB, Van Houtte JR, Villas-Boas SG. Analytical platform for metabolome analysis of microbial cells using methyl chloroformate derivatization followed by gas chromatography-mass spectrometry. Nat Protoc. 2010;5:1709–29.

50. Johnsen LG, Skou PB, Khakimov B, Bro R. Gas chromatography-mass spectrometry data processing made easy. J Chromatogr A. 2017;1503:57–64.

51. Grubbs FE. Procedures for detecting outlying observations in samples. Technometrics. 1969;11:1–21.

52. Dhabhar FS, Malarkey WB, Neri E, McEwen BS. Stress-induced redistribution of immune cells—from barracks to boulevards to battlefields: a tale of three hormones—Curt Richter Award winner. Psychoneuroendocrinology. 2012;37:1345–68.

53. Nikodemova M, Small AL, Kimyon RS, Watters JJ. Age-dependent differences in microglial responses to systemic inflammation are evident as early as middle age. Physiol Genomics. 2016;48:336–44.

54. Bardou I, Brothers HM, Kaercher RM, Hopp SC, Wenk GL. Differential effects of duration and age on the consequences of neuroinflammation in the hippocampus. Neurobiol Aging. 2013;34:2293–301.

55. Lee DC, Ruiz CR, Lebson L, Selenica ML, Rizer J, Hunt JB Jr., et al. Aging enhances classical activation but mitigates alternative activation in the central nervous system. Neurobiol Aging. 2013;34:1610–20.

56. Culshaw S, Millington OR, Brewer JM, McInnes IB. Murine neutrophils present class II restricted antigen. Immunol Lett. 2008;118:49–54.

57. Vono M, Lin A, Norrby-Teglund A, Koup RA, Liang F, Loré K. Neutrophils acquire the capacity for antigen presentation to memory CD4(+) T cells in vitro and ex vivo. Blood. 2017;129:1991–2001.

58. Dinan TG, Cryan JF. Gut instincts: microbiota as a key regulator of brain development, ageing and neurodegeneration. J Physiol. 2017;595:489–503.

59. Leung K, Thuret S. Gut microbiota: a modulator of brain plasticity and cognitive function in ageing. Healthcare (Basel). 2015;3:898–916.

60. Miyajima M, Zhang B, Sugiura Y, Sonomura K, Guerrini MM, Tsutsui Y, et al. Metabolic shift induced by systemic activation of T cells in PD-1-deficient mice perturbs brain monoamines and emotional behavior. Nat Immunol. 2017;18:1342–52.

61. Derecki NC, Cardani AN, Yang CH, Quinnies KM, Crihfield A, Lynch KR, et al. Regulation of learning and memory by meningeal immunity: a key role for IL-4. J Exp Med. 2010;207:1067–80.

62. Filiano AJ, Xu Y, Tustison NJ, Marsh RL, Baker W, Smirnov I, et al. Unexpected role of interferon-γ in regulating neuronal connectivity and social behaviour. Nature. 2016;535:425–9. advance online publication.

63. Sinclair LV, Rolf J, Emslie E, Shi YB, Taylor PM, Cantrell DA. Control of amino-acid transport by antigen receptors coordinates the metabolic reprogramming essential for T cell differentiation. Nat Immunol. 2013;14:500–8.

64. Lin R, Liu W, Piao M, Zhu H. A review of the relationship between the gut microbiota and amino acid metabolism. Amino Acids. 2017;49:2083–90.

65. Shen X, Miao J, Wan Q, Wang S, Li M, Pu F, et al. Possible correlation between gut microbiota and immunity among healthy middle-aged and elderly people in southwest China. Gut Pathog. 2018;10:4.

66. Varvel NH, Neher JJ, Bosch A, Wang W, Ransohoff RM, Miller RJ, et al. Infiltrating monocytes promote brain inflammation and exacerbate neuronal damage after status epilepticus. Proc Natl Acad Sci USA. 2016;113:E5665–74.

67. Möhle L, Mattei D, Heimesaat Markus M, Bereswill S, Fischer A, Alutis M, et al. Ly6Chi monocytes provide a link between antibiotic-induced changes in gut microbiota and adult hippocampal neurogenesis. Cell Rep. 2016;15:1945–56.

68. Korin B, Ben-Shaanan TL, Schiller M, Dubovik T, Azulay-Debby H, Boshnak NT, et al. High-dimensional, single-cell characterization of the brain’s immune compartment. Nat Neurosci. 2017;20:1300–9. advance online publication.

69. Mrdjen D, Pavlovic A, Hartmann FJ, Schreiner B, Utz SG, Leung BP, et al. High-dimensional single-cell mapping of central nervous system immune cells reveals distinct myeloid subsets in health, aging, and disease. Immunity. 2018;48:380–95 e6.

70. Getts DR, Terry RL, Getts MT, Müller M, Rana S, Shrestha B, et al. Ly6c(+) “inflammatory monocytes” are microglial precursors recruited in a pathogenic manner in West Nile virus encephalitis. J Exp Med. 2008;205:2319–37.

71. Wohleb ES, Powell ND, Godbout JP, Sheridan JF. Stress-induced recruitment of bone marrow-derived monocytes to the brain promotes anxiety-like behavior. J Neurosci. 2013;33:13820–33.

72. Sawicki CM, McKim DB, Wohleb ES, Jarrett BL, Reader BF, Norden DM, et al. Social defeat promotes a reactive endothelium in a brain region-dependent manner with increased expression of key adhesion molecules, selectins and chemokines associated with the recruitment of myeloid cells to the brain. Neuroscience. 2015;302:151–64.

73. Mildner A, Schmidt H, Nitsche M, Merkler D, Hanisch UK, Mack M, et al. Microglia in the adult brain arise from Ly-6ChiCCR2+monocytes only under defined host conditions. Nat Neurosci. 2007;10:1544–53.

74. Grabert K, Michoel T, Karavolos MH, Clohisey S, Baillie JK, Stevens MP, et al. Microglial brain region-dependent diversity and selective regional sensitivities to aging. Nat Neurosci. 2016;19:504–16. advance online publication.

75. Stirling DP, Cummins K, Mishra M, Teo W, Yong VW, Stys P. Toll-like receptor 2-mediated alternative activation of microglia is protective after spinal cord injury. Brain. 2014;137:707–23.

76. Erny D, Hrabe de Angelis AL, Jaitin D, Wieghofer P, Staszewski O, David E, et al. Host microbiota constantly control maturation and function of microglia in the CNS. Nat Neurosci. 2015;18:965–77.

77. Rea K, Dinan TG, Cryan JF. The microbiome: a key regulator of stress and neuroinflammation. Neurobiol Stress. 2016;4:23–33.

78. Vuong HE, Yano JM, Fung TC, Hsiao EY. The microbiome and host behavior. Annu Rev Neurosci. 2017;40:21–49.

79. Ang Z, Er JZ, Tan NS, Lu J, Liou YC, Grosse J, et al. Human and mouse monocytes display distinct signalling and cytokine profiles upon stimulation with FFAR2/FFAR3 short-chain fatty acid receptor agonists. Sci Rep. 2016;6:34145.

80. Wohleb ES, McKim DB, Sheridan JF, Godbout JP. Monocyte trafficking to the brain with stress and inflammation: a novel axis of immune-to-brain communication that influences mood and behavior. Front Neurosci. 2014;8:447.

81. Vazquez E, Barranco A, Ramirez M, Gruart A, Delgado-Garcia JM, Martinez-Lara E, et al. Effects of a human milk oligosaccharide, 2’-fucosyllactose, on hippocampal long-term potentiation and learning capabilities in rodents. J Nutr Biochem. 2015;26:455–65.

82. Mika A, Gaffney M, Roller R, Hills A, Bouchet CA, Hulen KA, et al. Feeding the developing brain: juvenile rats fed diet rich in prebiotics and bioactive milk fractions exhibit reduced anxiety-related behavior and modified gene expression in emotion circuits. Neurosci Lett. 2018;677:103–9.

83. Tarr AJ, Galley JD, Fisher Sydney E, Chichlowski M, Berg BM, Bailey MT. The prebiotics 3′ Sialyllactose and 6′ Sialyllactose diminish stressor-induced anxiety-like behavior and colonic microbiota alterations: evidence for effects on the gut–brain axis. Brain Behav Immunity. 2015;50:166–77.

84. Beilharz JE, Kaakoush NO, Maniam J, Morris MJ. Cafeteria diet and probiotic therapy: cross talk among memory, neuroplasticity, serotonin receptors and gut microbiota in the rat. Mol Psychiatry. 2017;23:351.

85. Fonken LK, Frank MG, D’Angelo HM, Heinze JD, Watkins LR, Lowry CA, et al. Mycobacterium vaccae immunization protects aged rats from surgery-elicited neuroinflammation and cognitive dysfunction. Neurobiol Aging. 2018;71:105–14.

86. Zhang S, Yang J, Henning SM, Lee R, Hsu M, Grojean E, et al. Dietary pomegranate extract and inulin affect gut microbiome differentially in mice fed an obesogenic diet. Anaerobe. 2017;48:184–93.

87. Vinolo MA, Rodrigues HG, Nachbar RT, Curi R. Regulation of inflammation by short chain fatty acids. Nutrients. 2011;3:858–76.

88. Huuskonen J, Suuronen T, Nuutinen T, Kyrylenko S, Salminen A. Regulation of microglial inflammatory response by sodium butyrate and short-chain fatty acids. Br J Pharmacol. 2004;141:874–80.

89. Odamaki T, Kato K, Sugahara H, Hashikura N, Takahashi S, Xiao JZ, et al. Age-related changes in gut microbiota composition from newborn to centenarian: a cross-sectional study. BMC Microbiol. 2016;16:90.

90. Yatsunenko T, Rey FE, Manary MJ, Trehan I, Dominguez-Bello MG, Contreras M, et al. Human gut microbiome viewed across age and geography. Nature. 2012;486:222.

91. Claesson MJ, Jeffery IB, Conde S, Power SE, O’Connor EM, Cusack S, et al. Gut microbiota composition correlates with diet and health in the elderly. Nature. 2012;488:178–84.

92. Claesson MJ, Cusack S, O’Sullivan O, Greene-Diniz R, de Weerd H, Flannery E, et al. Composition, variability, and temporal stability of the intestinal microbiota of the elderly. Proc Natl Acad Sci USA. 2011;108 Suppl 1:4586–91.

93. Gibson GR, Beatty ER, Wang X, Cummings JH. Selective stimulation of bifidobacteria in the human colon by oligofructose and inulin. Gastroenterology. 1995;108:975–82.

94. Hopkins MJ, Sharp R, Macfarlane GT. Age and disease related changes in intestinal bacterial populations assessed by cell culture, 16S rRNA abundance, and community cellular fatty acid profiles. Gut. 2001;48:198–205.

95. Everard A, Belzer C, Geurts L, Ouwerkerk JP, Druart C, Bindels LB, et al. Cross-talk between <em>Akkermansia muciniphila </em> and intestinal epithelium controls diet-induced obesity. Proc Natl Acad Sci USA. 2013;110:9066–71.

96. Bodogai M, O’Connell J, Kim K, Kim Y, Moritoh K, Chen C, et al. Commensal bacteria contribute to insulin resistance in aging by activating innate B1a cells. Sci Transl Med. 2018;10:eaat4271.