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Gut microbiota as the key controllers of 'healthy' aging of elderly people

Ragonnaud, Emeline, Biragyn, Arya·2021·Immunity & Ageing
DOI 10.1186/s12979-020-00213-wPMC PMC7784378
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Abstract

Extrinsic factors, such as lifestyle and diet, are shown to be essential in the control of human healthy aging, and thus, longevity. They do so by targeting at least in part the gut microbiome, a collection of commensal microorganisms (microbiota), which colonize the intestinal tract starting after birth, and is established by the age of three. The composition and abundance of individual microbiota appears to continue to change until adulthood, presumably reflecting lifestyle and geographic, racial, and individual differences. Although most of these changes appear to be harmless, a major shift in their composition in the gut (dysbiosis) can trigger harmful local and systemic inflammation. Recent reports indicate that dysbiosis is increased in aging and that the gut microbiota of elderly people is enriched in pro-inflammatory commensals at the expense of beneficial microbes. The clinical consequence of this change remains confusing due to contradictory reports and a high degree of variability of human microbiota and methodologies used. Here, we present the authors’ thoughts that underscore dysbiosis as a primary cause of aging-associated morbidities, and thus, premature death of elderly people. We provide evidence that the dysbiosis triggers a chain of pathological and inflammatory events. Examples include alteration of levels of microbiota-affected metabolites, impaired function and integrity of the gastrointestinal tract, and increased gut leakiness. All of these enhance systemic inflammation, which when associated with aging is termed inflammaging, and result in consequent aging-associated pathologies.

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Fig. 1 The composition of gut microbiota determines inflammation and possibly lifespan of elderly people. The lumen and particularly the mucin layer of the intestine of young adults are colonized by a diverse population of commensal microbes that co-exist with the host in a symbiotic relationship. Members of Verrucomicrobia phylum, particularly Akkermansia muciniphila, support gut barrier integrity and thus prevent leakage and subsequent induction of inflammation. In elderly people, the composition of the gut commensals is changed and microbial diversity is reduced due to accumulation of potentially pro-inflammatory commensals and decrease of beneficial microbes, such as members of Verrucomicrobia. It therefore leads to gut leakiness and consequent systemic inflammation that facilitates aging-associated morbidities and premature death. Although the microbiota of centenarians changes, its diversity and beneficial commensals are retained, thereby controlling overt inflammation and supporting healthy aging
Fig. 1 The composition of gut microbiota determines inflammation and possibly lifespan of elderly people. The lumen and particularly the mucin layer of the intestine of young adults are colonized by a diverse population of commensal microbes that co-exist with the host in a symbiotic relationship. Members of Verrucomicrobia phylum, particularly Akkermansia muciniphila, support gut barrier integrity and thus prevent leakage and subsequent induction of inflammation. In elderly people, the composition of the gut commensals is changed and microbial diversity is reduced due to accumulation of potentially pro-inflammatory commensals and decrease of beneficial microbes, such as members of Verrucomicrobia. It therefore leads to gut leakiness and consequent systemic inflammation that facilitates aging-associated morbidities and premature death. Although the microbiota of centenarians changes, its diversity and beneficial commensals are retained, thereby controlling overt inflammation and supporting healthy agingCC BY · PubMed Central
Fig. 2 Commensal microbes are sole producers of beneficial SCFAs. 1, In the gut of healthy young people, beneficial commensal bacterial members of Firmicutes produce SCFAs. 2, SCFAs provide energy to the microbiota and 3, thereby can inhibit the colonization of opportunistic bacteria; and 4, promote the production of protective mucus. 5, SCFAs are also source of energy for enterocytes and 6, immune cells. They can cross the gut epithelium layer to promote immune tolerance by 7, inducing TGFβ producing FoxP3+ regulatory T cells (Tregs), 8, IL-10 producing T cells; 9, activating anti-inflammatory responses in antigen presenting cells (APCs); and 10, promoting the production of IgA and IgG from B cells. 11, SCFAs also initiate anti-inflammatory responses in neutrophils and 12, affect their recruitment
Fig. 2 Commensal microbes are sole producers of beneficial SCFAs. 1, In the gut of healthy young people, beneficial commensal bacterial members of Firmicutes produce SCFAs. 2, SCFAs provide energy to the microbiota and 3, thereby can inhibit the colonization of opportunistic bacteria; and 4, promote the production of protective mucus. 5, SCFAs are also source of energy for enterocytes and 6, immune cells. They can cross the gut epithelium layer to promote immune tolerance by 7, inducing TGFβ producing FoxP3+ regulatory T cells (Tregs), 8, IL-10 producing T cells; 9, activating anti-inflammatory responses in antigen presenting cells (APCs); and 10, promoting the production of IgA and IgG from B cells. 11, SCFAs also initiate anti-inflammatory responses in neutrophils and 12, affect their recruitmentCC BY · PubMed Central
Fig. 3 Gut dysbiosis in the elderly increases risk of aging-associated diseases. The composition of the gut microbiota changes with age, causing a mild inflammation in the elderly. This change can be exacerbated by additional intrinsic and extrinsic factors, such as uptake of antibiotics and diet. Frail elderly people show increased gut dysbiosis, a severe decrease of beneficial commensal bacteria, such as Akkermansia muciniphila and SCFA-producing bacteria, and a marked increase of opportunistic and potentially proinflammatory commensal microbes. It leads to impairment of the intestinal epithelial integrity and increases gut leakiness and translocation of opportunistic bacteria and endotoxin into the circulation, causing a chain of inflammatory events that enhance the risk of developing aging-associated pathologies. For instance, in aged mice, the A. muciniphila loss-caused inflammation recruits and activates CCR2+ monocytes in the omentum, where they upregulate 4-1BB, CD40L and the production of IFNγ and convert B1a B cells into 4BL cells via 4-1BBL/4-1BB axis. The 4BL cells then promote insulin resistance in aged hosts
Fig. 3 Gut dysbiosis in the elderly increases risk of aging-associated diseases. The composition of the gut microbiota changes with age, causing a mild inflammation in the elderly. This change can be exacerbated by additional intrinsic and extrinsic factors, such as uptake of antibiotics and diet. Frail elderly people show increased gut dysbiosis, a severe decrease of beneficial commensal bacteria, such as Akkermansia muciniphila and SCFA-producing bacteria, and a marked increase of opportunistic and potentially proinflammatory commensal microbes. It leads to impairment of the intestinal epithelial integrity and increases gut leakiness and translocation of opportunistic bacteria and endotoxin into the circulation, causing a chain of inflammatory events that enhance the risk of developing aging-associated pathologies. For instance, in aged mice, the A. muciniphila loss-caused inflammation recruits and activates CCR2+ monocytes in the omentum, where they upregulate 4-1BB, CD40L and the production of IFNγ and convert B1a B cells into 4BL cells via 4-1BBL/4-1BB axis. The 4BL cells then promote insulin resistance in aged hostsCC BY · PubMed Central

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Cites

Research works printed but not linked: 88

  1. Galen, et al. Hygiene, Loeb classical library, vol. 2. Cambridge: Harvard University Press; 2018.
  2. Metchnikoff E, Mitchell PC. The prolongation of life; optimistic studies. London: W. Heinemann; G.P. Putnam's Sons. xx; 1907. p. 343.
  3. Gill SR, et al. Metagenomic analysis of the human distal gut microbiome. Science. 2006;312(5778):1355–9. · DOI · Paper page
  4. Honda K, Littman DR. The microbiota in adaptive immune homeostasis and disease. Nature. 2016;535(7610):75–84. · DOI · Paper page
  5. Atarashi K, et al. Th17 cell induction by adhesion of microbes to intestinal epithelial cells. Cell. 2015;163(2):367–80. · DOI · Paper page
  6. Satoh-Takayama N, et al. Bacteria-induced group 2 innate lymphoid cells in the stomach provide immune protection through induction of IgA. Immunity. 2020;52(4):635–649 e4. · DOI
  7. Hansson J, et al. Influence of gut microbiota on mouse B2 B cell ontogeny and function. Mol Immunol. 2011;48(9–10):1091–101. · DOI
  8. Magrone T, Jirillo E. The interaction between gut microbiota and age-related changes in immune function and inflammation. Immun Ageing. 2013;10(1):31. · DOI · Paper page
  9. Claesson MJ, et al. Gut microbiota composition correlates with diet and health in the elderly. Nature. 2012;488(7410):178–84. · DOI · Paper page
  10. Langille MG, et al. Microbial shifts in the aging mouse gut. Microbiome. 2014;2(1):50. · DOI · Paper page
  11. Hearps AC, et al. Aging is associated with chronic innate immune activation and dysregulation of monocyte phenotype and function. Aging Cell. 2012;11(5):867–75. · DOI · Paper page
  12. Bouchlaka MN, et al. Aging predisposes to acute inflammatory induced pathology after tumor immunotherapy. J Exp Med. 2013;210(11):2223–37. · DOI
  13. Biagi E, et al. Gut microbiota and extreme longevity. Curr Biol. 2016;26(11):1480–5. · DOI · Paper page
  14. Brestoff JR, Artis D. Commensal bacteria at the interface of host metabolism and the immune system. Nat Immunol. 2013;14(7):676–84. · DOI · Paper page
  15. Trompette A, et al. Gut microbiota metabolism of dietary fiber influences allergic airway disease and hematopoiesis. Nat Med. 2014;20(2):159–66. · DOI · Paper page
  16. Trompette A, et al. Dietary fiber confers protection against flu by shaping Ly6c(−) patrolling monocyte hematopoiesis and CD8(+) T cell metabolism. Immunity. 2018;48(5):992–1005 e8. · DOI · Paper page
  17. Ivanov II, et al. Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell. 2009;139(3):485–98. · DOI · Paper page
  18. Dominguez-Bello MG, et al. Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns. Proc Natl Acad Sci U S A. 2010;107(26):11971–5. · DOI · Paper page
  19. Hill CJ, et al. Evolution of gut microbiota composition from birth to 24 weeks in the INFANTMET cohort. Microbiome. 2017;5(1):4. · DOI · Paper page
  20. Nagpal R, et al. Evolution of gut Bifidobacterium population in healthy Japanese infants over the first three years of life: a quantitative assessment. Sci Rep. 2017;7(1):10097. · DOI
  21. Nagpal R, et al. Gut dysbiosis following C-section instigates higher colonisation of toxigenic Clostridium perfringens in infants. Benefic Microbes. 2017;8(3):353–65. · DOI
  22. Penders J, et al. Factors influencing the composition of the intestinal microbiota in early infancy. Pediatrics. 2006;118(2):511–21. · DOI · Paper page
  23. Tsuji H, et al. Molecular monitoring of the development of intestinal microbiota in Japanese infants. Benefic Microbes. 2012;3(2):113–25. · DOI
  24. Favier CF, et al. Molecular monitoring of succession of bacterial communities in human neonates. Appl Environ Microbiol. 2002;68(1):219–26. · DOI
  25. Cheng J, et al. Discordant temporal development of bacterial phyla and the emergence of core in the fecal microbiota of young children. ISME J. 2016;10(4):1002–14. · DOI
  26. Eckburg PB, et al. Diversity of the human intestinal microbial flora. Science. 2005;308(5728):1635–8. · DOI · Paper page
  27. Arumugam M, et al. Enterotypes of the human gut microbiome. Nature. 2011;473(7346):174–80. · DOI · Paper page
  28. Jeffery IB, et al. The microbiota link to irritable bowel syndrome: an emerging story. Gut Microbes. 2012;3(6):572–6. · DOI
  29. Wang N, et al. Enriched taxa were found among the gut microbiota of centenarians in East China. PLoS One. 2019;14(10):e0222763. · DOI
  30. Kong F, et al. Gut microbiota signatures of longevity. Curr Biol. 2016;26(18):R832–3. · DOI
  31. He F, et al. Differences in composition and mucosal adhesion of bifidobacteria isolated from healthy adults and healthy seniors. Curr Microbiol. 2001;43(5):351–4. · DOI
  32. Hopkins MJ, Macfarlane GT. Changes in predominant bacterial populations in human faeces with age and with Clostridium difficile infection. J Med Microbiol. 2002;51(5):448–54. · DOI
  33. Makivuokko H, et al. The effect of age and non-steroidal anti-inflammatory drugs on human intestinal microbiota composition. Br J Nutr. 2010;103(2):227–34. · DOI
  34. Mitchell EL, et al. Reduced intestinal motility, mucosal barrier function, and inflammation in aged monkeys. J Nutr Health Aging. 2017;21(4):354–61. · DOI
  35. Odamaki T, et al. Age-related changes in gut microbiota composition from newborn to centenarian: a cross-sectional study. BMC Microbiol. 2016;16:90. · DOI · Paper page
  36. Rea MC, et al. Clostridium difficile carriage in elderly subjects and associated changes in the intestinal microbiota. J Clin Microbiol. 2012;50(3):867–75. · DOI
  37. Konikoff T, Gophna U. Oscillospira: a central, enigmatic component of the human gut microbiota. Trends Microbiol. 2016;24(7):523–4. · DOI
  38. Waters JL, Ley RE. The human gut bacteria Christensenellaceae are widespread, heritable, and associated with health. BMC Biol. 2019;17(1):83. · DOI
  39. Schneeberger M, et al. Akkermansia muciniphila inversely correlates with the onset of inflammation, altered adipose tissue metabolism and metabolic disorders during obesity in mice. Sci Rep. 2015;5:16643. · DOI · Paper page
  40. Sela DA, et al. The genome sequence of Bifidobacterium longum subsp. infantis reveals adaptations for milk utilization within the infant microbiome. Proc Natl Acad Sci U S A. 2008;105(48):18964–9. · DOI
  41. Kinross J, Nicholson JK. Gut microbiota: dietary and social modulation of gut microbiota in the elderly. Nat Rev Gastroenterol Hepatol. 2012;9(10):563–4. · DOI
  42. Rooks MG, Garrett WS. Gut microbiota, metabolites and host immunity. Nat Rev Immunol. 2016;16(6):341–52. · DOI · Paper page
  43. Maffei VJ, et al. Biological aging and the human gut microbiota. J Gerontol A Biol Sci Med Sci. 2017;72(11):1474–82. · DOI · Paper page
  44. Jackson MA, et al. Signatures of early frailty in the gut microbiota. Genome Med. 2016;8(1):8. · DOI · Paper page
  45. Barcenilla A, et al. Phylogenetic relationships of butyrate-producing bacteria from the human gut. Appl Environ Microbiol. 2000;66(4):1654–61. · DOI
  46. Louis P, Flint HJ. Diversity, metabolism and microbial ecology of butyrate-producing bacteria from the human large intestine. FEMS Microbiol Lett. 2009;294(1):1–8. · DOI · Paper page
  47. Mueller S, 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(2):1027–33. · DOI · Paper page
  48. Correa-Oliveira R, et al. Regulation of immune cell function by short-chain fatty acids. Clin Transl Immunol. 2016;5(4):e73. · DOI · Paper page
  49. Ghorbani P, et al. Short-chain fatty acids affect cystic fibrosis airway inflammation and bacterial growth. Eur Respir J. 2015;46(4):1033–45. · DOI
  50. Thangaraju M, et al. GPR109A is a G-protein-coupled receptor for the bacterial fermentation product butyrate and functions as a tumor suppressor in colon. Cancer Res. 2009;69(7):2826–32. · DOI · Paper page
  51. Ulven T. Short-chain free fatty acid receptors FFA2/GPR43 and FFA3/GPR41 as new potential therapeutic targets. Front Endocrinol (Lausanne). 2012;3:111. · DOI
  52. Goncalves P, Araujo JR, Di Santo JP. A cross-talk between microbiota-derived short-chain fatty acids and the host mucosal immune system regulates intestinal homeostasis and inflammatory bowel disease. Inflamm Bowel Dis. 2018;24(3):558–72. · DOI
  53. Singh N, et al. Activation of Gpr109a, receptor for niacin and the commensal metabolite butyrate, suppresses colonic inflammation and carcinogenesis. Immunity. 2014;40(1):128–39. · DOI · Paper page
  54. Sun M, et al. Microbiota-derived short-chain fatty acids promote Th1 cell IL-10 production to maintain intestinal homeostasis. Nat Commun. 2018;9(1):3555. · DOI
  55. Daroqui MC, Augenlicht LH. Transcriptional attenuation in colon carcinoma cells in response to butyrate. Cancer Prev Res (Phila). 2010;3(10):1292–302. · DOI
  56. Davie JR. Inhibition of histone deacetylase activity by butyrate. J Nutr. 2003;133(7 Suppl):2485S–93S. · DOI · Paper page
  57. Sekhavat A, Sun JM, Davie JR. Competitive inhibition of histone deacetylase activity by trichostatin A and butyrate. Biochem Cell Biol. 2007;85(6):751–8. · DOI
  58. Thangaraju M, et al. Colon cancer cells maintain low levels of pyruvate to avoid cell death caused by inhibition of HDAC1/HDAC3. Biochem J. 2009;417(1):379–89. · DOI
  59. Wong JM, et al. Colonic health: fermentation and short chain fatty acids. J Clin Gastroenterol. 2006;40(3):235–43. · DOI · Paper page
  60. Mowat AM, Agace WW. Regional specialization within the intestinal immune system. Nat Rev Immunol. 2014;14(10):667–85. · DOI
  61. Schulthess J, et al. The short chain fatty acid butyrate imprints an antimicrobial program in macrophages. Immunity. 2019;50(2):432–445 e7. · DOI · Paper page
  62. Usami M, et al. Butyrate and trichostatin A attenuate nuclear factor kappaB activation and tumor necrosis factor alpha secretion and increase prostaglandin E2 secretion in human peripheral blood mononuclear cells. Nutr Res. 2008;28(5):321–8. · DOI
  63. Vinolo MA, et al. Suppressive effect of short-chain fatty acids on production of proinflammatory mediators by neutrophils. J Nutr Biochem. 2011;22(9):849–55. · DOI
  64. Thorburn AN, et al. Evidence that asthma is a developmental origin disease influenced by maternal diet and bacterial metabolites. Nat Commun. 2015;6:7320. · DOI
  65. Zhang Z, et al. Dietary fiber intake regulates intestinal microflora and inhibits ovalbumin-induced allergic airway inflammation in a mouse model. PLoS One. 2016;11(2):e0147778. · DOI
  66. Erny D, et al. Host microbiota constantly control maturation and function of microglia in the CNS. Nat Neurosci. 2015;18(7):965–77. · DOI · Paper page
  67. Sherry CL, et al. Sickness behavior induced by endotoxin can be mitigated by the dietary soluble fiber, pectin, through up-regulation of IL-4 and Th2 polarization. Brain Behav Immun. 2010;24(4):631–40. · DOI
  68. Kespohl M, et al. The microbial metabolite butyrate induces expression of Th1-associated factors in CD4(+) T cells. Front Immunol. 2017;8:1036. · DOI · Paper page
  69. Park J, et al. Author correction: bidirectional regulatory potentials of short-chain fatty acids and their G-protein-coupled receptors in autoimmune neuroinflammation. Sci Rep. 2019;9(1):17511. · DOI
  70. Sampson TR, et al. Gut microbiota regulate motor deficits and neuroinflammation in a model of Parkinson’s disease. Cell. 2016;167(6):1469–1480 e12. · DOI · Paper page
  71. Belzer C, et al. Microbial metabolic networks at the mucus layer lead to diet-independent butyrate and vitamin B12 production by intestinal symbionts. mBio. 2017;8(5). · DOI
  72. Fachi JL, et al. Butyrate protects mice from Clostridium difficile-induced colitis through an HIF-1-dependent mechanism. Cell Rep. 2019;27(3):750–761 e7. · DOI · Paper page
  73. Derrien M, et al. The Mucin degrader Akkermansia muciniphila is an abundant resident of the human intestinal tract. Appl Environ Microbiol. 2008;74(5):1646–8. · DOI
  74. Rampelli S, et al. Functional metagenomic profiling of intestinal microbiome in extreme ageing. Aging (Albany NY). 2013;5(12):902–12. · DOI · Paper page
  75. Byndloss MX, et al. Microbiota-activated PPAR-gamma signaling inhibits dysbiotic Enterobacteriaceae expansion. Science. 2017;357(6351):570–5. · DOI
  76. Cox MA, et al. Short-chain fatty acids act as antiinflammatory mediators by regulating prostaglandin E (2) and cytokines. World J Gastroenterol. 2009;15(44):5549–57. · DOI · Paper page
  77. Lee-Chang C, et al. Aging converts innate B1a cells into potent CD8+ T cell inducers. J Immunol. 2016;196(8):3385–97. · DOI
  78. Lee-Chang C, et al. Accumulation of 4-1BBL+ B cells in the elderly induces the generation of granzyme-B+ CD8+ T cells with potential antitumor activity. Blood. 2014;124(9):1450–9. · DOI · Paper page
  79. Woodmansey EJ. Intestinal bacteria and ageing. J Appl Microbiol. 2007;102(5):1178–86. · DOI
  80. Salazar N, et al. Age-associated changes in gut microbiota and dietary components related with the immune system in adulthood and old age: a cross-sectional study. Nutrients. 2019;11(8). · DOI
  81. Laurin D, et al. Fibre intake in elderly individuals with poor masticatory performance. J Can Dent Assoc. 1994;60(5):443–6, 449.
  82. Tiihonen K, Ouwehand AC, Rautonen N. Human intestinal microbiota and healthy ageing. Ageing Res Rev. 2010;9(2):107–16. · DOI
  83. Guinan J, et al. Antibiotic-induced decreases in the levels of microbial-derived short-chain fatty acids correlate with increased gastrointestinal colonization of Candida albicans. Sci Rep. 2019;9(1):8872. · DOI
  84. Bouskra D, et al. Lymphoid tissue genesis induced by commensals through NOD1 regulates intestinal homeostasis. Nature. 2008;456(7221):507–10. · DOI · Paper page
  85. Conley MN, et al. Aging and serum MCP-1 are associated with gut microbiome composition in a murine model. PeerJ. 2016;4:e1854. · DOI
  86. Fransen F, et al. Aged gut microbiota contributes to systemical inflammaging after transfer to germ-free mice. Front Immunol. 2017;8:1385. · DOI · Paper page
  87. Wachholz PA, et al. Effectiveness of probiotics on the occurrence of infections in older people: systematic review and meta-analysis. Age Ageing. 2018;47(4):527–36. · DOI
  88. Rera M, Clark RI, Walker DW. Intestinal barrier dysfunction links metabolic and inflammatory markers of aging to death in Drosophila. Proc Natl Acad Sci U S A. 2012;109(52):21528–33. · DOI

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Metadata

Authors
Ragonnaud, E., & Biragyn, A.
ORCID
Biragyn, Arya
Venue
Immunity & Ageing
Publisher
Springer Science and Business Media LLC
Published
2021-01-05
Volume
18
Issue
1
ISSN
1742-4933
DOI
10.1186/s12979-020-00213-w
PMC
PMC7784378
Cited by
383
References
35
Language
en
Licence
Funders
National Institute on Aging (IRP)

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