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Epigenetics and the Microbiome

  • Meirav Pevsner-Fischer
  • Niv Zmora
  • Sofia Braverman
  • Eran Elinav
Reference work entry

Abstract

The gut-resident commensal microbial ecosystem, collectively termed the microbiome, plays a vital role in host physiology and disease susceptibility. Being strategically situated in the intersection between the host and the external environment, the microbiome serves as a hub which integrates dietary and other environmental signals with a multitude of inherent host signals, and forms extensive communication networks with the host. Disruption of the delicate balance between the host and its microbiome can result in alterations in microbial composition, termed dysbiosis, which is associated with the etiology of multiple pathologies including metabolic disorders, inflammatory diseases, cancer, and neurodegeneration. Most mechanisms mediating these microbial effects on the host remain elusive. Microbial-induced host epigenetic modifications have been recently suggested as one such mechanism, by which the microbiome translates environmental signals to fine-tuning of the host gene expression and subsequently its corresponding systemic functions. In this chapter, we highlight recently studied examples exploring the mechanisms by which the microbiome may elicit epigenetic changes in the host, thereby affecting its physiology and pathology.

Keywords

Microbiome Microbiota Dysbiosis Epigenetics Intestine Immune cells Intestinal epithelial cells Diet Inflammatory bowel disease Tumorigenesis Metabolic syndrome 

List of Abbreviations

BMDM

Bone marrow-derived macrophages

CD

Crohn’s disease

DSS

Dextran sulfate sodium

GF

Germ-free

HDAC

Histone deacetylase

IECs

Intestinal epithelial cells

IFN-γ

Interferon-γ

ILCs

Innate lymphoid cells

iNKT

Invariant natural killer T cells

LMNA

Fatty acid synthase and lamin A/C

LP

Lamina propria

LPS

Lipopolysaccharide

NAFLD

Nonalcoholic fatty liver disease

NK

Natural killer

SCFAs

Short-chain fatty acids

SPF

Specific pathogen-free

Th

T helper

Tregs

Regulatory T cells

UC

Ulcerative colitis

WT

Wild-type

References

  1. Alenghat T, Artis D (2014) Epigenomic regulation of host-microbiota interactions. Trends Immunol 35(11):518–525CrossRefPubMedPubMedCentralGoogle Scholar
  2. Alenghat T, Osborne LC, Saenz SA, Kobuley D, Ziegler CG, Mullican SE, Choi I, Grunberg S, Sinha R, Wynosky-Dolfi M, Snyder A, Giacomin PR, Joyce KL, Hoang TB, Bewtra M, Brodsky IE, Sonnenberg GF, Bushman FD, Won KJ, Lazar MA, Artis D (2013) Histone deacetylase 3 coordinates commensal-bacteria-dependent intestinal homeostasis. Nature 504(7478):153–157CrossRefPubMedPubMedCentralGoogle Scholar
  3. Arpaia N, Campbell C, Fan X, Dikiy S, van der Veeken J, deRoos P, Liu H, Cross JR, Pfeffer K, Coffer PJ, Rudensky AY (2013) Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature 504(7480):451–455CrossRefPubMedPubMedCentralGoogle Scholar
  4. Artis D (2008) Epithelial-cell recognition of commensal bacteria and maintenance of immune homeostasis in the gut. Nat Rev Immunol 8(6):411–420CrossRefPubMedGoogle Scholar
  5. Asgari S (2014) Epigenetic modifications underlying symbiont-host interactions. Adv Genet 86:253–276CrossRefPubMedGoogle Scholar
  6. Asquith M, Powrie F (2010) An innately dangerous balancing act: intestinal homeostasis, inflammation, and colitis-associated cancer. J Exp Med 207(8):1573–1577CrossRefPubMedPubMedCentralGoogle Scholar
  7. 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(6015):337–341CrossRefPubMedGoogle Scholar
  8. Backhed F, Ley RE, Sonnenburg JL, Peterson DA, Gordon JI (2005) Host-bacterial mutualism in the human intestine. Science 307(5717):1915–1920CrossRefPubMedPubMedCentralGoogle Scholar
  9. Barish GD, Yu RT, Karunasiri M, Ocampo CB, Dixon J, Benner C, Dent AL, Tangirala RK, Evans RM (2010) Bcl-6 and NF-kappaB cistromes mediate opposing regulation of the innate immune response. Genes Dev 24(24):2760–2765CrossRefPubMedPubMedCentralGoogle Scholar
  10. Belcheva A, Irrazabal T, Robertson SJ, Streutker C, Maughan H, Rubino S, Moriyama EH, Copeland JK, Kumar S, Green B, Geddes K, Pezo RC, Navarre WW, Milosevic M, Wilson BC, Girardin SE, Wolever TM, Edelmann W, Guttman DS, Philpott DJ, Martin A (2014) Gut microbial metabolism drives transformation of MSH2-deficient colon epithelial cells. Cell 158(2):288–299CrossRefGoogle Scholar
  11. Bernink JH, Krabbendam L, Germar K, de Jong E, Gronke K, Kofoed-Nielsen M, Munneke JM, Hazenberg MD, Villaudy J, Buskens CJ, Bemelman WA, Diefenbach A, Blom B, Spits H (2015) Interleukin-12 and -23 control plasticity of CD127(+) group 1 and group 3 innate lymphoid cells in the intestinal lamina propria. Immunity 43(1):146–160CrossRefPubMedGoogle Scholar
  12. Biron CA, Nguyen KB, Pien GC, Cousens LP, Salazar-Mather TP (1999) Natural killer cells in antiviral defense: function and regulation by innate cytokines. Annu Rev Immunol 17:189–220CrossRefPubMedGoogle Scholar
  13. Bonelli M, Shih HY, Hirahara K, Singelton K, Laurence A, Poholek A, Hand T, Mikami Y, Vahedi G, Kanno Y, O’Shea JJ (2014) Helper T cell plasticity: impact of extrinsic and intrinsic signals on transcriptomes and epigenomes. Curr Top Microbiol Immunol 381:279–326PubMedPubMedCentralGoogle Scholar
  14. Brand S, Teich R, Dicke T, Harb H, Yildirim AO, Tost J, Schneider-Stock R, Waterland RA, Bauer UM, von Mutius E, Garn H, Pfefferle PI, Renz H (2011) Epigenetic regulation in murine offspring as a novel mechanism for transmaternal asthma protection induced by microbes. J Allergy Clin Immunol 128(3):618–625. e1–7CrossRefPubMedGoogle Scholar
  15. Brennan PJ, Brigl M, Brenner MB (2013) Invariant natural killer T cells: an innate activation scheme linked to diverse effector functions. Nat Rev Immunol 13(2):101–117CrossRefPubMedGoogle Scholar
  16. Brown EM, Sadarangani M, Finlay BB (2013) The role of the immune system in governing host-microbe interactions in the intestine. Nat Immunol 14(7):660–667CrossRefPubMedGoogle Scholar
  17. Cani PD, Amar J, Iglesias MA, Poggi M, Knauf C, Bastelica D, Neyrinck AM, Fava F, Tuohy KM, Chabo C, Waget A, Delmee E, Cousin B, Sulpice T, Chamontin B, Ferrieres J, Tanti JF, Gibson GR, Casteilla L, Delzenne NM, Alessi MC, Burcelin R (2007) Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes 56(7):1761–1772CrossRefPubMedGoogle Scholar
  18. Chandrakesan P, Roy B, Jakkula LU, Ahmed I, Ramamoorthy P, Tawfik O, Papineni R, Houchen C, Anant S, Umar S (2014) Utility of a bacterial infection model to study epithelial-mesenchymal transition, mesenchymal-epithelial transition or tumorigenesis. Oncogene 33(20):2639–2654CrossRefPubMedGoogle Scholar
  19. Chang PV, Hao L, Offermanns S, Medzhitov R (2014) The microbial metabolite butyrate regulates intestinal macrophage function via histone deacetylase inhibition. Proc Natl Acad Sci U S A 111(6):2247–2252CrossRefPubMedPubMedCentralGoogle Scholar
  20. Cortese R, Lu L, Yu Y, Ruden D, Claud EC (2016) Epigenome-microbiome crosstalk: a potential new paradigm influencing neonatal susceptibility to disease. Epigenetics 11(3):205–215CrossRefPubMedPubMedCentralGoogle Scholar
  21. Davie JR (2003) Inhibition of histone deacetylase activity by butyrate. J Nutr 133(7 Suppl):2485S–2493SCrossRefPubMedGoogle Scholar
  22. de Zoete MR, Palm NW, Zhu S, Flavell RA (2014) Inflammasomes. Cold Spring Harb Perspect Biol 6(12):a016287CrossRefPubMedPubMedCentralGoogle Scholar
  23. Dejea CM, Wick EC, Hechenbleikner EM, White JR, Mark Welch JL, Rossetti BJ, Peterson SN, Snesrud EC, Borisy GG, Lazarev M, Stein E, Vadivelu J, Roslani AC, Malik AA, Wanyiri JW, Goh KL, Thevambiga I, Fu K, Wan F, Llosa N, Housseau F, Romans K, Wu X, McAllister FM, Wu S, Vogelstein B, Kinzler KW, Pardoll DM, Sears CL (2014) Microbiota organization is a distinct feature of proximal colorectal cancers. Proc Natl Acad Sci U S A 111(51):18321–18326CrossRefPubMedPubMedCentralGoogle Scholar
  24. Dickson DW, Fujishiro H, Orr C, DelleDonne A, Josephs KA, Frigerio R, Burnett M, Parisi JE, Klos KJ, Ahlskog JE (2009) Neuropathology of non-motor features of Parkinson disease. Parkinsonism Relat Disord 15(Suppl 3):S1–S5CrossRefPubMedGoogle Scholar
  25. Ding SZ, Fischer W, Kaparakis-Liaskos M, Liechti G, Merrell DS, Grant PA, Ferrero RL, Crowe SE, Haas R, Hatakeyama M, Goldberg JB (2010) Helicobacter pylori-induced histone modification, associated gene expression in gastric epithelial cells, and its implication in pathogenesis. PLoS One 5(4):e9875CrossRefPubMedPubMedCentralGoogle Scholar
  26. Donohoe DR, Collins LB, Wali A, Bigler R, Sun W, Bultman SJ (2012) The Warburg effect dictates the mechanism of butyrate-mediated histone acetylation and cell proliferation. Mol Cell 48(4):612–626CrossRefPubMedPubMedCentralGoogle Scholar
  27. Donohoe DR, Holley D, Collins LB, Montgomery SA, Whitmore AC, Hillhouse A, Curry KP, Renner SW, Greenwalt A, Ryan EP, Godfrey V, Heise MT, Threadgill DS, Han A, Swenberg JA, Threadgill DW, Bultman SJ (2014) A gnotobiotic mouse model demonstrates that dietary fiber protects against colorectal tumorigenesis in a microbiota- and butyrate-dependent manner. Cancer Discov 4(12):1387–1397CrossRefPubMedPubMedCentralGoogle Scholar
  28. Feinberg AP, Vogelstein B (1983) Hypomethylation distinguishes genes of some human cancers from their normal counterparts. Nature 301(5895):89–92CrossRefPubMedGoogle Scholar
  29. Fuchs A, Vermi W, Lee JS, Lonardi S, Gilfillan S, Newberry RD, Cella M, Colonna M (2013) Intraepithelial type 1 innate lymphoid cells are a unique subset of IL-12- and IL-15-responsive IFN-gamma-producing cells. Immunity 38(4):769–781CrossRefPubMedPubMedCentralGoogle Scholar
  30. 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(7480):446–450CrossRefPubMedGoogle Scholar
  31. Ganal SC, Sanos SL, Kallfass C, Oberle K, Johner C, Kirschning C, Lienenklaus S, Weiss S, Staeheli P, Aichele P, Diefenbach A (2012) Priming of natural killer cells by nonmucosal mononuclear phagocytes requires instructive signals from commensal microbiota. Immunity 37(1):171–186CrossRefPubMedGoogle Scholar
  32. Gao Z, Yin J, Zhang J, Ward RE, Martin RJ, Lefevre M, Cefalu WT, Ye J (2009) Butyrate improves insulin sensitivity and increases energy expenditure in mice. Diabetes 58(7):1509–1517CrossRefPubMedPubMedCentralGoogle Scholar
  33. Geuking MB, Cahenzli J, Lawson MA, Ng DC, Slack E, Hapfelmeier S, McCoy KD, Macpherson AJ (2011) Intestinal bacterial colonization induces mutualistic regulatory T cell responses. Immunity 34(5):794–806CrossRefPubMedGoogle Scholar
  34. Gonneaud A, Turgeon N, Boudreau F, Perreault N, Rivard N, Asselin C (2016) Distinct roles for intestinal epithelial cell-specific Hdac1 and Hdac2 in the regulation of murine intestinal homeostasis. J Cell Physiol 231(2):436–448CrossRefPubMedGoogle Scholar
  35. Gonsky R, Deem RL, Targan SR (2009) Distinct methylation of IFNG in the gut. J Interf Cytokine Res 29(7):407–414CrossRefGoogle Scholar
  36. Gury-BenAri M, Thaiss CA, Serafini N, Winter DR, Giladi A, Lara-Astiaso D, Levy M, Salame TM, Weiner A, David E, Shapiro H, Dori-Bachash M, Pevsner-Fischer M, Lorenzo-Vivas E, Keren-Shaul H, Paul F, Harmelin A, Eberl G, Itzkovitz S, Tanay A, Di Santo JP, Elinav E, Amit I (2016) The spectrum and regulatory landscape of intestinal innate lymphoid cells are shaped by the microbiome. Cell 166(5):1231–1246. e13CrossRefPubMedGoogle Scholar
  37. Hayashi Y, Tsujii M, Wang J, Kondo J, Akasaka T, Jin Y, Li W, Nakamura T, Nishida T, Iijima H, Tsuji S, Kawano S, Hayashi N, Takehara T (2013) CagA mediates epigenetic regulation to attenuate let-7 expression in Helicobacter pylori-related carcinogenesis. Gut 62(11):1536–1546CrossRefPubMedGoogle Scholar
  38. Hoyler T, Klose CS, Souabni A, Turqueti-Neves A, Pfeifer D, Rawlins EL, Voehringer D, Busslinger M, Diefenbach A (2012) The transcription factor GATA-3 controls cell fate and maintenance of type 2 innate lymphoid cells. Immunity 37(4):634–648CrossRefPubMedPubMedCentralGoogle Scholar
  39. Hu S, Dong TS, Dalal SR, Wu F, Bissonnette M, Kwon JH, Chang EB (2011) The microbe-derived short chain fatty acid butyrate targets miRNA-dependent p21 gene expression in human colon cancer. PLoS One 6(1):e16221CrossRefPubMedPubMedCentralGoogle Scholar
  40. Hu S, Liu L, Chang EB, Wang JY, Raufman JP (2015) Butyrate inhibits pro-proliferative miR-92a by diminishing c-Myc-induced miR-17-92a cluster transcription in human colon cancer cells. Mol Cancer 14:180CrossRefPubMedPubMedCentralGoogle Scholar
  41. Humphreys KJ, Conlon MA, Young GP, Topping DL, Hu Y, Winter JM, Bird AR, Cobiac L, Kennedy NA, Michael MZ, Le Leu RK (2014) Dietary manipulation of oncogenic microRNA expression in human rectal mucosa: a randomized trial. Cancer Prev Res (Phila) 7(8):786–795CrossRefGoogle Scholar
  42. Huttenhower C, Kostic AD, Xavier RJ (2014) Inflammatory bowel disease as a model for translating the microbiome. Immunity 40(6):843–854CrossRefPubMedPubMedCentralGoogle Scholar
  43. Hyzd’alova M, Hofmanova J, Pachernik J, Vaculova A, Kozubik A (2008) The interaction of butyrate with TNF-alpha during differentiation and apoptosis of colon epithelial cells: role of NF-kappaB activation. Cytokine 44(1):33–43CrossRefPubMedGoogle Scholar
  44. Imhann F, Vich Vila A, Bonder MJ, Fu J, Gevers D, Visschedijk MC, Spekhorst LM, Alberts R, Franke L, van Dullemen HM, Ter Steege RW, Huttenhower C, Dijkstra G, Xavier RJ, Festen EA, Wijmenga C, Zhernakova A, Weersma RK (2016) Interplay of host genetics and gut microbiota underlying the onset and clinical presentation of inflammatory bowel disease. Gut.  https://doi.org/10.1136/gutjnl-2016-312135. [Epub ahead of print]
  45. Ipci K, Altintoprak N, Muluk NB, Senturk M, Cingi C (2016) The possible mechanisms of the human microbiome in allergic diseases. Eur Arch Otorhinolaryngol 274:617CrossRefPubMedGoogle Scholar
  46. Ivashkiv LB (2013) Epigenetic regulation of macrophage polarization and function. Trends Immunol 34(5):216–223CrossRefPubMedGoogle Scholar
  47. Jaenisch R, Bird A (2003) Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nat Genet 33(Suppl):245–254CrossRefGoogle Scholar
  48. Kau AL, Ahern PP, Griffin NW, Goodman AL, Gordon JI (2011) Human nutrition, the gut microbiome and the immune system. Nature 474(7351):327–336CrossRefPubMedPubMedCentralGoogle Scholar
  49. Kellermayer R, Balasa A, Zhang W, Lee S, Mirza S, Chakravarty A, Szigeti R, Laritsky E, Tatevian N, Smith CW, Shen L, Waterland RA (2010) Epigenetic maturation in colonic mucosa continues beyond infancy in mice. Hum Mol Genet 19(11):2168–2176CrossRefPubMedPubMedCentralGoogle Scholar
  50. Kiefer J, Beyer-Sehlmeyer G, Pool-Zobel BL (2006) Mixtures of SCFA, composed according to physiologically available concentrations in the gut lumen, modulate histone acetylation in human HT29 colon cancer cells. Br J Nutr 96(5):803–810CrossRefPubMedGoogle Scholar
  51. Klose CS, Flach M, Mohle L, Rogell L, Hoyler T, Ebert K, Fabiunke C, Pfeifer D, Sexl V, Fonseca-Pereira D, Domingues RG, Veiga-Fernandes H, Arnold SJ, Busslinger M, Dunay IR, Tanriver Y, Diefenbach A (2014) Differentiation of type 1 ILCs from a common progenitor to all helper-like innate lymphoid cell lineages. Cell 157(2):340–356CrossRefPubMedGoogle Scholar
  52. Kong YW, Ferland-McCollough D, Jackson TJ, Bushell M (2012) microRNAs in cancer management. Lancet Oncol 13(6):e249–e258CrossRefPubMedGoogle Scholar
  53. Kostic AD, Chun E, Robertson L, Glickman JN, Gallini CA, Michaud M, Clancy TE, Chung DC, Lochhead P, Hold GL, El-Omar EM, Brenner D, Fuchs CS, Meyerson M, Garrett WS (2013) Fusobacterium nucleatum potentiates intestinal tumorigenesis and modulates the tumor-immune microenvironment. Cell Host Microbe 14(2):207–215CrossRefPubMedPubMedCentralGoogle Scholar
  54. Kruidenier L, Chung CW, Cheng Z, Liddle J, Che K, Joberty G, Bantscheff M, Bountra C, Bridges A, Diallo H, Eberhard D, Hutchinson S, Jones E, Katso R, Leveridge M, Mander PK, Mosley J, Ramirez-Molina C, Rowland P, Schofield CJ, Sheppard RJ, Smith JE, Swales C, Tanner R, Thomas P, Tumber A, Drewes G, Oppermann U, Patel DJ, Lee K, Wilson DM (2012) A selective jumonji H3K27 demethylase inhibitor modulates the proinflammatory macrophage response. Nature 488(7411):404–408CrossRefPubMedPubMedCentralGoogle Scholar
  55. Kumar H, Lund R, Laiho A, Lundelin K, Ley RE, Isolauri E, Salminen S (2014) Gut microbiota as an epigenetic regulator: pilot study based on whole-genome methylation analysis. MBio 5(6):e02113–14.  https://doi.org/10.1128/mBio.02113-14
  56. Lee HS (2015) Impact of maternal diet on the epigenome during in utero life and the developmental programming of diseases in childhood and adulthood. Forum Nutr 7(11):9492–9507Google Scholar
  57. Ley RE, Turnbaugh PJ, Klein S, Gordon JI (2006) Microbial ecology: human gut microbes associated with obesity. Nature 444(7122):1022–1023CrossRefGoogle Scholar
  58. Li Y, Deuring J, Peppelenbosch MP, Kuipers EJ, de Haar C, van der Woude CJ (2012) IL-6-induced DNMT1 activity mediates SOCS3 promoter hypermethylation in ulcerative colitis-related colorectal cancer. Carcinogenesis 33(10):1889–1896CrossRefPubMedGoogle Scholar
  59. Liang X, Bushman FD, FitzGerald GA (2015) Rhythmicity of the intestinal microbiota is regulated by gender and the host circadian clock. Proc Natl Acad Sci U S A 112(33):10479–10484CrossRefPubMedPubMedCentralGoogle Scholar
  60. Lightfoot YL, Yang T, Sahay B, Mohamadzadeh M (2013) Targeting aberrant colon cancer-specific DNA methylation with lipoteichoic acid-deficient Lactobacillus acidophilus. Gut Microbes 4(1):84–88CrossRefPubMedPubMedCentralGoogle Scholar
  61. Lucas M, Schachterle W, Oberle K, Aichele P, Diefenbach A (2007) Dendritic cells prime natural killer cells by trans-presenting interleukin 15. Immunity 26(4):503–517CrossRefPubMedPubMedCentralGoogle Scholar
  62. Lukovac S, Belzer C, Pellis L, Keijser BJ, de Vos WM, Montijn RC, Roeselers G (2014) Differential modulation by Akkermansia muciniphila and Faecalibacterium prausnitzii of host peripheral lipid metabolism and histone acetylation in mouse gut organoids. MBio 5(4):e01438CrossRefPubMedPubMedCentralGoogle Scholar
  63. Macpherson AJ, Harris NL (2004) Interactions between commensal intestinal bacteria and the immune system. Nat Rev Immunol 4(6):478–485CrossRefPubMedGoogle Scholar
  64. Maekita T, Nakazawa K, Mihara M, Nakajima T, Yanaoka K, Iguchi M, Arii K, Kaneda A, Tsukamoto T, Tatematsu M, Tamura G, Saito D, Sugimura T, Ichinose M, Ushijima T (2006) High levels of aberrant DNA methylation in Helicobacter pylori-infected gastric mucosae and its possible association with gastric cancer risk. Clin Cancer Res 12(3 Pt 1):989–995CrossRefPubMedGoogle Scholar
  65. Manichanh C, Borruel N, Casellas F, Guarner F (2012) The gut microbiota in IBD. Nat Rev Gastroenterol Hepatol 9(10):599–608CrossRefPubMedGoogle Scholar
  66. Mathew OP, Ranganna K, Yatsu FM (2010) Butyrate, an HDAC inhibitor, stimulates interplay between different posttranslational modifications of histone H3 and differently alters G1-specific cell cycle proteins in vascular smooth muscle cells. Biomed Pharmacother 64(10):733–740CrossRefPubMedPubMedCentralGoogle Scholar
  67. Meijer K, de Vos P, Priebe MG (2010) Butyrate and other short-chain fatty acids as modulators of immunity: what relevance for health? Curr Opin Clin Nutr Metab Care 13(6):715–721CrossRefPubMedGoogle Scholar
  68. Mima K, Nishihara R, Qian ZR, Cao Y, Sukawa Y, Nowak JA, Yang J, Dou R, Masugi Y, Song M, Kostic AD, Giannakis M, Bullman S, Milner DA, Baba H, Giovannucci EL, Garraway LA, Freeman GJ, Dranoff G, Garrett WS, Huttenhower C, Meyerson M, Meyerhardt JA, Chan AT, Fuchs CS, Ogino S (2015) Fusobacterium nucleatum in colorectal carcinoma tissue and patient prognosis. Gut 65:1973CrossRefPubMedPubMedCentralGoogle Scholar
  69. Mjosberg J, Bernink J, Golebski K, Karrich JJ, Peters CP, Blom B, te Velde AA, Fokkens WJ, van Drunen CM, Spits H (2012) The transcription factor GATA3 is essential for the function of human type 2 innate lymphoid cells. Immunity 37(4):649–659CrossRefPubMedGoogle Scholar
  70. Narushima S, Sugiura Y, Oshima K, Atarashi K, Hattori M, Suematsu M, Honda K (2014) Characterization of the 17 strains of regulatory T cell-inducing human-derived Clostridia. Gut Microbes 5(3):333–339CrossRefPubMedPubMedCentralGoogle Scholar
  71. Nor C, Sassi FA, de Farias CB, Schwartsmann G, Abujamra AL, Lenz G, Brunetto AL, Roesler R (2013) The histone deacetylase inhibitor sodium butyrate promotes cell death and differentiation and reduces neurosphere formation in human medulloblastoma cells. Mol Neurobiol 48(3):533–543CrossRefPubMedGoogle Scholar
  72. Obata Y, Furusawa Y, Endo TA, Sharif J, Takahashi D, Atarashi K, Nakayama M, Onawa S, Fujimura Y, Takahashi M, Ikawa T, Otsubo T, Kawamura YI, Dohi T, Tajima S, Masumoto H, Ohara O, Honda K, Hori S, Ohno H, Koseki H, Hase K (2014) The epigenetic regulator Uhrf1 facilitates the proliferation and maturation of colonic regulatory T cells. Nat Immunol 15(6):571–579CrossRefPubMedGoogle Scholar
  73. Ohigashi S, Sudo K, Kobayashi D, Takahashi O, Takahashi T, Asahara T, Nomoto K, Onodera H (2013) Changes of the intestinal microbiota, short chain fatty acids, and fecal pH in patients with colorectal cancer. Dig Dis Sci 58(6):1717–1726CrossRefPubMedGoogle Scholar
  74. Olszak T, An D, Zeissig S, Vera MP, Richter J, Franke A, Glickman JN, Siebert R, Baron RM, Kasper DL, Blumberg RS (2012) Microbial exposure during early life has persistent effects on natural killer T cell function. Science 336(6080):489–493CrossRefPubMedPubMedCentralGoogle Scholar
  75. Pekow JR, Dougherty U, Mustafi R, Zhu H, Kocherginsky M, Rubin DT, Hanauer SB, Hart J, Chang EB, Fichera A, Joseph LJ, Bissonnette M (2012) miR-143 and miR-145 are downregulated in ulcerative colitis: putative regulators of inflammation and protooncogenes. Inflamm Bowel Dis 18(1):94–100CrossRefPubMedGoogle Scholar
  76. Pigeyre M, Yazdi FT, Kaur Y, Meyre D (2016) Recent progress in genetics, epigenetics and metagenomics unveils the pathophysiology of human obesity. Clin Sci (Lond) 130(12):943–986CrossRefGoogle Scholar
  77. Powrie F, Leach MW, Mauze S, Caddle LB, Coffman RL (1993) Phenotypically distinct subsets of CD4+ T cells induce or protect from chronic intestinal inflammation in C. B-17 scid mice. Int Immunol 5(11):1461–1471CrossRefPubMedGoogle Scholar
  78. Remely M, Aumueller E, Jahn D, Hippe B, Brath H, Haslberger AG (2014) Microbiota and epigenetic regulation of inflammatory mediators in type 2 diabetes and obesity. Benefic Microbes 5(1):33–43CrossRefGoogle Scholar
  79. Roediger B, Kyle R, Yip KH, Sumaria N, Guy TV, Kim BS, Mitchell AJ, Tay SS, Jain R, Forbes-Blom E, Chen X, Tong PL, Bolton HA, Artis D, Paul WE, Fazekas de St Groth B, Grimbaldeston MA, Le Gros G, Weninger W (2013) Cutaneous immunosurveillance and regulation of inflammation by group 2 innate lymphoid cells. Nat Immunol 14(6):564–573CrossRefPubMedPubMedCentralGoogle Scholar
  80. Ronn T, Volkov P, Gillberg L, Kokosar M, Perfilyev A, Jacobsen AL, Jorgensen SW, Brons C, Jansson PA, Eriksson KF, Pedersen O, Hansen T, Groop L, Stener-Victorin E, Vaag A, Nilsson E, Ling C (2015) Impact of age, BMI and HbA1c levels on the genome-wide DNA methylation and mRNA expression patterns in human adipose tissue and identification of epigenetic biomarkers in blood. Hum Mol Genet 24(13):3792–3813PubMedGoogle Scholar
  81. Saldanha SN, Kala R, Tollefsbol TO (2014) Molecular mechanisms for inhibition of colon cancer cells by combined epigenetic-modulating epigallocatechin gallate and sodium butyrate. Exp Cell Res 324(1):40–53CrossRefPubMedPubMedCentralGoogle Scholar
  82. Savona-Ventura C, Savona-Ventura S (2015) The inheritance of obesity. Best Pract Res Clin Obstet Gynaecol 29(3):300–308CrossRefPubMedGoogle Scholar
  83. Schwabe RF, Jobin C (2013) The microbiome and cancer. Nat Rev Cancer 13(11):800–812CrossRefPubMedPubMedCentralGoogle Scholar
  84. Sepulveda AR, Yao Y, Yan W, Park DI, Kim JJ, Gooding W, Abudayyeh S, Graham DY (2010) CpG methylation and reduced expression of O6-methylguanine DNA methyltransferase is associated with Helicobacter pylori infection. Gastroenterology 138(5):1836–1844CrossRefPubMedGoogle Scholar
  85. Shenderov BA, Midtvedt T (2014) Epigenomic programing: a future way to health? Microb Ecol Health Dis 25:24145Google Scholar
  86. Singh A, Settleman J (2010) EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer. Oncogene 29(34):4741–4751CrossRefPubMedPubMedCentralGoogle Scholar
  87. 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(6145):569–573CrossRefPubMedGoogle Scholar
  88. Sonnenberg GF, Artis D (2012) Innate lymphoid cell interactions with microbiota: implications for intestinal health and disease. Immunity 37(4):601–610CrossRefPubMedPubMedCentralGoogle Scholar
  89. Sookoian S, Rosselli MS, Gemma C, Burgueno AL, Fernandez Gianotti T, Castano GO, Pirola CJ (2010) Epigenetic regulation of insulin resistance in nonalcoholic fatty liver disease: impact of liver methylation of the peroxisome proliferator-activated receptor gamma coactivator 1alpha promoter. Hepatology 52(6):1992–2000CrossRefPubMedGoogle Scholar
  90. Strickertsson JA, Rasmussen LJ, Friis-Hansen L (2014) Enterococcus faecalis infection and reactive oxygen species down-regulates the miR-17-92 cluster in gastric adenocarcinoma cell culture. Genes (Basel) 5(3):726–738CrossRefGoogle Scholar
  91. Tachibana K, Sakurai K, Watanabe M, Miyaso H, Mori C (2016) Associations between changes in the maternal gut microbiome and differentially methylated regions of diabetes-associated genes in fetuses: a pilot study from a birth cohort study. J Diabetes Investig 8(4):550–553Google Scholar
  92. Tahara T, Shibata T, Nakamura M, Yamashita H, Yoshioka D, Okubo M, Maruyama N, Kamano T, Kamiya Y, Nakagawa Y, Fujita H, Nagasaka M, Iwata M, Takahama K, Watanabe M, Hirata I, Arisawa T (2009) Effect of MDR1 gene promoter methylation in patients with ulcerative colitis. Int J Mol Med 23(4):521–527CrossRefPubMedGoogle Scholar
  93. Tahoun A, Mahajan S, Paxton E, Malterer G, Donaldson DS, Wang D, Tan A, Gillespie TL, O’Shea M, Roe AJ, Shaw DJ, Gally DL, Lengeling A, Mabbott NA, Haas J, Mahajan A (2012) Salmonella transforms follicle-associated epithelial cells into M cells to promote intestinal invasion. Cell Host Microbe 12(5):645–656CrossRefPubMedGoogle Scholar
  94. Takahashi K, Sugi Y, Hosono A, Kaminogawa S (2009) Epigenetic regulation of TLR4 gene expression in intestinal epithelial cells for the maintenance of intestinal homeostasis. J Immunol 183(10):6522–6529CrossRefPubMedGoogle Scholar
  95. Takahashi K, Sugi Y, Nakano K, Tsuda M, Kurihara K, Hosono A, Kaminogawa S (2011) Epigenetic control of the host gene by commensal bacteria in large intestinal epithelial cells. J Biol Chem 286(41):35755–35762CrossRefPubMedPubMedCentralGoogle Scholar
  96. Tanoue T, Atarashi K, Honda K (2016) Development and maintenance of intestinal regulatory T cells. Nat Rev Immunol 16(5):295–309CrossRefPubMedGoogle Scholar
  97. Thaiss CA, Zeevi D, Levy M, Segal E, Elinav E (2015) A day in the life of the meta-organism: diurnal rhythms of the intestinal microbiome and its host. Gut Microbes 6(2):137–142CrossRefPubMedPubMedCentralGoogle Scholar
  98. Thaiss CA, Levy M, Korem T, Dohnalova L, Shapiro H, Jaitin DA, David E, Winter DR, Gury-BenAri M, Tatirovsky E, Tuganbaev T, Federici S, Zmora N, Zeevi D, Dori-Bachash M, Pevsner-Fischer M, Kartvelishvily E, Brandis A, Harmelin A, Shibolet O, Halpern Z, Honda K, Amit I, Segal E, Elinav E (2016a) Microbiota diurnal rhythmicity programs host transcriptome oscillations. Cell 167(6):1495–1510. e12CrossRefPubMedGoogle Scholar
  99. Thaiss CA, Zmora N, Levy M, Elinav E (2016b) The microbiome and innate immunity. Nature 535(7610):65–74CrossRefPubMedGoogle Scholar
  100. Tse C, Sera T, Wolffe AP, Hansen JC (1998) Disruption of higher-order folding by core histone acetylation dramatically enhances transcription of nucleosomal arrays by RNA polymerase III. Mol Cell Biol 18(8):4629–4638CrossRefPubMedPubMedCentralGoogle Scholar
  101. Turgeon N, Gagne JM, Blais M, Gendron FP, Boudreau F, Asselin C (2014) The acetylome regulators Hdac1 and Hdac2 differently modulate intestinal epithelial cell dependent homeostatic responses in experimental colitis. Am J Physiol Gastrointest Liver Physiol 306(7):G594–G605CrossRefPubMedGoogle Scholar
  102. Turnbaugh PJ, Quince C, Faith JJ, McHardy AC, Yatsunenko T, Niazi F, Affourtit J, Egholm M, Henrissat B, Knight R, Gordon JI (2010) Organismal, genetic, and transcriptional variation in the deeply sequenced gut microbiomes of identical twins. Proc Natl Acad Sci U S A 107(16):7503–7508CrossRefPubMedPubMedCentralGoogle Scholar
  103. Vivier E, Tomasello E, Baratin M, Walzer T, Ugolini S (2008) Functions of natural killer cells. Nat Immunol 9(5):503–510CrossRefPubMedGoogle Scholar
  104. Vollmers C, Schmitz RJ, Nathanson J, Yeo G, Ecker JR, Panda S (2012) Circadian oscillations of protein-coding and regulatory RNAs in a highly dynamic mammalian liver epigenome. Cell Metab 16(6):833–845CrossRefPubMedPubMedCentralGoogle Scholar
  105. Wahl S, Drong A, Lehne B, Loh M, Scott WR, Kunze S, Tsai PC, Ried JS, Zhang W, Yang Y, Tan S, Fiorito G, Franke L, Guarrera S, Kasela S, Kriebel J, Richmond RC, Adamo M, Afzal U, Ala-Korpela M, Albetti B, Ammerpohl O, Apperley JF, Beekman M, Bertazzi PA, Black SL, Blancher C, Bonder MJ, Brosch M, Carstensen-Kirberg M, de Craen AJ, de Lusignan S, Dehghan A, Elkalaawy M, Fischer K, Franco OH, Gaunt TR, Hampe J, Hashemi M, Isaacs A, Jenkinson A, Jha S, Kato N, Krogh V, Laffan M, Meisinger C, Meitinger T, Mok ZY, Motta V, Ng HK, Nikolakopoulou Z, Nteliopoulos G, Panico S, Pervjakova N, Prokisch H, Rathmann W, Roden M, Rota F, Rozario MA, Sandling JK, Schafmayer C, Schramm K, Siebert R, Slagboom PE, Soininen P, Stolk L, Strauch K, Tai ES, Tarantini L, Thorand B, Tigchelaar EF, Tumino R, Uitterlinden AG, van Duijn C, van Meurs JB, Vineis P, Wickremasinghe AR, Wijmenga C, Yang TP, Yuan W, Zhernakova A, Batterham RL, Smith GD, Deloukas P, Heijmans BT, Herder C, Hofman A, Lindgren CM, Milani L, van der Harst P, Peters A, Illig T, Relton CL, Waldenberger M, Jarvelin MR, Bollati V, Soong R, Spector TD, Scott J, McCarthy MI, Elliott P, Bell JT, Matullo G, Gieger C, Kooner JS, Grallert H, Chambers JC (2016) Epigenome-wide association study of body mass index, and the adverse outcomes of adiposity. Nature 541:81CrossRefPubMedPubMedCentralGoogle Scholar
  106. Walker JA, Barlow JL, McKenzie AN (2013) Innate lymphoid cells – how did we miss them? Nat Rev Immunol 13(2):75–87CrossRefPubMedGoogle Scholar
  107. Wang Y, Huang D, Chen KY, Cui M, Wang W, Huang X, Awadellah A, Li Q, Friedman A, Xin WW, Di Martino L, Cominelli F, Miron A, Chan R, Fox JG, Xu Y, Shen X, Kalady MF, Markowitz S, Maillard I, Lowe JB, Xin W, Zhou L (2017) Fucosylation deficiency in mice leads to colitis and adenocarcinoma. Gastroenterology 152(1):193–205. e10CrossRefPubMedGoogle Scholar
  108. Weir TL, Manter DK, Sheflin AM, Barnett BA, Heuberger AL, Ryan EP (2013) Stool microbiome and metabolome differences between colorectal cancer patients and healthy adults. PLoS One 8(8):e70803CrossRefPubMedPubMedCentralGoogle Scholar
  109. Wen XZ, Akiyama Y, Pan KF, Liu ZJ, Lu ZM, Zhou J, Gu LK, Dong CX, Zhu BD, Ji JF, You WC, Deng DJ (2010) Methylation of GATA-4 and GATA-5 and development of sporadic gastric carcinomas. World J Gastroenterol 16(10):1201–1208CrossRefPubMedPubMedCentralGoogle Scholar
  110. Wu CW, Dong YJ, Liang QY, He XQ, Ng SS, Chan FK, Sung JJ, Yu J (2013) MicroRNA-18a attenuates DNA damage repair through suppressing the expression of ataxia telangiectasia mutated in colorectal cancer. PLoS One 8(2):e57036CrossRefPubMedPubMedCentralGoogle Scholar
  111. Yin L, Chung WO (2011) Epigenetic regulation of human beta-defensin 2 and CC chemokine ligand 20 expression in gingival epithelial cells in response to oral bacteria. Mucosal Immunol 4(4):409–419CrossRefPubMedPubMedCentralGoogle Scholar
  112. Yu DH, Gadkari M, Zhou Q, Yu S, Gao N, Guan Y, Schady D, Roshan TN, Chen MH, Laritsky E, Ge Z, Wang H, Chen R, Westwater C, Bry L, Waterland RA, Moriarty C, Hwang C, Swennes AG, Moore SR, Shen L (2015) Postnatal epigenetic regulation of intestinal stem cells requires DNA methylation and is guided by the microbiome. Genome Biol 16:211CrossRefPubMedPubMedCentralGoogle Scholar
  113. Zeller G, Tap J, Voigt AY, Sunagawa S, Kultima JR, Costea PI, Amiot A, Bohm J, Brunetti F, Habermann N, Hercog R, Koch M, Luciani A, Mende DR, Schneider MA, Schrotz-King P, Tournigand C, Tran Van Nhieu J, Yamada T, Zimmermann J, Benes V, Kloor M, Ulrich CM, von Knebel Doeberitz M, Sobhani I, Bork P (2014) Potential of fecal microbiota for early-stage detection of colorectal cancer. Mol Syst Biol 10:766CrossRefPubMedPubMedCentralGoogle Scholar
  114. Zgouras D, Wachtershauser A, Frings D, Stein J (2003) Butyrate impairs intestinal tumor cell-induced angiogenesis by inhibiting HIF-1alpha nuclear translocation. Biochem Biophys Res Commun 300(4):832–838CrossRefPubMedGoogle Scholar
  115. Zhang X, Shen D, Fang Z, Jie Z, Qiu X, Zhang C, Chen Y, Ji L (2013) Human gut microbiota changes reveal the progression of glucose intolerance. PLoS One 8(8):e71108CrossRefPubMedPubMedCentralGoogle Scholar
  116. Zmora N, Zeevi D, Korem T, Segal E, Elinav E (2016) Taking it personally: personalized utilization of the human microbiome in health and disease. Cell Host Microbe 19(1):12–20CrossRefPubMedGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Meirav Pevsner-Fischer
    • 1
  • Niv Zmora
    • 1
  • Sofia Braverman
    • 1
  • Eran Elinav
    • 1
  1. 1.Department of ImmunologyWeizmann Institute of ScienceRehovotIsrael

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