Intestinal regulatory T cells: Their function and modulation by dietary nutrients

Nutritional Therapy and Metabolism

Volumn 32, Issue 4, 2014, Pages 157-165

  Magrone, Thea ^a   Jirillo, Emilio ^a  

^a UNIVERSITY OF BARI   (Italy)

Author keywords

Gut; Immunity; Microbiota; Nutrients; Regulatory T cells

Indexed keywords

EID: 84925299293     PISSN: 18286232     EISSN: None     Source Type: Journal    
DOI: 10.5301/NTM.2015.12893     Document Type: Review

References (128)

1. Cretney E, Kallies A, Nutt SL. Differentiation and function of Foxp3(+) effector regulatory T cells. Trends Immunol 2013; 34: 74-80.
2. Bennett CL, Christie J, Ramsdell F, et al. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat Genet 2001; 27: 20-1.
3. Brunkow ME, Jeffery EW, Hjerrild KA, et al. Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nat Genet 2001; 27: 68-73.
4. Wildin RS, Ramsdell F, Peake J, et al. X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy. Nat Genet 2001; 27: 18-20.
5. Wan YY, Flavell RA. Regulatory T-cell functions are subverted and converted owing to attenuated Foxp3 expression. Nature 2007; 445: 766-70.
6. Williams LM, Rudensky AY. Maintenance of the Foxp3-dependent developmental program in mature regulatory T cells requires continued expression of Foxp3. Nat Immunol 2007; 8: 277-84.
7. Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science 2003; 299: 1057-61.
8. Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol 2003; 4: 330-6.
9. Khattri R, Cox T, Yasayko SA, Ramsdell F. An essential role for Scurfin in CD4+CD25+ T regulatory cells. Nat Immunol 2003; 4: 337-42.
10. Sakaguchi S, Yamaguchi T, Nomura T, Ono M. Regulatory T cells and immune tolerance. Cell 2008; 133: 775-87.
11. Shevach EM. Mechanisms of foxp3+ T regulatory cell-mediated suppression. Immunity 2009; 30: 636-45.
12. Tang Q, Bluestone JA. The Foxp3+ regulatory T cell: a jack of all trades, master of regulation. Nat Immunol 2008; 9: 239-44.
13. Vignali DA, Collison LW, Workman CJ. How regulatory T cells work. Nat Rev Immunol 2008; 8: 523-32.
14. Picca CC, Larkin J 3rd, Boesteanu A, Lerman MA, Rankin AL, Caton AJ. Role of TCR specificity in CD4+ CD25+ regulatory T-cell selection. Immunol Rev 2006; 212: 74-85.
15. Chen W, Jin W, Hardegen N, et al. Conversion of peripheral CD4+CD25-naive T cells to CD4+CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3. J Exp Med 2003; 198: 1875-86.
16. Kretschmer K, Apostolou I, Hawiger D, Khazaie K, Nussenzweig MC, von Boehmer H. Inducing and expanding regulatory T cell populations by foreign antigen. Nat Immunol 2005; 6: 1219-27.
17. Selvaraj RK, Geiger TL. A kinetic and dynamic analysis of Foxp3 induced in T cells by TGF-beta. J Immunol 2007; 179: 11 p following 1390.
18. Zheng SG, Wang JH, Gray JD, Soucier H, Horwitz DA. Natural and induced CD4+CD25+ cells educate CD4+CD25-cells to develop suppressive activity: the role of IL-2, TGFbeta, and IL-10. J Immunol 2004; 172: 5213-21.
19. Mucida D, Kutchukhidze N, Erazo A, et al. Oral tolerance in the absence of naturally occurring Tregs. J Clin Invest 2005; 115: 1923-33.
20. Bonomo A, Kehn PJ, Shevach EM. Post-thymectomy autoimmunity: abnormal T-cell homeostasis. Immunol Today 1995; 16: 61-7.
21. Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol 1995; 155: 1151-64.
22. Asano M, Toda M, Sakaguchi N, Sakaguchi S. Autoimmune disease as a consequence of developmental abnormality of a T cell subpopulation. J Exp Med 199; 184: 387-96.
23. Yadav M, Louvet C, Davini D, et al. Neuropilin-1 distinguishes natural and inducible regulatory T cells among regulatory T cell subsets in vivo. J Exp Med 2012; 209: 1713-22, S1-19.
24. Huehn J, Polansky JK, Hamann A. Epigenetic control of FOXP3 expression: the key to a stable regulatory T-cell lineage? Nat Rev Immunol 2009; 9: 83-9.
25. Polansky JK, Kretschmer K, Freyer J, et al. DNA methylation controls Foxp3 gene expression. Eur J Immunol 2008; 38: 1654-63.
26. Haribhai D, Williams JB, Jia S, et al. A requisite role for induced regulatory T cells in tolerance based on expanding antigen receptor diversity. Immunity 2011; 35: 109-22.
27. Miyao T, Floess S, Setoguchi R, et al. Plasticity of Foxp3(+) T cells reflects promiscuous Foxp3 expression in conventional T cells but not reprogramming of regulatory T cells. Immunity 2012; 36: 262-75.
28. Ohkura N, Hamaguchi M, Morikawa H, et al. T cell receptor stimulation-induced epigenetic changes and Foxp3 expression are independent and complementary events required for Treg cell development. Immunity 2012; 37: 785-99.
29. Hsieh CS, Zheng Y, Liang Y, Fontenot JD, Rudensky AY. An intersection between the self-reactive regulatory and nonregulatory T cell receptor repertoires. Nat Immunol 2006; 7: 401-10.
30. Wong J, Mathis D, Benoist C. TCR-based lineage tracing: no evidence for conversion of conventional into regulatory T cells in response to a natural self-antigen in pancreatic islets. J Exp Med 2007; 204: 2039-45.
31. Curotto de Lafaille MA, Kutchukhidze N, Shen S, Ding Y, Yee H, Lafaille JJ. Adaptive Foxp3+ regulatory T cell-dependent and-independent control of allergic inflammation. Immunity 2008; 29: 114-26.
32. Belkaid Y, Oldenhove G. Tuning microenvironments: induction of regulatory T cells by dendritic cells. Immunity 2008; 29: 362-71.
33. Strauch UG, Obermeier F, Grunwald N, et al. Influence of intestinal bacteria on induction of regulatory T cells: lessons from a transfer model of colitis. Gut 2005; 54: 1546-52.
34. Ostman S, Rask C, Wold AE, Hultkrantz S, Telemo E. Impaired regulatory T cell function in germ-free mice. Eur J Immunol 2006; 36: 2336-46.
35. Ishikawa H, Tanaka K, Maeda Y, et al. Effect of intestinal microbiota on the induction of regulatory CD25+ CD4+ T cells. Clin Exp Immunol 2008; 153: 127-35.
36. Atarashi K, Tanoue T, Shima T, et al. Induction of colonic regulatory T cells by indigenous Clostridium species. Science 2011; 331: 337-41.
37. Round JL, Lee SM, Li J, et al. The Toll-like receptor 2 pathway establishes colonization by a commensal of the human microbiota. Science 2011; 332: 974-7.
38. Gaboriau-Routhiau V, Rakotobe S, Lécuyer E, et al. The key role of segmented filamentous bacteria in the coordinated maturation of gut helper T cell responses. Immunity 2009; 31: 677-89.
39. Ivanov II, Atarashi K, Manel N, et al. Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell 2009; 139: 485-98.
40. Coombes JL, Siddiqui KR, Arancibia-Cárcamo CV, et al. A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-beta and retinoic acid-dependent mechanism. J Exp Med 2007; 204: 1757-64.
41. Murai M, Krause P, Cheroutre H, Kronenberg M. Regulatory T-cell stability and plasticity in mucosal and systemic immune systems. Mucosal Immunol 2010; 3: 443-9.
42. Oldenhove G, Bouladoux N, Wohlfert EA, et al. Decrease of Foxp3+ Treg cell number and acquisition of effector cell phenotype during lethal infection. Immunity 2009; 31: 772-86.
43. Tsuji M, Komatsu N, Kawamoto S, et al. Preferential generation of follicular B helper T cells from Foxp3+ T cells in gut Peyer's patches. Science 2009; 323: 1488-92.
44. Komatsu N, Mariotti-Ferrandiz ME, Wang Y, Malissen B, Waldmann H, Hori S. Heterogeneity of natural Foxp3+ T cells: a committed regulatory T-cell lineage and an uncommitted minor population retaining plasticity. Proc Natl Acad Sci U S A 2009; 106: 1903-8.
45. DiPaolo RJ, Brinster C, Davidson TS, Andersson J, Glass D, Shevach EM. Autoantigen-specific TGFbeta-induced Foxp3+ regulatory T cells prevent autoimmunity by inhibiting dendritic cells from activating autoreactive T cells. J Immunol 2007; 179: 4685-93.
46. Nguyen TL, Sullivan NL, Ebel M, Teague RM, DiPaolo RJ. Antigen-specific TGF-β-induced regulatory T cells secrete chemokines, regulate T cell trafficking, and suppress ongoing autoimmunity. J Immunol 2011; 187: 1745-53.
47. Yadav M, Stephan S, Bluestone JA. Peripherally induced Tregs – role in immune homeostasis and autoimmunity. Front Immunol 2013; 4: 232.
48. Elias KM, Laurence A, Davidson TS, et al. Retinoic acid inhibits Th17 polarization and enhances FoxP3 expression through a Stat-3/Stat-5 independent signaling pathway. Blood 2008; 111: 1013-20.
49. Raverdeau M, Mills KH. Modulation of T cell and innate immune responses by retinoic acid. J Immunol 2014; 192: 2953-8.
50. Mucida D, Park Y, Kim G, Turovskaya O, Scott I, Kronenberg M, Cheroutre H. Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid. Science 2007; 317: 256-60.
51. Esterhazy D, Mucida D. Serum amyloid A proteins take retinol for a ride. Trends Immunol 2014; 35: 505-6.
52. Xiao S, Jin H, Korn T, et al. Retinoic acid increases Foxp3+ regulatory T cells and inhibits development of Th17 cells by enhancing TGF-beta-driven Smad3 signaling and inhibiting IL-6 and IL-23 receptor expression. J Immunol 2008; 181: 2277-84.
53. Mucida D, Pino-Lagos K, Kim G, et al. Retinoic acid can directly promote TGF-beta-mediated Foxp3(+) Treg cell conversion of naive T cells. Immunity 2009; 30: 471-2; author reply 472-3.
54. Hill JA, Hall JA, Sun CM, et al. Retinoic acid enhances Foxp3 induction indirectly by relieving inhibition from CD4+CD44hi cells. Immunity 2008; 29: 758-70.
55. Annacker O, Coombes JL, Malmstrom V, et al. Essential role for CD103 in the T cell-mediated regulation of experimental colitis. J Exp Med 2005; 202: 1051-61.
56. Benson MJ, Pino-Lagos K, Rosemblatt M, Noelle RJ. Alltrans retinoic acid mediates enhanced T reg cell growth, differentiation, and gut homing in the face of high levels of co-stimulation. J Exp Med 2007; 204: 1765-74.
57. Sun CM, Hall JA, Blank RB, et al. Small intestine lamina propria dendritic cells promote de novo generation of Foxp3 T reg cells via retinoic acid. J Exp Med 2007; 204: 1775-85.
58. Denning TL, Wang YC, Patel SR, Williams IR, Pulendran B. Lamina propria macrophages and dendritic cells differentially induce regulatory and interleukin 17-producing T cell responses. Nat Immunol 2007; 8: 1086-94.
59. Hall JA, Cannons JL, Grainger JR, et al. Essential role for retinoic acid in the promotion of CD4(+) T cell effector responses via retinoic acid receptor alpha. Immunity 2011; 35: 13-22.
60. DePaolo RW, Abadie V, Tang F, et al. Co-adjuvant effects of retinoic acid and IL-15 induce inflammatory immunity to dietary antigens. Nature 2011; 471: 220-4.
61. Ahmad SM, Haskell MJ, Raqib R, Stephensen CB. Vitamin A status is associated with T-cell responses in Bangladeshi men. Br J Nutr 2009; 102: 797-802.
62. Sudfeld CR, Navar AM, Halsey NA. Effectiveness of measles vaccination and vitamin A treatment. Int J Epidemiol 2010; 39 (Suppl 1): i48-55.
63. Mielke LA, Jones SA, Raverdeau M, et al. Retinoic acid expression associates with enhanced IL-22 production by γδ T cells and innate lymphoid cells and attenuation of intestinal inflammation. J Exp Med 2013; 210: 1117-24.
64. Racke MK, Burnett D, Pak SH, et al. Retinoid treatment of experimental allergic encephalomyelitis. IL-4 production correlates with improved disease course. J Immunol 1995; 154: 450-8.
65. Galvin KC, Dyck L, Marshall NA, et al. Blocking retinoic acid receptor-α enhances the efficacy of a dendritic cell vaccine against tumours by suppressing the induction of regulatory T cells. Cancer Immunol Immunother 2013; 62: 1273-82.
66. Rigby WF, Stacy T, Fanger MW. Inhibition of T lymphocyte mitogenesis by 1,25-dihydroxyvitamin D3 (calcitriol). J Clin Invest 1984; 74: 1451-5.
67. Bhalla AK, Amento EP, Krane SM. Differential effects of 1,25-dihydroxyvitamin D3 on human lymphocytes and monocyte/macrophages: inhibition of interleukin-2 and augmentation of interleukin-1 production. Cell Immunol 1986; 98: 311-22.
68. Reichel H, Koeffler HP, Tobler A, Norman AW. 1 Alpha,25-dihydroxyvitamin D3 inhibits gamma-interferon synthesis by normal human peripheral blood lymphocytes. Proc Natl Acad Sci U S A 1987; 84: 3385-9.
69. Barrat FJ, Cua DJ, Boonstra A, et al. In vitro generation of interleukin 10-producing regulatory CD4(+) T cells is induced by immunosuppressive drugs and inhibited by T helper type 1 (Th1)-and Th2-inducing cytokines. J Exp Med 2002; 195: 603-16.
70. Jeffery LE, Burke F, Mura M, et al. 1,25-Dihydroxyvitamin D3 and IL-2 combine to inhibit T cell production of inflammatory cytokines and promote development of regulatory T cells expressing CTLA-4 and FoxP3. J Immunol 2009; 183: 5458-67.
71. Piemonti L, Monti P, Sironi M, et al. Vitamin D3 affects differentation, maturation, and function of human monocytederived dendritic cells. J Immunol 2000; 164: 4443-51.
72. Griffin MD, Lutz W, Phan VA, Bachman LA, McKean DJ, Kumar R. Dendritic cell modulation by 1alpha,25 dihydroxyvitamin D3 and its analogs: a vitamin D receptor-dependent pathway that promotes a persistent state of immaturity in vitro and in vivo. Proc Natl Acad Sci U S A 2001; 98: 6800-5.
73. Penna G, Adorini L. 1 Alpha,25-dihydroxyvitamin D3 inhibits differentiation, maturation, activation, and survival of dendritic cells leading to impaired alloreactive T cell activation. J Immunol 2000; 164: 2405-11.
74. Penna G, Amuchastegui S, Giarratana N, et al. 1,25-Dihydroxyvitamin D3 selectively modulates tolerogenic properties in myeloid but not plasmacytoid dendritic cells. J Immunol 2007; 178: 145-53.
75. Penna G, Roncari A, Amuchastegui S, et al. Expression of the inhibitory receptor ILT3 on dendritic cells is dispensable for induction of CD4+Foxp3+ regulatory T cells by 1,25-dihydroxyvitamin D3. Blood 2005; 106: 3490-7.
76. Unger WW, Laban S, Kleijwegt FS, van der Slik AR, Roep BO. Induction of Treg by monocyte-derived DC modulated by vitamin D3 or dexamethasone: differential role for PD-L1. Eur J Immunol 2009; 39: 3147-59.
77. Bartels LE, Hvas CL, Agnholt J, Dahlerup JF, Agger R. Human dendritic cell antigen presentation and chemotaxis are inhibited by intrinsic 25-hydroxy vitamin D activation. Int Immunopharmacol 2010; 10: 922-8.
78. Bakdash G, van Capel TM, Mason LM, Kapsenberg ML, de Jong EC. Vitamin D3 metabolite calcidiol primes human dendritic cells to promote the development of immunomodulatory IL-10-producing T cells. Vaccine 2014; 32: 6294-302.
79. Provvedini DM, Tsoukas CD, Deftos LJ, Manolagas SC. 1,25-Dihydroxyvitamin D3 receptors in human leukocytes. Science 1983; 221: 1181-3.
80. Kongsbak M, von Essen MR, Boding L, et al. Vitamin D upregulates the vitamin D receptor by protecting it from proteasomal degradation in human CD4+ T cells. PLoS One 2014; 9: e96695.
81. Chun RF, Liu PT, Modlin RL, Adams JS, Hewison M. Impact of vitamin D on immune function: lessons learned from genome-wide analysis. Front Physiol 2014; 5: 151.
82. Chen J, Bruce D, Cantorna MT. Vitamin D receptor expression controls proliferation of naïve CD8+ T cells and development of CD8 mediated gastrointestinal inflammation. BMC Immunol 2014; 15: 6.
83. Kunisawa J, Hashimoto E, Ishikawa I, Kiyono H. A pivotal role of vitamin B9 in the maintenance of regulatory T cells in vitro and in vivo. PLoS One 2012; 7: e32094.
84. Kunisawa J, Kiyono H. Vitamins mediate immunological homeostasis and diseases at the surface of the body. Endocr Metab Immune Disord Drug Targets 2014; Oct 21 [Epub ahead of print].
85. de Jong AJ, Kloppenburg M, Toes RE, Ioan-Facsinay A. Fatty acids, lipid mediators, and T-cell function. Front Immunol 2014; 5: 483.
86. Wall R, Ross RP, Fitzgerald GF, Stanton C. Fatty acids from fish: the anti-inflammatory potential of long-chain omega-3 fatty acids. Nutr Rev 2010; 68: 280-9.
87. Kris-Etherton PM, Harris WS, Appel LJ; Nutrition Committee. Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease. Arterioscler Thromb Vasc Biol 2003; 23: e20-30.
88. Vessby B. Dietary fat and insulin action in humans. Br J Nutr 2000; 83 (Suppl 1): S91-6.
89. Marshall JA, Bessesen DH. Dietary fat and the development of type 2 diabetes. Diabetes Care 2002; 25: 620-2.
90. Stahl A, Gimeno RE, Tartaglia LA, Lodish HF. Fatty acid transport proteins: a current view of a growing family. Trends Endocrinol Metab 2001; 12: 266-73.
91. Haunerland NH, Spener F. Fatty acid-binding proteins – insights from genetic manipulations. Prog Lipid Res 2004; 43: 328-49.
92. Rolph MS, Young TR, Shum BO, et al. Regulation of dendritic cell function and T cell priming by the fatty acid-binding protein AP2. J Immunol 2006; 177: 7794-801.
93. Watson RR, Preedy VR, Zibaldi S, eds. Polyphenols in human health and disease, Vol 1. Elsevier/Academic Press, 2014.
94. Watson RR, Preedy VR, Zibaldi S, eds. Polyphenols in human health and disease, Vol 2. Elsevier/Academic Press, 2014.
95. Magrone T, Kumazawa Y, Jirillo E. Polyphenol-mediated beneficial effects in healthy status and disease with special reference to immune-based mechanisms. In: Watson RR, Preedy VR, Zibaldi S, eds. Polyphenols in human health and disease, Vol 1. Elsevier/Academic Press, 2014; 467-79.
96. Vinolo MA, Hirabara SM, Curi R. G-protein-coupled receptors as fat sensors. Curr Opin Clin Nutr Metab Care 2012; 15: 112-6.
97. Blad CC, Tang C, Offermanns S. G protein-coupled receptors for energy metabolites as new therapeutic targets. Nat Rev Drug Discov 2012; 11: 603-19.
98. Yonezawa T, Kurata R, Yoshida K, Murayama MA, Cui X, Hasegawa A. Free fatty acids-sensing G protein-coupled receptors in drug targeting and therapeutics. Curr Med Chem 2013; 20: 3855-71.
99. Briscoe CP, Tadayyon M, Andrews JL, et al. The orphan G protein-coupled receptor GPR40 is activated by medium and long chain fatty acids. J Biol Chem 2003; 278: 11303-11.
100. Marzulli G, Magrone T, Kawaguchi K, Kumazawa Y, Jirillo E. Fermented grape marc (FGM): immunomodulating properties and its potential exploitation in the treatment of neurodegenerative diseases. Curr Pharm Des 2012; 18: 43-50.
101. Lomax AR, Calder PC. Prebiotics, immune function, infection and inflammation: a review of the evidence. Br J Nutr 2009; 101: 633-58.
102. West CE. Prebiotics in infancy and childhood; clinical research warranted. Br J Nutr 2011; 106: 1628-9.
103. Scholtens PA, Alliet P, Raes M, et al. Fecal secretory immunoglobulin A is increased in healthy infants who receive a formula with short-chain galacto-oligosaccharides and longchain fructo-oligosaccharides. J Nutr 2008; 138: 1141-7.
104. Bode L. Human milk oligosaccharides: prebiotics and beyond. Nutr Rev 2009; 67 (Suppl 2): S183-91.
105. Bode L. Human milk oligosaccharides: every baby needs a sugar mama. Glycobiology 2012; 22: 1147-62.
106. Sela DA, Mills DA. Nursing our microbiota: molecular linkages between bifidobacteria and milk oligosaccharides. Trends Microbiol 2010; 18: 298-307.
107. Oozeer R, van Limpt K, Ludwig T, et al. Intestinal microbiology in early life: specific prebiotics can have similar functionalities as human-milk oligosaccharides. Am J Clin Nutr 2013; 98: 561S-71S.
108. West CE, Jenmalm MC, Prescott SL. The gut microbiota and its role in the development of allergic disease: a wider perspective. Clin Exp Allergy 2014; April 29 [Epub ahead of print].
109. Osborn DA, Sinn JK. Prebiotics in infants for prevention of allergy. Cochrane Database Syst Rev 2013; 3: CD006474.
110. van Baarlen P, Wells JM, Kleerebezem M. Regulation of intestinal homeostasis and immunity with probiotic lactobacilli. Trends Immunol 2013; 34: 208-15.
111. Bron PA, van Baarlen P, Kleerebezem M. Emerging molecular insights into the interaction between probiotics and the host intestinal mucosa. Nat Rev Microbiol 2011; 10: 66-78.
112. Lebeer S, Vanderleyden J, De Keersmaecker SC. Genes and molecules of lactobacilli supporting probiotic action. Microbiol Mol Biol Rev 2008; 72: 728-64.
113. Kwon HK, Lee CG, So JS, et al. Generation of regulatory dendritic cells and CD4+Foxp3+ T cells by probiotics administration suppresses immune disorders. Proc Natl Acad Sci U S A 2010; 107: 2159-64.
114. Jeon SG, Kayama H, Ueda Y, et al. Probiotic Bifidobacterium breve induces Il-10-producing Tr1 cells in the colon. PLoS Pathogen 2012; 8: e1002714.
115. Kaji R, Kiyoshima-Shibata J, Nagaoka M, Nanno M, Shida K. Bacterial teichoic acids reverse predominant IL-12 production induced by certain lactobacillus strains into predominant IL-10 production via TLR2-dependent ERK activation in macrophages. J Immunol 2010; 184: 3505-13.
116. Lavasani S, Dzhambazov B, Nouri M, et al. A novel probiotic mixture exerts a therapeutic effect on experimental autoimmune encephalomyelitis mediated by IL-10 producing regulatory T cells. PLoS One 2010; 5: e9009.
117. Sheil B, MacSharry J, O'Callaghan L, et al. Role of interleukin (IL-10) in probiotic-mediated immune modulation: an assessment in wild-type and IL-10 knock-out mice. Clin Exp Immunol 2006; 144: 273-80.
118. Magrone T, Jirillo E. The interplay between the gut immune system and microbiota in health and disease: nutraceutical intervention for restoring intestinal homeostasis. Curr Pharm Des 2013; 19: 1329-42.
119. Kabat AM, Srinivasan N, Maloy KJ. Modulation of immune development and function by intestinal microbiota. Trends Immunol 2014; 35: 507-17.
120. Kau AL, Ahern PP, Griffin NW, Goodman AL, Gordon JI. Human nutrition, the gut microbiome and the immune system. Nature 2011; 474: 327-36.
121. Valdez Y, Brown EM, Finlay BB. Influence of the microbiota on vaccine effectiveness. Trends Immunol 2014; 35: 526-37.
122. Alenghat T, Artis D. Epigenomic regulation of host-microbiota interactions. Trends Immunol 2014; 35: 518-25.
123. Obata Y, Furusawa Y, Endo TA, et al. The epigenetic regulator Uhrf1 facilitates the proliferation and maturation of colonic regulatory T cells. Nat Immunol 2014; 15: 571-9.
124. Arpaia N, Campbell C, Fan X, et al. Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature 2013; 504: 451-5.
125. Berndt BE, Zhang M, Owyang SY, et al. Butyrate increases IL-23 production by stimulated dendritic cells. Am J Physiol Gastrointest Liver Physiol 2012; 303: G1384-92.
126. Hamer HM, Jonkers DM, Vanhoutvin SA, et al. Effect of butyrate enemas on inflammation and antioxidant status in the colonic mucosa of patients with ulcerative colitis in remission. Clin Nutr 2010; 29: 738-44.
127. Diehl GE, Longman RS, Zhang JX, et al. Microbiota restricts trafficking of bacteria to mesenteric lymph nodes by CX(3) CR1(hi) cells. Nature 2013; 494: 116-20.
128. Tarrerias AL, Millecamps M, Alloui A, et al. Short-chain fatty acid enemas fail to decrease colonic hypersensitivity and inflammation in TNBS-induced colonic inflammation in rats. Pain 2002; 100: 91-7.