The Role of the Microbial Metabolites Including Tryptophan Catabolites and Short Chain Fatty Acids in the Pathophysiology of Immune-Inflammatory and Neuroimmune Disease

Molecular Neurobiology volume 54, pages4432–4451(2017)Cite this article

Abstract

There is a growing awareness that gut commensal metabolites play a major role in host physiology and indeed the pathophysiology of several illnesses. The composition of the microbiota largely determines the levels of tryptophan in the systemic circulation and hence, indirectly, the levels of serotonin in the brain. Some microbiota synthesize neurotransmitters directly, e.g., gamma-amino butyric acid, while modulating the synthesis of neurotransmitters, such as dopamine and norepinephrine, and brain-derived neurotropic factor (BDNF). The composition of the microbiota determines the levels and nature of tryptophan catabolites (TRYCATs) which in turn has profound effects on aryl hydrocarbon receptors, thereby influencing epithelial barrier integrity and the presence of an inflammatory or tolerogenic environment in the intestine and beyond. The composition of the microbiota also determines the levels and ratios of short chain fatty acids (SCFAs) such as butyrate and propionate. Butyrate is a key energy source for colonocytes. Dysbiosis leading to reduced levels of SCFAs, notably butyrate, therefore may have adverse effects on epithelial barrier integrity, energy homeostasis, and the T helper 17/regulatory/T cell balance. Moreover, dysbiosis leading to reduced butyrate levels may increase bacterial translocation into the systemic circulation. As examples, we describe the role of microbial metabolites in the pathophysiology of diabetes type 2 and autism.

This is a preview of subscription content, log in to check access.

Access options

Buy single article

Instant access to the full article PDF.

US$ 39.95

Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2
Fig. 3

References

  1. 1.

    Heijtz RD, Wang S, Anuar F, Qian Y, Bjorkholm B, Samuelsson A, Hibberd ML, Forssberg H et al (2011) Normal gut microbiota modulates brain development and behavior. Proc Natl Acad Sci U S A 108:3047–3052

    CAS  PubMed Central  Article  Google Scholar 

  2. 2.

    Vijay-Kumar M, Aitken JD, Carvalho FA, Cullender TC, Mwangi S, Srinivasan S, Sitaraman SV, Knight R et al (2010) Metabolic syndrome and altered gut microbiota in mice lacking Toll-like receptor 5. Science 328:228–231

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  3. 3.

    Maslowski KM, Vieira AT, Ng A, Kranich J, Sierro F, Yu D, Schilter HC, Rolph MS et al (2009) Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43. Nature 461:1282–1286

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  4. 4.

    Uronis JM, Muhlbauer M, Herfarth HH, Rubinas TC, Jones GS, Jobin C (2009) Modulation of the intestinal microbiota alters colitis-associated colorectal cancer susceptibility. PLoS One 4:e6026

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  5. 5.

    De Filippo C, Cavalieri D, Di Paola M, Ramazzotti M, Poullet JB, Massart S, Collini S, Pieraccini G et al (2010) Impact of diet in shaping gut microbiota revealed by a comparative study in children from Europe and rural Africa. Proc Natl Acad Sci U S A 107:14691–14696

    PubMed  PubMed Central  Article  Google Scholar 

  6. 6.

    De Palma G, Collins S, Bercik P, Verdu E (2014) The microbiota-gut-brain axis in gastrointestinal disorders: stressed bugs, stressed brain or both? J Physiol 592:2989–2997

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  7. 7.

    Burokas A, Moloney R, Dinan T, Cryan J (2015) Microbiota regulation of the mammalian gut-brain axis. Adv Appl Microbiol 9:1–62

    Google Scholar 

  8. 8.

    Carabotti M, Scirocco A, Maselli M, Severia C (2015) The gut-brain axis: interactions between enteric microbiota, central and enteric nervous systems. Ann Gastroenterol 28:203–209

    PubMed  PubMed Central  Google Scholar 

  9. 9.

    Maes M, Kubera M, Leunis JC (2008) The gut-brain barrier in major depression: intestinal mucosal dysfunction with an increased translocation of LPS from gram negative enterobacteria (leaky gut) plays a role in the inflammatory pathophysiology of depression. Neuro Endocrinol Lett 29:117–124

    PubMed  Google Scholar 

  10. 10.

    Stilling R, Dinan T, Cryan J (2013) Microbial genes, brain & behaviour—epigenetic regulation of the gut-brain axis. Genes Brain Behav 13:69–86

    PubMed  Article  Google Scholar 

  11. 11.

    Grenham S, Clarke G, Cryan JF, Dinan TG (2011) Brain–gut–microbe communication in health and disease. Front Physiol 2:1–15. doi:10.3389/fphys.2011.00094

    Article  Google Scholar 

  12. 12.

    Maes M, Mihaylova I, Ruyter M, Kubera M, Bosmans E (2007) The immune effects of TRYCATs (tryptophan catabolites along the IDO pathway): relevance for depression—and other conditions involving inflammation. Neuro Endocrinol Lett 28:826–831

    CAS  PubMed  Google Scholar 

  13. 13.

    Borre Y, Moloney R, Clarke G, Dinan T, Cryan J (2014) The impact of microbiota on brain and behavior: mechanisms & therapeutic potential. Adv Exp Med Biol 817:373–403

    CAS  PubMed  Article  Google Scholar 

  14. 14.

    Gur T, Worly B, Bailey M (2015) Stress and the commensal microbiota: importance in parturition and infant neurodevelopment. Front Psychiatry 6:5

    PubMed  PubMed Central  Article  Google Scholar 

  15. 15.

    Galley J, Bailey M (2014) Impact of stressor exposure on the interplay between commensal microbiota and host inflammation. Gut Microbes 5:390–396

    PubMed  PubMed Central  Article  Google Scholar 

  16. 16.

    Bailey M (2012) The contributing role of the intestinal microbiota in stressor-induced increases in susceptibility to enteric infection and systemic immunomodulation. Horm Behav 62:286–294

    CAS  PubMed  Article  Google Scholar 

  17. 17.

    Bailey M, Dowd S, Galley J, Hufnagle A, Allen R, Lyte M (2011) Exposure to a social stressor alters the structure of the intestinal microbiota: implications for stressor-induced immunomodulation. Brain Behav Immun 25:397–407

    CAS  PubMed  Article  Google Scholar 

  18. 18.

    Chassaing B, Koren O, Goodrich JK et al (2015) Dietary emulsifiers impact the mouse gut microbiota promoting colitis and metabolic syndrome. Nature 519:92–96

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  19. 19.

    Murphy EA, Velazquez KT, Herbert KM (2015) Influence of high-fat diet on gut microbiota: a driving force for chronic disease risk. Curr Opin Clin Nutr Metab Care 18:515–520

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  20. 20.

    Morris G, Maes M (2012) A neuro-immune model of myalgic encephalomyelitis/chronic fatigue syndrome. Metabolic Brain Dis 28:523–540

    Article  CAS  Google Scholar 

  21. 21.

    Morris G, Berk M, Galecki P, Walder K, Maes M (2016) The neuro-immune pathophysiology of central and peripheral fatigue in systemic immune-inflammatory and neuro-immune diseases. Mol Neurobiol 53(2):1195–1219

    CAS  PubMed  Article  Google Scholar 

  22. 22.

    Maes M, Leonard B, Myint A, Kubera M, Verkerk R (2011) The new ‘5-HT’ hypothesis of depression: cell-mediated immune activation induces indoleamine 2,3-dioxygenase, which leads to lower plasma tryptophan and an increased synthesis of detrimental tryptophan catabolites (TRYCATs), both of which contribute to the onset of depression. Prog NeuroPsychopharmacol Biol Psychiatry 35:702–721

    CAS  PubMed  Article  Google Scholar 

  23. 23.

    Maes M, Rief W (2012) Diagnostic classifications in depression and somatization should include biomarkers, such as disorders in the tryptophan catabolite (TRYCAT) pathway. Psychiatry Res 196:243–249

    CAS  PubMed  Article  Google Scholar 

  24. 24.

    Huda-Faujan N, Abdulamir AS, Fatimah AB, Anas OM, Shuhaimi M, Yazid AM, Loong YY (2010) The impact of the level of the intestinal short chain fatty acids in inflammatory bowel disease patients versus healthy subjects. Open Biochem J 4:53–58

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  25. 25.

    Vernia P, Caprilli R, Latella G, Barbetti F, Magliocca FM, Cittadini M (1988) Fecal lactate and ulcerative colitis. Gastroenterology 95:1564–1568

    CAS  PubMed  Article  Google Scholar 

  26. 26.

    Murphy EF, Cotter PD, Healy S, Marques TM, O’Sullivan O, Fouhy F, Clarke SF, O’Toole PW et al (2010) Composition and energy harvesting capacity of the gut microbiota: relationship to diet, obesity and time in mouse models. Gut 59:1635–1642

    CAS  PubMed  Article  Google Scholar 

  27. 27.

    McIntyre A, Gibson PR, Young GP (1993) Butyrate production from dietary fibre and protection against large bowel cancer in a rat model. Gut 34:386–391

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  28. 28.

    Schwiertz A, Taras D, Schafer K, Beijer S, Bos NA, Donus C, Hardt PD (2010) Microbiota and SCFA in lean and overweight healthy subjects. Obesity 18:190–195

    PubMed  Article  Google Scholar 

  29. 29.

    Qiu J, Heller JJ, Guo X, Chen ZM, Fish K, Fu YX, Zhou L (2012) The aryl hydrocarbon receptor regulates gut immunity through modulation of innate lymphoid cells. Immunity 36:92–104

    CAS  PubMed  Article  Google Scholar 

  30. 30.

    Veldhoen M, Hirota K, Westendorf AM, Buer J, Dumoutier L, Renauld JC, Stockinger B (2008) The aryl hydrocarbon receptor links TH17-cell-mediated autoimmunity to environmental toxins. Nature 453:106–109

    CAS  PubMed  Article  Google Scholar 

  31. 31.

    Mjösberg J, Bernink J, Peters C, Spits H (2012) Transcriptional control of innate lymphoid cells. Eur J Immunol 42:1916–1923

    PubMed  Article  CAS  Google Scholar 

  32. 32.

    Julliard W, Fechner J, Mezrich J (2014) The aryl hydrocarbon receptor meets immunology: friend or foe? A little of both. Front Immunol 5:458

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  33. 33.

    Mezrich J, Fechner J, Zhang X, Johnson B, Burlingham W, Bradfield C (2010) An interaction between kynurenine and the aryl hydrocarbon receptor can generate regulatory T cells. J Immunol 185:3190–3198

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  34. 34.

    Opitz CA, Litzenburger UM, Sahm F, Ott M, Tritschler I, Trump S, Schumacher T, Jestaedt L et al (2011) An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor. Nature 478:197–203

    CAS  PubMed  Article  Google Scholar 

  35. 35.

    Qiu J, Guo X, Chen Z, He L, Sonnenberg G, Artis D, Fu Y, Zhou L (2013) Group 3 innate lymphoid cells inhibit T-cell-mediated intestinal inflammation through aryl hydrocarbon receptor signaling and regulation of microflora. Immunity 39:386–399

    CAS  PubMed  Article  Google Scholar 

  36. 36.

    Fallarino F, Grohmann U, Puccetti P (2012) Indoleamine 2,3-dioxygenase: from catalyst to signaling function. Eur J Immunol 42:1932–1937

    CAS  PubMed  Article  Google Scholar 

  37. 37.

    Nguyen N, Kimura A, Nakahama T, Chinen I, Masuda K, Nohara K, Fujii-Kuriyama Y, Kishimoto T (2010) Aryl hydrocarbon receptor negatively regulates dendritic cell immunogenicity via a kynurenine-dependent mechanism. Proc Natl Acad Sci 107:19961–19966

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  38. 38.

    Nguyen N, Nakahama T, Le D, Van Son L, Chu H, Kishimoto T (2014) Aryl hydrocarbon receptor and kynurenine: recent advances in autoimmune disease research. Front Immunol 5:551

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  39. 39.

    Li Y, Innocentin S, Withers DR, Roberts NA, Gallagher AR, Grigorieva EF, Wilhelm C, Veldhoen M (2011) Exogenous stimuli maintain intraepithelial lymphocytes via aryl hydrocarbon receptor activation. Cell 147:629–640. doi:10.1016/j.cell.2011.09.025

    CAS  PubMed  Article  Google Scholar 

  40. 40.

    Hashimoto T, Perlot T, Rehman A, Trichereau J, Ishiguro H, Paolino M, Sigl V, Hanada T et al (2012) ACE2 links amino acid malnutrition to microbial ecology and intestinal inflammation. Nature 487:477–481

    CAS  PubMed  Article  Google Scholar 

  41. 41.

    Maes M, Leunis JC, Geffard M, Berk M (2014) Evidence for the existence of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) with and without abdominal discomfort (irritable bowel) syndrome. Neuro Endocrinol Lett 35:445–453

    PubMed  Google Scholar 

  42. 42.

    Moylan S, Berk M, Dean OM, Samuni Y, Williams LJ, O’Neil A, Hayley AC, Pasco JA et al (2014) Oxidative & nitrosative stress in depression: why so much stress? Neurosci Biobehav Rev 45:46–62

    CAS  PubMed  Article  Google Scholar 

  43. 43.

    Connor T, Starr N, O’Sullivan J, Harkin A (2008) Induction of indolamine 2,3-dioxygenase and kynurenine 3-monooxygenase in rat brain following a systemic inflammatory challenge: a role for IFN-γ? Neurosci Lett 441:29–34

    CAS  PubMed  Article  Google Scholar 

  44. 44.

    Romani L, Zelante T, De Luca A, Fallarino F, Puccetti P (2008) IL-17 and therapeutic kynurenines in pathogenic inflammation to fungi. J Immunol 180:5157–5162

    CAS  PubMed  Article  Google Scholar 

  45. 45.

    Tourino M, de Oliveira E, Bellé L, Knebel F, Albuquerque R, Dörr F, Okada S, Migliorini S et al (2013) Tryptamine and dimethyltryptamine inhibit indoleamine 2,3 dioxygenase and increase the tumor-reactive effect of peripheral blood mononuclear cells. Cell Biochem Funct 31:361–364

    CAS  PubMed  Article  Google Scholar 

  46. 46.

    Veldhoen M, Hirota K, Christensen J, O’Garra A, Stockinger B (2008) Natural agonists for aryl hydrocarbon receptor in culture medium are essential for optimal differentiation of Th17 T cells. J Exp Med 206:43–49

    PubMed  Article  CAS  Google Scholar 

  47. 47.

    Stephens G, Wang Q, Swerdlow B, Bhat G, Kolbeck R, Fung M (2013) Kynurenine 3-monooxygenase mediates inhibition of Th17 differentiation via catabolism of endogenous aryl hydrocarbon receptor ligands. Eur J Immunol 43:1727–1734

    CAS  PubMed  Article  Google Scholar 

  48. 48.

    Dinan T, Borre Y, Cryan J (2014) Genomics of schizophrenia: time to consider the gut microbiome? Mol Psychiatry 19:1252–1257

    CAS  PubMed  Article  Google Scholar 

  49. 49.

    Clarke G, Grenham S, Fitzgerald P, Moloney R, Shanahan F, Dinan T, Cryan J (2012) Su1992 regulation of serotonergic neurotransmission and behaviour by the brain-gut-microbiome axis. Gastroenterology 142:S–555

    Google Scholar 

  50. 50.

    Forsythe P, Kunze W, Bienenstock J (2012) On communication between gut microbes and the brain. Curr Opin Gastroenterol 28:557–562

    PubMed  Article  Google Scholar 

  51. 51.

    Clarke G, Stilling R, Kennedy P, Stanton C, Cryan J, Dinan T (2014) Minireview: Gut microbiota: the neglected endocrine organ. Mol Endocrinol 28:1221–1238

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  52. 52.

    Bercik P, Verdu EF, Foster JA et al (2010) Chronic gastrointestinal inflammation induces anxiety-like behavior and alters central nervous system biochemistry in mice. Gastroenterology 139:2102–2112.e1

    CAS  PubMed  Article  Google Scholar 

  53. 53.

    Barry S, Clarke G, Scully P, Dinan T (2008) Kynurenine pathway in psychosis: evidence of increased tryptophan degradation. J Psychopharmacol 23:287–294

    PubMed  Article  Google Scholar 

  54. 54.

    Schwarcz R, Bruno JP, Muchowski PJ, Wu HQ (2012) Kynurenines in the mammalian brain: when physiology meets pathology. Nat Rev Neurosci 13:465–477

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  55. 55.

    Stone TW, Stoy N, Darlington LG (2013) An expanding range of targets for kynurenine metabolites of tryptophan. Trends Pharmacol Sci 34:136–143

    CAS  PubMed  Article  Google Scholar 

  56. 56.

    Hsiao EY (2013) Immune dysregulation in autism spectrum disorder. Int Rev Neurobiol 113:269–302

    CAS  PubMed  Article  Google Scholar 

  57. 57.

    Yanofsky C (2007) RNA-based regulation of genes of tryptophan synthesis and degradation, in bacteria. RNA 13:1141–1154

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  58. 58.

    Shishov VA, Kirovskaia TA, Kudrin VS, Oleskin AV (2009) Amine neuromediators, their precursors, and oxidation products in the culture of Escherichia coli K-12 [in Russian]. Prikl Biokhim Mikrobiol 45:550–554

    CAS  PubMed  Google Scholar 

  59. 59.

    Mawe G, Hoffman J (2013) Serotonin signalling in the gut—functions, dysfunctions and therapeutic targets. Nat Rev Gastroenterol Hepatol 10:564–564

    Article  Google Scholar 

  60. 60.

    O’Mahony S, Clarke G, Borre Y, Dinan T, Cryan J (2015) Serotonin, tryptophan metabolism and the brain-gut-microbiome axis. Behav Brain Res 277:32–48

    PubMed  Article  CAS  Google Scholar 

  61. 61.

    Dash S, Clarke G, Berk M, Jacka F (2015) The gut microbiome and diet in psychiatry. Curr Opin Psychiatry 28:1–6

    PubMed  Article  Google Scholar 

  62. 62.

    Keightley P, Koloski N, Talley N (2015) Pathways in gut-brain communication: evidence for distinct gut-to-brain and brain-to-gut syndromes. Aust N Z J Psychiatry 49:207–214

    PubMed  Article  Google Scholar 

  63. 63.

    Zhang Y, Song L, Gao Q, Yu S, Li L, Gao N (2012) The two-step biotransformation of monosodium glutamate to GABA by Lactobacillus brevis growing and resting cells. Appl Microbiol Biotechnol 94:1619–1627

    CAS  PubMed  Article  Google Scholar 

  64. 64.

    Barrett E, Ross R, O’Toole P, Fitzgerald G, Stanton C (2012) γ-Aminobutyric acid production by culturable bacteria from the human intestine. J Appl Microbiol 113:411–417

    CAS  PubMed  Article  Google Scholar 

  65. 65.

    Bravo JA, Julio-Pieper M, Forsythe P, Kunze W, Dinan TG, Bienenstock J et al (2012) Communication between gastrointestinal bacteria and the nervous system. Curr Opin Pharmacol 12:667–672. doi:10.1016/j.coph.2012.09.010

    CAS  PubMed  Article  Google Scholar 

  66. 66.

    Matsumoto M, Kibe R, Ooga T, Aiba Y, Sawaki E, Koga Y, Benno Y (2013) Cerebral low-molecular metabolites influenced by intestinal microbiota: a pilot study. Front Syst Neurosci 7:9

    PubMed  PubMed Central  Article  Google Scholar 

  67. 67.

    Neufeld KM, Kang N, Bienenstock J, Foster JA (2011) Reduced anxiety-like behavior and central neurochemical change in germ-free mice. Neurogastroenterol Motil 23(3):255–264. e119

    CAS  PubMed  Article  Google Scholar 

  68. 68.

    Sudo N, Chida Y, Aiba Y, Sonoda J, Oyama N, Yu XN, Kubo C, Koga Y (2004) Postnatal microbial colonization programs the hypothalamic-pituitary-adrenal system for stress response in mice. J Physiol 558:263–275

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  69. 69.

    Markelov V, Trushin M (2007) Multiple sclerosis and neurochemical disturbances. Pak J Med Sci 23:145–149

    Google Scholar 

  70. 70.

    Lucas K, Morris G, Anderson G, Maes M (2015) The Toll-like receptor radical cycle pathway: a new drug target in immune-related chronic fatigue. CNS Neurol Disord Drug Targets 14:838–854

    CAS  PubMed  Article  Google Scholar 

  71. 71.

    Itoh Y, Kawamata Y, Harada M, Kobayashi M, Fujii R, Fukusumi S, Ogi K, Hosoya M et al (2003) Free fatty acids regulate insulin secretion from pancreatic beta cells through GPR40. Nature 422:173–176

    CAS  PubMed  Article  Google Scholar 

  72. 72.

    Maa C, Chang MY, Hsieh MY, Chen YJ, Yang CJ, Chen ZC, Li YK, Yen CK et al (2010) Butyrate reduced lipopolysaccharide-mediated macrophage migration by suppression Maa of Src enhancement and focal adhesion kinase activity. J Nutr Biochem 21:1186–1192

    CAS  PubMed  Article  Google Scholar 

  73. 73.

    Owen KA, Pixley FJ, Thomas KS, Vicente-Manzanares M, Ray BJ, Horwitz AF, Parsons JT, Beggs HE et al (2007) Regulation of lamellipodial persistence, adhesion turnover, and motility in macrophages by focal adhesion kinase. J Cell Biol 179:1275–1287

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  74. 74.

    Zapolska-Downar D, Naruszewicz M (2009) Propionate reduces the cytokine-induced VCAM-1 and ICAM-1 expression by inhibiting nuclear factor-kappa B (NF-kappaB) activation. J Physiol Pharmacol 60:123–131

    CAS  PubMed  Google Scholar 

  75. 75.

    Nilsson NE, Kotarsky K, Owman C, Olde B (2003) Identification of a free fatty acid receptor, FFA2R, expressed on leukocytes and activated by short-chain fatty acid. Biochem Biophys Res Commun 303:1047–1052

    CAS  PubMed  Article  Google Scholar 

  76. 76.

    Zapolska-Downar D, Siennicka A, Kaczmarczyk M, Kolodziej B, Naruszewicz M (2004) Butyrate inhibits cytokine-induced VCAM-1 and ICAM-1 expression in cultured endothelial cells: the role of NF-kappaB and PPARalpha. J Nutr Biochem 15:220–228

    CAS  PubMed  Article  Google Scholar 

  77. 77.

    Mahowald MA, Rey FE, Seedorf H, Turnbaugh PJ, Fulton RS, Wollam A, Shah N, Wang C et al (2009) Characterizing a model human gut microbiota composed of members of its two dominant bacterial phyla. Proc Natl Acad Sci U S A 106:5859–5864

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  78. 78.

    Bocker U, Nebe T, Herweck F, Holt L, Panja A, Jobin C, Rossol S, Sartor RB et al (2003) Butyrate modulates intestinal epithelial cell-mediated neutrophil migration. Clin Exp Immunol 131:53–60

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  79. 79.

    Fusunyan RD, Quinn JJ, Fujimoto M, MacDermott RP, Sanderson IR (1999) Butyrate switches the pattern of chemokine secretion by intestinal epithelial cells through histone acetylation. Mol Med 5:631–640

    CAS  PubMed  PubMed Central  Google Scholar 

  80. 80.

    Inatomi O, Andoh A, Kitamura K, Yasui H, Zhang Z, Fujiyama Y (2005) Butyrate blocks interferon-gamma-inducible protein-10 release in human intestinal subepithelial myofibroblasts. J Gastroenterol 40:483–489

    CAS  PubMed  Article  Google Scholar 

  81. 81.

    Menzel T, Luhrs H, Zirlik S, Schauber J, Kudlich T, Gerke T, Gostner A, Neumann M et al (2004) Butyrate inhibits leukocyte adhesion to endothelial cells via modulation of VCAM-1. Inflamm Bowel Dis 10:122–128

    PubMed  Article  Google Scholar 

  82. 82.

    Bohmig GA, Krieger PM, Saemann MD, Wenhardt C, Pohanka E, Zlabinger GJ (1997) n-Butyrate downregulates the stimulatory function of peripheral blood-derived antigen-presenting cells: a potential mechanism for modulating T-cell responses by short-chain fatty acids. Immunology 92:234–243

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  83. 83.

    Dianzani C, Cavalli R, Zara GP, Gallicchio M, Lombardi G, Gasco MR, Panzanelli P, Fantozzi R (2006) Cholesteryl butyrate solid lipid nanoparticles inhibit adhesion of human neutrophils to endothelial cells. Br J Pharmacol 148:648–656

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  84. 84.

    Allport JR, Ding HT, Ager A, Steeber DA, Tedder TF, Luscinskas FW (1997) L-selectin shedding does not regulate human neutrophil attachment, rolling, or transmigration across human vascular endothelium in vitro. J Immunol 158:4365–4372

    CAS  PubMed  Google Scholar 

  85. 85.

    Griffin WS (2006) Inflammation and neurodegenerative diseases. Am J Clin Nutr 83:470S–474S

    CAS  PubMed  Google Scholar 

  86. 86.

    Boyle JJ (2005) Macrophage activation in atherosclerosis: pathogenesis and pharmacology of plaque rupture. Curr Vasc Pharmacol 3:63–68

    CAS  PubMed  Article  Google Scholar 

  87. 87.

    Chakravortty D, Koide N, Kato Y, Sugiyama T, Mu MM, Yoshida T, Yokochi T (2000) The inhibitory action of butyrate on lipopolysaccharide-induced nitric oxide production in RAW 264.7 murine macrophage cells. J Endotoxin Res 6:243–247

    CAS  PubMed  Article  Google Scholar 

  88. 88.

    Kim MH, Kang SG, Park JH, Yanagisawa M, Kim CH (2013) Short-chain fatty acids activate GPR41 and GPR43 on intestinal epithelial cells to promote inflammatory responses in mice. Gastroenterology 145:396–406. doi:10.1053/j.gastro.2013.04.056

    CAS  PubMed  Article  Google Scholar 

  89. 89.

    Perez R, Stevenson F, Johnson J, Morgan M, Erickson K, Hubbard NE, Morand L, Rudich S et al (1998) Sodium butyrate upregulates Kupffer cell PGE2 production and modulates immune function. J Surg Res 78:1–6

    CAS  PubMed  Article  Google Scholar 

  90. 90.

    Waldecker M, Kautenburger T, Daumann H, Busch C, Schrenk D (2008) Inhibition of histone-deacetylase activity by short-chain fatty acids and some polyphenol metabolites formed in the colon. J Nutr Biochem 19:587–593

    CAS  PubMed  Article  Google Scholar 

  91. 91.

    Glozak MA, Sengupta N, Zhang X, Seto E (2005) Acetylation and deacetylation of non-histone proteins. Gene 363:15–23

    CAS  PubMed  Article  Google Scholar 

  92. 92.

    Cox MA, Jackson J, Stanton M, Rojas-Triana A, Bober L, Laverty M, Yang X, Zhu F et al (2009) Short-chain fatty acids act as antiinflammatory mediators by regulating prostaglandin E(2) and cytokines. World J Gastroenterol 15:5549–5557

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  93. 93.

    Yao C, Sakata D, Esaki Y, Li Y, Matsuoka T, Kuroiwa K, Sugimoto Y, Narumiya S (2009) Prostaglandin E2-EP4 signaling promotes immune inflammation through Th1 cell differentiation and Th17 cell expansion. Nat Med 15:633–640

    CAS  PubMed  Article  Google Scholar 

  94. 94.

    Sakata D, Yao C, Narumiya S (2010) Prostaglandin E2, an immunoactivator. J Pharmacol Sci 112:1–5

    CAS  PubMed  Article  Google Scholar 

  95. 95.

    Zaibi MS, Stocker CJ, O’Dowd J, Davies A, Bellahcene M, Cawthorne MA, Brown AJ, Smith DM et al (2010) Roles of GPR41 and GPR43 in leptin secretory responses of murine adipocytes to short chain fatty acids. FEBS Lett 584:2381–2386

    CAS  PubMed  Article  Google Scholar 

  96. 96.

    Plaisancie P, Dumoulin V, Chayvialle JA, Cuber JC (1996) Luminal peptide YY-releasing factors in the isolated vascularly perfused rat colon. J Endocrinol 151:421–429

    CAS  PubMed  Article  Google Scholar 

  97. 97.

    Luster AD, Alon R, von Andrian UH (2005) Immune cell migration in inflammation: present and future therapeutic targets. Nat Immunol 6:1182–1190

    CAS  PubMed  Article  Google Scholar 

  98. 98.

    Vinolo MA, Rodrigues HG, Hatanaka E, Sato FT, Sampaio SC, Curi R (2011) Suppressive effect of short chain fatty acids on production of proinflammatory mediators by neutrophils. J Nutr Biochem 22:849–855

    CAS  PubMed  Article  Google Scholar 

  99. 99.

    Miller SJ, Zaloga GP, Hoggatt AM, Labarrere C, Faulk WP (2005) Short-chain fatty acids modulate gene expression for vascular endothelial cell adhesion molecules. Nutrition 21:740–748

    CAS  PubMed  Article  Google Scholar 

  100. 100.

    Vinolo MA, Rodrigues HG, Hatanaka E, Hebeda CB, Farsky SH, Curi R (2009) Short-chain fatty acids stimulate the migration of neutrophils to inflammatory sites. Clin Sci 117:331–338

    CAS  PubMed  Article  Google Scholar 

  101. 101.

    Sina C, Gavrilova O, Forster M, Till A, Derer S, Hildebrand F, Raabe B, Chalaris A et al (2009) G protein-coupled receptor 43 is essential for neutrophil recruitment during intestinal inflammation. J Immunol 183:7514–7522

    CAS  PubMed  Article  Google Scholar 

  102. 102.

    Vinolo MA, Ferguson GJ, Kulkarni S, Damoulakis G, Anderson K, Bohlooly YM, Stephens L, Hawkins PT et al (2011) SCFAs induce mouse neutrophil chemotaxis through the GPR43 receptor. PLoS One 6, e21205

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  103. 103.

    Blais M, Seidman EG, Asselin C (2007) Dual effect of butyrate on IL-1beta-mediated intestinal epithelial cell inflammatory response. DNA Cell Biol 26:133–147

    CAS  PubMed  Article  Google Scholar 

  104. 104.

    Leung CH, Lam W, Ma DL, Gullen EA, Cheng YC (2009) Butyrate mediates nucleotide-binding and oligomerisation domain (NOD) 2-dependent mucosal immune responses against peptidoglycan. Eur J Immunol 39:3529–3537

    CAS  PubMed  Article  Google Scholar 

  105. 105.

    Furusawa Y, Obata Y, Fukuda S, Endo T, Nakato G, Takahashi D, Nakanishi Y, Uetake C et al (2013) Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature 504:446–450

    CAS  PubMed  Article  Google Scholar 

  106. 106.

    Arpaia N, Campbell C, Fan X, Dikiy S, van der Veeken J, deRoos P, Liu H, Cross J et al (2013) Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature 504:451–455

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  107. 107.

    Hoeppli R, Wu D, Cook L, Levings M (2015) The environment of regulatory T cell biology: cytokines, metabolites, and the microbiome. Front Immunol 6:61

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  108. 108.

    Smith P, Howitt M, Panikov N, Michaud M, Gallini C, Bohlooly-Y M, Glickman J, Garrett W (2013) The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science 341:569–573

    CAS  PubMed  Article  Google Scholar 

  109. 109.

    Singh N, Gurav A, Sivaprakasam S, Brady E, Padia R, Shi H, Thangaraju M, Prasad P et al (2014) Activation of Gpr109a, receptor for niacin and the commensal metabolite butyrate, suppresses colonic inflammation and carcinogenesis. Immunity 40:128–139

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  110. 110.

    Kim C, Park J, Kim M (2014) Gut microbiota-derived short-chain fatty acids, T cells, and inflammation. Immune Netw 14:277

    PubMed  PubMed Central  Article  Google Scholar 

  111. 111.

    Chang P, Hao L, Offermanns S, Medzhitov R (2014) The microbial metabolite butyrate regulates intestinal macrophage function via histone deacetylase inhibition. Proc Natl Acad Sci 111:2247–2252

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  112. 112.

    Park J, Kim M, Kang S, Jannasch A, Cooper B, Patterson J, Kim C (2014) Short-chain fatty acids induce both effector and regulatory T cells by suppression of histone deacetylases and regulation of the mTOR–S6K pathway. Mucosal Immunol 8:80–93

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  113. 113.

    Dennis PB, Jaeschke A, Saitoh M, Fowler B, Kozma SC, Thomas G (2001) Mammalian TOR: a homeostatic ATP sensor. Science 294:1102–1105

    CAS  PubMed  Article  Google Scholar 

  114. 114.

    Delgoffe GM, Kole TP, Zheng Y, Zarek PE, Matthews KL, Xiao B, Worley PF, Kozma SC et al (2009) The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment. Immunity 30:832–844

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  115. 115.

    Hinnebusch BF, Meng S, Wu JT, Archer SY, Hodin RA (2002) The effects of short-chain fatty acids on human colon cancer cell phenotype are associated with histone hyperacetylation. J Nutr 132:1012–1017

    CAS  PubMed  Google Scholar 

  116. 116.

    Haberland M, Montgomery RL, Olson EN (2009) The many roles of histone deacetylases in development and physiology: implications for disease and therapy. Nat Rev Genet 10:32–42

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  117. 117.

    Yu X, Shahir AM, Sha J, Feng Z, Eapen B, Nithianantham S, Das B, Karn J et al (2014) Short-chain fatty acids from periodontal pathogens suppress histone deacetylases, EZH2, and SUV39H1 to promote Kaposi’s sarcoma-associated herpesvirus replication. J Virol 88:4466–4479

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  118. 118.

    Singh N, Thangaraju M, Prasad PD, Martin PM, Lambert NA, Boettger T, Offermanns S, Ganapathy V (2010) Blockade of dendritic cell development by bacterial fermentation products butyrate and propionate through a transporter (Slc5a8)-dependent inhibition of histone deacetylases. J Biol Chem 285:27601–27608

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  119. 119.

    Berndt BE, Zhang M, Owyang SY, Cole TS, Wang TW, Luther J, Veniaminova NA, Merchant JL et al (2012) Butyrate increases IL-23 production by stimulated dendritic cells. Am J Physiol Gastrointest Liver Physiol 303:G1384–G1392

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  120. 120.

    Frikeche J, Simon T, Brissot E, Gregoire M, Gaugler B, Mohty M (2012) Impact of valproic acid on dendritic cells function. Immunobiology 217:704–710

    CAS  PubMed  Article  Google Scholar 

  121. 121.

    Mace TA, King SA, Ameen Z, Elnaggar O, Young G, Riedl KM, Schwartz SJ, Clinton SK et al (2014) Bioactive compounds or metabolites from black raspberries modulate T lymphocyte proliferation, myeloid cell differentiation and Jak/STAT signaling. Cancer Immunol Immunother 63:889–900

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  122. 122.

    Wang A, Gu Z, Heid B, Akers RM, Jiang H (2009) Identification and characterization of the bovine G protein-coupled receptor GPR41 and GPR43 genes. J Dairy Sci 92:2696–2705

    CAS  PubMed  Article  Google Scholar 

  123. 123.

    Tazoe H, Otomo Y, Karaki S, Kato I, Fukami Y, Terasaki M, Kuwahara A (2009) Expression of short-chain fatty acid receptor GPR41 in the human colon. Biomed Res 30:149–156

    CAS  PubMed  Article  Google Scholar 

  124. 124.

    Stringer RE, Hart CA, Edwards SW (1996) Sodium butyrate delays neutrophil apoptosis: role of protein biosynthesis in neutrophil survival. Br J Haematol 92:169–175

    CAS  PubMed  Article  Google Scholar 

  125. 125.

    Nakao S, Moriya Y, Furuyama S, Niederman R, Sugiya H (1998) Propionic acid stimulates superoxide generation in human neutrophils. Cell Biol Int 22:331–337

    CAS  PubMed  Article  Google Scholar 

  126. 126.

    Liu Q, Shimoyama T, Suzuki K, Umeda T, Nakaji S, Sugawara K (2001) Effect of sodium butyrate on reactive oxygen species generation by human neutrophils. Scand J Gastroenterol 36:744–750

    CAS  PubMed  Article  Google Scholar 

  127. 127.

    Sandoval A, Trivinos F, Sanhueza A, Carretta D, Hidalgo MA, Hancke JL, Burgos RA (2007) Propionate induces pH(i) changes through calcium flux, ERK1/2, p38, and PKC in bovine neutrophils. Vet Immunol Immunopathol 115:286–298. doi:10.1016/j.vetimm.2006.11

    CAS  PubMed  Article  Google Scholar 

  128. 128.

    Huuskonen J, Suuronen T, Nuutinen T, Kyrylenko S, Salminen A (2004) Regulation of microglial inflammatory response by sodium butyrate and short-chain fatty acids. Br J Pharmacol 141:874–880

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  129. 129.

    Park JS, Woo MS, Kim SY, Kim WK, Kim HS (2005) Repression of interferon-gamma-induced inducible nitric oxide synthase (iNOS) gene expression in microglia by sodium butyrate is mediated through specific inhibition of ERK signaling pathways. J Neuroimmunol 168:56–64

    CAS  PubMed  Article  Google Scholar 

  130. 130.

    Chen PS, Wang CC, Bortner CD, Peng GS, Wu X, Pang H, Lu RB, Gean PW et al (2007) Valproic acid and other histone deacetylase inhibitors induce microglial apoptosis and attenuate lipopolysaccharide-induced dopaminergic neurotoxicity. Neuroscience 149:203–212

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  131. 131.

    Kim HJ, Rowe M, Ren M, Hong JS, Chen PS, Chuang DM (2007) Histone deacetylase inhibitors exhibit anti-inflammatory and neuroprotective effects in a rat permanent ischemic model of stroke: multiple mechanisms of action. J Pharmacol Exp Ther 321:892–901

    CAS  PubMed  Article  Google Scholar 

  132. 132.

    Bischoff SC, Barbara G, Buurman W, Ockhuizen T, Schulzke JD, Serino M, Tilg H, Watson A et al (2014) Intestinal permeability—a new target for disease prevention and therapy. BMC Gastroenterol 14:189. doi:10.1186/s12876-014-0189-7

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  133. 133.

    Ferreira T, Leonel A, Melo M, Santos R, Cara D, Cardoso V, Correia M, Alvarez-Leite J (2012) Oral supplementation of butyrate reduces mucositis and intestinal permeability associated with 5-fluorouracil administration. Lipids 47:669–678

    CAS  PubMed  Article  Google Scholar 

  134. 134.

    Canani R (2011) Potential beneficial effects of butyrate in intestinal and extraintestinal diseases. World J Gastroenterol 17:1519

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  135. 135.

    Peng L, Li Z, Green R, Holzman I, Lin J (2009) Butyrate enhances the intestinal barrier by facilitating tight junction assembly via activation of AMP-activated protein kinase in Caco-2 cell monolayers. J Nutr 139:1619–1625

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  136. 136.

    Kelly C, Zheng L, Campbell E, Saeedi B, Scholz C, Bayless A, Wilson K, Glover L et al (2015) Crosstalk between microbiota-derived short-chain fatty acids and intestinal epithelial HIF augments tissue barrier function. Cell Host Microbe 17:662–671

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  137. 137.

    Tolhurst G, Heffron H, Lam YS, Parker HE, Habib AM, Diakogiannaki E, Cameron J, Grosse J et al (2012) Short-chain fatty acids stimulate glucagon-like peptide-1 secretion via the G-protein-coupled receptor FFAR2. Diabetes 61:364–371. doi:10.2337/db11-1019

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  138. 138.

    Hadjiyanni I, Li K, Drucker D (2009) Glucagon-like peptide-2 reduces intestinal permeability but does not modify the onset of type 1 diabetes in the nonobese diabetic mouse. Endocrinol 150:592–599

    CAS  Article  Google Scholar 

  139. 139.

    Psichas A, Sleeth ML, Murphy KG, Brooks L, Bewick GA, Hanyaloglu AC, Ghatei MA, Bloom SR et al (2015) The short chain fatty acid propionate stimulates GLP-1 and PYY secretion via free fatty acid receptor 2 in rodents. Int J Obes (Lond) 39:424–429. doi:10.1038/ijo.2014.153

    CAS  Article  Google Scholar 

  140. 140.

    Kaji I, Karaki S, Kuwahara A (2014) Short-chain fatty acid receptor and its contribution to glucagon-like peptide-1 release. Digestion 89:31–36. doi:10.1159/000356211

    CAS  PubMed  Article  Google Scholar 

  141. 141.

    Brubaker PL, Drucker DJ (2004) Minireview: Glucagon-like peptides regulate cell proliferation and apoptosis in the pancreas, gut, and central nervous system. Endocrinol 145:2653–2659

    CAS  Article  Google Scholar 

  142. 142.

    Geurts L, Lazarevic V, Derrien M, Everard A, Van Roye M, Knauf C, Valet P, Girard M et al (2011) Altered gut microbiota and endocannabinoid system tone in obese and diabetic leptin-resistant mice: impact on apelin regulation in adipose tissue. Front Microbiol 2:149

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  143. 143.

    Muccioli GG, Naslain D, Backhed F, Reigstad CS, Lambert DM, Delzenne NM, Cani PD (2010) The endocannabinoid system links gut microbiota to adipogenesis. Mol Syst Biol 6:392

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  144. 144.

    Everard A, Lazarevic V, Derrien M, Girard M, Muccioli GG, Neyrinck AM, Possemiers S, Van Holle A et al (2011) Responses of gut microbiota and glucose and lipid metabolism to prebiotics in genetic obese and diet-induced leptin-resistant mice. Diabetes 60:2775–2786

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  145. 145.

    Cani PD, Possemiers S, Van de Wiele T, Guiot Y, Everard A, Rottier O, Geurts L, Naslain D et al (2009) Changes in gut microbiota control inflammation in obese mice through a mechanism involving GLP‐2‐driven improvement of gut permeability. Gut 58:1091–1103

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  146. 146.

    Cani PD, Bibiloni R, Knauf C, Waget A, Neyrinck AM, Delzenne NM, Burcelin R (2008) Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice. Diabetes 57:1470–1481

    CAS  PubMed  Article  Google Scholar 

  147. 147.

    Cani P (2012) Crosstalk between the gut microbiota and the endocannabinoid system: impact on the gut barrier function and the adipose tissue. Clin Microbiol Infect 18:50–53

    CAS  PubMed  Article  Google Scholar 

  148. 148.

    Puddu A, Sanguineti R, Montecucco F, Viviani G (2014) Evidence for the gut microbiota short-chain fatty acids as key pathophysiological molecules improving diabetes. Mediators Inflamm 2014:1–9

    Google Scholar 

  149. 149.

    Cani PD, Amar J, Iglesias MA, Poggi M, Knauf C, Bastelica D, Neyrinck AM, Fava F et al (2007) Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes 56:1761–1772

    CAS  PubMed  Article  Google Scholar 

  150. 150.

    Cummings JH, Pomare EW, Branch WJ, Naylor CP, Macfarlane GT (1987) Short chain fatty acids in human large intestine, portal, hepatic and venous blood. Gut 28:1221–1227

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  151. 151.

    den Besten G, van Eunen K, Groen A, Venema K, Reijngoud D, Bakker B (2013) The role of short-chain fatty acids in the interplay between diet, gut microbiota, and host energy metabolism. J Lipid Res 54:2325–2340

    Article  CAS  Google Scholar 

  152. 152.

    Fushimi T, Suruga K, Oshima Y, Fukiharu M, Tsukamoto Y, Goda T (2006) Dietary acetic acid reduces serum cholesterol and triacylglycerols in rats fed a cholesterol-rich diet. Br J Nutr 95:916–924

    CAS  PubMed  Article  Google Scholar 

  153. 153.

    Demigné C, Morand C, Levrat MA, Besson C, Moundras C, Rémésy C (1995) Effect of propionate on fatty acid and cholesterol synthesis and on acetate metabolism in isolated rat hepatocytes. Br J Nutr 74:209–219

    PubMed  Article  Google Scholar 

  154. 154.

    Todesco T, Rao AV, Bosello O, Jenkins DJ (1991) Propionate lowers blood glucose and alters lipid metabolism in healthy subjects. Am J Clin Nutr 54:860–865

    CAS  PubMed  Google Scholar 

  155. 155.

    Topping DL, Clifton PM (2001) Short-chain fatty acids and human colonic function: roles of resistant starch and non-starch polysaccharides. Physiol Rev 81:1031–1064

    CAS  PubMed  Google Scholar 

  156. 156.

    Stoddart N, Smith J, Milligan G (2008) International union of pharmacology. LXXI. Free fatty acid receptors FFA1, -2, and -3: pharmacology and pathophysiological functions. Pharmacol Rev 60(no. 4):405–417

    CAS  PubMed  Article  Google Scholar 

  157. 157.

    Vrieze A, Van Nood E, Holleman F, Salojärvi J, Kootte RS, Bartelsman JF, Dallinga-Thie GM, Ackermans MT et al (2012) Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome. Gastroenterol 143:e913–e917

    Article  CAS  Google Scholar 

  158. 158.

    Udayappan SD, Hartstra AV, Dallinga-Thie GM, Nieuwdorp M (2014) Intestinal microbiota and faecal transplantation as treatment modality for insulin resistance and type 2 diabetes mellitus. Clin Exper Immunol 177:24–29

    CAS  Article  Google Scholar 

  159. 159.

    Holst JJ (2007) The physiology of glucagon-like peptide 1. Physiol Rev 87:1409–1439

    CAS  PubMed  Article  Google Scholar 

  160. 160.

    Ross SA, Ekoé J (2010) Incretin agents in type 2 diabetes. Can Fam Physician 56:639–648

    PubMed  PubMed Central  Google Scholar 

  161. 161.

    Remely M, Aumueller E, Merold C, Dworzak S, Hippe B, Zanner J, Pointner A, Brath H et al (2014) Effects of short chain fatty acid producing bacteria on epigenetic regulation of FFAR3 in type 2 diabetes and obesity. Gene 537:85–92

    CAS  PubMed  Article  Google Scholar 

  162. 162.

    Ge H, Li X, Weiszmann J, Wang P, Baribault H, Chen J, Tian H, Li Y (2008) Activation of G protein-coupled receptor 43 in adipocytes leads to inhibition of lipolysis and suppression of plasma free fatty acids. Endocrinol 149:4519–4526

    CAS  Article  Google Scholar 

  163. 163.

    Yamashita H, Fujisawa K, Ito E, Idei S, Kawaguchi N, Kimoto M, Hiemori M, Tsuji H (2007) Improvement of obesity and glucose tolerance by acetate in type 2 diabetic Otsuka Long-Evans Tokushima fatty (OLETF) rats. Biosci Biotechnol Biochem 71:1236–124

    CAS  PubMed  Article  Google Scholar 

  164. 164.

    Wright RS, Anderson JW, Bridges SR (1990) Propionate inhibits hepatocyte lipid synthesis. Proc Soc Exp Biol Med 195:26–29

    CAS  PubMed  Article  Google Scholar 

  165. 165.

    Boey D, Lin S, Karl T, Baldock P, Lee N, Enriquez R, Couzens M, Slack K et al (2006) Peptide YY ablation in mice leads to the development of hyperinsulinaemia and obesity. Diabetologia 49:1360–1370

    CAS  PubMed  Article  Google Scholar 

  166. 166.

    Freeland KR, Wolever TM (2010) Acute effects of intravenous and rectal acetate on glucagon-like peptide-1, peptide YY, ghrelin, adiponectin and tumour necrosis factor-alpha. Br J Nutr 103:460–466

    CAS  PubMed  Article  Google Scholar 

  167. 167.

    Kimura I, Inoue D, Maeda T, Hara T, Ichimura A, Miyauchi S, Kobayashi M, Hirasawa A et al (2011) Short-chain fatty acids and ketones directly regulate sympathetic nervous system via G protein-coupled receptor 41 (GPR41). Proc Natl Acad Sci 108:8030–8035

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  168. 168.

    Inoue D, Kimura I, Wakabayashi M, Tsumoto H, Ozawa K, Hara T, Takei Y, Hirasawa A et al (2012) Short-chain fatty acid receptor GPR41-mediated activation of sympathetic neurons involves synapsin 2b phosphorylation. FEBS Lett 586:1547–1554

    CAS  PubMed  Article  Google Scholar 

  169. 169.

    Tilg H, Kaser A (2011) Gut microbiome, obesity, and metabolic dysfunction. The J Clin Invest 121:2126–2132

    CAS  PubMed  Article  Google Scholar 

  170. 170.

    Tremaroli V, Bäckhed F (2012) Functional interactions between the gut microbiota and host metabolism. Nature 489:242–249

    CAS  PubMed  Article  Google Scholar 

  171. 171.

    Karlsson F, Tremaroli V, Nookaew I, Bergström G, Behre C, Fagerberg B, Nielsen J, Bäckhed F (2013) Gut metagenome in European women with normal, impaired and diabetic glucose control. Nature 498:99–103

    CAS  PubMed  Article  Google Scholar 

  172. 172.

    Qin J, Li Y, Cai Z, Li S, Zhu J, Zhang F, Liang S, Zhang W et al (2012) A metagenome-wide association study of gut microbiota in type 2 diabetes. Nature 490:55–60

    CAS  PubMed  Article  Google Scholar 

  173. 173.

    Vrieze A, Van Nood E, Holleman F, Salojärvi J, Kootte R, Bartelsman J, Dallinga–Thie G, Ackermans M et al (2012) Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome. Gastroenterol 143:913–916.e7

    CAS  Article  Google Scholar 

  174. 174.

    Sato J, Kanazawa A, Ikeda F, Yoshihara T, Goto H, Abe H, Komiya K, Kawaguchi M et al (2014) Gut dysbiosis and detection of “live gut bacteria” in blood of Japanese patients with type 2 diabetes. Diabetes Care 37(8):2343–2350

    CAS  PubMed  Article  Google Scholar 

  175. 175.

    Xiong Y, Miyamoto N, Shibata K, Valasek MA, Motoike T, Kedzierski RM, Yanagisawa M (2004) Short-chain fatty acids stimulate leptin production in adipocytes through the G protein-coupled receptor GPR41. Proc Natl Acad Sci 101:1045–1050. doi:10.1073/pnas.2637002100

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  176. 176.

    Al-Lahham SH et al (2010) Regulation of adipokine production in human adipose tissue by propionic acid. Eur J Clin Invest 40:401–407

    CAS  PubMed  Article  Google Scholar 

  177. 177.

    Amar J, Serino M, Lange C, Chabo C, Iacovoni J, Mondot S, Lepage P, Klopp C et al (2011) Involvement of tissue bacteria in the onset of diabetes in humans: evidence for a concept. Diabetologia 54:3055–3061

    CAS  PubMed  Article  Google Scholar 

  178. 178.

    Dixon A, Valsamakis G, Hanif M, Field A, Boutsiadis A, Harte A, McTernan P, Barnett A et al (2008) Effect of the orlistat on serum endotoxin lipopolysaccharide and adipocytokines in South Asian individuals with impaired glucose tolerance. Int J Clin Prac 62:1124–1129

    CAS  Article  Google Scholar 

  179. 179.

    Pussinen P, Havulinna A, Lehto M, Sundvall J, Salomaa V (2011) Endotoxemia is associated with an increased risk of incident diabetes. Diabetes Care 34:392–397

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  180. 180.

    Amar J, Chabo C, Waget A, Klopp P, Vachoux C, Bermúdez-Humarán L, Smirnova N, Bergé M et al (2011) Intestinal mucosal adherence and translocation of commensal bacteria at the early onset of type 2 diabetes: molecular mechanisms and probiotic treatment. EMBO Mol Med 3:559–572

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  181. 181.

    Diamant M, Blaak E, de Vos W (2010) Do nutrient-gut-microbiota interactions play a role in human obesity, insulin resistance and type 2 diabetes? Obesity Rev 12:272–281

    Article  CAS  Google Scholar 

  182. 182.

    Everard A, Cani P (2013) Diabetes, obesity and gut microbiota. Best Pract Res Clin Gastroenterol 27:73–83

    CAS  PubMed  Article  Google Scholar 

  183. 183.

    Musso G, Gambino R, Cassader M (2010) Gut microbiota as a regulator of energy homeostasis and ectopic fat deposition: mechanisms and implications for metabolic disorders. Curr Opin Lipidol 21:76–83

    CAS  PubMed  Article  Google Scholar 

  184. 184.

    Shoelson S (2006) Inflammation and insulin resistance. J Clin Invest 116:1793–1801

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  185. 185.

    Dandona P (2005) Metabolic syndrome: a comprehensive perspective based on interactions between obesity, diabetes, and inflammation. Circulation 111:1448–1454

    PubMed  Article  Google Scholar 

  186. 186.

    Shoelson S, Herrero L, Naaz A (2007) Obesity, inflammation, and insulin resistance. Gastroenterol 132:2169–2180

    CAS  Article  Google Scholar 

  187. 187.

    Pickup JC, Crook MA (1998) Is type II diabetes mellitus a disease of the innate immune system? Diabetologia 41:1241–1248. doi:10.1007/s001250051058

    CAS  PubMed  Article  Google Scholar 

  188. 188.

    Chung S, Lapoint K, Martinez K, Kennedy A, Boysen Sandberg M, McIntosh MK (2006) Preadipocytes mediate lipopolysaccharide-induced inflammation and insulin resistance in primary cultures of newly differentiated human adipocytes. Endocrinol 147:5340–5351. doi:10.1210/en.2006-0536

    CAS  Article  Google Scholar 

  189. 189.

    Cucak H, Mayer C, Tonnesen M, Thomsen L, Grunnet L, Rosendahl A (2014) Macrophage contact dependent and independent TLR4 mechanisms induce β-cell dysfunction and apoptosis in a mouse model of type 2 diabetes. PLoS One 9:e90685

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  190. 190.

    Garay-Malpartida H, Mourão R, Mantovani M, Santos I, Sogayar M, Goldberg A (2011) Toll-like receptor 4 (TLR4) expression in human and murine pancreatic beta-cells affects cell viability and insulin homeostasis. BMC Immunol 12:18

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  191. 191.

    Zhang C, Xiao C, Wang P, Xu W, Zhang A, Li Q, Xu X (2014) The alteration of Th1/Th2/Th17/Treg paradigm in patients with type 2 diabetes mellitus: relationship with diabetic nephropathy. Human Immunol 75:289–296

    CAS  Article  Google Scholar 

  192. 192.

    Zeng C, Shi X, Zhang B, Liu H, Zhang L, Ding W, Zhao Y (2011) The imbalance of Th17/Th1/Tregs in patients with type 2 diabetes: relationship with metabolic factors and complications. J Mol Med 90:175–186

    PubMed  Article  CAS  Google Scholar 

  193. 193.

    Liang H, Hussey S, Sanchez-Avila A, Tantiwong P, Musi N (2013) Effect of lipopolysaccharide on inflammation and insulin action in human muscle. PLoS One 8:e63983

    PubMed  PubMed Central  Article  Google Scholar 

  194. 194.

    van Maren WW, Jacobs JF, de Vries IJ, Nierkens S, Adema GJ (2008) Toll-like receptor signalling on Tregs: to suppress or not to suppress? Immunol 124:445–452. doi:10.1111/j.1365-2567.2008.02871

    Article  CAS  Google Scholar 

  195. 195.

    Doan H, Bowen K, Evers B (2009) QS296. Toll-like receptor 4 activation in human colorectal cancer cells induces PI3K/AKT signaling. J Surgical Res 151:295

    Article  Google Scholar 

  196. 196.

    Basu S, Hubbard B, Shevach E (2014) Foxp3-mediated inhibition of Akt inhibits Glut1 (glucose transporter 1) expression in human T regulatory cells. J Leukoc Biol 97:279–283

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  197. 197.

    Nyirenda M, Sanvito L, Darlington P, O’Brien K, Zhang G, Constantinescu C, Bar-Or A, Gran B (2011) TLR2 stimulation drives human naive and effector regulatory T cells into a Th17-like phenotype with reduced suppressive function. J Immunol 187:2278–2290

    CAS  PubMed  Article  Google Scholar 

  198. 198.

    Al-Daghri N, Al-Attas O, Alokail M, Alkharfy K, Draz H, Agliardi C, Mohammed A, Guerini F et al (2012) Vitamin D receptor gene polymorphisms and HLA DRB1*04 cosegregation in Saudi type 2 diabetes patients. J Immunol 188:1325–1332

    CAS  PubMed  Article  Google Scholar 

  199. 199.

    Mangge H, Summers K, Meinitzer A, Zelzer S, Almer G, Prassl R, Schnedl W, Reininghaus E et al (2013) Obesity-related dysregulation of the tryptophan-kynurenine metabolism: role of age and parameters of the metabolic syndrome. Obesity 22:195–201

    PubMed  Article  CAS  Google Scholar 

  200. 200.

    Oxenkrug G (2013) Insulin resistance and dysregulation of tryptophan–kynurenine and kynurenine–nicotinamide adenine dinucleotide metabolic pathways. Mol Neurobiol 48:294–301

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  201. 201.

    Oxenkrug G, Ratner R, Summergrad P (2013) Kynurenines and vitamin B6: link between diabetes and depression. J Bioinform Diabetes 1:1–10

    Article  Google Scholar 

  202. 202.

    Oxenkrug G (2015) Increased plasma levels of xanthurenic and kynurenic acids in type 2 diabetes. Mol Neurobiol 52:805–810

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  203. 203.

    Reginaldo C, Jacques P, Scott T, Oxenkrug G, Selhub J, Paul L (2015) Xanthurenic acid is associated with higher insulin resistance and higher odds of diabetes. FASEB 29:919.20

    Google Scholar 

  204. 204.

    Nix W, Zirwes R, Bangert V, Kaiser R, Schilling M, Hostalek U, Obeid R (2015) Vitamin B status in patients with type 2 diabetes mellitus with and without incipient nephropathy. Diabetes Res Clin Pract 107:157–165

    CAS  PubMed  Article  Google Scholar 

  205. 205.

    Oxenkrug G (2010) Metabolic syndrome, age-associated neuroendocrine disorders, and dysregulation of tryptophan-kynurenine metabolism. Ann N Y Acad Sci 1199:1–14

    CAS  PubMed  Article  Google Scholar 

  206. 206.

    Allison D, Ditor D (2014) The common inflammatory etiology of depression and cognitive impairment: a therapeutic target. J Neuroinflamm 11:151

    Article  CAS  Google Scholar 

  207. 207.

    Midttun O, Ulvik A, Pedersen E, Ebbing M, Bleie O et al (2011) Low plasma vitamin B-6 status affects metabolism through the kynurenine pathway in cardiovascular patients with systemic inflammation. J Nutr 141:611–617

    CAS  PubMed  Article  Google Scholar 

  208. 208.

    Kimoto M, Ogawa T, Tokushima Sasaoka K (1991) Accumulation of 3-hydroxy-L-kynurenine sulfate and ethanolamine in urine of the rat injected with 1-aminoproline. J Exp Med 38:37–44

    CAS  Google Scholar 

  209. 209.

    Rogers KS, Evangelista SJ (1985) 3-Hydroxykynurenine, 3-hydroxyanthranilic acid, and o-aminophenol inhibit leucine-stimulated insulin release from rat pancreatic islets. Proc Soc Exp Biol Med 178:275–278

    CAS  PubMed  Article  Google Scholar 

  210. 210.

    Sarkar SA, Wong R, Hackl SI, Moua O, Gill RC et al (2007) Induction of indoleamine 2,3-dioxygenase by interferon-gamma in human islets. Diabetes 56:72–79

    CAS  PubMed  Article  Google Scholar 

  211. 211.

    Meyramov G, Korchin V, Kocheryzkina N (1984) Diabetogenic activity of xanturenic acid determined by its chelating properties? Acta Vitaminol Enzymol 6:221–228

    Google Scholar 

  212. 212.

    Ikeda S, Kotake Y (1986) Urinary excretion of xanthurenic acid and zinc in diabetes: (3). Occurrence of xanthurenic acid-Zn2+ complex in urine of diabetic patients and of experimentally-diabetic rats. Ital J Biochem 35:232–241

    CAS  PubMed  Google Scholar 

  213. 213.

    Kotaki Y, Ueda T, Mori T, Igaki S, Hattori M (1975) Abnormal tryptophan metabolism and experimental diabetes by xanthurenic acid (XA). Acta Vitaminol Enzymol 29:236–239

    Google Scholar 

  214. 214.

    Sakakeeny L, Roubenoff R, Obin M, Fontes J, Benjamin E, Bujanover Y, Jacques P, Selhub J (2012) Plasma pyridoxal-5-phosphate is inversely associated with systemic markers of inflammation in a population of U.S. adults. J Nutr 142:1280–1285

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  215. 215.

    Ulvik A, Midttun O, Pedersen E, Eussen S, Nygard O, Ueland P (2014) Evidence for increased catabolism of vitamin B-6 during systemic inflammation. Am J Clin Nutr 100:250–255

    CAS  PubMed  Article  Google Scholar 

  216. 216.

    Vasilaki A, McMillan D, Kinsella J, Duncan A, O’Reilly D, Talwar D (2008) Relation between pyridoxal and pyridoxal phosphate concentrations in plasma, red cells, and white cells in patients with critical illness. Am J Clin Nutr 88:140–146

    CAS  PubMed  Google Scholar 

  217. 217.

    Rosenfeld C (2015) Microbiome disturbances and autism spectrum disorders. Drug Metab Dispos 43:1557–1571

    CAS  PubMed  Article  Google Scholar 

  218. 218.

    MacFabe D (2012) Short-chain fatty acid fermentation products of the gut microbiome implications in autism spectrum disorders. Microb Ecol Health Dis 23. doi: 10.3402/mehd.v23i0.19260

  219. 219.

    Mayer E, Padua D, Tillisch K (2014) Altered brain-gut axis in autism: comorbidity or causative mechanisms? Bioessays 36:933–939

    PubMed  Article  Google Scholar 

  220. 220.

    Mayer E, Savidge T, Shulman R (2014) Brain-gut microbiome interactions and functional bowel disorders. Gastroenterol 146:1500–1512

    CAS  Article  Google Scholar 

  221. 221.

    Wang L, Conlon M, Christophersen C, Sorich M, Angley M (2014) Gastrointestinal microbiota and metabolite biomarkers in children with autism spectrum disorders. Biomark Med 8:331–344

    PubMed  Article  CAS  Google Scholar 

  222. 222.

    Krajmalnik-Brown R, Lozupone C, Kang D, Adams J (2015) Gut bacteria in children with autism spectrum disorders: challenges and promise of studying how a complex community influences a complex disease. Microbial Ecology in Health & Disease 26

  223. 223.

    Hsiao EY, McBride SW, Hsien S, Sharon G, Hyde ER, McCue T, Codelli JA et al (2013) Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders. Cell 155:1451–1463. doi:10.1016/j.cell.2013.11.024

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  224. 224.

    Boukthir S, Matoussi N, Belhadj A, Mammou S, Dlala SB, Helayem M, Rocchiccioli F, Bouzaidis Abdennebi M (2010) Abnormal intestinal permeability in children with autism. Tunis Med 88:685–686

    PubMed  Google Scholar 

  225. 225.

    de Magistris L, Familiari V, Pascotto A, Sapone A, Frolli A, Iardino P, Carteni M, De Rosa M et al (2010) Alterations of the intestinal barrier in patients with autism spectrum disorders and in their first-degree relatives. J Pediatr Gastroenterol Nutr 51:418–424

    PubMed  Article  Google Scholar 

  226. 226.

    Emanuele E, Orsi P, Boso M, Broglia D, Brondino N, Barale F, di Nemi S, Politi P (2010) Low-grade endotoxemia in patients with severe autism. Neurosci Lett 471:162–165

    CAS  PubMed  Article  Google Scholar 

  227. 227.

    Adams JB, Johansen LJ, Powell LD, Quig D, Rubin RA (2011) Gastrointestinal flora and gastrointestinal status in children with autism—comparisons to typical children and correlation with autism severity. BMC Gastroenterol 11:22

    PubMed  PubMed Central  Article  Google Scholar 

  228. 228.

    Finegold SM, Dowd SE, Gontcharova V, Liu C, Henley KE, Wolcott RD, Youn E, Summanen PH et al (2010) Pyrosequencing study of fecal microflora of autistic and control children. Anaerobe 16:444–453

    CAS  PubMed  Article  Google Scholar 

  229. 229.

    Finegold SM, Downes J, Summanen PH (2012) Microbiology of regressive autism. Anaerobe 18:260–262

    CAS  PubMed  Article  Google Scholar 

  230. 230.

    Gondalia SV, Palombo EA, Knowles SR, Cox SB, Meyer D, Austin DW (2012) Molecular characterisation of gastrointestinal microbiota of children with autism (with and without gastrointestinal dysfunction) and their neurotypical siblings. Autism Res 5:419–427

    PubMed  Article  Google Scholar 

  231. 231.

    Kang DW, Park JG, Ilhan ZE, Wallstrom G, Labaer J, Adams JB, Krajmalnik-Brown R (2013) Reduced incidence of and other fermenters in intestinal microflora of autistic children. PLoS One 8, e68322

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  232. 232.

    Parracho HM, Bingham MO, Gibson GR, McCartney AL (2005) Differences between the gut microflora of children with autistic spectrum disorders and that of healthy children. J Med Microbiol 54:987–991

    PubMed  Article  Google Scholar 

  233. 233.

    Williams BL et al (2011) Impaired carbohydrate digestion and transport and mucosal dysbiosis in the intestines of children with autism and gastrointestinal disturbances. PLoS One 6, e24585

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  234. 234.

    Williams BL, Hornig M, Parekh T, Lipkin WI (2012) Application of novel PCR-based methods for detection, quantitation, and phylogenetic characterization of Sutterella species in intestinal biopsy samples from children with autism and gastrointestinal disturbances. MBio 3. doi: 10.1128/mBio.00261-11. Print 2012.

  235. 235.

    Song Y, Liu C, Finegold SM (2004) Real-time PCR quantitation of clostridia in feces of autistic children. Appl Environ Microbiol 70:6459–6465

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  236. 236.

    Finegold SM (2011) Desulfovibrio species are potentially important in regressive autism. Med Hypotheses 77:270–274

    PubMed  Article  Google Scholar 

  237. 237.

    Finegold S (2011) State of the art; microbiology in health and disease. Intestinal bacterial flora in autism. Anaerobe 17:367–368

    PubMed  Article  Google Scholar 

  238. 238.

    Finegold SM, Molitoris D, Song Y, Liu C, Vaisanen ML, Bolte E et al (2002) Gastrointestinal microflora studies in late-onset autism. Clin Infect Dis 35:S6–S16

    PubMed  Article  Google Scholar 

  239. 239.

    Thomas RH, Meeking MM, Mepham JR, Tichenoff L, Possmayer F, Liu S et al (2012) The enteric bacterial metabolite propionic acid alters brain and plasma phospholipid molecular species: further development of a rodent model of autism spectrum disorders. J Neuroinflamm 9:153

    CAS  Article  Google Scholar 

  240. 240.

    Shultz SR, MacFabe DF, Ossenkopp KP, Scratch S, Whelan J, Taylor R et al (2008) Intracerebroventricular injection of propionic acid, an enteric bacterial metabolic end-product, impairs social behavior in the rat: implications for an animal model of autism. Neuropharmacology 54:901–911

    CAS  PubMed  Article  Google Scholar 

  241. 241.

    MacFabe DF, Cain DP, Rodriguez-Capote K, Franklin AE, Hoffman JE, Boon F et al (2007) Neurobiological effects of intraventricular propionic acid in rats: possible role of short chain fatty acids on the pathogenesis and characteristics of autism spectrum disorders. Behav Brain Res 176:149–169

    CAS  PubMed  Article  Google Scholar 

  242. 242.

    Sherer TB, Richardson JR, Testa CM, Seo BB, Panov AV, Yagi T et al (2007) Mechanism of toxicity of pesticides acting at complex I: relevance to environmental etiologies of Parkinson’s disease. J Neurochem 100:1469–1479

    CAS  PubMed  Google Scholar 

  243. 243.

    Morris G, Berk M (2015) The many roads to mitochondrial dysfunction in neuroimmune and neuropsychiatric disorders. BMC Med 13:68

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  244. 244.

    Schwab MA, Sauer SW, Okun JG, Nijtmans LG, Rodenburg RJ, van den Heuvel LP et al (2006) Secondary mitochondrial dysfunction in propionic aciduria: a pathogenic role for endogenous mitochondrial toxins. Biochem J 398:107–112

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  245. 245.

    Brass EP (1992) Interaction of carnitine and propionate with pyruvate oxidation by hepatocytes from clofibrate-treated rats: importance of coenzyme A availability. J Nutr 122:234–240

    CAS  PubMed  Google Scholar 

  246. 246.

    Clarke JT, Clark-Taylor BE (2004) Is autism a disorder of fatty acid metabolism? Possible dysfunction of mitochondrial beta oxidation by long chain acyl-CoA dehydrogenase. Med Hypotheses 62:970–975

    Article  CAS  Google Scholar 

  247. 247.

    Filipek P, Juranek J, Nguyen M, Cummings C, Gargus J (2004) Relative carnitine deficiency in autism. J Autism Dev Disord 34:615–623

    PubMed  Article  Google Scholar 

  248. 248.

    Frye R (2012) Biomarkers of abnormal energy metabolism in children with autism spectrum disorder. N A J Med Sci 5:141–147

    Article  Google Scholar 

  249. 249.

    Jones LL, McDonald DA, Borum PR (2010) Acylcarnitines: role in brain. Prog Lipid Res 49:61–75

    CAS  PubMed  Article  Google Scholar 

  250. 250.

    Kekuda R, Manoharan P, Baseler W, Sundaram U (2013) Monocarboxylate 4 mediated butyrate transport in a rat intestinal epithelial cell line. Dig Dis Sci 58:660–667

    CAS  PubMed  Article  Google Scholar 

  251. 251.

    Maurer M (2004) Correlation between local monocarboxylate transporter 1 (MCT1) and glucose transporter 1 (GLUT1) densities in the adult rat brain. Neurosci Lett 355:105–108

    CAS  PubMed  Article  Google Scholar 

  252. 252.

    Peinado A, Yuste R, Katz LC (1993) Extensive dye coupling between rat neocortical neurons during the period of circuit formation. Neuron 10:103–114

    CAS  PubMed  Article  Google Scholar 

  253. 253.

    Pierre K, Pellerin L (2005) Monocarboxylate transporters in the central nervous system: distribution, regulation and function. J Neurochem 94:1–14

    CAS  PubMed  Article  Google Scholar 

  254. 254.

    Pellerin L (2005) How astrocytes feed hungry neurons. Mol Neurobiol 32:059–072

    CAS  Article  Google Scholar 

  255. 255.

    Rafiki A, Boulland J, Halestrap A, Ottersen O, Bergersen L (2003) Highly differential expression of the monocarboxylate transporters MCT2 and MCT4 in the developing rat brain. Neurosci 122:677–688

    CAS  Article  Google Scholar 

  256. 256.

    Hara H, Haga S, Aoyama Y, Kiriyama S (1999) Short-chain fatty acids suppress cholesterol synthesis in rat liver and intestine. J Nutr 129:942–948

    CAS  PubMed  Google Scholar 

  257. 257.

    DeCastro M, Nankova B, Shah P, Patel P, Mally P, Mishra R, La Gamma E (2005) Short chain fatty acids regulate tyrosine hydroxylase gene expression through a cAMP-dependent signaling pathway. Mol Brain Res 142:28–38

    CAS  PubMed  Article  Google Scholar 

  258. 258.

    Wajner M, Latini A, Wyse AT, Dutra-Filho CS (2004) The role of oxidative damage in the neuropathology of organic acidurias: insights from animal studies. J Inherit Metab Dis 27:427–448

    CAS  PubMed  Article  Google Scholar 

  259. 259.

    Neuhaus E, Beauchaine TP, Bernier R (2010) Neurobiological correlates of social functioning in autism. Clin Psychol Rev 30:733–748

    PubMed  Article  Google Scholar 

  260. 260.

    El-Ansary AK, Ben BA, Kotb M (2012) Etiology of autistic features: the persisting neurotoxic effects of propionic acid. J Neuroinflammation 9:74

    CAS  PubMed  PubMed Central  Google Scholar 

  261. 261.

    Severson CA, Wang W, Pieribone VA, Dohle CI, Richerson GB (2003) Midbrain serotonergic neurons are central pH chemoreceptors. Nat Neurosci 6:1139–1140

    CAS  PubMed  Article  Google Scholar 

  262. 262.

    Shah P, Nankova BB, Parab S, La Gamma EF (2006) Short chain fatty acids induce TH gene expression via ERK-dependent phosphorylation of CREB protein. Brain Res 1107:13–23

    CAS  PubMed  Article  Google Scholar 

  263. 263.

    Ming X, Julu PO, Brimacombe M, Connor S, Daniels ML (2005) Reduced cardiac parasympathetic activity in children with autism. Brain Dev 27:509–516

    PubMed  Article  Google Scholar 

  264. 264.

    Liu Z, Li N, Neu J (2005) Tight junctions, leaky intestines, and pediatric diseases. Acta Paediatr 94:386–393

    CAS  PubMed  Article  Google Scholar 

  265. 265.

    Nicholson JK, Holmes E, Kinross J, Burcelin R, Gibson G, Jia W, Pettersson S (2012) Host-gut microbiota metabolic interactions. Science 336:1262–1267

    CAS  PubMed  Article  Google Scholar 

  266. 266.

    Anderson G, Maes M (2014) Redox regulation and the autistic spectrum: role of tryptophan catabolites, immuno-inflammation, autoimmunity and the amygdala. Curr Neuropharmacol 12:148–167

    CAS  PubMed  PubMed Central  Article  Google Scholar 

Download references

Acknowledgments

MB is supported by a NHMRC Senior Principal Research Fellowship 1059660.

Author information

Affiliations

  1. Tir Na Nog, Bryn Road seaside 87, Llanelli, SA152LW, Wales, UK

    Gerwyn Morris

  2. IMPACT Strategic Research Centre, School of Medicine, Barwon Health, Deakin University, P.O. Box 291, Geelong, VIC, 3220, Australia

    Michael Berk & Michael Maes

  3. Orygen Youth Health Research Centre and the Centre of Youth Mental Health, The Florey Institute for Neuroscience and Mental Health and the Department of Psychiatry, University of Melbourne, Parkville, 3052, Australia

    Michael Berk

  4. Department of Clinical Medicine and Translational Psychiatry Research Group, Faculty of Medicine, Federal University of Ceará, Fortaleza, CE, 60430-040, Brazil

    Andre Carvalho

  5. Department of Pharmacology, School of Medicine, University Complutense of Madrid, Avda. Complutense s/n, 28040, Madrid, Spain

    Javier R. Caso

  6. Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Avda. Complutense s/n, 28040, Madrid, Spain

    Javier R. Caso

  7. Instituto de Investigación Hospital 12 de Octubre (Imas12), Avda. Complutense s/n, 28040, Madrid, Spain

    Javier R. Caso

  8. Microbial Ecology, Nutrition & Health Research Unit, Institute of Agrochemistry and Food Technology, National Research Council (IATA-CSIC), Av. Agustin Escardino 7, 46980, Paterna, Valencia, Spain

    Yolanda Sanz

  9. Health Sciences Postgraduate Program, Health Sciences Center, State University of Londrina, Londrina, Parana, Brazil

    Michael Maes

  10. Centre for Molecular and Medical Research, School of Medicine, Deakin University, Geelong, Australia

    Ken Walder

Authors
  1. Gerwyn Morris
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Michael Berk
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Andre Carvalho
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Javier R. Caso
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yolanda Sanz
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ken Walder
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Michael Maes
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michael Maes.

Ethics declarations

Conflict of Interest

MB has received grants from the NIH, Simons Autism Foundation, Stanley Medical Research Foundation, NHMRC, and CRC for Mental Health; he has been a paid consultant for Astra Zeneca, Eli Lilly, Glaxo SmithKline, Janssen Cilag, Lundbeck, and Pfizer and a paid speaker for Astra Zeneca, Eli Lilly, Glaxo SmithKline, Lundbeck, and Merck. FNJ has received grants from the Brain and Behaviour Research Institute, NHMRC, Australian Rotary Health, and the Meat and Livestock Board and has been a paid speaker for Sanofi-Synthelabo, Janssen Cilag, Servier, and Health Ed. The other authors have no conflicts to declare.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Morris, G., Berk, M., Carvalho, A. et al. The Role of the Microbial Metabolites Including Tryptophan Catabolites and Short Chain Fatty Acids in the Pathophysiology of Immune-Inflammatory and Neuroimmune Disease. Mol Neurobiol 54, 4432–4451 (2017). https://doi.org/10.1007/s12035-016-0004-2

Download citation

Keywords

  • Leaky gut
  • Bacterial translocation
  • Diabetes type 2
  • Autism
  • Immune inflammation
  • Oxidative stress