The role of short-chain fatty acids in microbiota–gut–brain communication

Abstract

Short-chain fatty acids (SCFAs), the main metabolites produced by bacterial fermentation of dietary fibre in the gastrointestinal tract, are speculated to have a key role in microbiota–gut–brain crosstalk. However, the pathways through which SCFAs might influence psychological functioning, including affective and cognitive processes and their neural basis, have not been fully elucidated. Furthermore, research directly exploring the role of SCFAs as potential mediators of the effects of microbiota-targeted interventions on affective and cognitive functioning is sparse, especially in humans. This Review summarizes existing knowledge on the potential of SCFAs to directly or indirectly mediate microbiota–gut–brain interactions. The effects of SCFAs on cellular systems and their interaction with gut–brain signalling pathways including immune, endocrine, neural and humoral routes are described. The effects of microbiota-targeted interventions such as prebiotics, probiotics and diet on psychological functioning and the putative mediating role of SCFA signalling will also be discussed, as well as the relationship between SCFAs and psychobiological processes. Finally, future directions to facilitate direct investigation of the effect of SCFAs on psychological functioning are outlined.

Key points

  • Short-chain fatty acids (SCFAs) are speculated to have a mediational role in the microbiota–gut–brain axis crosstalk.

  • SCFAs might influence psychological functioning via interactions with G protein-coupled receptors or histone deacetylases and exert their effects on the brain via direct humoral effects, indirect hormonal and immune pathways and neural routes.

  • Dietary intervention studies indirectly implicate a mediational role for SCFAs in cognition and emotion.

  • Animal studies provide direct evidence of the effects of SCFAs on neuropsychiatric disorders and psychological functioning, whereas human studies are sparse, suffer from methodological limitations and offer inconsistent conclusions.

  • SCFAs should be quantified in the systemic circulation in dietary intervention studies, in which the effects on psychological functioning and psychopathology are an outcome of interest.

  • SCFAs could ultimately be used as interventional substances to target microbiota–gut–brain interactions in humans.

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Fig. 1: Metabolism of SCFAs from dietary fibre to systemic circulation.
Fig. 2: SCFA cellular signalling pathways.
Fig. 3: Potential gut–brain pathways through which SCFAs might modulate brain function.

References

  1. 1.

    Mayer, E. A. Gut feelings: the emerging biology of gut-brain communication. Nat. Rev. Neurosci. 12, 453–466 (2011).

  2. 2.

    Cryan, J. F. & Dinan, T. G. Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour. Nat. Rev. Neurosci. 13, 701–712 (2012).

  3. 3.

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

  4. 4.

    Kleiman, S. C. et al. The intestinal microbiota in acute anorexia nervosa and during renourishment: relationship to depression, anxiety, and eating disorder psychopathology. Psychosom. Med. 77, 969–981 (2015).

  5. 5.

    Kang, D. W. et al. Reduced incidence of Prevotella and other fermenters in intestinal microflora of autistic children. PLOS ONE 8, e68322 (2013).

  6. 6.

    Jiang, H. et al. Altered fecal microbiota composition in patients with major depressive disorder. Brain. Behav. Immun. 48, 186–194 (2015).

  7. 7.

    Liu, X., Cao, S. & Zhang, X. Modulation of gut microbiota–brain axis by probiotics, prebiotics, and diet. J. Agr. Food. Chem. 63, 7885–7895 (2015).

  8. 8.

    Stilling, R. M. et al. The neuropharmacology of butyrate: the bread and butter of the microbiota-gut-brain axis? Neurochem. Int. 99, 110–132 (2016).

  9. 9.

    Clarke, G. et al. Minireview: gut microbiota: the neglected endocrine organ. Mol. Endocrinol. 28, 1221–1238 (2014).

  10. 10.

    Miller, T. L. & Wolin, M. J. Pathways of acetate, propionate, and butyrate formation by the human fecal microbial flora. Appl. Environ. Microbiol. 62, 1589–1592 (1996).

  11. 11.

    Bergman, E. N. Energy contributions of volatile fatty acids from the gastrointestinal tract in various species. Physiol. Rev. 70, 567–590 (1990).

  12. 12.

    Macfarlane, S. & Macfarlane, G. T. Regulation of short-chain fatty acid production. Proc. Nutr. Soc. 62, 67–72 (2003).

  13. 13.

    Cummings, J. H., Pomare, E. W., Branch, W. J., Naylor, C. P. & Macfarlane, G. T. Short chain fatty acids in human large intestine, portal, hepatic and venous blood. Gut 28, 1221–1227 (1987).

  14. 14.

    Stumpff, F. A look at the smelly side of physiology: transport of short chain fatty acids. Pflugers Arch. 470, 571–598 (2018).

  15. 15.

    Schonfeld, P. & Wojtczak, L. Short- and medium-chain fatty acids in energy metabolism: the cellular perspective. J. Lipid Res. 57, 943–954 (2016).

  16. 16.

    Bloemen, J. G. et al. Short chain fatty acids exchange across the gut and liver in humans measured at surgery. Clin. Nutr. 28, 657–661 (2009).

  17. 17.

    Boets, E. et al. Systemic availability and metabolism of colonic-derived short-chain fatty acids in healthy subjects: a stable isotope study. J. Physiol. 595, 541–555 (2017).

  18. 18.

    Hellman, L., Rosenfeld, R. S. & Gallagher, T. F. Cholesterol synthesis from C14-acetate in man. J. Clin. Invest. 33, 142–149 (1954).

  19. 19.

    Hellerstein, M. K. et al. Measurement of de novo hepatic lipogenesis in humans using stable isotopes. J. Clin. Invest. 87, 1841–1852 (1991).

  20. 20.

    Wiltrout, D. W. & Satter, L. D. Contribution of propionate to glucose synthesis in the lactating and nonlactating cow. J. Dairy Sci. 55, 307–317 (1972).

  21. 21.

    Boets, E. et al. Quantification of in vivo colonic short chain fatty acid production from inulin. Nutrients 7, 8916–8929 (2015).

  22. 22.

    Layden, B. T., Angueira, A. R., Brodsky, M., Durai, V. & Lowe, W. L. Jr. Short chain fatty acids and their receptors: new metabolic targets. Transl Res. 161, 131–140 (2013).

  23. 23.

    Yamashita, H., Kaneyuki, T. & Tagawa, K. Production of acetate in the liver and its utilization in peripheral tissues. Biochim. Biophys. Acta 1532, 79–87 (2001).

  24. 24.

    Bell-Parikh, L. C. & Guengerich, F. P. Kinetics of cytochrome P450 2E1-catalyzed oxidation of ethanol to acetic acid via acetaldehyde. J. Biol. Chem. 274, 23833–23840 (1999).

  25. 25.

    Bugaut, M. Occurrence, absorption and metabolism of short chain fatty acids in the digestive tract of mammals. Comp. Biochem. Physiol. B 86, 439–472 (1987).

  26. 26.

    Mitchell, R. W., On, N. H., Del Bigio, M. R., Miller, D. W. & Hatch, G. M. Fatty acid transport protein expression in human brain and potential role in fatty acid transport across human brain microvessel endothelial cells. J. Neurochem. 117, 735–746 (2011).

  27. 27.

    Vijay, N. & Morris, M. E. Role of monocarboxylate transporters in drug delivery to the brain. Curr. Pharm. Des. 20, 1487–1498 (2014).

  28. 28.

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

  29. 29.

    Oldendorf, W. Carrier-mediated blood-brain barrier transport of short-chain monocarboxylic organic acids. Am. J. Physiol. 224, 1450–1453 (1973).

  30. 30.

    Bachmann, C., Colombo, J.-P. & Berüter, J. Short chain fatty acids in plasma and brain: quantitative determination by gas chromatography. Clin. Chim. Acta 92, 153–159 (1979).

  31. 31.

    Frost, G. et al. The short-chain fatty acid acetate reduces appetite via a central homeostatic mechanism. Nat. Commun. 5, 3611 (2014).

  32. 32.

    Kim, S. W. et al. Whole-body pharmacokinetics of HDAC inhibitor drugs, butyric acid, valproic acid and 4-phenylbutyric acid measured with carbon-11 labeled analogs by PET. Nucl. Med. Biol. 40, 912–918 (2013).

  33. 33.

    Song, W. S., Nielson, B. R., Banks, K. P. & Bradley, Y. C. Normal organ standard uptake values in carbon-11 acetate PET imaging. Nucl. Med. Commun. 30, 462–465 (2009).

  34. 34.

    Seltzer, M. A. et al. Radiation dose estimates in humans for (11)C-acetate whole-body PET. J. Nucl. Med. 45, 1233–1236 (2004).

  35. 35.

    Lewis, K. et al. Enhanced translocation of bacteria across metabolically stressed epithelia is reduced by butyrate. Inflamm. Bowel. Dis. 16, 1138–1148 (2010).

  36. 36.

    Peng, L., Li, Z. R., Green, R. S., Holzman, I. R. & Lin, J. 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 (2009).

  37. 37.

    Daly, K. & Shirazi-Beechey, P. S. P. Microarray analysis of butyrate regulated genes in colonic epithelial cells. DNA Cell. Biol. 25, 49–62 (2006).

  38. 38.

    Allen, A. & Flemstrom, G. Gastroduodenal mucus bicarbonate barrier: protection against acid and pepsin. Am. J. Physiol. Cell. Physiol. 288, C1–C19 (2005).

  39. 39.

    Pelaseyed, T. et al. The mucus and mucins of the goblet cells and enterocytes provide the first defense line of the gastrointestinal tract and interact with the immune system. Immunol. Rev. 260, 8–20 (2014).

  40. 40.

    Barcelo, A. et al. Mucin secretion is modulated by luminal factors in the isolated vascularly perfused rat colon. Gut 46, 218–224 (2000).

  41. 41.

    Gaudier, E., Rival, M., Buisine, M. P., Robineau, I. & Hoebler, C. Butyrate enemas upregulate Muc genes expression but decrease adherent mucus thickness in mice colon. Physiol. Res. 58, 111–119 (2009).

  42. 42.

    Scheppach, W. et al. Effect of butyrate enemas on the colonic mucosa in distal ulcerative colitis. Gastroenterology 103, 51–56 (1992).

  43. 43.

    Cherbut, C. et al. Short-chain fatty acids modify colonic motility through nerves and polypeptide YY release in the rat. Am. J. Physiol. 275, G1415–G1422 (1998).

  44. 44.

    Dass, N. B. et al. The relationship between the effects of short-chain fatty acids on intestinal motility in vitro and GPR43 receptor activation. Neurogastroenterol. Motil. 19, 66–74 (2007).

  45. 45.

    Fukumoto, S. et al. Short-chain fatty acids stimulate colonic transit via intraluminal 5-HT release in rats. Am. J. Physiol. Regul. Integr. Comp. Physiol. 284, R1269–R1276 (2003).

  46. 46.

    Ropert, A. et al. Colonic fermentation and proximal gastric tone in humans. Gastroenterology 111, 289–296 (1996).

  47. 47.

    Jouet, P. et al. Effect of short-chain fatty acids and acidification on the phasic and tonic motor activity of the human colon. Neurogastroenterol. Motil. 25, 943–949 (2013).

  48. 48.

    Greer, J. B. & O’Keefe, S. J. Microbial induction of immunity, inflammation, and cancer. Front. Physiol. 1, 168 (2011).

  49. 49.

    Encarnação, J. C., Abrantes, A. M., Pires, A. S. & Botelho, M. F. Revisit dietary fiber on colorectal cancer: butyrate and its role on prevention and treatment. Cancer Metastasis Rev. 34, 465–478 (2015).

  50. 50.

    O’Keefe, S. J. Diet, microorganisms and their metabolites, and colon cancer. Nat. Rev. Gastroenterol. Hepatol. 13, 691–706 (2016).

  51. 51.

    Brown, A. J. et al. The Orphan G protein-coupled receptors GPR41 and GPR43 are activated by propionate and other short chain carboxylic acids. J. Biol. Chem. 278, 11312–11319 (2003).

  52. 52.

    Karaki, S.-i et al. Short-chain fatty acid receptor, GPR43, is expressed by enteroendocrine cells and mucosal mast cells in rat intestine. Cell Tissue Res. 324, 353–360 (2006).

  53. 53.

    Maslowski, K. M. et al. Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43. Nature 461, 1282 (2009).

  54. 54.

    Tazoe, H. et al. Expression of short-chain fatty acid receptor GPR41 in the human colon. Biomed. Res. 30, 149–156 (2009).

  55. 55.

    Nohr, M. K. et al. Expression of the short chain fatty acid receptor GPR41/FFAR3 in autonomic and somatic sensory ganglia. Neuroscience 290, 126–137 (2015).

  56. 56.

    Le Poul, E. et al. Functional characterization of human receptors for short chain fatty acids and their role in polymorphonuclear cell activation. J. Biol. Chem. 278, 25481–25489 (2003).

  57. 57.

    Thangaraju, M. et al. GPR109A is a G-protein-coupled receptor for the bacterial fermentation product butyrate and functions as a tumor suppressor in colon. Cancer Res. 69, 2826–2832 (2009).

  58. 58.

    Ahmed, K., Tunaru, S. & Offermanns, S. GPR109A, GPR109B and GPR81, a family of hydroxy-carboxylic acid receptors. Trends. Pharmacol. Sci. 30, 557–562 (2009).

  59. 59.

    Bonini, J. A., Anderson, S. M. & Steiner, D. F. Molecular cloning and tissue expression of a novel orphan G protein-coupled receptor from rat lung. Biochem. Biophys. Res. Commun. 234, 190–193 (1997).

  60. 60.

    Kimura, I. et al. Short-chain fatty acids and ketones directly regulate sympathetic nervous system via G protein-coupled receptor 41 (GPR41). Proc. Natl Acad. Sci. USA 108, 8030–8035 (2011).

  61. 61.

    De Vadder, F. et al. Microbiota-generated metabolites promote metabolic benefits via gut-brain neural circuits. Cell 156, 84–96 (2014).

  62. 62.

    Marks, P. A., Richon, V. M., Miller, T. & Kelly, W. K. Histone deacetylase inhibitors. Adv. Cancer Res. 91, 137–168 (2004).

  63. 63.

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

  64. 64.

    Soliman, M. L. & Rosenberger, T. A. Acetate supplementation increases brain histone acetylation and inhibits histone deacetylase activity and expression. Mol. Cell. Biochem. 352, 173–180 (2011).

  65. 65.

    Volmar, C.-H. & Wahlestedt, C. Histone deacetylases (HDACs) and brain function. Neuroepigenetics 1, 20–27 (2015).

  66. 66.

    Whittle, N. & Singewald, N. HDAC inhibitors as cognitive enhancers in fear, anxiety and trauma therapy: where do we stand? Biochem. Soc. Trans. 42, 569–581 (2014).

  67. 67.

    Schroeder, F. A., Lin, C. L., Crusio, W. E. & Akbarian, S. Antidepressant-like effects of the histone deacetylase inhibitor, sodium butyrate, in the mouse. Biol. Psychiatry 62, 55–64 (2007).

  68. 68.

    Fischer, A., Sananbenesi, F., Wang, X., Dobbin, M. & Tsai, L. H. Recovery of learning and memory is associated with chromatin remodelling. Nature 447, 178–182 (2007).

  69. 69.

    Stafford, J. M., Raybuck, J. D., Ryabinin, A. E. & Lattal, K. M. Increasing histone acetylation in the hippocampus-infralimbic network enhances fear extinction. Biol. Psychiatry 72, 25–33 (2012).

  70. 70.

    Cousens, L. S., Gallwitz, D. & Alberts, B. M. Different accessibilities in chromatin to histone acetylase. J. Biol. Chem. 254, 1716–1723 (1979).

  71. 71.

    Soliman, M. L., Smith, M. D., Houdek, H. M. & Rosenberger, T. A. Acetate supplementation modulates brain histone acetylation and decreases interleukin-1β expression in a rat model of neuroinflammation. J. Neuroinflamm. 9, 51 (2012).

  72. 72.

    Kratsman, N., Getselter, D. & Elliott, E. Sodium butyrate attenuates social behavior deficits and modifies the transcription of inhibitory/excitatory genes in the frontal cortex of an autism model. Neuropharmacology 102, 136–145 (2016).

  73. 73.

    Gagliano, H., Delgado-Morales, R., Sanz-Garcia, A. & Armario, A. High doses of the histone deacetylase inhibitor sodium butyrate trigger a stress-like response. Neuropharmacology 79, 75–82 (2014).

  74. 74.

    Nishitsuji, K. et al. Analysis of the gut microbiome and plasma short-chain fatty acid profiles in a spontaneous mouse model of metabolic syndrome. Sci. Rep. 7, 15876 (2017).

  75. 75.

    Val-Laillet, D. et al. Oral sodium butyrate impacts brain metabolism and hippocampal neurogenesis, with limited effects on gut anatomy and function in pigs. FASEB J. 32, 2160–2171 (2018).

  76. 76.

    Carrer, A. et al. Impact of a high-fat diet on tissue Acyl-CoA and histone acetylation levels. J. Biol. Chem. 292, 3312–3322 (2017).

  77. 77.

    Krautkramer, K. A. et al. Diet-microbiota interactions mediate global epigenetic programming in multiple host tissues. Mol. Cell. 64, 982–992 (2016).

  78. 78.

    Sabari, B. R. et al. Intracellular crotonyl-CoA stimulates transcription through p300-catalyzed histone crotonylation. Mol. Cell. 58, 203–215 (2015).

  79. 79.

    Fellows, R. et al. Microbiota derived short chain fatty acids promote histone crotonylation in the colon through histone deacetylases. Nat. Commun. 9, 105 (2018).

  80. 80.

    Miller, A. H. & Raison, C. L. The role of inflammation in depression: from evolutionary imperative to modern treatment target. Nat. Rev. Immunol. 16, 22–34 (2016).

  81. 81.

    Segerstrom, S. C. & Miller, G. E. Psychological stress and the human immune system: a meta-analytic study of 30 years of inquiry. Psychol. Bull. 130, 601 (2004).

  82. 82.

    Capuron, L. & Miller, A. H. Immune system to brain signaling: neuropsychopharmacological implications. Pharmacol. Ther. 130, 226–238 (2011).

  83. 83.

    Frick, L. R., Williams, K. & Pittenger, C. Microglial dysregulation in psychiatric disease. Clin. Dev. Immunol. 2013, 608654 (2013).

  84. 84.

    Correa-Oliveira, R., Fachi, J. L., Vieira, A., Sato, F. T. & Vinolo, M. A. Regulation of immune cell function by short-chain fatty acids. Clin. Transl Immunol. 5, e73 (2016).

  85. 85.

    Rodrigues, H. G., Takeo Sato, F., Curi, R. & Vinolo, M. A. R. Fatty acids as modulators of neutrophil recruitment, function and survival. Eur. J. Pharmacol. 785, 50–58 (2016).

  86. 86.

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

  87. 87.

    Kim, C. H., Park, J. & Kim, M. Gut microbiota-derived short-chain fatty acids, T cells, and inflammation. Immune Netw. 14, 277–288 (2014).

  88. 88.

    Singh, N. et al. Activation of Gpr109a, receptor for niacin and the commensal metabolite butyrate, suppresses colonic inflammation and carcinogenesis. Immunity 40, 128–139 (2014).

  89. 89.

    Gurav, A. et al. Slc5a8, a Na+-coupled high-affinity transporter for short-chain fatty acids, is a conditional tumour suppressor in colon that protects against colitis and colon cancer under low-fibre dietary conditions. Biochem. J. 469, 267–278 (2015).

  90. 90.

    Furusawa, Y. et al. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature 504, 446 (2013).

  91. 91.

    Chen, S. et al. Effect of inhibiting the signal of mammalian target of rapamycin on memory T cells. Transplant. Proc. 46, 1642–1648 (2014).

  92. 92.

    Delgoffe, G. M. et al. The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment. Immunity 30, 832–844 (2009).

  93. 93.

    Park, J. et al. 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 (2015).

  94. 94.

    Arpaia, N. et al. Metabolites produced by commensal bacteria promote peripheral regulatory T cell generation. Nature 504, 451–455 (2013).

  95. 95.

    Ang, Z. et al. Human and mouse monocytes display distinct signalling and cytokine profiles upon stimulation with FFAR2/FFAR3 short-chain fatty acid receptor agonists. Sci. Rep. 6, 34145 (2016).

  96. 96.

    Möhle, L. et al. Ly6Chi monocytes provide a link between antibiotic-induced changes in gut microbiota and adult hippocampal neurogenesis. Cell Rep. 15, 1945–1956 (2016).

  97. 97.

    McLoughlin, R. F., Berthon, B. S., Jensen, M. E., Baines, K. J. & Wood, L. G. Short-chain fatty acids, prebiotics, synbiotics, and systemic inflammation: a systematic review and meta-analysis. Am. J. Clin. Nutr. 106, 930–945 (2017).

  98. 98.

    Freeland, K. R. & Wolever, T. M. 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 (2010).

  99. 99.

    Canfora, E. E. et al. Colonic infusions of short-chain fatty acid mixtures promote energy metabolism in overweight/obese men: a randomized crossover trial. Sci. Rep. 7, 2360 (2017).

  100. 100.

    Hamer, H. M. et al. Butyrate modulates oxidative stress in the colonic mucosa of healthy humans. Clin. Nutr. 28, 88–93 (2009).

  101. 101.

    Hamer, H. M. et al. Effect of butyrate enemas on inflammation and antioxidant status in the colonic mucosa of patients with ulcerative colitis in remission. Clin. Nutr. 29, 738–744 (2010).

  102. 102.

    van der Beek, C. M. et al. Distal, not proximal, colonic acetate infusions promote fat oxidation and improve metabolic markers in overweight/obese men. Clin. Sci. 130, 2073–2082 (2016).

  103. 103.

    Lecerf, J. M. et al. Xylo-oligosaccharide (XOS) in combination with inulin modulates both the intestinal environment and immune status in healthy subjects, while XOS alone only shows prebiotic properties. Br. J. Nutr. 108, 1847–1858 (2012).

  104. 104.

    Clarke, S. T. et al. beta2-1 Fructan supplementation alters host immune responses in a manner consistent with increased exposure to microbial components: results from a double-blinded, randomised, cross-over study in healthy adults. Br. J. Nutr. 115, 1748–1759 (2016).

  105. 105.

    Queenan, K. M. et al. Concentrated oat beta-glucan, a fermentable fiber, lowers serum cholesterol in hypercholesterolemic adults in a randomized controlled trial. Nutr. J. 6, 6 (2007).

  106. 106.

    Stewart, M. L., Nikhanj, S. D., Timm, D. A., Thomas, W. & Slavin, J. L. Evaluation of the effect of four fibers on laxation, gastrointestinal tolerance and serum markers in healthy humans. Ann. Nutr. Metab. 56, 91–98 (2010).

  107. 107.

    Macfarlane, S., Cleary, S., Bahrami, B., Reynolds, N. & Macfarlane, G. T. Synbiotic consumption changes the metabolism and composition of the gut microbiota in older people and modifies inflammatory processes: a randomised, double-blind, placebo-controlled crossover study. Aliment. Pharmacol. Ther. 38, 804–816 (2013).

  108. 108.

    Varatharaj, A. & Galea, I. The blood-brain barrier in systemic inflammation. Brain. Behav. Immun. 60, 1–12 (2017).

  109. 109.

    Hoogland, I. C. M., Houbolt, C., van Westerloo, D. J., van Gool, W. A. & van de Beek, D. Systemic inflammation and microglial activation: systematic review of animal experiments. J. Neuroinflamm. 12, 114 (2015).

  110. 110.

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

  111. 111.

    Erny, D. et al. Host microbiota constantly control maturation and function of microglia in the CNS. Nat. Neurosci. 18, 965–977 (2015).

  112. 112.

    Savignac, H. M. et al. Prebiotic administration normalizes lipopolysaccharide (LPS)-induced anxiety and cortical 5-HT2A receptor and IL1-β levels in male mice. Brain. Behav. Immun. 52, 120–131 (2016).

  113. 113.

    Neyrinck, A. M. et al. Gut microbiota fermentation of prebiotics increases satietogenic and incretin gut peptide production with consequences for appetite sensation and glucose response after a meal. Am. J. Clin. Nutr. 90, 1236–1243 (2009).

  114. 114.

    Tolhurst, G. et al. Short-chain fatty acids stimulate glucagon-like peptide-1 secretion via the G-protein-coupled receptor FFAR2. Diabetes 61, 364–371 (2012).

  115. 115.

    Psichas, A. et al. The short chain fatty acid propionate stimulates GLP-1 and PYY secretion via free fatty acid receptor 2 in rodents. Int. J. Obes. 39, 424–429 (2015).

  116. 116.

    Larraufie, P. et al. SCFAs strongly stimulate PYY production in human enteroendocrine cells. Sci. Rep. 8, 74 (2018).

  117. 117.

    Sam, A. H., Troke, R. C., Tan, T. M. & Bewick, G. A. The role of the gut/brain axis in modulating food intake. Neuropharmacology 63, 46–56 (2012).

  118. 118.

    Trapp, S. & Richards, J. E. The gut hormone glucagon-like peptide-1 produced in brain: is this physiologically relevant? Curr. Opin. Pharmacol. 13, 964–969 (2013).

  119. 119.

    Katsurada, K. & Yada, T. Neural effects of gut- and brain-derived glucagon-like peptide-1 and its receptor agonist. J. Diabetes Investig. 7 (Suppl. 1), 64–69 (2016).

  120. 120.

    Alvarez, E. et al. The expression of GLP-1 receptor mRNA and protein allows the effect of GLP-1 on glucose metabolism in the human hypothalamus and brainstem. J. Neurochem. 92, 798–806 (2005).

  121. 121.

    van Bloemendaal, L. et al. GLP-1 receptor activation modulates appetite- and reward-related brain areas in humans. Diabetes 63, 4186 (2014).

  122. 122.

    Anderberg, R. H. et al. GLP-1 is both anxiogenic and antidepressant; divergent effects of acute and chronic GLP-1 on emotionality. Psychoneuroendocrinology 65, 54–66 (2016).

  123. 123.

    Gil-Lozano, M. et al. GLP-1(7–36)-amide and Exendin-4 stimulate the HPA axis in rodents and humans. Endocrinology 151, 2629–2640 (2010).

  124. 124.

    During, M. J. et al. Glucagon-like peptide-1 receptor is involved in learning and neuroprotection. Nat. Med. 9, 1173–1179 (2003).

  125. 125.

    Isacson, R. et al. The glucagon-like peptide 1 receptor agonist exendin-4 improves reference memory performance and decreases immobility in the forced swim test. Eur. J. Pharmacol. 650, 249–255 (2011).

  126. 126.

    McClean, P. L., Parthsarathy, V., Faivre, E. & Holscher, C. The diabetes drug liraglutide prevents degenerative processes in a mouse model of Alzheimer’s disease. J. Neurosci. 31, 6587–6594 (2011).

  127. 127.

    Porter, D. W., Irwin, N., Flatt, P. R., Hölscher, C. & Gault, V. A. Prolonged GIP receptor activation improves cognitive function, hippocampal synaptic plasticity and glucose homeostasis in high-fat fed mice. Eur. J. Pharmacol. 650, 688–693 (2011).

  128. 128.

    Morimoto, R. et al. Expression of peptide YY in human brain and pituitary tissues. Nutrition 24, 878–884 (2008).

  129. 129.

    Murphy, K. G. & Bloom, S. R. Gut hormones and the regulation of energy homeostasis. Nature 444, 854–859 (2006).

  130. 130.

    Nonaka, N., Shioda, S., Niehoff, M. L. & Banks, W. A. Characterization of blood-brain barrier permeability to PYY3-36 in the mouse. J. Pharmacol. Exp. Ther. 306, 948–953 (2003).

  131. 131.

    Koda, S. et al. The role of the vagal nerve in peripheral PYY3-36-induced feeding reduction in rats. Endocrinology 146, 2369–2375 (2005).

  132. 132.

    Waise, T. M. Z., Dranse, H. J. & Lam, T. K. T. The metabolic role of vagal afferent innervation. Nat. Rev. Gastroenterol. Hepatol. 15, 625–636 (2018).

  133. 133.

    Painsipp, E., Herzog, H. & Holzer, P. The gut-mood axis: a novel role of the gut hormone peptide YY on emotional-affective behaviour in mice. BMC Pharmacol. 9, A13 (2009).

  134. 134.

    Painsipp, E., Herzog, H., Sperk, G. & Holzer, P. Sex-dependent control of murine emotional-affective behaviour in health and colitis by peptide YY and neuropeptide Y. Br. J. Pharmacol. 163, 1302–1314 (2011).

  135. 135.

    Tschenett, A. et al. Reduced anxiety and improved stress coping ability in mice lacking NPY-Y2 receptors. Eur. J. Neurosci. 18, 143–148 (2003).

  136. 136.

    Heilig, M. The NPY system in stress, anxiety and depression. Neuropeptides 38, 213–224 (2004).

  137. 137.

    Byrne, C. S. et al. Increased colonic propionate reduces anticipatory reward responses in the human striatum to high-energy foods. Am. J. Clin. Nutr. 104, 5–14 (2016).

  138. 138.

    Chambers, E. S. et al. Effects of targeted delivery of propionate to the human colon on appetite regulation, body weight maintenance and adiposity in overweight adults. Gut 64, 1744–1754 (2015).

  139. 139.

    Hube, F. et al. Difference in leptin mRNA levels between omental and subcutaneous abdominal adipose tissue from obese humans. Horm. Metab. Res. 28, 690–693 (1996).

  140. 140.

    Elias, C. F. et al. Leptin differentially regulates NPY and POMC neurons projecting to the lateral hypothalamic area. Neuron 23, 775–786 (1999).

  141. 141.

    Byrne, C. S., Chambers, E. S., Morrison, D. J. & Frost, G. The role of short chain fatty acids in appetite regulation and energy homeostasis. Int. J. Obes. 39, 1331–1338 (2015).

  142. 142.

    Xiong, Y. et al. Short-chain fatty acids stimulate leptin production in adipocytes through the G protein-coupled receptor GPR41. Proc. Natl Acad. Sci. USA 101, 1045–1050 (2004).

  143. 143.

    Hong, Y. H. et al. Acetate and propionate short chain fatty acids stimulate adipogenesis via GPCR43. Endocrinology 146, 5092–5099 (2005).

  144. 144.

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

  145. 145.

    Ivan, J. et al. The short-chain fatty acid propionate inhibits adipogenic differentiation of human chorion-derived mesenchymal stem cells through the free fatty acid receptor 2. Stem Cells Dev. 26, 1724–1733 (2017).

  146. 146.

    Zaibi, M. S. et al. Roles of GPR41 and GPR43 in leptin secretory responses of murine adipocytes to short chain fatty acids. FEBS Lett. 584, 2381–2386 (2010).

  147. 147.

    Lin, H. V. et al. Butyrate and propionate protect against diet-induced obesity and regulate gut hormones via free fatty acid receptor 3-independent mechanisms. PLOS ONE 7, e35240 (2012).

  148. 148.

    Samuel, B. S. et al. Effects of the gut microbiota on host adiposity are modulated by the short-chain fatty-acid binding G protein-coupled receptor, Gpr41. Proc. Natl Acad. Sci. USA 105, 16767–16772 (2008).

  149. 149.

    Frost, G. et al. Effect of short chain fatty acids on the expression of free fatty acid receptor 2 (Ffar2), Ffar3 and early-stage adipogenesis. Nutr. Diabetes 4, e128 (2014).

  150. 150.

    Banks, W. A. Leptin transport across the blood-brain barrier: implications for the cause and treatment of obesity. Curr. Pharm. Des. 7, 125–133 (2001).

  151. 151.

    Kastin, A. J. & Pan, W. Dynamic regulation of leptin entry into brain by the blood–brain barrier. Regul. Pept. 92, 37–43 (2000).

  152. 152.

    Banks, W. A., Niehoff, M. L., Martin, D. & Farrell, C. L. Leptin transport across the blood-brain barrier of the Koletsky rat is not mediated by a product of the leptin receptor gene. Brain Res. 950, 130–136 (2002).

  153. 153.

    Sachot, C., Rummel, C., Bristow, A. F. & Luheshi, G. N. The role of the vagus nerve in mediating the long-term anorectic effects of leptin. J. Neuroendocrinol. 19, 250–261 (2007).

  154. 154.

    de Lartigue, G., Ronveaux, C. C. & Raybould, H. E. Deletion of leptin signaling in vagal afferent neurons results in hyperphagia and obesity. Mol. Metab. 3, 595–607 (2014).

  155. 155.

    Morrison, C. D. Leptin signaling in brain: a link between nutrition and cognition? Biochim. Biophys. Acta 1792, 401–408 (2009).

  156. 156.

    Farr, O. M., Tsoukas, M. A. & Mantzoros, C. S. Leptin and the brain: influences on brain development, cognitive functioning and psychiatric disorders. Metabolism 64, 114–130 (2015).

  157. 157.

    Olszewski, P. K., Schiöth, H. B. & Levine, A. S. Ghrelin in the CNS: From hunger to a rewarding and memorable meal? Brain. Res. Rev. 58, 160–170 (2008).

  158. 158.

    Date, Y. Ghrelin and the vagus nerve. Methods Enzymol. 514, 261–269 (2012).

  159. 159.

    Cabral, A., De Francesco, P. N. & Perello, M. Brain circuits mediating the orexigenic action of peripheral ghrelin: narrow gates for a vast kingdom. Front. Endocrinol. 6, 44 (2015).

  160. 160.

    Wren, A. et al. Ghrelin enhances appetite and increases food intake in humans. J. Clin. Endocrinol. Metab. 86, 5992 (2001).

  161. 161.

    Fukumori, R. et al. Plasma ghrelin concentration is decreased by short chain fatty acids in wethers. Domest. Anim. Endocrinol. 41, 50–55 (2011).

  162. 162.

    Tarini, J. & Wolever, T. M. The fermentable fibre inulin increases postprandial serum short-chain fatty acids and reduces free-fatty acids and ghrelin in healthy subjects. Appl. Physiol. Nutr. Metab. 35, 9–16 (2010).

  163. 163.

    Rahat-Rozenbloom, S., Fernandes, J., Cheng, J. & Wolever, T. M. S. Acute increases in serum colonic short-chain fatty acids elicited by inulin do not increase GLP-1 or PYY responses but may reduce ghrelin in lean and overweight humans. Eur. J. Clin. Nutr. 71, 953 (2016).

  164. 164.

    Malik, S., McGlone, F., Bedrossian, D. & Dagher, A. Ghrelin modulates brain activity in areas that control appetitive behavior. Cell Metab. 7, 400–409 (2008).

  165. 165.

    Diano, S. et al. Ghrelin controls hippocampal spine synapse density and memory performance. Nat. Neurosci. 9, 381–388 (2006).

  166. 166.

    Li, E. et al. Ghrelin directly stimulates adult hippocampal neurogenesis: implications for learning and memory. Endocr. J. 60, 781–789 (2013).

  167. 167.

    Bali, A. & Jaggi, A. S. An integrative review on role and mechanisms of ghrelin in stress, anxiety and depression. Curr. Drug Targets 17, 495–507 (2016).

  168. 168.

    Wilcox, G. Insulin and insulin resistance. Clin. Biochem. Rev. 26, 19–39 (2005).

  169. 169.

    Horino, M., Machlin, L. J., Hertelendy, F. & Kipnis, D. M. Effect of short-chain fatty acids on plasma insulin in ruminant and nonruminant species. Endocrinology 83, 118–128 (1968).

  170. 170.

    Trenkle, A. Effects of short-chain fatty acids, feeding, fasting and type of diet on plasma insulin levels in sheep. J. Nutr. 100, 1323–1330 (1970).

  171. 171.

    Robertson, M. D., Bickerton, A. S., Dennis, A. L., Vidal, H. & Frayn, K. N. Insulin-sensitizing effects of dietary resistant starch and effects on skeletal muscle and adipose tissue metabolism. Am. J. Clin. Nutr. 82, 559–567 (2005).

  172. 172.

    Gray, S. M., Meijer, R. I. & Barrett, E. J. Insulin regulates brain function, but how does it get there? Diabetes 63, 3992–3997 (2014).

  173. 173.

    Daniel, L., Pnina, V. & Konstantin, B. Anti-diabetic and neuroprotective effects of pancreatic islet transplantation into the central nervous system. Diabetes. Metab. Res. Rev. 32, 11–20 (2016).

  174. 174.

    Craft, S. et al. Intranasal insulin therapy for alzheimer disease and amnestic mild cognitive impairment: a pilot clinical trial. Arch. Neurol. 69, 29–38 (2012).

  175. 175.

    Reger, M. A. et al. Intranasal insulin improves cognition and modulates β-amyloid in early AD. Neurology 70, 440–448 (2008).

  176. 176.

    Stanley, M., Macauley, S. L. & Holtzman, D. M. Changes in insulin and insulin signaling in Alzheimer’s disease: cause or consequence? J. Exp. Med. 213, 1375–1385 (2016).

  177. 177.

    Swaminathan, S. K. et al. Insulin differentially affects the distribution kinetics of amyloid beta 40 and 42 in plasma and brain. J. Cerebr. Blood Flow Metab. 38, 904–918 (2017).

  178. 178.

    McIntyre, R. S. et al. A randomized, double-blind, controlled trial evaluating the effect of intranasal insulin on neurocognitive function in euthymic patients with bipolar disorder. Bipolar Disord. 14, 697–706 (2012).

  179. 179.

    LeBlanc, J. G. et al. Beneficial effects on host energy metabolism of short-chain fatty acids and vitamins produced by commensal and probiotic bacteria. Microb. Cell Fact. 16, 79 (2017).

  180. 180.

    Ryan, J. P., Sheu, L. K., Critchley, H. D. & Gianaros, P. J. A. Neural circuitry linking insulin resistance to depressed mood. Psychosom. Med. 74, 476–482 (2012).

  181. 181.

    Benedict, C. et al. Intranasal insulin improves memory in humans. Psychoneuroendocrinology 29, 1326–1334 (2004).

  182. 182.

    Bohringer, A., Schwabe, L., Richter, S. & Schachinger, H. Intranasal insulin attenuates the hypothalamic–pituitary–adrenal axis response to psychosocial stress. Psychoneuroendocrinology 33, 1394–1400 (2008).

  183. 183.

    Perry, R. J. et al. Acetate mediates a microbiome–brain–β-cell axis to promote metabolic syndrome. Nature 534, 213 (2016).

  184. 184.

    Bonaz, B., Bazin, T. & Pellissier, S. The vagus nerve at the interface of the microbiota-gut-brain axis. Front. Neurosci. 12, 49 (2018).

  185. 185.

    Li, Y., Hao, Y., Zhu, J. & Owyang, C. Serotonin released from intestinal enterochromaffin cells mediates luminal non-cholecystokinin-stimulated pancreatic secretion in rats. Gastroenterology 118, 1197–1207 (2000).

  186. 186.

    Strader, A. D. & Woods, S. C. Gastrointestinal hormones and food intake. Gastroenterology 128, 175–191 (2005).

  187. 187.

    Ressler, K. J. & Mayberg, H. S. Targeting abnormal neural circuits in mood and anxiety disorders: from the laboratory to the clinic. Nat. Neurosci. 10, 1116–1124 (2007).

  188. 188.

    Hosoi, T., Okuma, Y., Matsuda, T. & Nomura, Y. Novel pathway for LPS-induced afferent vagus nerve activation: possible role of nodose ganglion. Auton. Neurosci. 120, 104–107 (2005).

  189. 189.

    Bravo, J. A. et al. Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve. Proc. Natl Acad. Sci. USA 108, 16050–16055 (2011).

  190. 190.

    Bercik, P. et al. The anxiolytic effect of Bifidobacterium longum NCC3001 involves vagal pathways for gut-brain communication. Neurogastroenterol. Motil. 23, 1132–1139 (2011).

  191. 191.

    Lal, S., Kirkup, A. J., Brunsden, A. M., Thompson, D. G. & Grundy, D. Vagal afferent responses to fatty acids of different chain length in the rat. Am. J. Physiol. Gastrointest. Liver. Physiol. 281, G907–G915 (2001).

  192. 192.

    Goswami, C., Iwasaki, Y. & Yada, T. Short-chain fatty acids suppress food intake by activating vagal afferent neurons. J. Nutr. Biochem. 57, 130–135 (2018).

  193. 193.

    Braniste, V. et al. The gut microbiota influences blood-brain barrier permeability in mice. Sci. Transl Med. 6, 263ra158 (2014).

  194. 194.

    Hoyles, L. et al. Microbiome–host systems interactions: protective effects of propionate upon the blood–brain barrier. Microbiome 6, 55 (2018).

  195. 195.

    Nankova, B. B., Agarwal, R., MacFabe, D. F. & La Gamma, E. F. Enteric bacterial metabolites propionic and butyric acid modulate gene expression, including CREB-dependent catecholaminergic neurotransmission, in PC12 cells—possible relevance to autism spectrum disorders. PLOS ONE 9, e103740 (2014).

  196. 196.

    Nagatsu, T. Tyrosine hydroxylase: human isoforms, structure and regulation in physiology and pathology. Essays Biochem. 30, 15–35 (1995).

  197. 197.

    Morís, G. & Vega, J. A. Neurotrophic factors: basis for their clinical application. Neurologia 18, 18–28 (2003).

  198. 198.

    Savignac, H. M. et al. Prebiotic feeding elevates central brain derived neurotrophic factor, N-methyl-D-aspartate receptor subunits and D-serine. Neurochem. Int. 63, 756–764 (2013).

  199. 199.

    Varela, R. B. et al. Sodium butyrate and mood stabilizers block ouabain-induced hyperlocomotion and increase BDNF, NGF and GDNF levels in brain of Wistar rats. J. Psychiatr. Res. 61, 114–121 (2015).

  200. 200.

    Sun, J. et al. Antidepressant-like effects of sodium butyrate and its possible mechanisms of action in mice exposed to chronic unpredictable mild stress. Neurosci. Lett. 618, 159–166 (2016).

  201. 201.

    Intlekofer, K. A. et al. Exercise and sodium butyrate transform a subthreshold learning event into long-term memory via a brain-derived neurotrophic factor-dependent mechanism. Neuropsychopharmacology 38, 2027–2034 (2013).

  202. 202.

    Barichello, T. et al. Sodium butyrate prevents memory impairment by re-establishing BDNF and GDNF expression in experimental pneumococcal meningitis. Mol. Neurobiol. 52, 734–740 (2015).

  203. 203.

    Kim, H. J., Leeds, P. & Chuang, D. M. The HDAC inhibitor, sodium butyrate, stimulates neurogenesis in the ischemic brain. J. Neurochem. 110, 1226–1240 (2009).

  204. 204.

    Wu, X. et al. Histone deacetylase inhibitors up-regulate astrocyte GDNF and BDNF gene transcription and protect dopaminergic neurons. Int. J. Neuropsychopharmacol. 11, 1123–1134 (2008).

  205. 205.

    Gershon, M. D. & Tack, J. The serotonin signaling system: from basic understanding to drug development for functional GI disorders. Gastroenterology 132, 397–414 (2007).

  206. 206.

    Lucki, I. The spectrum of behaviors influenced by serotonin. Biol. Psychiatry. 44, 151–162 (1998).

  207. 207.

    Reigstad, C. S. et al. Gut microbes promote colonic serotonin production through an effect of short-chain fatty acids on enterochromaffin cells. FASEB J. 29, 1395–1403 (2015).

  208. 208.

    Yano, J. M. et al. Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis. Cell 161, 264–276 (2015).

  209. 209.

    Stasi, C., Bellini, M., Bassotti, G., Blandizzi, C. & Milani, S. Serotonin receptors and their role in the pathophysiology and therapy of irritable bowel syndrome. Tech. Coloproctol. 18, 613–621 (2014).

  210. 210.

    Bonnin, A. & Levitt, P. Fetal, maternal and placental sources of serotonin and new implications for developmental programming of the brain. Neuroscience 197, 1–7 (2011).

  211. 211.

    Côté, F. et al. Maternal serotonin is crucial for murine embryonic development. Proc. Natl Acad. Sci. USA 104, 329 (2007).

  212. 212.

    Browning, K. N. Role of central vagal 5-HT(3) receptors in gastrointestinal physiology and pathophysiology. Front. Neurosci. 9, 413 (2015).

  213. 213.

    Sanders, M. E. Probiotics: definition, sources, selection, and uses. Clin. Infect. Dis. 46, S58–S61 (2008).

  214. 214.

    Gibson, G. R. et al. Expert consensus document: the International Scientific Association for Probiotics and Prebiotics (ISAPP) consensus statement on the definition and scope of prebiotics. Nat. Rev. Gastroenterol. Hepatol. 14, 491–502 (2017).

  215. 215.

    Garcia-Mantrana, I., Selma-Royo, M., Alcantara, C. & Collado, M. C. Shifts on gut microbiota associated to mediterranean diet adherence and specific dietary intakes on general adult population. Front. Microbiol. 9, 890–890 (2018).

  216. 216.

    Macfarlane, G. T. & Macfarlane, S. Fermentation in the human large intestine: its physiologic consequences and the potential contribution of prebiotics. J. Clin. Gastroenterol. 45, S120–S127 (2011).

  217. 217.

    Koh, A., De Vadder, F., Kovatcheva-Datchary, P. & Backhed, F. From dietary fiber to host physiology: short-chain fatty acids as key bacterial metabolites. Cell 165, 1332–1345 (2016).

  218. 218.

    Roberfroid, M. et al. Prebiotic effects: metabolic and health benefits. Br. J. Nutr. 104, S1–S63 (2010).

  219. 219.

    Verbeke, K. A. et al. Towards microbial fermentation metabolites as markers for health benefits of prebiotics. Nutr. Res. Rev. 28, 42–66 (2015).

  220. 220.

    Derrien, M. & van Hylckama Vlieg, J. E. Fate, activity, and impact of ingested bacteria within the human gut microbiota. Trends Microbiol. 23, 354–366 (2015).

  221. 221.

    Sakata, T., Kojima, T., Fujieda, M., Takahashi, M. & Michibata, T. Influences of probiotic bacteria on organic acid production by pig caecal bacteria in vitro. Proc. Nutr. Soc. 62, 73–80 (2003).

  222. 222.

    David, L. A. et al. Diet rapidly and reproducibly alters the human gut microbiome. Nature 505, 559–563 (2014).

  223. 223.

    De Filippis, F. et al. High-level adherence to a Mediterranean diet beneficially impacts the gut microbiota and associated metabolome. Gut 65, 1812–1821 (2016).

  224. 224.

    Gutierrez-Diaz, I., Fernandez-Navarro, T., Sanchez, B., Margolles, A. & Gonzalez, S. Mediterranean diet and faecal microbiota: a transversal study. Food Funct. 7, 2347–2356 (2016).

  225. 225.

    Sandhu, K. V. et al. Feeding the microbiota-gut-brain axis: diet, microbiome, and neuropsychiatry. Transl Res. 179, 223–244 (2017).

  226. 226.

    Liu, J. et al. Neuroprotective effects of Clostridium butyricum against vascular dementia in mice via metabolic butyrate. Biomed. Res. Int. 2015, 412946 (2015).

  227. 227.

    Burokas, A. et al. Targeting the microbiota-gut-brain axis: prebiotics have anxiolytic and antidepressant-like effects and reverse the impact of chronic stress in mice. Biol. Psychiatry 82, 472–487 (2017).

  228. 228.

    Kao, A. C., Spitzer, S., Anthony, D. C., Lennox, B. & Burnet, P. W. J. Prebiotic attenuation of olanzapine-induced weight gain in rats: analysis of central and peripheral biomarkers and gut microbiota. Transl Psychiatry 8, 66 (2018).

  229. 229.

    Gronier, B. et al. Increased cortical neuronal responses to NMDA and improved attentional set-shifting performance in rats following prebiotic (B-GOS((R))) ingestion. Eur. Neuropsychopharmacol. 28, 211–224 (2018).

  230. 230.

    Hopfner, F. et al. Gut microbiota in Parkinson disease in a northern German cohort. Brain Res. 1667, 41–45 (2017).

  231. 231.

    Li, W. et al. Structural changes of gut microbiota in Parkinson’s disease and its correlation with clinical features. Sci. China Life. Sci. 60, 1223–1233 (2017).

  232. 232.

    Bedarf, J. R. et al. Functional implications of microbial and viral gut metagenome changes in early stage L-DOPA-naïve Parkinson’s disease patients. Genome Med. 9, 39 (2017).

  233. 233.

    Keshavarzian, A. et al. Colonic bacterial composition in Parkinson’s disease. Mov. Disord. 30, 1351–1360 (2015).

  234. 234.

    Unger, M. M. et al. Short chain fatty acids and gut microbiota differ between patients with Parkinson’s disease and age-matched controls. Parkinsonism Relat. Disord. 32, 66–72 (2016).

  235. 235.

    Paiva, I. et al. Sodium butyrate rescues dopaminergic cells from alpha-synuclein-induced transcriptional deregulation and DNA damage. Hum. Mol. Genet. 26, 2231–2246 (2017).

  236. 236.

    Laurent, R. S., O’Brien, L. M. & Ahmad, S. T. Sodium butyrate improves locomotor impairment and early mortality in a rotenone-induced Drosophila model of Parkinson’s disease. Neuroscience 246, 382–390 (2013).

  237. 237.

    Sharma, S., Taliyan, R. & Singh, S. Beneficial effects of sodium butyrate in 6-OHDA induced neurotoxicity and behavioral abnormalities: modulation of histone deacetylase activity. Behav. Brain. Res. 291, 306–314 (2015).

  238. 238.

    Sampson, T. R. et al. Gut microbiota regulate motor deficits and neuroinflammation in a model of Parkinson’s disease. Cell 167, 1469–1480 (2016).

  239. 239.

    Govindarajan, N., Agis-Balboa, R. C., Walter, J., Sananbenesi, F. & Fischer, A. Sodium butyrate improves memory function in an Alzheimer’s disease mouse model when administered at an advanced stage of disease progression. J. Alzheimers Dis. 26, 187–197 (2011).

  240. 240.

    Ho, L. et al. Protective roles of intestinal microbiota derived short chain fatty acids in Alzheimer’s disease-type beta-amyloid neuropathological mechanisms. Expert Rev. Neurother. 18, 83–90 (2018).

  241. 241.

    Adams, J. B., Johansen, L. J., Powell, L. D., Quig, D. & Rubin, R. A. Gastrointestinal flora and gastrointestinal status in children with autism – comparisons to typical children and correlation with autism severity. BMC Gastroenterol. 11, 22 (2011).

  242. 242.

    Wang, L. et al. Elevated fecal short chain fatty acid and ammonia concentrations in children with autism spectrum disorder. Digest. Dis. Sci. 57, 2096–2102 (2012).

  243. 243.

    de Theije, C. G. et al. Altered gut microbiota and activity in a murine model of autism spectrum disorders. Brain. Behav. Immun. 37, 197–206 (2014).

  244. 244.

    MacFabe, D. F. Enteric short-chain fatty acids: microbial messengers of metabolism, mitochondria, and mind: implications in autism spectrum disorders. Microb. Ecol. Health. Dis. 26, 28177 (2015).

  245. 245.

    Szczesniak, O., Hestad, K. A., Hanssen, J. F. & Rudi, K. Isovaleric acid in stool correlates with human depression. Nutr. Neurosci. 19, 279–283 (2016).

  246. 246.

    Skonieczna-Zydecka, K. et al. Faecal short chain fatty acids profile is changed in Polish depressive women. Nutrients 10, E1939 (2018).

  247. 247.

    Kelly, J. R. et al. Transferring the blues: depression-associated gut microbiota induces neurobehavioural changes in the rat. J. Psychiatr. Res. 82, 109–118 (2016).

  248. 248.

    Michels, N., Van de Wiele, T. & De Henauw, S. Chronic psychosocial stress and gut health in children: associations with calprotectin and fecal short-chain fatty acids. Psychosom. Med. 79, 927–935 (2017).

  249. 249.

    Moretti, M. et al. Behavioral and neurochemical effects of sodium butyrate in an animal model of mania. Behav. Pharmacol. 22, 766–772 (2011).

  250. 250.

    Resende, W. R. et al. Effects of sodium butyrate in animal models of mania and depression: implications as a new mood stabilizer. Behav. Pharmacol. 24, 569–579 (2013).

  251. 251.

    Kiraly, D. D. et al. Alterations of the host microbiome affect behavioral responses to cocaine. Sci. Rep. 6, 35455 (2016).

  252. 252.

    Joseph, J., Depp, C., Shih, P.-a.B., Cadenhead, K. S. & Schmid-Schönbein, G. Modified mediterranean diet for enrichment of short chain fatty acids: potential adjunctive therapeutic to target immune and metabolic dysfunction in schizophrenia? Front. Neurosci. 11, 155 (2017).

  253. 253.

    Arnoldussen, I. A. C. et al. Butyrate restores HFD-induced adaptations in brain function and metabolism in mid-adult obese mice. Int. J. Obes. 41, 935 (2017).

  254. 254.

    Powers, L. et al. Assay of the concentration and stable isotope enrichment of short-chain fatty acids by gas chromatography/mass spectrometry. J. Mass Spectrom. 30, 747–754 (1995).

  255. 255.

    Nguyen, T. L. A., Vieira-Silva, S., Liston, A. & Raes, J. How informative is the mouse for human gut microbiota research? Dis. Model. Mech. 8, 1–16 (2015).

  256. 256.

    Lamendella, R., Domingo, J. W., Ghosh, S., Martinson, J. & Oerther, D. B. Comparative fecal metagenomics unveils unique functional capacity of the swine gut. BMC Microbiol. 11, 103 (2011).

  257. 257.

    Moeller, A. H. et al. Chimpanzees and humans harbor compositionally similar gut enterotypes. Nat. Commun. 3, 1179–1179 (2012).

  258. 258.

    Nestler, E. J. & Hyman, S. E. Animal models of neuropsychiatric disorders. Nat. Neurosci. 13, 1161–1169 (2010).

  259. 259.

    Blackwood, D. H. R. et al. Schizophrenia and affective disorders—cosegregation with a translocation at chromosome 1q42 that directly disrupts brain-expressed genes: clinical and P300 findings in a family. Am. J. Hum. Genet. 69, 428–433 (2001).

  260. 260.

    Anderzhanova, E., Kirmeier, T. & Wotjak, C. T. Animal models in psychiatric research: the RDoC system as a new framework for endophenotype-oriented translational neuroscience. Neurobiol. Stress 7, 47–56 (2017).

  261. 261.

    Salgado, J. V. & Sandner, G. A critical overview of animal models of psychiatric disorders: challenges and perspectives. Braz. J. Psychiatry 35, S77–S81 (2013).

  262. 262.

    Kelly, J. R. et al. Lost in translation? The potential psychobiotic Lactobacillus rhamnosus (JB-1) fails to modulate stress or cognitive performance in healthy male subjects. Brain. Behav. Immun. 61, 50–59 (2017).

  263. 263.

    Annison, G., Illman, R. J. & Topping, D. L. Acetylated, propionylated or butyrylated starches raise large bowel short-chain fatty acids preferentially when fed to rats. J. Nutr. 133, 3523–3528 (2003).

  264. 264.

    Basson, A., Trotter, A., Rodriguez-Palacios, A. & Cominelli, F. Mucosal interactions between genetics, diet, and microbiome in inflammatory bowel disease. Front. Immunol. 7, 290 (2016).

  265. 265.

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

  266. 266.

    Halestrap, A. P. & Meredith, D. The SLC16 gene family-from monocarboxylate transporters (MCTs) to aromatic amino acid transporters and beyond. Pflugers Arch. 447, 619–628 (2004).

  267. 267.

    Sepponen, K., Ruusunen, M., Pakkanen, J. A. & Poso, A. R. Expression of CD147 and monocarboxylate transporters MCT1, MCT2 and MCT4 in porcine small intestine and colon. Vet. J. 174, 122–128 (2007).

  268. 268.

    Ganapathy, V. et al. Sodium-coupled monocarboxylate transporters in normal tissues and in cancer. AAPS J. 10, 193–199 (2008).

  269. 269.

    Coady, M. J. et al. The human tumour suppressor gene SLC5A8 expresses a Na+-monocarboxylate cotransporter. J. Physiol. 557, 719–731 (2004).

  270. 270.

    Martin, P. M. et al. Identity of SMCT1 (SLC5A8) as a neuron-specific Na+-coupled transporter for active uptake of L-lactate and ketone bodies in the brain. J. Neurochem. 98, 279–288 (2006).

  271. 271.

    Srinivas, S. R. et al. Cloning and functional identification of slc5a12 as a sodium-coupled low-affinity transporter for monocarboxylates (SMCT2). Biochem. J. 392, 655–664 (2005).

  272. 272.

    Gopal, E. et al. Cloning and functional characterization of human SMCT2 (SLC5A12) and expression pattern of the transporter in kidney. Biochim. Biophys. Acta 1768, 2690–2697 (2007).

  273. 273.

    Shin, H. J. et al. Novel liver-specific organic anion transporter OAT7 that operates the exchange of sulfate conjugates for short chain fatty acid butyrate. Hepatology 45, 1046–1055 (2007).

  274. 274.

    Anzai, N., Kanai, Y. & Endou, H. Organic anion transporter family: current knowledge. J. Pharmacol. Sci. 100, 411–426 (2006).

  275. 275.

    Islam, R. et al. Mouse organic anion transporter 2 (mOat2) mediates the transport of short chain fatty acid propionate. J. Pharmacol. Sci. 106, 525–528 (2008).

  276. 276.

    Nøhr, M. K. et al. GPR41/FFAR3 and GPR43/FFAR2 as cosensors for short-chain fatty acids in enteroendocrine cells versus FFAR3 in enteric neurons and FFAR2 in enteric leukocytes. Endocrinology 154, 3552–3564 (2013).

  277. 277.

    Smith, P. M. et al. The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science 341, 569 (2013).

  278. 278.

    Nakajima, A. et al. The short chain fatty acid receptor GPR43 regulates inflammatory signals in adipose tissue M2-type macrophages. PLOS ONE 12, e0179696 (2017).

  279. 279.

    Macia, L. et al. Metabolite-sensing receptors GPR43 and GPR109A facilitate dietary fibre-induced gut homeostasis through regulation of the inflammasome. Nat. Commun. 6, 6734 (2015).

  280. 280.

    Priori, D. et al. The olfactory receptor OR51E1 is present along the gastrointestinal tract of pigs, co-localizes with enteroendocrine cells and is modulated by intestinal microbiota. PLOS ONE 10, e0129501 (2015).

  281. 281.

    Pluznick, J. L. et al. Olfactory receptor responding to gut microbiota-derived signals plays a role in renin secretion and blood pressure regulation. Proc. Natl Acad. Sci. USA 110, 4410–4415 (2013).

  282. 282.

    Gelis, L. et al. Functional characterization of the odorant receptor 51E2 in human melanocytes. J. Biol. Chem. 291, 17772–17786 (2016).

  283. 283.

    Puhl Iii, H. L., Won, Y.-J., Lu, V. B. & Ikeda, S. R. Human GPR42 is a transcribed multisite variant that exhibits copy number polymorphism and is functional when heterologously expressed. Sci. Rep. 5, 12880 (2015).

  284. 284.

    Liaw, C. W. & Connolly, D. T. Sequence polymorphisms provide a common consensus sequence for GPR41 and GPR42. DNA Cell Biol. 28, 555–560 (2009).

  285. 285.

    Li, L., Ma, L. & Fu, P. Gut microbiota-derived short-chain fatty acids and kidney diseases. Drug. Des. Devel. Ther. 11, 3531–3542 (2017).

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Acknowledgements

The financial support for B.D. from an unrestricted grant from Nestlé is highly appreciated.

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B.D. performed the literature review and wrote the manuscript. L.V.O., B.V. and K.V. revised the intellectual content of the manuscript critically.

Correspondence to Kristin Verbeke.

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Dalile, B., Van Oudenhove, L., Vervliet, B. et al. The role of short-chain fatty acids in microbiota–gut–brain communication. Nat Rev Gastroenterol Hepatol 16, 461–478 (2019). https://doi.org/10.1038/s41575-019-0157-3

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