J Med Food 17(12): 1261-1272

The Gut Microbiome and the Brain

Foundation for Integrated Medicine, New York, New York, USA.

Address correspondence to: Leo Galland, MD,Foundation for Integrated Medicine,, New York, NY, 10011, USA, E-mail:moc.loa@dmdnallagL.

Received 2014 Sep 9; Accepted 2014 Oct 9.

Abstract

The human gut microbiome impacts human brain health in numerous ways: (1) Structural bacterial components such as lipopolysaccharides provide low-grade tonic stimulation of the innate immune system. Excessive stimulation due to bacterial dysbiosis, small intestinal bacterial overgrowth, or increased intestinal permeability may produce systemic and/or central nervous system inflammation. (2) Bacterial proteins may cross-react with human antigens to stimulate dysfunctional responses of the adaptive immune system. (3) Bacterial enzymes may produce neurotoxic metabolites such as D-lactic acid and ammonia. Even beneficial metabolites such as short-chain fatty acids may exert neurotoxicity. (4) Gut microbes can produce hormones and neurotransmitters that are identical to those produced by humans. Bacterial receptors for these hormones influence microbial growth and virulence. (5) Gut bacteria directly stimulate afferent neurons of the enteric nervous system to send signals to the brain via the vagus nerve. Through these varied mechanisms, gut microbes shape the architecture of sleep and stress reactivity of the hypothalamic-pituitary-adrenal axis. They influence memory, mood, and cognition and are clinically and therapeutically relevant to a range of disorders, including alcoholism, chronic fatigue syndrome, fibromyalgia, and restless legs syndrome. Their role in multiple sclerosis and the neurologic manifestations of celiac disease is being studied. Nutritional tools for altering the gut microbiome therapeutically include changes in diet, probiotics, and prebiotics.

Key Words: : D-lactic acid, endotoxin, microbial endocrinology, microbiome, prebiotics, probiotics, short-chain fatty acids, trimethylamine oxide (TMAO)

Abstract

References

1. Venter JC, Adams MD, Myers EW, et al: The sequence of the human genome. Science 2001;291:1304–1351 [[PubMed][Google Scholar]
2. Jacquemin J, Ammiraju JS, Haberer G, et al: Fifteen million years of evolution in the Oryza genus shows extensive gene family expansion. Mol Plant 2014;7:642–656 [[PubMed][Google Scholar]
3. Surjyadipta B, Lukiw WJ, Alzheimer's disease and the microbiome. Front Cell Neurosci 2013;7:153–160
4. Qin J, Li R, Raes J, Arumugam M, et al: A human gut microbial gene catalogue established by metagenomic sequencing. Nature 2010;464:59–65 [Google Scholar]
5. Hooper LV: Bacterial contributions to mammalian gut development. Trends Microbiol 2004;12:129–134 [[PubMed]
6. Li M, Wang B, Zhang M, et al: Symbiotic gut microbes modulate human metabolic phenotypes. PNAS 2008;105:2117–2122 [Google Scholar]
7. Jacobsen UP, Nielsen HB, Hildebrand F, et al: The chemical interactome space between the human host and the genetically defined gut metabotypes. ISME J 2013;7:730–742 [Google Scholar]
8. Wikoff WR, Anfora AT, Liu J, et al: Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites. Proc Natl Acad Sci USA 2009;106:3698–3703 [Google Scholar]
9. Neufeld KM, Kang N, Bienenstock J, Foster JA: Reduced anxiety-like behavior and central neurochemical change in germ-free mice. Neurogastroenterol Motil 2011;23:255–264, e119. [[PubMed]
10. Diamond B, Huerta PT, Tracey K, Volpe BT: It takes guts to grow a brain: increasing evidence of the important role of the intestinal microflora in neuro- and immune-modulatory functions during development and adulthood. Bioessays 2011;33:588–591
11. Diaz Heijtz R, Wang S, Anuar F, et al: Normal gut microbiota modulates brain development and behavior. Proc Natl Acad Sci USA 2011;108:3047–3052 [Google Scholar]
12. Bercik P, Park AJ, Sinclair D, et al: The anxiolytic effect of Bifidobacterium longum NCC3001 involves vagal pathways for gut-brain communication. Neurogastroenterol Motil 2011;23:1132–1139 [Google Scholar]
13. Sudo N, Chida Y, Aiba Y, et al: Postnatal microbial colonization programs the hypothalamic-pituitary-adrenal system for stress response in mice. J Physiol 2004;558(Pt 1):263–275 [Google Scholar]
14. Crumeyrolle-Arias M, Jaglin M, Bruneau A, et al: Absence of the gut microbiota enhances anxiety-like behavior and neuroendocrine response to acute stress in rats. Psychoneuroendocrinology 2014;42:207–217 [[PubMed][Google Scholar]
15. Bested AC, Logan AC, Selhub EM: Intestinal microbiota, probiotics and mental health: from Metchnikoff to modern advances: Part II—contemporary contextual research. Gut Pathog 2013;5:3.
16. Conti LH, Costello DG, Martin LA, et al: Mouse strain differences in the behavioral effects of corticotropin-releasing factor (CRF) and the CRF antagonist alpha-helical CRF9-41. Pharmacol Biochem Behav 1994;48:497–503 [[PubMed][Google Scholar]
17. Cryan JF, Dinan TG: Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour. Nat Rev Neurosci 2012;13:701–712 [[PubMed]
18. Duerkop BA, Vaishnava S, Hooper LV: Immune responses to the microbiota at the intestinal mucosal surface. Immunity 2009;31:368–376 [[PubMed]
19. Heumann D, Barras C, Severin A, Glauser MP, Tomasz A: Gram-positive cell walls stimulate synthesis of tumor necrosis factor alpha and interleukin-6 by human monocytes. Infect Immun 1994;62:2715–2721
20. Ulevitch RJ, Tobias PS: Receptor-dependent mechanisms of cell stimulation by bacterial endotoxin. Annu Rev Immunol 1995;13:437–457 [[PubMed]
21. Alam MN, McGinty D, Bashir T, et al: Interleukin-1beta modulates state-dependent discharge activity of preoptic area and basal forebrain neurons: role in sleep regulation. Eur J Neurosci 2004;20:207–216 [[PubMed][Google Scholar]
22. Schuld A, Haack M, Hinze-Selch D, et al: [Experimental studies on the interaction between sleep and the immune system in humans]. Psychother Psychosom Med Psychol 2005;55:29–35 [[PubMed][Google Scholar]
23. Kubota T, Fang J, Brown RA, Krueger JM: Interleukin-18 promotes sleep in rabbits and rats. Am J Physiol Regul Integr Comp Physiol 2001;281:R828–R838 [[PubMed]
24. Cermakian N, Lange T, Golombek D, et al: Crosstalk between the circadian clock circuitry and the immune system. Chronobiol Int 2013;30:870–888 [[PubMed][Google Scholar]
25. Marshall L, Born J: Brain-immune interactions in sleep. Int Rev Neurobiol 2002;52:93–131 [[PubMed]
26. Yang JY, Huang JW, Chiang CK, et al: Higher plasma interleukin-18 levels associated with poor quality of sleep in peritoneal dialysis patients. Nephrol Dial Transplant 2007;22:3606–3609 [[PubMed][Google Scholar]
27. Grigoleit JS, Kullmann JS, Wolf OT, et al: Dose-dependent effects of endotoxin on neurobehavioral functions in humans. PLoS One 2011;6:e28330. [Google Scholar]
28. Benson S, Kattoor J, Wegner A, et al: Acute experimental endotoxemia induces visceral hypersensitivity and altered pain evaluation in healthy humans. Pain 2012;153:794–799 [[PubMed][Google Scholar]
29. Schiffrin EJ, Parlesak A, Bode C, et al: Probiotic yogurt in the elderly with intestinal bacterial overgrowth: endotoxaemia and innate immune functions. Br J Nutr 2009;101:961–966 [[PubMed][Google Scholar]
30. Bauer TM, Schwacha H, Steinbrückner B, et al: Small intestinal bacterial overgrowth in human cirrhosis is associated with systemic endotoxemia. Am J Gastroenterol 2002;97:2364–2370 [[PubMed][Google Scholar]
31. Bondarenko VM, Lykova EA, Matsulevich TV: [Microecological aspects of small intestinal bacterial overgrowth syndrome]. Zh Mikrobiol Epidemiol Immunobiol 2006;(6):57–63 [[PubMed]
32. Grimaldi D, Guivarch E, Neveux N, et al: Markers of intestinal injury are associated with endotoxemia in successfully resuscitated patients. Resuscitation 2013;84:60–65 [[PubMed][Google Scholar]
33. Elamin E, Masclee A, Dekker J, Jonkers D: Ethanol disrupts intestinal epithelial tight junction integrity through intracellular calcium-mediated Rho/ROCK activation. Am J Physiol Gastrointest Liver Physiol 2014;306:G677–G685 [[PubMed]
34. Neves AL, Coelho J, Couto L, et al: Metabolic endotoxemia: a molecular link between obesity and cardiovascular risk. J Mol Endocrinol 2013;51:R51–R64 [[PubMed][Google Scholar]
35. Leclercq S, De Saeger C, Delzenne N, et al: Role of inflammatory pathways, blood mononuclear cells, and gut-derived bacterial products in alcohol dependence. Biol Psychiatry 2014;76:725–733 [[PubMed][Google Scholar]
36. Leclercq S, Matamoros S, Cani PD, et al: Intestinal permeability, gut-bacterial dysbiosis, and behavioral markers of alcohol-dependence severity. Proc Natl Acad Sci USA 2014;pii: [Google Scholar]
37. Maes M, Mihaylova I, Leunis JC: Increased serum IgA and IgM against LPS of enterobacteria in chronic fatigue syndrome (CFS): indication for the involvement of gram-negative enterobacteria in the etiology of CFS and for the presence of an increased gut-intestinal permeability. J Affect Disord 2007;99:237–240 [[PubMed]
38. Goebel A, Buhner S, Schedel R, et al: Altered intestinal permeability in patients with primary fibromyalgia and in patients with complex regional pain syndrome. Rheumatology (Oxford) 2008;47:1223–1227 [[PubMed][Google Scholar]
39. Lauritano EC, Valenza V, Sparano L, et al: Small intestinal bacterial overgrowth and intestinal permeability. Scand J Gastroenterol 2010;45:1131–1132 [[PubMed][Google Scholar]
40. Wallace DJ, Hallegua DS: Fibromyalgia: the gastrointestinal link. Curr Pain Headache Rep 2004;8:364–368 [[PubMed]
41. Weinstock LB, Fern SE, Duntley SP: Restless legs syndrome in patients with irritable bowel syndrome: response to small intestinal bacterial overgrowth therapy. Dig Dis Sci 2008;53:1252–1256 [[PubMed]
42. Severance EG, Gressitt KL, Stallings CR, et al: Discordant patterns of bacterial translocation markers and implications for innate immune imbalances in schizophrenia. Schizophr Res 2013;148:130–137 [Google Scholar]
43. Berer K, Krishnamoorthy G: Commensal gut flora and brain autoimmunity: a love or hate affair? Acta Neuropathol 2012;123:639–651 [[PubMed]
44. Hornig M: The role of microbes and autoimmunity in the pathogenesis of neuropsychiatric illness. Curr Opin Rheumatol 2013;25:488–795 [[PubMed]
45. Berer K, Mues M, Koutrolos M, et al: Commensal microbiota and myelin autoantigen cooperate to trigger autoimmune demyelination. Nature 2011;479:538–541 [[PubMed][Google Scholar]
46. Pozo-Rubio T, Olivares M, Nova E, et al: Immune development and intestinal microbiota in celiac disease. Clin Dev Immunol 2012;2012:654143. [Google Scholar]
47. Hadjivassiliou M, Sanders DS, Grünewald RA, et al: Gluten sensitivity: from gut to brain. Lancet Neurol 2010;9:318–330 [[PubMed][Google Scholar]
48. de Meij TG, Budding AE, Grasman ME, et al: Composition and diversity of the duodenal mucosa-associated microbiome in children with untreated coeliac disease. Scand J Gastroenterol 2013;48:530–536 [[PubMed][Google Scholar]
49. Sánchez E, Donat E, Ribes-Koninckx C, et al: Duodenal-mucosal bacteria associated with celiac disease in children. Appl Environ Microbiol 2013;79:5472–5479 [Google Scholar]
50. Cheng J, Kalliomäki M, Heilig HG, et al: Duodenal microbiota composition and mucosal homeostasis in pediatric celiac disease. BMC Gastroenterol 2013;13:113. [Google Scholar]
51. Francavilla R, Ercolini D, Piccolo M, et al: Salivary microbiota and metabolome associated with celiac disease. Appl Environ Microbiol 2014;80:3416–3425 [Google Scholar]
52. Collado MC, Donat E, Ribes-Koninckx C, et al: Specific duodenal and faecal bacterial groups associated with paediatric coeliac disease. J Clin Pathol 2009;62:264–269 [[PubMed][Google Scholar]
53. Collado MC, Donat E, Ribes-Koninckx C, et al: Imbalances in faecal and duodenal Bifidobacterium species composition in active and non-active coeliac disease. BMC Microbiol 2008;8:232. [Google Scholar]
54. Olivares M, Neef A, Castillejo G, et al: The HLA-DQ2 genotype selects for early intestinal microbiota composition in infants at high risk of developing coeliac disease. Gut 2014;pii: [[PubMed][Google Scholar]
55. Laparra JM, Sanz Y: Bifidobacteria inhibit the inflammatory response induced by gliadins in intestinal epithelial cells via modifications of toxic peptide generation during digestion. J Cell Biochem 2010;109:801–807 [[PubMed]
56. De Palma G, Cinova J, Stepankova R, et al: Pivotal advance: bifidobacteria and gram-negative bacteria differentially influence immune responses in the proinflammatory milieu of celiac disease. J Leukoc Biol 2010;87:765–778 [[PubMed][Google Scholar]
57. Mårild K, Ye W, Lebwohl B, Green PH, et al: Antibiotic exposure and the development of coeliac disease: a nationwide case-control study. BMC Gastroenterol 2013;13:109. [Google Scholar]
58. Laparra JM, Olivares M, Gallina O, Sanz Y: Bifidobacterium longum CECT 7347 modulates immune responses in a gliadin-induced enteropathy animal model. PLoS One 2012;7:e30744.
59. Medina M, De Palma G, Ribes-Koninckx C, et al: Bifidobacterium strains suppress in vitro the pro-inflammatory milieu triggered by the large intestinal microbiota of coeliac patients. J Inflamm (Lond) 2008;5:19. [Google Scholar]
60. Thurn JR, Pierpont GL, Ludvigsen CW, Eckfeldt JH: D-lactate encephalopathy. Am J Med 1985;79:717–721 [[PubMed]
61. Qureshi MO, Khokhar N, Shafqat F: Ammonia levels and the severity of hepatic encephalopathy. J Coll Physicians Surg Pak 2014;24:160–163 [[PubMed]
62. Qiao Z, Li Z, Li J, et al: Bacterial translocation and change in intestinal permeability in patients after abdominal surgery. J Huazhong Univ Sci Technolog Med Sci 2009;29:486–491 [[PubMed][Google Scholar]
63. Zhao Y, Qin G, Sun Z, et al: Effects of soybean agglutinin on intestinal barrier permeability and tight junction protein expression in weaned piglets. Int J Mol Sci 2011;12:8502–8512 [Google Scholar]
64. Ying C, Chunmin Y, Qingsen L, et al: Effects of simulated weightlessness on tight junction protein occludin and Zonula Occluden-1 expression levels in the intestinal mucosa of rats. J Huazhong Univ Sci Technolog Med Sci 2011;31:26–32 [[PubMed][Google Scholar]
65. Sheedy JR, Wettenhall RE, Scanlon D, et al: Increased d-lactic acid intestinal bacteria in patients with chronic fatigue syndrome. In Vivo 2009;23:621–628 [[PubMed][Google Scholar]
66. Maes M, Leunis JC: Normalization of leaky gut in chronic fatigue syndrome (CFS) is accompanied by a clinical improvement: effects of age, duration of illness and the translocation of LPS from gram-negative bacteria. Neuro Endocrinol Lett 2008;29:902–910 [[PubMed]
67. Pimentel M, Hallegue D, Chow EJ, et al: Eradication of small intestinal bacterial overgrowth decreases symptoms in chronic fatigue syndrome: a double blind randomized study. Gastroenterology 2000;118:A414 [PubMed][Google Scholar]
68. Munakata S, Arakawa C, Kohira R, et al: A case of D-lactic acid encephalopathy associated with use of probiotics. Brain Dev 2010;32:691–694 [[PubMed][Google Scholar]
69. Mack DR: D(-)-lactic acid-producing probiotics, D(-)-lactic acidosis and infants. Can J Gastroenterol 2004;18:671–675 [[PubMed]
70. Ewaschuk JB, Johnson IR, Madsen KL, et al: Barley-derived β-glucans increases gut permeability, ex vivo epithelial cell binding to E. coli, and naive T-cell proportions in weanling pigs. J Anim Sci 2012;90:2652–2662 [[PubMed][Google Scholar]
71. Takahashi K, Terashima H, Kohno K, Ohkohchi N: A stand-alone synbiotic treatment for the prevention of D-lactic acidosis in short bowel syndrome. Int Surg 2013;98:110–113
72. Respondek F, Goachet AG, Julliand V: Effects of dietary short-chain fructooligosaccharides on the intestinal microflora of horses subjected to a sudden change in diet. J Anim Sci 2008;86:316–323 [[PubMed]
73. Skowrońska M, Albrecht J: Alterations of blood brain barrier function in hyperammonemia: an overview. Neurotox Res 2012;21:236–244
74. Kawaguchi T, Taniguchi E, Sata M: Effects of oral branched-chain amino acids on hepatic encephalopathy and outcome in patients with liver cirrhosis. Nutr Clin Pract 2013;28:580–588 [[PubMed]
75. Irimia R, Stanciu C, Cojocariu C, et al: Oral glutamine challenge improves the performance of psychometric tests for the diagnosis of minimal hepatic encephalopathy in patients with liver cirrhosis. J Gastrointestin Liver Dis 2013;22:277–281 [[PubMed][Google Scholar]
76. Montgomery JY, Bajaj JS: Advances in the evaluation and management of minimal hepatic encephalopathy. Curr Gastroenterol Rep 2011;13:26–33 [[PubMed]
77. Quero Guillén JC, Groeneweg M, Jiménez Sáenz M, et al: Is it a medical error if we do not screen cirrhotic patients for minimal hepatic encephalopathy? Rev Esp Enferm Dig 2002;94:544–557 [[PubMed][Google Scholar]
78. Bajaj JS, Ridlon JM, Hylemon PB, et al: Linkage of gut microbiome with cognition in hepatic encephalopathy. Am J Physiol Gastrointest Liver Physiol 2012;302:G168–G175 [Google Scholar]
79. Bajaj JS, Hylemon PB, Ridlon JM, et al: Colonic mucosal microbiome differs from stool microbiome in cirrhosis and hepatic encephalopathy and is linked to cognition and inflammation. Am J Physiol Gastrointest Liver Physiol 2012;303:G675–G685 [Google Scholar]
80. Zhang Z, Zhai H, Geng J, et al: Large-scale survey of gut microbiota associated with MHE Via 16S rRNA-based pyrosequencing. Am J Gastroenterol 2013;108:1601–1611 [[PubMed][Google Scholar]
81. Sharma BC, Sharma P, Lunia MK, et al: A randomized, double-blind, controlled trial comparing rifaximin plus lactulose with lactulose alone in treatment of overt hepatic encephalopathy. Am J Gastroenterol 2013;108:1458–1463 [[PubMed][Google Scholar]
82. Malaguarnera M, Greco F, Barone G, et al: Bifidobacterium longum with fructo-oligosaccharide (FOS) treatment in minimal hepatic encephalopathy: a randomized, double-blind, placebo-controlled study. Dig Dis Sci 2007;52:3259–3265 [[PubMed][Google Scholar]
83. Liu Q, Duan ZP, Ha DK, et al: Synbiotic modulation of gut flora: effect on minimal hepatic encephalopathy in patients with cirrhosis. Hepatology 2004;39:1441–1449 [[PubMed][Google Scholar]
84. Macfarlane GT, Macfarlane S: Fermentation in the human large intestine: its physiologic consequences and the potential contribution of prebiotics. J Clin Gastroenterol 2011;45Suppl:S120–S127 [[PubMed]
85. Subarić D, Ačkar D, Babić J, Miličević B: Starch for health. Med Glas (Zenica) 2012;9:17–22 [[PubMed]
86. De Preter V, Geboes KP, Bulteel V, Vandermeulen G: Kinetics of butyrate metabolism in the normal colon and in ulcerative colitis: the effects of substrate concentration and carnitine on the β-oxidation pathway. Aliment Pharmacol Ther 2011;34:526–532 [[PubMed]
87. Segain JP, Raingeard de la Blétière D, Bourreille A, et al: Butyrate inhibits inflammatory responses through NFkappaB inhibition: implications for Crohn's disease. Gut 2000;47:397–403 [Google Scholar]
88. Al-Lahham SH, Peppelenbosch MP, Roelofsen H, et al: Biological effects of propionic acid in humans; metabolism, potential applications and underlying mechanisms. Biochim Biophys Acta 2010;1801:1175–1183 [[PubMed][Google Scholar]
89. Tan J, McKenzie C, Potamitis M, et al: The role of short-chain fatty acids in health and disease. Adv Immunol 2014;121:91–119 [[PubMed][Google Scholar]
90. Harrison IF, Dexter DT: Epigenetic targeting of histone deacetylase: therapeutic potential in Parkinson's disease? Pharmacol Ther 2013;140:34–52 [[PubMed]
91. Mahgoub M, Monteggia LM: Epigenetics and psychiatry. Neurotherapeutics 2013;10:734–741
92. Haberland M, Montgomery RL, Olson EN: The many roles of histone deacetylases in development and physiology: implications for disease and therapy. Nat Rev Genet 2009;8:32–42
93. Konsoula Z, Barile FA: Epigenetic histone acetylation and deacetylation mechanisms in experimental models of neurodegenerative disorders. J Pharmacol Toxicol Methods 2012;66:215–220 [[PubMed]
94. Gräff J, Tsai LH: The potential of HDAC inhibitors as cognitive enhancers. Annu Rev Pharmacol Toxicol 2013;53:311–330 [[PubMed]
95. Wauson EM, Lorente-Rodríguez A, Cobb MH: Minireview: nutrient sensing by G protein-coupled receptors. Mol Endocrinol 2013;27:1188–1197
96. Heng BC, Aubel D, Fussenegger M: An overview of the diverse roles of G-protein coupled receptors (GPCRs) in the pathophysiology of various human diseases. Biotechnol Adv 2013;31:1676–1694 [[PubMed]
97. Tazoe H, Otomo Y, Kaji I, et al: Roles of short-chain fatty acids receptors, GPR41 and GPR43 on colonic functions. J Physiol Pharmacol 2008;59Suppl 2:251–262 [[PubMed][Google Scholar]
98. Kimura I, Inoue D, Maeda T, 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 2011;108:8030–8035 [Google Scholar]
99. Puertollano E, Kolida S, Yaqoob P: Biological significance of short-chain fatty acid metabolism by the intestinal microbiome. Curr Opin Clin Nutr Metab Care 2014;17:139–144 [[PubMed]
100. MacFabe D. Autism: metabolism, mitochondria, and the microbiome. Global Adv Health Med 2013;2:52–66
101. Wang L, Christophersen CT, Sorich MJ, et al: Elevated fecal short chain fatty acid and ammonia concentrations in children with autism spectrum disorder. Dig Dis Sci 2012;57:2096–2102 [[PubMed][Google Scholar]
102. Wang L, et al: Gut bacterial and fermentation profiles are altered in children with autism. J Gastroenterol Hepatol 2010;25(Suppl. 3):A116–A119 [PubMed][Google Scholar]
103. Gondalia SV, Palombo EA, Knowles SR, et al: Molecular characterisation of gastrointestinal microbiota of children with autism (with and without gastrointestinal dysfunction) and their neurotypical siblings. Autism Res 2012;5:419–427 [[PubMed][Google Scholar]
104. Kang DW, Park JG, Ilhan ZE, et al: Reduced incidence of Prevotella and other fermenters in intestinal microflora of autistic children. PLoS One 2013;8:e68322. [Google Scholar]
105. Parracho HM, Bingham MO, Gibson GR, McCartney AL. Differences between the gut microflora of children with autistic spectrum disorders and that of healthy children. J Med Microbiol 2005;54:987–991 [[PubMed]
106. Song Y, Liu C, Finegold SM. Real-time PCR quantitation of clostridia in feces of autistic children. Appl Environ Microbiol 2004;70:6459–6465
107. Wang L, Christophersen CT, Sorich MJ, et al: Low relative abundances of the mucolytic bacterium Akkermansia muciniphila and Bifidobacterium spp. in feces of children with autism. Appl Environ Microbiol 2011;77:6718–6721 [Google Scholar]
108. Tanoue Y, Oda S: Weaning time of children with infantile autism. J Autism Dev Disord 1989;19:425–434 [[PubMed]
109. Macia L, Viltart O, Verwaerde C, et al: Genes involved in obesity: adipocytes, brain and microflora. Genes Nutr 2006;1:189–212 [Google Scholar]
110. Williams BL, Hornig M, Buie T, et al: Impaired carbohydrate digestion and transport and mucosal dysbiosis in the intestines of children with autism and gastrointestinal disturbances. PLoS One 2011;6:e24585. [Google Scholar]
111. Williams BL, Hornig M, Parekh T, Lipkin WI: 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 2012;3:pii:
112. Engberg J, On SL, Harrington CS, Gerner-Smidt P: Prevalence of Campylobacter, Arcobacter, Helicobacter, and Sutterella spp. in human fecal samples as estimated by a reevaluation of isolation methods for Campylobacters. J Clin Microbiol 2000;38:286–291
113. Wang L, Christophersen CT, Sorich MJ, et al: Increased abundance of Sutterella spp. and Ruminococcus torques in feces of children with autism spectrum disorder. Mol Autism 2013;4:42. [Google Scholar]
114. Mulle JG, Sharp WG, Cubells JF: The gut microbiome: a new frontier in autism research. Curr Psychiatry Rep 2013;15:337.
115. De Angelis M, Piccolo M, Vannini L, et al: Fecal microbiota and metabolome of children with autism and pervasive developmental disorder not otherwise specified. PLoS One 2013;8:e76993. [Google Scholar]
116. Stoner R, Chow ML, Boyle MP, et al: Patches of disorganization in the neocortex of children with autism. N Engl J Med 2014;370:1209–1219 [Google Scholar]
117. Hsiao EY, McBride SW, Hsien S, et al: Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders. Cell 2013;155:1451–1463 [Google Scholar]
118. Freestone PP, Sandrini SM, Haigh RD, Lyte M: Microbial endocrinology: how stress influences susceptibility to infection. Trends Microbiol 2008;16:55–64 [[PubMed]
119. Lyte M: Microbial endocrinology and infectious disease in the 21st century. Trends Microbiol 2004;12:14–20 [[PubMed]
120. Sperandio V, Torres AG, Jarvis B, et al: Bacteria-host communication: the language of hormones. Proc Natl Acad Sci USA 2003;100:8951–8956 [Google Scholar]
121. Bailey MT, Dowd SE, Galley JD, et al: Exposure to a social stressor alters the structure of the intestinal microbiota: implications for stressor-induced immunomodulation. Brain Behav Immun 2011;25:397–407 [Google Scholar]
122. Knowles SR, Nelson EA, Palombo EA: Investigating the role of perceived stress on bacterial flora activity and salivary cortisol secretion: a possible mechanism underlying susceptibility to illness. Biol Psychol 2008;77:132–137 [[PubMed]
123. Elmadfa I, Klein P, Meyer AL: Immune-stimulating effects of lactic acid bacteria in vivo and in vitro. Proc Nutr Soc 2010;69:416–420 [[PubMed]
124. Li CY, Lin HC, Lai CH, et al: Immunomodulatory effects of lactobacillus and Bifidobacterium on both murine and human mitogen-activated T cells. Int Arch Allergy Immunol 2011;156:128–136 [[PubMed][Google Scholar]
125. Charlier C, Cretenet M, Even S, Le Loir Y: Interactions between Staphylococcus aureus and lactic acid bacteria: an old story with new perspectives. Int J Food Microbiol 2009;131:30–39 [[PubMed]
126. Messaoudi M, Lalonde R, Violle N, et al: Assessment of psychotropic-like properties of a probiotic formulation (Lactobacillus helveticus R0052 and Bifidobacterium longum R0175) in rats and human subjects. Br J Nutr 2011;105:755–764 [[PubMed][Google Scholar]
127. Arseneault-Bréard J, Rondeau I, Gilbert K, et al: Combination of Lactobacillus helveticus R0052 and Bifidobacterium longum R0175 reduces post-myocardial infarction depression symptoms and restores intestinal permeability in a rat model. Br J Nutr 2012;107:1793–1799 [[PubMed][Google Scholar]
128. Girard SA, Bah TM, Kaloustian S, et al: Lactobacillus helveticus and Bifidobacterium longum taken in combination reduce the apoptosis propensity in the limbic system after myocardial infarction in a rat model. Br J Nutr 2009;102:1420–1425 [[PubMed][Google Scholar]
129. Tillisch K, Labus J, Kilpatrick L, et al: Consumption of fermented milk product with probiotic modulates brain activity. Gastroenterology 2013;144:1394–1401 [Google Scholar]
130. Benton D, Williams C, Brown A: Impact of consuming a milk drink containing a probiotic on mood and cognition. Eur J Clin Nutr 2007;61:355–361 [[PubMed]
131. Rao AV, Bested AC, Beauline TM, et al: A randomized double-blind, placebo-controlled pilot study of a probiotic in emotional symptoms of chronic fatigue syndrome. Gut Pathog 2009;1:6. [Google Scholar]
132. Sullivan A, Nord CE, Evengård B: Effect of supplement with lactic-acid producing bacteria on fatigue and physical activity in patients with chronic fatigue syndrome. Nutr J 2009;8:4.
133. Diop L, Guillou S, Durand H: Probiotic food supplement reduces stress-induced gastrointestinal symptoms in volunteers: a double-blind, placebo-controlled, randomized trial. Nutr Res 2008;28:1–5 [[PubMed]
134. Forsythe P, Kunze WA, Bienenstock J: On communication between gut microbes and the brain. Curr Opin Gastroenterol 2012;28:557–562 [[PubMed]
135. Bravo JA, Forsythe P, Chew MV, 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 2011;108:16050–16055 [Google Scholar]
136. Mao YK, Kasper DL, Wang B, et al: Bacteroides fragilis polysaccharide A is necessary and sufficient for acute activation of intestinal sensory neurons. Nat Commun 2013;4:1465. [[PubMed][Google Scholar]
137. Bercik P, Denou E, Collins J, et al: The intestinal microbiota affect central levels of brain-derived neurotropic factor and behavior in mice. Gastroenterology 2011;141:599–609, 609.e1–e3. [[PubMed][Google Scholar]
138. Sanders ME: Impact of probiotics on colonizing microbiota of the gut. J Clin Gastroenterol 2011;45Suppl:S115–S119 [[PubMed]
139. Filippo C, Cavalieri D, Di Paola M, Ramazzotti M, Poullet JB, Massart S, Collini S, Pieraccini G, Lionetti P: Impact of diet in shaping gut microbiota revealed by a comparative study in children from Europe and rural Africa. Proc Natl Acad Sci USA 2010;107:14691–14696
140. Eckburg PB, Bik EM, Bernstein CN, Purdom E, Dethlefsen L, Sargent M, Gill SR, Nelson KE, Relman DA: Diversity of the human intestinal microbial flora. Science 2005;308:1635–1638
141. Turnbaugh PJ, Quince C, Faith JJ, McHardy AC, Yatsunenko T, Niazi F, Affourtit J, Egholm M, Henrissat B, Knight R, Gordon JI: Organismal, genetic, and transcriptional variation in the deeply sequenced gut microbiomes of identical twins. Proc Natl Acad Sci USA 2010;107:7503–7508
142. Turnbaugh PJ, Gordon JI: The core gut microbiome, energy balance, and obesity. J Physiol 2009;587:4153–4158
143. Rajilic-Stojanovic M, Heilig HG, Molenaar D, Kajander K, Surakka A, Smidt H, de Vos WM: Development and application of the human intestinal tract chip, a phylogenetic microarray: analysis of universally conserved phylotypes in the abundant microbiota of young and elderly adults. Environ Microbiol 2009;11:1736–1751
144. Dethlefsen L, Eckburg PB, Bik EM, Relman DA: Assembly of the human intestinal microbiota. Trends Ecol Evol 2006;21:517–523 [[PubMed]
145. Booijink CC, El-Aidy S, Rajilić-Stojanović M, et al: High temporal and inter-individual variation detected in the human ileal microbiota. Environ Microbiol 2010;12:3213–3227 [[PubMed][Google Scholar]
146. Galland L: Patient-centered care: antecedents, triggers, and mediators. Altern Ther Health Med 2006;12:62–70 [[PubMed]
147. Tap J, Mondot S, Levenez F, Pelletier E, et al: Towards the human intestinal microbiota phylogenetic core. Environ Microbiol 2009;11:2574–2584 [[PubMed][Google Scholar]
148. Wu GD, Chen J, Hoffmann C, et al: Linking long-term dietary patterns with gut microbial enterotypes. Science 2011;334:105–108 [Google Scholar]
149. Walker WA: Initial intestinal colonization in the human infant and immune homeostasis. Ann Nutr Metab 2013;63Suppl 2:8–15 [[PubMed]
150. Mayne AJ, Handy DJ, Preece MA, et al: Dietary management of D-lactic acidosis in short bowel syndrome. Arch Dis Child 1990;65:229–231 [Google Scholar]
151. Dorrestein PC, Mazmanian SK, Knight R: Finding the missing links among metabolites, microbes, and the host. Immunity 2014;40:824–832
152. Kaneko T, Mori H, Iwata M, Meguro S: Growth stimulator for bifidobacteria produced by Propionibacterium freudenreichii and several intestinal bacteria. J Dairy Sci 1994;77:393–404 [[PubMed]
153. Suzuki A, Mitsuyama K, Koga H, et al: Bifidogenic growth stimulator for the treatment of active ulcerative colitis: a pilot study. Nutrition 2006;22:76–81 [[PubMed][Google Scholar]
154. Joyce SA, Gahan CG: The gut microbiota and the metabolic health of the host. Curr Opin Gastroenterol 2014;30:120–127 [[PubMed]
155. Albenberg LG, Wu GD: Diet and the intestinal microbiome: associations, functions, and implications for health and disease. Gastroenterology 2014;146:1564–1572
156. Jeffery IB, O'Toole PW: Diet-microbiota interactions and their implications for healthy living. Nutrients 2013;5:234–252
157. Tang WH, Wang Z, Levison BS, et al: Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk. N Engl J Med 2013;368:1575–1584 [Google Scholar]
158. Koeth RA, Wang Z, Levison BS, et al: Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat Med 2013;19:576–585 [Google Scholar]
159. Laparra JM, Sanz Y: Interactions of gut microbiota with functional food components and nutraceuticals. Pharmacol Res 2010;61:219–225 [[PubMed]
160. Van Wey AS, Cookson AL, Roy NC, et al: Bacterial biofilms associated with food particles in the human large bowel. Mol Nutr Food Res 2011;55:969–978 [[PubMed][Google Scholar]