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The interplay between the intestinal microbiota and the brain

Nature Reviews Microbiology volume 10, pages 735–742 (2012)Cite this article

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Abstract

The intestinal microbiota consists of a vast bacterial community that resides primarily in the lower gut and lives in a symbiotic relationship with the host. A bidirectional neurohumoral communication system, known as the gut–brain axis, integrates the host gut and brain activities. Here, we describe the recent advances in our understanding of how the intestinal microbiota communicates with the brain via this axis to influence brain development and behaviour. We also review how this extended communication system might influence a broad spectrum of diseases, including irritable bowel syndrome, psychiatric disorders and demyelinating conditions such as multiple sclerosis.

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Figure 1: The bidirectional microbiota–gut–brain axis.

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References

  1. Qin, J. et al. A human gut microbial gene catalogue established by metagenomic sequencing. Nature 464, 59–65 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Schiano, T. D. Treatment options for hepatic encephalopathy. Pharmacotherapy 30, S16–S21 (2010).

    Article  Google Scholar 

  3. Wu, J. C. Psychological co-morbidity in functional gastrointestinal disorders: epidemiology, mechanisms and management. J. Neurogastroenterol. Motil. 18, 13–18 (2012).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  5. Tracey, K. J. Reflex control of immunity. Nature Rev. Immunol. 9, 418–428 (2009).

    Article  CAS  Google Scholar 

  6. Mawdsley, J. E. & Rampton, D. S. Psychological stress in IBD: new insights into pathogenic and therapeutic implications. Gut 54, 1481–1491 (2005).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. DuPont, A. W. & DuPont, H. L. The intestinal microbiota and chronic disorders of the gut. Nature Rev. Gastroenterol. Hepatol. 8, 523–531 (2011).

    Article  Google Scholar 

  8. Collins, S. M. & Bercik, P. The relationship between intestinal microbiota and the central nervous system in normal gastrointestinal function and disease. Gastroenterology 136, 2003–2014 (2009).

    Article  PubMed  Google Scholar 

  9. Freestone, P. P., Sandrini, S. M., Haigh, R. D. & Lyte, M. Microbial endocrinology: how stress influences susceptibility to infection. Trends Microbiol. 16, 55–64 (2008).

    Article  CAS  PubMed  Google Scholar 

  10. Kaper, J. B. & Sperandio, V. Bacterial cell-to-cell signaling in the gastrointestinal tract. Infect. Immun. 73, 3197–3209 (2005).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. Crawley, J. N. Behavioral phenotyping strategies for mutant mice. Neuron 57, 809–818 (2008).

    Article  CAS  PubMed  Google Scholar 

  12. Sudo, N. et al. Postnatal microbial colonization programs the hypothalamic–pituitary–adrenal system for stress response in mice. J. Physiol. 558, 263–275 (2004).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Neufeld, K. M., Kang, N., Bienenstock, J. & Foster, J. A. Reduced anxiety-like behavior and central neurochemical change in germ-free mice. Neurogastroenterol. Motil. 23, 255–264 (2011).

    Article  CAS  PubMed  Google Scholar 

  14. Heijtz, R. D. et al. Normal gut microbiota modulates brain development and behavior. Proc. Natl Acad. Sci. USA 108, 3047–3052 (2011).

    Article  CAS  PubMed Central  Google Scholar 

  15. Gareau, M. G. et al. Bacterial infection causes stress-induced memory dysfunction in mice. Gut 60, 307–317 (2011).

    Article  PubMed  Google Scholar 

  16. Costello, E. K. et al. Bacterial community variation in human body habitats across space and time. Science 326, 1694–1697 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Jalanka-Tuovinen, J. et al. Intestinal microbiota in healthy adults: temporal analysis reveals individual and common core and relation to intestinal symptoms. PLoS ONE 6, e23035 (2011).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Li, W., Dowd, S. E., Scurlock, B., Acosta-Martinez, V. & Lyte, M. Memory and learning behavior in mice is temporally associated with diet-induced alterations in gut bacteria. Physiol. Behav. 96, 557–567 (2009).

    Article  CAS  PubMed  Google Scholar 

  19. Bercik, P. et al. The intestinal microbiota affect central levels of brain-derived neurotropic factor and behavior in mice. Gastroenterology 141, 599–609 (2011).

    Article  CAS  PubMed  Google Scholar 

  20. Salonen, A., de Vos, W. M. & Palva, A. Gastrointestinal microbiota in irritable bowel syndrome: present state and perspectives. Microbiology 156, 3205–3215 (2010).

    Article  CAS  PubMed  Google Scholar 

  21. Abouesh, A., Stone, C. & Hobbs, W. R. Antimicrobial-induced mania (antibiomania): a review of spontaneous reports. J. Clin. Psychopharmacol. 22, 71–81 (2002).

    Article  PubMed  Google Scholar 

  22. Desbonnet, L., Garrett, L., Clarke, G., Bienenstock, J. & Dinan, T. G. The probiotic Bifidobacteria infantis: an assessment of potential antidepressant properties in the rat. J. Psychiatr. Res. 2, 164–174 (2008).

    Article  Google Scholar 

  23. Desbonnet, L. et al. Effects of the probiotic Bifidobacterium infantis in the maternal separation model of depression. Neuroscience 170, 1179–1188 (2010).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  25. 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, 10650–16055 (2011).

    Article  Google Scholar 

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

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. Kunze, W. A. et al. Lactobacillus reuteri enhances excitability of colonic AH neurons by inhibiting calcium-dependent potassium channel opening. J. Cell. Mol. Med. 13, 2261–2270 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  28. Wikoff, W. R. et al. Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites. Proc. Natl Acad. Sci. USA 106, 3698–3703 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Hanstock, T. L., Mallet, P. E. & Clayton, E. H. Increased plasma D-lactic acid associated with impaired memory in rats. Physiol. Behav. 101, 653–659 (2010).

    Article  CAS  PubMed  Google Scholar 

  30. Tana, C. et al. Altered profiles of intestinal microbiota and organic acids may be the origin of symptoms in irritable bowel syndrome. Neurogastroenterol. Motil. 22, 512–519 (2010).

    CAS  PubMed  Google Scholar 

  31. Ledochowski, M. et al. Carbohydrate malabsorption syndromes and early signs of mental depression in females. Dig. Dis. Sci. 45, 1255–1259 (2000).

    Article  CAS  PubMed  Google Scholar 

  32. Myint, A. M. Kynurenines: from the perspective of major psychiatric disorders. FEBS J. 279, 1375–1385 (2012).

    Article  CAS  PubMed  Google Scholar 

  33. Barrett, E. et al. γ-Aminobuyric acid production by culturable bacteria from the human intestine. J. Appl. Microbiol. 113, 411–417 (2012).

    Article  CAS  PubMed  Google Scholar 

  34. Lyte, M. Probiotics function mechanistically as delivery vehicles for neuroactive compounds: microbial endocrinology in the design and use of probiotics. Bioessays 33, 574–581 (2011).

    Article  CAS  PubMed  Google Scholar 

  35. Macpherson, A. J. & Harris, N. L. Interactions between commensal intestinal bacteria and the immune system. Nature Rev. Immunol. 4, 478–485 (2004).

    Article  CAS  Google Scholar 

  36. Salzman, N. H. Microbiota–immune system interaction: an uneasy alliance. Curr. Opin. Microbiol. 14, 99–105 (2011).

    Article  PubMed  Google Scholar 

  37. Derecki, N. C. et al. Regulation of learning and memory by meningeal immunity: a key role for IL-4. J. Exp. Med. 207, 1067–1080 (2010).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  38. Lotrich, F. E., El-Gabalawy, H., Guenther, L. C. & Ware, C. F. The role of inflammation in the pathophysiology of depression: different treatments and their effects. J. Rheumatol. 88, 48–54 (2011).

    CAS  Google Scholar 

  39. O'Mahony, L. et al. Lactobacillus and bifidobacterium in irritable bowel syndrome: symptom responses and relationship to cytokine profiles. Gastroenterology 128, 541–551 (2005).

    Article  PubMed  Google Scholar 

  40. Honda, K. & Takeda, K. Regulatory mechanisms of immune responses to intestinal bacteria. Mucosal Immunol. 2, 187–196 (2009).

    Article  CAS  PubMed  Google Scholar 

  41. Uribe, A., Alam, M., Johansson, O., Midtvedt, T. & Theodorsson, E. Microflora modulates endocrine cells in the gastrointestinal mucosa of the rat. Gastroenterology 107, 1259–1269 (1994).

    Article  CAS  PubMed  Google Scholar 

  42. Bailey, M. T. et al. Exposure to a social stressor alters the structure of the intestinal microbiota: implications for stressor-induced immunomodulation. Brain Behav. Immun. 25, 397–407 (2011).

    Article  CAS  PubMed  Google Scholar 

  43. Lyte, M., Vulchanova, L. & Brown, D. R. Stress at the intestinal surface: catecholamines and mucosa–bacteria interactions. Cell Tissue Res. 2431, 23–32 (2011).

    Article  Google Scholar 

  44. Bajaj, J. S. et al. Linkage of gut microbiome with cognition in hepatic encephalopathy. Am. J. Physiol. Gastrointest. Liver Physiol. 302, G168–G175 (2012).

    Article  CAS  PubMed  Google Scholar 

  45. Lee, Y. K., Menezes, J. S., Umesaki, Y. & Mazmanian, S. K. Proinflammatory T-cell responses to gut microbiota promote experimental autoimmune encephalomyelitis. Proc. Natl Acad. Sci. USA 108, 4615–4622 (2011).

    Article  CAS  PubMed  Google Scholar 

  46. Berer, K. et al. Commensal microbiota and myelin autoantigen cooperate to trigger autoimmune demyelination. Nature 479, 538–541 (2011).

    Article  CAS  PubMed  Google Scholar 

  47. Finegold, S. M., Downes, J. & Summanen, P. H. Microbiology of regressive autism. Anaerobe 18, 260–262 (2012).

    Article  CAS  PubMed  Google Scholar 

  48. Wang, L. et al. Low relative abundances of the mucolytic bacterium Akkermansia muciniphila and Bifidobacterium spp. in feces of children with autism. Appl. Environ. Microbiol. 77, 6718–6721 (2011).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  49. Williams, B. L., Hornig, M., Parekh, T. & Lipkin, W. I. 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, e00261–e00211 (2012).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  51. Sandler, R. H. et al. Short-term benefit from oral vancomycin treatment of regressive-onset autism. J. Child Neurol. 15, 429–435 (2000).

    Article  CAS  PubMed  Google Scholar 

  52. MacFabe, D. F. et al. 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 (2007).

    Article  CAS  PubMed  Google Scholar 

  53. Rendeiro, C. P. et al. Flavonoids as modulators of memory and learning: molecular interactions resulting in behavioural effects. Proc. Nutr. Soc. 71, 246–262 (2012).

    Article  CAS  PubMed  Google Scholar 

  54. Juárez, I., Gratton, A. & Flores, G. Ontogeny of altered dendritic morphology in the rat prefrontal cortex, hippocampus, and nucleus accumbens following cesarean delivery and birth anoxia. J. Comp. Neurol. 507, 1734–1747 (2008).

    Article  PubMed  Google Scholar 

  55. Kim, H. R. et al. Delivery modes and neonatal EEG: spatial pattern analysis. Early Hum. Dev. 75, 35–53 (2003).

    Article  PubMed  Google Scholar 

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Acknowledgements

The authors' work cited in this paper was supported by the Canadian Institutes of Health Research (CIHR) and the Crohn's and Colitis Foundation of Canada (CCFC). Support to S.M.C. and P.B. was also received from the Nestle Research Center.

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Authors and Affiliations

  1. Department of Medicine, Stephen M. Collins, Michael Surette and Premysl Bercik are at the Farncombe Family Digestive Health Research Institute, Faculty of Health Sciences, McMaster University, 1200 Main Street West, Hamilton L8N 3Z5, Ontario, Canada.,

    Stephen M. Collins, Michael Surette & Premysl Bercik

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  1. Stephen M. Collins
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Correspondence to Stephen M. Collins.

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Competing interests

Stephen M. Collins and Premysl Bercik are the recipients of a grant from the Nestle Research Centre. Michael Surette declares no competing financial interests.

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Farmcombe Family Digestive Health Research Institute, McMaster University

Glossary

5-hydroxytryptamine

(5-HT). A neurotransmitter that is produced mainly by the enteroendocrine cells of the gut, where it is an important regulator of gut physiology (particularly motility); however, 10% of 5-HT is found in the central nervous system, where it contributes to mood. 5-HT, also called serotonin, is derived from tryptophan via the formation of 5-hydroxytryptophan.

Brain-derived neurotrophic factor

A protein that is widely distributed in the nervous system. In the brain, it is found in the hippocampus, amygdala and cortex. It contributes to a range of functions, including memory, mood and learning.

Core microbiome

The 50–100 bacterial species that are common to the microbiomes of many individuals. Outside of these core species, there is considerable diversity in the microbiome components among healthy subjects.

Dysbiosis

A compositional change in the microbiota and/or an abnormality in the interactions between the host and the commensal microbiota.

Encephalopathy

An impairment of brain function, ranging in severity from mild confusion to deep coma. Severe liver disease is a common cause.

GABA

(γ-aminobutyric acid). An inhibitory neurotransmitter that is found throughout the nervous system, including in the central and enteric nervous systems.

Postsynaptic density protein 95

A component of the postsynaptic density, a lattice-like array of proteins that is crucial for synaptic function.

Probiotic

According to the WHO: “Live microorganisms which when administered in adequate amounts confer a health benefit on the host.”

Specific-pathogen-free mice

Laboratory mice that are free of defined pathogens.

Synaptophysin

An integral membrane protein of small synaptic vesicles. Initially considered a synaptic marker, it is now thought to have several roles in synaptic function throughout the nervous system.

Toll-like receptors

Transmembrane proteins that recognize highly conserved molecules of microbial origin and subsequently trigger activation of the innate immune system.

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Collins, S., Surette, M. & Bercik, P. The interplay between the intestinal microbiota and the brain. Nat Rev Microbiol 10, 735–742 (2012). https://doi.org/10.1038/nrmicro2876

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