1932

Abstract

Preclinical evidence has firmly established bidirectional interactions among the brain, the gut, and the gut microbiome. Candidate signaling molecules and at least three communication channels have been identified. Communication within this system is nonlinear, is bidirectional with multiple feedback loops, and likely involves interactions between different channels. Alterations in gut–brain–microbiome interactions have been identified in rodent models of several digestive, psychiatric, and neurological disorders. While alterations in gut–brain interactions have clearly been established in irritable bowel syndrome, a causative role of the microbiome in irritable bowel syndrome remains to be determined. In the absence of specific microbial targets for more effective therapies, current approaches are limited to dietary interventions and centrally targeted pharmacological and behavioral approaches. A more comprehensive understanding of causative influences within the gut–brain–microbiome system and well-designed randomized controlled trials are needed to translate these exciting preclinical findings into effective therapies.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-med-042320-014032
2022-01-27
2024-10-05
Loading full text...

Full text loading...

/deliver/fulltext/med/73/1/annurev-med-042320-014032.html?itemId=/content/journals/10.1146/annurev-med-042320-014032&mimeType=html&fmt=ahah

Literature Cited

  1. 1. 
    Osadchiy V, Martin CR, Mayer EA. 2019.. The gut–brain axis and the microbiome: mechanisms and clinical implications. . Clin. Gastroenterol. Hepatol. 17::32232
    [Google Scholar]
  2. 2. 
    Mayer EA. 2011.. Gut feelings: the emerging biology of gut–brain communication. . Nat. Rev. Neurosci. 12::45366
    [Google Scholar]
  3. 3. 
    Schwetz I, Bradesi S, Mayer EA. 2003.. Current insights into the pathophysiology of irritable bowel syndrome. . Curr. Gastroenterol. Rep. 5::33136
    [Google Scholar]
  4. 4. 
    Drossman DA, Hasler WL. 2016.. Rome IV—functional GI disorders: disorders of gut–brain interaction. . Gastroenterology 150::125761
    [Google Scholar]
  5. 5. 
    Mayer EA, Naliboff BD, Craig AD. 2006.. Neuroimaging of the brain–gut axis: from basic understanding to treatment of functional GI disorders. . Gastroenterology 131::192542
    [Google Scholar]
  6. 6. 
    El Aidy S, Dinan TG, Cryan JF. 2015.. Gut microbiota: the conductor in the orchestra of immune–neuroendocrine communication. . Clin. Ther. 37::95467
    [Google Scholar]
  7. 7. 
    Martin CR, Osadchiy V, Kalani A, Mayer EA. 2018.. The brain–gut–microbiome axis. . Cell Mol. Gastroenterol. Hepatol. 6::13348
    [Google Scholar]
  8. 8. 
    Bonaz B, Lane RD, Oshinsky ML, et al. 2021.. Diseases, disorders, and comorbidities of interoception. . Trends Neurosci. 44::3951
    [Google Scholar]
  9. 9. 
    Carabotti M, Scirocco A, Maselli MA, Severi C. 2015.. The gut–brain axis: interactions between enteric microbiota, central and enteric nervous systems. . Ann. Gastroenterol. 28::2039
    [Google Scholar]
  10. 10. 
    Mayer EA, Tillisch K. 2011.. The brain–gut axis in abdominal pain syndromes. . Annu. Rev. Med. 62::38196
    [Google Scholar]
  11. 11. 
    Porreca F, Ossipov MH, Gebhart GF. 2002.. Chronic pain and medullary descending facilitation. . Trends Neurosci. 25::31925
    [Google Scholar]
  12. 12. 
    Needham BD, Kaddurah-Daouk R, Mazmanian SK. 2020.. Gut microbial molecules in behavioural and neurodegenerative conditions. . Nat. Rev. Neurosci. 21::71731
    [Google Scholar]
  13. 13. 
    Walsh KT, Zemper AE. 2019.. The enteric nervous system for epithelial researchers: basic anatomy, techniques, and interactions with the epithelium. . Cell Mol. Gastroenterol. Hepatol. 8::36978
    [Google Scholar]
  14. 14. 
    Yano JM, Yu K, Donaldson GP, et al. 2015.. Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis. . Cell 161::26476
    [Google Scholar]
  15. 15. 
    Mills S, Stanton C, Lane JA, et al. 2019.. Precision nutrition and the microbiome. Part I: Current state of the science. . Nutrients 11::923
    [Google Scholar]
  16. 16. 
    Dalile B, Van Oudenhove L, Vervliet B, Verbeke K. 2019.. The role of short-chain fatty acids in microbiota–gut–brain communication. . Nat. Rev. Gastroenterol. Hepatol. 16::46178
    [Google Scholar]
  17. 17. 
    Needham BD, Adame MD, Serena G, et al. 2021.. Plasma and fecal metabolite profiles in autism spectrum disorder. . Biol. Psychiatry 89::45162
    [Google Scholar]
  18. 18. 
    Muller PA, Schneeberger M, Matheis F, et al. 2020.. Microbiota modulate sympathetic neurons via a gut–brain circuit. . Nature 583::44146
    [Google Scholar]
  19. 19. 
    Backhed F, Ding H, Wang T, et al. 2004.. The gut microbiota as an environmental factor that regulates fat storage. . PNAS 101::1571823
    [Google Scholar]
  20. 20. 
    Magnusson MK, Isaksson S, Ohman L. 2020.. The anti-inflammatory immune regulation induced by butyrate is impaired in inflamed intestinal mucosa from patients with ulcerative colitis. . Inflammation 43::50717
    [Google Scholar]
  21. 21. 
    Clarke G, Grenham S, Scully P, et al. 2013.. The microbiome–gut–brain axis during early life regulates the hippocampal serotonergic system in a sex-dependent manner. . Mol. Psychiatry 18::66673
    [Google Scholar]
  22. 22. 
    Marin IA, Goertz JE, Ren T, et al. 2017.. Microbiota alteration is associated with the development of stress-induced despair behavior. . Sci. Rep. 7::43859
    [Google Scholar]
  23. 23. 
    Hubbard TD, Murray IA, Perdew GH. 2015.. Indole and tryptophan metabolism: endogenous and dietary routes to Ah receptor activation. . Drug Metab. Dispos. 43::152235
    [Google Scholar]
  24. 24. 
    Morton GJ, Kaiyala KJ, Foster-Schubert KE, et al. 2014.. Carbohydrate feeding dissociates the postprandial FGF19 response from circulating bile acid levels in humans. . J. Clin. Endocrinol. Metab. 99::E24145
    [Google Scholar]
  25. 25. 
    Hsuchou H, Pan W, Kastin AJ. 2013.. Fibroblast growth factor 19 entry into brain. . Fluids Barriers CNS 10::32
    [Google Scholar]
  26. 26. 
    Perry RJ, Lee S, Ma L, et al. 2015.. FGF1 and FGF19 reverse diabetes by suppression of the hypothalamic-pituitary-adrenal axis. . Nat. Commun. 6::6980
    [Google Scholar]
  27. 27. 
    Wang Y, Telesford KM, Ochoa-Repáraz J, et al. 2014.. An intestinal commensal symbiosis factor controls neuroinflammation via TLR2-mediated CD39 signalling. . Nat. Commun. 5::4432
    [Google Scholar]
  28. 28. 
    Baker JM, Al-Nakkash L, Herbst-Kralovetz MM. 2017.. Estrogen–gut microbiome axis: physiological and clinical implications. . Maturitas 103::4553
    [Google Scholar]
  29. 29. 
    Plottel CS, Blaser MJ. 2011.. Microbiome and malignancy. . Cell Host Microbe 10::32435
    [Google Scholar]
  30. 30. 
    Fuhrman BJ, Feigelson HS, Flores R, et al. 2014.. Associations of the fecal microbiome with urinary estrogens and estrogen metabolites in postmenopausal women. . J. Clin. Endocrinol. Metab. 99::463240
    [Google Scholar]
  31. 31. 
    Mulak A, Tache Y, Larauche M. 2014.. Sex hormones in the modulation of irritable bowel syndrome. . World J. Gastroenterol. 20::243348
    [Google Scholar]
  32. 32. 
    Rogier R, Koenders MI, Abdollahi-Roodsaz S. 2015.. Toll-like receptor mediated modulation of T cell response by commensal intestinal microbiota as a trigger for autoimmune arthritis. . J. Immunol. Res. 2015::527696
    [Google Scholar]
  33. 33. 
    Dantzer R, O'Connor JC, Freund GG, et al. 2008.. From inflammation to sickness and depression: when the immune system subjugates the brain. . Nat. Rev. Neurosci. 9::4656
    [Google Scholar]
  34. 34. 
    Sampson TR, Mazmanian SK. 2015.. Control of brain development, function, and behavior by the microbiome. . Cell Host Microbe 17::56576
    [Google Scholar]
  35. 35. 
    Raison CL, Capuron L, Miller AH. 2006.. Cytokines sing the blues: inflammation and the pathogenesis of depression. . Trends Immunol. 27::2431
    [Google Scholar]
  36. 36. 
    Penders J, Thijs C, van den Brandt PA, et al. 2007.. Gut microbiota composition and development of atopic manifestations in infancy: the KOALA Birth Cohort Study. . Gut 56::66167
    [Google Scholar]
  37. 37. 
    Mueller NT, Bakacs E, Combellick J, et al. 2015.. The infant microbiome development: Mom matters. . Trends Mol. Med. 21::10917
    [Google Scholar]
  38. 38. 
    Kelly JR, Kennedy PJ, Cryan JF, et al. 2015.. Breaking down the barriers: the gut microbiome, intestinal permeability and stress-related psychiatric disorders. . Front. Cell Neurosci. 9::392
    [Google Scholar]
  39. 39. 
    Macfarlane S, Dillon JF. 2007.. Microbial biofilms in the human gastrointestinal tract. . J. Appl. Microbiol. 102::118796
    [Google Scholar]
  40. 40. 
    Desai MS, Seekatz AM, Koropatkin NM, et al. 2016.. A dietary fiber–deprived gut microbiota degrades the colonic mucus barrier and enhances pathogen susceptibility. . Cell 167::133953
    [Google Scholar]
  41. 41. 
    Johansson ME, Larsson JM, Hansson GC. 2011.. The two mucus layers of colon are organized by the MUC2 mucin, whereas the outer layer is a legislator of host microbial interactions. . PNAS 108:(Suppl. 1):465965
    [Google Scholar]
  42. 42. 
    Cani PD, Amar J, Iglesias MA, et al. 2007.. Metabolic endotoxemia initiates obesity and insulin resistance. . Diabetes 56::176172
    [Google Scholar]
  43. 43. 
    Vaishnava S, Behrendt CL, Ismail AS, et al. 2008.. Paneth cells directly sense gut commensals and maintain homeostasis at the intestinal host microbial interface. . PNAS 105::2085863
    [Google Scholar]
  44. 44. 
    Braniste V, Al-Asmakh M, Kowal C, et al. 2014.. The gut microbiota influences blood–brain barrier permeability in mice. . Sci. Transl. Med. 6::263ra158
    [Google Scholar]
  45. 45. 
    Alaish SM, Smith AD, Timmons J, et al. 2013.. Gut microbiota, tight junction protein expression, intestinal resistance, bacterial translocation and mortality following cholestasis depend on the genetic background of the host. . Gut Microbes 4::292305
    [Google Scholar]
  46. 46. 
    Brown AJ, Goldsworthy SM, Barnes AA, et al. 2003.. The orphan G protein–coupled receptors GPR41 and GPR43 are activated by propionate and other short chain carboxylic acids. . J. Biol. Chem. 278::1131229
    [Google Scholar]
  47. 47. 
    Freestone P. 2013.. Communication between bacteria and their hosts. . Scientifica 2013::361073
    [Google Scholar]
  48. 48. 
    Deaver JA, Eum SY, Toborek M. 2018.. Circadian disruption changes gut microbiome taxa and functional gene composition. . Front. Microbiol. 9::737
    [Google Scholar]
  49. 49. 
    Khanijow V, Prakash P, Emsellem HA, et al. 2015.. Sleep dysfunction and gastrointestinal diseases. . Gastroenterol. Hepatol. 11::81725
    [Google Scholar]
  50. 50. 
    Da Silva S, Robbe-Masselot C, Ait-Belgnaoui A, et al. 2014.. Stress disrupts intestinal mucus barrier in rats via mucin O-glycosylation shift: prevention by a probiotic treatment. . Am. J. Physiol. Gastrointest. Liver Physiol. 307::G42029
    [Google Scholar]
  51. 51. 
    Lauffer A, Vanuytsel T, Vanormelingen C, et al. 2016.. Subacute stress and chronic stress interact to decrease intestinal barrier function in rats. . Stress 19::22534
    [Google Scholar]
  52. 52. 
    Longstreth GF, Thompson WG, Chey WD, et al. 2006.. Functional bowel disorders. . Gastroenterology 130::148091
    [Google Scholar]
  53. 53. 
    Mayer EA, Labus J, Aziz Q, et al. 2019.. Role of brain imaging in disorders of brain–gut interaction: a Rome Working Team Report. . Gut 68::170115
    [Google Scholar]
  54. 54. 
    Simrén M, Barbara G, Flint HJ, et al. 2013.. Intestinal microbiota in functional bowel disorders: a Rome foundation report. . Gut 62::15976
    [Google Scholar]
  55. 55. 
    Jeffery IB, O'Toole PW, Ohman L, et al. 2012.. An irritable bowel syndrome subtype defined by species-specific alterations in faecal microbiota. . Gut 61::9971006
    [Google Scholar]
  56. 56. 
    Labus JS, Hollister EB, Jacobs J, et al. 2017.. Differences in gut microbial composition correlate with regional brain volumes in irritable bowel syndrome. . Microbiome 5::49
    [Google Scholar]
  57. 57. 
    Tap J, Derrien M, Törnblom H, et al. 2017.. Identification of an intestinal microbiota signature associated with severity of irritable bowel syndrome. . Gastroenterology 152::11123.e8
    [Google Scholar]
  58. 58. 
    Gargari G, Taverniti V, Gardana C, et al. 2018.. Fecal Clostridiales distribution and short-chain fatty acids reflect bowel habits in irritable bowel syndrome. . Environ. Microbiol. 20::320113
    [Google Scholar]
  59. 59. 
    Kang DW, Park JG, Ilhan ZE, et al. 2013.. Reduced incidence of Prevotella and other fermenters in intestinal microflora of autistic children. . PLOS ONE 8::e68322
    [Google Scholar]
  60. 60. 
    Crouzet L, Gaultier E, Del'Homme C, et al. 2013.. The hypersensitivity to colonic distension of IBS patients can be transferred to rats through their fecal microbiota. . Neurogastroenterol. Motil. 25::e27282
    [Google Scholar]
  61. 61. 
    Kennedy PJ, Cryan JF, Dinan TG, Clarke G. 2014.. Irritable bowel syndrome: a microbiome–gut–brain axis disorder?. World J. Gastroenterol. 20::1410525
    [Google Scholar]
  62. 62. 
    Moloney RD, Johnson AC, O'Mahony SM, et al. 2016.. Stress and the microbiota–gut–brain axis in visceral pain: relevance to irritable bowel syndrome. . CNS Neurosci. Ther. 22::10217
    [Google Scholar]
  63. 63. 
    McKernan DP, Fitzgerald P, Dinan TG, Cryan JF. 2010.. The probiotic Bifidobacterium infantis 35624 displays visceral antinociceptive effects in the rat. . Neurogastroenterol. Motil. 22::102935
    [Google Scholar]
  64. 64. 
    Lackner JM, Ma CX, Keefer L, et al. 2013.. Type, rather than number, of mental and physical comorbidities increases the severity of symptoms in patients with irritable bowel syndrome. . Clin. Gastroenterol. Hepatol. 11::114757
    [Google Scholar]
  65. 65. 
    Margolis KG, Cryan JF, Mayer EA. 2021.. The microbiota–gut–brain axis: from motility to mood. . Gastroenterology 160::1486501
    [Google Scholar]
  66. 66. 
    Marshall JK, Thabane M, Garg AX, et al. 2010.. Eight year prognosis of postinfectious irritable bowel syndrome following waterborne bacterial dysentery. . Gut 59::60511
    [Google Scholar]
  67. 67. 
    Dunlop SP, Jenkins D, Neal KR, Spiller RC. 2003.. Relative importance of enterochromaffin cell hyperplasia, anxiety, and depression in postinfectious IBS. . Gastroenterology 125::165159
    [Google Scholar]
  68. 68. 
    Messaoudi M, Lalonde R, Violle N, et al. 2011.. Assessment of psychotropic-like properties of a probiotic formulation (Lactobacillus helveticus R0052 and Bifidobacterium longum R0175) in rats and human subjects. . Br. J. Nutr. 105::75564
    [Google Scholar]
  69. 69. 
    Dinan TG, Butler MI, Cryan JF. 2021.. Psychobiotics: evolution of novel antidepressants. . Mod. Trends Psychiatry 32::13443
    [Google Scholar]
  70. 70. 
    Algera J, Colomier E, Simrén M. 2019.. The dietary management of patients with irritable bowel syndrome: a narrative review of the existing and emerging evidence. . Nutrients 11::2162
    [Google Scholar]
  71. 71. 
    Magge S, Lembo A. 2012.. Low-FODMAP diet for treatment of irritable bowel syndrome. . Gastroenterol. Hepatol. 8::73945
    [Google Scholar]
  72. 72. 
    Nanayakkara WS, Skidmore PM, O'Brien L, et al. 2016.. Efficacy of the low FODMAP diet for treating irritable bowel syndrome: the evidence to date. . Clin. Exp. Gastroenterol. 9::13142
    [Google Scholar]
  73. 73. 
    Cox SR, Lindsay JO, Fromentin S, et al. 2020.. Effects of low FODMAP diet on symptoms, fecal microbiome, and markers of inflammation in patients with quiescent inflammatory bowel disease in a randomized trial. . Gastroenterology 158::17688.e7
    [Google Scholar]
  74. 74. 
    Adan RAH, van der Beek EM, Buitelaar JK, et al. 2019.. Nutritional psychiatry: towards improving mental health by what you eat. . Eur. Neuropsychopharmacol. 29::132132
    [Google Scholar]
  75. 75. 
    Drossman DA. 2006.. The functional gastrointestinal disorders and the Rome III process. . Gastroenterology 130::137790
    [Google Scholar]
  76. 76. 
    Lackner JM, Keefer L, Jaccard J, et al. 2012.. The Irritable Bowel Syndrome Outcome Study (IBSOS): rationale and design of a randomized, placebo-controlled trial with 12 month follow up of self- versus clinician-administered CBT for moderate to severe irritable bowel syndrome. . Contemp. Clin. Trials 33::1293310
    [Google Scholar]
  77. 77. 
    Lackner JM, Jaccard J, Radziwon CD, et al. 2019.. Durability and decay of treatment benefit of cognitive behavioral therapy for irritable bowel syndrome: 12-month follow-up. . Am. J. Gastroenterol. 114::33038
    [Google Scholar]
  78. 78. 
    Ford AC, Lacy BE, Harris LA, et al. 2019.. Effect of antidepressants and psychological therapies in irritable bowel syndrome: an updated systematic review and meta-analysis. . Am. J. Gastroenterol. 114::2139
    [Google Scholar]
  79. 78a. 
    Jacobs JP, Gupta A, Bhatt RR, et al. 2021.. Cognitive behavioral therapy for irritable bowel syndrome induces bidirectional alterations in the brain-gut-microbiome axis associated with gastrointestinal symptom improvement. . Microbiome. In press
    [Google Scholar]
  80. 79. 
    Trinkley KE, Nahata MC. 2014.. Medication management of irritable bowel syndrome. . Digestion 89::25367
    [Google Scholar]
  81. 80. 
    Chey WD, Shah ED, DuPont HL. 2020.. Mechanism of action and therapeutic benefit of rifaximin in patients with irritable bowel syndrome: a narrative review. . Ther. Adv. Gastroenterol. 13::1756284819897531
    [Google Scholar]
  82. 81. 
    Fodor AA, Pimentel M, Chey WD, et al. 2019.. Rifaximin is associated with modest, transient decreases in multiple taxa in the gut microbiota of patients with diarrhoea-predominant irritable bowel syndrome. . Gut Microbes 10::2233
    [Google Scholar]
  83. 82. 
    Halkjaer SI, Christensen AH, Lo BZS, et al. 2018.. Faecal microbiota transplantation alters gut microbiota in patients with irritable bowel syndrome: results from a randomised, double-blind placebo-controlled study. . Gut 67::210715
    [Google Scholar]
  84. 83. 
    Morais LH, Schreiber HL 4th, Mazmanian SK 2021.. The gut microbiota-brain axis in behaviour and brain disorders. . Nat. Rev. Microbiol. 19::24455
    [Google Scholar]
/content/journals/10.1146/annurev-med-042320-014032
Loading
/content/journals/10.1146/annurev-med-042320-014032
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error