Skip to main content
SpringerLink
Log in

A biological framework for emotional dysregulation in alcohol misuse: from gut to brain

  • Expert Review
  • Published:
Molecular Psychiatry Submit manuscript

Abstract

Alcohol use disorder (AUD) has been associated with impairments in social and emotional cognition that play a crucial role in the development and maintenance of addiction. Repeated alcohol intoxications trigger inflammatory processes and sensitise the immune system. In addition, emerging data point to perturbations in the gut microbiome as a key regulator of the inflammatory cascade in AUD. Inflammation and social cognition are potent modulators of one another. At the same time, accumulating evidence implicates the gut microbiome in shaping emotional and social cognition, suggesting the possibility of a common underlying loop of crucial importance for addiction. Here we propose an integrative microbiome neuro-immuno-affective framework of how emotional dysregulation and alcohol-related microbiome dysbiosis could accelerate the cycle of addiction. We outline the overlapping effects of chronic alcohol use, inflammation and microbiome alterations on the fronto-limbic circuitry as a convergence hub for emotional dysregulation. We discuss the interdependent relationship of social cognition, immunity and the microbiome in relation to alcohol misuse- from binge drinking to addiction. In addition, we emphasise adolescence as a sensitive period for the confluence of alcohol harmful effects and emotional dysregulation in the developing gut–brain axis.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1: Effects of alcohol misuse in the gut–brain axis.
Fig. 2: Overlapping brain hubs for the interlinked effects of alcohol misuse, inflammation and gut microbes.
Fig. 3: Integration of the microbiome neuro-immuno-affective framework in the addiction cycle.
Fig. 4: Adolescent vulnerability to binge drinking from a microbiome neuro-immuno-affective perspective.

Similar content being viewed by others

References

  1. Enoch MA. The role of early life stress as a predictor for alcohol and drug dependence. Psychopharmacology. 2011;214:17–31.

    CAS  PubMed  Google Scholar 

  2. Tawa EA, Hall SD, Lohoff FW. Overview of the genetics of alcohol use disorder. Alcohol Alcohol. 2016;51:507–14.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Stavro K, Pelletier J, Potvin S. Widespread and sustained cognitive deficits in alcoholism: a meta‐analysis. Addiction Biol. 2013;18:203–13.

    Google Scholar 

  4. Le Berre AP. Emotional processing and social cognition in alcohol use disorder. Neuropsychology. 2019;33:808–21.

    PubMed  PubMed Central  Google Scholar 

  5. Schulte T, Müller-Oehring EM, Pfefferbaum A, Sullivan EV. Neurocircuitry of emotion and cognition in alcoholism: contributions from white matter fiber tractography. Dialogues Clin Neurosci. 2010;12:554–60.

    PubMed  PubMed Central  Google Scholar 

  6. Voon V, Grodin E, Mandali A, Morris L, Weidacker K, Kwako, et al. Addictions NeuroImaging Assessment (ANIA): towards an integrative framework for alcohol use disorder. Neurosci Biobehav Rev. 2020;113:492–506.

    PubMed  Google Scholar 

  7. Crews FT, Sarkar DK, Qin L, Zou J, Boyadjieva N, Vetreno RP. Neuroimmune function and the consequences of alcohol exposure. Alcohol Res: Curr Rev. 2015;37:331.

    Google Scholar 

  8. Alasmari F, Goodwani S, McCullumsmith RE, Sari Y. Role of glutamatergic system and mesocorticolimbic circuits in alcohol dependence. Prog Neurobiol. 2018;171:32–49.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Koob GF, Volkow ND. Neurobiology of addiction: a neurocircuitry analysis. Lancet Psychiatry. 2016;3:760–73.

    PubMed  PubMed Central  Google Scholar 

  10. Hillemacher T, Bachmann O, Kahl KG, Frieling H. Alcohol, microbiome, and their effect on psychiatric disorders. Prog Neuro-Psychopharmacol Biol Psychiatry. 2018;85:105–15.

    CAS  Google Scholar 

  11. Koob GF. Negative reinforcement in drug addiction: the darkness within. Curr Opin Neurobiol. 2013;23:559–63.

    CAS  PubMed  Google Scholar 

  12. Leclercq S, Cani PD, Neyrinck AM, Stärkel P, Jamar F, Mikolajczak M, et al. Role of intestinal permeability and inflammation in the biological and behavioral control of alcohol-dependent subjects. Brain Behav Immun. 2012;26:911–8.

    CAS  PubMed  Google Scholar 

  13. Meckel KR, Kiraly DD. A potential role for the gut microbiome in substance use disorders. Psychopharmacology. 2019;236:1513–30.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Temko JE, Bouhlal S, Farokhnia M, Lee MR, Cryan JF, Leggio L. The microbiota, the gut and the brain in eating and alcohol use disorders: a ‘Ménage à Trois’? Alcohol Alcohol. 2017;52:403–13.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Herd P, Palloni A, Rey F, Dowd JB. Social and population health science approaches to understand the human microbiome. Nat Hum Behav. 2018;2:808–15.

    PubMed  PubMed Central  Google Scholar 

  16. Sherwin E, Bordenstein SR, Quinn JL, Dinan TG, Cryan JF. Microbiota and the social brain. Science. 2019;366:eaar2016.

    CAS  PubMed  Google Scholar 

  17. Kraynak TE, Marsland AL, Wager TD, Gianaros PJ. Functional neuroanatomy of peripheral inflammatory physiology: a meta-analysis of human neuroimaging studies. Neurosci Biobehav Rev. 2018;94:76–92.

    PubMed  PubMed Central  Google Scholar 

  18. Cryan JF, Dinan TG. Decoding the role of the microbiome on amygdala function and social behaviour. Neuropsychopharmacology. 2019;44:233–4.

    PubMed  Google Scholar 

  19. Leclercq S, de Timary P, Delzenne NM, Stärkel P. The link between inflammation, bugs, the intestine and the brain in alcohol dependence. Transl Psychiatry. 2017;7:e1048.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Casey BJ, Heller AS, Gee DG, Cohen AO. Development of the emotional brain. Neurosci Lett. 2019;693:29–34.

    CAS  PubMed  Google Scholar 

  21. Sawyer SM, Azzopardi PS, Wickremarathne D, Patton GC. The age of adolescence. Lancet Child Adolesc Health. 2018;2:223 228.

    PubMed  Google Scholar 

  22. National Institute of Alcohol Abuse and Alcoholism. NIAAA council approves definition of binge drinking. NIAAA Newslett. 2004;3:3. http://pubs.niaaa.nih.gov/publications/Newsletter/winter2004/Newsletter_Number3.pdf

    Google Scholar 

  23. Spear LP. Effects of adolescent alcohol consumption on the brain and behaviour. Nat Rev Neurosci. 2018;19:197–214.

    CAS  PubMed  Google Scholar 

  24. Lannoy S, Benzerouk F, Maurage P, Barrière S, Billieux J, Naassila M, et al. Disrupted fear and sadness recognition in binge drinking: a combined group and individual analysis. Alcohol: Clin Exp Res. 2019;43:1978–85.

    Google Scholar 

  25. Blakemore SJ. The social brain in adolescence. Nat Rev Neurosci. 2008;9:267–77.

    CAS  PubMed  Google Scholar 

  26. Borre YE, O’Keeffe GW, Clarke G, Stanton C, Dinan TG, Cryan JF. Microbiota and neurodevelopmental windows: implications for brain disorders. Trends Mol Med. 2014;20:509–18.

    PubMed  Google Scholar 

  27. McVey Neufeld KA, Luczynski P, Dinan TG, Cryan JF. Reframing the teenage wasteland: adolescent microbiota-gut-brain axis. Can J Psychiatry. 2016;61:214–21.

    PubMed  PubMed Central  Google Scholar 

  28. Romeo RD. The teenage brain: the stress response and the adolescent brain. Curr Dir Psychol Sci. 2013;22:140–5.

    PubMed  PubMed Central  Google Scholar 

  29. Frith CD, Frith U. Social cognition in humans. Curr Biol. 2007;17:R724–R732.

    CAS  PubMed  Google Scholar 

  30. Green MF, Penn DL, Bentall R, Carpenter WT, Gaebel W, Gur RC, et al. Social cognition in schizophrenia: an NIMH workshop on definitions, assessment, and research opportunities. Schizophr Bull. 2008;34:1211–20.

    PubMed  PubMed Central  Google Scholar 

  31. Pabst A, Heeren A, Maurage P. Socio-affective processing biases in severe alcohol use disorders: experimental and therapeutic perspectives. Addic Behav. 2020;106:106382.

    Google Scholar 

  32. Freeman CR, Wiers CE, Sloan ME, Zehra A, Ramirez V, Wang GJ, et al. Emotion recognition biases in alcohol use disorder. Alcohol: Clin Exp Res. 2018;42:1541–7.

    Google Scholar 

  33. Bora E, Zorlu N. Social cognition in alcohol use disorder: a meta‐analysis. Addiction. 2017;112:40–48.

    PubMed  Google Scholar 

  34. D’Hondt F, Campanella S, Kornreich C, Philippot P, Maurage P. Below and beyond the recognition of emotional facial expressions in alcohol dependence: from basic perception to social cognition. Neuropsychiatr Dis Treat. 2014;10:2177–82.

    PubMed  PubMed Central  Google Scholar 

  35. Kornreich C, Brevers D, Canivet D, Ermer E, Naranjo C, Constant E, et al. Impaired processing of emotion in music, faces and voices supports a generalized emotional decoding deficit in alcoholism. Addiction. 2013;108:80–88.

    PubMed  Google Scholar 

  36. Maurage P, Campanella S, Philippot P, Charest I, Martin S, de Timary P. Impaired emotional facial expression decoding in alcoholism is also present for emotional prosody and body postures. Alcohol Alcohol. 2009;44:476–85.

    PubMed  Google Scholar 

  37. Monnot M, Lovallo WR, Nixon SJ, Ross E. Neurological basis of deficits in affective prosody comprehension among alcoholics and fetal alcohol-exposed adults. J Neuropsychiatry Clin Neurosci. 2002;14:321–8.

    CAS  PubMed  Google Scholar 

  38. Brion M, D’Hondt F, Lannoy S, Pitel AL, Davidoff DA, Maurage P. Crossmodal processing of emotions in alcohol-dependence and Korsakoff syndrome. Cogn Neuropsychiatry. 2017;22:436–51.

    PubMed  Google Scholar 

  39. Maurage P, Campanella S, Philippot P, Pham TH, Joassin F. The crossmodal facilitation effect is disrupted in alcoholism: a study with emotional stimuli. Alcohol Alcohol. 2007;42:552–9.

    CAS  PubMed  Google Scholar 

  40. Maurage P, Bestelmeyer PE, Rouger J, Charest I, Belin P. Binge drinking influences the cerebral processing of vocal affective bursts in young adults. Neuroimage: Clin. 2013;3:218–25.

    Google Scholar 

  41. Maurage P, Campanella S, Philippot P, Martin S, De Timary P. Face processing in chronic alcoholism: a specific deficit for emotional features. Alcohol: Clin Exp Res. 2008;32:600–6.

    CAS  Google Scholar 

  42. Maurage P, Campanella S, Philippot P, Vermeulen N, Constant E, Luminet O, et al. Electrophysiological correlates of the disrupted processing of anger in alcoholism. Int J Psychophysiol. 2008;70:50–62.

    PubMed  Google Scholar 

  43. Foisy ML, Kornreich C, Fobe A, D’Hondt L, Pelc I, Hanak C, et al. Impaired emotional facial expression recognition in alcohol dependence: do these deficits persist with midterm abstinence? Alcohol: Clin Exp Res. 2007;31:404–10.

    Google Scholar 

  44. Alba-Ferrara L, Müller-Oehring EM, Sullivan EV, Pfefferbaum A, Schulte T. Brain responses to emotional salience and reward in alcohol use disorder. Brain Imaging Behav. 2016;10:136–46.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Oscar-Berman M, Valmas MM, Sawyer KS, Ruiz SM, Luhar RB, & Gravitz ZR. Profiles of impaired, spared, and recovered neuropsychologic processes in alcoholism. In Handbook of clinical neurology 2014; Elsevier. Vol. 125, pp. 183–210.

  46. Schulte T, Oberlin BG, Kareken DA, Marinkovic K, Müller‐Oehring EM, Meyerhoff DJ, et al. How acute and chronic alcohol consumption affects brain networks: insights from multimodal neuroimaging. Alcohol: Clin Exp Res. 2012;36:2017–27.

    CAS  Google Scholar 

  47. LaBar KS, Cabeza R. Cognitive neuroscience of emotional memory. Nat Rev Neurosci. 2006;7:54–64.

    CAS  PubMed  Google Scholar 

  48. Gorka SM, Fitzgerald DA, King AC, Phan KL. Alcohol attenuates amygdala–frontal connectivity during processing social signals in heavy social drinkers. Psychopharmacology. 2013;229:141–54.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Sripada CS, Angstadt M, McNamara P, King AC, Phan KL. Effects of alcohol on brain responses to social signals of threat in humans. Neuroimage. 2011;55:371–80.

    CAS  PubMed  Google Scholar 

  50. Courtney KE, Infante MA, Brown GG, Tapert SF, Simmons AN, Smith TL, et al. The relationship between regional cerebral blood flow estimates and alcohol problems at 5‐year follow‐up: the role of level of response. Alcohol: Clin Exp Res. 2019;43:812–21.

    Google Scholar 

  51. Shakra MA, Leyton M, Moghnieh H, Pruessner J, Dagher A, Pihl R. Neurobiological correlates and predictors of two distinct personality trait pathways to escalated alcohol use. EBioMedicine. 2018;27:86–93.

    PubMed  Google Scholar 

  52. Aloi J, Blair KS, Crum KI, Meffert H, White SF, Tyler PM, et al. Adolescents show differential dysfunctions related to Alcohol and Cannabis Use Disorder severity in emotion and executive attention neuro-circuitries. NeuroImage: Clin. 2018;19:782–92.

    Google Scholar 

  53. Volkow ND, Koob GF, McLellan AT. Neurobiologic advances from the brain disease model of addiction. N Engl J Med. 2016;374:363–71.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Connell AM, Patton E, McKillop H. Binge drinking, depression, and electrocortical responses to emotional images. Psychol Addic Behav. 2015;29:673–82.

    Google Scholar 

  55. Lannoy S, Dormal V, Brion M, Gaudelus B, Billieux J, Maurage P. Affective impairments in binge drinking: Investigation through emotional facial expression decoding. Compr Psychiatry. 2018;83:59–63.

    PubMed  Google Scholar 

  56. Leganes-Fonteneau M, Pi-Ruano M, Tejero P. Early signs of emotional recognition deficits in adolescent high-binge drinkers. Subst Use Misuse. 2020;55:218–29.

    PubMed  Google Scholar 

  57. Huang S, Holcomb LA, Cruz SM, Marinkovic K. Altered oscillatory brain dynamics of emotional processing in young binge drinkers. Cogn Affect Behav Neurosci. 2018;18:43–57.

    PubMed  PubMed Central  Google Scholar 

  58. Elsayed NM, Kim MJ, Fields KM, Olvera RL, Hariri AR, Williamson DE. Trajectories of alcohol initiation and use during adolescence: the role of stress and amygdala reactivity. J Am Acad Child Adolesc Psychiatry. 2018;57:550–60.

    PubMed  PubMed Central  Google Scholar 

  59. Schaafsma SM, Pfaff DW, Spunt RP, Adolphs R. Deconstructing and reconstructing theory of mind. Trends Cogn Sci. 2015;19:65–72.

    PubMed  Google Scholar 

  60. Onuoha RC, Quintana DS, Lyvers M, Guastella AJ. A meta-analysis of theory of mind in alcohol use disorders. Alcohol Alcohol. 2016;51:410–5.

    PubMed  Google Scholar 

  61. O’Daly OG, Trick L, Scaife J, Marshall J, Ball D, Phillips ML, et al. Withdrawal-associated increases and decreases in functional neural connectivity associated with altered emotional regulation in alcoholism. Neuropsychopharmacology. 2012;37:2267–76.

    PubMed  PubMed Central  Google Scholar 

  62. Salloum JB, Ramchandani VA, Bodurka J, Rawlings R, Momenan R, George D, et al. Blunted rostral anterior cingulate response during a simplified decoding task of negative emotional facial expressions in alcoholic patients. Alcohol, Clin Exp Res. 2007;31:1490–504.

    Google Scholar 

  63. Xiao P, Dai Z, Zhong J, Zhu Y, Shi H, Pan P. Regional gray matter deficits in alcohol dependence: a meta-analysis of voxel-based morphometry studies. Drug Alcohol Depend. 2015;153:22–28.

    PubMed  Google Scholar 

  64. Maurage F, de Timary P, Tecco JM, Lechantre S, Samson D. Theory of mind difficulties in patients with alcohol dependence: beyond the prefrontal cortex dysfunction hypothesis. Alcohol: Clin Exp Res. 2015;39:980–8.

    Google Scholar 

  65. Laghi F, Bianchi D, Pompili S, Lonigro A, Baiocco R. Heavy episodic drinking in late adolescents: the role of theory of mind and conformity drinking motives. Addict Behav. 2019;96:18–25.

    PubMed  Google Scholar 

  66. Lannoy S, Gilles F, Benzerouk F, Henry A, Oker A, Raucher-Chéné D, et al. Disentangling the role of social cognition processes at early steps of alcohol abuse: the influence of affective theory of mind. Addict Behav. 2020;102:106187.

    PubMed  Google Scholar 

  67. Brady KT, Back SE, Waldrop AE, McRae AL, Anton RF, Upadhyaya HP, et al. Cold pressor task reactivity: predictors of alcohol use among alcohol‐dependent individuals with and without comorbid posttraumatic stress disorder. Alcohol: Clin Exp Res. 2006;30:938–46.

    Google Scholar 

  68. Brady KT, Waldrop AE, Mcrae AL, Back SE, Saladin ME, Upadhyaya HP, et al. The impact of alcohol dependence and posttraumatic stress disorder on cold pressor task response. J Stud alcohol. 2006;67:700–6.

    PubMed  Google Scholar 

  69. Milivojevic V, Sinha R. Central and peripheral biomarkers of stress response for addiction risk and relapse vulnerability. Trends Mol Med. 2018;24:173–86.

    PubMed  PubMed Central  Google Scholar 

  70. Leyro TM, Zvolensky MJ, Bernstein A. Distress tolerance and psychopathological symptoms and disorders: a review of the empirical literature among adults. Psychol Bull. 2010;136:576–600.

    PubMed  PubMed Central  Google Scholar 

  71. Howell A, Leyro T, Hogan J, Buckner J, Zvolensky M. Anxiety sensitivity, distress tolerance, and discomfort intolerance in relation to coping and conformity motives for alcohol use and alcohol use problems among young adult drinkers. Addict Behav. 2010;35:1144–7.

    PubMed  PubMed Central  Google Scholar 

  72. Gorka SM, Ali B, Daughters SB. The role of distress tolerance in the relationship between depressive symptoms and problematic alcohol use. Psychol Addict Behav. 2012;26:621.

    PubMed  Google Scholar 

  73. Poncin M, Vermeulen N, De Timary P. Distress response to the failure to an insoluble anagrams task: maladaptive emotion regulation strategies in binge drinking students. Front Psychol. 2017;8:1795.

    PubMed  PubMed Central  Google Scholar 

  74. Pedrelli P, MacPherson L, Khan AJ, Shapero BG, Fisher LB, Nyer M, et al. Sex differences in the association between heavy drinking and behavioral distress tolerance and emotional reactivity among non-depressed college students. Alcohol Alcohol. 2018;53:674–81.

    PubMed  PubMed Central  Google Scholar 

  75. Winward JL, Bekman NM, Hanson KL, Lejuez CW, Brown SA. Changes in emotional reactivity and distress tolerance among heavy drinking adolescents during sustained abstinence. Alcohol: Clin Exp Res. 2014;38:1761–9.

    Google Scholar 

  76. Frank DW, Dewitt M, Hudgens-Haney M, Schaeffer DJ, Ball BH, Schwarz NF, et al. Emotion regulation: quantitative meta-analysis of functional activation and deactivation. Neurosci Biobehav Rev. 2014;45:202–11.

    CAS  PubMed  Google Scholar 

  77. Ahmed SP, Bittencourt-Hewitt A, Sebastian CL. Neurocognitive bases of emotion regulation development in adolescence. Dev Cogn Neurosci. 2015;15:11–25.

    PubMed  PubMed Central  Google Scholar 

  78. Herman AM, Duka T. Facets of impulsivity and alcohol use: what role do emotions play? Neurosci Biobehav Rev. 2019;106:202–16.

    PubMed  Google Scholar 

  79. Cyders MA, Smith GT. Emotion-based dispositions to rash action: positive and negative urgency. Psychol Bull. 2008;134:807–28.

    PubMed  PubMed Central  Google Scholar 

  80. Lannoy S, Billieux J, Poncin M, Maurage P. Binging at the campus: motivations and impulsivity influence binge drinking profiles in university students. Psychiatry Res. 2017;250:146–54.

    PubMed  Google Scholar 

  81. Smith GT, Cyders MA. Integrating affect and impulsivity: the role of positive and negative urgency in substance use risk. Drug Alcohol Depend. 2016;163:S3–S12.

    PubMed  PubMed Central  Google Scholar 

  82. Coskunpinar A, Dir AL, Cyders MA. Multidimensionality in impulsivity and alcohol use: a meta‐analysis using the UPPS model of impulsivity. Alcohol: Clin Exp Res. 2013;37:1441–50.

    Google Scholar 

  83. Braunstein LM, Gross JJ, Ochsner KN. Explicit and implicit emotion regulation: a multi-level framework. Soc Cogn Affect Neurosci. 2017;12:1545–57.

    PubMed  PubMed Central  Google Scholar 

  84. Schweizer S, Gotlib IH, Blakemore SJ. The role of affective control in emotion regulation during adolescence. Emotion. 2020;20:80–86.

    PubMed  PubMed Central  Google Scholar 

  85. Carbia C, López-Caneda E, Corral M, Cadaveira F. A systematic review of neuropsychological studies involving young binge drinkers. Neurosci Biobehav Rev. 2018;90:332–349.

    PubMed  Google Scholar 

  86. Lannoy S, Billieux J, Maurage P. Beyond inhibition: a dual-process perspective to renew the exploration of binge drinking. Front Hum Neurosci. 2014;8:405.

    PubMed  PubMed Central  Google Scholar 

  87. Schulte T, Jung YC, Sullivan EV, Pfefferbaum A, Serventi M, Müller-Oehring EM. The neural correlates of priming emotion and reward systems for conflict processing in alcoholics. Brain Imaging Behav. 2017;11:1751–68.

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Herman AM, Critchley HD, Duka T. The role of emotions and physiological arousal in modulating impulsive behaviour. Biol Psychol. 2018;133:30–43.

    PubMed  Google Scholar 

  89. Lees B, Stapinski LA, Prior K, Sunderland M, Newton N, Baillie A, et al. Exploring the complex inter-relations between internalising symptoms, executive functioning and alcohol use in young adults. Addict Behav. 2020;106:106351.

    PubMed  Google Scholar 

  90. Carbia C, Corral M, Caamaño-Isorna F, Cadaveira F. Emotional memory bias in binge drinking women. Drug alcohol Depend. 2020;209:107888.

    CAS  PubMed  Google Scholar 

  91. Hu S, Ide JS, Chao HH, Zhornitsky S, Fischer KA, Wang W, et al. Resting state functional connectivity of the amygdala and problem drinking in non-dependent alcohol drinkers. Drug Alcohol Depend. 2018;185:173–80.

    PubMed  PubMed Central  Google Scholar 

  92. Zhang R, Volkow ND. Brain default-mode network dysfunction in addiction. Neuroimage. 2019;200:313–31.

    CAS  PubMed  Google Scholar 

  93. Lee E, Ku J, Jung YC, Lee H, An SK, Kim KR, et al. Neural evidence for emotional involvement in pathological alcohol craving. Alcohol Alcohol. 2013;48:288–94.

    CAS  PubMed  Google Scholar 

  94. Cohen-Gilbert JE, Nickerson LD, Sneider JT, Oot EN, Seraikas AM, Rohan ML, et al. College binge drinking associated with decreased frontal activation to negative emotional distractors during inhibitory control. Front Psychol. 2017;8:1650.

    PubMed  PubMed Central  Google Scholar 

  95. Herman AM, Critchley HD, Duka T. Binge drinking is associated with attenuated frontal and parietal activation during successful response inhibition in fearful context. Eur J Neurosci. 2019;50:2297–310.

    PubMed  Google Scholar 

  96. Marshall SA, McClain JA, Kelso ML, Hopkins DM, Pauly JR, Nixon K. Microglial activation is not equivalent to neuroinflammation in alcohol-induced neurodegeneration: the importance of microglia phenotype. Neurobiol Dis. 2013;54:239–51.

    CAS  PubMed  PubMed Central  Google Scholar 

  97. McClain JA, Morris SA, Deeny MA, Marshall SA, Hayes DM, Kiser ZM, et al. Adolescent binge alcohol exposure induces long-lasting partial activation of microglia. Brain Behav Immun. 2011;25:S120–S128.

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Coleman LG, & Crews FT. Innate immune signaling and alcohol use disorders. In: The neuropharmacology of alcohol. 2018. Springer, Cham.

  99. Pascual M, Montesinos J, Guerri C. Role of the innate immune system in the neuropathological consequences induced by adolescent binge drinking. J Neurosci Res. 2018;96:765–80.

    CAS  PubMed  Google Scholar 

  100. Crews FT, Walter TJ, Coleman LG Jr, Vetreno RP. Toll-like receptor signaling and stages of addiction. Psychopharmacology. 2017;234:1483–1498.

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Bajaj JS. Alcohol, liver disease and the gut microbiota. Nat Rev Gastroenterol Hepatol. 2019;16:235–46.

    PubMed  Google Scholar 

  102. Bala S, Marcos M, Gattu A, Catalano D, Szabo G. Acute binge drinking increases serum endotoxin and bacterial DNA levels in healthy individuals. PloS ONE. 2014;9:e96864.

    PubMed  PubMed Central  Google Scholar 

  103. Orio L, Antón M, Rodríguez‐Rojo IC, Correas Á, García‐Bueno B, Corral M, et al. Young alcohol binge drinkers have elevated blood endotoxin, peripheral inflammation and low cortisol levels: neuropsychological correlations in women. Addict Biol. 2018;23:1130–44.

    CAS  PubMed  Google Scholar 

  104. Hillmer AT, Nadim H, Devine L, Jatlow P, O’Malley SS. Acute alcohol consumption alters the peripheral cytokines IL-8 and TNF-α. Alcohol. 2019;85:95–99. https://doi.org/10.1016/j.alcohol.2019.11.005

    Article  CAS  PubMed  Google Scholar 

  105. Blednov YA, Benavidez JM, Geil C, Perra S, Morikawa H, Harris RA. Activation of inflammatory signaling by lipopolysaccharide produces a prolonged increase of voluntary alcohol intake in mice. Brain Behav Immun. 2011;25:S92–S105.

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Milivojevic V, Ansell E, Simpson C, Siedlarz KM, Sinha R, Fox HC. Peripheral immune system adaptations and motivation for alcohol in non‐dependent problem drinkers. Alcohol: Clin Exp Res. 2017;41:585–95.

    CAS  Google Scholar 

  107. Lopez RB, Denny BT, Fagundes CP. Neural mechanisms of emotion regulation and their role in endocrine and immune functioning: a review with implications for treatment of affective disorders. Neurosci Biobehav Rev. 2018;95:508–14.

    CAS  PubMed  Google Scholar 

  108. Harrison NA, Brydon L, Walker C, Gray MA, Steptoe A, Dolan RJ, et al. Neural origins of human sickness in interoceptive responses to inflammation. Biol Psychiatry. 2009;66:415–22.

    PubMed  PubMed Central  Google Scholar 

  109. Inagaki TK, Muscatell KA, Irwin MR, Cole SW, Eisenberger NI. Inflammation selectively enhances amygdala activity to socially threatening images. Neuroimage. 2012;59:3222–6.

    PubMed  Google Scholar 

  110. Moieni M, Eisenberger NI. Effects of inflammation on social processes and implications for health. Ann NY Acad Sci. 2018;1428:5–13.

    PubMed  Google Scholar 

  111. Eisenberger NI, Berkman ET, Inagaki TK, Rameson LT, Mashal NM, Irwin MR. Inflammation-induced anhedonia: endotoxin reduces ventral striatum responses to reward. Biol Psychiatry. 2010;68:748–54.

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Phan KL, Wager T, Taylor SF, Liberzon I. Functional neuroanatomy of emotion: a meta-analysis of emotion activation studies in PET and fMRI. Neuroimage. 2002;16:331–48.

    PubMed  Google Scholar 

  113. Eisenberger NI, Moieni M, Inagaki TK, Muscatell KA, Irwin MR. In sickness and in health: the co-regulation of inflammation and social behavior. Neuropsychopharmacology. 2017;42:242–53.

    CAS  PubMed  Google Scholar 

  114. Tang YY, Posner MI, Rothbart MK, Volkow ND. Circuitry of self-control and its role in reducing addiction. Trends Cogn Sci. 2015;19:439–44.

    PubMed  Google Scholar 

  115. Shenhav A, Botvinick MM, Cohen JD. The expected value of control: an integrative theory of anterior cingulate cortex function. Neuron. 2013;79:217–240.

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Moieni M, Irwin MR, Jevtic I, Breen EC, Eisenberger NI. Inflammation impairs social cognitive processing: a randomized controlled trial of endotoxin. Brain Behav Immun. 2015;48:132–138.

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Cryan JF, Dinan TG. Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour. Nat Rev Neurosci. 2012;13:701–12.

    CAS  PubMed  Google Scholar 

  118. Mayer EA. Gut feelings: the emerging biology of gut–brain communication. Nat Rev Neurosci. 2011;12:453–66.

    CAS  PubMed  Google Scholar 

  119. Cryan JF, O’Riordan KJ, Sandhu K, Peterson V, Dinan TG. The gut microbiome in neurological disorders. Lancet Neurol. 2020;19:179–94.

    CAS  PubMed  Google Scholar 

  120. Rooks MG, Garrett WS. Gut microbiota, metabolites and host immunity. Nat Rev Immunol. 2016;16:341–52.

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Chung H, Pamp SJ, Hill JA, Surana NK, Edelman SM, Troy EB, et al. Gut immune maturation depends on colonization with a host-specific microbiota. Cell. 2012;149:1578–93.

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Stewart CJ, Ajami NJ, O’Brien JL, Hutchinson DS, Smith DP, Wong MC, et al. Temporal development of the gut microbiome in early childhood from the TEDDY study. Nature. 2018;562:583–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Erny D, de Angelis ALH, Jaitin D, Wieghofer P, Staszewski O, David E, et al. Host microbiota constantly control maturation and function of microglia in the CNS. Nat Neurosci. 2015;18:965–77.

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Sudo N, Chida Y, Aiba Y, Sonoda J, Oyama N, Yu XN, et al. Postnatal microbial colonization programs the hypothalamic–pituitary–adrenal system for stress response in mice. J Physiol. 2004;558:263–75.

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Rea K, Dinan TG, Cryan JF. The microbiome: a key regulator of stress and neuroinflammation. Neurobiol Stress. 2016;4:23–33.

    PubMed  PubMed Central  Google Scholar 

  126. Rohleder N. Stress and inflammation-The need to address the gap in the transition between acute and chronic stress effects. Psychoneuroendocrinology. 2019;105:164–71.

    PubMed  Google Scholar 

  127. Clarke G, Stilling RM, Kennedy PJ, Stanton C, Cryan JF, Dinan TG. Minireview: Gut microbiota: the neglected endocrine organ. Mol Endocrinol. 2014;28:1221–1238.

    PubMed  PubMed Central  Google Scholar 

  128. González-Arancibia C, Urrutia-Piñones J, Illanes-González J, Martinez-Pinto J, Sotomayor-Zárate R, Julio-Pieper M, et al. Do your gut microbes affect your brain dopamine? Psychopharmacology. 2019;236:1611–22.

    PubMed  Google Scholar 

  129. Han W, Tellez LA, Perkins MH, Perez IO, Qu T, Ferreira J, et al. A neural circuit for gut-induced reward. Cell. 2018;175:665–78.

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Jadhav KS, Peterson VL, Halfon O, Ahern G, Fouhy F, Stanton C, et al. Gut microbiome correlates with altered striatal dopamine receptor expression in a model of compulsive alcohol seeking. Neuropharmacology. 2018;141:249–259.

    CAS  PubMed  Google Scholar 

  131. Lee K, Vuong HE, Nusbaum DJ, Hsiao EY, Evans CJ, Taylor AM. The gut microbiota mediates reward and sensory responses associated with regimen-selective morphine dependence. Neuropsychopharmacology. 2018;43:2606–14.

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Kiraly DD, Walker DM, Calipari ES, Labonte B, Issler O, Pena CJ, et al. Alterations of the host microbiome affect behavioral responses to cocaine. Sci Rep. 2016;6:35455.

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Simpson S, Kimbrough A, Boomhower B, McLellan R, Hughes M, Shankar K, et al. Depletion of the microbiome alters the recruitment of neuronal ensembles of oxycodone intoxication and withdrawal. Eneuro. 2020;7. https://doi.org/10.1523/ENEURO.0312-19.2020

  134. Hsiao SW, McBride S, Hsien G, Sharon ER, Hyde T, McCue JA, et al. Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders. Cell. 2013;155:1451–63.

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Cowan CS, Hoban AE, Ventura‐Silva AP, Dinan TG, Clarke G, Cryan JF. Gutsy moves: the amygdala as a critical node in microbiota to brain signaling. BioEssays. 2018;40:1700172.

    Google Scholar 

  136. Luczynski P, McVey Neufeld KA, Oriach CS, Clarke G, Dinan TG, Cryan JF. Growing up in a bubble: using germ-free animals to assess the influence of the gut microbiota on brain and behavior. Int J Neuropsychopharmacol. 2016;19:pyw020.

    PubMed  PubMed Central  Google Scholar 

  137. Heijtz RD, Wang S, Anuar F, Qian Y, Björkholm B, Samuelsson A, et al. Normal gut microbiota modulates brain development and behavior. Proc Natl Acad Sci. 2011;108:3047–52.

    CAS  Google Scholar 

  138. Ogbonnaya ES, Clarke G, Shanahan F, Dinan TG, Cryan JF, O’Leary OF. Adult hippocampal neurogenesis is regulated by the microbiome. Biol Psychiatry. 2015;78:e7–e9.

    PubMed  Google Scholar 

  139. Luby JL, Belden A, Harms MP, Tillman R, Barch DM. Preschool is a sensitive period for the influence of maternal support on the trajectory of hippocampal development. Proc Natl Acad Sci. 2016;113:5742–7.

    CAS  PubMed  Google Scholar 

  140. Desbonnet L, Clarke G, Traplin A, et al. Gut microbiota depletion from early adolescence in mice: Implications for brain and behaviour. Brain Behav Immun. 2015;48:165–173.

    CAS  PubMed  Google Scholar 

  141. Bercik P, Denou E, Collins J, Jackson W, Lu J, Jury J, et al. The intestinal microbiota affect central levels of brain-derived neurotropic factor and behavior in mice. Gastroenterology. 2011;141:599–609. 609.e1–3

    CAS  PubMed  Google Scholar 

  142. Stilling RM, Dinan TG, Cryan JF. Microbial genes, brain & behaviour - epigenetic regulation of the gut-brain axis. Genes Brain Behav. 2014;13:69–86.

    CAS  PubMed  Google Scholar 

  143. Gronier B, Savignac HM, Di Miceli M, Idriss SM, Tzortzis G, Anthony D, et al. Increased cortical neuronal responses to NMDA and improved attentional set-shifting performance in rats following prebiotic (B-GOS®) ingestion. Eur Neuropsychopharmacol. 2018;28:211–24.

    CAS  PubMed  PubMed Central  Google Scholar 

  144. Hoban A, Stilling R, Ryan F, Cryan F. Regulation of prefrontal cortex myelination by the microbiota. Transl Psychiatry. 2016;6:e774. https://doi.org/10.1038/tp.2016.42

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Dixon ML, Thiruchselvam R, Todd R, Christoff K. Emotion and the prefrontal cortex: an integrative review. Psychological Bull. 2017;143:1033.

    Google Scholar 

  146. Gacias M, Gaspari S, Santos PMG, Tamburini S, Andrade M, Zhang F, et al. Microbiota-driven transcriptional changes in prefrontal cortex override genetic differences in social behavior. Elife. 2016;5:e13442. https://doi.org/10.7554/eLife.13442

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Hoban AE, Stilling RM, Moloney GM, Moloney RD, Shanahan F, Dinan TG, et al. Microbial regulation of microRNA expression in the amygdala and prefrontal cortex. Microbiome. 2017;5:102. https://doi.org/10.1186/s40168-017-0321-3. Published 2017 Aug 25

    Article  PubMed  PubMed Central  Google Scholar 

  148. Desbonnet L, Clarke G, Shanahan F, Dinan TG, Cryan JF. Microbiota is essential for social development in the mouse. Mol Psychiatry. 2014;1 9:146–148.

    Google Scholar 

  149. Luczynski P, Whelan SO, O’Sullivan C, Clarke G, Shanahan F, Dinan TG, et al. Adult microbiota‐deficient mice have distinct dendritic morphological changes: differential effects in the amygdala and hippocampus. Eur J Neurosci. 2016;44:2654–66.

    PubMed  PubMed Central  Google Scholar 

  150. Dinan TG, Stanton C, Cryan JF. Psychobiotics: a novel class of psychotropic. Biol Psychiatry. 2013;74:720–726.

    CAS  PubMed  Google Scholar 

  151. Sgritta M, Dooling SW, Buffington SA, Momin EN, Francis MB, Britton RA, et al. Mechanisms underlying microbial-mediated changes in social behavior in mouse models of autism spectrum disorder. Neuron. 2019;101:246–.e6. https://doi.org/10.1016/j.neuron.2018.11.018

    Article  CAS  PubMed  Google Scholar 

  152. Chong HX, Yusoff NAA, Hor YY, Lew LC, Jaafar MH, Choi SB, et al. Lactobacillus plantarum DR7 alleviates stress and anxiety in adults: a randomised, double-blind, placebo-controlled study. Beneficial Microbes. 2019;10:355–73.

    CAS  PubMed  Google Scholar 

  153. Bagga D, Reichert JL, Koschutnig K, Aigner CS, Holzer P, Koskinen K, et al. Probiotics drive gut microbiome triggering emotional brain signatures. Gut Microbes. 2018;9:486–96.

    CAS  PubMed  PubMed Central  Google Scholar 

  154. Tillisch K, Labus J, Kilpatrick L, Jiang Z, Stains J, Ebrat B, et al. Consumption of fermented milk product with probiotic modulates brain activity. Gastroenterology. 2013;144:1394–401.

    CAS  PubMed  Google Scholar 

  155. Chu C, Murdock MH, Jing D, Won TH, Chung H, Kressel AM, et al. The microbiota regulate neuronal function and fear extinction learning. Nature. 2019;574:543–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  156. Hoban AE, Stilling RM, Moloney G, Shanahan F, Dinan TG, Clarke G, et al. The microbiome regulates amygdala-dependent fear recall. Mol Psychiatry. 2018;23:1134.

    CAS  PubMed  Google Scholar 

  157. Stilling RM, Ryan FJ, Hoban AE, Shanahan F, Clarke G, Claesson MJ, et al. Microbes & neurodevelopment-Absence of microbiota during early life increases activity-related transcriptional pathways in the amygdala. Brain Behav Immun. 2015;50:209–220.

    PubMed  Google Scholar 

  158. Stilling RM, Moloney GM, Ryan FJ, Hoban AE, Bastiaanssen TF, Shanahan F, et al. Social interaction-induced activation of RNA splicing in the amygdala of microbiome-deficient mice. Elife. 2018;7:e33070.

    PubMed  PubMed Central  Google Scholar 

  159. Bishehsari F, Magno E, Swanson G, Desai V, Voigt RM, Forsyth CB, et al. Alcohol and gut-derived inflammation. Alcohol Res: Curr Rev. 2017;38:163.

    Google Scholar 

  160. Engen PA, Green SJ, Voigt RM, Forsyth CB, Keshavarzian A. The gastrointestinal microbiome: alcohol effects on the composition of intestinal microbiota. Alcohol Res: Curr Rev. 2015;37:223.

    Google Scholar 

  161. Bull-Otterson L, Feng W, Kirpich I, Wang Y, Qin X, Liu Y, et al. Metagenomic analyses of alcohol induced pathogenic alterations in the intestinal microbiome and the effect of Lactobacillus rhamnosus GG treatment. PloS ONE. 2013;8:e53028.

    CAS  PubMed  PubMed Central  Google Scholar 

  162. Leclercq S, Matamoros S, Cani PD, Neyrinck AM, Jamar F, Stärkel P, et al. Intestinal permeability, gut-bacterial dysbiosis, and behavioral markers of alcohol-dependence severity. Proc Natl Acad Sci. 2014;111:E4485–E4493.

    CAS  PubMed  Google Scholar 

  163. Mutlu EA, Gillevet PM, Rangwala H, Sikaroodi M, Naqvi A, Engen PA, et al. Colonic microbiome is altered in alcoholism. Am J Physiol-Gastrointest Liver Physiol. 2012;302:G966–G978.

    CAS  PubMed  PubMed Central  Google Scholar 

  164. Peterson VL, Jury NJ, Cabrera-Rubio R, Draper LA, Crispie F, Cotter PD, et al. Drunk bugs: chronic vapour alcohol exposure induces marked changes in the gut microbiome in mice. Behav Brain Res. 2017; 323:172–6. https://doi.org/10.1016/j.bbr.2017.01.049

  165. Xiao HW, Ge C, Feng GX, Li Y, Luo D, Dong JL, et al. Gut microbiota modulates alcohol withdrawal-induced anxiety in mice. Toxicol Lett. 2018;287:23–30.

    CAS  PubMed  PubMed Central  Google Scholar 

  166. Bjørkhaug ST, Aanes H, Neupane SP, Bramness JG, Malvik S, Henriksen C, et al. Characterization of gut microbiota composition and functions in patients with chronic alcohol overconsumption. Gut Microbes. 2019;10:663–75.

    PubMed  PubMed Central  Google Scholar 

  167. Litwinowicz K, Choroszy M, Waszczuk E. Changes in the composition of the human intestinal microbiome in alcohol use disorder: a systematic review. Am J Drug Alcohol Abus. 2020;46:4–12.

    Google Scholar 

  168. Cox SML, Frank MJ, Larcher K, Fellows LK, Clark CA, Leyton M, et al. Striatal D1 and D2 signaling differentially predict learning from positive and negative outcomes. Neuroimage. 2015;109:95–101.

    CAS  PubMed  Google Scholar 

  169. Peterson VL, Richards JB, Meyer PJ, Cabrera-Rubio R, Tripi JA, King CP, et al. Sex-dependent associations between addiction-related behaviors and the microbiome in outbred rats. EBio Med. 2020;55:102769.

    Google Scholar 

  170. Vetreno RP, Massey V, Crews, FT. Long-lasting microbial dysbiosis and altered enteric neurotransmitters in adult rats following adolescent binge ethanol exposure. Addict Biol. 2019; e12869. https://doi.org/10.1111/adb.12869

  171. Zallar LJ, Beurmann S, Tunstall BJ, Fraser CM, Koob GF, Vendruscolo LF, et al. Ghrelin receptor deletion reduces binge‐like alcohol drinking in rats. J Neuroendocrinol. 2019;31:e12663.

    PubMed  Google Scholar 

  172. Llopis M, Cassard AM, Wrzosek L, Boschat L, Bruneau A, Ferrere G, et al. Intestinal microbiota contributes to individual susceptibility to alcoholic liver disease. Gut. 2016;65:830–9.

    CAS  PubMed  Google Scholar 

  173. Bajaj JS, Gavis EA, Fagan A, Wade JB, Thacker LR, Fuchs M, et al., A randomized clinical trial of fecal microbiota transplant for alcohol use disorder. Hepatology. 2020. https://doi.org/10.1002/hep.31496

  174. Fuhrmann D, Knoll LJ, Blakemore SJ. Adolescence as a sensitive period of brain development. Trends Cogn Sci. 2015;19:558–66.

    PubMed  Google Scholar 

  175. Crone EA, Dahl RE. Understanding adolescence as a period of social–affective engagement and goal flexibility. Nat Rev Neurosci. 2012;13:636–50.

    CAS  PubMed  Google Scholar 

  176. Brenhouse HC, Schwarz JM. Immunoadolescence: neuroimmune development and adolescent behavior. Neurosci Biobehav Rev. 2016;70:288–99.

    PubMed  PubMed Central  Google Scholar 

  177. Schulz KM, Molenda-Figueira HA, Sisk CL. Back to the future: the organizational-activational hypothesis adapted to puberty and adolescence. Hormones Behav. 2009;55:597–604.

    CAS  Google Scholar 

  178. Hollister EB, Riehle K, Luna RA, Weidler EM, Rubio-Gonzales M, Mistretta TA, et al. Structure and function of the healthy pre-adolescent pediatric gut microbiome. Microbiome. 2015;3:36.

    PubMed  PubMed Central  Google Scholar 

  179. Schloss PD, Iverson KD, Petrosino JF, Schloss SJ. The dynamics of a family’s gut microbiota reveal variations on a theme. Microbiome. 2014;2:25.

    PubMed  PubMed Central  Google Scholar 

  180. Agans R, Rigsbee L, Kenche H, Michail S, Khamis HJ, Paliy O. Distal gut microbiota of adolescent children is different from that of adults. FEMS Microbiol Ecol. 2011;77:404–12.

    CAS  PubMed  PubMed Central  Google Scholar 

  181. Flannery J, Callaghan B, Sharpton T, Fisher P, Pfeifer J. Is adolescence the missing developmental link in Microbiome–Gut–Brain axis communication? Dev Psychobiol. 2019;61:783–95.

    PubMed  PubMed Central  Google Scholar 

  182. Foster JA, Neufeld KAM. Gut–brain axis: how the microbiome influences anxiety and depression. Trends Neurosci. 2013;36:305–12.

    CAS  PubMed  Google Scholar 

  183. Zeraati M, Enayati M, Kafami L, Shahidi SH, Salari AA. Gut microbiota depletion from early adolescence alters adult immunological and neurobehavioral responses in a mouse model of multiple sclerosis. Neuropharmacology. 2019;157:107685.

    CAS  PubMed  Google Scholar 

  184. Robertson RC, Oriach CS, Murphy K, Moloney GM, Cryan JF, Dinan TG, et al. Omega-3 polyunsaturated fatty acids critically regulate behaviour and gut microbiota development in adolescence and adulthood. Brain Behav Immun. 2017;59:21–37.

    CAS  PubMed  Google Scholar 

  185. Murray E, Sharma R, Smith KB, Mar KD, Barve R, Lukasik M, et al. Probiotic consumption during puberty mitigates LPS-induced immune responses and protects against stress-induced depression-and anxiety-like behaviors in adulthood in a sex-specific manner. Brain Behav Immun. 2019;81:198–212.

    CAS  PubMed  Google Scholar 

  186. Bohnsack JP, Teppen T, Kyzar EJ, Dzitoyeva S, Pandey SC. The lncRNA BDNF-AS is an epigenetic regulator in the human amygdala in early onset alcohol use disorders. Transl Psychiatry. 2019;9:34. https://doi.org/10.1038/s41398-019-0367-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Kyzar EJ, Floreani C, Teppen TL, Pandey SC. Adolescent alcohol exposure: burden of epigenetic reprogramming, synaptic remodeling, and adult psychopathology. Front Neurosci. 2016;10:222.

    PubMed  PubMed Central  Google Scholar 

  188. Pandey SC, Kyzar EJ, Zhang H. Epigenetic basis of the dark side of alcohol addiction. Neuropharmacology. 2017;122:74–84.

    CAS  PubMed  PubMed Central  Google Scholar 

  189. Lees B, Mewton L, Stapinski LA, Squeglia LM, Rae CD, Teesson M. Neurobiological and cognitive profile of young binge drinkers: a systematic review and meta-analysis. Neuropsychol. Rev. 2019;29:357–85.

    PubMed  PubMed Central  Google Scholar 

  190. Blaine SK, Nautiyal N, Hart R, Guarnaccia JB, Sinha R. Craving, cortisol and behavioral alcohol motivation responses to stress and alcohol cue contexts and discrete cues in binge and non‐binge drinkers. Addict Biol. 2019;24:1096–108.

    CAS  PubMed  Google Scholar 

  191. Sinha R. How does stress lead to risk of alcohol relapse? Alcohol Res: Curr Rev. 2012;34:432–40.

    Google Scholar 

  192. Hall GS. Adolescence: Its psychology and its relations to physiology, anthropology, sociology, sex, crime, religion, and education. New York: D. Appleton & Co; 1904.

    Google Scholar 

  193. Camarini R, Marianno P, & Rae M. Social factors in ethanol sensitization. In International review of neurobiology (2018) (Vol. 140, pp. 53-80). Academic Press.

  194. Quadir SG, Santos JRBD, Campbell RR, Wroten MG, Singh N, Holloway JJ, et al. H omer2 regulates alcohol and stress cross‐sensitization. Addiction Biol. 2016;21:613–33.

    CAS  Google Scholar 

  195. Agoglia AE, Herman MA. The center of the emotional universe: alcohol, stress, and CRF1 amygdala circuitry. Alcohol. 2018;72:61–73.

    CAS  PubMed  PubMed Central  Google Scholar 

  196. Uhart M, Wand GS. Stress, alcohol and drug interaction: an update of human research. Addict Biol. 2009;14:43–64.

    CAS  PubMed  Google Scholar 

  197. Robinson TE, Berridge KC. Incentive‐sensitization and addiction. Addiction. 2001;96:103–14.

    CAS  PubMed  Google Scholar 

  198. Ironside M, Kumar P, Kang MS, Pizzagalli DA. Brain mechanisms mediating effects of stress on reward sensitivity. Curr Opin Behav Sci. 2018;22:106–13.

    PubMed  PubMed Central  Google Scholar 

  199. Gladwin TE, Figner B, Crone EA, Wiers RW. Addiction, adolescence, and the integration of control and motivation. Developmental Cogn Neurosci. 2011;1:364–76.

    Google Scholar 

  200. Koob GF, Le Moal M. Drug abuse: hedonic homeostatic dysregulation. Science. 1997;278:52–58.

    CAS  PubMed  Google Scholar 

  201. Koob GF. The dark side of emotion: the addiction perspective. Eur J Pharmacol. 2015;753:73–87.

    CAS  PubMed  PubMed Central  Google Scholar 

  202. Koob GF, Schulkin J. Addiction and stress: an allostatic view. Neurosci Biobehav Rev. 2019;106:245–62.

    PubMed  Google Scholar 

  203. Everitt BJ, Robbins TW. Neural systems of reinforcement for drug addiction: from actions to habits to compulsion. Nat Neurosci. 2005;8:1481–9.

    CAS  PubMed  Google Scholar 

  204. George O, Koob GF. Individual differences in the neuropsychopathology of addiction. Dialogues Clin Neurosci. 2017;19:217.

    PubMed  PubMed Central  Google Scholar 

  205. Koob G, Kreek MJ. Stress, dysregulation of drug reward pathways, and the transition to drug dependence. Am J Psychiatry. 2007;164:1149–59.

    PubMed  PubMed Central  Google Scholar 

  206. Goldstein RZ, Bechara A, Garavan H, Childress AR, Paulus MP, Volkow ND. The neurocircuitry of impaired insight in drug addiction. Trends Cogn Sci. 2009;13:372–80.

    PubMed  PubMed Central  Google Scholar 

  207. Zilverstand A, Huang AS, Alia-Klein N, Goldstein RZ. Neuroimaging impaired response inhibition and salience attribution in human drug addiction: a systematic review. Neuron. 2018;98:886–903.

    CAS  PubMed  PubMed Central  Google Scholar 

  208. Xu Z, Knight R. Dietary effects on human gut microbiome diversity. Br J Nutr. 2015;113:S1–S5.

    CAS  PubMed  Google Scholar 

  209. Lozupone CA, Stombaugh JI, Gordon JI, Jansson JK, Knight R. Diversity, stability and resilience of the human gut microbiota. Nature. 2012;489:220–30.

    CAS  PubMed  PubMed Central  Google Scholar 

  210. Mayer EA, Labus J, Aziz Q, Tracey I, Kilpatrick L, Elsenbruch S, et al. Role of brain imaging in disorders of brain–gut interaction: a Rome Working Team Report. Gut. 2019;68:1701–15.

    CAS  PubMed  PubMed Central  Google Scholar 

  211. Engen HG, Anderson MC. Memory control: a fundamental mechanism of emotion regulation. Trends Cogn Sci. 2018;22:982–95.

    PubMed  PubMed Central  Google Scholar 

  212. Shields GS, Kuchenbecker SY, Pressman SD, Sumida KD, Slavich GM. Better cognitive control of emotional information is associated with reduced pro-inflammatory cytokine reactivity to emotional stress. Stress. 2016;19:63–68.

    CAS  PubMed  PubMed Central  Google Scholar 

  213. Kopec AM, Smith CJ, Bilbo SD. Neuro-immune mechanisms regulating social behavior: dopamine as mediator? Trends Neurosci. 2019;42:337–48.

    CAS  PubMed  PubMed Central  Google Scholar 

  214. Compton RJ, Hofheimer J, Kazinka R. Stress regulation and cognitive control: evidence relating cortisol reactivity and neural responses to errors. Cogn Affect Behav Neurosci. 2013;13:152–163.

    PubMed  PubMed Central  Google Scholar 

  215. Bauer ME, Teixeira AL. Inflammation in psychiatric disorders: what comes first? Ann NY Acad Sci. 2019;1437:57–67.

    CAS  PubMed  Google Scholar 

  216. Crews FT, Lawrimore CJ, Walter TJ, Coleman LG Jr. The role of neuroimmune signaling in alcoholism. Neuropharmacology. 2017;122:56–73.

    CAS  PubMed  PubMed Central  Google Scholar 

  217. Miller AH, Haroon E, Raison CL, Felger JC. Cytokine targets in the brain: impact on neurotransmitters and neurocircuits. Depression Anxiety. 2013;30:297–306.

    CAS  PubMed  Google Scholar 

  218. Yirmiya R, Goshen I. Immune modulation of learning, memory, neural plasticity and neurogenesis. Brain Behav Immun. 2011;25:181–213.

    CAS  PubMed  Google Scholar 

  219. Falony G, Joossens M, Vieira-Silva S, Wang J, Darzi Y, Faust K, et al. Population-level analysis of gut microbiome variation. Science. 2016;352:560–4.

    CAS  PubMed  Google Scholar 

  220. Proctor LM. The human microbiome project in 2011 and beyond. Cell Host Microbe. 2011;10:287–91.

    CAS  PubMed  Google Scholar 

  221. Morris LS, Voon V, Leggio L. Stress, motivation, and the gut–brain axis: a focus on the ghrelin system and alcohol use disorder. Alcohol: Clin Exp Res. 2018;42:1378–89.

    Google Scholar 

  222. Farokhnia M, Faulkner ML, Piacentino D, Lee MR, Leggio L. Ghrelin: From a gut hormone to a potential therapeutic target for alcohol use disorder. Physiol Behav. 2019;204:49–57.

    CAS  PubMed  Google Scholar 

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

    PubMed  PubMed Central  Google Scholar 

  224. Cussotto S, Sandhu KV, Dinan TG, Cryan JF. The neuroendocrinology of the microbiota-gut-brain axis: a behavioural perspective. Front Neuroendocrinol. 2018;51:80–101.

    CAS  PubMed  Google Scholar 

  225. Dalile B, Van Oudenhove L, Vervliet B, Verbeke K. The role of short-chain fatty acids in microbiota–gut–brain communication. Nat Rev Gastroenterol Hepatol. 2019;16:461–78.

    PubMed  Google Scholar 

  226. Kennedy PJ, Cryan JF, Dinan TG, Clarke G. Kynurenine pathway metabolism and the microbiota-gut-brain axis. Neuropharmacology. 2017;112:399–412.

    CAS  PubMed  Google Scholar 

  227. Sarkar A, Lehto SM, Harty S, Dinan TG, Cryan JF, Burnet PW. Psychobiotics and the manipulation of bacteria–gut–brain signals. Trends Neurosci. 2016;39:763–81.

    CAS  PubMed  PubMed Central  Google Scholar 

  228. Rodriguez-Gonzalez A, & Orio L. Microbiota and alcohol use disorder: are psychobiotics a novel therapeutic strategy? Curr Pharm Des. 2020; https://doi.org/10.2174/1381612826666200122153541

  229. Forsyth CB, Farhadi A, Jakate SM, Tang Y, Shaikh M, Keshavarzian A. Lactobacillus GG treatment ameliorates alcohol-induced intestinal oxidative stress, gut leakiness, and liver injury in a rat model of alcoholic steatohepatitis. Alcohol. 2009;43:163–72.

    CAS  PubMed  PubMed Central  Google Scholar 

  230. Leclercq S, Stärkel P, Delzenne NM, de Timary P. The gut microbiota: a new target in the management of alcohol dependence? Alcohol. 2018;74:105–11.

    PubMed  Google Scholar 

  231. Kirpich IA, et al. Probiotics restore bowel flora and improve liver enzymes in human alcohol-induced liver injury: a pilot study. Alcohol. 2008;42:675–82.

    CAS  PubMed  PubMed Central  Google Scholar 

  232. Stadlbauer V, Mookerjee RP, Hodges S, Wright GA, Davies NA, Jalan R. Effect of probiotic treatment on deranged neutrophil function and cytokine responses in patients with compensated alcoholic cirrhosis. J Hepatol. 2008;48:945–51.

    CAS  PubMed  Google Scholar 

  233. So D, Whelan K, Rossi M, Morrison M, Holtmann G, Kelly JT, et al. Dietary fiber intervention on gut microbiota composition in healthy adults: a systematic review and meta-analysis. Am J Clin Nutr. 2018;107:965–83.

    PubMed  Google Scholar 

  234. Tang Y, Forsyth CB, Banan A, Fields JZ, Keshavarzian A. Oats supplementation prevents alcohol-induced gut leakiness in rats by preventing alcoholinduced oxidative tissue damage. J Pharmacol Exp Ther. 2009;329:952–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  235. Yan AW, E. Fouts D, Brandl J, Stärkel P, Torralba M, Schott E, et al. Enteric dysbiosis associated with a mouse model of alcoholic liver disease. Hepatology. 2011;53:96–105.

    CAS  PubMed  Google Scholar 

  236. Markowiak P, Śliżewska K. Effects of probiotics, prebiotics, and synbiotics on human health. Nutrients. 2017;9:1021.

    PubMed Central  Google Scholar 

  237. Schmidt K, Cowen PJ, Harmer CJ, Tzortzis G, Errington S, Burnet PW. Prebiotic intake reduces the waking cortisol response and alters emotional bias in healthy volunteers. Psychopharmacology. 2015;232:1793–801.

    CAS  PubMed  Google Scholar 

  238. Benton D, Williams C, Brown A. Impact of consuming a milk drink containing a probiotic on mood and cognition. Eur J Clin Nutr. 2007;61:355–61.

    CAS  PubMed  Google Scholar 

  239. Steenbergen L, Sellaro R, van Hemert S, Bosch JA, Colzato LS. A randomized controlled trial to test the effect of multispecies probiotics on cognitive reactivity to sad mood. Brain Behav Immun. 2015;48:258–64.

    PubMed  Google Scholar 

  240. Veiga P, Suez J, Derrien M, Elinav E. Moving from probiotics to precision probiotics. Nat Microbiol. 2020;5:878–80.

    PubMed  Google Scholar 

Download references

Acknowledgements

CC has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No. 754535. SL has received support from the Belgian American Educational Foundation. PM (Senior Research Associate) is funded by the Belgian Fund for Scientific Research (F.R.S.-FNRS, Brussels, Belgium). EL-C was supported by the Portuguese Foundation for Science and Technology (FCT), within the scope of the Individual Call to Scientific Employment Stimulus (CEECIND/02979/2018).

Author information

Authors and Affiliations

  1. APC Microbiome Ireland, University College Cork, Cork, Ireland

    Carina Carbia, Kenneth J. O’Riordan, Timothy G. Dinan & John F. Cryan

  2. Stanford University, Department of Psychiatry and Behavioral Sciences, Stanford, CA, USA

    Séverine Lannoy

  3. Louvain Experimental Psychopathology Research Group (LEP), Psychological Sciences Research Institute, UCLouvain, Louvain-la-Neuve, Belgium

    Pierre Maurage

  4. Psychological Neuroscience Laboratory, Research Center in Psychology (CIPsi), School of Psychology, University of Minho, Campus Gualtar, Braga, Portugal

    Eduardo López-Caneda

  5. Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland

    Timothy G. Dinan

  6. Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland

    John F. Cryan

Authors
  1. Carina Carbia
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Séverine Lannoy
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Pierre Maurage
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Eduardo López-Caneda
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kenneth J. O’Riordan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Timothy G. Dinan
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. John F. Cryan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to John F. Cryan.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Carbia, C., Lannoy, S., Maurage, P. et al. A biological framework for emotional dysregulation in alcohol misuse: from gut to brain. Mol Psychiatry 26, 1098–1118 (2021). https://doi.org/10.1038/s41380-020-00970-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41380-020-00970-6

  • Springer Nature Limited

This article is cited by

Search

Navigation