A potential role for the gut microbiome in substance use disorders

Abstract

Pathological substance use disorders represent a major public health crisis with limited effective treatment options. While much work has been done to understand the neuronal signaling networks and intracellular signaling cascades associated with prolonged drug use, these studies have yielded few successful treatment options for substance use disorders. In recent years, there has been a growing interest to explore interactions between the peripheral immune system, the gut microbiome, and the CNS. In this review, we will present a summary of existing evidence, suggesting a potential role for gut dysbiosis in the pathogenesis of substance use disorders. Clinical evidence of gut dysbiosis in human subjects with substance use disorder and preclinical evidence of gut dysbiosis in animal models of drug addiction are discussed in detail. Additionally, we examine how changes in the gut microbiome and its metabolites may not only be a consequence of substance use disorders but may in fact play a role in mediating behavioral response to drugs of abuse. While much work still needs to be done, understanding the interplay of gut microbiome in substance use disorders may offer a promising avenue for future therapeutic development.

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

References

  1. Acharya C, Betrapally NS, Gillevet PM et al (2017) Chronic opioid use is associated with altered gut microbiota and predicts readmissions in patients with cirrhosis. Aliment Pharmacol Ther 45:319–331. https://doi.org/10.1111/apt.13858

    CAS  Article  PubMed  Google Scholar 

  2. Adolph TE, Grander C, Moschen AR, Tilg H (2018) Liver-microbiome axis in health and disease. Trends Immunol 39:712–723. https://doi.org/10.1016/j.it.2018.05.002

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  3. Agus A, Planchais J, Sokol H (2018) Gut microbiota regulation of tryptophan metabolism in health and disease. Cell Host Microbe 23:716–724. https://doi.org/10.1016/j.chom.2018.05.003

    CAS  Article  PubMed  Google Scholar 

  4. Aguzzi A, Barres BA, Bennett ML (2013) Microglia: scapegoat, saboteur, or something else? Science 339:156–161. https://doi.org/10.1126/science.1227901

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  5. Ayata P, Badimon A, Strasburger HJ et al (2018) Epigenetic regulation of brain region-specific microglia clearance activity. Nat Neurosci 21:1049–1060. https://doi.org/10.1038/s41593-018-0192-3

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  6. Aziz Q, Doré J, Emmanuel A et al (2013) Gut microbiota and gastrointestinal health: current concepts and future directions. Neurogastroenterol Motil 25:4–15. https://doi.org/10.1111/nmo.12046

    CAS  Article  PubMed  Google Scholar 

  7. Babrowski T, Holbrook C, Moss J et al (2012) Pseudomonas aeruginosa virulence expression is directly activated by morphine and is capable of causing lethal gut derived sepsis in mice during chronic morphine administration. Ann Surg 255:386–393. https://doi.org/10.1097/SLA.0b013e3182331870

    Article  PubMed  PubMed Central  Google Scholar 

  8. Bagot RC, Labonté B, Peña CJ, Nestler EJ (2014) Epigenetic signaling in psychiatric disorders: stress and depression. Dialogues Clin Neurosci 16:281–295

    PubMed  PubMed Central  Google Scholar 

  9. Bala S, Marcos M, Gattu A et al (2014) Acute binge drinking increases serum endotoxin and bacterial DNA levels in healthy individuals. PLoS One 9:e96864. https://doi.org/10.1371/journal.pone.0096864

    Article  PubMed  PubMed Central  Google Scholar 

  10. Balzan S, de Almeida Quadros C, de Cleva R et al (2007) Bacterial translocation: overview of mechanisms and clinical impact. J Gastroenterol Hepatol 22:464–471. https://doi.org/10.1111/j.1440-1746.2007.04933.x

    CAS  Article  PubMed  Google Scholar 

  11. Banerjee S, Sindberg G, Wang F et al (2016) Opioid-induced gut microbial disruption and bile dysregulation leads to gut barrier compromise and sustained systemic inflammation. Mucosal Immunol 9:1418–1428. https://doi.org/10.1038/mi.2016.9

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  12. Barengolts E, Green SJ, Eisenberg Y et al (2018) Gut microbiota varies by opioid use, circulating leptin and oxytocin in African American men with diabetes and high burden of chronic disease. PLoS One 13:e0194171. https://doi.org/10.1371/journal.pone.0194171

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  13. Barker JM, Taylor JR, De Vries TJ, Peters J (2015) Brain-derived neurotrophic factor and addiction: pathological versus therapeutic effects on drug seeking. Brain Res 1628:68–81. https://doi.org/10.1016/j.brainres.2014.10.058

    CAS  Article  PubMed  Google Scholar 

  14. Belkaid Y, Hand TW (2014) Role of the microbiota in immunity and inflammation. Cell 157:121–141. https://doi.org/10.1016/j.cell.2014.03.011

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  15. Benton D, Williams C, Brown A (2007) Impact of consuming a milk drink containing a probiotic on mood and cognition. Eur J Clin Nutr 61:355–361. https://doi.org/10.1038/sj.ejcn.1602546

    CAS  Article  PubMed  Google Scholar 

  16. Bercik P, Denou E, Collins J et al (2011a) The intestinal microbiota affect central levels of brain-derived neurotropic factor and behavior in mice. Gastroenterology 141:599–609, 609.e1–3. https://doi.org/10.1053/j.gastro.2011.04.052

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  17. Bercik P, Park AJ, Sinclair D et al (2011b) The anxiolytic effect of Bifidobacterium longum NCC3001 involves vagal pathways for gut-brain communication. Neurogastroenterol Motil 23:1132–1139. https://doi.org/10.1111/j.1365-2982.2011.01796.x

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. Betrapally NS, Gillevet PM, Bajaj JS (2017) Gut microbiome and liver disease. Transl Res 179:49–59. https://doi.org/10.1016/j.trsl.2016.07.005

    CAS  Article  PubMed  Google Scholar 

  19. Bishehsari F, Magno E, Swanson G et al (2017) Alcohol and gut-derived inflammation. Alcohol Res 38:163–171

    PubMed  PubMed Central  Google Scholar 

  20. Blednov YA, Benavidez JM, Geil C et al (2011) Activation of inflammatory signaling by lipopolysaccharide produces a prolonged increase of voluntary alcohol intake in mice. Brain Behav Immun 25(Suppl 1):S92–S105. https://doi.org/10.1016/j.bbi.2011.01.008

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  21. Bonaz B, Bazin T, Pellissier S (2018) The vagus nerve at the interface of the microbiota-gut-brain axis. Front Neurosci 12:49. https://doi.org/10.3389/fnins.2018.00049

    Article  PubMed  PubMed Central  Google Scholar 

  22. 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. https://doi.org/10.1126/scitranslmed.3009759

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  23. Bravo JA, Forsythe P, Chew MV et al (2011) Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve. Proc Natl Acad Sci U S A 108:16050–16055. https://doi.org/10.1073/pnas.1102999108

    Article  PubMed  PubMed Central  Google Scholar 

  24. Breit S, Kupferberg A, Rogler G, Hasler G (2018) Vagus nerve as modulator of the brain-gut axis in psychiatric and inflammatory disorders. Front Psychiatry 9:44. https://doi.org/10.3389/fpsyt.2018.00044

    Article  PubMed  PubMed Central  Google Scholar 

  25. Breslow JM, Monroy MA, Daly JM et al (2011) Morphine, but not trauma, sensitizes to systemic Acinetobacter baumannii infection. J NeuroImmune Pharmacol 6:551–565. https://doi.org/10.1007/s11481-011-9303-6

    Article  PubMed  PubMed Central  Google Scholar 

  26. Bull-Otterson L, Feng W, Kirpich I et al (2013) Metagenomic analyses of alcohol induced pathogenic alterations in the intestinal microbiome and the effect of Lactobacillus rhamnosus GG treatment. PLoS One 8:e53028. https://doi.org/10.1371/journal.pone.0053028

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  27. Calipari ES, Godino A, Peck EG et al (2018) Granulocyte-colony stimulating factor controls neural and behavioral plasticity in response to cocaine. Nat Commun 9:9. https://doi.org/10.1038/s41467-017-01881-x

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  28. Chiang JYL (2013) Bile acid metabolism and signaling. Compr Physiol 3:1191–1212. https://doi.org/10.1002/cphy.c120023

    Article  PubMed  PubMed Central  Google Scholar 

  29. Childs JE, DeLeon J, Nickel E, Kroener S (2017) Vagus nerve stimulation reduces cocaine seeking and alters plasticity in the extinction network. Learn Mem 24:35–42. https://doi.org/10.1101/lm.043539.116

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  30. Cruz C, Meireles M, Silva SM (2017) Chronic ethanol intake induces partial microglial activation that is not reversed by long-term ethanol withdrawal in the rat hippocampal formation. Neurotoxicology 60:107–115. https://doi.org/10.1016/J.NEURO.2017.04.005

    CAS  Article  PubMed  Google Scholar 

  31. Cryan JF, Dinan TG (2012) Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour. Nat Rev Neurosci. https://doi.org/10.1038/nrn3346

    CAS  Article  Google Scholar 

  32. De Biase LM, Schuebel KE, Fusfeld ZH et al (2017) Local cues establish and maintain region-specific phenotypes of basal ganglia microglia. Neuron 95:341–356.e6. https://doi.org/10.1016/j.neuron.2017.06.020

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  33. de Timary P, Leclercq S, Stärkel P, Delzenne N (2015) A dysbiotic subpopulation of alcohol-dependent subjects. Gut Microbes 6:388–391. https://doi.org/10.1080/19490976.2015.1107696

    CAS  Article  PubMed  Google Scholar 

  34. de Timary P, Stärkel P, Delzenne NM, Leclercq S (2017) A role for the peripheral immune system in the development of alcohol use disorders? Neuropharmacology 122:148–160. https://doi.org/10.1016/J.NEUROPHARM.2017.04.013

    Article  PubMed  Google Scholar 

  35. Degenhardt L, Baxter AJ, Lee YY et al (2014) The global epidemiology and burden of psychostimulant dependence: findings from the Global Burden of Disease Study 2010. Drug Alcohol Depend 137:36–47. https://doi.org/10.1016/j.drugalcdep.2013.12.025

    Article  PubMed  Google Scholar 

  36. DeGruttola AK, Low D, Mizoguchi A, Mizoguchi E (2016) Current understanding of dysbiosis in disease in human and animal models. Inflamm Bowel Dis 22:1137–1150. https://doi.org/10.1097/MIB.0000000000000750

    Article  PubMed  PubMed Central  Google Scholar 

  37. Derrien M, van Hylckama Vlieg JET (2015) Fate, activity, and impact of ingested bacteria within the human gut microbiota. Trends Microbiol 23:354–366. https://doi.org/10.1016/j.tim.2015.03.002

    CAS  Article  PubMed  Google Scholar 

  38. Diaz Heijtz R, Wang S, Anuar F et al (2011) Normal gut microbiota modulates brain development and behavior. Proc Natl Acad Sci U S A 108:3047–3052. https://doi.org/10.1073/pnas.1010529108

    Article  Google Scholar 

  39. Eisenstein TK, Rahim RT, Feng P et al (2006) Effects of opioid tolerance and withdrawal on the immune system. J NeuroImmune Pharmacol 1:237–249. https://doi.org/10.1007/s11481-006-9019-1

    Article  PubMed  Google Scholar 

  40. Engen PA, Green SJ, Voigt RM et al (2015) The gastrointestinal microbiome: alcohol effects on the composition of intestinal microbiota. Alcohol Res 37:223–236. https://doi.org/10.13140/RG.2.1.4342.9285

    Article  PubMed  PubMed Central  Google Scholar 

  41. Erny D, Hrabě De Angelis AL, Jaitin D et al (2015) Host microbiota constantly control maturation and function of microglia in the CNS. Nat Neurosci 18:965–977. https://doi.org/10.1038/nn.4030

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  42. Faith JJ, Rey FE, O’Donnell D et al (2010) Creating and characterizing communities of human gut microbes in gnotobiotic mice. ISME J 4:1094–1098. https://doi.org/10.1038/ismej.2010.110

    Article  PubMed  PubMed Central  Google Scholar 

  43. Faith JJ, Guruge JL, Charbonneau M et al (2013) The long-term stability of the human gut microbiota. Science 341:1237439. https://doi.org/10.1126/science.1237439

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  44. Fan Y, Ya-E Z, Ji-Dong W et al (2018) Comparison of microbial diversity and composition in jejunum and colon of the alcohol-dependent rats. J Microbiol Biotechnol 28:1883–1895. https://doi.org/10.4014/jmb.1806.06050

    Article  PubMed  Google Scholar 

  45. Felipe Palma-Álvarez R, Ros-Cucurull E, Amaro-Hosey K et al (2017) Peripheral levels of BDNF and opiate-use disorder: literature review and update. Rev Neurosci 28:499–508. https://doi.org/10.1515/revneuro-2016-0078

    CAS  Article  Google Scholar 

  46. Feng P, Truant AL, Meissler JJ et al (2006) Morphine withdrawal lowers host defense to enteric bacteria: spontaneous sepsis and increased sensitivity to oral Salmonella enterica serovar Typhimurium infection. Infect Immun 74:5221–5226. https://doi.org/10.1128/IAI.00208-06

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  47. Franzosa EA, Morgan XC, Segata N et al (2014) Relating the metatranscriptome and metagenome of the human gut. Proc Natl Acad Sci U S A 111:E2329–E2338. https://doi.org/10.1073/pnas.1319284111

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  48. Gacias M, Gaspari S, Santos P-MG, et al (2016) Microbiota-driven transcriptional changes in prefrontal cortex override genetic differences in social behavior. Elife 5:. https://doi.org/10.7554/eLife.13442

  49. Gao J, Xu K, Liu H et al (2018) Impact of the gut microbiota on intestinal immunity mediated by tryptophan metabolism. Front Cell Infect Microbiol 8:13. https://doi.org/10.3389/fcimb.2018.00013

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  50. Gibson GR, Beatty ER, Wang X, Cummings JH (1995) Selective stimulation of bifidobacteria in the human volon by oligofructose and inulin. Gastroenterology 108:975–982

    CAS  Article  Google Scholar 

  51. Glattard E, Welters ID, Lavaux T et al (2010) Endogenous morphine levels are increased in sepsis: a partial implication of neutrophils. PLoS One 5:e8791. https://doi.org/10.1371/journal.pone.0008791

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  52. Gupta NK, Thaker AI, Kanuri N et al (2012) Serum analysis of tryptophan catabolism pathway: correlation with Crohn’s disease activity. Inflamm Bowel Dis 18:1214–1220. https://doi.org/10.1002/ibd.21849

    Article  PubMed  Google Scholar 

  53. Han W, Tellez LA, Perkins MH et al (2018) A neural circuit for gut-induced reward in brief. Cell 175:665–678. https://doi.org/10.1016/j.cell.2018.08.049

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  54. Harris RA, Bajo M, Bell RL et al (2017) Genetic and pharmacologic manipulation of TLR4 has minimal impact on ethanol consumption in rodents. J Neurosci 37:1139–1155. https://doi.org/10.1523/JNEUROSCI.2002-16.2016

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  55. Heller EA, Hamilton PJ, Burek DD et al (2016) Targeted epigenetic remodeling of the Cdk5 gene in nucleus accumbens regulates cocaine- and stress-evoked behavior. J Neurosci 36:4690–4697. https://doi.org/10.1523/JNEUROSCI.0013-16.2016

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  56. Hilburger ME, Adler MW, Truant AL et al (1997) Morphine induces sepsis in mice. J Infect Dis 176:183–188

  57. Hillemacher T, Bachmann O, Kahl KG, Frieling H (2018) Alcohol, microbiome, and their effect on psychiatric disorders. https://doi.org/10.1016/j.pnpbp.2018.04.015

    CAS  Article  Google Scholar 

  58. Hoban AE, Stilling RM, Ryan FJ et al (2016) Regulation of prefrontal cortex myelination by the microbiota. Transl Psychiatry 6:e774–e774. https://doi.org/10.1038/tp.2016.42

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  59. Hofford RS, Russo SJ, Kiraly DD (2018) Neuroimmune mechanisms of psychostimulant and opioid use disorders. Eur J Neurosci. https://doi.org/10.1111/ejn.14143

    Article  Google Scholar 

  60. Jadhav KS, Peterson VL, Halfon O et al (2018) Gut microbiome correlates with altered striatal dopamine receptor expression in a model of compulsive alcohol seeking. Neuropharmacology 141:249–259. https://doi.org/10.1016/J.NEUROPHARM.2018.08.026

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  61. Joseph J, Depp C, Shih PB et al (2017) Modified Mediterranean diet for enrichment of short chain fatty acids: potential adjunctive therapeutic to target immune and metabolic dysfunction in schizophrenia? Front Neurosci 11:155. https://doi.org/10.3389/fnins.2017.00155

    Article  PubMed  PubMed Central  Google Scholar 

  62. Kang M, Mischel RA, Bhave S et al (2017) The effect of gut microbiome on tolerance to morphine mediated antinociception in mice. Sci Rep 7:1–17. https://doi.org/10.1038/srep42658

    CAS  Article  Google Scholar 

  63. Kato-Kataoka A, Nishida K, Takada M et al (2016) Fermented milk containing Lactobacillus casei strain Shirota prevents the onset of physical symptoms in medical students under academic examination stress. Benefic Microbes 7:153–156. https://doi.org/10.3920/BM2015.0100

    CAS  Article  Google Scholar 

  64. Kelly D, Conway S, Aminov R (2005) Commensal gut bacteria: mechanisms of immune modulation. Trends Immunol 26:326–333. https://doi.org/10.1016/j.it.2005.04.008

    CAS  Article  PubMed  Google Scholar 

  65. 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. https://doi.org/10.3389/fncel.2015.00392

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  66. Kennedy PJ, Feng J, Robison AJ et al (2013) Class I HDAC inhibition blocks cocaine-induced plasticity by targeted changes in histone methylation. Nat Neurosci 16:434–440. https://doi.org/10.1038/nn.3354

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  67. Keshavarzian A, Farhadi A, Forsyth CB et al (2009) Evidence that chronic alcohol exposure promotes intestinal oxidative stress, intestinal hyperpermeability and endotoxemia prior to development of alcoholic steatohepatitis in rats. J Hepatol 50:538–547. https://doi.org/10.1016/j.jhep.2008.10.028

    CAS  Article  PubMed  Google Scholar 

  68. Kiraly DD, Walker DM, Calipari ES et al (2016) Alterations of the host microbiome affect behavioral responses to cocaine. Sci Rep 6:1–12. https://doi.org/10.1038/srep35455

    CAS  Article  Google Scholar 

  69. Kirpich IA, Solovieva NV, Leikhter SN et al (2008) Probiotics restore bowel flora and improve liver enzymes in human alcohol-induced liver injury: a pilot study. Alcohol 42:675–682. https://doi.org/10.1016/j.alcohol.2008.08.006

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  70. Koh A, De Vadder F, Kovatcheva-Datchary P, Bäckhed F (2016) From dietary fiber to host physiology: short-chain fatty acids as key bacterial metabolites. Cell 165:1332–1345. https://doi.org/10.1016/j.cell.2016.05.041

    CAS  Article  PubMed  Google Scholar 

  71. Krishnan S, Ding Y, Saedi N et al (2018) Gut microbiota-derived tryptophan metabolites modulate inflammatory response in hepatocytes and macrophages. Cell Rep 23:1099–1111. https://doi.org/10.1016/J.CELREP.2018.03.109

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  72. Kyzar EJ, Pandey SC (2015) Molecular mechanisms of synaptic remodeling in alcoholism. Neurosci Lett 601:11–19. https://doi.org/10.1016/j.neulet.2015.01.051

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  73. Lacagnina MJ, Kopec AM, Cox SS et al (2017) Opioid self-administration is attenuated by early-life experience and gene therapy for anti-inflammatory IL-10 in the nucleus accumbens of male rats. Neuropsychopharmacology 42:2128–2140. https://doi.org/10.1038/npp.2017.82

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  74. Lainiola M, Linden A-M (2017) Alcohol intake in two different mouse drinking models after recovery from the lipopolysaccharide-induced sickness reaction. Alcohol 65:1–10. https://doi.org/10.1016/J.ALCOHOL.2017.06.002

    CAS  Article  PubMed  Google Scholar 

  75. Lal S, Kirkup AJ, Brunsden AM et al (2001) Vagal afferent responses to fatty acids of different chain length in the rat. Am J Physiol Gastrointest Liver Physiol 281:G907–G915. https://doi.org/10.1152/ajpgi.2001.281.4.G907

    CAS  Article  PubMed  Google Scholar 

  76. Laughlin RS, Musch MW, Hollbrook CJ et al (2000) The key role of Pseudomonas aeruginosa PA-I lectin on experimental gut-derived sepsis. Ann Surg 232:133–142

    CAS  Article  Google Scholar 

  77. Leclercq S, Cani PD, Neyrinck AM, et al (2012) Role of intestinal permeability and inflammation in the biological and behavioral control of alcohol-dependent subjects. 26:911–918. https://doi.org/10.1016/j.bbi.2012.04.001

    CAS  Article  Google Scholar 

  78. Leclercq S, De Saeger C, Delzenne N et al (2014a) Role of inflammatory pathways, blood mononuclear cells, and gut-derived bacterial products in alcohol dependence. Biol Psychiatry 76:725–733. https://doi.org/10.1016/j.biopsych.2014.02.003

    CAS  Article  PubMed  Google Scholar 

  79. Leclercq S, Matamoros S, Cani PD et al (2014b) Intestinal permeability, gut-bacterial dysbiosis, and behavioral markers of alcohol-dependence severity. Proc Natl Acad Sci 111:E4485–E4493. https://doi.org/10.1073/pnas.1415174111

    CAS  Article  PubMed  Google Scholar 

  80. Lee K, Vuong HE, Nusbaum DJ et al (2018) The gut microbiota mediates reward and sensory responses associated with regimen-selective morphine dependence. Neuropsychopharmacology 1. https://doi.org/10.1038/s41386-018-0211-9

    CAS  Article  Google Scholar 

  81. Lefebvre P, Cariou B, Lien F, et al (2009) Role of bile acids and bile acid receptors in metabolic regulation. https://doi.org/10.1152/physrev.00010.2008.-The

  82. Levy M, Thaiss CA, Elinav E (2016) Metabolites: messengers between the microbiota and the immune system. Genes Dev 30:1589–1597. https://doi.org/10.1101/gad.284091.116

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  83. Lewitus GM, Konefal SC, Greenhalgh AD et al (2016) Microglial TNF-α suppresses cocaine-induced plasticity and behavioral sensitization. Neuron 90:483–491. https://doi.org/10.1016/j.neuron.2016.03.030

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  84. Li X, Wolf ME (2015) Multiple faces of BDNF in cocaine addiction. Behav Brain Res 279:240–254. https://doi.org/10.1016/j.bbr.2014.11.018

    CAS  Article  PubMed  Google Scholar 

  85. Li Z, Quan G, Jiang X et al (2018) Effects of metabolites derived from gut microbiota and hosts on pathogens. Front Cell Infect Microbiol 8:314. https://doi.org/10.3389/fcimb.2018.00314

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  86. Maes M, Yirmyia R, Noraberg J et al (2009) The inflammatory & neurodegenerative (I&ND) hypothesis of depression: leads for future research and new drug developments in depression. Metab Brain Dis 24:27–53. https://doi.org/10.1007/s11011-008-9118-1

    CAS  Article  PubMed  Google Scholar 

  87. Malvaez M, Sanchis-Segura C, Vo D et al (2010) Modulation of chromatin modification facilitates extinction of cocaine-induced conditioned place preference. Biol Psychiatry 67:36–43. https://doi.org/10.1016/j.biopsych.2009.07.032

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  88. Meng J, Yu H, Ma J et al (2013) Morphine induces bacterial translocation in mice by compromising intestinal barrier function in a TLR-dependent manner. PLoS One 8:e54040. https://doi.org/10.1371/journal.pone.0054040

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  89. Meng J, Banerjee S, Li D et al (2015a) Opioid exacerbation of gram-positive sepsis, induced by gut microbial modulation, is rescued by IL-17A neutralization. Sci Rep 5:10918. https://doi.org/10.1038/srep10918

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  90. Meng J, Sindberg GM, Roy S (2015b) Disruption of gut homeostasis by opioids accelerates HIV disease progression. Front Microbiol 6:643. https://doi.org/10.3389/fmicb.2015.00643

    Article  PubMed  PubMed Central  Google Scholar 

  91. Messaoudi M, Lalonde R, Violle N et al (2011a) Assessment of psychotropic-like properties of a probiotic formulation (Lactobacillus helveticus R0052 and Bifidobacterium longum R0175) in rats and human subjects. Br J Nutr 105:755–764. https://doi.org/10.1017/S0007114510004319

    CAS  Article  PubMed  Google Scholar 

  92. Messaoudi M, Violle N, Bisson J-F et al (2011b) Beneficial psychological effects of a probiotic formulation (Lactobacillus helveticus R0052 and Bifidobacterium longum R0175) in healthy human volunteers. Gut Microbes 2:256–261. https://doi.org/10.4161/gmic.2.4.16108

    Article  PubMed  Google Scholar 

  93. Miguel-Hidalgo JJ (2009) The role of glial cells in drug abuse. Curr Drug Abuse Rev 2:76–82

    CAS  Article  Google Scholar 

  94. Morrison DJ, Preston T (2016) Formation of short chain fatty acids by the gut microbiota and their impact on human metabolism. Gut Microbes 7:189–200. https://doi.org/10.1080/19490976.2015.1134082

    Article  PubMed  PubMed Central  Google Scholar 

  95. Mortha A, Chudnovskiy A, Hashimoto D et al (2014) Microbiota-dependent crosstalk between macrophages and ILC3 promotes intestinal homeostasis. Science 343:1249288. https://doi.org/10.1126/science.1249288

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  96. Murray CJL, Vos T, Lozano R et al (2012) Disability-adjusted life years (DALYs) for 291 diseases and injuries in 21 regions, 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet (London, England) 380:2197–2223. https://doi.org/10.1016/S0140-6736(12)61689-4

    Article  Google Scholar 

  97. Mutlu E, Keshavarzian A, Engen P et al (2009) Intestinal dysbiosis: a possible mechanism of alcohol-induced endotoxemia and alcoholic steatohepatitis in rats. Alcohol Clin Exp Res 33:1836–1846. https://doi.org/10.1111/j.1530-0277.2009.01022.x

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  98. Mutlu EA, Gillevet PM, Rangwala H, et al (2012) Colonic microbiome is altered in alcoholism. 302:. https://doi.org/10.1152/ajpgi.00380.2011

    CAS  Article  Google Scholar 

  99. Ning T, Gong X, Xie L, Ma B (2017) Gut microbiota analysis in rats with methamphetamine-induced conditioned place preference. Front Microbiol 8:1–9. https://doi.org/10.3389/fmicb.2017.01620

    Article  Google Scholar 

  100. Niwa M, Nitta A, Yamada Y et al (2007) Tumor necrosis factor-α and its inducer inhibit morphine-induced rewarding effects and sensitization. Biol Psychiatry 62:658–668. https://doi.org/10.1016/J.BIOPSYCH.2006.10.009

    CAS  Article  PubMed  Google Scholar 

  101. Northcutt AL, Hutchinson MR, Wang X et al (2015) DAT isn’t all that: cocaine reward and reinforcement require toll-like receptor 4 signaling. Mol Psychiatry 20:1525–1537. https://doi.org/10.1038/mp.2014.177

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  102. O’Hara AM, Shanahan F (2006) The gut flora as a forgotten organ. EMBO Rep 7:688–693. https://doi.org/10.1038/sj.embor.7400731

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  103. O’Mahony SM, Clarke G, Borre YE, et al (2015) Serotonin, tryptophan metabolism and the brain-gut-microbiome axis. Behav Brain Res 277

  104. Ocasio FM, Jiang Y, House SD, Chang SL (2004) Chronic morphine accelerates the progression of lipopolysaccharide-induced sepsis to septic shock. J Neuroimmunol 149:90–100. https://doi.org/10.1016/j.jneuroim.2003.12.016

    CAS  Article  PubMed  Google Scholar 

  105. Pan W, Stone KP, Hsuchou H et al (2011) Cytokine signaling modulates blood-brain barrier function. Curr Pharm Des 17:3729–3740

    CAS  Article  Google Scholar 

  106. Pandey SC (2016) A critical role of brain-derived neurotrophic factor in alcohol consumption. Biol Psychiatry 79:427–429. https://doi.org/10.1016/j.biopsych.2015.12.020

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  107. Parthasarathy G, Chen J, Chen X et al (2016) Relationship between microbiota of the colonic mucosa vs feces and symptoms, colonic transit, and methane production in female patients with chronic constipation. Gastroenterology 150:367–79.e1. https://doi.org/10.1053/j.gastro.2015.10.005

    Article  PubMed  Google Scholar 

  108. Peña CJ, Bagot RC, Labonté B, Nestler EJ (2014) Epigenetic signaling in psychiatric disorders. J Mol Biol 426:3389–3412. https://doi.org/10.1016/j.jmb.2014.03.016

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  109. Peterson VL, Jury NJ, Cabrera-Rubio R et al (2017) Drunk bugs: chronic vapour alcohol exposure induces marked changes in the gut microbiome in mice. Behav Brain Res 323:172–176. https://doi.org/10.1016/j.bbr.2017.01.049

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  110. Rao R (2009) Endotoxemia and gut barrier dysfunction in alcoholic liver disease. Hepatology 50:638–644. https://doi.org/10.1002/hep.23009

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  111. Rao RK, Seth A, Sheth P (2004) Recent advances in alcoholic liver disease I. Role of intestinal permeability and endotoxemia in alcoholic liver disease https://doi.org/10.1152/ajpgi.00006.2004.-A

  112. Raybould HE (2010) Gut chemosensing: interactions between gut endocrine cells and visceral afferents. Auton Neurosci 153:41–46. https://doi.org/10.1016/j.autneu.2009.07.007

    CAS  Article  PubMed  Google Scholar 

  113. Reddy IA, Smith NK, Erreger K et al (2018) Bile diversion, a bariatric surgery, and bile acid signaling reduce central cocaine reward. PLoS Biol 16:e2006682. https://doi.org/10.1371/journal.pbio.2006682

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  114. Reigstad CS, Salmonson CE, Rainey JF, et al (2015) Gut microbes promote colonic serotonin production through an effect of short-chain fatty acids on enterochromaffin cells. FASEB J 29:. https://doi.org/10.1096/fj.14-259598

    CAS  Article  Google Scholar 

  115. Rhee SH, Pothoulakis C, Mayer EA (2009) Principles and clinical implications of the brain-gut-enteric microbiota axis. Nat Rev Gastroenterol Hepatol 6:306–314. https://doi.org/10.1038/nrgastro.2009.35

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  116. Riottot M, Sacquet E (1985) Increase in the ileal absorption rate of sodium taurocholate in germ-free or conventional rats given an amylomaize-starch diet. Br J Nutr 53:307–310

    CAS  Article  Google Scholar 

  117. Roager HM, Licht TR (2018) Microbial tryptophan catabolites in health and disease. Nat Commun 9:3294. https://doi.org/10.1038/s41467-018-05470-4

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  118. Rogge GA, Wood MA (2013) The role of histone acetylation in cocaine-induced neural plasticity and behavior. Neuropsychopharmacology 38:94–110. https://doi.org/10.1038/npp.2012.154

    CAS  Article  PubMed  Google Scholar 

  119. Romieu P, Host L, Gobaille S et al (2008) Histone deacetylase inhibitors decrease cocaine but not sucrose self-administration in rats. J Neurosci 28:9342–9348. https://doi.org/10.1523/JNEUROSCI.0379-08.2008

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  120. Romieu P, Deschatrettes E, Host L et al (2011) The inhibition of histone deacetylases reduces the reinstatement of cocaine-seeking behavior in rats. Curr Neuropharmacol 9:21–25. https://doi.org/10.2174/157015911795017317

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  121. Rothhammer V, Mascanfroni ID, Bunse L et al (2016) Type I interferons and microbial metabolites of tryptophan modulate astrocyte activity and central nervous system inflammation via the aryl hydrocarbon receptor. Nat Med 22:586–597. https://doi.org/10.1038/nm.4106

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  122. Samuelson DR, Shellito JE, Maffei VJ et al (2017) Alcohol-associated intestinal dysbiosis impairs pulmonary host defense against Klebsiella pneumoniae. PLoS Pathog 13:e1006426. https://doi.org/10.1371/journal.ppat.1006426

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  123. Sandhu KV, Sherwin E, Schellekens H et al (2017) Feeding the microbiota-gut-brain axis: diet, microbiome, and neuropsychiatry. Transl Res 179:223–244. https://doi.org/10.1016/j.trsl.2016.10.002

    CAS  Article  PubMed  Google Scholar 

  124. Sarkar A, Lehto SM, Harty S et al (2016) Psychobiotics and the manipulation of bacteria-gut-brain signals. Trends Neurosci 39:763–781. https://doi.org/10.1016/j.tins.2016.09.002

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  125. Sayin SI, Wahlström A, Felin J et al (2013) Gut microbiota regulates bile acid metabolism by reducing the levels of Tauro-beta-muricholic acid, a naturally occurring FXR antagonist. Cell Metab 17:225–235. https://doi.org/10.1016/j.cmet.2013.01.003

    CAS  Article  PubMed  Google Scholar 

  126. Schafer DP, Stevens B (2013) Phagocytic glial cells: sculpting synaptic circuits in the developing nervous system. Curr Opin Neurobiol 23:1034–1040. https://doi.org/10.1016/j.conb.2013.09.012

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  127. Schafer DP, Stevens B (2015) Microglia function in central nervous system development and plasticity. Cold Spring Harb Perspect Biol 7:a020545. https://doi.org/10.1101/cshperspect.a020545

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  128. Schirmer M, Smeekens SP, Vlamakis H et al (2016) Linking the human gut microbiome to inflammatory cytokine production capacity. Cell 167:1125–1136.e8. https://doi.org/10.1016/j.cell.2016.10.020

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  129. Schnabl B, Brenner DA (2014) Interactions between the intestinal microbiome and liver diseases. Gastroenterology 146:1513–1524. https://doi.org/10.1053/j.gastro.2014.01.020

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  130. Scorza C, Piccini C, Busi MM et al (2019) Alterations in the gut microbiota of rats chronically exposed to volatilized cocaine and its active adulterants caffeine and phenacetin. Neurotox Res 35:111–121. https://doi.org/10.1007/s12640-018-9936-9

    CAS  Article  PubMed  Google Scholar 

  131. Shorter D, Domingo CB, Kosten TR (2015) Emerging drugs for the treatment of cocaine use disorder: a review of neurobiological targets and pharmacotherapy. Expert Opin Emerg Drugs 20:15–29. https://doi.org/10.1517/14728214.2015.985203

    CAS  Article  PubMed  Google Scholar 

  132. Sindberg GM, Callen SE, Banerjee S et al (2018) Morphine potentiates dysbiotic microbial and metabolic shifts in acute SIV infection. J NeuroImmune Pharmacol. https://doi.org/10.1007/s11481-018-9805-6

    Article  Google Scholar 

  133. Singh RK, Chang H-W, Yan D et al (2017) Influence of diet on the gut microbiome and implications for human health. J Transl Med 15:73. https://doi.org/10.1186/s12967-017-1175-y

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  134. Skosnik PD, Cortes-Briones JA (2016) Targeting the ecology within: the role of the gut-brain axis and human microbiota in drug addiction. Med Hypotheses 93:77–80. https://doi.org/10.1016/j.mehy.2016.05.021

    CAS  Article  PubMed  Google Scholar 

  135. Slykerman RF, Hood F, Wickens K et al (2017) Effect of lactobacillus rhamnosus HN001 in pregnancy on postpartum symptoms of depression and anxiety: a randomised double-blind placebo-controlled trial. EBioMedicine 24:159–165. https://doi.org/10.1016/j.ebiom.2017.09.013

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  136. Smith TH, Grider JR, Dewey WL, Akbarali HI (2012) Morphine decreases enteric neuron excitability via inhibition of sodium channels. PLoS One 7:e45251. https://doi.org/10.1371/journal.pone.0045251

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  137. Smith PM, Howitt MR, Panikov N et al (2013) The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science 341:569–573. https://doi.org/10.1126/science.1241165

    CAS  Article  Google Scholar 

  138. Sofia MA, Ciorba MA, Meckel K et al (2018) Tryptophan metabolism through the kynurenine pathway is associated with endoscopic inflammation in ulcerative colitis. Inflamm Bowel Dis 24. https://doi.org/10.1093/ibd/izy103

    Article  Google Scholar 

  139. Soyka M, Müller CA (2017) Pharmacotherapy of alcoholism—an update on approved and off-label medications. Expert Opin Pharmacother 18:1187–1199. https://doi.org/10.1080/14656566.2017.1349098

    CAS  Article  PubMed  Google Scholar 

  140. Staels B, Fonseca VA (2009) Bile acids and metabolic regulation: mechanisms and clinical responses to bile acid sequestration. Diabetes Care 32(Suppl 2):S237–S245. https://doi.org/10.2337/dc09-S355

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  141. Stain-Texier F, Sandouk P, Scherrmann J-M (1998) Intestinal absorption and stability of morphine 6-glucuronide in different physiological compartments of the rat. Drug Metab Dispos 26:383–387

    CAS  PubMed  Google Scholar 

  142. Steenbergen L, Sellaro R, van Hemert S et al (2015) A randomized controlled trial to test the effect of multispecies probiotics on cognitive reactivity to sad mood. Brain Behav Immun 48:258–264. https://doi.org/10.1016/J.BBI.2015.04.003

    Article  PubMed  Google Scholar 

  143. Stilling RM, Dinan TG, Cryan JF (2014) Microbial genes, brain & behaviour—epigenetic regulation of the gut-brain axis. Genes, Brain Behav 13:69–86. https://doi.org/10.1111/gbb.12109

    CAS  Article  Google Scholar 

  144. Subedi L, Huang H, Pant A et al (2017) Plasma brain-derived neurotrophic factor levels in newborn infants with neonatal abstinence syndrome. Front Pediatr 5:238. https://doi.org/10.3389/fped.2017.00238

    Article  PubMed  PubMed Central  Google Scholar 

  145. Substance Abuse and Mental Health Services Administration (2016) Facing addiction in America: the surgeon general’s report on alcohol, drugs, and health. In: U.S. Department of Health and Human Services (HHS) O of the SG (ed) Facing Addiction in America: The Surgeon General’s Report on Alcohol, Drugs, and Health. HHS, Washington (DC), p ch. 6

  146. Sudo N, Chida Y, Aiba Y et al (2004) Postnatal microbial colonization programs the hypothalamic-pituitary-adrenal system for stress response in mice. J Physiol 558:263–275. https://doi.org/10.1113/jphysiol.2004.063388

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  147. Sun J, Chang EB (2014) Exploring gut microbes in human health and disease: pushing the envelope. Genes Dis 1:132–139. https://doi.org/10.1016/j.gendis.2014.08.001

    CAS  Article  PubMed  PubMed Central  Google Scholar 

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

    CAS  Article  Google Scholar 

  149. Temko JE, Bouhlal S, Farokhnia M et al (2017) The microbiota, the gut and the brain in eating and alcohol use disorders: a “ménage à trois”. Alcohol Alcohol 52:403–413. https://doi.org/10.1093/alcalc/agx024

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  150. Thion MS, Low D, Silvin A et al (2018) Microbiome influences prenatal and adult microglia in a sex-specific manner. Cell 172:500–516.e16. https://doi.org/10.1016/j.cell.2017.11.042

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  151. Thomas DM, Kuhn DM (2005) Attenuated microglial activation mediates tolerance to the neurotoxic effects of methamphetamine. J Neurochem 92:790–797. https://doi.org/10.1111/j.1471-4159.2004.02906.x

    CAS  Article  PubMed  Google Scholar 

  152. Thomas DM, Dowgiert J, Geddes TJ et al (2004a) Microglial activation is a pharmacologically specific marker for the neurotoxic amphetamines. Neurosci Lett 367:349–354. https://doi.org/10.1016/J.NEULET.2004.06.065

    CAS  Article  PubMed  Google Scholar 

  153. Thomas DM, Walker PD, Benjamins JA et al (2004b) Methamphetamine neurotoxicity in dopamine nerve endings of the striatum is associated with microglial activation. J Pharmacol Exp Ther 311:1–7. https://doi.org/10.1124/jpet.104.070961

    CAS  Article  PubMed  Google Scholar 

  154. Tripathi A, Debelius J, Brenner DA et al (2018) The gut–liver axis and the intersection with the microbiome. Nat Rev Gastroenterol Hepatol 15:397–411. https://doi.org/10.1038/s41575-018-0011-z

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  155. Turnbaugh PJ, Ridaura VK, Faith JJ et al (2009) The effect of diet on the human gut microbiome: a metagenomic analysis in humanized gnotobiotic mice. Sci Transl Med 1:6ra14. https://doi.org/10.1126/scitranslmed.3000322

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  156. Umesaki Y (2014) Use of gnotobiotic mice to identify and characterize key microbes responsible for the development of the intestinal immune system. Proc Jpn Acad Ser B Phys Biol Sci 90:313–332. https://doi.org/10.2183/PJAB.90.313

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  157. Ursell LK, Haiser HJ, Van Treuren W et al (2014) The intestinal metabolome: an intersection between microbiota and host. Gastroenterology 146:1470–1476. https://doi.org/10.1053/j.gastro.2014.03.001

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  158. van de Wouw M, Schellekens H, Dinan TG, Cryan JF (2017) Microbiota-gut-brain axis: modulator of host metabolism and appetite. J Nutr 147:727–745. https://doi.org/10.3945/jn.116.240481

    CAS  Article  Google Scholar 

  159. Vécsei L, Szalárdy L, Fülöp F, Toldi J (2013) Kynurenines in the CNS: recent advances and new questions. Nat Rev Drug Discov 12:64–82. https://doi.org/10.1038/nrd3793

    CAS  Article  PubMed  Google Scholar 

  160. Verdam FJ, Fuentes S, De Jonge C et al (2013) Human intestinal microbiota composition is associated with local and systemic inflammation in obesity. Obesity 21:607–615. https://doi.org/10.1002/oby.20466

    CAS  Article  Google Scholar 

  161. Vincent C, Miller MA, Edens TJ et al (2016) Bloom and bust: intestinal microbiota dynamics in response to hospital exposures and Clostridium difficile colonization or infection. Microbiome 4:12. https://doi.org/10.1186/s40168-016-0156-3

    Article  PubMed  PubMed Central  Google Scholar 

  162. Volpe GE, Ward H, Mwamburi M et al (2014) Associations of cocaine use and HIV infection with the intestinal microbiota, microbial translocation, and inflammation. J Stud Alcohol Drugs 75:347–357

    Article  Google Scholar 

  163. Waclawiková B, El Aidy S, Waclawiková B, El Aidy S (2018) Role of microbiota and tryptophan metabolites in the remote effect of intestinal inflammation on brain and depression. Pharmaceuticals 11:63. https://doi.org/10.3390/ph11030063

    CAS  Article  PubMed Central  Google Scholar 

  164. Wahlström A, Sayin SI, Marschall H-U, Bäckhed F (2016) Intestinal crosstalk between bile acids and microbiota and its impact on Host metabolism. Cell Metab 24:41–50. https://doi.org/10.1016/j.cmet.2016.05.005

    CAS  Article  PubMed  Google Scholar 

  165. Wang F-B, Powley TL (2007) Vagal innervation of intestines: afferent pathways mapped with new en bloc horseradish peroxidase adaptation. Cell Tissue Res 329:221–230. https://doi.org/10.1007/s00441-007-0413-7

    Article  PubMed  Google Scholar 

  166. Wang F, Roy S (2017) Gut homeostasis, microbial dysbiosis, and opioids. Toxicol Pathol 45:150–156. https://doi.org/10.1177/0192623316679898

    CAS  Article  PubMed  Google Scholar 

  167. Wang F, Meng J, Zhang L et al (2018a) Morphine induces changes in the gut microbiome and metabolome in a morphine dependence model. Sci Rep 8:3596. https://doi.org/10.1038/s41598-018-21915-8

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  168. Wang G, Liu Q, Guo L et al (2018b) Gut microbiota and relevant metabolites analysis in alcohol dependent mice. Front Microbiol 9:1874. https://doi.org/10.3389/fmicb.2018.01874

    Article  PubMed  PubMed Central  Google Scholar 

  169. Wong M-L, Inserra A, Lewis MD et al (2016) Inflammasome signaling affects anxiety- and depressive-like behavior and gut microbiome composition. Mol Psychiatry 21:797–805. https://doi.org/10.1038/mp.2016.46

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  170. Wu H, Esteve E, Tremaroli V et al (2017) Metformin alters the gut microbiome of individuals with treatment-naive type 2 diabetes, contributing to the therapeutic effects of the drug. Nat Med 23:850–858. https://doi.org/10.1038/nm.4345

    CAS  Article  PubMed  Google Scholar 

  171. Xiao H, Ge C, Feng G et al (2018) Gut microbiota modulates alcohol withdrawal-induced anxiety in mice. Toxicol Lett 287:23–30. https://doi.org/10.1016/J.TOXLET.2018.01.021

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  172. Xu Y, Xie Z, Wang H et al (2017) Bacterial diversity of intestinal microbiota in patients with substance use disorders revealed by 16S rRNA gene deep sequencing. Sci Rep 7:1–9. https://doi.org/10.1038/s41598-017-03706-9

    CAS  Article  Google Scholar 

  173. Xu Z, Wang C, Dong X et al (2018) Chronic alcohol exposure induced gut microbiota dysbiosis and its correlations with neuropsychic behaviors and brain BDNF/Gabra1 changes in mice. BioFactors. https://doi.org/10.1002/biof.1469

    Article  Google Scholar 

  174. Yan AW, Fouts DE, Brandl J et al (2011) Enteric dysbiosis associated with a mouse model of alcoholic liver disease. Hepatology 53:96–105. https://doi.org/10.1002/hep.24018

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  175. Yano JM, Yu K, Donaldson GP, et al (2015) Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis. Cell 161:. https://doi.org/10.1016/j.cell.2015.02.047

    CAS  Article  Google Scholar 

  176. Yarlagadda A, Alfson E, Clayton AH (2009) The blood brain barrier and the role of cytokines in neuropsychiatry. Psychiatry (Edgmont) 6:18–22

    Google Scholar 

  177. Zallar LJ, Beurmann S, Tunstall BJ et al (2018) Ghrelin receptor deletion reduces binge-like alcohol drinking in rats. J Neuroendocrinol:e12663. https://doi.org/10.1111/jne.12663

  178. Zhang L, Kitaichi K, Fujimoto Y et al (2006) Protective effects of minocycline on behavioral changes and neurotoxicity in mice after administration of methamphetamine. Prog Neuro-Psychopharmacol Biol Psychiatry 30:1381–1393. https://doi.org/10.1016/J.PNPBP.2006.05.015

    CAS  Article  Google Scholar 

  179. Zhang D, Chen G, Manwani D et al (2015) Neutrophil ageing is regulated by the microbiome. Nature 525:528–532. https://doi.org/10.1038/nature15367

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  180. Zhang R, Meng J, Lian Q et al (2018) Prescription opioids are associated with higher mortality in patients diagnosed with sepsis: a retrospective cohort study using electronic health records. PLoS One 13:e0190362. https://doi.org/10.1371/journal.pone.0190362

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  181. Zheng P, Zeng B, Zhou C et al (2016) Gut microbiome remodeling induces depressive-like behaviors through a pathway mediated by the host’s metabolism. Mol Psychiatry 21:786–796. https://doi.org/10.1038/mp.2016.44

    CAS  Article  PubMed  Google Scholar 

  182. Zhernakova A, Kurilshikov A, Bonder MJ et al (2016) Population-based metagenomics analysis reveals markers for gut microbiome composition and diversity. Science 352:565–569. https://doi.org/10.1126/science.aad3369

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  183. Zhu L, Liu W, Alkhouri R et al (2014) Structural changes in the gut microbiome of constipated patients. Physiol Genomics 46:679–686. https://doi.org/10.1152/physiolgenomics.00082.2014

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  184. Zuo Z, Fan H, Tang X et al (2017) Effect of different treatments and alcohol addiction on gut microbiota in minimal hepatic encephalopathy patients. Exp Ther Med. https://doi.org/10.3892/etm.2017.5141

Download references

Funding

This work was supported by NIH grant DA044308, a NARSAD young investigator grant, and startup funds from the Icahn School of Medicine at Mount Sinai all to D.D.K.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Drew D. Kiraly.

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

Verify currency and authenticity via CrossMark

Cite this article

Meckel, K.R., Kiraly, D.D. A potential role for the gut microbiome in substance use disorders. Psychopharmacology 236, 1513–1530 (2019). https://doi.org/10.1007/s00213-019-05232-0

Download citation

Keywords

  • Addiction
  • Microbiome
  • Microbiota
  • Dysbiosis
  • Metabolites
  • Opioid
  • Cocaine
  • Alcohol
  • Gut-brain