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Alterations in gut microbiota affect behavioral and inflammatory responses to methamphetamine in mice

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Abstract

Rationale and objectives

Methamphetamine (METH) is a highly addictive and widely abused drug that causes severe neuroinflammation in the human brain. The gut microbiota has a tremendous impact on the core symptoms of neuropsychiatric disorders via the microbiota-gut-brain (MGB) axis. However, it is not clear whether alterations in the gut microbiota are involved in METH exposure.

Methods

We established a mouse model with chronic, escalating doses of METH exposure. Intervene in gut microbiota with antibiotics to observe the changes of locomotor activity caused by METH exposure in mice. qPCR and 16S rRNA gene sequencing were used to analyze the gut microbiota profiles. In addition, we tested the levels of inflammatory factors in the nucleus accumbens (NAc), prefrontal cortex (mPFC), hippocampus (HIp), and spleen. Finally, short-chain fatty acids (SCFAs) were supplemented to determine the interaction between behavior changes and the structure of gut microbiota.

Results

In this research, METH increased the locomotor activity of mice, while antibiotics changed the effect. Antibiotics enhanced the expression of pro-inflammatory cytokines in mPFC, HIp, and spleen of METH-exposed mice. METH altered the gut microbiota of mice after antibiotic treatment, such as Butyricicoccus and Roseburia, which are related to butyrate metabolism. Supplementation with SCFAs changed the behavior of METH-exposed mice and decreased Parabacteroides and increased Lactobacillus in METH-exposed mice gut.

Conclusions

This research showed that antibiotics affected the behavior of METH-exposed mice and promoted inflammation. Our findings suggest that SCFAs might regulate METH-induced gut microbiota changes and behavior.

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References

  • Anderson SM, Pierce RC (2005) Cocaine-induced alterations in dopamine receptor signaling: implications for reinforcement and reinstatement. Pharmacol Ther 106:389–403

    Article  CAS  PubMed  Google Scholar 

  • Azad MAK, Sarker M, Li T, Yin J (2018) Probiotic species in the modulation of gut microbiota: an overview. Biomed Res Int 2018:9478630

    PubMed  PubMed Central  Google Scholar 

  • Baek EJ, Kim H, Basova LA, Rosander A, Kesby JP, Semenova S, Marcondes MCG (2020) Sex differences and Tat expression affect dopaminergic receptor expression and response to antioxidant treatment in methamphetamine-sensitized HIV Tat transgenic mice. Neuropharmacology 178:108245

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bercik P, Verdu EF, Foster JA, Macri J, Potter M, Huang X, Malinowski P, Jackson W, Blennerhassett P, Neufeld KA, Lu J, Khan WI, Corthesy-Theulaz I, Cherbut C, Bergonzelli GE, Collins SM (2010) Chronic gastrointestinal inflammation induces anxiety-like behavior and alters central nervous system biochemistry in mice. Gastroenterology 139(2102–2112):e1

    Google Scholar 

  • Binda C, Lopetuso LR, Rizzatti G, Gibiino G, Cennamo V, Gasbarrini A (2018) Actinobacteria: a relevant minority for the maintenance of gut homeostasis. Dig Liver Dis 50:421–428

    Article  PubMed  Google Scholar 

  • Boesmans L, Valles-Colomer M, Wang J, Eeckhaut V, Falony G, Ducatelle R, Van Immerseel F, Raes J, Verbeke K (2018) Butyrate producers as potential next-generation probiotics: safety assessment of the administration of Butyricicoccus pullicaecorum to healthy volunteers. mSystems 3

  • Bravo JA, Forsythe P, Chew MV, Escaravage E, Savignac HM, Dinan TG, Bienenstock J, Cryan JF (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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cahenzli J, Koller Y, Wyss M, Geuking MB, McCoy KD (2013) Intestinal microbial diversity during early-life colonization shapes long-term IgE levels. Cell Host Microbe 14:559–570

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Carbia C, Lannoy S, Maurage P, Lopez-Caneda E, O’Riordan KJ, Dinan TG, Cryan JF (2021) A biological framework for emotional dysregulation in alcohol misuse: from gut to brain. Mol Psychiatry 26:1098–1118

    Article  PubMed  Google Scholar 

  • Crowe SE (2019) Helicobacter pylori Infection. N Engl J Med 380:1158–1165

    Article  PubMed  Google Scholar 

  • Dalile B, Van Oudenhove L, Vervliet B, Verbeke K (2019) The role of short-chain fatty acids in microbiota-gut-brain communication. Nat Rev Gastroenterol Hepatol 16:461–478

    Article  PubMed  Google Scholar 

  • De Palma G, Collins SM, Bercik P (2014) The microbiota-gut-brain axis in functional gastrointestinal disorders. Gut Microbes 5:419–429

    Article  PubMed  PubMed Central  Google Scholar 

  • Ding J, Hu S, Meng Y, Li C, Huang J, He Y, Qiu P (2020) Alpha-Synuclein deficiency ameliorates chronic methamphetamine induced neurodegeneration in mice. Toxicology 438:152461

    Article  CAS  PubMed  Google Scholar 

  • Dong N, Zhu J, Han W, Wang S, Yan Z, Ma D, Goh E, Chen T (2018) Maternal methamphetamine exposure causes cognitive impairment and alteration of neurodevelopment-related genes in adult offspring mice. Neuropharmacology 140:25–34

    Article  CAS  PubMed  Google Scholar 

  • Eeckhaut V, Machiels K, Perrier C, Romero C, Maes S, Flahou B, Steppe M, Haesebrouck F, Sas B, Ducatelle R, Vermeire S, Van Immerseel F (2013) Butyricicoccus pullicaecorum in inflammatory bowel disease. Gut 62:1745–1752

    Article  CAS  PubMed  Google Scholar 

  • Erny D, Hrabe de Angelis AL, Jaitin D, Wieghofer P, Staszewski O, David E, Keren-Shaul H, Mahlakoiv T, Jakobshagen K, Buch T, Schwierzeck V, Utermohlen O, Chun E, Garrett WS, McCoy KD, Diefenbach A, Staeheli P, Stecher B, Amit I, Prinz M (2015) Host microbiota constantly control maturation and function of microglia in the CNS. Nat Neurosci 18:965–977

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Frohlich EE, Farzi A, Mayerhofer R, Reichmann F, Jacan A, Wagner B, Zinser E, Bordag N, Magnes C, Frohlich E, Kashofer K, Gorkiewicz G, Holzer P (2016) Cognitive impairment by antibiotic-induced gut dysbiosis: analysis of gut microbiota-brain communication. Brain Behav Immun 56:140–155

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Garcia-Cabrerizo R, Carbia C, KJ OR, Schellekens H, Cryan JF (2021) Microbiota-gut-brain axis as a regulator of reward processes. J Neurochem 157: 1495-1524

  • Gareau MG, Wine E, Rodrigues DM, Cho JH, Whary MT, Philpott DJ, Macqueen G, Sherman PM (2011) Bacterial infection causes stress-induced memory dysfunction in mice. Gut 60:307–317

    Article  PubMed  Google Scholar 

  • Gomaa EZ (2020) Human gut microbiota/microbiome in health and diseases: a review. Antonie Van Leeuwenhoek 113:2019–2040

    Article  PubMed  Google Scholar 

  • Grochowska M, Laskus T, Radkowski M (2019) Gut microbiota in neurological disorders. Arch Immunol Ther Exp (warsz) 67:375–383

    Article  CAS  Google Scholar 

  • Itzhak Y, Ergui I, Young JI (2015) Long-term parental methamphetamine exposure of mice influences behavior and hippocampal DNA methylation of the offspring. Mol Psychiatry 20:232–239

    Article  CAS  PubMed  Google Scholar 

  • Kasahara K, Krautkramer KA, Org E, Romano KA, Kerby RL, Vivas EI, Mehrabian M, Denu JM, Backhed F, Lusis AJ, Rey FE (2018) Interactions between Roseburia intestinalis and diet modulate atherogenesis in a murine model. Nat Microbiol 3:1461–1471

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kim B, Yun J, Park B (2020) Methamphetamine-induced neuronal damage: neurotoxicity and neuroinflammation. Biomol Ther (seoul) 28:381–388

    Article  Google Scholar 

  • Kiraly DD, Walker DM, Calipari ES, Labonte B, Issler O, Pena CJ, Ribeiro EA, Russo SJ, Nestler EJ (2016) Alterations of the host microbiome affect behavioral responses to cocaine. Sci Rep 6:35455

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kobeissy FH, Mitzelfelt JD, Fishman I, Morgan D, Gaskins R, Zhang Z, Gold MS, Wang KK (2012) Methods in drug abuse models: comparison of different models of methamphetamine paradigms. Methods Mol Biol 829:269–278

    Article  CAS  PubMed  Google Scholar 

  • Koh A, De Vadder F, Kovatcheva-Datchary P, Backhed F (2016) From dietary fiber to host physiology: short-chain fatty acids as key bacterial metabolites. Cell 165:1332–1345

    Article  CAS  PubMed  Google Scholar 

  • Kollef MH (2005) Bench-to-bedside review: antimicrobial utilization strategies aimed at preventing the emergence of bacterial resistance in the intensive care unit. Crit Care 9:459–464

    Article  PubMed  PubMed Central  Google Scholar 

  • Lei E, Vacy K, Boon WC (2016) Fatty acids and their therapeutic potential in neurological disorders. Neurochem Int 95:75–84

    Article  CAS  PubMed  Google Scholar 

  • Li Y, Wang X, Li N, Qu L, Wang P, Ge SN, Wang XL (2020) The NAc lesions disrupted the hippocampus-mPFC theta coherence during intravenous cocaine administration in rats. Neurosci Lett 729:134986

    Article  CAS  PubMed  Google Scholar 

  • Lucerne KE, Osman A, Meckel KR, Kiraly DD (2021) Contributions of neuroimmune and gut-brain signaling to vulnerability of developing substance use disorders. Neuropharmacology 192:108598

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Margiotta E, Miragoli F, Callegari ML, Vettoretti S, Caldiroli L, Meneghini M, Zanoni F, Messa P (2020) Gut microbiota composition and frailty in elderly patients with Chronic Kidney Disease. PLoS ONE 15:e0228530

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Meckel KR, Kiraly DD (2019) A potential role for the gut microbiome in substance use disorders. Psychopharmacology 236:1513–1530

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Moore JE, Corcoran D, Dooley JS, Fanning S, Lucey B, Matsuda M, McDowell DA, Megraud F, Millar BC, O’Mahony R, O’Riordan L, O’Rourke M, Rao JR, Rooney PJ, Sails A, Whyte P (2005) Campylobacter. Vet Res 36:351–382

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  PubMed  PubMed Central  Google Scholar 

  • Ning T, Gong X, Xie L, Ma B (2017) Gut microbiota analysis in rats with methamphetamine-induced conditioned place preference. Front Microbiol 8:1620

    Article  PubMed  PubMed Central  Google Scholar 

  • Ohira H, Tsutsui W, Fujioka Y (2017) Are short chain fatty acids in gut microbiota defensive players for inflammation and atherosclerosis? J Atheroscler Thromb 24:660–672

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Park M, Kim HJ, Lim B, Wylegala A, Toborek M (2013) Methamphetamine-induced occludin endocytosis is mediated by the Arp2/3 complex-regulated actin rearrangement. J Biol Chem 288:33324–33334

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Peterson VL, Richards JB, Meyer PJ, Cabrera-Rubio R, Tripi JA, King CP, Polesskaya O, Baud A, Chitre AS, Bastiaanssen TFS, Woods LS, Crispie F, Dinan TG, Cotter PD, Palmer AA, Cryan JF (2020) Sex-dependent associations between addiction-related behaviors and the microbiome in outbred rats. EBioMedicine 55:102769

    Article  PubMed  PubMed Central  Google Scholar 

  • Pimentel E, Sivalingam K, Doke M, Samikkannu T (2020) Effects of drugs of abuse on the blood-brain barrier: a brief overview. Front Neurosci 14:513

    Article  PubMed  PubMed Central  Google Scholar 

  • Prakash MD, Tangalakis K, Antonipillai J, Stojanovska L, Nurgali K, Apostolopoulos V (2017) Methamphetamine: effects on the brain, gut and immune system. Pharmacol Res 120:60–67

    Article  CAS  PubMed  Google Scholar 

  • Prut L, Belzung C (2003) The open field as a paradigm to measure the effects of drugs on anxiety-like behaviors: a review. Eur J Pharmacol 463:3–33

    Article  CAS  PubMed  Google Scholar 

  • Rakoff-Nahoum S, Paglino J, Eslami-Varzaneh F, Edberg S, Medzhitov R (2004) Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis. Cell 118:229–241

    Article  CAS  PubMed  Google Scholar 

  • Reikvam DH, Erofeev A, Sandvik A, Grcic V, Jahnsen FL, Gaustad P, McCoy KD, Macpherson AJ, Meza-Zepeda LA, Johansen FE (2011) Depletion of murine intestinal microbiota: effects on gut mucosa and epithelial gene expression. PLoS ONE 6:e17996

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Robinson TE, Berridge KC (1993) The neural basis of drug craving: an incentive-sensitization theory of addiction. Brain Res Brain Res Rev 18:247–291

    Article  CAS  PubMed  Google Scholar 

  • Rosales RS, Puleio R, Loria GR, Catania S, Nicholas RAJ (2017) Mycoplasmas: brain invaders? Res Vet Sci 113:56–61

    Article  PubMed  Google Scholar 

  • Salamanca SA, Sorrentino EE, Nosanchuk JD, Martinez LR (2014) Impact of methamphetamine on infection and immunity. Front Neurosci 8:445

    PubMed  Google Scholar 

  • Segal DS, Kuczenski R (1997) Repeated binge exposures to amphetamine and methamphetamine: behavioral and neurochemical characterization. J Pharmacol Exp Ther 282:561–573

    CAS  PubMed  Google Scholar 

  • Selvanantham T, Lin Q, Guo CX, Surendra A, Fieve S, Escalante NK, Guttman DS, Streutker CJ, Robertson SJ, Philpott DJ, Mallevaey T (2016) NKT cell-deficient mice harbor an altered microbiota that fuels intestinal inflammation during chemically induced colitis. J Immunol 197:4464–4472

    Article  CAS  PubMed  Google Scholar 

  • Shansky RM (2019) Are hormones a “female problem” for animal research? Science 364:825–826

    Article  CAS  PubMed  Google Scholar 

  • Silva YP, Bernardi A, Frozza RL (2020) The role of short-chain fatty acids from gut microbiota in gut-brain communication. Front Endocrinol (lausanne) 11:25

    Article  Google Scholar 

  • Sinha R, Jastreboff AM (2013) Stress as a common risk factor for obesity and addiction. Biol Psychiatry 73:827–835

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Smith PM, Howitt MR, Panikov N, Michaud M, Gallini CA, Bohlooly YM, Glickman JN, Garrett WS (2013) The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science 341:569–573

    Article  CAS  PubMed  Google Scholar 

  • Strandwitz P (2018) Neurotransmitter modulation by the gut microbiota. Brain Res 1693:128–133

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tenk CM, Foley KA, Kavaliers M, Ossenkopp KP (2007) Neonatal immune system activation with lipopolysaccharide enhances behavioural sensitization to the dopamine agonist, quinpirole, in adult female but not male rats. Brain Behav Immun 21:935–945

    Article  CAS  PubMed  Google Scholar 

  • Tocharus J, Khonthun C, Chongthammakun S, Govitrapong P (2010) Melatonin attenuates methamphetamine-induced overexpression of pro-inflammatory cytokines in microglial cell lines. J Pineal Res 48:347–352

    Article  CAS  PubMed  Google Scholar 

  • Vinolo MA, Rodrigues HG, Nachbar RT, Curi R (2011) Regulation of inflammation by short chain fatty acids. Nutrients 3:858–876

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang Y, Zhang J, Deji C, Fan J, Miao X, Li S, Zeng X, Guan F (2021) Differential perturbations of gut microbial profiles and co-occurrence networks among phases of methamphetamine-induced conditioned place preference. J Neurosci Res

  • World Drug Report (2021) United Nations publication, Sales No. E.21.XI.8

  • Yang C, Fu X, Hao W, Xiang X, Liu T, Yang BZ, Zhang X (2021a) Gut dysbiosis associated with the rats’ responses in methamphetamine-induced conditioned place preference. Addict Biol 26:e12975

    CAS  PubMed  Google Scholar 

  • Yang Y, Yu X, Liu X, Liu G, Zeng K, Wang G (2021b) Altered fecal microbiota composition in individuals who abuse methamphetamine. Sci Rep 11:18178

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhu J, Zhao N, Chen Y, Zhu L, Zhong Q, Liu J, Chen T (2017) Sodium butyrate modulates a methamphetamine-induced conditioned place preference. J Neurosci Res 95:1044–1052

    Article  CAS  PubMed  Google Scholar 

  • Zhu C, Song K, Shen Z, Quan Y, Tan B, Luo W, Wu S, Tang K, Yang Z, Wang X (2018) Roseburia intestinalis inhibits interleukin17 excretion and promotes regulatory T cells differentiation in colitis. Mol Med Rep 17:7567–7574

    CAS  PubMed  PubMed Central  Google Scholar 

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Funding

This work was supported by research grants from the National Natural Science Foundation of China (grant numbers 81871537).

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Authors and Affiliations

  1. Department of Immunology and Pathogenic Biology, College of Basic Medicine, Xi’an Jiaotong University Health Science Center, Xi’an, People’s Republic of China

    Simin Lai, Jing Wang, Biao Wang & Yanjiong Chen

  2. Forensic Medicine College, Key Laboratory of the Health Ministry for Forensic Medicine, Xi’an Jiaotong University, Xi’an, People’s Republic of China

    Rui Wang & Teng Chen

  3. National Local Joint Engineering Research Center of Biodiagnostics and Biotherapy, the Second Affiliated Hospital of Xi’an Jiaotong University College of Medicin, Xi’an, People’s Republic of China

    Guodong Li

  4. Department of Laboratory Medicine, Baoji Maternal and Child Health Hospital, Baoji, People’s Republic of China

    Yuwei Jia

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  1. Simin Lai
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  2. Jing Wang
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  3. Biao Wang
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Correspondence to Yanjiong Chen.

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Lai, S., Wang, J., Wang, B. et al. Alterations in gut microbiota affect behavioral and inflammatory responses to methamphetamine in mice. Psychopharmacology 239, 1–16 (2022). https://doi.org/10.1007/s00213-022-06154-0

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