Opioid-induced dysbiosis of maternal gut microbiota during gestation alters offspring gut microbiota and pain sensitivity

References

• Hirai AH, Ko JY, Owens PL, Stocks C, Patrick SW. Neonatal abstinence syndrome and maternal opioid-related diagnoses in the US, 2010-2017. JAMA - J Am Med Assoc. 2021;325(2):146–38. doi:10.1001/jama.2020.24991.
   PubMed Web of Science ®Google Scholar
• Ko JY, D’Angelo DV, Haight SC, Morrow B, Cox S, Salvesen von Essen B, Strahan AE, Harrison L, Tevendale HD, Warner L, et al. Vital signs: prescription opioid pain reliever use during pregnancy — 34 U.S. Jurisdictions, 2019. MMWR Morb Mortal Wkly Rep. 2020;69:897–903.
   PubMed Web of Science ®Google Scholar
• Opioid use and opioid use disorder in pregnancy. Committee Opinion No. 711. American College of Obstetricians and Gynecologists. Obstet Gynecol. 2017:130:e81–94.
   PubMedGoogle Scholar
• Minozzi S, Amato L, Jahanfar S, Bellisario C, Ferri M, Davoli M. Maintenance agonist treatments for opiate-dependent pregnant women. Cochrane Database Syst Rev. 2020;2020(11): CD006318. doi:10.1002/14651858.CD006318.pub4.
   Google Scholar
• Jones HE, Kaltenbach K, Heil SH, Stine SM, Coyle MG, Arria AM, Ogrady KE, Selby P, Martin PR, Fischer G. Neonatal abstinence syndrome after methadone or buprenorphine exposure. Obstet Gynecol Surv. 2011;66(4):191–193. doi:10.1097/OGX.0b013e318225c419.
   Web of Science ®Google Scholar
• Abu Y, Roy S. Prenatal opioid exposure and vulnerability to future substance use disorders in offspring. Exp Neurol [Internet]. 2021;339:113621. doi:10.1016/j.expneurol.2021.113621.
   PubMed Web of Science ®Google Scholar
• Ross EJ, Graham DL, Money KM, Stanwood GD. Developmental consequences of fetal exposure to drugs: what we know and what we still must learn. Neuropsychopharmacology [Internet]. 2015;40(1):61–87. doi:10.1038/npp.2014.147.
   PubMed Web of Science ®Google Scholar
• McQueen K, Murphy-Oikonen J, Longo DL. Neonatal abstinence syndrome. N Engl J Med. 2016;375(25):2468–2479. doi:10.1056/NEJMra1600879.
   PubMed Web of Science ®Google Scholar
• Ornoy A, Segal J, Bar-Hamburger R, Greenbaum C. Developmental outcome of school-age children born to mothers with heroin dependency: importance of environmental factors. Dev Med Child Neurol. 2001;43(10):668–675. doi:10.1111/j.1469-8749.2001.tb00140.x.
   PubMed Web of Science ®Google Scholar
• Hunt RW, Tzioumi D, Collins E, Jeffery HE. Adverse neurodevelopmental outcome of infants exposed to opiate in-utero. Early Hum Dev. 2008;84(1):29–35. doi:10.1016/j.earlhumdev.2007.01.013.
   PubMed Web of Science ®Google Scholar
• Nygaard E, Slinning K, Moe V, Walhovd KB. Cognitive function of youths born to mothers with opioid and poly-substance abuse problems during pregnancy. Child Neuropsychol [Internet]. 2017;23:159–187. doi:10.1080/09297049.2015.1092509.
   PubMed Web of Science ®Google Scholar
• Ditre JW, Zale EL, Larowe LR. A reciprocal model of pain and substance use: Transdiagnostic Considerations, clinical implications, and future directions. Annu Rev Clin Psychol. 2019;15(1):503–528. doi:10.1146/annurev-clinpsy-050718-095440.
   PubMedGoogle Scholar
• Compton P, Charuvastra VC, Kintaudi K, Ling W. Pain responses in methadone-maintained opioid abusers. J Pain Symptom Manage. 2000;20(4):237–245. doi:10.1016/S0885-3924(00)00191-3.
   PubMed Web of Science ®Google Scholar
• Doverty M, White JM, Somogyi AA, Bochner F, Ali R, Ling W. Hyperalgesic responses in methadone maintenance patients. Pain. 2001;90(1):91–96. doi:10.1016/S0304-3959(00)00391-2.
   PubMed Web of Science ®Google Scholar
• Lehofer M, Liebmann PM, Moser M, Legl T, Pernhaupt G, Schauenstein K, Zapotoczky HG. Decreased nociceptive sensitivity: A biological risk marker for opiate dependence? Addiction. 1997;92(2):163–166. doi:10.1111/j.1360-0443.1997.tb03648.x.
   PubMed Web of Science ®Google Scholar
• Compton MA. Cold-pressor pain tolerance in opiate and cocaine abusers: correlates of drug type and use status. J Pain Symptom Manage. 1994;9(7):462–473. doi:10.1016/0885-3924(94)90203-8.
   PubMed Web of Science ®Google Scholar
• Brands B, Blake J, Sproule B, Gourlay D, Busto U. Prescription opioid abuse in patients presenting for methadone maintenance treatment. Drug Alcohol Depend. 2004;73:199–207. doi:10.1016/j.drugalcdep.2003.10.012.
   PubMed Web of Science ®Google Scholar
• Oji-Mmuo CN, Speer RR, Gardner FC, Marvin MM, Hozella AC, Doheny KK. Prenatal opioid exposure heightens sympathetic arousal and facial expressions of pain/distress in term neonates at 24–48 hours post birth. J Matern Neonatal Med [Internet]. 2020;33:3879–3886. doi:10.1080/14767058.2019.1588876.
   PubMed Web of Science ®Google Scholar
• Schubach NE, Mehler K, Roth B, Korsch E, Laux R, Singer D, von der Wense A, Treszl A, Hünseler C. Skin conductance in neonates suffering from abstinence syndrome and unexposed newborns. Eur J Pediatr [Internet]. 2016;175(6):859–868. doi:10.1007/s00431-016-2716-8.
   PubMed Web of Science ®Google Scholar
• Wallin CM, Bowen SE, Roberge CL, Richardson LM, Brummelte S. Gestational buprenorphine exposure: effects on pregnancy, development, neonatal opioid withdrawal syndrome, and behavior in a translational rodent model. Drug Alcohol Depend [Internet]. 2019;205. doi:10.1016/j.drugalcdep.2019.107625.
   PubMed Web of Science ®Google Scholar
• Chiang YC, Ye LC, Hsu KY, Liao CW, Hung TW, Lo WJ, Ho IK, Tao PL. Beneficial effects of co-treatment with dextromethorphan on prenatally methadone-exposed offspring. J Biomed Sci. 2015;22(1):1–12. doi:10.1186/s12929-015-0126-2.
   PubMedGoogle Scholar
• Morreale C, Bresesti I, Bosi A, Baj A, Giaroni C, Agosti M, Salvatore S. Microbiota and Pain: Save Your Gut Feeling. Cells. 2022;11(6):1–18. doi:10.3390/cells11060971.
   Web of Science ®Google Scholar
• Romano-Keeler J, Weitkamp JH. Maternal influences on fetal microbial colonization and immune development. Pediatr Res. 2015;77(1–2):189–195. doi:10.1038/pr.2014.163.
   PubMed Web of Science ®Google Scholar
• Metsälä J, Lundqvist A, Virta LJ, Kaila M, Gissler M, Virtanen SM. Prenatal and post-natal exposure to antibiotics and risk of asthma in childhood. Clin Exp Allergy. 2015;45(1):137–145. doi:10.1111/cea.12356.
   PubMed Web of Science ®Google Scholar
• Kim S, Kim H, Yim YS, Ha S, Atarashi K, Guan T, Longman RS, Littman DR, Choi GB, Jun R, et al. 2017. Maternal gut bacteria promote neurodevelopmental abnormalities in mouse offspring. Nature. 549:528–532. doi: 10.1038/nature23910.
   PubMed Web of Science ®Google Scholar
• Dunlop AL, Mulle JG, Ferranti EP, Edwards S, Dunn AB, Corwin EJ. Maternal microbiome and pregnancy outcomes that impact infant health: a review. Adv Neonatal Care. 2015;15(6):377–385. doi:10.1097/ANC.0000000000000218.
   PubMed Web of Science ®Google Scholar
• Codagnone MG, Spichak S, O’Mahony SM, O’Leary OF, Clarke G, Stanton C, Dinan TG, Cryan JF. Programming bugs: microbiota and the developmental origins of brain health and disease. Biol Psychiatry [Internet]. 2019;85:150–163. doi:10.1016/j.biopsych.2018.06.014.
   PubMed Web of Science ®Google Scholar
• Nyangahu DD, Lennard KS, Brown BP, Darby MG, Wendoh JM, Havyarimana E, Smith P, Butcher J, Stintzi A, Mulder N, et al. Disruption of maternal gut microbiota during gestation alters offspring microbiota and immunity. Microbiome. 2018;6(1):1–10. doi:10.1186/s40168-018-0511-7.
   PubMedGoogle Scholar
• Abu Y, Tao J, Dutta R, Yan Y, Vitari N, Kolli U, Roy S. Brief hydromorphone exposure during pregnancy sufficient to induce maternal and neonatal microbial dysbiosis. J Neuroimmune Pharmacol [Internet]. 2021;17(1–2):367–375. doi:10.1007/s11481-021-10019-2.
   PubMed Web of Science ®Google Scholar
• Antoine D, Singh PK, Tao J, Roy S. Neonatal morphine results in long-lasting alterations to the gut microbiome in adolescence and adulthood in a murine model. Pharmaceutics. 2022;14(9):14. doi:10.3390/pharmaceutics14091879.
   Web of Science ®Google Scholar
• Lyu Z, Schmidt RR, Martin RE, Green MT, Kinkade JA, Mao J, Bivens NJ, Joshi T, Rosenfeld CS. Long-term effects of developmental exposure to oxycodone on gut microbiota and relationship to adult behaviors. mSystems. 2022;7:1–14. doi:10.1128/msystems.00336-22.
   Web of Science ®Google Scholar
• Grecco GG, Gao Y, Gao H, Liu Y, Atwood BK. Prenatal opioid administration induces shared alterations to the maternal and offspring gut microbiome: a preliminary analysis. Drug Alcohol Depend. 2022;227:1–13. doi:10.1016/j.drugalcdep.2021.108914.
   Web of Science ®Google Scholar
• Deuis JR, Dvorakova LS, Vetter I. Methods used to evaluate pain behaviors in rodents. Front Mol Neurosci. 2017;10:1–17. doi:10.3389/fnmol.2017.00284.
   PubMed Web of Science ®Google Scholar
• Turner PV, Pang DSJ, Lofgren JLS. A review of pain assessment Methods in laboratory rodents. Comp Med. 2019;69(6):451–467. doi:10.30802/AALAS-CM-19-000042.
   PubMed Web of Science ®Google Scholar
• Gregory N, Harris A, Robinson C, Dougherty P, Fuchs5 P, Sluka K. An overview of animal models of pain: disease models and outcome measures. J Pain [Internet]. 2013;14:1255–1269. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3624763/pdf/nihms412728.pdf. doi:10.1016/j.jpain.2013.06.008.
   PubMed Web of Science ®Google Scholar
• Substance Abuse and Mental Health Services Administration. Clinical guidance for treating pregnant and parenting women with opioid use disorder and their infants. HHS Publication No. (SMA) 18-5054. Rockville, MD: Substance Abuse and Mental Health Services Administration; 2018. https://www.samhsa.gov/resource/ebp/clinical-guidance-treating-pregnant-parenting-women-opioid-use-disorder-their-infants
   Google Scholar
• D’Amour F, Smith L. A method for determining loss of pain sensation. J Pharmacol Exp Ther. 1941;72:74–79.
   Google Scholar
• Zhang L, Meng J, Ban Y, Jalodia R, Chupikova I, Fernandez I, Brito N, Sharma U, Abreu MT, Ramakrishnan S, et al. Morphine tolerance is attenuated in germfree mice and reversed by probiotics, implicating the role of gut microbiome. Proc Natl Acad Sci U S A. 2019;116(27):13523–13532. doi:10.1073/pnas.1901182116.
   PubMed Web of Science ®Google Scholar
• Jalodia R, Kolli U, Braniff RG, Tao J, Abu YF, Chupikova I, Moidunny S, Ramakrishnan S, Roy S. Morphine mediated neutrophil infiltration in intestinal tissue play essential role in histological damage and microbial dysbiosis. Gut Microbes [Internet]. 2022;14(1):1–17. doi:10.1080/19490976.2022.2143225.
   Web of Science ®Google Scholar
• Callahan BJ, McMurdie PJ, Rosen MJ, Han AW, Johnson AJA, Holmes SP. DADA2: High-resolution sample inference from Illumina amplicon data. Nat Methods. 2016;13(7):581–583. doi:10.1038/nmeth.3869.
   PubMed Web of Science ®Google Scholar
• Ward T, Larson J, Meulemans J, Hillmann B, Lynch J, Sidiropoulos D, Spear JR, Caporaso G, Blekhman R, Knight R, et al. BugBase predicts organism-level microbiome phenotypes. bioRxiv. 2017. doi:10.1016/j.sciaf.2019.e00146.
   Google Scholar
• Chong J, Liu P, Zhou G, Xia J. Using MicrobiomeAnalyst for comprehensive statistical, functional, and meta-analysis of microbiome data. Nat Protoc [Internet]. 2020;15(3):799–821. doi:10.1038/s41596-019-0264-1.
   PubMed Web of Science ®Google Scholar
• Segata N, Izard J, Waldron L, Gevers D, Miropolsky L, Garrett WS, Huttenhower C. Metagenomic biomarker discovery and explanation. Genome Biol. 2011;12(6):12. doi:10.1186/gb-2011-12-6-r60.
   Web of Science ®Google Scholar
• Yang J, Zheng P, Li Y, Wu J, Tan X, Zhou J, Sun Z, Chen X, Zhang G, Zhang H, et al. 2020. Landscapes of bacterial and metabolic signatures and their interaction in major depressive disorders. Sci Adv. 6:6. doi: 10.1126/sciadv.aba8555.
   Web of Science ®Google Scholar
• Kongstorp M, Bogen IL, Stiris T, Andersen JM. High accumulation of methadone compared with buprenorphine in fetal rat brain after maternal exposure. J Pharmacol Exp Ther. 2019;371(1):130–137. doi:10.1124/jpet.119.259531.
   PubMed Web of Science ®Google Scholar
• Fjelldal MF, Hadera MG, Kongstorp M, Austdal LPE, Šulović A, Andersen JM, Paulsen RE. Opioid receptor-mediated changes in the NMDA receptor in developing rat and chicken. Int J Dev Neurosci. 2019;78(1):19–27. doi:10.1016/j.ijdevneu.2019.07.009.
   PubMedGoogle Scholar
• Byrnes EM, Vassoler FM. Modeling prenatal opioid exposure in animals: Current findings and future directions. Front Neuroendocrinol. 2018;51:1–13. doi:10.1016/j.yfrne.2017.09.001.
   PubMed Web of Science ®Google Scholar
• Jalodia R, Abu YF, Oppenheimer MR, Herlihy B, Meng J, Chupikova I, Tao J, Ghosh N, Dutta RK, Kolli U, et al. 2022. Opioid use, gut dysbiosis, inflammation, and the nervous system. J Neuroimmune Pharmacol [Internet]. 17:76–93. doi: 10.1007/s11481-021-10046-z.
   PubMed Web of Science ®Google Scholar
• Morais LH, Schreiber HL, Mazmanian SK. The gut microbiota–brain axis in behaviour and brain disorders. Nat Rev Microbiol [Internet]. 2021;19(4):241–255. doi:10.1038/s41579-020-00460-0.
   PubMed Web of Science ®Google Scholar
• Frese SA, Hutton AA, Contreras LN, Shaw CA, Palumbo MC, Casaburi G, Xu G, Davis JCC, Lebrilla CB, Henrick BM. Persistence of supplemented Bifidobacterium longum subsp. infantis EVC001 in breastfed infants. mSphere. 2017;2:1–15. doi:10.1128/mSphere.00501-17.
   Web of Science ®Google Scholar
• Yousuf EI, Carvalho M, Dizzell SE, Kim S, Gunn E, Twiss J, Giglia L, Stuart C, Hutton EK, Morrison KM, et al. 2020. Persistence of suspected probiotic organisms in preterm infant gut microbiota weeks after probiotic supplementation in the NICU. Front Microbiol. 11:1–11. doi: 10.3389/fmicb.2020.574137.
   PubMed Web of Science ®Google Scholar
• Samara J, Moossavi S, Alshaikh B, Ortega VA, Pettersen VK, Ferdous T, Hoops SL, Soraisham A, Vayalumkal J, Dersch-Mills D, et al. Supplementation with a probiotic mixture accelerates gut microbiome maturation and reduces intestinal inflammation in extremely preterm infants. Cell Host & Microbe. 2022;30(5):696–711.e5. doi:10.1016/j.chom.2022.04.005.
   PubMed Web of Science ®Google Scholar
• Hui Y, Smith B, Mortensen MS, Krych L, Sørensen SJ, Greisen G, Krogfelt KA, Nielsen DS. The effect of early probiotic exposure on the preterm infant gut microbiome development. Gut Microbes [Internet]. 2021;13(1):1–15. doi:10.1080/19490976.2021.1951113.
   Web of Science ®Google Scholar
• Guo R, Chen L, Xing C, Liu T. Pain regulation by gut microbiota: molecular mechanisms and therapeutic potential. Br J Anaesth [Internet]. 2019;123:637–654. doi:10.1016/j.bja.2019.07.026.
   PubMed Web of Science ®Google Scholar
• Jantzie LL, Maxwell JR, Newville JC, Yellowhair TR, Kitase Y, Madurai N, Ramachandra S, Bakhireva LN, Northington FJ, Gerner G, et al. 2020. Prenatal opioid exposure: The next neonatal neuroinflammatory disease. Brain Behav Immun [Internet]. 84:45–58. doi: 10.1016/j.bbi.2019.11.007.
   PubMed Web of Science ®Google Scholar
• Gleeson JP, Fein KC, Chaudhary N, Doerfler R, Newby AN, Whitehead KA. The enhanced intestinal permeability of infant mice enables oral protein and macromolecular absorption without delivery technology. Int J Pharm [Internet]. 2021;593:120120. doi:10.1016/j.ijpharm.2020.120120.
   PubMed Web of Science ®Google Scholar
• Jovel J, Dieleman LA, Kao D, Mason AL, Wine E. The Human Gut Microbiome in Health and Disease. Metagenomics Perspectives, Methods, and Applications. Academic Press; 2018. p. 197–213. doi:10.1016/B978-0-08-102268-9.00010-0.
   Google Scholar
• Jalodia R, Abu YF, Oppenheimer MR, Herlihy B, Meng J, Chupikova I, Tao J, Ghosh N, Dutta RK, Kolli U, et al. 2022. Opioid use, gut dysbiosis, inflammation, and the nervous system. J Neuroimmune Pharmacol [Internet]. 17:76–93. doi: 10.1007/s11481-021-10046-z.
   PubMed Web of Science ®Google Scholar
• Ghosh N, Kesh K, Ramakrishnan S, Roy S. Opioid use in murine model results in severe gastric pathology that May be attenuated by Proton pump inhibition. Am J Pathol [Internet]. 2022;192:1136–1150. doi:10.1016/j.ajpath.2022.04.005.
   PubMed Web of Science ®Google Scholar
• Wang F, Meng J, Zhang L, Johnson T, Chen C, Roy S. Morphine induces changes in the gut microbiome and metabolome in a morphine dependence model. Sci Rep [Internet]. 2018;8(1):1–15. doi:10.1038/s41598-018-21915-8.
   PubMed Web of Science ®Google Scholar
• Baptista-de-Souza D, Pelarin V, Canto-de-Souza L, Nunes-de-Souza RL, Canto-de-Souza A. Interplay between 5-HT 2C and 5-HT 1A receptors in the dorsal periaqueductal gray in the modulation of fear-induced antinociception in mice. Neuropharmacology [Internet]. 2018;140:100–106. doi:10.1016/j.neuropharm.2018.07.027.
   PubMed Web of Science ®Google Scholar
• de Oliveira R, de Oliveira RC, Falconi-Sobrinho LL, da Silva Soares R, Coimbra NC. 5-Hydroxytryptamine2A/2C receptors of nucleus raphe magnus and gigantocellularis/paragigantocellularis pars α reticular nuclei modulate the unconditioned fear-induced antinociception evoked by electrical stimulation of deep layers of the superior collicul. Behav Brain Res [Internet]. 2017;316:294–304. doi:10.1016/j.bbr.2016.09.016.
   PubMed Web of Science ®Google Scholar
• McGaraughty S, Farr DA, Heinricher MM. Lesions of the periaqueductal gray disrupt input to the rostral ventromedial medulla following microinjections of morphine into the medial or basolateral nuclei of the amygdala. Brain Res. 2004;1009(1–2):223–227. doi:10.1016/j.brainres.2004.02.048.
   PubMed Web of Science ®Google Scholar
• Freund W, Wunderlich AP, Stuber G, Mayer F, Steffen P, Mentzel M, Schmitz B, Weber F. The role of periaqueductal gray and cingulate cortex during suppression of pain in complex regional pain syndrome. Clin J Pain. 2011;27(9):796–804. doi:10.1097/AJP.0b013e31821d9063.
   PubMed Web of Science ®Google Scholar
• Daft JG, Ptacek T, Kumar R, Morrow C, Lorenz RG. Cross-fostering immediately after birth induces a permanent microbiota shift that is shaped by the nursing mother. Microbiome. 2015;3(1):3. doi:10.1186/s40168-015-0080-y.
   PubMedGoogle Scholar
• Grecco GG, Gao Y, Gao H, Liu Y, Atwood BK. Prenatal opioid administration induces shared alterations to the maternal and offspring gut microbiome: a preliminary analysis. Drug Alcohol Depend [Internet]. 2021;227:108914. doi:10.1016/j.drugalcdep.2021.108914.
   PubMed Web of Science ®Google Scholar
• Takeuchi Y, Mizukami H, Kudoh K, Osonoi S, Sasaki T, Kushibiki H, Ogasawara S, Hara Y, Igawa A, Pan X, et al. 2022. The diversity and abundance of gut microbiota are associated with the pain sensation threshold in the Japanese population. Neurobiol Dis [Internet]. 173:105839. doi: 10.1016/j.nbd.2022.105839.
   PubMed Web of Science ®Google Scholar
• Eeckhaut V, Machiels K, Perrier C, Romero C, Flahou B, Steppe M, Haesebrouck F, Sas B, Ducatelle R, Vermeire S, et al. 2013. Butyricicoccus pullicaecorum in inflammatory bowel disease. Gut. 62:1745–1752. doi: 10.1136/gutjnl-2012-303611.
   PubMed Web of Science ®Google Scholar
• Yang W, Lee Y, Lu H, Chou C, Id CW. Analysis of gut microbiota and the effect of lauric acid against necrotic enteritis in Clostridium perfringens and Eimeria side-by- side challenge model. PLoS ONE. 2019;14:e0205784. doi:10.1371/journal.pone.0205784.
   PubMed Web of Science ®Google Scholar
• Marrs T, Jo J, Perkin MR, Rivett DW, Witney AA, Bruce KD, Logan K, Craven J, Radulovic S, Versteeg SA, et al. 2021. Gut microbiota development during infancy: Impact of introducing allergenic foods. J Allergy Clin Immunol. 147:613–621. doi: 10.1016/j.jaci.2020.09.042.
   PubMed Web of Science ®Google Scholar
• Li YJ, Li J, Dai C. The role of intestinal microbiota and mast cell in a rat model of visceral hypersensitivity. J Neurogastroenterol Motil. 2020;26(4):529–538. doi:10.5056/jnm20004.
   PubMed Web of Science ®Google Scholar
• Liang JQ, Li T, Nakatsu G, Chen Y-X, Yau TO, Chu E, Wong S, Szeto CH, Ng SC, Chan FKL, et al. A novel faecal Lachnoclostridium marker for the non- ­ invasive diagnosis of colorectal adenoma and cancer. Gut. 2020;69(7):1248–1257. doi:10.1136/gutjnl-2019-318532.
   PubMed Web of Science ®Google Scholar
• Bannerman CA, Douchant K, Sheth PM, Ghasemlou N. The gut-brain axis and beyond: microbiome control of spinal cord injury pain in humans and rodents. Neurobiol Pain [Internet]. 2021;9:100059. doi:10.1016/j.ynpai.2020.100059.
   PubMedGoogle Scholar
• Beller A, Maurice M. Specific microbiota enhances intestinal IgA levels by inducing TGF- β in T follicular helper cells of Peyer ’s patches in mice. Eur J Immunol. 2020;50:783–794. doi:10.1002/eji.201948474.
   PubMed Web of Science ®Google Scholar
• Yang C, Fang X, Zhan G, Huang N, Li S, Bi J, Jiang R, Yang L, Miao L, Zhu B. Key role of gut microbiota in anhedonia- like phenotype in rodents with neuropathic pain. Transl Psychiatry [Internet]. 2019;9(1). doi:10.1038/s41398-019-0379-8.
   Google Scholar
• Guimarães MR, Anjo SI, Cunha AM, Esteves M, Sousa N, Almeida A, Manadas B, Leite-Almeida H. Chronic pain susceptibility is associated with anhedonic behavior and alterations in the accumbal ubiquitin-proteasome system. Pain. 2021;162(6):1722–1731. doi:10.1097/j.pain.0000000000002192.
   PubMed Web of Science ®Google Scholar
• Venegas DP, La Fuente MK D, Landskron G, González MJ, Quera R, Dijkstra G, Harmsen HJM, Faber KN, Hermoso MA. Short chain fatty acids (SCFAs)mediated gut epithelial and immune regulation and its relevance for inflammatory bowel diseases. Front Immunol. 2019;10:277. doi: 10.3389/fimmu.2019.00277.
   PubMed Web of Science ®Google Scholar
• Cirstea M, Radisavljevic N, Finlay BB. Good bug, bad bug: breaking through microbial stereotypes. Cell Host Microbe [Internet]. 2018;23:10–13. doi:10.1016/j.chom.2017.12.008.
   PubMed Web of Science ®Google Scholar
• Heintz-Buschart A, Pandey U, Wicke T, Sixel-Döring F, Janzen A, Sittig-Wiegand E, Trenkwalder C, Oertel WH, Mollenhauer B, Wilmes P. The nasal and gut microbiome in Parkinson’s disease and idiopathic rapid eye movement sleep behavior disorder. Mov Disord. 2018;33(1):88–98. doi:10.1002/mds.27105.
   PubMed Web of Science ®Google Scholar
• Hill-Burns EM, Debelius JW, Morton JT, Wissemann WT, Lewis MR, Wallen ZD, Peddada SD, Factor SA, Molho E, Zabetian CP, et al. 2017. Parkinson’s disease and Parkinson’s disease medications have distinct signatures of the gut microbiome. Mov Disord. 32:739–749. doi: 10.1002/mds.26942.
   PubMed Web of Science ®Google Scholar
• Berer K, Gerdes LA, Cekanaviciute E, Jia X, Xiao L, Xia Z, Liu C, Klotz L, Stauffer U, Baranzini SE, et al. Gut microbiota from multiple sclerosis patients enables spontaneous autoimmune encephalomyelitis in mice. Proc Natl Acad Sci U S A. 2017;114(40):10719–10724. doi:10.1073/pnas.1711233114.
   PubMed Web of Science ®Google Scholar
• Cekanaviciute E, Yoo BB, Runia TF, Debelius JW, Singh S, Nelson CA, Kanner R, Bencosme Y, Lee YK, Hauser SL, et al. Gut bacteria from multiple sclerosis patients modulate human T cells and exacerbate symptoms in mouse models. Proc Natl Acad Sci U S A. 2017;114(40):10713–10718. doi:10.1073/pnas.1711235114.
   PubMed Web of Science ®Google Scholar
• Vogt NM, Kerby RL, Dill-McFarland KA, Harding SJ, Merluzzi AP, Johnson SC, Carlsson CM, Asthana S, Zetterberg H, Blennow K, et al. Gut microbiome alterations in Alzheimer’s disease. Sci Rep [Internet]. 2017;7(1):1–11. doi:10.1038/s41598-017-13601-y.
   PubMedGoogle Scholar
• Parker BJ, Wearsch PA, Veloo ACM, Rodriguez-Palacios A. The genus Alistipes: gut bacteria with emerging implications to inflammation, cancer, and mental health. Front Immunol. 2020;11:1–15. doi:10.3389/fimmu.2020.00906.
   PubMed Web of Science ®Google Scholar
• Lee K, Vuong HE, Nusbaum DJ, Hsiao EY, Evans CJ, Taylor AMW. The gut microbiota mediates reward and sensory responses associated with regimen-selective morphine dependence. Neuropsychopharmacology [Internet]. 2018;43(13):2606–2614. doi:10.1038/s41386-018-0211-9.
   PubMed Web of Science ®Google Scholar
• Distrutti E, Reilly JO, Mcdonald C, Cipriani S, Renga B, Lynch MA, Fiorucci S. Modulation of intestinal microbiota by the probiotic VSL # 3 resets brain gene expression and ameliorates the age-related deficit in LTP. PLoS ONE. 2014;9:e106503. doi:10.1371/journal.pone.0106503.
   PubMed Web of Science ®Google Scholar
• Distrutti E, Cipriani S, Mencarelli A, Renga B, Fiorucci S, Tache Y. Probiotics VSL # 3 protect against development of visceral pain in murine model of irritable bowel syndrome. PLoS ONE. 2013;8(5):e63893. doi:10.1371/journal.pone.0063893.
   PubMed Web of Science ®Google Scholar
• Boonma P, Shapiro JM, Hollister EB, Badu S, Wu Q, Weidler EM, Abraham BP, Devaraj S, Shulman RJ. Probiotic VSL # 3 treatment reduces colonic permeability and abdominal pain symptoms in patients with irritable bowel syndrome. Front Pain Res. 2021;2. doi:10.3389/fpain.2021.691689.
   Google Scholar
• Cheng F-S, Pan D, Chang B, Jiang M, Sang L-X. Probiotic mixture VSL#3: an overview of basic and clinical studies in chronic diseases. World J Clin Cases. 2020;8:1361–1385. doi:10.12998/wjcc.v8.i8.1361.
   PubMed Web of Science ®Google Scholar
• Blaser MJ, Devkota S, McCoy KD, Relman DA, Yassour M, Young VB. Lessons learned from the prenatal microbiome controversy. Microbiome. 2021;9(1):1–7. doi:10.1186/s40168-020-00946-2.
   PubMed Web of Science ®Google Scholar
• Walker RW, Clemente JC, Peter I, Loos RJF. The prenatal gut microbiome: are we colonized with bacteria in utero? Pediatr Obes. 2017;12(S1):3–17. doi:10.1111/ijpo.12217.
   PubMedGoogle Scholar
• de Goffau MC, Lager S, Sovio U, Gaccioli F, Cook E, Peacock SJ, Parkhill J, Charnock-Jones DS, Smith GCS. Human placenta has no microbiome but can contain potential pathogens. Nature [Internet]. 2019;572(7769):329–334. doi:http://dx.doi.org/10.1038/s41586-019-1451-5.
   Google Scholar
• Aagaard K, Ma J, Antony K, Ganu R, Petrosino J, Versalovic J. The Placenta Harbors a Unique Microbiome. Sci Transl Med. 2014;6(237):229–262. doi:10.1126/scitranslmed.3008599.
   Web of Science ®Google Scholar
• Mogil JS, Chesler EJ, Wilson SG, Juraska JM, Sternberg WF. Sex differences in thermal nociception and morphine antinociception in rodents depend on genotype. Neurosci Biobehav Rev. 2000;24(3):375–389. doi:10.1016/S0149-7634(00)00015-4.
   PubMed Web of Science ®Google Scholar
• Ribeiro S, Yang P, REYES-VAZQUEZ C, SWANN A, DAFNY N. Sex differences in tail-flick latencyof non-stressed and stressed rats. Int J Neurosci. 2005;115(10):1383–1395. doi:10.1080/00207450590956404.
   PubMed Web of Science ®Google Scholar
• Traccis F, Frau R, Melis M. Gender differences in the outcome of offspring prenatally exposed to drugs of abuse. Front Behav Neurosci. 2020;14:14. doi:10.3389/fnbeh.2020.00072.
   PubMed Web of Science ®Google Scholar
• Suffet F, Brotman R. A comprehensive Care program for pregnant addicts: obstetrical, neonatal, and Child development outcomes. Int J Addict. 1984;19(2):199–219. doi:10.3109/10826088409057176.
   PubMed Web of Science ®Google Scholar
• Nygaard E, Moe V, Slinning K, Walhovd KB. Longitudinal cognitive development of children born to mothers with opioid and polysubstance use. Pediatr Res. 2015;78(3):330–335. doi:10.1038/pr.2015.95.
   PubMed Web of Science ®Google Scholar
• Terasaki LS, Gomez J, Schwarz JM. An examination of sex differences in the effects of early-life opiate and alcohol exposure. Philos Trans R Soc B Biol Sci. 2016;371:371. doi:10.1098/rstb.2015.0123.
   Web of Science ®Google Scholar
• Nasiraei-Moghadam S, Sherafat MA, Safari M-S, Moradi F, Ahmadiani A, Dargahi L. Reversal of prenatal morphine exposure-induced memory deficit in male but not female rats. J Mol Neurosci. 2013;50(1):58–69. doi:10.1007/s12031-012-9860-z.
   PubMed Web of Science ®Google Scholar
• Hamilton KL, Harris AC, Gewirtz JC, Sparber SB, Schrott LM. HPA axis dysregulation following prenatal opiate exposure and postnatal withdrawal. Neurotoxicol Teratol. 2005;27(1):95–103. doi:10.1016/j.ntt.2004.09.004.
   PubMed Web of Science ®Google Scholar
• Klausz B, Pintér O, Sobor M, Gyarmati Z, Fürst Z, Tímár J, Zelena D. Changes in adaptability following perinatal morphine exposure in juvenile and adult rats. Eur J Pharmacol [Internet]. 2011;654:166–172. doi:10.1016/j.ejphar.2010.11.025.
   PubMed Web of Science ®Google Scholar
• Dennis T, Bendersky M, Ramsay D, Lewis M. Reactivity and regulation in children prenatally exposed to cocaine. Dev Psychol. 2006;42(4):688–697. doi:10.1037/0012-1649.42.4.688.
   PubMed Web of Science ®Google Scholar
• Singer LT, Minnes S, Short E, Arendt R, Farkas K, Lewis B, Klein N, Russ S, Min MO, Kirchner HL. Cognitive outcomes of preschool children with prenatal cocaine exposure. JAMA. 2004;291:2448–2456. doi:10.1001/jama.291.20.2448.
   PubMed Web of Science ®Google Scholar
• Bennett D, Bendersky M, Lewis M. Preadolescent health risk behavior as a function of prenatal cocaine exposure and gender. J Dev Behav Pediatr. 2007;28(6):467–472. doi:10.1097/DBP.0b013e31811320d8.
   PubMed Web of Science ®Google Scholar
• Nordstrom Bailey B, Sood BG, Sokol RJ, Ager J, Janisse J, Hannigan JH, Covington C, Delaney-Black V. Gender and alcohol moderate prenatal cocaine effects on teacher-report of child behavior. Neurotoxicol Teratol. 2005;27(2):181–189. doi:10.1016/j.ntt.2004.10.004.
   PubMed Web of Science ®Google Scholar
• LaGasse LL, Derauf C, Smith LM, Newman E, Shah R, Neal C, Arria A, Huestis MA, DellaGrotta S, Lin H, et al. Prenatal methamphetamine exposure and childhood behavior problems at 3 and 5 years of age. Pediatrics. 2012;129(4):681–688. doi:10.1542/peds.2011-2209.
   PubMed Web of Science ®Google Scholar
• Skumlien M, Ibsen IO, Kesmodel US, Nygaard E. Sex differences in early cognitive development after prenatal exposure to opioids. J Pediatr Psychol. 2020;45(5):475–485. doi:10.1093/jpepsy/jsaa008.
   PubMed Web of Science ®Google Scholar
• Moe V, Slinning K. Children prenatally exposed to substances: gender-related differences in outcome from infancy to 3 years of age. Infant Ment Health J. 2001;22(3):334–350. doi:10.1002/imhj.1005.
   Web of Science ®Google Scholar
• Willoughby M, Greenberg M, Blair C, Stifter C. Neurobehavioral consequences of prenatal exposure to smoking at 6 to 8 months of age. Infancy. 2007;12(3):273–301. doi:10.1111/j.1532-7078.2007.tb00244.x.
   Web of Science ®Google Scholar
• Sikic A, Frie JA, Khokhar JY, Murray JE. Sex differences in the behavioural outcomes of prenatal Nicotine and tobacco exposure. Front Neurosci. 2022;16:1–9. doi:10.3389/fnins.2022.921429.
   Web of Science ®Google Scholar
• Jašarević E, Morrison KE, Bale TL. Sex differences in the gut microbiome – brain axis across the lifespan. Philos Trans R Soc L B Biol Sci. 2016;371:371. doi:10.1098/rstb.2015.0122.
   Web of Science ®Google Scholar
• Jašarević E, Howerton CL, Howard CD, Bale TL. Alterations in the vaginal microbiome by maternal stress are associated with metabolic reprogramming of the offspring gut and brain. Endocrinology. 2015;156(9):3265–3276. doi:10.1210/en.2015-1177.
   PubMed Web of Science ®Google Scholar
• Jašarević E, Howard CD, Misic AM, Beiting DP, Bale TL. Stress during pregnancy alters temporal and spatial dynamics of the maternal and offspring microbiome in a sex-specific manner. Sci Rep [Internet]. 2017;7(1):1–13. doi:10.1038/srep44182.
   PubMedGoogle Scholar
• Moloney RD, Johnson AC, O’Mahony SM, Dinan TG, Greenwood-Van Meerveld B, Cryan JF. Stress and the microbiota-gut-brain axis in visceral PaRelevance to Irritable bowel syndrome. CNS Neurosci Ther. 2016;22:102–117. doi:10.1111/cns.12490.
   PubMed Web of Science ®Google Scholar
• Green PG, Alvarez P, Levine JD. A role for gut microbiota in early-life stress-induced widespread muscle pain in the adult rat. Mol Pain. 2021;17:17. doi:10.1177/17448069211022952.
   Web of Science ®Google Scholar
• Berg BM, Waworuntu RV, Neufeld KAM, O’Mahony SM, Dinan TG, Cryan JF. A blend of dietary prebiotics and the probiotic LGG modulate behavioral and cognitive responses to maternal separation stress. Brain Behav Immun [Internet]. 2015;49:e45. doi:10.1016/j.bbi.2015.06.168.
   Google Scholar
• Lucarini E, Di Pilato V, Parisio C, Micheli L, Toti A, Pacini A, Bartolucci G, Baldi S, Niccolai E, Amedei A, et al. Visceral sensitivity modulation by faecal microbiota transplantation: the active role of gut bacteria in pain persistence. Pain. 2022;163(5):861–877. doi:10.1097/j.pain.0000000000002438.
   PubMed Web of Science ®Google Scholar
• Radhakrishna U, Nath SK, Vishweswaraiah S, Uppala LV, Forray A, Muvvala SB, Mishra NK, Southekal S, Guda C, Govindamangalam H, et al. 2021. Maternal opioid use disorder: placental transcriptome analysis for neonatal opioid withdrawal syndrome. Genomics [Internet]. 113:3610–3617. doi: 10.1016/j.ygeno.2021.08.001.
   PubMed Web of Science ®Google Scholar
• Guo H, Enters EK, Mcdowell KP, Robinson SE. The effect of prenatal exposure to methadone on neurotransmitters in neonatal rats. Dev Brain Res. 1990;7:290–298. doi:10.1016/0165-3806(90)90056-5.
   Google Scholar
• Wu VW, Mo Q, Yabe T, Schwartz JP, Robinson SE. Perinatal opioids reduce striatal nerve growth factor content in rat striatum. Eur J Pharmacol. 2001;414(2–3):211–214. doi:10.1016/S0014-2999(01)00807-X.
   PubMed Web of Science ®Google Scholar
• Robinson SE, Maher JR, Wallace MJ, Kunko PM. Perinatal methadone exposure affects dopamine, norepinephrine, and serotonin in the weanling rat. Neurotoxicol Teratol. 1997;19:295–303. doi:10.1016/S0892-0362(97)00018-4.
   PubMed Web of Science ®Google Scholar
• Wu CC, Hung CJ, Shen CH, Chen WY, Chang CY, Pan HC, Liao SL, Chen CJ. Prenatal buprenorphine exposure decreases neurogenesis in rats. Toxicol Lett [Internet]. 2014;225:92–101. doi:10.1016/j.toxlet.2013.12.001.
   PubMed Web of Science ®Google Scholar
• Erbs E, Faget L, Ceredig RA, Matifas A, Vonesch JL, Kieffer BL, Massotte D. Impact of chronic morphine on delta opioid receptor-expressing neurons in the mouse hippocampus. Neuroscience. 2016;313:46–56. doi:10.1016/j.neuroscience.2015.10.022.
   PubMed Web of Science ®Google Scholar
• Alipio JB, Haga C, Fox ME, Arakawa K, Balaji R, Cramer N, Lobo MK, Keller A. Perinatal fentanyl exposure leads to long-lasting impairments in Somatosensory circuit function and behavior. J Neurosci. 2021;41(15):3400–3417. doi:10.1523/JNEUROSCI.2470-20.2020.
   PubMed Web of Science ®Google Scholar
• Vestal-Laborde AA, Eschenroeder AC, Bigbee JW, Robinson SE, Sato-Bigbee C. The opioid system and brain development: effects of methadone on the oligodendrocyte lineage and the early stages of myelination. Dev Neurosci. 2014;36(5):409–421. doi:10.1159/000365074.
   PubMed Web of Science ®Google Scholar
• Sanchez ES, Bigbee JW, Fobbs W, Robinson SE, Sato-Bigbee C. Opioid addiction and pregnancy: perinatal exposure to buprenorphine affects myelination in the developing brain. Glia. 2008;56(9):1017–1027. doi:10.1002/glia.20675.
   PubMed Web of Science ®Google Scholar
• Merhar SL, Jiang W, Parikh NA, Yin W, Zhou Z, Tkach JA, Wang L, Kline-Fath BM, He L, Braimah A, et al. 2021. Effects of prenatal opioid exposure on functional networks in infancy. Dev Cogn Neurosci [Internet]. 51:100996. doi: 10.1016/j.dcn.2021.100996.
   PubMed Web of Science ®Google Scholar
• Chen HH, Chiang YC, Yuan ZF, Kuo CC, Lai MD, Hung TW, Ho IK, Chen ST. Buprenorphine, methadone, and morphine treatment during pregnancy: behavioral effects on the offspring in rats. Neuropsychiatr Dis Treat. 2015;11:609–618. doi:10.2147/NDT.S70585.
   PubMed Web of Science ®Google Scholar
• Van Wagoner S, Risser J, Moyer M, Lasky D. Effect of maternally administered methadone on discrimination learning of rat offspring. Percept Mot Skills. 1980;50(3_suppl):1119–1124. doi:10.2466/pms.1980.50.3c.1119.
   PubMed Web of Science ®Google Scholar
• Alipio JB, Brockett AT, Fox ME, Tennyson SS, deBettencourt CA, El-Metwally D, Francis NA, Kanold PO, Lobo MK, Roesch MR, et al. Enduring consequences of perinatal fentanyl exposure in mice. Addict Biol. 2021;26:1–13.
   Web of Science ®Google Scholar
• Martin RE, Green MT, Kinkade JA, Schmidt RR, Willemse TE, Schenk AK, Mao J, Rosenfeld CS. Maternal oxycodone treatment results in neurobehavioral disruptions in mice offspring. eNeuro. 2021;8(4):ENEURO.0150–21.2021. doi:10.1523/ENEURO.0150-21.2021.
   PubMed Web of Science ®Google Scholar
• Yang SN, Liu C-A, Chung M-Y, Huang H-C, Yeh G-C, Wong C-S, Lin W-W, Yang C-H, Tao P-L. Alterations of Postsynaptic density proteins in the hippocampus of rat offspring from the morphine-addicted mother: beneficial effect of dextromethorphan. Hippocampus. 2006;16(6):521–530. doi:10.1002/hipo.20179.
   PubMed Web of Science ®Google Scholar
• Monnelly VJ, Hamilton R, Chappell FM, Mactier H, Boardman JP. Childhood neurodevelopment after prescription of maintenance methadone for opioid dependency in pregnancy: a systematic review and meta-analysis. Dev Med Child Neurol. 2019;61(7):750–760. doi:10.1111/dmcn.14117.
   PubMed Web of Science ®Google Scholar
• Yeoh SL, Eastwood J, Wright IM, Morton R, Melhuish E, Ward M, Oei JL. Cognitive and motor outcomes of children with prenatal opioid exposure: a systematic review and meta-analysis. JAMA Netw Open. 2019;2:1–14. doi:10.1001/jamanetworkopen.2019.7025.
   Web of Science ®Google Scholar
• Arter SJ, Tyler B, McAllister J, Kiel E, Güler A, Cameron Hay M. Longitudinal outcomes of children exposed to opioids in-utero: a systematic review. J Nurs Scholarsh. 2021;53(1):55–64. doi:10.1111/jnu.12609.
   PubMed Web of Science ®Google Scholar
• Lee SJ, Bora S, Austin NC, Westerman A, Henderson JMT. Neurodevelopmental outcomes of children born to opioid-dependent mothers: a systematic review and meta-analysis. Acad Pediatr [Internet]. 2020;20:308–318. doi:10.1016/j.acap.2019.11.005.
   PubMed Web of Science ®Google Scholar
• Nelson LF, Yocum VK, Patel KD, Qeadan F, Hsi A, Weitzen S. Cognitive outcomes of young children after prenatal exposure to medications for opioid use disorder: a systematic review and meta-analysis. JAMA Netw Open. 2020;3:1–14. doi:10.1001/jamanetworkopen.2020.1195.
   Web of Science ®Google Scholar
• Andersen JM, Høiseth G, Nygaard E. Prenatal exposure to methadone or buprenorphine and long-term outcomes: a meta-analysis. Early Hum Dev [Internet]. 2020;143:104997. doi:10.1016/j.earlhumdev.2020.104997.
   PubMed Web of Science ®Google Scholar
• Meng X, Zhang Y, Lao L, Saito R, Li A, Bäckman CM, Berman BM, Ren K, Wei PK, Zhang RX. Spinal interleukin-17 promotes thermal hyperalgesia and NMDA NR1 phosphorylation in an inflammatory pain rat model. Pain [Internet]. 2013;154(2):294–305. doi:10.1016/j.pain.2012.10.022.
   Google Scholar
• Kleinschnitz C, Hofstetter HH, Meuth SG, Braeuninger S, Sommer C, Stoll G. T cell infiltration after chronic constriction injury of mouse sciatic nerve is associated with interleukin-17 expression. Exp Neurol. 2006;200(2):480–485. doi:10.1016/j.expneurol.2006.03.014.
   PubMed Web of Science ®Google Scholar
• Noma N, Khan J, Chen IF, Markman S, Benoliel R, Hadlaq E, Imamura Y, Eliav E. Interleukin-17 levels in rat models of nerve damage and neuropathic pain. Neurosci Lett [Internet]. 2011;493:86–91. doi:10.1016/j.neulet.2011.01.079.
   PubMed Web of Science ®Google Scholar
• Kim CF, Moalem-Taylor G. Interleukin-17 contributes to neuroinflammation and neuropathic pain following peripheral nerve injury in mice. J Pain [Internet]. 2011;12:370–383. doi:10.1016/j.jpain.2010.08.003.
   PubMed Web of Science ®Google Scholar
• McNamee KE, Alzabin S, Hughes JP, Anand P, Feldmann M, Williams RO, Inglis JJ. IL-17 induces hyperalgesia via TNF-dependent neutrophil infiltration. Pain [Internet]. 2011;152(8):1838–1845. doi:10.1016/j.pain.2011.03.035.
   Google Scholar
• Pinto LG, Cunha TM, Vieira SM, Lemos HP, Verri WA, Cunha FQ, Ferreira SH. IL-17 mediates articular hypernociception in antigen-induced arthritis in mice. Pain [Internet]. 2010;148(2):247–256. doi:10.1016/j.pain.2009.11.006.
   Google Scholar
• Kabat AM, Srinivasan N, Maloy KJ. Modulation of immune development and function by intestinal microbiota. Trends Immunol [Internet]. 2014;35:507–517. doi:10.1016/j.it.2014.07.010.
   PubMed Web of Science ®Google Scholar