Skip to content
naulon
Get started

No retraction, correction or concern found when last checked on Oct 31, 2026.

The microbial metabolite p-Cresol induces autistic-like behaviors in mice by remodeling the gut microbiota

Patricia Bermudez-Martin, Jérôme A. J. Becker, Nicolas Caramello and 17 more

Microbiome · 2021 · CC BY

doi:10.1186/s40168-021-01103-z

Abstract

Background. Autism spectrum disorders (ASD) are associated with dysregulation of the microbiota-gut-brain axis, changes in microbiota composition as well as in the fecal, serum, and urine levels of microbial metabolites. Yet a causal relationship between dysregulation of the microbiota-gut-brain axis and ASD remains to be demonstrated. Here, we hypothesized that the microbial metabolite p-Cresol, which is more abundant in ASD patients compared to neurotypical individuals, could induce ASD-like behavior in mice.

Results. Mice exposed to p-Cresol for 4 weeks in drinking water presented social behavior deficits, stereotypies, and perseverative behaviors, but no changes in anxiety, locomotion, or cognition. Abnormal social behavior induced by p-Cresol was associated with decreased activity of central dopamine neurons involved in the social reward circuit. Further, p-Cresol induced changes in microbiota composition and social behavior deficits could be transferred from p-Cresol-treated mice to control mice by fecal microbiota transplantation (FMT). We also showed that mice transplanted with the microbiota of p-Cresol-treated mice exhibited increased fecal p-Cresol excretion, compared to mice transplanted with the microbiota of control mice. In addition, we identified possible p-Cresol bacterial producers. Lastly, the microbiota of control mice rescued social interactions, dopamine neurons excitability, and fecal p-Cresol levels when transplanted to p-Cresol-treated mice.

Conclusions. The microbial metabolite p-Cresol induces selectively ASD core behavioral symptoms in mice. Social behavior deficits induced by p-Cresol are dependant on changes in microbiota composition. Our study paves the way for therapeutic interventions targeting the microbiota and p-Cresol production to treat patients with ASD. Video abstract

Supplementary Information. The online version contains supplementary material available at 10.1186/s40168-021-01103-z.

References 98

  1. 1.

    Vuong HE, Hsiao EY. Emerging roles for the gut microbiome in autism spectrum disorder. Biol Psychiatry. 2017;81(5):411-423.

    Not in our library10.1016/j.biopsych.2016.08.024

  2. 2.

    Fombonne E, MacFarlane H, Salem AC. Epidemiological surveys of ASD: advances and remaining challenges. J Autism Dev Disord. 2021. 10.1007/s10803-021-05005-9.

    Not in our library10.1007/s10803-021-05005-9

  3. 3.

    Bourgeron T. Current knowledge on the genetics of autism and propositions for future research. C R Biol. 2016;339(7-8):300-307.

    Not in our library10.1016/j.crvi.2016.05.004

  4. 4.

    Lai MC, Lombardo MV, Baron-Cohen S. Autism. Lancet. 2014;383(9920):896-910.

    Not in our library10.1016/s0140-6736(13)61539-1

  5. 5.

    Mazurek MO, Vasa RA, Kalb LG, Kanne SM, Rosenberg D, Keefer A, Murray DS, Freedman B, Lowery LA. Anxiety, sensory over-responsivity, and gastrointestinal problems in children with autism spectrum disorders. J Abnorm Child Psychol. 2013;41(1):165-176.

    Not in our library10.1007/s10802-012-9668-x

  6. 6.

    Nikolov RN, Bearss KE, Lettinga J, Erickson C, Rodowski M, Aman MG, McCracken JT, McDougle CJ, Tierney E, Vitiello B, et al. Gastrointestinal symptoms in a sample of children with pervasive developmental disorders. J Autism Dev Disord. 2009;39(3):405-413.

    Not in our library10.1007/s10803-008-0637-8

  7. 7.

    Gorrindo P, Williams KC, Lee EB, Walker LS, McGrew SG, Levitt P. Gastrointestinal dysfunction in autism: parental report, clinical evaluation, and associated factors. Autism Res. 2012;5(2):101-108.

    Not in our library10.1002/aur.237

  8. 8.
    Association Between Gut Microbiota and Autism Spectrum Disorder: A Systematic Review and Meta-Analysis · 2019
    No notice
  9. 9.
    Composition of Gut Microbiota in Children with Autism Spectrum Disorder: A Systematic Review and Meta-Analysis · 2020
    No notice
  10. 10.
    Altered composition and function of intestinal microbiota in autism spectrum disorders: a systematic review · 2019
    No notice
  11. 11.
    Long-term benefit of Microbiota Transfer Therapy on autism symptoms and gut microbiota · 2019
    No notice
  12. 12.

    Emond P, Mavel S, Aidoud N, Nadal-Desbarats L, Montigny F, Bonnet-Brilhault F, Barthelemy C, Merten M, Sarda P, Laumonnier F, et al. GC-MS-based urine metabolic profiling of autism spectrum disorders. Anal Bioanal Chem. 2013;405(15):5291-5300.

    Not in our library10.1007/s00216-013-6934-x

  13. 13.

    Yap IK, Angley M, Veselkov KA, Holmes E, Lindon JC, Nicholson JK. Urinary metabolic phenotyping differentiates children with autism from their unaffected siblings and age-matched controls. J Proteome Res. 2010;9(6):2996-3004.

    Not in our library10.1021/pr901188e

  14. 14.

    Altieri L, Neri C, Sacco R, Curatolo P, Benvenuto A, Muratori F, Santocchi E, Bravaccio C, Lenti C, Saccani M, Rigardetto R, Gandione M, Urbani A, Persico AM. Urinary p-cresol is elevated in small children with severe autism spectrum disorder. Biomarkers. 2011;16(3):252-260.

    Not in our library10.3109/1354750x.2010.548010

  15. 15.

    Gabriele S, Sacco R, Cerullo S, Neri C, Urbani A, Tripi G, Malvy J, Barthelemy C, Bonnet-Brihault F, Persico AM. Urinary p-cresol is elevated in young French children with autism spectrum disorder: a replication study. Biomarkers. 2014;19(6):463-470.

    Not in our library10.3109/1354750x.2014.936911

  16. 16.

    Dieme B, Mavel S, Blasco H, Tripi G, Bonnet-Brilhault F, Malvy J, Bocca C, Andres CR, Nadal-Desbarats L, Emond P. Metabolomics study of urine in autism spectrum disorders using a multiplatform analytical methodology. J Proteome Res. 2015;14(12):5273-5282.

    Not in our library10.1021/acs.jproteome.5b00699

  17. 17.
    Short-chain fatty acid fermentation products of the gut microbiome: implications in autism spectrum disorders · 2012
    No notice
  18. 18.
    Fecal Microbiota and Metabolome of Children with Autism and Pervasive Developmental Disorder Not Otherwise Specified · 2013
    No notice
  19. 19.

    Kang DW, Ilhan ZE, Isern NG, Hoyt DW, Howsmon DP, Shaffer M, Lozupone CA, Hahn J, Adams JB, Krajmalnik-Brown R. Differences in fecal microbial metabolites and microbiota of children with autism spectrum disorders. Anaerobe. 2017;49:121-131.

    Not in our library10.1016/j.anaerobe.2017.12.007

  20. 20.

    Hsiao EY, McBride SW, Hsien S, Sharon G, Hyde ER, McCue T, Codelli JA, Chow J, Reisman SE, Petrosino JF, et al. Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders. Cell. 2013;155(7):1451-1463.

    Not in our library10.1016/j.cell.2013.11.024

  21. 21.

    Buffington SA, Di Prisco GV, Auchtung TA, Ajami NJ, Petrosino JF, Costa-Mattioli M. Microbial reconstitution reverses maternal diet-induced social and synaptic deficits in offspring. Cell. 2016;165(7):1762-1775.

    Not in our library10.1016/j.cell.2016.06.001

  22. 22.

    Sgritta M, Dooling SW, Buffington SA, Momin EN, Francis MB, Britton RA, Costa-Mattioli M. Mechanisms underlying microbial-mediated changes in social behavior in mouse models of autism spectrum disorder. Neuron. 2019;101(2):246-259.

    Not in our library10.1016/j.neuron.2018.11.018

  23. 23.

    Golubeva AV, Joyce SA, Moloney G, Burokas A, Sherwin E, Arboleya S, Flynn I, Khochanskiy D, Moya-Perez A, Peterson V, et al. Microbiota-related changes in bile acid & tryptophan metabolism are associated with gastrointestinal dysfunction in a mouse model of autism. EBioMedicine. 2017;24:166-178.

    Not in our library10.1016/j.ebiom.2017.09.020

  24. 24.

    de Theije CG, Wopereis H, Ramadan M, van Eijndthoven T, Lambert J, Knol J, Garssen J, Kraneveld AD, Oozeer R. Altered gut microbiota and activity in a murine model of autism spectrum disorders. Brain Behav Immun. 2014;37:197-206.

    Not in our library10.1016/j.bbi.2013.12.005

  25. 25.

    Sharon G, Cruz NJ, Kang DW, Gandal MJ, Wang B, Kim YM, Zink EM, Casey CP, Taylor BC, Lane CJ, Bramer LM, Isern NG, Hoyt DW, Noecker C, Sweredoski MJ, Moradian A, Borenstein E, Jansson JK, Knight R, Metz TO, Lois C, Geschwind DH, Krajmalnik-Brown R, Mazmanian SK. Human gut microbiota from autism spectrum disorder promote behavioral symptoms in mice. Cell. 2019;177(6):1600-1618.

    Not in our library10.1016/j.cell.2019.05.004

  26. 26.

    Needham BD, Kaddurah-Daouk R, Mazmanian SK: Gut microbial molecules in behavioural and neurodegenerative conditions. Nat Rev Neurosci. 2020;21(12):717–31. 10.1038/s41583-020-00381-0. Epub 2020 Oct 16.

    Not in our library10.1038/s41583-020-00381-0

  27. 27.

    Needham BD, Adame MD, Serena G, Rose DR, Preston GM, Conrad MC, Campbell AS, Donabedian DH, Fasano A, Ashwood P, Mazmanian SK. Plasma and fecal metabolite profiles in autism spectrum disorder. Biol Psychiatry. 2021;89(5):451-462.

    Not in our library10.1016/j.biopsych.2020.09.025

  28. 28.

    Gevi F, Belardo A, Zolla L. A metabolomics approach to investigate urine levels of neurotransmitters and related metabolites in autistic children. Biochim Biophys Acta Mol Basis Dis. 1866;2020(10):165859.

    Not in our library10.1016/j.bbadis.2020.165859

  29. 29.

    Persico AM, Napolioni V. Urinary p-cresol in autism spectrum disorder. Neurotoxicol Teratol. 2013;36:82-90.

    Not in our library10.1016/j.ntt.2012.09.002

  30. 30.

    Saito Y, Sato T, Nomoto K, Tsuji H: Identification of phenol- and p-cresol-producing intestinal bacteria by using media supplemented with tyrosine and its metabolites. FEMS Microbiol Ecol. 2018;94(9):fiy125. 10.1093/femsec/fiy125.

    Not in our library10.1093/femsec/fiy125

  31. 31.

    Passmore IJ, Letertre MPM, Preston MD, Bianconi I, Harrison MA, Nasher F, Kaur H, Hong HA, Baines SD, Cutting SM, Swann JR, Wren BW, Dawson LF. Para-cresol production by Clostridium difficile affects microbial diversity and membrane integrity of Gram-negative bacteria. Plos Pathog. 2018;14(9):e1007191.

    Not in our library10.1371/journal.ppat.1007191

  32. 32.

    Hung LW, Neuner S, Polepalli JS, Beier KT, Wright M, Walsh JJ, Lewis EM, Luo L, Deisseroth K, Dolen G, et al. Gating of social reward by oxytocin in the ventral tegmental area. Science. 2017;357(6358):1406-1411.

    Not in our library10.1126/science.aan4994

  33. 33.

    Supekar K, Kochalka J, Schaer M, Wakeman H, Qin S, Padmanabhan A, Menon V. Deficits in mesolimbic reward pathway underlie social interaction impairments in children with autism. Brain. 2018;141(9):2795-2805.

    Not in our library10.1093/brain/awy191

  34. 34.

    Krishnan V, Stoppel DC, Nong Y, Johnson MA, Nadler MJ, Ozkaynak E, Teng BL, Nagakura I, Mohammad F, Silva MA, et al. Autism gene Ube3a and seizures impair sociability by repressing VTA Cbln1. Nature. 2017;543(7646):507-512.

    Not in our library10.1038/nature21678

  35. 35.
    Role of VTA dopamine neurons and neuroligin 3 in sociability traits related to nonfamiliar conspecific interaction · 2018
    No notice
  36. 36.

    Bariselli S, Tzanoulinou S, Glangetas C, Prevost-Solie C, Pucci L, Viguie J, Bezzi P, O'Connor EC, Georges F, Luscher C, et al. SHANK3 controls maturation of social reward circuits in the VTA. Nat Neurosci. 2016;19(7):926-934.

    Not in our library10.1038/nn.4319

  37. 37.

    Lecca S, Luchicchi A, Scherma M, Fadda P, Muntoni AL, Pistis M. Delta(9)-tetrahydrocannabinol during adolescence attenuates disruption of dopamine function induced in rats by maternal immune activation. Front Behav Neurosci. 2019;13:202.

    Not in our library10.3389/fnbeh.2019.00202

  38. 38.

    Mandal S, Van Treuren W, White RA, Eggesbo M, Knight R, Peddada SD. Analysis of composition of microbiomes: a novel method for studying microbial composition. Microb Ecol Health Dis. 2015;26:27663.

    Not in our library10.3402/mehd.v26.27663

  39. 39.
    Normalization and microbial differential abundance strategies depend upon data characteristics · 2017
    No notice
  40. 40.

    Challand MR, Martins FT, Roach PL. Catalytic activity of the anaerobic tyrosine lyase required for thiamine biosynthesis in Escherichia coli. J Biol Chem. 2010;285(8):5240-5248.

    Not in our library10.1074/jbc.m109.056606

All 98 references

Cited by papers we hold 4

Reads

Read by people on this page

None yet.

Checked or read by AI through naulon

None yet.

A person counts once a day per paper. We keep no cookie and no address: a reader is a hash that changes every day. Any month under five reads shows no number.

Are you an author?

Is this your paper?

Claim it to add your note and be paid when agents cite it. Free.