{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T16:47:37Z","timestamp":1789577257380,"version":"build-2803163510"},"reference-count":56,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T00:00:00Z","timestamp":1778803200000},"content-version":"vor","delay-in-days":14,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T00:00:00Z","timestamp":1777593600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal of Neurochemistry"],"published-print":{"date-parts":[[2026,5]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Autism spectrum disorder (ASD) is a diverse group of neurodevelopmental disorders that share similar behavioral patterns. Many individuals with ASD also exhibit gastrointestinal disturbances, likely linked to alterations in the composition and activity of intestinal bacteria, resulting in the overproduction and release of toxic metabolites into the systemic circulation. These toxins may reach the central nervous system (CNS) and activate microglia, which release inflammatory cytokines, ultimately impairing neuronal function. This microbiota\u2010gut\u2010brain axis has been suggested to play a crucial role in the pathogenesis of ASD.\n                    <jats:italic>Para<\/jats:italic>\n                    \u2010cresol (\n                    <jats:italic>p<\/jats:italic>\n                    \u2010Cresol) is one of these intestinal metabolites and could potentially contribute to ASD, as its urinary levels are elevated in autistic children under the age of 8 and correlate with symptom severity. Here, we aim to investigate the effect of\n                    <jats:italic>p<\/jats:italic>\n                    \u2010Cresol on various brain\u2010cell types to speculate on their specific contributions to ASD\u2010related synaptic dysfunctions. Immunocytochemistry assays revealed a significant decrease in excitatory (vesicular glutamate transporter VGLUT, postsynaptic density protein 95 PSD95) and inhibitory (vesicular GABA transporter VGAT) synaptic markers in\n                    <jats:italic>p<\/jats:italic>\n                    \u2010Cresol\u2010treated neurons during synaptogenesis. These effects were exacerbated in SH3 and multiple ankyrin repeat domains 3 (Shank3) knockdown neurons, which exhibit increased susceptibility of their synapses.\n                    <jats:italic>p<\/jats:italic>\n                    \u2010Cresol also induced a dose\u2010dependent inflammatory response in both astrocytes and microglia, characterized by the overexpression and release of inflammatory cytokines and chemokines such as interleukin 6 (IL6), interleukin 1\u03b2 (IL1\u03b2), and C\u2010C\u2010 motif chemokine ligand 3 (CCL3). Our results suggest that\n                    <jats:italic>p<\/jats:italic>\n                    \u2010Cresol exerts cell\u2010specific effects on astrocytes and microglia, and the release of inflammatory cytokines and chemokines in response to\n                    <jats:italic>p<\/jats:italic>\n                    \u2010Cresol treatment may contribute to synaptic dysfunction, in addition to its direct effect on neurons.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                      <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc70457-gra-0001-m.png\">\n                        <jats:alt-text>image<\/jats:alt-text>\n                      <\/jats:graphic>\n                    <\/jats:boxed-text>\n                  <\/jats:p>","DOI":"10.1111\/jnc.70457","type":"journal-article","created":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T13:08:53Z","timestamp":1778850533000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Unveiling the Molecular Mechanism of Intestinal Metabolite\n                    <i>para<\/i>\n                    \u2010Cresol in Modulating Neuroinflammation and Synaptic Dysfunction: Implications for Autism Spectrum Disorder"],"prefix":"10.1111","volume":"170","author":[{"given":"Wenjie","family":"Liao","sequence":"first","affiliation":[{"name":"Department of Biomedical, Metabolic and Neural Sciences University of Modena and Reggio Emilia  Modena Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristy","family":"Antonioni","sequence":"additional","affiliation":[{"name":"Department of Biomedical, Metabolic and Neural Sciences University of Modena and Reggio Emilia  Modena Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federica","family":"Silvestri","sequence":"additional","affiliation":[{"name":"Department of Biomedical, Metabolic and Neural Sciences University of Modena and Reggio Emilia  Modena Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monica","family":"Piemontese","sequence":"additional","affiliation":[{"name":"Department of Biomedical, Metabolic and Neural Sciences University of Modena and Reggio Emilia  Modena Italy"},{"name":"International School of Advanced Studies University of Camerino  Camerino Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina","family":"Bodria","sequence":"additional","affiliation":[{"name":"Department of Biomedical, Metabolic and Neural Sciences University of Modena and Reggio Emilia  Modena Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleonora","family":"Daini","sequence":"additional","affiliation":[{"name":"Department of Biomedical, Metabolic and Neural Sciences University of Modena and Reggio Emilia  Modena Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8910-4479","authenticated-orcid":false,"given":"Antonio M.","family":"Persico","sequence":"additional","affiliation":[{"name":"Department of Biomedical, Metabolic and Neural Sciences University of Modena and Reggio Emilia  Modena Italy"},{"name":"Child &amp; Adolescent Neuropsychiatry Program Modena University Hospital  Modena Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michele","family":"Zoli","sequence":"additional","affiliation":[{"name":"Department of Biomedical, Metabolic and Neural Sciences University of Modena and Reggio Emilia  Modena Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas M.","family":"Grabrucker","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences University of Limerick  Limerick Ireland"},{"name":"Bernal Institute University of Limerick  Limerick Ireland"},{"name":"Health Research Institute (HRI) University of Limerick  Limerick Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonietta","family":"Vilella","sequence":"additional","affiliation":[{"name":"Department of Biomedical, Metabolic and Neural Sciences University of Modena and Reggio Emilia  Modena Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,5,15]]},"reference":[{"key":"e_1_2_13_2_1","doi-asserted-by":"publisher","DOI":"10.3109\/1354750X.2010.548010"},{"key":"e_1_2_13_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-00868-y"},{"key":"e_1_2_13_4_1","doi-asserted-by":"publisher","DOI":"10.1177\/13623613211019547"},{"key":"e_1_2_13_5_1","doi-asserted-by":"publisher","DOI":"10.1186\/s11689-024-09572-7"},{"key":"e_1_2_13_6_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40168-021-01103-z"},{"key":"e_1_2_13_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-023-05737-9"},{"key":"e_1_2_13_8_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.85279"},{"key":"e_1_2_13_9_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.676255"},{"key":"e_1_2_13_10_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.08-04-01454.1988"},{"key":"e_1_2_13_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng1933"},{"key":"e_1_2_13_12_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms26041513"},{"key":"e_1_2_13_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2008.01.012"},{"key":"e_1_2_13_14_1","doi-asserted-by":"publisher","DOI":"10.1080\/14767050701483298"},{"key":"e_1_2_13_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2014.10.023"},{"key":"e_1_2_13_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbi.2017.05.015"},{"key":"e_1_2_13_17_1","doi-asserted-by":"publisher","DOI":"10.1111\/jnc.15604"},{"key":"e_1_2_13_18_1","doi-asserted-by":"publisher","DOI":"10.14573\/altex.2009.2.83"},{"key":"e_1_2_13_19_1","doi-asserted-by":"publisher","DOI":"10.21037\/tp.2019.09.09"},{"key":"e_1_2_13_20_1","doi-asserted-by":"publisher","DOI":"10.3390\/bs6040029"},{"key":"e_1_2_13_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbi.2023.05.002"},{"key":"e_1_2_13_22_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4939-8994-2_10"},{"key":"e_1_2_13_23_1","doi-asserted-by":"publisher","DOI":"10.1111\/jnc.13713"},{"key":"e_1_2_13_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbi.2024.03.040"},{"key":"e_1_2_13_25_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.6708"},{"key":"e_1_2_13_26_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-neuro-060909-153204"},{"key":"e_1_2_13_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2012.08.029"},{"key":"e_1_2_13_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)63921-1"},{"key":"e_1_2_13_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcmgh.2016.11.008"},{"key":"e_1_2_13_30_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.072348"},{"key":"e_1_2_13_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbi.2019.04.037"},{"key":"e_1_2_13_32_1","doi-asserted-by":"publisher","DOI":"10.15252\/embj.2023113796"},{"key":"e_1_2_13_33_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11481-012-9342-7"},{"key":"e_1_2_13_34_1","doi-asserted-by":"publisher","DOI":"10.1093\/cercor\/bhad451"},{"key":"e_1_2_13_35_1","doi-asserted-by":"publisher","DOI":"10.1002\/glia.21153"},{"key":"e_1_2_13_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbi.2013.01.084"},{"key":"e_1_2_13_37_1","doi-asserted-by":"publisher","DOI":"10.3390\/brainsci10040233"},{"key":"e_1_2_13_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2014.12.020"},{"key":"e_1_2_13_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2008.11.015"},{"key":"e_1_2_13_40_1","doi-asserted-by":"publisher","DOI":"10.1155\/2012\/486359"},{"key":"e_1_2_13_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbi.2013.12.020"},{"key":"e_1_2_13_42_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M600236200"},{"key":"e_1_2_13_43_1","doi-asserted-by":"publisher","DOI":"10.1002\/aur.1226"},{"key":"e_1_2_13_44_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms19010275"},{"key":"e_1_2_13_45_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2178-07.2007"},{"key":"e_1_2_13_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.psychres.2024.116245"},{"key":"e_1_2_13_47_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13346-023-01409-5"},{"key":"e_1_2_13_48_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.braindev.2012.05.013"},{"key":"e_1_2_13_49_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.20315"},{"key":"e_1_2_13_50_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-017-1736-4"},{"key":"e_1_2_13_51_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature10110"},{"key":"e_1_2_13_52_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2012.01.011"},{"key":"e_1_2_13_53_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2016.07.013"},{"key":"e_1_2_13_54_1","doi-asserted-by":"publisher","DOI":"10.1002\/aur.2696"},{"key":"e_1_2_13_55_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms231911013"},{"key":"e_1_2_13_56_1","doi-asserted-by":"publisher","DOI":"10.1002\/mco2.497"},{"key":"e_1_2_13_57_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41380-020-0682-z"}],"container-title":["Journal of Neurochemistry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/jnc.70457","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/jnc.70457","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/jnc.70457","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T06:32:36Z","timestamp":1779863556000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/jnc.70457"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5]]},"references-count":56,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2026,5]]}},"alternative-id":["10.1111\/jnc.70457"],"URL":"https:\/\/doi.org\/10.1111\/jnc.70457","archive":["Portico"],"relation":{},"ISSN":["0022-3042","1471-4159"],"issn-type":[{"value":"0022-3042","type":"print"},{"value":"1471-4159","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5]]},"assertion":[{"value":"2025-03-17","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-04-22","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-05-15","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70457"}}