Cognitive and autism-like abnormalities are associated with gut microbiome alterations in a mouse model of Neurofibromatosis type I

Cognitive and autism-like abnormalities are associated with gut microbiome alterations in a mouse model of Neurofibromatosis type I | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Cognitive and autism-like abnormalities are associated with gut microbiome alterations in a mouse model of Neurofibromatosis type I Anthony Hannan, Sonali Reisinger, Nicholas van de Garde, Geraldine Kong, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6083730/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 27 Apr, 2026 Read the published version in Molecular Psychiatry → Version 1 posted 10 You are reading this latest preprint version Abstract Neurofibromatosis type 1 (NF1) is a common genetic condition presenting with variable symptomatology, however most individuals will demonstrate cognitive and behavioural difficulties including autism. Currently, it is unknown whether individuals with NF1 present with alterations in their gut microbiota, despite accumulating evidence for a role of gut microbiota in the pathophysiology of many brain disorders. Using a heterozygous germline knockout mouse model of NF1 (Nf1 +/-), we performed an in-depth behavioural evaluation encompassing all relevant domains: learning and memory, stereotypy, social interaction, anxiety- and depression-like behaviour. Anatomical and functional studies of the brain and gastrointestinal tract were also performed, followed by the first investigation of gut microbiota composition (via full-length 16S rRNA sequencing) in a Nf1 +/- mouse model. Our findings indicate that the cognitive and autism-like behavioural phenotype seen in Nf1 +/- mice is accompanied by a striking increase in relative brain size which is highly relevant to clinical NF1. Furthermore, brain size was correlated with behaviour, supporting a potential mechanistic link. Nf1 +/- mice showed significant alterations in gut microbiota composition, with males additionally showing significant changes to species abundance of the Clostridium and Blautia genera, and the Lachnospiraceae family, findings which partially overlap with those in preclinical and clinical autism. These findings significantly expand our understanding of brain and behavioural abnormalities in this preclinical model of NF1 and, importantly, have uncovered gut microbiota as a highly promising new area of research and a novel therapeutic target for cognitive and behavioural symptom clusters. Biological sciences/Neuroscience Health sciences/Diseases/Psychiatric disorders/Autism spectrum disorders Health sciences/Biomarkers/Diagnostic markers Health sciences/Diseases/Psychiatric disorders/ADHD Biological sciences/Physiology Full Text Additional Declarations The authors have declared there is NO conflict of interest to disclose All animal experiments were performed in accordance with the Australian Code for the Care and Use of Animals for Scientific Purposes, with experiments vetted and approved by the Animal Ethics Committee of the Florey Institute of Neuroscience and Mental Health (project #22-017). Supplementary Files Supp2.png Supplementary figure 2 Supp1.png Supplementary figure 1 NF1microbiotaMolPsychSupplementary250218ajh.docx Supplementary figures and tables Cite Share Download PDF Status: Published Journal Publication published 27 Apr, 2026 Read the published version in Molecular Psychiatry → Version 1 posted Editorial decision: revise 09 Dec, 2025 Review # 2 received at journal 12 Nov, 2025 Reviewer # 2 agreed at journal 26 Oct, 2025 Review # 1 received at journal 30 Sep, 2025 Reviewer # 1 agreed at journal 13 Sep, 2025 Reviewers invited by journal 11 Sep, 2025 Editor assigned by journal 25 Feb, 2025 Submission checks completed at journal 25 Feb, 2025 First submitted to journal 24 Feb, 2025 Unknown event 24 Feb, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6083730","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":557558193,"identity":"539442e3-3601-41db-9014-f4922a325991","order_by":0,"name":"Anthony 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