Sex-Specific Gut Microbiota-Metabolite Interactions in Autism Spectrum Disorder: Dysbiosis, Metabolic Disruptions, and Niche Competition Dynamics

Sex-Specific Gut Microbiota-Metabolite Interactions in Autism Spectrum Disorder: Dysbiosis, Metabolic Disruptions, and Niche Competition Dynamics | 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 Research Article Sex-Specific Gut Microbiota-Metabolite Interactions in Autism Spectrum Disorder: Dysbiosis, Metabolic Disruptions, and Niche Competition Dynamics Shirong Lai, Wenkai Lai, Yuchen Zhang, Furong Tang, Fuxin Lin, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8401620/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 7 You are reading this latest preprint version Abstract Background: Autism Spectrum Disorder (ASD), a neurodevelopmental disorder, is marked by impaired social interaction, communication difficulties, and repetitive behaviors. Gut microbiota influences host metabolism and behavior via the microbiota-gut-brain axis, yet how gut microbial dysbiosis contributes to ASD is unclear. This study aimed to identify potential microbial and metabolic markers for an ASD predictive diagnostic model using gut microbiome data. Results: Analysis of 16S rRNA sequencing data from the GMrepo v2 database showed significant differences (LDAscore > 0) in gut microbiota abundance in ASD individuals at genus levels (e.g., Pseudomonas, Pseudoflavonifractor, Enterococcus). These microbes may be involved in immune regulation, etc. Metabolic flux analysis identified metabolites like L-methionine (p < 0.01) associated with ASD, participating in antioxidant defense. Mediation analysis supported a “microbiota-metabolite-disease” pathway (Pmedi < 0.001). Sex-based stratification revealed more pronounced alterations in males with ASD. Over 90% of microbial species showed stronger metabolic competition. Conclusions : This study elucidates a complex gut microbiota-host metabolism interaction network in ASD, identifying markers with mechanistic and diagnostic value. Emphasizing sex’s importance, it proposes altered niche competition may affect community stability, offering new insights into ASD’s microbial mechanisms and a foundation for gut microbiota-targeted interventions. Autism Spectrum Disorder Gut microbiota biomarkers Flux balance analysis Full Text Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Reviews received at journal 06 Jan, 2026 Reviewers agreed at journal 27 Dec, 2025 Reviewers invited by journal 23 Dec, 2025 Editor invited by journal 21 Dec, 2025 Editor assigned by journal 20 Dec, 2025 Submission checks completed at journal 20 Dec, 2025 First submitted to journal 19 Dec, 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. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-8401620","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":564717052,"identity":"bbf0f10a-d8c1-4bbe-b95d-e4cd65830c07","order_by":0,"name":"Shirong Lai","email":"","orcid":"","institution":"Fujian Medical University","correspondingAuthor":false,"prefix":"","firstName":"Shirong","middleName":"","lastName":"Lai","suffix":""},{"id":564717053,"identity":"447d20e5-f760-4e18-ae7f-e2a1eb063ff0","order_by":1,"name":"Wenkai Lai","email":"","orcid":"","institution":"Fujian Medical 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Dynamics","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-microbiology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"mcro","sideBox":"Learn more about [BMC Microbiology](http://bmcmicrobiol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/mcro","title":"BMC Microbiology","twitterHandle":"#bmcmicrobiology","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC 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Gut microbiota influences host metabolism and behavior via the microbiota-gut-brain axis, yet how gut microbial dysbiosis contributes to ASD is unclear. This study aimed to identify potential microbial and metabolic markers for an ASD predictive diagnostic model using gut microbiome data.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e Analysis of 16S rRNA sequencing data from the GMrepo v2 database showed significant differences (LDAscore \u0026gt; 0) in gut microbiota abundance in ASD individuals at genus levels (e.g., Pseudomonas, Pseudoflavonifractor, Enterococcus). These microbes may be involved in immune regulation, etc. Metabolic flux analysis identified metabolites like L-methionine (p \u0026lt; 0.01) associated with ASD, participating in antioxidant defense. Mediation analysis supported a “microbiota-metabolite-disease” pathway (Pmedi \u0026lt; 0.001). Sex-based stratification revealed more pronounced alterations in males with ASD. Over 90% of microbial species showed stronger metabolic competition.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e: This study elucidates a complex gut microbiota-host metabolism interaction network in ASD, identifying markers with mechanistic and diagnostic value. Emphasizing sex’s importance, it proposes altered niche competition may affect community stability, offering new insights into ASD’s microbial mechanisms and a foundation for gut microbiota-targeted interventions.\u003c/p\u003e","manuscriptTitle":"Sex-Specific Gut Microbiota-Metabolite Interactions in Autism Spectrum Disorder: Dysbiosis, Metabolic Disruptions, and Niche Competition Dynamics","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-24 09:30:53","doi":"10.21203/rs.3.rs-8401620/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2026-01-06T10:00:20+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"318665737673136534743813217891503726299","date":"2025-12-28T01:35:21+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-12-23T07:51:10+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-12-22T03:57:42+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-12-20T05:04:23+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-12-20T05:02:52+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Microbiology","date":"2025-12-19T06:54:16+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-microbiology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"mcro","sideBox":"Learn more about [BMC Microbiology](http://bmcmicrobiol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/mcro","title":"BMC Microbiology","twitterHandle":"#bmcmicrobiology","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"c88321c3-ecc5-49e1-b733-4bcd5cb5d55e","owner":[],"postedDate":"December 24th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2025-12-24T09:30:53+00:00","versionOfRecord":[],"versionCreatedAt":"2025-12-24 09:30:53","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8401620","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8401620","identity":"rs-8401620","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}