Synergy between HMOs and Postbiotics: A New Strategy in Preventing Intestinal Inflammation in Preterm and Surgical Neonates

Synergy between HMOs and Postbiotics: A New Strategy in Preventing Intestinal Inflammation in Preterm and Surgical Neonates | 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 Synergy between HMOs and Postbiotics: A New Strategy in Preventing Intestinal Inflammation in Preterm and Surgical Neonates Pasqua Betta, Carmine Mattia, Nunzia Decembrino, Roberta Leonardi, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6732551/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 5 You are reading this latest preprint version Abstract Background Early modulation of the neonatal gut microbiota is emerging as a strategy to mitigate late-onset sepsis (LOS) and enhance enteral feeding tolerance in high-risk infants. Postbiotics—non-viable microbial preparations with immunomodulatory metabolites—may offer probiotic-like benefits while avoiding the risks associated with live organisms. We compared a daily postbiotic–synbiotic blend with bovine lactoferrin, another milk-derived bioactive, in preterm and surgical neonates. Methods In a single-centre, randomised (1:1), open-label trial conducted in a tertiary NICU (January 2022–March 2024), 130 infants (mean gestational age 34 ± 3 weeks; 44 with major surgical conditions) received either (i) 1 mL·day⁻¹ of a preparation containing 2′-fucosyllactose, lactase, and heat-inactivated Lactobacillus acidophilus (10⁹ cells) or (ii) bovine lactoferrin 100 mg·day⁻¹. Primary endpoint was culture-proven sepsis; secondary endpoints included time to full enteral feeds, days of parenteral nutrition, length of stay (LOS), discharge weight, and colonisation rates. Categorical data were analysed with χ²/Fisher’s exact test; continuous variables with Mann–Whitney U or t -test as appropriate (α = 0.05). Results Overall sepsis incidence was low (7.7%) and did not differ significantly between groups (postbiotic 3/65 vs lactoferrin 7/65, P = 0.39). The postbiotic cohort achieved complete enteral feeding markedly earlier (median 8.3 ± 4.7 days vs 30 ± 8.3 days; P < 0.001), required fewer parenteral-nutrition days, and had a shorter LOS (20.6 ± 17 vs 29 ± 20 days; P = 0.01). Discharge weight was higher in the postbiotic group (2872 ± 632 g vs 2695 ± 335 g; P = 0.04). Colonisation rates were comparable. Conclusions A synbiotic postbiotic formulation accelerated transition to full enteral nutrition, reduced hospital stay, and improved growth without increasing colonisation or sepsis risk relative to lactoferrin. Larger, multi-centre trials are warranted to confirm potential infection-protective effects and to explore synergistic combinations of postbiotics with lactoferrin in vulnerable neonatal populations. postbiotic synbiotic lactoferrin preterm infant surgical neonate gut microbiota late-onset sepsis enteral feeding Full Text Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Major revision 18 Jul, 2025 Reviewers agreed at journal 12 Jun, 2025 Reviewers invited by journal 12 Jun, 2025 Editor assigned by journal 03 Jun, 2025 First submitted to journal 31 May, 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-6732551","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":470423486,"identity":"b39e8438-811a-4e8d-be5b-a28905ba8c50","order_by":0,"name":"Pasqua Betta","email":"","orcid":"","institution":"Neonatal Intensive Care Unit, University Hospital Policlinico “G. Rodolico San Marco”, University of Catania, Catania, Italy","correspondingAuthor":false,"prefix":"","firstName":"Pasqua","middleName":"","lastName":"Betta","suffix":""},{"id":470423487,"identity":"cb9b169d-e1f0-4ca3-8c34-2b4abbbf1860","order_by":1,"name":"Carmine Mattia","email":"","orcid":"","institution":"Neonatal Intensive Care Unit, University Hospital Policlinico “G. Rodolico San Marco”, University of Catania, Catania, Italy","correspondingAuthor":false,"prefix":"","firstName":"Carmine","middleName":"","lastName":"Mattia","suffix":""},{"id":470423488,"identity":"f512edf8-0b91-482c-939d-bc8e6445ea30","order_by":2,"name":"Nunzia Decembrino","email":"","orcid":"","institution":"Neonatal Intensive Care Unit, University Hospital Policlinico “G. Rodolico San Marco”, University of Catania, Catania, Italy","correspondingAuthor":false,"prefix":"","firstName":"Nunzia","middleName":"","lastName":"Decembrino","suffix":""},{"id":470423489,"identity":"fb22ed7d-5038-42fa-ba02-7cf3f14acb4e","order_by":3,"name":"Roberta Leonardi","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABCklEQVRIie3PsWrDMBCA4QsGeTmi1caheQUJgzPEJa/iULCXLN0yGgLtEsjqxwgEMmW4YlAXP0BHTZkypFsLHuo6dYYi04wd9A+SMXw6CcBm+4cNL5uDzcLaT/69aAABjpmwX0SAn8MgT1piNh2BKxHUkZ4xzF0p/XmYjiAolX4/1OPwdT3RyTIOweVkJKgyuT5mCMM0k8VRyH1VyTyp0qj3Yt4i8pBKBMQoQBKD/dtC5vOnMu4l41Pk1x2pScx2xV/Eaw//IUBivvUupP9imKbBiDJkyJpHUfhQVOqxaN4SMscRJsLdUvknms44Okp/0N395nm1PZ+XsdzwF20ccx13wx+bzWaz3doXYK9S04ZqWdQAAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0002-5566-4387","institution":"University of Catania: Universita degli Studi di Catania","correspondingAuthor":true,"prefix":"","firstName":"Roberta","middleName":"","lastName":"Leonardi","suffix":""},{"id":470423490,"identity":"435212f0-8d10-40ba-a24a-bb61d47ab873","order_by":4,"name":"Vassiliki Griva","email":"","orcid":"","institution":"AAST Sette Laghi, Università dell’Insubria","correspondingAuthor":false,"prefix":"","firstName":"Vassiliki","middleName":"","lastName":"Griva","suffix":""},{"id":470423491,"identity":"490b3633-f3a4-426d-a7b7-ce65d98412b2","order_by":5,"name":"Vincenzo Di Benedetto","email":"","orcid":"","institution":"Division of Pediatric Surgery, University Hospital Policlinico G. Rodolico-San Marco, University of Catania, 95123 Catania, Italy","correspondingAuthor":false,"prefix":"","firstName":"Vincenzo","middleName":"Di","lastName":"Benedetto","suffix":""},{"id":470423492,"identity":"8d038129-123f-4a5d-9b1c-5de9068918de","order_by":6,"name":"Maria Grazia Scuderi","email":"","orcid":"","institution":"Division of Pediatric Surgery, University Hospital Policlinico G. Rodolico-San Marco, University of Catania, 95123 Catania, Italy","correspondingAuthor":false,"prefix":"","firstName":"Maria","middleName":"Grazia","lastName":"Scuderi","suffix":""},{"id":470423493,"identity":"7199450e-e384-4971-a89e-cdf0d1580fd7","order_by":7,"name":"Giovanni Corsello","email":"","orcid":"https://orcid.org/0000-0002-0218-8110","institution":"Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties \"G. D'Alessandro\", University of Palermo, Palermo, Italy","correspondingAuthor":false,"prefix":"","firstName":"Giovanni","middleName":"","lastName":"Corsello","suffix":""}],"badges":[],"createdAt":"2025-05-23 11:39:04","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6732551/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6732551/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":84701536,"identity":"1617ab96-40b8-4058-b6ed-5b1e85ac8ced","added_by":"auto","created_at":"2025-06-16 11:36:12","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":717683,"visible":true,"origin":"","legend":"","description":"","filename":"manuscriptgastermaxdef.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6732551/v1_covered_b4fb2b09-5287-48f4-bf67-de0cf87d236e.pdf"}],"financialInterests":"","formattedTitle":"Synergy between HMOs and Postbiotics: A New Strategy in Preventing Intestinal Inflammation in Preterm and Surgical Neonates","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":true,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"italian-journal-of-pediatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"itjp","sideBox":"Learn more about [Italian Journal of Pediatrics](http://ijponline.biomedcentral.com)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ITJP/default.aspx","title":"Italian Journal of Pediatrics","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"postbiotic, synbiotic, lactoferrin, preterm infant, surgical neonate, gut microbiota, late-onset sepsis, enteral feeding","lastPublishedDoi":"10.21203/rs.3.rs-6732551/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6732551/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eEarly modulation of the neonatal gut microbiota is emerging as a strategy to mitigate late-onset sepsis (LOS) and enhance enteral feeding tolerance in high-risk infants. Postbiotics\u0026mdash;non-viable microbial preparations with immunomodulatory metabolites\u0026mdash;may offer probiotic-like benefits while avoiding the risks associated with live organisms. We compared a daily postbiotic\u0026ndash;synbiotic blend with bovine lactoferrin, another milk-derived bioactive, in preterm and surgical neonates.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eIn a single-centre, randomised (1:1), open-label trial conducted in a tertiary NICU (January 2022\u0026ndash;March 2024), 130 infants (mean gestational age 34\u0026thinsp;\u0026plusmn;\u0026thinsp;3 weeks; 44 with major surgical conditions) received either (i) 1 mL\u0026middot;day⁻\u0026sup1; of a preparation containing 2\u0026prime;-fucosyllactose, lactase, and heat-inactivated \u003cem\u003eLactobacillus acidophilus\u003c/em\u003e (10⁹ cells) or (ii) bovine lactoferrin 100 mg\u0026middot;day⁻\u0026sup1;. Primary endpoint was culture-proven sepsis; secondary endpoints included time to full enteral feeds, days of parenteral nutrition, length of stay (LOS), discharge weight, and colonisation rates. Categorical data were analysed with χ\u0026sup2;/Fisher\u0026rsquo;s exact test; continuous variables with Mann\u0026ndash;Whitney U or \u003cem\u003et\u003c/em\u003e-test as appropriate (α\u0026thinsp;=\u0026thinsp;0.05).\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eOverall sepsis incidence was low (7.7%) and did not differ significantly between groups (postbiotic 3/65 vs lactoferrin 7/65, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.39). The postbiotic cohort achieved complete enteral feeding markedly earlier (median 8.3\u0026thinsp;\u0026plusmn;\u0026thinsp;4.7 days vs 30\u0026thinsp;\u0026plusmn;\u0026thinsp;8.3 days; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), required fewer parenteral-nutrition days, and had a shorter LOS (20.6\u0026thinsp;\u0026plusmn;\u0026thinsp;17 vs 29\u0026thinsp;\u0026plusmn;\u0026thinsp;20 days; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.01). Discharge weight was higher in the postbiotic group (2872\u0026thinsp;\u0026plusmn;\u0026thinsp;632 g vs 2695\u0026thinsp;\u0026plusmn;\u0026thinsp;335 g; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.04). Colonisation rates were comparable.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eA synbiotic postbiotic formulation accelerated transition to full enteral nutrition, reduced hospital stay, and improved growth without increasing colonisation or sepsis risk relative to lactoferrin. Larger, multi-centre trials are warranted to confirm potential infection-protective effects and to explore synergistic combinations of postbiotics with lactoferrin in vulnerable neonatal populations.\u003c/p\u003e","manuscriptTitle":"Synergy between HMOs and Postbiotics: A New Strategy in Preventing Intestinal Inflammation in Preterm and Surgical Neonates","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-06-16 11:20:01","doi":"10.21203/rs.3.rs-6732551/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revision","date":"2025-07-18T09:01:51+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2025-06-12T13:53:17+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-06-12T13:51:57+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-06-03T13:48:55+00:00","index":"","fulltext":""},{"type":"submitted","content":"Italian Journal of Pediatrics","date":"2025-05-31T14:02:24+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"italian-journal-of-pediatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"itjp","sideBox":"Learn more about [Italian Journal of Pediatrics](http://ijponline.biomedcentral.com)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ITJP/default.aspx","title":"Italian Journal of Pediatrics","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"2bcd5986-d910-47b0-82d2-910d59d5f398","owner":[],"postedDate":"June 16th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-01-26T19:11:45+00:00","versionOfRecord":[],"versionCreatedAt":"2025-06-16 11:20:01","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6732551","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6732551","identity":"rs-6732551","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}