{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,6]],"date-time":"2026-04-06T15:48:40Z","timestamp":1775490520677,"version":"3.50.1"},"reference-count":100,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2023,9,29]],"date-time":"2023-09-29T00:00:00Z","timestamp":1695945600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Spector Family Foundation","award":["825033"],"award-info":[{"award-number":["825033"]}]},{"name":"MGH ECOR Feasibility","award":["825033"],"award-info":[{"award-number":["825033"]}]},{"name":"Fulbright Foundation","award":["825033"],"award-info":[{"award-number":["825033"]}]},{"name":"Uehara Memorial Foundation","award":["825033"],"award-info":[{"award-number":["825033"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The intestinal barrier comprises a single layer of epithelial cells tightly joined to form a physical barrier. Disruption or compromise of the intestinal barrier can lead to the inadvertent activation of immune cells, potentially causing an increased risk of chronic inflammation in various tissues. Recent research has suggested that specific dietary components may influence the function of the intestinal barrier, potentially offering a means to prevent or mitigate inflammatory disorders. However, the precise mechanism underlying these effects remains unclear. Bovine colostrum (BC), the first milk from cows after calving, is a natural source of nutrients with immunomodulatory, anti-inflammatory, and gut-barrier fortifying properties. This novel study sought to investigate the transcriptome in BC-treated Zonulin transgenic mice (Ztm), characterized by dysbiotic microbiota, intestinal hyperpermeability, and mild hyperactivity, applying RNA sequencing. Seventy-five tissue samples from the duodenum, colon, and brain of Ztm and wild-type (WT) mice were dissected, processed, and RNA sequenced. The expression profiles were analyzed and integrated to identify differentially expressed genes (DEGs) and differentially expressed transcripts (DETs). These were then further examined using bioinformatics tools. RNA-seq analysis identified 1298 DEGs and 20,952 DETs in the paired (Ztm treatment vs. Ztm control) and reference (WT controls) groups. Of these, 733 DEGs and 10,476 DETs were upregulated, while 565 DEGs and 6097 DETs were downregulated. BC-treated Ztm female mice showed significant upregulation of cingulin (Cgn) and claudin 12 (Cldn12) duodenum and protein interactions, as well as molecular pathways and interactions pertaining to tight junctions, while BC-treated Ztm males displayed an upregulation of transcripts like occludin (Ocln) and Rho\/Rac guanine nucleotide exchange factor 2 (Arhgf2) and cellular structures and interfaces, protein\u2013protein interactions, and organization and response mechanisms. This comprehensive analysis reveals the influence of BC treatment on tight junctions (TJs) and Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) signaling pathway gene expressions. The present study is the first to analyze intestinal and brain samples from BC-treated Ztm mice applying high-throughput RNA sequencing. This study revealed molecular interaction in intestinal barrier function and identified hub genes and their functional pathways and biological processes in response to BC treatment in Ztm mice. Further research is needed to validate these findings and explore their implications for dietary interventions aimed at improving intestinal barrier integrity and function. The MGH Institutional Animal Care and Use Committee authorized the animal study (2013N000013).<\/jats:p>","DOI":"10.3390\/ijms241914730","type":"journal-article","created":{"date-parts":[[2023,9,29]],"date-time":"2023-09-29T07:42:08Z","timestamp":1695973328000},"page":"14730","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Evaluating Prophylactic Effect of Bovine Colostrum on Intestinal Barrier Function in Zonulin Transgenic Mice: A Transcriptomic Study"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2369-6309","authenticated-orcid":false,"given":"Birna","family":"Asbjornsdottir","sequence":"first","affiliation":[{"name":"Department of Pediatric Gastroenterology and Nutrition, Mucosal Immunology and Biology Research Center, Massachusetts General Hospital, Boston, MA 02114, USA"},{"name":"School of Health Sciences, Faculty of Medicine, University of Iceland, 102 Reykjavik, Iceland"},{"name":"Unit for Nutrition Research, Landspitali University Hospital, Faculty of Food Science and Nutrition, University of Iceland, 102 Reykjavik, Iceland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4860-6311","authenticated-orcid":false,"given":"Snaevar","family":"Sigurdsson","sequence":"additional","affiliation":[{"name":"School of Health Sciences, Faculty of Medicine, University of Iceland, 102 Reykjavik, Iceland"},{"name":"Biomedical Center, University of Iceland, 102 Reykjavik, Iceland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alba","family":"Miranda-Ribera","sequence":"additional","affiliation":[{"name":"Department of Pediatric Gastroenterology and Nutrition, Mucosal Immunology and Biology Research Center, Massachusetts General Hospital, Boston, MA 02114, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria","family":"Fiorentino","sequence":"additional","affiliation":[{"name":"Department of Pediatric Gastroenterology and Nutrition, Mucosal Immunology and Biology Research Center, Massachusetts General Hospital, Boston, MA 02114, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9339-3864","authenticated-orcid":false,"given":"Takumi","family":"Konno","sequence":"additional","affiliation":[{"name":"Department of Pediatric Gastroenterology and Nutrition, Mucosal Immunology and Biology Research Center, Massachusetts General Hospital, Boston, MA 02114, USA"},{"name":"Department of Cell Science, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo 060-8556, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jinggang","family":"Lan","sequence":"additional","affiliation":[{"name":"Department of Pediatric Gastroenterology and Nutrition, Mucosal Immunology and Biology Research Center, Massachusetts General Hospital, Boston, MA 02114, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4660-1111","authenticated-orcid":false,"given":"Larus S.","family":"Gudmundsson","sequence":"additional","affiliation":[{"name":"School of Health Sciences, Faculty of Pharmaceutical Sciences, University of Iceland, 102 Reykjavik, Iceland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Magnus","family":"Gottfredsson","sequence":"additional","affiliation":[{"name":"School of Health Sciences, Faculty of Medicine, University of Iceland, 102 Reykjavik, Iceland"},{"name":"Department of Scientific Affairs, Landspitali University Hospital, 102 Reykjavik, Iceland"},{"name":"Department of Infectious Diseases, Landspitali University Hospital, 102 Reykjavik, Iceland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bertrand","family":"Lauth","sequence":"additional","affiliation":[{"name":"School of Health Sciences, Faculty of Medicine, University of Iceland, 102 Reykjavik, Iceland"},{"name":"Department of Child and Adolescent Psychiatry, Landspitali University Hospital, 102 Reykjavik, Iceland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5788-4551","authenticated-orcid":false,"given":"Bryndis Eva","family":"Birgisdottir","sequence":"additional","affiliation":[{"name":"Unit for Nutrition Research, Landspitali University Hospital, Faculty of Food Science and Nutrition, University of Iceland, 102 Reykjavik, Iceland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2134-0261","authenticated-orcid":false,"given":"Alessio","family":"Fasano","sequence":"additional","affiliation":[{"name":"Department of Pediatric Gastroenterology and Nutrition, Mucosal Immunology and Biology Research Center, Massachusetts General Hospital, Boston, MA 02114, USA"},{"name":"Department of Pediatrics, Harvard Medical School, Harvard University, Boston, MA 02138, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,9,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1463","DOI":"10.1016\/j.jcmgh.2021.02.007","article-title":"Regulation of Intestinal Barrier Function by Microbial Metabolites","volume":"11","author":"Ghosh","year":"2021","journal-title":"Cell. Mol. Gastroenterol. Hepatol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e196","DOI":"10.1038\/ctg.2016.54","article-title":"Human Intestinal Barrier Function in Health and Disease","volume":"7","author":"Wells","year":"2016","journal-title":"Clin. Transl. Gastroenterol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1152\/physrev.00003.2008","article-title":"Zonulin and Its Regulation of Intestinal Barrier Function: The Biological Door to Inflammation, Autoimmunity, and Cancer","volume":"91","author":"Fasano","year":"2011","journal-title":"Physiol. Rev."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1","DOI":"10.12688\/f1000research.20510.1","article-title":"All Disease Begins in the (Leaky) Gut: Role of Zonulin-Mediated Gut Permeability in the Pathogenesis of Some Chronic Inflammatory Diseases","volume":"9","author":"Fasano","year":"2020","journal-title":"F1000Research"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1007\/s12016-011-8291-x","article-title":"Leaky Gut and Autoimmune Diseases","volume":"42","author":"Fasano","year":"2012","journal-title":"Clin. Rev. Allergy Immunol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e1251384","DOI":"10.1080\/21688370.2016.1251384","article-title":"Zonulin, a Regulator of Epithelial and Endothelial Barrier Functions, and Its Involvement in Chronic Inflammatory Diseases","volume":"4","author":"Sturgeon","year":"2016","journal-title":"Tissue Barriers"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.jpeds.2017.05.038","article-title":"Serum Zonulin, Gut Permeability, and the Pathogenesis of Autism Spectrum Disorders: Cause, Effect, or an Epiphenomenon?","volume":"188","author":"Fasano","year":"2017","journal-title":"J. Pediatr."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1007\/s00018-012-1070-x","article-title":"Regulation of Intestinal Epithelial Permeability by Tight Junctions","volume":"70","author":"Suzuki","year":"2013","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1111\/j.1749-6632.2012.06538.x","article-title":"Zonulin, Regulation of Tight Junctions, and Autoimmune Diseases","volume":"1258","author":"Fasano","year":"2012","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1111\/j.1749-6632.2000.tb05244.x","article-title":"Regulation of Intercellular Tight Junctions by Zonula Occludens Toxin and Its Eukaryotic Analogue Zonulin","volume":"915","author":"Fasano","year":"2006","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e13357","DOI":"10.1111\/asj.13357","article-title":"Regulation of the Intestinal Barrier by Nutrients: The Role of Tight Junctions","volume":"91","author":"Suzuki","year":"2020","journal-title":"Anim. Sci. J."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1007\/s13594-015-0258-x","article-title":"Composition and Properties of Bovine Colostrum: A Review","volume":"96","author":"McGrath","year":"2016","journal-title":"Dairy Sci. Technol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1515\/jcim-2014-0039","article-title":"Bovine Colostrum: An Emerging Nutraceutical","volume":"12","author":"Bagwe","year":"2015","journal-title":"J. Complement. Integr. Med."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Playford, R.J., and Weiser, M.J. (2021). Bovine Colostrum: Its Constituents and Uses. Nutrients, 13.","DOI":"10.3390\/nu13010265"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"49","DOI":"10.2174\/1872214810666160219163118","article-title":"Antibacterial and Antiinflammatory Properties of Bovine Colostrum","volume":"10","author":"Yadav","year":"2016","journal-title":"Recent Pat. Inflamm. Allergy Drug Discov."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3168\/jds.2019-16959","article-title":"Invited Review: MicroRNAs in Bovine Colostrum\u2014Focus on Their Origin and Potential Health Benefits for the Calf","volume":"103","author":"Goossens","year":"2020","journal-title":"J. Dairy Sci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1007\/s13238-013-2119-9","article-title":"Immune Modulatory Function of Abundant Immune-Related MicroRNAs in Microvesicles from Bovine Colostrum","volume":"4","author":"Sun","year":"2013","journal-title":"Protein Cell"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1186\/s43014-022-00104-1","article-title":"Shiva Bioactive Compounds, Nutritional Profile and Health Benefits of Colostrum: A Review","volume":"4","author":"Poonia","year":"2022","journal-title":"Food Prod. Process. Nutr."},{"key":"ref_19","first-page":"2000299","article-title":"The Zonulin-Transgenic Mouse Displays Behavioral Alterations Ameliorated via Depletion of the Gut Microbiota","volume":"10","author":"Serena","year":"2021","journal-title":"Tissue Barriers"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Asbjornsdottir, B., Miranda-Ribera, A., Fiorentino, M., Konno, T., Cetinbas, M., Lan, J., Sadreyev, R.I., Gudmundsson, L.S., Gottfredsson, M., and Lauth, B. (2022). Prophylactic Effect of Bovine Colostrum on Intestinal Microbiota and Behavior in Wild-Type and Zonulin Transgenic Mice. Biomedicines, 11.","DOI":"10.3390\/biomedicines11010091"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2233","DOI":"10.3389\/fimmu.2019.02233","article-title":"Exploiting the Zonulin Mouse Model to Establish the Role of Primary Impaired Gut Barrier Function on Microbiota Composition and Immune Profiles","volume":"10","author":"Ennamorati","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_22","unstructured":"Wizemann, T.M. (2001). Exploring the Biological Contributions to Human Health: Does Sex Matter?, National Academies Press (US)."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1016\/j.molmet.2018.05.016","article-title":"Sexual Dimorphism of Cardiometabolic Dysfunction: Gut Microbiome in the Play?","volume":"15","author":"Cross","year":"2018","journal-title":"Mol. Metab."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"314","DOI":"10.5056\/jnm20208","article-title":"Roles of Sex Hormones and Gender in the Gut Microbiota","volume":"27","author":"Yoon","year":"2021","journal-title":"J. Neurogastroenterol. Motil."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Sender, R., Fuchs, S., and Milo, R. (2016). Revised Estimates for the Number of Human and Bacteria Cells in the Body. PLoS Biol., 14.","DOI":"10.1101\/036103"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"995","DOI":"10.1101\/gr.5217506","article-title":"Tissue-Specific Expression and Regulation of Sexually Dimorphic Genes in Mice","volume":"16","author":"Yang","year":"2006","journal-title":"Genome Res."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Kasimatis, K.R., S\u00e1nchez-Ram\u00edrez, S., and Stevenson, Z.C. (2021). Sexual Dimorphism through the Lens of Genome Manipulation, Forward Genetics, and Spatiotemporal Sequencing. Genome Biol. Evol., 13.","DOI":"10.1093\/gbe\/evaa243"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/j.semcdb.2014.08.011","article-title":"Architecture of Tight Junctions and Principles of Molecular Composition","volume":"36","author":"Anderson","year":"2014","journal-title":"Semin. Cell Dev. Biol."},{"key":"ref_29","unstructured":"Hou, J., and Hou, J. (2020). A Laboratory Guide to the Tight Junction, Academic Press."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"26923","DOI":"10.1038\/srep26923","article-title":"Arhgap17, a RhoGTPase Activating Protein, Regulates Mucosal and Epithelial Barrier Function in the Mouse Colon","volume":"6","author":"Lee","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Svec, K.V., and Howe, A.K. (2022). Protein Kinase A in Cellular Migration\u2014Niche Signaling of a Ubiquitous Kinase. Front. Mol. Biosci., 9.","DOI":"10.3389\/fmolb.2022.953093"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Mosaddeghzadeh, N., and Ahmadian, M.R. (2021). The RHO Family GTPases: Mechanisms of Regulation and Signaling. Cells, 10.","DOI":"10.3390\/cells10071831"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1016\/j.cell.2009.08.048","article-title":"Dissociation of EphB2 Signaling Pathways Mediating Progenitor Cell Proliferation and Tumor Suppression","volume":"139","author":"Genander","year":"2009","journal-title":"Cell"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"442","DOI":"10.3390\/nu3040442","article-title":"Perspectives on Immunoglobulins in Colostrum and Milk","volume":"3","author":"Hurley","year":"2011","journal-title":"Nutrients"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.nfs.2021.10.001","article-title":"Bovine Colostrum: A Source of Bioactive Compounds for Prevention and Treatment of Gastrointestinal Disorders","volume":"25","author":"Gomes","year":"2021","journal-title":"NFS J."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Grigalevi\u010di\u016bt\u0117, R., Matusevi\u010dius, P., Plan\u010di\u016bnien\u0117, R., Stankevi\u010dius, R., Radzevi\u010di\u016bt\u0117-Val\u010diuk\u0117, E., Balevi\u010di\u016bt\u0117, A., \u017delvys, A., Zinkevi\u010dien\u0117, A., Zigmantait\u0117, V., and Ku\u010dinskas, A. (2023). Understanding the Immunomodulatory Effects of Bovine Colostrum: Insights into IL-6\/IL-10 Axis-Mediated Inflammatory Control. Vet. Sci., 10.","DOI":"10.3390\/vetsci10080519"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Chandwe, K., and Kelly, P. (2021). Colostrum Therapy for Human Gastrointestinal Health and Disease. Nutrients, 13.","DOI":"10.3390\/nu13061956"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1159\/000048890","article-title":"Endotoxin Inactivation by Enterally Applied Colostrum of Different Composition","volume":"34","author":"Seifert","year":"2002","journal-title":"Eur. Surg. Res."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Mart\u00edn-\u00e1lvarez, E., Diaz-Castro, J., Pe\u00f1a-Caballero, M., Serrano-L\u00f3pez, L., Moreno-Fern\u00e1ndez, J., S\u00e1nchez-Mart\u00ednez, B., Mart\u00edn-Peregrina, F., Alonso-Moya, M., Maldonado-Lozano, J., and Hurtado-Suazo, J.A. (2020). Oropharyngeal Colostrum Positively Modulates the Inflammatory Response in Preterm Neonates. Nutrients, 12.","DOI":"10.3390\/nu12020413"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"17477","DOI":"10.1038\/s41598-017-17475-y","article-title":"The Human Blood-Nerve Barrier Transcriptome","volume":"7","author":"Palladino","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1002\/ibd.21851","article-title":"Control of NOD2 and Rip2-Dependent Innate Immune Activation by GEF-H1","volume":"18","author":"Zhao","year":"2012","journal-title":"Inflamm. Bowel. Dis."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Fukazawa, A., Alonso, C., Kurachi, K., Gupta, S., Lesser, C.F., McCormick, B.A., and Reinecker, H.-C. (2008). GEF-H1 Mediated Control of NOD1 Dependent NF-KappaB Activation by Shigella Effectors. PLoS Pathog., 4.","DOI":"10.1371\/journal.ppat.1000228"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Hrncir, T. (2022). Gut Microbiota Dysbiosis: Triggers, Consequences, Diagnostic and Therapeutic Options. Microorganisms, 10.","DOI":"10.3390\/microorganisms10030578"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Stolfi, C., Maresca, C., Monteleone, G., and Laudisi, F. (2022). Implication of Intestinal Barrier Dysfunction in Gut Dysbiosis and Diseases. Biomedicines, 10.","DOI":"10.3390\/biomedicines10020289"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"114206","DOI":"10.1016\/j.ecoenv.2022.114206","article-title":"Gut Microbiota Dysbiosis Exaggerates Ammonia-Induced Tracheal Injury Via TLR4 Signaling Pathway","volume":"246","author":"Zhou","year":"2022","journal-title":"Ecotoxicol. Environ. Saf."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Kopp, T.I., Andersen, V., Tjonneland, A., and Vogel, U. (2015). Polymorphisms in NFKB1 and TLR4 and Interaction with Dietary and Life Style Factors in Relation to Colorectal Cancer in a Danish Prospective Case-Cohort Study. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0116394"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1186\/s12974-020-01873-7","article-title":"27-Hydroxycholesterol Contributes to Cognitive Deficits in APP\/PS1 Transgenic Mice through Microbiota Dysbiosis and Intestinal Barrier Dysfunction","volume":"17","author":"Wang","year":"2020","journal-title":"J. Neuroinflamm."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1233","DOI":"10.1007\/s00018-020-03656-y","article-title":"TLR4 and CD14 Trafficking and Its Influence on LPS-Induced pro-Inflammatory Signaling","volume":"78","author":"Ciesielska","year":"2021","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"17023","DOI":"10.1038\/sigtrans.2017.23","article-title":"NF-\u039aB Signaling in Inflammation","volume":"2","author":"Liu","year":"2017","journal-title":"Signal Transduct. Target Ther."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1038\/s41586-019-1856-1","article-title":"Frequent Mutations That Converge on the NFKBIZ Pathway in Ulcerative Colitis","volume":"577","author":"Kakiuchi","year":"2020","journal-title":"Nature"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1016\/j.brainresbull.2018.08.021","article-title":"Crocin, a Natural Product Attenuates Lipopolysaccharide-Induced Anxiety and Depressive-like Behaviors through Suppressing NF-KB and NLRP3 Signaling Pathway","volume":"142","author":"Zhang","year":"2018","journal-title":"Brain Res. Bull."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1002\/jlb.67.4.450","article-title":"Toll-like Receptors: A Growing Family of Immune Receptors That Are Differentially Expressed and Regulated by Different Leukocytes","volume":"67","author":"Muzio","year":"2000","journal-title":"J. Leukoc. Biol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1555","DOI":"10.1136\/gutjnl-2017-314759","article-title":"Increased Human Intestinal Barrier Permeability Plasma Biomarkers Zonulin and FABP2 Correlated with Plasma LPS and Altered Gut Microbiome in Anxiety or Depression","volume":"67","author":"Stevens","year":"2018","journal-title":"Gut"},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Wang, L.B., Chen, L.J., Wang, Q., and Xie, X.L. (2022). Silencing the Tlr4 Gene Alleviates Methamphetamine-Induced Hepatotoxicity by Inhibiting Lipopolysaccharide-Mediated Inflammation in Mice. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23126810"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1831","DOI":"10.1113\/JP273269","article-title":"Western Diet Induces Colonic Nitrergic Myenteric Neuropathy and Dysmotility in Mice via Saturated Fatty Acid- and Lipopolysaccharide-Induced TLR4 Signalling","volume":"595","author":"Reichardt","year":"2017","journal-title":"J. Physiol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1038\/s41420-022-01015-3","article-title":"Overabundance of Veillonella Parvula Promotes Intestinal Inflammation by Activating Macrophages via LPS-TLR4 Pathway","volume":"8","author":"Zhan","year":"2022","journal-title":"Cell Death Discov."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1017\/S0007114500002270","article-title":"Oligosaccharides and Glycoconjugates in Bovine Milk and Colostrum","volume":"84","author":"Gopal","year":"2000","journal-title":"Br. J. Nutr."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1111\/nure.12089","article-title":"Clinical Applications of Bovine Colostrum Therapy: A Systematic Review","volume":"72","author":"Rathe","year":"2014","journal-title":"Nutr. Rev."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"350","DOI":"10.3389\/fnut.2021.651721","article-title":"Bovine Colostrum and Its Potential for Human Health and Nutrition","volume":"8","author":"Arslan","year":"2021","journal-title":"Front. Nutr."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1015","DOI":"10.1007\/s00439-017-1790-y","article-title":"Alternative Splicing: The Pledge, the Turn, and the Prestige: The Key Role of Alternative Splicing in Human Biological Systems","volume":"136","author":"Bordone","year":"2017","journal-title":"Hum. Genet."},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Catalanotto, C., Cogoni, C., and Zardo, G. (2016). MicroRNA in Control of Gene Expression: An Overview of Nuclear Functions. Int. J. Mol. Sci., 17.","DOI":"10.3390\/ijms17101712"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1775","DOI":"10.1242\/jcs.069104","article-title":"MicroRNAs and Their Roles in Mammalian Stem Cells","volume":"124","author":"Yi","year":"2011","journal-title":"J. Cell Sci."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1161\/ATVBAHA.112.300068","article-title":"MicroRNAs in Immune Response and Macrophage Polarization","volume":"33","author":"Liu","year":"2013","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Modepalli, V., Kumar, A., Hinds, L.A., Sharp, J.A., Nicholas, K.R., and Lefevre, C. (2014). Differential Temporal Expression of Milk MiRNA during the Lactation Cycle of the Marsupial Tammar Wallaby (Macropus Eugenii). BMC Genom., 15.","DOI":"10.1186\/1471-2164-15-1012"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"2201","DOI":"10.3945\/jn.115.218586","article-title":"The Intestinal Transport of Bovine Milk Exosomes Is Mediated by Endocytosis in Human Colon Carcinoma Caco-2 Cells and Rat Small Intestinal IEC-6 Cells","volume":"145","author":"Wolf","year":"2015","journal-title":"J. Nutr."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"705350","DOI":"10.3389\/fgene.2021.705350","article-title":"Identification of Bovine MiRNAs with the Potential to Affect Human Gene Expression","volume":"12","author":"Myrzabekova","year":"2021","journal-title":"Front. Genet."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.molimm.2014.10.014","article-title":"Model Systems to Analyze the Role of MiRNAs and Commensal Microflora in Bovine Mucosal Immune System Development","volume":"66","author":"Liang","year":"2015","journal-title":"Mol. Immunol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"97","DOI":"10.12703\/P6-97","article-title":"MyD88: A Central Player in Innate Immune Signaling","volume":"6","author":"Deguine","year":"2014","journal-title":"F1000Prime Rep."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1170","DOI":"10.21037\/atm-20-5709","article-title":"Exploration of MicroRNA Profiles in Human Colostrum","volume":"8","author":"Wu","year":"2020","journal-title":"Ann. Transl. Med."},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Mehra, R., Singh, R., Nayan, V., Buttar, H.S., Kumar, N., Kumar, S., Bhardwaj, A., Kaushik, R., and Kumar, H. (2021). Nutritional Attributes of Bovine Colostrum Components in Human Health and Disease: A Comprehensive Review. Food Biosci., 40.","DOI":"10.1016\/j.fbio.2021.100907"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"01100","DOI":"10.3389\/fphar.2020.01100","article-title":"Therapeutic Applications of Human and Bovine Colostrum in the Treatment of Gastrointestinal Diseases and Distinctive Cancer Types: The Current Evidence","volume":"11","author":"Yadav","year":"2020","journal-title":"Front. Pharmacol."},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Sangild, P.T., Vonderohe, C., Melendez Hebib, V., and Burrin, D.G. (2021). Potential Benefits of Bovine Colostrum in Pediatric Nutrition and Health. Nutrients, 13.","DOI":"10.3390\/nu13082551"},{"key":"ref_73","unstructured":"Artym, J., and Zimecki, M. (2007). The Effects of Lactoferrin on Myelopoiesis: Can We Resolve the Controversy?. Postepy. Hig. Med. Dosw. (Online), 61."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"800","DOI":"10.5604\/17322693.1061635","article-title":"Milk-Derived Proteins and Peptides in Clinical Trials","volume":"67","author":"Artym","year":"2013","journal-title":"Postepy Hig. Med. Dosw. (Online)"},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Bukowska-O\u015bko, I., Sulejczak, D., Kaczy\u0144ska, K., Kleczkowska, P., Kramkowski, K., Popiel, M., Wietrak, E., and Kowalczyk, P. (2022). Lactoferrin as a Human Genome \u201cGuardian\u201d\u2014An Overall Point of View. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23095248"},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Ghosh, S., and Iacucci, M. (2021). Diverse Immune Effects of Bovine Colostrum and Benefits in Human Health and Disease. Nutrients, 13.","DOI":"10.3390\/nu13113798"},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Drago-Serrano, M.E., Campos-Rodr\u00edguez, R., Carrero, J.C., and Delagarza, M. (2017). Lactoferrin: Balancing Ups and Downs of Inflammation Due to Microbial Infections. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18030501"},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Cutone, A., Rosa, L., Ianiro, G., Lepanto, M.S., Di Patti, M.C.B., Valenti, P., and Musci, G. (2020). Lactoferrin\u2019s Anti-Cancer Properties: Safety, Selectivity, and Wide Range of Action. Biomolecules, 10.","DOI":"10.3390\/biom10030456"},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"Gruden, \u0160., and Ulrih, N.P. (2021). Diverse Mechanisms of Antimicrobial Activities of Lactoferrins, Lactoferricins, and Other Lactoferrin-Derived Peptides. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222011264"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"139","DOI":"10.2174\/1389203719666180514150921","article-title":"Lactoferrin: Major Physiological Functions and Applications","volume":"20","author":"Hao","year":"2018","journal-title":"Curr. Protein. Pept. Sci."},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Kowalczyk, P., Kaczy\u0144ska, K., Kleczkowska, P., Bukowska-o\u015bko, I., Kramkowski, K., and Sulejczak, D. (2022). The Lactoferrin Phenomenon\u2014A Miracle Molecule. Molecules, 27.","DOI":"10.3390\/molecules27092941"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1438","DOI":"10.3389\/fimmu.2017.01438","article-title":"Lactoferrin in a Context of Inflammation-Induced Pathology","volume":"8","author":"Kruzel","year":"2017","journal-title":"Front. Immunol."},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Lepanto, M.S., Rosa, L., Paesano, R., Valenti, P., and Cutone, A. (2019). Lactoferrin in Aseptic and Septic Inflammation. Molecules, 24.","DOI":"10.3390\/molecules24071323"},{"key":"ref_84","doi-asserted-by":"crossref","unstructured":"Zarzosa-Moreno, D., Avalos-G\u00f3mez, C., Ram\u00edrez-Texcalco, L.S., Torres-L\u00f3pez, E., Ram\u00edrez-Mondrag\u00f3n, R., Hern\u00e1ndez-Ram\u00edrez, J.O., Serrano-Luna, J., and de la Garza, M. (2020). Lactoferrin and Its Derived Peptides: An Alternative for Combating Virulence Mechanisms Developed by Pathogens. Molecules, 25.","DOI":"10.3390\/molecules25245763"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"1056","DOI":"10.3945\/jn.110.128702","article-title":"Prophylactic Application of Bovine Colostrum Ameliorates Murine Colitis via Induction of Immunoregulatory Cells","volume":"141","author":"Bodammer","year":"2011","journal-title":"J. Nutr."},{"key":"ref_86","doi-asserted-by":"crossref","unstructured":"Menchetti, L., Curone, G., Filipescu, I.E., Barbato, O., Leonardi, L., Guelfi, G., Traina, G., Casagrande-Proietti, P., Riva, F., and Casano, A.B. (2020). The Prophylactic Use of Bovine Colostrum in a Murine Model of TNBS-Induced Colitis. Animals, 10.","DOI":"10.3390\/ani10030492"},{"key":"ref_87","doi-asserted-by":"crossref","unstructured":"Sanctuary, M.R., Kain, J.N., Chen, S.Y., Kalanetra, K., Lemay, D.G., Rose, D.R., Yang, H.T., Tancrediid, D.J., German, J.B., and Slupsky, C.M. (2019). Pilot Study of Probiotic\/Colostrum Supplementation on Gut Function in Children with Autism and Gastrointestinal Symptoms. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0210064"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1767","DOI":"10.1093\/nar\/gkp1137","article-title":"The Sanger FASTQ File Format for Sequences with Quality Scores, and the Solexa\/Illumina FASTQ Variants","volume":"38","author":"Cock","year":"2009","journal-title":"Nucleic Acids Res."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1038\/nmeth.1923","article-title":"Fast Gapped-Read Alignment with Bowtie 2","volume":"9","author":"Langmead","year":"2012","journal-title":"Nat. Methods"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/1471-2105-12-323","article-title":"RSEM: Accurate Transcript Quantification from RNA-Seq Data with or without a Reference Genome","volume":"12","author":"Li","year":"2011","journal-title":"BMC Bioinform."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13059-014-0550-8","article-title":"Moderated Estimation of Fold Change and Dispersion for RNA-Seq Data with DESeq2","volume":"15","author":"Love","year":"2014","journal-title":"Genome Biol."},{"key":"ref_92","unstructured":"(2023, May 06). CRAN\u2014Package Pheatmap. Available online: https:\/\/cran.r-project.org\/web\/packages\/pheatmap\/."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"D325","DOI":"10.1093\/nar\/gkaa1113","article-title":"The Gene Ontology Resource: Enriching a GOld Mine","volume":"49","author":"Carbon","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1038\/75556","article-title":"Gene Ontology: Tool for the Unification of Biology","volume":"25","author":"Ashburner","year":"2000","journal-title":"Nat. Genet."},{"key":"ref_95","unstructured":"(2023, May 08). Dr. Tom Data Visualisation Solution. Available online: https:\/\/www.bgi.com\/global\/service\/dr-tom."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1093\/nar\/28.1.27","article-title":"KEGG: Kyoto Encyclopedia of Genes and Genomes","volume":"28","author":"Kanehisa","year":"2000","journal-title":"Nucleic Acids Res."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"1947","DOI":"10.1002\/pro.3715","article-title":"Toward Understanding the Origin and Evolution of Cellular Organisms","volume":"28","author":"Kanehisa","year":"2019","journal-title":"Protein Sci."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"D587","DOI":"10.1093\/nar\/gkac963","article-title":"KEGG for Taxonomy-Based Analysis of Pathways and Genomes","volume":"51","author":"Kanehisa","year":"2023","journal-title":"Nucleic Acids Res."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1080\/00949658508810839","article-title":"Computer Generation of Hypergeometric Random Variates","volume":"22","author":"Kachitvichyanukul","year":"1985","journal-title":"J. Stat. Comput. Simul."},{"key":"ref_100","unstructured":"(2023, May 08). Bioconductor\u2014Qvalue. Available online: https:\/\/bioconductor.org\/packages\/release\/bioc\/html\/qvalue.html."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/19\/14730\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:01:56Z","timestamp":1760130116000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/19\/14730"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,9,29]]},"references-count":100,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2023,10]]}},"alternative-id":["ijms241914730"],"URL":"https:\/\/doi.org\/10.3390\/ijms241914730","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,9,29]]}}}