{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T14:29:23Z","timestamp":1790692163168,"version":"4.1.0"},"reference-count":55,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,9,17]],"date-time":"2021-09-17T00:00:00Z","timestamp":1631836800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>As the first line of defense against intestinal bacteria and toxins, intestinal epithelial cells are always exposed to bacteria or lipopolysaccharide (LPS), whereas pathogenic bacteria or LPS can cause intestinal epithelial cell damage. Previous studies have shown that konjac mannan oligosaccharides (KMOS) have a positive effect on maintaining intestinal integrity, and <jats:italic>Bacillus subtilis<\/jats:italic> (BS) can promote the barrier effect of the intestine. However, it is still unknown whether KMOS and BS have a synergistic protective effect on the intestines. In this study, we used the LPS-induced Caco-2 cell injury model and mouse intestinal injury model to study the synergistic effects of KMOS and BS. Compared with KMOS or BS alone, co-treatment with KMOS and BS significantly enhanced the activity and antioxidant capacity of Caco-2 cell, protected mouse liver and ileum from LPS-induced oxidative damage, and repaired tight junction and mucus barrier damage by up-regulating the expression of Claudin-1, ZO-1 and MUC-2. Our results demonstrate that the combination of KMOS and BS has a synergistic repair effect on inflammatory and oxidative damage of Caco-2 cells and aIIeviates LPS-induced acute intestinal injury in mice.<\/jats:p>","DOI":"10.3389\/fimmu.2021.696148","type":"journal-article","created":{"date-parts":[[2021,9,17]],"date-time":"2021-09-17T05:43:59Z","timestamp":1631857439000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":27,"title":["Synergistic Protective Effect of Konjac Mannan Oligosaccharides and Bacillus subtilis on Intestinal Epithelial Barrier Dysfunction in Caco-2 Cell Model and Mice Model of Lipopolysaccharide Stimulation"],"prefix":"10.3389","volume":"12","author":[{"given":"Lupeng","family":"Chen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuai","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shi","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhuqing","family":"Ren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guoquan","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,9,17]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2014.06.068","article-title":"Epithelial Homeostasis","volume":"24","author":"Macara","year":"2014","journal-title":"Curr Biol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1097\/00005176-200402000-00004","article-title":"Interaction Between Resident Luminal Bacteria and the Host: Can a Healthy Relationship Turn Sour","volume":"38","author":"Haller","year":"2004","journal-title":"J Pediatr Gastroenterol Nutr"},{"key":"B3","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1038\/mi.2009.124","article-title":"The Role of TLRs, NLRs, and RLRs in Mucosal Innate Immunity and Homeostasis","volume":"3","author":"Lavelle","year":"2010","journal-title":"Mucosal Immunol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.8345","article-title":"Mitophagy in TGEV Infection Counteracts Oxidative Stress and Apoptosis","volume":"7","author":"Zhu","year":"2016","journal-title":"Oncotarget"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.3892\/etm.2020.9284","article-title":"Inhibition of miRNA-29a Regulates Intestinal Barrier Function in Diarrhea-Predominant Irritable Bowel Syndrome by Upregulating ZO-1 and CLDN1","volume":"20","author":"Zhu","year":"2020","journal-title":"Exp Ther Med"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1096\/fj.07-8319com","article-title":"Formation of Tight Junction: Determinants of Homophilic Interaction Between Classic Claudins","volume":"22","author":"Piontek","year":"2008","journal-title":"FASEB J"},{"key":"B7","doi-asserted-by":"publisher","first-page":"a029314","DOI":"10.1101\/cshperspect.a029314","article-title":"Cell Biology of Tight Junction Barrier Regulation and Mucosal Disease","volume":"10","author":"Buckley","year":"2018","journal-title":"Cold Spring Harb Perspect Biol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.4162\/nrp.2015.9.4.343","article-title":"Butyrate Modulates Bacterial Adherence on LS174T Human Colorectal Cells by Stimulating Mucin Secretion and MAPK Signaling Pathway","volume":"9","author":"Jung","year":"2015","journal-title":"Nutr Res Pract"},{"key":"B9","doi-asserted-by":"publisher","first-page":"392","DOI":"10.1016\/j.ijpharm.2015.10.010","article-title":"Enhanced Antioxidation via Encapsulation of Isooctyl P-Methoxycinnamate With Sodium Deoxycholate-Mediated Liposome Endocytosis","volume":"496","author":"Zhang","year":"2015","journal-title":"Int J Pharm"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2019.109246","article-title":"The Protective Effect of Icariin and Phosphorylated Icariin Against LPS-Induced Intestinal Epithelial Cells Injury","volume":"118","author":"Xiong","year":"2019","journal-title":"BioMed Pharmacother"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.25435","article-title":"LPS Induces Hyper-Permeability of Intestinal Epithelial Cells","volume":"232","author":"Bein","year":"2017","journal-title":"J Cell Physiol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2020.00376","article-title":"Ferulic Acid Ameliorates Lipopolysaccharide-Induced Barrier Dysfunction via MicroRNA-200c-3p-Mediated Activation of PI3K\/AKT Pathway in Caco-2 Cells","volume":"11","author":"He","year":"2020","journal-title":"Front Pharmacol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1096\/fj.202000042R","article-title":"The Early Life Microbiota Protects Neonatal Mice From Pathological Small Intestinal Epithelial Cell Shedding","volume":"34","author":"Hughes","year":"2020","journal-title":"FASEB J"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijbiomac.2016.07.098","article-title":"Konjac Glucomannan, a Promising Polysaccharide of Amorphophallus Konjac K. Koch in Health Care","volume":"92","author":"Behera","year":"2016","journal-title":"Int J Biol Macromol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2016.08.040","article-title":"The Effects of Konjac Oligosaccharide on TNBS-Induced Colitis in Rats","volume":"40","author":"Liu","year":"2016","journal-title":"Int Immunopharmacol"},{"key":"B16","doi-asserted-by":"publisher","first-page":"e2001010","DOI":"10.1002\/mnfr.202001010","article-title":"Konjac Glucomannan Oligosaccharides Prevent Intestinal Inflammation Through SIGNR1-Mediated Regulation of Alternatively Activated Macrophages","author":"Tang","year":"2021","journal-title":"Mol Nutr Food Res"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1111\/1750-3841.14376","article-title":"Prebiotic, Immunomodulating, and Antifatigue Effects of Konjac Oligosaccharide","volume":"83","author":"Zeng","year":"2018","journal-title":"J Food Sci"},{"key":"B18","doi-asserted-by":"publisher","first-page":"1705","DOI":"10.3390\/nu11081705","article-title":"Effect of Konjac Mannan Oligosaccharides on Glucose Homeostasis via the Improvement of Insulin and Leptin Resistance In Vitro and In Vivo","volume":"11","author":"Zhu","year":"2019","journal-title":"Nutrients"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1039\/c8fo00209f","article-title":"Mannan-Oligosaccharide Modulates the Obesity and Gut Microbiota in High-Fat Diet-Fed Mice","volume":"9","author":"Wang","year":"2018","journal-title":"Food Funct"},{"key":"B20","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1016\/j.foodres.2018.02.014","article-title":"Preparation and Cellular Protection Against Oxidation of Konjac Oligosaccharides Obtained by Combination of \u03b3-Irradiation and Enzymatic Hydrolysis","volume":"107","author":"Jian","year":"2018","journal-title":"Food Res Int"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1128\/AEM.01374-16","article-title":"Inclusion of Konjac Flour in the Gestation Diet Changes the Gut Microbiota, Alleviates Oxidative Stress, and Improves Insulin Sensitivity in Sows","volume":"82","author":"Tan","year":"2016","journal-title":"Appl Environ Microbiol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1186\/s12934-017-0649-1","article-title":"High-Level Extracellular Protein Production in Bacillus Subtilis Using an Optimized Dual-Promoter Expression System","volume":"16","author":"Zhang","year":"2017","journal-title":"Microb Cell Fact"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1111\/jpn.13082","article-title":"Bacillus Subtilis B21 and Bacillus Licheniformis B26 Improve Intestinal Health and Performance of Broiler Chickens With Clostridium Perfringens-Induced Necrotic Enteritis","volume":"103","author":"Musa","year":"2019","journal-title":"J Anim Physiol Anim Nutr (Berl)"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.18502\/ijm.v11i3.1336","article-title":"The Effects of Supplementation of Bacillus Subtilis and Bacillus Coagulans Spores on the Intestinal Microflora and Growth Performance in Rat","volume":"11","author":"Mazkour","year":"2019","journal-title":"Iran J Microbiol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2020.622354","article-title":"Prevention and Alleviation of Dextran Sulfate Sodium Salt-Induced Inflammatory Bowel Disease in Mice With Bacillus Subtilis-Fermented Milk via Inhibition of the Inflammatory Responses and Regulation of the Intestinal Flora","volume":"11","author":"Zhang","year":"2020","journal-title":"Front Microbiol"},{"key":"B26","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1016\/j.fct.2020.111962","article-title":"Protective Effects of Bacillus Subtilis ASAG 216 on Growth Performance, Antioxidant Capacity, Gut Microbiota and Tissues Residues of Weaned Piglets Fed Deoxynivalenol Contaminated Diets","volume":"148","author":"Jia","year":"2021","journal-title":"Food Chem Toxicol"},{"key":"B27","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1016\/j.fct.2019.02.009","article-title":"Probiotic Bacillus Subtilis CW14 Reduces Disruption of the Epithelial Barrier and Toxicity of Ochratoxin A to Caco-2 Cells","volume":"126","author":"Peng","year":"2019","journal-title":"Food Chem Toxicol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1039\/c9fo00123a","article-title":"Dietary L-Tryptophan Alleviated LPS-Induced Intestinal Barrier Injury by Regulating Tight Junctions in a Caco-2 Cell Monolayer Model","volume":"10","author":"Chen","year":"2019","journal-title":"Food Funct"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.4172\/2329-8901.1000159","article-title":"Probiotic Lactobacillus Species Strengthen Intestinal Barrier Function and Tight Junction Integrity in Experimental Necrotizing Enterocolitis","volume":"5","author":"Blackwood","year":"2017","journal-title":"J Probiotics Health"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1159\/000079152","article-title":"Lactobacillus Acidophilus Protects Tight Junctions From Aspirin Damage in HT-29 Cells","volume":"69","author":"Montalto","year":"2004","journal-title":"Digestion"},{"key":"B31","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1016\/j.rvsc.2020.09.005","article-title":"Effects of Different Doses Lipopolysaccharides on the Mucosal Barrier in Mouse Intestine","volume":"133","author":"Li","year":"2020","journal-title":"Res Vet Sci"},{"key":"B32","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1002\/0470090480.ch9","article-title":"The Epithelium in Inflammatory Bowel Disease: Potential Role of Endocytosis of Junctional Proteins in Barrier Disruption","volume":"263","author":"Ivanov","year":"2004","journal-title":"Novartis Found Symp"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.2845","article-title":"You Are What You Eat","volume":"32","author":"Br\u00fcssow","year":"2014","journal-title":"Nat Biotechnol"},{"key":"B34","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1186\/s13567-016-0355-8","article-title":"Influence of Orally Fed a Select Mixture of Bacillus Probiotics on Intestinal T-Cell Migration in Weaned MUC4 Resistant Pigs Following Escherichia Coli Challenge","volume":"47","author":"Yang","year":"2016","journal-title":"Vet Res"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2012.10.014","article-title":"Lipopolysaccharide Causes an Increase in Intestinal Tight Junction Permeability In Vitro and In Vivo by Inducing Enterocyte Membrane Expression and Localization of TLR-4 and CD14","volume":"182","author":"Guo","year":"2013","journal-title":"Am J Pathol"},{"key":"B36","doi-asserted-by":"publisher","first-page":"4999","DOI":"10.4049\/jimmunol.1402598","article-title":"Lipopolysaccharide Regulation of Intestinal Tight Junction Permeability Is Mediated by TLR4 Signal Transduction Pathway Activation of FAK and Myd88","volume":"195","author":"Guo","year":"2015","journal-title":"J Immunol"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1152\/ajpgi.00124.2010","article-title":"Human-Derived Probiotic Lactobacillus Reuteri Strains Differentially Reduce Intestinal Inflammation","volume":"299","author":"Liu","year":"2010","journal-title":"Am J Physiol Gastrointest Liver Physiol"},{"key":"B38","doi-asserted-by":"publisher","first-page":"e0161635","DOI":"10.1371\/journal.pone.0161635","article-title":"Protective Effects of Bifidobacterium on Intestinal Barrier Function in LPS-Induced Enterocyte Barrier Injury of Caco-2 Monolayers and in a Rat NEC Model","volume":"11","author":"Ling","year":"2016","journal-title":"PloS One"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1600960","article-title":"IL-6 Signaling Regulates Small Intestinal Crypt Homeostasis","volume":"199","author":"Jeffery","year":"2017","journal-title":"J Immunol"},{"key":"B40","doi-asserted-by":"publisher","first-page":"1405","DOI":"10.1053\/j.gastro.2017.12.016","article-title":"Villin-1 and Gelsolin Regulate Changes in Actin Dynamics That Affect Cell Survival Signaling Pathways and Intestinal Inflammation","volume":"154","author":"Roy","year":"2018","journal-title":"Gastroenterology"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1016\/j.jss.2006.07.050","article-title":"Loss of the Tight Junction Protein ZO-1 in Dextran Sulfate Sodium Induced Colitis","volume":"140","author":"Poritz","year":"2007","journal-title":"J Surg Res"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.E11-09-0791","article-title":"Zonula Occludens-1 and -2 Regulate Apical Cell Structure and the Zonula Adherens Cytoskeleton in Polarized Epithelia","volume":"23","author":"Fanning","year":"2012","journal-title":"Mol Biol Cell"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2012-304241","article-title":"Claudin-1 Regulates Intestinal Epithelial Homeostasis Through the Modulation of Notch-Signalling","volume":"63","author":"Pope","year":"2014","journal-title":"Gut"},{"key":"B44","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1089\/jir.2015.0030","article-title":"Effects of Bacillus Subtilis on Epithelial Tight Junctions of Mice With Inflammatory Bowel Disease","volume":"36","author":"Gong","year":"2016","journal-title":"J Interferon Cytokine Res"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jafc.0c01658","article-title":"Novel Biomedical Functions of Surfactin A From Bacillus Subtilis in Wound Healing Promotion and Scar Inhibition","volume":"68","author":"Yan","year":"2020","journal-title":"J Agric Food Chem"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2020.101500","article-title":"Breaking the Vicious Loop Between Inflammation, Oxidative Stress and Coagulation, A Novel Anti-Thrombus Insight of Nattokinase by Inhibiting LPS-Induced Inflammation and Oxidative Stress","volume":"32","author":"Wu","year":"2020","journal-title":"Redox Biol"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.3164\/jcbn.08-182","article-title":"In Vitro Effects of the Reduced Form of Coenzyme Q(10) on Secretion Levels of TNF-Alpha and Chemokines in Response to LPS in the Human Monocytic Cell Line THP-1","volume":"44","author":"Schmelzer","year":"2009","journal-title":"J Clin Biochem Nutr"},{"key":"B48","doi-asserted-by":"publisher","first-page":"693","DOI":"10.1016\/j.jhep.2016.12.018","article-title":"HBV Inhibits LPS-Induced NLRP3 Inflammasome Activation and IL-1\u03b2 Production via Suppressing the NF-\u03bab Pathway and ROS Production","volume":"66","author":"Yu","year":"2017","journal-title":"J Hepatol"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.2174\/1389200215666141125121659","article-title":"Cytochrome P450s: Mechanisms and Biological Implications in Drug Metabolism and its Interaction With Oxidative Stress","volume":"15","author":"Sudip","year":"2014","journal-title":"Curr Drug Metab"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1080\/08923973.2019.1568451","article-title":"Sinomenine Regulates CD14\/TLR4, JAK2\/STAT3 Pathway and Calcium Signal via \u03b17nachr to Inhibit Inflammation in LPS-Stimulated Macrophages","volume":"41","author":"Zhu","year":"2019","journal-title":"Immunopharmacol Immunotoxicol"},{"key":"B51","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1186\/s12986-019-0341-z","article-title":"Stingless Bee Honey Protects Against Lipopolysaccharide Induced-Chronic Subclinical Systemic Inflammation and Oxidative Stress by Modulating Nrf2, NF-\u03bab and P38 MAPK","volume":"16","author":"Ranneh","year":"2019","journal-title":"Nutr Metab (Lond)"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1155\/2019\/8597159","article-title":"Melatonin Inhibits Lipopolysaccharide-Induced Inflammation and Oxidative Stress in Cultured Mouse Mammary Tissue","volume":"2019","author":"Yu","year":"2019","journal-title":"Mediators Inflamm"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.3390\/molecules23092120","article-title":"The Liver Protection Effects of Maltol, A Flavoring Agent, on Carbon Tetrachloride-Induced Acute Liver Injury in Mice via Inhibiting Apoptosis and Inflammatory Response","volume":"23","author":"Liu","year":"2018","journal-title":"Molecules"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1093\/ecco-jcc\/jjw096","article-title":"Germ-Free and Antibiotic-Treated Mice Are Highly Susceptible to Epithelial Injury in DSS Colitis","volume":"10","author":"Hern\u00e1ndez-Chirlaque","year":"2016","journal-title":"J Crohns Colitis"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1186\/s40168-015-0079-4","article-title":"Xylo-Oligosaccharides and Virginiamycin Differentially Modulate Gut Microbial Composition in Chickens","volume":"3","author":"Pourabedin","year":"2015","journal-title":"Microbiome"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.696148\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,9,17]],"date-time":"2021-09-17T05:44:03Z","timestamp":1631857443000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.696148\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,17]]},"references-count":55,"alternative-id":["10.3389\/fimmu.2021.696148"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2021.696148","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,17]]},"article-number":"696148"}}