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Original Articles
Dyslipidemia and hyperglycemia synergistically increase the risk of intestinal barrier dysfunction: evidence from a case-control study in China
Chao Zhang, Dandan Lin, He Yu, Ying Yang, Zongtao Chen
Received July 31, 2025  Accepted October 30, 2025  Published online May 7, 2026  
DOI: https://doi.org/10.5217/ir.2025.00163    [Epub ahead of print]
AbstractAbstract PDFPubReaderePub
Background/Aims
Previous evidence regarding the combined effects of metabolic disorders on intestinal barrier function (IBF) remains limited. We hypothesized that metabolic disorders interact to increase the risk of intestinal barrier dysfunction.
Methods
This retrospective case-control study included 4,289 individuals who underwent IBF assessment. Controls with normal biomarker levels were propensity score–matched to cases with abnormal D-lactic acid, diamine oxidase (DAO), or endotoxin. Logistic regression and interaction models were applied to assess associations between metabolic indicators and intestinal barrier dysfunction.
Results
Hypertension (odds ratio [OR], 1.36; 95% confidence interval [CI], 1.20–1.55; P< 0.001), dyslipidemia (OR, 1.70; 95% CI, 1.49–1.96; P< 0.001), and hyperglycemia (OR, 1.80; 95% CI, 1.57–2.08; P< 0.001) were significantly associated with intestinal barrier dysfunction. Subgroup analyses confirmed that dyslipidemia and hyperglycemia were independently associated with elevated DAO, D-lactic acid, and endotoxin levels. Both multiplicative and additive interactions were observed between key metabolic factors. Particularly, dyslipidemia and hyperglycemia showed significant additive interactions (relative excess risk due to interaction, 0.79 [95% CI, 0.19–1.35, P= 0.008]; attributable proportion due to interaction, 0.29 [95% CI, 0.06–0.46, P= 0.008]; synergy index, 1.82 [95% CI, 1.13–3.41, P= 0.008]). When stratified by age and sex, broadly similar trends were observed in participants aged ≥ 50 years and in males.
Conclusions
Dyslipidemia and hyperglycemia are associated with intestinal barrier dysfunction and show a synergistic combined effect. Individuals with both should receive prioritized IBF monitoring and early metabolic intervention to protect barrier integrity.
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Intestinal barrier integrity and function in infants with cholestasis
Nagla H. Abu Faddan, Tahra M. K. Sherif, Omnia A. Mohammed, Khalid A. Nasif, Ebtesam M. El Gezawy
Intest Res 2017;15(1):118-123.   Published online January 31, 2017
DOI: https://doi.org/10.5217/ir.2017.15.1.118
AbstractAbstract PDFPubReaderePub
<b>Background/Aims</b><br/>

The safety of the human body is maintained by effective monitoring of the mucosal surface integrity and protection against potentially harmful compounds. This function of the gut called intestinal barrier function can be affected by cholestasis and the absence of bile in the intestinal lumen. We aimed to determine whether the gut barrier integrity is impaired in infants with cholestasis by evaluation of the intestinal fatty acid binding proteins (I-FABP) and ileal bile acid binding protein (I-BABP) as markers of intestinal epithelial cell damage and plasma D-lactate level as a marker of gut wall permeability.

Methods

This case-control study included 53 infants with cholestasis and 29 controls. Serum levels of I-FABP, I-BABP, and D-lactate were measured in all subjects.

Results

Both groups of patients with neonatal hepatitis and biliary atresia showed significantly higher levels of I-FABP and I-BABP than the controls. There were no differences in the serum D-lactate level between the cases and controls. There was no difference between the two groups of patients (I and II) regarding any of the parameters studied. No significant correlations between serum levels of I-FABP, I-BABP, or D-lactate and total or direct bilirubin levels were found in the cholestatic infants.

Conclusions

The intestinal epithelial barrier integrity is breached nearly in all parts of the intestine in infants with cholestasis. Further research is recommended to determine the impact of this finding on the management of these infants. The relationship between physical intestinal barrier damage and its functional failure remains subject for further research.

Citations

Citations to this article as recorded by  
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    Frontiers in Cell and Developmental Biology.2021;[Epub]     CrossRef
  • Noninvasive Biomarkers of Gut Barrier Function in Patients Suffering from Diarrhea Predominant-IBS: An Update
    Michele Linsalata, Giuseppe Riezzo, Caterina Clemente, Benedetta D’Attoma, Francesco Russo, Roberta Rizzo
    Disease Markers.2020; 2020: 1.     CrossRef
  • A novel role for coinhibitory receptors/checkpoint proteins in the immunopathology of sepsis
    Eleanor A Fallon, Bethany M Biron-Girard, Chun-Shiang Chung, Joanne Lomas-Neira, Daithi S Heffernan, Sean F Monaghan, Alfred Ayala
    Journal of Leukocyte Biology.2018; 103(6): 1151.     CrossRef
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Review
Intestinal Permeability Regulation by Tight Junction: Implication on Inflammatory Bowel Diseases
Sung Hee Lee
Intest Res 2015;13(1):11-18.   Published online January 29, 2015
DOI: https://doi.org/10.5217/ir.2015.13.1.11
AbstractAbstract PDFPubReader

Epithelial tight junctions (TJs) are the key structures regulating paracellular trafficking of macromolecules. The TJ is multi-protein complex that forms a selective permeable seal between adjacent epithelial cells and demarcates the boundary between apical and basolateral membrane domains. Disruption of the intestinal TJ barrier, followed by permeation of luminal noxious molecules, induces a perturbation of the mucosal immune system and inflammation, which can act as a trigger for the development of intestinal and systemic diseases. Inflammatory bowel disease (IBD) patients demonstrate increased intestinal paracellular permeability. Although it remains unclear whether barrier dysfunction precedes disease or results from active inflammation, increased intestinal TJ disruption is observed in IBD patients suggest that dysregulation of TJ barrier integrity may predispose or enhance IBD progression. Therefore, therapeutic target to restore the TJ barrier integrity may provide effective therapeutic and preventive approaches against IBD. This review discusses the molecular structure and regulation of intestinal TJs and the involvement of intestinal TJs in IBD pathogenesis.

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  • Resveratrol in Intestinal Health and Disease: Focusing on Intestinal Barrier
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  • Effects of Caulis Spatholobi Polysaccharide on Immunity, Intestinal Mucosal Barrier Function, and Intestinal Microbiota in Cyclophosphamide-Induced Immunosuppressive Chickens
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  • An in vitro intestinal model captures immunomodulatory properties of the microbiota in inflammation
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  • The GLIM Criteria Represent a More Appropriate Tool for Nutritional Assessment in Patients With Crohn's Disease
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  • Lactobacillus paracasei from koumiss ameliorates diarrhea in mice via tight junctions modulation
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  • Microbial Imbalance Induces Inflammation by Promoting Salmonella Penetration through the Mucosal Barrier
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    ACS Infectious Diseases.2022; 8(5): 969.     CrossRef
  • Microscopic Visualization of Cell-Cell Adhesion Complexes at Micro and Nanoscale
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  • Modulation of microRNAs and claudin-7 in Caco-2 cell line treated with Blastocystis sp., subtype 3 soluble total antigen
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  • Stachyose protects intestinal mucosal barrier via promotion of tight junction and Lactobacillus casei-drived inhibition of apoptosis in juvenile turbot, Scophthalmus maximus L.
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  • The Effect of Probiotics on Intestinal Tight Junction Protein Expression in Animal  Models: A Meta-Analysis
    Sung-Il Ahn, Sangbuem Cho, Eunjeong Jeon, Myungsun Park, Byungho Chae, Isaac Celestin Poaty Ditengou, Nag-Jin Choi
    Applied Sciences.2022; 12(9): 4680.     CrossRef
  • Modulating effects of a functional food containing Dendrobium officinale on immune response and gut microbiota in mice treated with cyclophosphamide
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  • L-glutamine for sickle cell disease: more than reducing redox
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  • The Increase of miR-195-5p Reduces Intestinal Permeability in Ulcerative Colitis, Modulating Tight Junctions’ Expression
    Viviana Scalavino, Emanuele Piccinno, Giusy Bianco, Nicolò Schena, Raffaele Armentano, Gianluigi Giannelli, Grazia Serino
    International Journal of Molecular Sciences.2022; 23(10): 5840.     CrossRef
  • Ischemic stroke and intestinal flora: an insight into brain–gut axis
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  • Protective Effects of Oxyberberine in 5-Fluorouracil-Induced Intestinal Mucositis in the Mice Model
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  • Effects of Tannic Acid Supplementation on Growth Performance, Oocyst Shedding, and Gut Health of in Broilers Infected with Eimeria Maxima
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  • Incorporation of Fructooligosaccharides in Diets Influence Growth Performance, Digestive Enzyme Activity, and Expression of Intestinal Barrier Function Genes in Tropical Gar (Atractosteus tropicus) Larvae
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  • Comparison of Selenium-Enriched Lactobacillusparacasei, Selenium-Enriched Yeast, and Selenite for the Alleviation of DSS-Induced Colitis in Mice
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  • Lactobacillus acidophilus Supplementation Restores Gut Epithelial Integrities and Barrier Functions in Non-specific Diarrhea
    Hossain Ferdaus Mohd ALTAF, Sumaiya Islam FARZANA, Khan PARVEZ, Zahran EMAN, Atif Shaikh MUHAMMAD, Uddin Md NAZIM, Zinnah Kazi Mohammad ALİ, Khan IMDAD ULLAH, Rahman Md MASUDUR
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  • Gut Microbiota-Derived Indole-3-Carboxylate Influences Mucosal Integrity and Immunity Through the Activation of the Aryl Hydrocarbon Receptors and Nutrient Transporters in Broiler Chickens Challenged With Eimeria maxima
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  • Role of ErbB1 in the Underlying Mechanism of Lapatinib‐Induced Diarrhoea: A Review
    Raja Nur Firzanah Syaza Raja Sharin, Jesmine Khan, Mohamad Johari Ibahim, Mudiana Muhamad, Joanne Bowen, Wan Nor I’zzah Wan Mohamad Zain, Supat Chupradit
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  • Role of CB1 receptors in the acute regulation of small intestinal permeability: effects of high-fat diet
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  • Roasted garlic protects against leaky gut syndrome in dextran sodium sulfate-induced colitis mice
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  • Role of the Endocannabinoid System in the Regulation of Intestinal Homeostasis
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  • Ameliorating Effects of TRIM67 against Intestinal Inflammation and Barrier Dysfunction Induced by High Fat Diet in Obese Mice
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  • Sanhuang Xiexin decoction ameliorates DSS-induced colitis in mice by regulating intestinal inflammation, intestinal barrier, and intestinal flora
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  • Nanoparticles for oral delivery: targeted therapy for inflammatory bowel disease
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  • Comprehensive overview of COVID-19-related respiratory failure: focus on cellular interactions
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  • Intestinal Osteopontin Protects From Alcohol-induced Liver Injury by Preserving the Gut Microbiome and the Intestinal Barrier Function
    Sukanta Das, Zhuolun Song, Hui Han, Xiaodong Ge, Romain Desert, Dipti Athavale, Sai Santosh Babu Komakula, Fernando Magdaleno, Wei Chen, Daniel Lantvit, Grace Guzman, Natalia Nieto
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  • Pterostilbene attenuates intestinal epithelial barrier loss induced by high loading intensity of exercise
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  • Stem Cell-Based Therapies for Inflammatory Bowel Disease
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    International Journal of Molecular Sciences.2022; 23(15): 8494.     CrossRef
  • Sex-dependent Lupus Blautia (Ruminococcus) gnavus strain induction of zonulin-mediated intestinal permeability and autoimmunity
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  • Mannose ameliorates experimental colitis by protecting intestinal barrier integrity
    Lijun Dong, Jingwen Xie, Youyi Wang, Honglian Jiang, Kai Chen, Dantong Li, Jing Wang, Yunzhi Liu, Jia He, Jia Zhou, Liyun Zhang, Xiao Lu, Xiaoming Zou, Xiang-Yang Wang, Qingqing Wang, Zhengliang Chen, Daming Zuo
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    International Journal of Molecular Sciences.2022; 23(16): 9036.     CrossRef
  • Regulatory Effect of Isomaltodextrin on a High-Fat Diet Mouse Model with LPS-Induced Low-Grade Chronic Inflammation
    Yijun Liu, Yuhan Zeng, Yixin Liu, Xiaoya Wang, Yuhuan Chen, Dion Lepp, Rong Tsao, Tsuyoshi Sadakiyo, Hua Zhang, Yoshinori Mine
    Journal of Agricultural and Food Chemistry.2022; 70(36): 11258.     CrossRef
  • Hemp-Derived Nanovesicles Protect Leaky Gut and Liver Injury in Dextran Sodium Sulfate-Induced Colitis
    Jung-Young Eom, Sang-Hun Choi, Hyun-Jin Kim, Dong-ha Kim, Ju-Hyun Bae, Gi-Seok Kwon, Dong-hee Lee, Jin-Hyeon Hwang, Do-Kyun Kim, Moon-Chang Baek, Young-Eun Cho
    International Journal of Molecular Sciences.2022; 23(17): 9955.     CrossRef
  • Bifidobacterium breve Alleviates DSS-Induced Colitis in Mice by Maintaining the Mucosal and Epithelial Barriers and Modulating Gut Microbes
    Meng-Meng Niu, Huan-Xin Guo, Jun-Wu Cai, Xiang-Chen Meng
    Nutrients.2022; 14(18): 3671.     CrossRef
  • High Molecular Weight Fucoidan Restores Intestinal Integrity by Regulating Inflammation and Tight Junction Loss Induced by Methylglyoxal-Derived Hydroimidazolone-1
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    Marine Drugs.2022; 20(9): 580.     CrossRef
  • Traditional Chinese Medicine and Natural Products: Potential Approaches for Inflammatory Bowel Disease
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    World Journal of Gastroenterology.2022; 28(36): 5265.     CrossRef
  • Gut dysfunction may be the source of pathological aggregation of alpha-synuclein in the central nervous system through Paraquat exposure in mice
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  • Matrix metalloproteinase 7 contributes to intestinal barrier dysfunction by degrading tight junction protein Claudin-7
    Ying Xiao, Haifeng Lian, Xiaoying S. Zhong, Srikruthi S. Krishnachaitanya, Yingzi Cong, Roderick H. Dashwood, Tor C. Savidge, Don W. Powell, Xiaowei Liu, Qingjie Li
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  • Pretreatment with probiotics Enterococcus faecium NCIMB 11181 attenuated Salmonella Typhimurium-induced gut injury through modulating intestinal microbiome and immune responses with barrier function in broiler chickens
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  • Investigation of murine host sex as a biological variable in epithelial barrier function and muscle contractility in human intestinal organoids
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    Journal of Neurogastroenterology and Motility.2022; 28(4): 517.     CrossRef
  • Senegalia macrostachya seed polysaccharides attenuate inflammation-induced intestinal epithelial barrier dysfunction in a Caco-2 and RAW264.7 macrophage co-culture model by inhibiting the NF-κB/MLCK pathway
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  • Zearalenone-Induced Mechanical Damage of Intestinal Barrier via the RhoA/ROCK Signaling Pathway in IPEC-J2 Cells
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    Anam Naz, Ayesha Obaid, Faryal M. Awan, Aqsa Ikram, Jamil Ahmad, Amjad Ali
    Frontiers in Microbiology.2017;[Epub]     CrossRef
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    U. Gadde, S. T. Oh, Y. S. Lee, E. Davis, N. Zimmerman, T. Rehberger, Hyun S. Lillehoj
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    PLOS ONE.2017; 12(1): e0170537.     CrossRef
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    World Journal of Gastroenterology.2017; 23(12): 2175.     CrossRef
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    Frontiers in Immunology.2017;[Epub]     CrossRef
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    Elisabeth Norén, Sven Almer, Jan Söderman
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    Food & Function.2017; 8(8): 2865.     CrossRef
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    Fraser L. Collins, Naiomy D. Rios-Arce, Shelby Atkinson, Hayley Bierhalter, Daniel Schoenherr, Jason N. Bazil, Laura R. McCabe, Narayanan Parameswaran
    Physiological Reports.2017; 5(9): e13263.     CrossRef
  • IL-22 Increases Permeability of Intestinal Epithelial Tight Junctions by Enhancing Claudin-2 Expression
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  • Chlorogenic acid suppresses lipopolysaccharide-induced nitric oxide and interleukin-1β expression by inhibiting JAK2/STAT3 activation in RAW264.7 cells
    Sang-Hun Kim, Sun-Young Park, Young-Lan Park, Dae-Seong Myung, Jong-Sun Rew, Young-Eun Joo
    Molecular Medicine Reports.2017; 16(6): 9224.     CrossRef
  • Western diet enhances intestinal tumorigenesis in Min/+ mice, associating with mucosal metabolic and inflammatory stress and loss of Apc heterozygosity
    Mikael Niku, Anne-Maria Pajari, Laura Sarantaus, Essi Päivärinta, Markus Storvik, Anu Heiman-Lindh, Santeri Suokas, Minna Nyström, Marja Mutanen
    The Journal of Nutritional Biochemistry.2017; 39: 126.     CrossRef
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    Nutrition and Cancer.2017; 69(1): 168.     CrossRef
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    World Journal of Gastroenterology.2017; 23(12): 2106.     CrossRef
  • Animal models for studying epithelial barriers in neonatal necrotizing enterocolitis, inflammatory bowel disease and colorectal cancer
    Tiaosi Xing, Rolando Camacho Salazar, Yan-Hua Chen
    Tissue Barriers.2017; 5(4): e1356901.     CrossRef
  • Variants of β-casofensin, a bioactive milk peptide, differently modulate the intestinal barrier: In vivo and ex vivo studies in rats
    Jérémie Bruno, Aurélie Nicolas, Sandra Pesenti, Jessica Schwarz, Jean-Luc Simon, Joëlle Léonil, Pascale Plaisancié
    Journal of Dairy Science.2017; 100(5): 3360.     CrossRef
  • The Yin and Yang of bile acid action on tight junctions in a model colonic epithelium
    Jayashree Sarathy, Sally Jo Detloff, Mei Ao, Nabihah Khan, Sydney French, Hafsa Sirajuddin, Tanushree Nair, Mrinalini C. Rao
    Physiological Reports.2017;[Epub]     CrossRef
  • Dietary Propolis Ameliorates Dextran Sulfate Sodium-Induced Colitis and Modulates the Gut Microbiota in Rats Fed a Western Diet
    Kai Wang, Xiaolu Jin, Mengmeng You, Wenli Tian, Richard Leu, David Topping, Michael Conlon, Liming Wu, Fuliang Hu
    Nutrients.2017; 9(8): 875.     CrossRef
  • Helicobacter suis induces changes in gastric inflammation and acid secretion markers in pigs of different ages
    C. De Witte, B. Devriendt, B. Flahou, I. Bosschem, R. Ducatelle, A. Smet, F. Haesebrouck
    Veterinary Research.2017;[Epub]     CrossRef
  • Vitamin D3 induces vitamin D receptor and HDAC11 binding to relieve the promoter of the tight junction proteins
    Feng-Hua Liu, Shan-Shan Li, Xiao-Xi Li , Shuai Wang , Mao-Gang Li , Li Guan, Tian-Gang Luan, Zhi-Gang Liu, Zhan-Ju Liu, Ping-Chang Yang
    Oncotarget.2017; 8(35): 58781.     CrossRef
  • Aryl hydrocarbon receptor activation maintained the intestinal epithelial barrier function through Notch1 dependent signaling pathway
    Zhongze Liu, Liangzi Li, Weigang Chen, Qimeng Wang, Weidong Xiao, Yuanhang Ma, Baifa Sheng, Xiang Li, Lihua Sun, Min Yu, Hua Yang
    International Journal of Molecular Medicine.2017;[Epub]     CrossRef
  • The Host Microbiome Regulates and Maintains Human Health: A Primer and Perspective for Non-Microbiologists
    Sunil Thomas, Jacques Izard, Emily Walsh, Kristen Batich, Pakawat Chongsathidkiet, Gerard Clarke, David A. Sela, Alexander J. Muller, James M. Mullin, Korin Albert, John P. Gilligan, Katherine DiGuilio, Rima Dilbarova, Walker Alexander, George C. Prenderg
    Cancer Research.2017; 77(8): 1783.     CrossRef
  • The prevalence of bacterial overgrowth syndrome and its associated factors in patients with inflammatory bowel diseases (according to the data of the Novosibirsk registry)
    Yu A Kulygina, M F Osipenko, M I Skalinskaya, K D Palchunova
    Terapevticheskii arkhiv.2017; 89(2): 15.     CrossRef
  • The Effect of DA-6034 on Intestinal Permeability in an Indomethacin-Induced Small Intestinal Injury Model
    Dong Shin Kwak, Oh Young Lee, Kang Nyeong Lee, Dae Won Jun, Hang Lak Lee, Byung Chul Yoon, Ho Soon Choi
    Gut and Liver.2016;[Epub]     CrossRef
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    Loubna Abdel Hadi, Clara Di Vito, Laura Riboni
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    John Youshia, Alf Lamprecht
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    American Journal of Physiology-Gastrointestinal and Liver Physiology.2016; 310(8): G599.     CrossRef
  • Hydrogen sulfide improves colonic barrier integrity in DSS-induced inflammation in Caco-2 cells and mice
    Hongyu Zhao, Rui Yan, Xiaogang Zhou, Fang Ji, Bing Zhang
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  • Advances in nutritional therapy in inflammatory bowel diseases: Review
    Andrzej Wędrychowicz
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    Qi Zhang, Cuiping Zhang, Xiaoyu Li, Yanan Yu, Kun Liang, Xinzhi Shan, Kun Zhao, Qinghui Niu, Zibin Tian
    Disease Markers.2016; 2016: 1.     CrossRef
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    Frontiers in Cellular and Infection Microbiology.2016;[Epub]     CrossRef
  • Effects of Supplementation of the Synbiotic Ecologic® 825/FOS P6 on Intestinal Barrier Function in Healthy Humans: A Randomized Controlled Trial
    E. Wilms, J. Gerritsen, H. Smidt, I. Besseling-van der Vaart, G. T. Rijkers, A. R. Garcia Fuentes, A. A. M. Masclee, F. J. Troost, John Green
    PLOS ONE.2016; 11(12): e0167775.     CrossRef
  • Adherens Junctions Modulate Diffusion between Epithelial Cells inTrichoplax adhaerens
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    Lorena Ruiz, Susana Delgado, Patricia Ruas-Madiedo, Abelardo Margolles, Borja Sánchez
    Frontiers in Microbiology.2016;[Epub]     CrossRef
  • Tuning constitutive and pathological inflammation in the gut via the interaction of dietary nitrate and polyphenols with host microbiome
    Bárbara S. Rocha, Carla Nunes, João Laranjinha
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    PLOS ONE.2016; 11(2): e0149652.     CrossRef
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    Scientific Reports.2016;[Epub]     CrossRef
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    RSC Advances.2015; 5(112): 92008.     CrossRef
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