Key Takeaways & Executive Findings
- •• Lutonarin (LU) protects against LPS-induced intestinal epithelial barrier dysfunction in Caco-2 cell monolayers by preserving TEER and reducing paracellular permeability. • LU pretreatment restores the expression of tight junction proteins ZO-1 and Occludin, which are downregulated by LPS. • LU shows no significant cytotoxicity up to 96 μM, and 12 μM is an effective concentration for barrier protection. • These findings suggest LU as a potential natural therapeutic agent for inflammatory bowel disease and other intestinal barrier-related disorders.
Abstract
Inflammation, while essential for host defense, can contribute to diseases like inflammatory bowel disease (IBD) when dysregulated. IBD involves chronic intestinal inflammation linked to bacterial infection and disruption of the intestinal epithelial barrier (IEB). The IEB maintains intestinal homeostasis, preventing the entry of harmful substances like lipopolysaccharide (LPS) while allowing nutrient absorption. Preserving IEB function is crucial in managing various diseases. Current IBD treatments often have adverse effects, including facial swelling and acne from corticosteroids, and allergic reactions, nausea, elevated liver tests, and pancreatitis from immunomodulators, increasing interest in natural products. Flavonoids, a diverse class of plant metabolites, have shown promising anti-inflammatory properties. Lutonarin (LU), a flavonoid abundant in barley seedlings, has exhibited various biological activities, including anti-inflammatory effects in LPS-stimulated macrophages. However, its specific impacts on IEB function remain unclear. This study aims to investigate the protective effects of LU against LPS-induced IEB dysfunction using an in vitro Caco-2 cell monolayer model. To assess the possible cytotoxicity of LU and optimize the suitable concentration, the viability of Caco-2 cells was assessed by CCK-8 assay. LU concentrations up to 96 μM did not significantly affect cell viability after 24 and 48 h of exposure. To evaluate the protective effect of LU against LPS-induced cytotoxicity, Caco-2 cells were pretreated with LU (3‒96 μM) for 48 h prior to exposure to 15 μg/mL LPS for 24 h. LPS significantly reduced cell viability, while LU pretreatment attenuated this reduction in a concentration-dependent manner. Concentrations of 12 μM LU were selected for subsequent experiments to minimize potential off-target effects. The Caco-2 cell monolayer model, a well-established in vitro system for investigating IEB function, was employed to study the effects of LU on IEB integrity. Barrier integrity was evaluated using transepithelial electrical resistance (TEER) measurements. LPS treatment significantly reduced TEER, indicating impaired barrier function. Pretreatment with 12 μM LU preserved TEER values, suggesting a protective effect against LPS-induced barrier disruption. Furthermore, paracellular permeability was evaluated using fluorescein isothiocyanate-dextran 4 (FITC-dextran, 4 kDa). LPS significantly increased FITC-dextran (FD4) flux, indicating increased permeability. LU pretreatment markedly attenuated this effect, confirming its ability to prevent LPS-induced permeability changes. To detect if LPS and LU pretreatment changes the expressions of tight junction (TJ) proteins Zonula occludens-1 (ZO-1) and Occludin, real-time qPCR and immunofluorescence staining assays were applied. LPS treatment significantly reduced mRNA expression levels of TJ proteins ZO-1 and Occludin. LU pretreatment effectively mitigated this downregulation, restoring their expression to levels comparable to the CON group.
1. Introduction
Inflammation, while essential for host defense, can contribute to diseases like inflammatory bowel disease (IBD) when dysregulated. IBD involves chronic intestinal inflammation linked to bacterial infection and disruption of the intestinal epithelial barrier (IEB). The IEB maintains intestinal homeostasis, preventing the entry of harmful substances like lipopolysaccharide (LPS) while allowing nutrient absorption [1]. Preserving IEB function is crucial in managing various diseases.
Current IBD treatments often have adverse effects, including facial swelling and acne from corticosteroids, and allergic reactions, nausea, elevated liver tests, and pancreatitis from immunomodulators [2], increasing interest in natural products. Flavonoids, a diverse class of plant metabolites, have shown promising anti-inflammatory properties [3,4]. Lutonarin (LU), a flavonoid abundant in barley seedlings, has exhibited various biological activities [5–7], including anti-inflammatory effects in LPS-stimulated macrophages [8]. However, its specific impacts on IEB function remain unclear.
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Qian Du, Jing Li, Guyanan Li, Zihan Wang, Siran Yu, Lihua Wang, Xiangyu Guo, Dali Wang, Bin Hui, Yuehua Tu, Wenguang Sun, Xuan Zhang, Wei Chen (2026). Lutonarin attenuates LPS-induced intestinal epithelial barrier dysfunction: a functional and transcriptomic analysis. Acta Biochimica et Biophysica Sinica. https://doi.org/10.3724/abbs.2025069
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Frequently Asked Questions
What is the main finding of this study?
Lutonarin (LU) attenuates LPS-induced intestinal epithelial barrier dysfunction by preserving barrier integrity, reducing permeability, and restoring tight junction protein expression in Caco-2 cell monolayers.
How does Lutonarin protect the intestinal barrier?
LU pretreatment prevents LPS-induced decreases in transepithelial electrical resistance (TEER) and reduces FITC-dextran flux, while also restoring mRNA expression of tight junction proteins ZO-1 and Occludin.
What concentration of Lutonarin was used in this study?
A concentration of 12 μM Lutonarin was selected for experiments to minimize off-target effects while providing significant protection against LPS-induced barrier dysfunction.
What is the significance of this research?
This study highlights Lutonarin as a potential natural therapeutic agent for inflammatory bowel disease and other conditions involving intestinal barrier disruption, offering an alternative to current treatments with adverse effects.
What experimental model was used?
The study used an in vitro Caco-2 cell monolayer model, a well-established system for investigating intestinal epithelial barrier function.
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