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Gut microbes and common chemicals regulate intestinal junctional complexes in a complex manner. (a), many beneficial microbes (e.g., L. plantarum, A. muciniphila, B. longum) promote the gut barrier integrity and reduce cytokine release and inflammation. (b), detrimental microbes (e.g., C. albicans, E. faecalis, S. aureus) undermine gut barrier integrity by diminishing junctional protein expression and organization. (c), a summary of microbes and chemicals that are known to affect gut barrier permeability through diverse mechanisms.
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The intestinal barrier, an indispensable guardian of gastrointestinal health, mediates the intricate exchange between internal and external environments. Anchored by evolutionarily conserved junctional complexes, this barrier meticulously regulates paracellular permeability in essentially all living organisms. Disruptions in intestinal junctional c...
Citations
... Multiple signal transduction pathways are known to regulate TJs. Among them myosin light chain kinase (MLCK), a Ca 2+ /calmodulin-dependent serine/threonine kinase, stands out as a primary player (Markovich et al. 2024). MLC phosphorylation increases paracellular permeability in response to nutrients and is linked to Na + -nutrient transport (H. ...
The intestinal barrier function (IBF) is essential for intestinal homeostasis. Its alterations have been linked to intestinal and systemic disease. Regulation of intestinal permeability is key in the maintenance of the IBF, in which the intestinal epithelium and tight junctions, the mucus layer, sIgA, and antimicrobial peptides are important factors. This review addresses the concept of IBF, focusing on permeability, and summarizes state‐of‐the‐art information on how starvation and macronutrients regulate it. Novel mechanisms regulate intestinal permeability, like its induction by the normal process of nutrient absorption, the contribution of starvation‐induced autophagy, or the stimulation of sIgA production by high‐protein diets in a T‐cell‐independent fashion. In addition, observations evidence that starvation and protein restriction increase intestinal permeability, compromising mucin, antimicrobial peptides, and/or intestinal sIgA production. Regarding specific macronutrients, substantial evidence indicates that casein (compared to other protein sources), specific protein‐derived peptides and glutamine reinforce IBF. Dietary carbohydrates regulate intestinal permeability in a structure‐ and composition‐dependent fashion; fructose, glucose, and sucrose increase it, while nondigestible oligosaccharides (NDOs) decrease it. Among NDOs, human milk oligosaccharides (HMOs) stand as a promising tool. NODs effects are mediated by intestinal microbiota modulation, production of short‐chain fatty acids, and direct interactions with intestinal cells. Finally, evidence supports avoiding high‐fat diets for their detrimental effects on IBF. Most studies have been carried out in vitro or in animal models. More information is needed from clinical studies to substantiate beneficial effects and the use of macronutrients in the treatment and prevention of IBF‐related diseases.
... Intestinal barrier integrity is fundamental to intestinal health, and its dysregulation relates to the pathophysiology of numerous gastrointestinal diseases [30]. Preservation and restoration of this barrier are key targets in the management of gastrointestinal disorders. ...
Inflammatory bowel disease (IBD) represents a significant challenge to global health, characterized by intestinal inflammation, impaired barrier function, and dysbiosis, with limited therapeutic options. In this study, we isolated a novel strain of Bacillus subtilis (B. subtilis) and observed promising effects in protecting against disruption of the gut barrier. Our findings indicate that the enhancement of intestinal barrier function is primarily attributed to its metabolites. We identified a novel metabolite, 2‐hydroxy‐4‐methylpentanoic acid (HMP), derived from B. subtilis, that significantly improved intestinal barrier function. We also show that growth arrest and DNA damage 45A (GADD45A) is a key regulator of mucosal barrier integrity, which is activated by HMP and subsequently activates the downstream Wnt/β‐catenin pathway. Our findings potentially contribute to the development of probiotics‐derived metabolites or targeted “postbiotics” as novel therapeutics for the treatment or prevention of IBD and other diseases associated with intestinal barrier dysfunction.
Prickle 1, an ortholog found in Drosophila, was localized at the Sertoli cell-spermatid interface consistent with its role of supporting the Vangl2 planar cell polarity (PCP), is an integral membrane protein that creates the PCP protein complex of Vangl2 (Van Gogh-like 2)/Prickle1. Together with the asymmetrically localized transmembrane protein Frizzled (Fzd) and its unique adaptor proteins Disheveled (Dvl) and Inversin (Inv), Vangl2/Prickle1 and Fzd/Dvl/Inv are the two heterodimeric interacting PCP proteins between Sertoli cells and condensed spermatids to confer spermatid PCP across the plane of the seminiferous epithelium. Our initial intention was to examine if the distribution and expression of Prickle1 using a primary Sertoli cell in vitro model and Sprague-Dawley rats in vivo would mimic much of the earlier reported findings of Vangl2. Unexpectedly, these findings indicated that Prickle1 supported the PCP protein Vangl2, however, Prickle1 is also a multifunctional protein. First, Prickle1 knockdown (KD) by RNAi impeded Sertoli cell TJ-function by perturbing the distribution of the BTB-associated proteins at the cell-cell interface, through disruption of the microtubule (MT) and actin cytoskeletal organization including their respective polymerization (and/or bundling) capability. Second, these findings were reproduced using an in vivo model of RNAi by KD of Prickle 1 in the testis. Third, using Co-Immunoprecipitation (Co-IP), Prickle 1 was found to interact with a host of adaptor proteins crucial to support PCP including Dvl, but also regulatory cytoskeletal proteins of MT and actin networks, including RhoA, Arp3, Cdc42, ZO-1, and ß-catenin by IP-MS (Immunoprecipitation-Mass Spectrometry) using the String Protein Interaction Tool.
