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The antimicrobial peptide derived from insulin-like growth factor-binding protein 5 (AMP-IBP5) exhibits antimicrobial activities and immunomodulatory functions in keratinocytes and fibroblasts. However, its role in regulating skin barrier function remains unclear. Here, we investigated the effects of AMP-IBP5 on the skin barrier and its role in the pathogenesis of atopic dermatitis (AD). 2,4-Dinitrochlorobenzene was used to induce AD-like skin inflammation. Transepithelial electrical resistance and permeability assays were used to investigate tight junction (TJ) barrier function in normal human epidermal keratinocytes and mice. AMP-IBP5 increased the expression of TJ-related proteins and their distribution along the intercellular borders. AMP-IBP5 also improved TJ barrier function through activation of the atypical protein kinase C and Rac1 pathways. In AD mice, AMP-IBP5 ameliorated dermatitis-like symptoms restored the expression of TJ-related proteins, suppressed the expression of inflammatory and pruritic cytokines, and improved skin barrier function. Interestingly, the ability of AMP-IBP5 to alleviate inflammation and improve skin barrier function in AD mice was abolished in mice treated with an antagonist of the low-density lipoprotein receptor-related protein-1 (LRP1) receptor. Collectively, these findings indicate that AMP-IBP5 may ameliorate AD-like inflammation and enhance skin barrier function through LRP1, suggesting a possible role for AMP-IBP5 in the treatment of AD.

Atopic dermatitis (AD) is an eczematous skin disorder characterized by type 2 inflammation, barrier disruption, and intense itch. In addition to type 2 cytokines, many other cytokines, such as interferon gamma (IFN-γ), interleukin 17 (IL-17), and interleukin 22 (IL-22), play roles in the pathogenesis of AD. It has been reported that the extracellular signal-regulated kinase (ERK) is downstream of such cytokines. However, the involvement of the ERK pathway in the pathogenesis of AD has not yet been investigated. We examined the expression of p-ERK in mouse and human AD skin. We also investigated the effects of the topical application of an ERK inhibitor on the dermatitis score, transepidermal water loss (TEWL), histological change, and expression of filaggrin, using an AD-like NC/Nga murine model. The effects of an ERK inhibitor on filaggrin expression in normal human epidermal keratinocytes (NHEKs) and on chemokine production from bone marrow-derived dendritic cells (BMDCs) were also evaluated. p-ERK was highly expressed in mouse and human AD skin. Topical application of an ERK inhibitor alleviated the clinical symptoms, histological changes, TEWL, and decrease in expression of filaggrin in the AD-like NC/Nga murine model. The ERK inhibitor also restored the IL-4 induced reduction in the expression of filaggrin in NHEK, and inhibited chemokine production from BMDC induced by IL-4. These results indicate that the ERK pathway is involved in the pathogenesis of AD, and suggest that the ERK pathway has potential as a therapeutic target for AD in the future.

5-aminosalicylic acid (5-ASA) is widely used in the treatment of ulcerative colitis (UC), but its anti-inflammatory mechanism is complex and has not been fully understood. DSS model was used to test the effect of 5-ASA. Tight junction and Ki-67 were detected by western blot, immunofluorescence, and immunohistochemistry or qPCR. 16S rRNA gene sequencing of gut microbiota and subsequent bioinformatics and statistical analysis were performed to identify the specific bacteria which were associated with the treatment effect of 5-ASA. GC-MS was performed to test short-chain fatty acids (SCFAs). Antibiotic-treated mice were used to demonstrate the key role of endogenous gut microbiota. Here, we found that 5-ASA alleviated dextran sulfate sodium (DSS)-induced colitis in mice. Moreover, 5-ASA significantly repaired the intestinal barrier. At the molecular level, 5-ASA markedly raised the expression of tight junction proteins including JAM-A and occludin and cell proliferation marker Ki-67 in mice. In addition, bacterial 16S rRNA gene sequencing and bioinformatics analysis showed that 5-ASA significantly modulated the DSS-induced gut bacterial dysbiosis. In detail, it stimulated the growth of protective bacteria belonging to Faecalibaculum and Dubosiella , which were negatively correlated with colitis parameters, and blocked the expansion of pro-inflammatory bacteria such as Escherichia-Shigella and Oscillibacter , which were positively correlated with colitis in mice. Meanwhile, 5-ASA increased the cecal acetate level. Most notably, 5-ASA was no longer able to treat colitis and reverse gut barrier dysfunction in antibiotic-treated mice that lacked endogenous gut microbiota. Our data suggested that the anti-inflammatory activity of 5-ASA required the inherent intestinal flora, and the gut microbiota was a potential and effective target for the treatment of ulcerative colitis.

Bacillus velezensis-based probiotics are increasingly recognized for their potential to enhance intestinal health in companion animals, yet their mechanisms of action in canine epithelial systems remain incompletely defined. This study aimed to evaluate whether a live Bacillus velezensis probiotic consortia (BC) modulates epithelial barrier integrity, immune signaling, apoptosis-renewal pathways, and metabolic activity in canine-relevant intestinal and macrophage cell models. MCA-B1 proximal gastrointestinal epithelial cells and DH82 macrophage-like cells were exposed to BC cultures, followed by quantification of tight-junction expression, permeability (FITC-Dextran), cytokine responses, phagocytic activity, apoptosis-related markers, and metabolomic profiles. BC treatment significantly strengthened the epithelial barrier, inducing a marked upregulation of Claudin 1 (CLDN1) (11.3 fold), CLDN4 (2.4 fold), Occludin (OCLN, 1.7 fold), and increasing key proteins including ZO-2 and cingulin while reducing LPS-induced FITC-Dextran permeability to 94.5%. BC concurrently modulated innate immune signaling, increasing MyD88 (33.2%), IL-8 (14.6 fold), IL-18 (2.6 fold), and IFNB1 protein levels, while enhancing anti-inflammatory regulation, including a robust rise in DH82-derived IL-10. Apoptosis-renewal markers shifted toward physiological turnover, with increased BCL2 (1.9 fold) and reduced BAK1. Metabolomic profiling of BC activity revealed elevated AMP, abundant Peptide Transporter 1 (PEPT1)-transportable peptides, increased γ-glutamyl metabolites, and lower Glutathione disulfide (GSSG), consistent with AMPK-linked tight-junction assembly and glutathione-supported redox buffering. Together, these data indicate that Bacillus velezensis-derived metabolites positively influence barrier-related, immunological, and metabolic responses in a canine proximal intestinal epithelial system and modulate functional responses in macrophage-like cells. These in vitro findings contribute to the mechanistic understanding of host cellular responses to Bacillus-associated metabolites.

Damage of intestinal barrier function (BF) after ischemia/reperfusion (I/R) injury can induce serious complications and high mortality. MicroRNAs (miRNAs) are involved in intestinal mucosal BF and epithelial proliferation after I/R injury have been reported. We aimed to investigate the role and regulatory mechanism of miR-142-3p (miR-142) in intestinal epithelial proliferation and BF after I/R injury. We detected the proliferation, barrier function and miR-142 expression in clinical ischemic intestinal tissues. Furthermore, we induced an in vivo intestinal I/R injury mouse model and in vitro IEC-6 cells hypoxia/reoxygenation (H/R) injury model. After increasing and decreasing expression of miR-142, we detected the proliferation and barrier function of intestinal epithelial cells after I/R or H/R injury. We found that miR-142 expression was significantly increased in clinical ischemic intestinal mucosa and mouse intestinal mucosa exposed to I/R injury, and there was an inverse relationship between miR-142 and proliferation/BF. Inhibition of miR-142 significant promoted intestinal epithelial proliferation and BF after I/R injury. Furthermore, inhibition of miR-142 improved overall survival rate of mice after I/R injury. MiR-142 directly targeted FoxM1 which was identified by bioinformatics analysis and luciferase activity assay in IEC-6 cells. Inhibition of miR-142 promotes intestinal epithelial proliferation and BF after I/R injury in a FoxM1-mediated manner.

This study sought to explore the impact of dietary Cu deficiency on colonic health, including assessments of histopathology, barrier function, inflammatory response, and gut microbiota composition. Weaned mice were fed a copper-deficient diet for four weeks, followed by one week of intraperitoneal copper sulfate administration as a proof-of-concept rescue intervention. Colonic pathology was assessed by H&E staining, goblet cell changes by AB-PAS staining, and intestinal barrier integrity by immunofluorescence. Inflammatory cytokine levels were measured by ELISA, while protein and mRNA expression of inflammatory markers were detected by Western blot and qRT-PCR. Gut microbiota composition, diversity, and signature genus abundance were analyzed by 16S sequencing. Compared to the control group, CuD mice exhibited histopathological damage in the colon, including mucosal thinning and inflammatory cell infiltration. The number of goblet cells and the expression of mucin MUC2 were significantly reduced, and the expression of tight junction proteins (ZO-1, Occludin) was downregulated, indicating impairment of both the physical and chemical intestinal barriers. Concurrently, Cu deficiency markedly elevated systemic and colonic levels of pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6), and enhanced NF-κB phosphorylation. To explore potential microbial contributions to these colonic alterations, we subsequently analyzed the gut microbiota composition by 16S rRNA sequencing. This analysis revealed that Cu deficiency significantly reduced the α-diversity and species richness of the gut microbiota. This dysbiosis was characterized by a decreased abundance of beneficial bacteria (e.g., Bacteroidota, Muribaculaceae) and an increased abundance of Desulfobacterota, a pro-inflammatory taxon, as well as Akkermansia, a mucin-degrading bacterium with context-dependent effects on gut health. Intraperitoneal administration of copper sulfate (CuD + CuSO ) partially reversed the histopathological and inflammatory changes; its effect on the gut microbiota was not assessed. Dietary Cu deficiency is associated with colonic injury, and these alterations were accompanied by intestinal barrier disruption, an activated inflammatory response, and gut microbiota dysbiosis. These findings provide experimental evidence highlighting the importance of copper nutrition in maintaining colonic homeostasis, though further mechanistic studies are needed to establish causal relationships.

Multicellular life arose in a world dominated by microorganisms, a reality that has imposed a constant and pervasive selective pressure on all subsequent complex organisms. The immune system has been historically defined by its role in pathogen clearance through resistance mechanisms. However, a complementary and equally critical strategy is to enable the peaceful and inevitable coexistence with microorganisms, allowing each host species to shelter a unique associated microbiome. The term tolerance holds multiple meanings in immunology, yet all underlie a balanced and cooperative host-microorganism relationship. Each represents a different aspect of how the immune system limits tissue damage while maintaining functionality in the presence of microbial or inflammatory stimuli. Using the intestinal mucosa as a paradigm, we explore how epithelial barrier integrity, toxin neutralization, tissue repair, and stress response underpin disease tolerance; how microbial exposure calibrates innate immunity via epigenetic and metabolic reprogramming (LPS tolerance); and how the gut microenvironment fosters the generation of tolerogenic antigen-presenting cells and microbe-specific regulatory T cells to enforce immunological tolerance. We further explore how the microbiota itself is a potent inducer of these tolerogenic pathways and highlight IL-10 as a major hub, connecting different tolerogenic circuits. Finally, we examine the hygiene hypothesis, arguing that lifestyle changes during the Anthropocene disrupt these finely tuned tolerance mechanisms, thereby contributing to the rising incidence of immune-mediated diseases. We posit that these tolerance programs are fundamental prerequisites for engendering host-microbiota symbiosis, a relationship forged over millennia of co-evolution and endangered in the contemporary world.

Spotted fever group rickettsioses are devastating human infections. Vascular endothelial cells are the primary targets of infection. Spotted fever group rickettsioses (SFRs) are devastating human infections. Vascular endothelial cells (ECs) are the primary targets of rickettsial infection. Edema resulting from EC barrier dysfunction occurs in the brain and lungs in most cases of lethal SFR, but the underlying mechanisms remain unclear. The aim of the study was to explore the potential role of Rickettsia -infected, EC-derived exosomes (Exos) during infection. Using size exclusion chromatography (SEC), we purified Exos from conditioned, filtered, bacterium-free media collected from Rickettsia parkeri -infected human umbilical vein ECs (HUVECs) ( R -ECExos) and plasma of Rickettsia australis - or R. parkeri -infected mice ( R -plsExos). We observed that rickettsial infection increased the release of heterogeneous plsExos, but endothelial exosomal size, morphology, and production were not significantly altered following infection. Compared to normal plsExos and ECExos, both R -plsExos and R -ECExos induced dysfunction of recipient normal brain microvascular ECs (BMECs). The effect of R -plsExos on mouse recipient BMEC barrier function is dose dependent. The effect of R -ECExos on human recipient BMEC barrier function is dependent on the exosomal RNA cargo. Next-generation sequencing analysis and stem-loop quantitative reverse transcription-PCR (RT-qPCR) validation revealed that rickettsial infection triggered the selective enrichment of endothelial exosomal mir-23a and mir-30b, which potentially target the endothelial barrier. To our knowledge, this is the first report on the functional role of extracellular vesicles following infection by obligately intracellular bacteria. IMPORTANCE Spotted fever group rickettsioses are devastating human infections. Vascular endothelial cells are the primary targets of infection. Edema resulting from endothelial barrier dysfunction occurs in the brain and lungs in most cases of lethal rickettsioses, but the underlying mechanisms remain unclear. The aim of the study was to explore the potential role of Rickettsia -infected, endothelial cell-derived exosomes during infection. We observed that rickettsial infection increased the release of heterogeneous plasma Exos, but endothelial exosomal size, morphology, and production were not significantly altered following infection. Rickettsia -infected, endothelial cell-derived exosomes induced dysfunction of human recipient normal brain microvascular endothelial cells. The effect is dependent on the exosomal RNA cargo. Next-generation sequencing analysis revealed that rickettsial infection triggered the selective enrichment of endothelial exosomal mir-23a and mir-30b, which potentially target the endothelial barrier. To our knowledge, this is the first report on the functional role of extracellular vesicles following infection by obligately intracellular bacteria.

This study aimed to evaluate the anti-colitis potential of platinum nanoparticles (PtNPs). 5-, 30- and 70-nm PtNPs were administered to C57BL/6 mice once daily by intragastric gavage for 8 d during and after 5-d dextran sodium sulfate treatment. According to body weight change, stool blood and consistency, and colon length and histopathology, PtNPs size-dependently alleviated DSS-induced murine colitis. PtNPs enhanced gut-barrier function by upregulating the colonic expressions of heat-shock protein 25 and tight junction proteins. Based on colonic myeloperoxidase activity, colonic and peripheral levels of interleukin-6 and tumor necrosis factor-α, and peripheral counts of white blood cells, PtNPs attenuated colonic and systemic inflammation. By suppressing lipopolysaccharide-triggered production of proinflammatory mediators, including nitric oxide, tumor necrosis factor-α and interleukin-6, PtNPs exerted direct anti-inflammatory activities in RAW264.7 macrophages through a mechanism involving intracellular reactive oxygen species scavenging and Toll-like receptor 4/NF-κB signaling suppression. High-throughput 16S rRNA sequencing of fecal samples unveiled that PtNPs induced gut dysbiosis by unfavorably altering α-diversity, Firmicutes/Bacteroidetes ratio, and richness of certain specific bacteria. PtNPs are a promising anti-colitis agent, but may negatively impact gut-microbiota.

Exosomes, which are molecular cargo-containing, nanosized extracellular vesicles formed through double invagination of the plasma membrane, have emerged as important mediators of intercellular communication within the gastrointestinal tract. In addition to its established function in digestion and nutrient uptake, the gastrointestinal tract is central to immune regulation and maintenance of epithelial barrier integrity. Exosomes derived from intestinal epithelial cells, the gut microbiota and gut resident immune cells are key in sustaining intestinal homeostasis and regulating host-microbiota interactions. Dysregulation of these vesicles is increasingly linked to gastrointestinal disease pathogenesis, including inflammatory bowel disease. Currently, exosomes are being explored for use as diagnostic biomarkers and therapeutic agents in gastrointestinal ailments. In this review, we examine the roles of exosomes in gastrointestinal health and disease, highlighting their contributions in the regulation of epithelial barrier function, modulation of immune responses and communication with the gut microbiota. We further discuss the dysregulation of exosome-mediated signaling pathways in IBD and assess their potential as next-generation therapies for gastrointestinal disorders.