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Staphylococcus aureus is a gram-positive bacterium that may cause intestinal inflammation by secreting enterotoxins, which commonly cause food-poisoning and gastrointestinal injuries. Staphylococcal enterotoxin B (SEB) acts as a superantigen (SAg) by binding in a bivalent manner the T-cell receptor (TCR) and the costimulatory receptor CD28, thus stimulating T cells to produce large amounts of inflammatory cytokines, which may affect intestinal epithelial barrier integrity and functions. However, the role of T cell-mediated SEB inflammatory activity remains unknown. Here we show that inflammatory cytokines produced by T cells following SEB stimulation induce dysfunctions in Caco-2 intestinal epithelial cells by promoting actin cytoskeleton remodelling and epithelial cell-cell junction down-regulation. We also found that SEB-activated inflammatory T cells promote the up-regulation of epithelial-mesenchymal transition transcription factors (EMT-TFs) in a nuclear factor-κB (NF-κB)- and STAT3-dependent manner. Finally, by using a structure-based design approach, we identified a SEB mimetic peptide (pSEB 116-132 ) that, by blocking the binding of SEB to CD28, dampens inflammatory-mediated dysregulation of intestinal epithelial barrier.

The gut microbiota can significantly affect the function of the intestinal barrier. Some intestinal probiotics (such as Lactobacillus , Bifidobacteria , a few Escherichia coli strains, and a new generation of probiotics including Bacteroides thetaiotaomicron and Akkermansia muciniphila ) can maintain intestinal epithelial homeostasis and promote health. This review first summarizes probiotics’ regulation of the intestinal epithelium via their surface compounds. Surface layer proteins, flagella, pili and capsular polysaccharides constitute microbial-associated molecular patterns and specifically bind to pattern recognition receptors, which can regulate signaling pathways to produce cytokines or inhibit apoptosis, thereby attenuating inflammation and enhancing the function of the gut epithelium. The review also explains the effects of metabolites (such as secreted proteins, organic acids, indole, extracellular vesicles and bacteriocins) of probiotics on host receptors and the mechanisms by which these metabolites regulate gut epithelial barrier function. Previous reviews summarized the role of the surface macromolecules or metabolites of gut microbes (including both probiotics and pathogens) in human health. However, these reviews were mostly focused on the interactions between these substances and the intestinal mucosal immune system. In the current review, we only focused on probiotics and discussed the molecular interaction between these bacteria and the gut epithelial barrier.

The intestinal epithelial barrier plays a key protective role in the gut lumen. Bovine lactoferrin (bLF) has been reported to improve the intestinal epithelial barrier function, but its impact on tight junction (TJ) proteins has been rarely described. Human intestinal epithelial crypt cells (HIECs) were more similar to those in the human small intestine, compared with the well-established Caco-2 cells. Accordingly, both HIECs and Caco-2 cells were investigated in this study to determine the effects of bioactive protein bLF on their growth promotion and intestinal barrier function. The results showed that bLF promoted cell growth and arrested cell-cycle progression at the G2/M-phase. Moreover, bLF decreased paracellular permeability and increased alkaline phosphatase activity and transepithelial electrical resistance, strengthening barrier function. Immunofluorescence, western blot and quantitative real-time polymerase chain reaction revealed that bLF significantly increased the expression of three tight junction proteins—claudin-1, occludin, and ZO-1—at both the mRNA and protein levels, and consequently strengthened the barrier function of the two cell models. bLF in general showed higher activity in Caco-2 cells, however, HIECs also exhibited desired responses to barrier function. Therefore, bLF may be incorporated into functional foods for treatment of inflammatory bowel diseases which are caused by loss of barrier integrity.

Radiotherapy is an important treatment for abdominal tumors. A critical side effect for this therapy is enteritis. In this review, we aim to summarize recent findings in radiation enteritis, in particular the role of gut microbiota dysbiosis in the development and therapy of the disease. Gut microbiota dysbiosis plays an important role in the occurrence of various diseases, such as radiation enteritis. Abdominal radiation results in changes in the composition of microbiota and reduces its diversity, which is mainly reflected in the decrease of Lactobacillus spp. and Bifidobacterium spp. and increase of Escherichia coli and Staphylococcus spp. Gut microbiota dysbiosis aggravates radiation enteritis, weakens intestinal epithelial barrier function, and promotes inflammatory factor expression. Pathogenic Escherichia coli induce the rearrangement and redistribution of claudin-1, occludin, and ZO-1 in tight junctions, a critical component in intestinal epithelial barrier. In view of the role that microbiome plays in radiation enteritis, we believe that intestinal flora could be a potential biomarker for the disease. Correction of microbiome by application of probiotics, fecal microbiota transplantation (FMT), and antibiotics could be an effective method for the prevention and treatment of radiation-induced enteritis.

The gut microbiota is a crucial factor in maintaining homeostasis. The presence of commensal microorganisms leads to the stimulation of the immune system and its maturation. In turn, dysbiosis with an impaired intestinal barrier leads to accelerated contact of microbiota with the host’s immune cells. Microbial structural parts, i.e., pathogen-associated molecular patterns (PAMPs), such as flagellin (FLG), peptidoglycan (PGN), lipoteichoic acid (LTA), and lipopolysaccharide (LPS), induce inflammation via activation of pattern recognition receptors. Microbial metabolites can also develop chronic low-grade inflammation, which is the cause of many metabolic diseases. This article aims to systematize information on the influence of microbiota on chronic inflammation and the benefits of microbiota modification through dietary changes, prebiotics, and probiotic intake. Scientific research indicates that the modification of the microbiota in various disease states can reduce inflammation and improve the metabolic profile. However, since there is no pattern for a healthy microbiota, there is no optimal way to modify it. The methods of influencing microbiota should be adapted to the type of dysbiosis. Although there are studies on the microbiota and its effects on inflammation, this subject is still relatively unknown, and more research is needed in this area.

Background Enteric pathogens have developed mechanisms to disrupt tight junctions and increase gut permeability. Many studies have analysed the ability of live probiotics to protect intestinal epithelial cells against tight junction damage caused by bacterial pathogens. Escherichia coli Nissle 1917 (EcN) is among the probiotics that positively modulates the intestinal epithelial barrier by regulating expression and distribution of tight junction proteins. We previously reported that regulation of ZO-1, claudin-14 and claudin-2 is mediated by EcN secreted factors, either free-released or associated with outer membrane vesicles (OMVs). Factors secreted by commensal ECOR63 elicited comparable effects in intact epithelial T-84 and Caco-2 cell monolayers. Results Here we analyse the ability of OMVs and soluble secreted factors to protect epithelial barrier function in polarized T-84 and Caco-2 cells infected with enteropathogenic Escherichia coli (EPEC). Transepithelial electrical resistance, paracellular permeability, mRNA levels and subcellular distribution of tight junction proteins were monitored in the absence or presence of EcN and ECOR63 extracellular fractions. EPEC downregulated expression of ZO-1 ZO-2, occludin and claudin-14 and altered the subcellular localization of ZO-1, occludin and F-actin cytoskeleton. OMVs and soluble factors secreted by EcN and ECOR63 counteracted EPEC-altered transepithelial resistance and paracellular permeability, preserved occludin and claudin-14 mRNA levels, retained ZO-1 and occludin at tight junctions in the cell boundaries and ameliorated F-actin disorganization. Redistribution of ZO-1 was not accompanied by changes at mRNA level. Conclusion This study provides new insights on the role of microbiota secreted factors on the modulation of intestinal tight junctions, expanding their barrier-protective effects against pathogen-induced disruption.

Sphingosine-1-phospate (S1P) receptor agonists (eg, ozanimod) desensitize migrating lymphocytes by irreversibly binding to S1P receptors (S1PR) and triggering their proteasomal degradation. Desensitized lymphocytes cannot sense S1P, therefore, halting lymphocyte recirculation. The S1P lyase (SPL) irreversibly degrades S1P and its inhibition disrupts the S1P gradient. We previously found that systemic SPL inhibitors induce central immunosuppression. Here, we examined whether SPL inhibition may attenuate colitis without systemic immunotoxicity. We first analyzed SPL expression and localization in mice using qRT-PCR and immunohistochemistry. SPL inhibitors 4-deoxypyridoxine hydrochloride (DOP) and 2-acetyl-4-(tetrahydroxybutyl) imidazole (THI) were used to inhibit SPL systemically, whereas a conditional intestinal epithelial cell (IEC)-specific SPL-deficient mouse was used to evaluate the effects of IEC-specific SPL inhibition on survival, disease activity, histological severity of dextran sulfate sodium-induced colitis, S1P levels, and intestinal permeability. Sgpl1 mRNA transcripts and protein were ubiquitously expressed in gastrointestinal (GI) tract leukocytes and IEC. Systemic SPL inhibitors did not induce colitis by themselves but depleted CD4+ and CD8+ T cells from blood. However, contrary to its therapeutic effects on ileitis, systemic inhibition reduced survival, accelerated weight loss, worsened histopathological inflammation indices, and tissue damage. We then examined the effects of IEC-specific inhibition on peripheral cell counts and severity of colitis. We found that while it spared peripheral immunity, it similarly hastened colitis. Finally, we examined whether colitis acceleration was due to epithelial barrier compromise after disruption of the S1P gradient. We found that not only systemic but also IEC-specific SPL inhibition increased local S1P levels and led to IEC barrier compromise. Homeostatic intestinal S1P levels are critical for the regulation of IEC barrier function. Further studies using adaptive immunity-based inflammatory bowel diseases (IBD) models are required to assess the translational value of IEC-specific SPL inhibition as a therapeutic target for human IBD.

Monogenic causes of inflammatory bowel diseases (IBD) are increasingly being discovered. To date, much attention has been placed in those resulting from inborn errors of immunity. Therapeutic efforts have been largely focused on offering personalized immune modulation or curative bone marrow transplant for patients with IBD and underlying immune disorders. To date, less emphasis has been placed on monogenic causes of IBD that pertain to impairment of the intestinal epithelial barrier. Here, we provide a comprehensive review of monogenic causes of IBD that result in impaired intestinal epithelial barrier that are categorized into 6 important functions: (1) epithelial cell organization, (2) epithelial cell intrinsic functions, (3) epithelial cell apoptosis and necroptosis, (4) complement activation, (5) epithelial cell signaling, and (6) control of RNA degradation products. We illustrate how impairment of any of these categories can result in IBD. This work reviews the current understanding of the genes involved in maintaining the intestinal barrier, the inheritance patterns that result in dysfunction, features of IBD resulting from these disorders, and pertinent translational work in this field. Lay Summary A comprehensive review of monogenic causes of IBD that result in impaired intestinal epithelial barrier is detailed, including genes involved in maintaining the intestinal barrier, features of IBD resulting from these disorders, and pertinent translational work in this field.

Enteric glial cells (EGCs) of the enteric nervous system are critically involved in the maintenance of intestinal epithelial barrier function (IEB). The underlying mechanisms remain undefined. Glial cell line-derived neurotrophic factor (GDNF) contributes to IEB maturation and may therefore be the predominant mediator of this process by EGCs. Using GFAPcre x Ai14floxed mice to isolate EGCs by Fluorescence-activated cell sorting (FACS), we confirmed that they synthesize GDNF in vivo as well as in primary cultures demonstrating that EGCs are a rich source of GDNF in vivo and in vitro. Co-culture of EGCs with Caco2 cells resulted in IEB maturation which was abrogated when GDNF was either depleted from EGC supernatants, or knocked down in EGCs or when the GDNF receptor RET was blocked. Further, TNFα-induced loss of IEB function in Caco2 cells and in organoids was attenuated by EGC supernatants or by recombinant GDNF. These barrier-protective effects were blunted when using supernatants from GDNF-deficient EGCs or by RET receptor blockade. Together, our data show that EGCs produce GDNF to maintain IEB function in vitro through the RET receptor.

Intestinal microecology is the main component of human microecology. Intestinal microecology consists of intestinal microbiota, intestinal epithelial cells, and intestinal mucosal immune system. These components are interdependent and establish a complex interaction network that restricts each other. According to the impact on the human body, there are three categories of symbiotic bacteria, opportunistic pathogens, and pathogenic bacteria. The intestinal microecology participates in digestion and absorption, and material metabolism, and inhibits the growth of pathogenic microorganisms. It also acts as the body's natural immune barrier, regulates the innate immunity of the intestine, controls the mucosal barrier function, and also participates in the intestinal epithelial cells' physiological activities such as hyperplasia or apoptosis. When the steady‐state balance of the intestinal microecology is disturbed, the existing core intestinal microbiota network changes and leads to obesity, diabetes, and many other diseases, especially irritable bowel syndrome, inflammatory bowel disease (IBD), and colorectal malignancy. Intestinal diseases, including tumors, are particularly closely related to intestinal microecology. This article systematically discusses the research progress on the relationship between IBD and intestinal microecology from the pathogenesis, treatment methods of IBD, and the changes in intestinal microbiota. The article systematically discussed the research progress of the relationship between inflammatory bowel disease and intestinal microecology from the pathogenesis and treatment methods of inflammatory bowel disease and the changes in intestinal flora.