Ferroptosis has been shown to play a significant role in the pathogenesis of ulcerative colitis (UC). This study investigated the effects of 1,25(OH)2D3 supplementation on ferroptosis in dextran sulfate sodium (DSS)-evoked colitis. Intestinal VDR was reduced in UC patients. Accordingly, GPX4 was downregulated and ACSL4 was upregulated in the intestine of UC patients. Animal experiments indicated that vitamin D deficiency exacerbated DSS-induced intestinal ferroptosis in mice. Conversely, pretreatment with 1,25(OH)2D3 alleviated DSS-induced ferroptosis in mouse intestine. Similarly, 1,25(OH)2D3 supplementation inhibited DSS-induced ferroptosis in HT-29 cells. Furthermore, we found decreased intestinal SIRT3 protein and increased acetylated superoxide dismutase 2 (Ac-SOD2) in UC patients. Pretreatment with 1,25(OH)2D3 attenuated DSS-induced downregulation of SIRT3 and acetylation of SOD2 in both mouse intestine and HT-29 cells. Moreover, 1,25(OH)2D3 pretreatment inhibited mitochondrial reactive oxygen species (mtROS) in DSS-treated HT-29 cells. Finally, transfection with SIRT3 siRNA antagonized the protective effect of 1,25(OH)2D3 on ferroptosis in DSS-treated HT-29 cells. Overall, our results suggest that 1,25(OH)2D3 alleviates DSS-induced intestinal ferroptosis via the SIRT3-SOD2-mtROS pathway, further supporting the potential use of 1,25(OH)2D3 supplementation in UC treatment.

Addictive substance use disorder has a wide range of effects on the intestinal barrier, including damage to the biological, chemical, mechanical, and immune barriers. Damage to the intestinal barrier caused by addictive substance use disorder allows harmful substances and bacteria to cross the intestinal barrier into the circulatory system, leading to systemic inflammatory responses and immune imbalances. In addition, the interaction between the gut flora and the central nervous system is recognized as an important component of the gut-brain axis. Gut barrier damage leads to dysbiosis, which in turn affects brain function by activating immune cells and releasing inflammatory factors. This may lead to altered mood and cognitive function, increased addictive substance cravings, and dependence. Recent research has indicated that reshaping the gut-brain axis and adjusting the composition and abundance of gut microbiota holds promise in alleviating withdrawal symptoms with addictive substance dependence. This article reviews the effects of addictive substance use disorder on the intestinal barrier and explores the possibility of improving addictive substance dependence by treating gut barrier damage.

Ulcerative colitis (UC) is a lifelong chronic inflammatory disease that is characterized by the absence of specific markers for diagnosis and prognosis. TPM3 is an integral component of the thin filament, responsible for the structural stability of actin filaments and modulation of cytoskeletal function. This study investigated the regulatory role of TPM3 in UC and its potential mechanisms.

At the clinical level, TPM3 levels were assessed in serum and mucosal tissues of UC and other enteric disease. At the cellular level, the effects of TMP3 overexpressing lentivirus on Caco-2 cell phenotype and the barrier of IL-1β-induced UC model were explored. At the animal level, the effects of TMP3 overexpressing lentivirus on symptoms and colonic damage in a DSS-induced UC model were explored.

TPM3 expression in serum of UC patients was significantly lower than that of other enteric disease, and TPM3 levels in the intestinal mucosa showed a negative correlation with the Mayo score of UC patients. TPM3 overexpression alleviates IL-1β-induced apoptosis and inhibition of invasion and migration in UC model in vitro. In monolayer Caco-2 cells, TPM3 overexpression rescued the IL-1β-induced decrease in transepithelial electrical resistance and tight junction markers (ZO-1 and Occludin) and increase in permeability. In animal experiments, TPM3 overexpression increased body weight and colon length and decreased disease activity index in a DSS-induced UC model. In tissue staining, it alleviated pathological damage and upregulated Occuludin and TPM3 levels in the colon.

TPM3 levels correlated with UC disease course and TPM3 overexpression alleviated symptoms/phenotypes and barrier damage in UC models in vivo and in vitro. TPM3 may serve as a potential novel biomarker for UC diagnosis and prognosis.

Histological mucosal healing has become a paramount target goal to achieve in the treatment of inflammatory bowel diseases. However, there is still a lack of agreement on the best way to reach this goal, since numerous histological scores are available worldwide.

We investigated whether claudin-2, a member of claudin family involved in the regulation of intestinal tight junctions, might be useful to assess the presence of active disease in patients with inflammatory bowel diseases.

Biopsies from 123 patients with ulcerative colitis, Crohn's disease, infectious colitides and irritable bowel syndrome patients where tested with immunohistochemistry for claudin-2.

Claudin-2 appeared to be a very sensitive marker of disease activity in inflammatory bowel diseases, but was negative in the other kinds of patients. In addition, immunohistochemistry for claudin-2 showed good reproducibility by different pathologists.

Should these findings be confirmed in more numerous cohorts of patients, and especially in those with minimal or focal residual disease activity, this simple assessment could be useful in the routine daily practice to facilitate the task of pathologists and clinicians in the diagnosis and management of patients with inflammatory bowel diseases.

Ulcerative colitis (UC) is a chronic autoimmune disease and seriously affects the normal life of patients. Conventional therapeutic drugs are difficult to meet clinical needs. Traditional Chinese medicine (TCM) ingredients could effectively alleviate the symptoms of UC by anti-inflammatory, anti-oxidative, regulating the gut microbiota, and repairing the colonic epithelial barrier, but their low solubility and bioavailability severely limit their clinical application. Nano-drug delivery systems (NDDS) combined with TCM ingredients is a promising option for treating UC, and they could significantly enhance the stability, solubility, and bioavailability of TCM ingredients. The review describes the anti-UC mechanisms of TCM ingredients, systematically summarizes various kinds of NDDS for TCM ingredients according to different routes of administration, and highlights the advantages of NDDS for TCM ingredients in the treatmentof UC. In addition, we discuss the limitations of existing NDDS for TCM ingredients and the development direction in the future. This review will provide a basis for the future development of anti-UC NDDS for TCM ingredients.

Ulcerative colitis (UC) is a chronic inflammatory disease affecting the colorectum, posing a significant global health burden. Recent studies highlight the critical role of gut microbiota and its metabolites, particularly bile acids (BAs), in UC's pathogenesis. The relationship between BAs and gut microbiota is bidirectional: microbiota influence BA composition, while BAs regulate microbiota diversity and activity through receptors like Farnesoid X receptor (FXR) and Takeda G protein-coupled receptor 5 (TGR5). Targeting bile-acid metabolism to reshape gut microbiota presents a promising therapeutic strategy for UC. This review examines the classification and synthesis of BAs, their interactions with gut microbiota, and the potential of nutritional and microbial interventions. By focusing on these therapies, we aim to offer innovative approaches for effective UC management.

Background: COPD is a heterogenous disease of the respiratory tract caused by diverse genetic factors along with environmental and lifestyle-related effects such as industrial dust inhalation and, most frequently, cigarette smoking. These factors lead to airflow obstruction and chronic respiratory symptoms. Additionally, the increased risk of infections exacerbates airway inflammation in COPD patients. As a consequence of the complex pathomechanisms and difficulty in treatment, COPD is among the leading causes of mortality both in the western countries and in the developing world. Results: The management of COPD is still a challenge for the clinicians; however, alternative interventions such as smoking cessation and lifestyle changes from a sedentary life to moderate physical activity with special attention to the diet may ameliorate patients' health. Here, we reviewed the effects of different dietary components and supplements on the conditions of COPD. Conclusions: COPD patients are continuously exposed to heavy metals, which are commonly present in cigarette smoke and polluted air. Meanwhile, they often experience significant nutrient deficiencies, which affect the detoxification of these toxic metals. This in turn can further disrupt nutritional balance by interfering with the absorption, metabolism, and utilization of essential micronutrients. Therefore, awareness and deliberate efforts should be made to check levels of micronutrients, with special attention to ensuring adequate levels of antioxidants, vitamin D, vitamin K2, magnesium, and iron, as these may be particularly important in reducing the risk of COPD development and limiting disease severity.

Deer oil (DO), a byproduct of deer meat processing, possesses high nutritional value. This study aims to evaluate the protective effects of DO on dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) in mice and to explore its potential mechanisms of action.

DO was found to inhibit weight loss and colon shortening in colitis mice, significantly reduce disease activity index scores, and notably enhance the levels of tight junction proteins in colon tissues, thus improving intestinal barrier function. ELISA results indicated that DO markedly alleviated the mice's oxidative stress and inflammatory responses. Western blot analysis further demonstrated that DO significantly inhibited the phosphorylation of NF-κB while up-regulating the expression levels of Nrf2 and HO-1 proteins. Additionally, DO increased the abundance of beneficial bacteria such as Odoribacter, Blautia, and Muribaculum, reduced the abundance of harmful bacteria such as Bacteroides, Helicobacter, and Escherichia-Shigella, and promoted the production of short-chain fatty acids.

Our study provides the first evidence that DO can effectively improve DSS-induced UC in mice. The underlying mechanisms may involve maintaining intestinal barrier function, inhibiting inflammation, alleviating oxidative stress, and modulation of gut microbiota. These findings offer valuable insights for developing DO as an adjunct treatment for UC and as a functional food. © 2024 Society of Chemical Industry.

Intestinal epithelial tight junctions (TJs), a dynamically regulated barrier structure composed of occludin and claudin family of proteins, mediate the interaction between the host and the external environment by allowing selective paracellular permeability between the luminal and serosal compartments of the intestine. TJs are highly dynamic structures and can undergo constant architectural remodeling in response to various external stimuli. This is mediated by an array of intracellular signaling pathways that alters TJ protein expression and localization. Dysfunctional regulation of TJ components compromising the barrier homeostasis is an important pathogenic factor for pathological conditions including inflammatory bowel disease (IBD). Previous studies have elucidated the significance of TJ barrier integrity and key regulatory mechanisms through various in vitro and in vivo models. In recent years, considerable efforts have been made to understand the crosstalk between various signaling pathways that regulate formation and disassembly of TJs. This review provides a comprehensive view on the novel mechanisms that regulate the TJ barrier and permeability. We discuss the latest evidence on how ion transport, cytoskeleton and extracellular matrix proteins, signaling pathways, and cell survival mechanism of autophagy regulate intestinal TJ barrier function. We also provide a perspective on the context-specific outcomes of the TJ barrier modulation. The knowledge on the diverse TJ barrier regulatory mechanisms will provide further insights on the relevance of the TJ barrier defects and potential target molecules/pathways for IBD.

Diarrhea associated with enteric infections, gut inflammation, and genetic defects poses a major health burden and results in significant morbidity and mortality. Impaired fluid and electrolyte absorption or secretion in the intestine are the hallmark of diarrhea. Electroneutral NaCl absorption in the mammalian GI tract involves the coupling of Na+/H+ and Cl-/HCO3- exchangers. SLC26A3 (Down Regulated in Adenoma, DRA) is the major anion exchanger involved in luminal Cl- absorption and HCO3- secretion. Mutations in the SLC26A3 gene cause a severe disease called congenital chloride diarrhea (CLD). Multiple studies have shown that DRA function or expression is downregulated in infectious diarrheal disorders caused by EPEC, C rodentium, Salmonella, Clostridioides difficile and Cryptosporidium parvum infection. In addition, DRA levels are severely depleted in colonic mucosa of IBD patients and in mouse models of IBD (eg, DSS, TNBS, adoptive T-cell transfer, anti-CD-40, and IL-10 KO colitis). In addition, genetic defects exhibiting diarrhea including microvillus inclusion disease (MVID), keratin-8 depletion, knock-out mouse models of transcriptional factors (eg, CDX-2 and HNF1α/1β) also exhibit severe down regulation of DRA. Also, recent studies have shown that DRA is not only critical for chloride absorption but also plays a key role in maintaining gut epithelial barrier integrity, microbiome composition, and has now emerged as an IBD susceptibility gene. In this review, we provide strong evidence that DRA may serve as a novel therapeutic target with dual benefits in not only correcting diarrheal phenotype but also improving gut barrier integrity and inflammation in pathogen infection or IBD.

Pancreatitis is an inflammatory disease of the pancreas that can arise due to various factors, including environmental risks such as diet, alcohol, and smoking, as well as genetic predispositions. In some cases, pancreatitis may progress and become chronic, leading to irreversible damage and impaired pancreatic function. Genome-wide association studies (GWAS) have identified polymorphisms at the X-linked CLDN2 locus as risk factors for both sporadic and alcohol-related chronic pancreatitis. CLDN2 encodes claudin-2 (CLDN2), a paracellular cation-selective channel localized at tight junctions and expressed in the pancreas and other secretory organs. However, whether and how CLDN2 may modify pancreatitis susceptibility remains poorly understood. We aimed to clarify the potential role of CLDN2 in the onset and progression of pancreatitis. We employed multiple methodologies to examine the role of CLDN2 in human pancreatic tissue, caerulein-induced experimental pancreatitis mouse model, and pancreatic ductal epithelial organoids. In both human chronic pancreatitis tissues and caerulein-induced experimental pancreatitis, CLDN2 protein was significantly upregulated in pancreatic ductal epithelial cells. Our studies using pancreatic ductal epithelial organoids and mice demonstrated the inflammatory cytokine IFNγ upregulates claudin-2 expression at both RNA and protein levels. Following caerulein treatment, Ifng KO mice had diminished upregulation of CLDN2 relative to WT mice, indicating that caerulein-induced claudin-2 expression is partially driven by IFNγ. Functionally, Cldn2 knockout mice developed more severe caerulein-induced experimental pancreatitis, indicating CLDN2 plays a protective role in pancreatitis development. Pancreatic ductal epithelial organoid-based studies demonstrated that CLDN2 is critical for sodium-dependent water transport and necessary for cAMP-driven, CFTR-dependent fluid secretion. These findings suggest that functional crosstalk between CLDN2 and CFTR is essential for fluid transport in pancreatic ductal epithelium, which may protect against pancreatitis by adjusting pancreatic ductal secretion to prevent worsening autodigestion and inflammation. In conclusion, our studies suggest CLDN2 upregulation during pancreatitis may play a protective role in limiting disease development, and decreased CLDN2 function may increase pancreatitis severity. These results point to the possibility of modulating pancreatic ductal CLDN2 function as an approach for therapeutic intervention of pancreatitis.

Exposure to toxic substances, introduced into our daily lives during industrialization and modernization, can disrupt the epithelial barriers in the skin, respiratory, and gastrointestinal systems, leading to microbial dysbiosis and inflammation. Athletes and physically active individuals are at increased risk of exposure to agents that damage the epithelial barriers and microbiome, and their extreme physical exercise exerts stress on many organs, resulting in tissue damage and inflammation. Epithelial barrier-damaging substances include surfactants and enzymes in cleaning products, laundry and dishwasher detergents, chlorine in swimming pools, microplastics, air pollutants such as ozone, particulate matter, and diesel exhaust. Athletes' high-calorie diet often relies on processed foods that may contain food emulsifiers and other additives that may cause epithelial barrier dysfunction and microbial dysbiosis. The type of the material used in the sport equipment and clothing and their extensive exposure may increase the inflammatory effects. Excessive travel-related stress, sleep disturbances and different food and microbe exposure may represent additional factors. Here, we review the detrimental impact of toxic agents on epithelial barriers and microbiome; bring a new perspective on the factors affecting the health and performance of athletes and physically active individuals.

The pathogenesis of inflammatory bowel diseases such as ulcerative colitis and Crohn's disease is not well understood. This study investigated the roles and regulation of the claudin-1, -2, -3, and -4 isoforms in the pathogenesis of ulcerative colitis, and the potential therapeutic effects of nobiletin.

Colitis was induced in rats by administering dextran sulfate sodium [DSS] in drinking water for seven days. Animals were treated daily with nobiletin [oral, 60 mg/Kg body weight] and studied in four groups, C [non-colitis control], D [DSS-induced colitis], CN [nobiletin-treated non-colitis control], and DN [nobiletin-treated DSS-induced colitis]. On day seven, the animals were sacrificed, and colonic tissues were collected and analyzed.

Both macroscopic and microscopic findings suggest the progression of colitis. In the inflamed colon, claudin-1 and -4 proteins were decreased, claudin-2 increased, while the claudin-3 protein remained unchanged. Except for claudin-1, these changes were not paralleled by mRNA expression, indicating a complex regulatory mechanism. Uniform β-actin expression along with consistent quality and yield of total RNA indicated selectivity of these changes. Nobiletin treatment reversed these changes.

Altered expression of the claudin isoforms -1, -2, and -4 disrupts tight junctions, exposing the lamina propria to microflora, leading to electrolyte disturbance and the development of ulcerative colitis. Nobiletin with its anti-inflammatory properties may be useful in IBD.

Epithelial homeostasis is fundamental for the physiological functions of colon tissue. Dysregulation of colon epithelial structure leads to abnormal immune responses and diseases such as inflammatory bowel disease. In this work we found long non-coding RNA DANCR was a novel regulator to colon epithelial homeostasis. Silencing DANCR resulted in decreased expression of epithelial barrier proteins and enhanced susceptibility to TNFα stimulation, which was accompanied by hyperactivation of the NF-κB pathway. Mechanistical studies revealed DANCR modulated the expression of a protein methyltransferase SET7 to suppress responses to TNFα, as well as the activity of NF-κB pathway. In summary, DANCR regulated colon epithelial homeostasis through modulating the TNFα/NF-κB axis. These findings cast light on the discovery of novel regulators to colon epithelial homeostasis and added new evidence to the physiological functions of DANCR.

Recent studies have shown that age-related aging evolution is accompanied by imbalances in intestinal homeostasis. Marine red yeast (MRY) is a functional probiotic that has been shown to have antioxidant, immune and other properties. Therefore, we chose 900 healthy Hy-Line Brown hens at 433 d old as the research subjects and evaluated the correlation between intestinal health, laying performance, and egg quality in aged hens through the supplementation of MRY. These laying hens were assigned into 5 groups and received diet supplementation with 0%, 0.5%, 1.0%, 1.5%, and 2% MRY for 12 weeks. The results showed that MRY supplementation increased egg production rate, average egg weight, and egg quality, and decreased feed conversion ratio and daily feed intake (P < 0.05). The MRY supplement improved antioxidant indicators such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), stimulated villus height, and increased the villus height to crypt depth ratio (V/C ratio) in the intestine (P < 0.05). It also regulated the expression of intestinal inflammatory factors (transforming growth factor-β [TGF-β], interleukin [IL]-1β, IL-8, tumor necrosis factor-α [TNF-α]) while increasing serum immunoglobulin G (IgG) levels (P < 0.05). Furthermore, MRY supplementation upregulated the mRNA expression of tight junction proteins (occludin and zonula occludens-1 [ZO-1]), anti-apoptotic gene (Bcl-2), and autophagy-related proteins (beclin-1 and light chain 3I [LC3I]) in the intestine (P < 0.05). The MRY supplement also led to an increase in the concentration of short-chain fatty acids in the cecum, and the relative abundance of the phylum Bacteroidetes, and genera Bacteroides and Rikenellaceae_RC9_gut_group. The LEfSe analysis revealed an enrichment of Sutterella and Akkermansia muciniphila. In conclusion, the results of this experiment indicated that the additional supplementation of MRY can improve the production performance of laying hens and may contribute to the restoration and balance of intestinal homeostasis, which supports the application potential of MRY as a green and efficient feed additive for improving the laying performance in chickens.

This review investigates the oral microbiome's composition, functions, influencing factors, connections to oral and systemic diseases, and personalized oral care strategies.

The oral microbiome is a complex ecosystem consisting of bacteria, fungi, archaea, and viruses that contribute to oral health. Various factors, such as diet, smoking, alcohol consumption, lifestyle choices, and medical conditions, can affect the balance of the oral microbiome and lead to dysbiosis, which can result in oral health issues like dental caries, gingivitis, periodontitis, oral candidiasis, and halitosis. Importantly, our review explores novel associations between the oral microbiome and systemic diseases including gastrointestinal, cardiovascular, endocrinal, and neurological conditions, autoimmune diseases, and cancer. We comprehensively review the efficacy of interventions like dental probiotics, xylitol, oral rinses, fluoride, essential oils, oil pulling, and peptides in promoting oral health by modulating the oral microbiome.

This review emphasizes the critical functions of the oral microbiota in dental and overall health, providing insights into the effects of microbial imbalances on various diseases. It underlines the significant connection between the oral microbiota and general health. Furthermore, it explores the advantages of probiotics and other dental care ingredients in promoting oral health and addressing common oral issues, offering a comprehensive strategy for personalized oral care.

IA-0130 is a derivative of 3-(1,3-diarylallylidene)oxindoles, which is a selective estrogen receptor modulator (SERM). A previous study demonstrated that SERM exhibits anti-inflammatory effects on colitis by promoting the anti-inflammatory phenotype of monocytes in murine colitis. However, the therapeutic effects of oxindole on colitis remain unknown. Therefore, we evaluated the efficacy of IA-0130 on dextran sulfate sodium (DSS)-induced mouse colitis.

The DSS-induced colitis mouse model was established by administration of 2.5% DSS for 5 days. Mice were orally administered with IA-0130 (0.01 mg/kg or 0.1 mg/kg) or cyclosporin A (CsA; 30 mg/kg). Body weight, disease activity index score and colon length of mice were calculated and histological features of mouse colonic tissues were analyzed using hematoxylin and eosin staining. The expression of inflammatory cytokines and tight junction (TJ) proteins were analyzed using quantitative real-time PCR and enzyme-linked immunosorbent assay. The expression of interleukin-6 (IL-6) signaling molecules in colonic tissues were investigated using Western blotting and immunohistochemistry (IHC).

IA-0130 (0.1 mg/kg) and CsA (30 mg/kg) prevented colitis symptom, including weight loss, bleeding, colon shortening, and expression of pro-inflammatory cytokines in colon tissues. IA-0130 treatment regulated the mouse intestinal barrier permeability and inhibited abnormal TJ protein expression. IA-0130 down-regulated IL-6 expression and prevented the phosphorylation of signaling molecules in colonic tissues.

This study demonstrated that IA-0130 suppressed colitis progression by inhibiting the gp130 signaling pathway and expression of pro-inflammatory cytokines, and maintaining TJ integrity.

Given China's prohibition on the utilization of antibiotics as feed additives in 2020, we aim to investigate nutrition additives that are both efficient and safe. Lactobacillus, a well-recognized beneficial probiotic, has explicitly been investigated for its effects on health status of the host and overall impact on food industry. To evaluate effects of Lactobacillus plantarum (LW) supplementation on broiler chicken, we conducted comprehensive multi-omics analysis, growth performance evaluation, RT-qPCR analysis, and immunofluorescence. The findings revealed that LW supplementation resulted in a substantial progress in growth performance (approximately 205 g increase in final body weight in comparison to the control group (p < 0.01)). Additionally, LW exhibited promising potential for enhancing antioxidant properties of serum and promoting gut integrity and growth as evidenced by improved antioxidant indices (p < 0.01), intestinal villus morphology (p < 0.01), and enhanced gut barrier function (p < 0.01). Meanwhile, the multi-omics analysis, including 16S rRNA sequencing and liquid chromatography-tandem mass spectrometry, revealed an enrichment of beneficial microbes in the gut of broilers that were supplemented with LW, while simultaneously depleting harmful microorganisms. Moreover, a noteworthy modification was observed in gut metabolic profiling subsequent to the execution of the probiotic strategy. Specifically, variations were noticed in the levels of metabolites and metabolic pathways such as parathyroid hormone synthesis, inflammatory mediator regulation of TRP channels, oxidative phosphorylation, and mineral absorption. Taken together, our findings validate that LW administration produces valuable effects on the health and growth performance of broilers owing to its capability to boost the gut microbiota homeostasis and intestinal metabolism. Present findings signify the potential of LW as a dietary additive to promote growth and development in broiler chickens.

The gut barrier is a sophisticated and dynamic system that forms the frontline defense between the external environment and the body's internal milieu and includes various structural and functional components engaged not only in digestion and nutrient absorption but also in immune regulation and overall health maintenance.

When one or more components of the intestinal barrier lose their structure and escape their function, this may result in a leaky gut. Mounting evidence emphasizes the crucial role of the gut microbiome in preserving the integrity of the gut barrier and provides insights into the pathophysiological implications of conditions related to leaky gut in humans. Assessment of intestinal permeability has evolved from invasive techniques to noninvasive biomarkers, but challenges remain in achieving consensus about the best testing methods and their accuracy. Research on the modulation of gut permeability is just starting, and although no medical guidelines for the treatment of leaky gut syndrome are available, several treatment strategies are under investigation with promising results.

This review discusses the composition of the intestinal barrier, the pathophysiology of the leaky gut and its implications on human health, the measurement of intestinal permeability, and the therapeutic strategies to restore gut barrier integrity.

The emergence of inflammatory diseases is a heavy burden on modern societies. Cannabis has been used for several millennia to treat inflammatory disorders such as rheumatism or gout. Since the characterization of cannabinoid receptors, CB1 and CB2, the potential of cannabinoid pharmacotherapy in inflammatory conditions has received great interest. Several studies have identified the importance of these receptors in immune cell migration and in the production of inflammatory mediators. As the presence of the CB2 receptor was documented to be more predominant in immune cells, several pharmacological agonists and antagonists have been designed to treat inflammation. To better define the potential of the CB2 receptor, three online databases, PubMed, Google Scholar and clinicaltrial.gov, were searched without language restriction. The full texts of articles presenting data on the endocannabinoid system, the CB2 receptor and its role in modulating inflammation in vitro, in animal models and in the context of clinical trials were reviewed. Finally, we discuss the clinical potential of the latest cannabinoid-based therapies in inflammatory diseases.

Growing evidence suggests that impaired gut permeability and gut microbiota alterations are involved in the pathogenesis of Inflammatory Bowel Diseases (IBDs), which include Ulcerative Colitis (UC) and Crohn's Disease (CD). Vedolizumab is an anti-α4β7 antibody approved for IBD treatment, used as the first treatment or second-line therapy when the first line results in inadequate effectiveness. The aim of this study is to develop a mathematical model capable of describing the pathophysiological mechanisms of Vedolizumab treatment in IBD patients. In particular, the relationship between drug concentration in the blood, colonic mucosal permeability and fecal microbiota composition was investigated and modeled to detect and predict trends in order to support and tailor Vedolizumab therapies. To pursue this aim, clinical data from a pilot study on a cluster of 11 IBD patients were analyzed. Enrolled patients underwent colonoscopy in three phases (before (t0), after 24 weeks of (t1) and after 52 weeks of (t2 ) Vedolizumab treatment) to collect mucosal biopsies for transepithelial electrical resistance (TEER) evaluation (permeability to ions), intestinal permeability measurement and histological analysis. Moreover, fecal samples were collected for the intestinal microbiota analysis at the three time points. The collected data were compared to those of 11 healthy subjects at t0, who underwent colonoscopy for screening surveillance, and used to implement a three-compartmental mathematical model (comprising central blood, peripheral blood and the intestine). The latter extends previous evidence from the literature, based on the regression of experimental data, to link drug concentration in the peripheral blood compartment with Roseburia abundance and intestinal permeability. The clinical data showed that Vedolizumab treatment leads to an increase in TEER and a reduction in intestinal permeability to a paracellular probe, improving tissue inflammation status. Microbiota analysis showed increasing values of Roseburia, albeit not statistically significant. This trend was adequately reproduced by the mathematical model, which offers a useful tool to describe the pathophysiological effects of Vedolizumab therapy on colonic mucosal permeability and fecal microbiota composition. The model's satisfactory predictive capabilities and simplicity shed light on the relationship between the drug, the microbiota and permeability and allow for its straightforward extension to diverse therapeutic conditions.

Soybean is an important source of high-quality vegetable protein with various health-improving properties, and its main bioactive substances are small peptides produced by in vitro enzymatic hydrolytic processes. In traditional layer breeding, the nutritional health of roosters is frequently neglected, ultimately affecting the quality and quantity of offspring. This study investigated the effects of various quantities (0%, 0.15%, 0.30%, 0.45%, and 0.60%) of soybean bioactive peptide (SBP) feed additives on immunological and antioxidant functions, gut health, and reproductive performance of roosters. SBP supplementation significantly improved male growth and reproductive performance, including growth rate, feed conversion ratio, reproductive organ development, and semen quality. SBP also increased immune and antioxidant levels, boosted the integrity of the small intestinal physiological structure and barrier function, and diversity of cecal microbes, and decreased the apoptotic ratio of small intestinal epithelial cells. The effects of SBP on various functions of males showed a quadratic trend, with the optimal concentration determined to be 0.45%.

Lysozyme is a β-1,4-glycosidase that hydrolyzes the polysaccharide backbone of bacterial cell walls. With an additional bactericidal function mediated by a separate protein domain, lysozyme is considered a uniquely important antimicrobial molecule contributing to the host's innate immune response to infection. Elevated lysozyme production is found in various inflammatory conditions while patients with genetic risks for inflammatory bowel diseases demonstrate abnormal lysozyme expression, granule packaging, and secretion in Paneth cells. However, it remains unclear how a gain- or loss-of-function in host lysozyme may impact the host inflammatory responses to pathogenic infection. We challenged Lyz1-/- and ectopic Lyz1-expressing (Villin-Lyz1TG) mice with S. Typhimurium and then comprehensively assessed the inflammatory disease progression. We conducted proteomics analysis to identify molecules derived from human lysozyme-mediated processing of live Salmonella. We examined the barrier-impairing effects of these identified molecules in human intestinal epithelial cell monolayer and enteroids. Lyz1-/- mice are protected from infection in terms of morbidity, mortality, and barrier integrity, whereas Villin-Lyz1TG mice demonstrate exacerbated infection and inflammation. The growth and invasion of Salmonella in vitro are not affected by human or chicken lysozyme, whereas lysozyme encountering of live Salmonella stimulates the release of barrier-disrupting factors, InvE-sipC and Lpp1, which directly or indirectly impair the tight junctions. The direct engagement of host intestinal lysozyme with an enteric pathogen such as Salmonella promotes the release of virulence factors that are barrier-impairing and pro-inflammatory. Controlling lysozyme function may help alleviate the inflammatory progression.

Vedolizumab (VDZ) is used for treating inflammatory bowel disease (IBD) patients. A study investigating colonic epithelial barrier function ex vivo following VDZ is lacking. This work aims to evaluate ex vivo the colonic epithelial barrier function in IBD patients at baseline and during VDZ treatment, and to investigate the relationships between barrier function and clinical parameters. Colonic specimens were obtained from 23 IBD patients before, and at 24 and 52 weeks after VDZ treatment, and from 26 healthy volunteers (HV). Transepithelial electrical resistance (TEER, permeability to ions) and paracellular permeability were measured in Ussing chambers. IBD patients showed increased epithelial permeability to ions (TEER, 13.80 ± 1.04 Ω × cm2 vs. HV 20.70 ± 1.52 Ω × cm2, p < 0.001) without changes in paracellular permeability of a 4 kDa probe. VDZ increased TEER (18.09 ± 1.44 Ω × cm2, p < 0.001) after 52 weeks. A clinical response was observed in 58% and 25% of patients at week 24, and in 62% and 50% at week 52, in ulcerative colitis and Crohn's disease, respectively. Clinical and endoscopic scores were strongly associated with TEER. TEER < 14.65 Ω × cm2 predicted response to VDZ (OR 11; CI 2-59). VDZ reduces the increased permeability to ions observed in the colonic epithelium of IBD patients before treatment, in parallel to a clinical, histological (inflammatory infiltrate), and endoscopic improvement. A low TEER predicts clinical response to VDZ therapy.

The aim of the study is to investigate the function and mechanism of Zinc Gluconate (ZG) on intestinal mucosal barrier damage in antibiotics and Lipopolysaccharide (LPS)-induced mice.

We established a composite mouse model by inducing intestinal mucosal barrier damage using antibiotics and LPS. The animals were divided into five groups: Control (normal and model) and experimental (low, medium, and high-dose ZG treatments). We evaluated the intestinal mucosal barrier using various methods, including monitoring body weight and fecal changes, assessing pathological damage and ultrastructure of the mouse ileum, analyzing expression levels of tight junction (TJ)-related proteins and genes, confirming the TLR4/NF-κB signaling pathway, and examining the structure of the intestinal flora.

In mice, the dual induction of antibiotics and LPS led to weight loss, fecal abnormalities, disruption of ileocecal mucosal structure, increased intestinal barrier permeability, and disorganization of the microbiota structure. ZG restored body weight, alleviated diarrheal symptoms and pathological damage, and maintained the structural integrity of intestinal epithelial cells (IECs). Additionally, ZG reduced intestinal mucosal permeability by upregulating TJ-associated proteins (ZO-1, Occludin, Claudin-1, and JAM-A) and downregulating MLCK, thereby repairing intestinal mucosal barrier damage induced by dual induction of antibiotics and LPS. Moreover, ZG suppressed the TLR4/NF-κB signaling pathway, demonstrating anti-inflammatory properties and preserving barrier integrity. Furthermore, ZG restored gut microbiota diversity and richness, evidenced by increased Shannon and Observed features indices, and decreased Simpson's index. ZG also modulated the relative abundance of beneficial human gut bacteria (Bacteroidetes, Firmicutes, Verrucomicrobia, Parabacteroides, Lactobacillus, and Akkermansia) and harmful bacteria (Proteobacteria and Enterobacter), repairing the damage induced by dual administration of antibiotics and LPS.

ZG attenuates the dual induction of antibiotics and LPS-induced intestinal barrier damage and also protects the intestinal barrier function in mice.

Allergic inflammation, which is the pathogenesis of allergic rhinitis and asthma, is associated with disruption of the airway epithelial barrier due to the effects of type 2 inflammatory cytokines, i.e. interleukin-4 and interleukin-13 (IL-4/13). The anti-allergic inflammatory effect of β-eudesmol (BE) on the tight junction (TJ) of the airway epithelium has not previously been reported. Herein, the barrier protective effect of BE was determined by measurement of transepithelial electrical resistance and by paracellular permeability assay in an IL-4/13-treated 16HBE14o- monolayer. Pre-treatment of BE concentration- and time- dependently inhibited IL-4/13-induced TJ barrier disruption, with the most significant effect observed at 20 μM. Cytotoxicity analyses showed that BE, either alone or in combination with IL-4/13, had no effect on cell viability. Western blot and immunofluorescence analyses showed that BE inhibited IL-4/13-induced mislocalization of TJ components, including occludin and zonula occludens-1 (ZO-1), without affecting the expression of these two proteins. In addition, the mechanism of the TJ-protective effect of BE was mediated by inhibition of IL-4/13-induced STAT6 phosphorylation, in which BE might serve as an antagonist of cytokine receptors. In silico molecular docking analysis demonstrated that BE potentially interacted with the site I pocket of the type 2 IL-4 receptor, likely at Asn-126 and Tyr-127 amino acid residues. It can therefore be concluded that BE is able to prevent IL-4/13-induced TJ disassembly by interfering with cytokine-receptor interaction, leading to suppression of STAT6-induced mislocalization of occludin and ZO-1. BE is a promising candidate for a therapeutic intervention for inflammatory airway epithelial disorders driven by IL-4/13.

Host molecular responses to fecal microbiota transplantation (FMT) in ulcerative colitis are not well understood. Here, we profile the human colonic mucosal transcriptome prior to and following FMT or placebo to identify molecules regulated during disease remission. FMT alters the transcriptome above the effect of placebo (n = 75 vs 3 genes, q < 0.05), including modulation of structural, metabolic and inflammatory pathways. This response is attributed to responders with no consistency observed in non-responders. Regulated pathways in responders include tight junctions, calcium signalling and xenobiotic metabolism. Genes significantly regulated longitudinally in responders post-FMT could discriminate them from responders and non-responders at baseline and non-responders post-FMT, with GBP5 and IRF4 downregulation being associated with remission. Female mice with a deletion of GBP5 are more resistant to developing colitis than their wild-type littermates, showing higher colonic IRF4 phosphorylation. The colonic mucosal response discriminates UC remission following FMT, with GBP5 playing a detrimental role in colitis.

Glycosylated mucin proteins contribute to the essential barrier function of the intestinal epithelium. The transmembrane mucin MUC13 is an abundant intestinal glycoprotein with important functions for mucosal maintenance that are not yet completely understood. We demonstrate that in human intestinal epithelial monolayers, MUC13 localized to both the apical surface and the tight junction (TJ) region on the lateral membrane. MUC13 deletion resulted in increased transepithelial resistance (TEER) and reduced translocation of small solutes. TEER buildup in ΔMUC13 cells could be prevented by addition of MLCK, ROCK or protein kinase C (PKC) inhibitors. The levels of TJ proteins including claudins and occludin were highly increased in membrane fractions of MUC13 knockout cells. Removal of the MUC13 cytoplasmic tail (CT) also altered TJ composition but did not affect TEER. The increased buildup of TJ complexes in ΔMUC13 and MUC13-ΔCT cells was dependent on PKC. The responsible PKC member might be PKCδ (or PRKCD) based on elevated protein levels in the absence of full-length MUC13. Our results demonstrate for the first time that a mucin protein can negatively regulate TJ function and stimulate intestinal barrier permeability.

At the intestinal front, several lines of defense are in place to resist infection and injury, the mucus layer, gut microbiome and strong epithelial junctions, to name a few. Their collaboration creates a resilient barrier. In intestinal disorders, such as inflammatory bowel disease (IBD), barrier function is compromised, which results in rampant inflammation and tissue injury. In response to the destruction, the intestinal epithelium releases adenosine, a small but powerful nucleoside that functions as an alarm signal. Amidst the chaos of inflammation, adenosine aims to restore order. Within the scope of its effects is the ability to regulate intestinal epithelial barrier integrity. This review aims to define the contributions of adenosine to mucus production, microbiome-dependent barrier protection, tight junction dynamics, chloride secretion and acid-base balance to reinforce its importance in the intestinal epithelial barrier.

Heme-oxidized IRP2 ubiquitin ligase-1 (HOIL1)-deficient patients experience chronic intestinal inflammation and diarrhea as well as increased susceptibility to bacterial infections. HOIL1 is a component of the linear ubiquitin chain assembly complex that regulates immune signaling pathways, including NF-κB-activating pathways. We have shown previously that HOIL1 is essential for survival following Citrobacter rodentium gastrointestinal infection of mice, but the mechanism of protection by HOIL1 was not examined. C. rodentium is an important murine model for human attaching and effacing pathogens, enteropathogenic and enterohemorrhagic Escherichia coli that cause diarrhea and foodborne illnesses and lead to severe disease in children and immunocompromised individuals. In this study, we found that C. rodentium infection resulted in severe colitis and dissemination of C. rodentium to systemic organs in HOIL1-deficient mice. HOIL1 was important in the innate immune response to limit early replication and dissemination of C. rodentium. Using bone marrow chimeras and cell type-specific knockout mice, we found that HOIL1 functioned in radiation-resistant cells and partly in radiation-sensitive cells and in myeloid cells to limit disease, but it was dispensable in intestinal epithelial cells. HOIL1 deficiency significantly impaired the expansion of group 3 innate lymphoid cells and their production of IL-22 during C. rodentium infection. Understanding the role HOIL1 plays in type 3 inflammation and in limiting the pathogenesis of attaching and effacing lesion-forming bacteria will provide further insight into the innate immune response to gastrointestinal pathogens and inflammatory disorders.

The intestinal barrier is composed of several essential elements including luminal enzymes, bile acids, water layer, epithelial layer, and enterocyte layer. It acts as a dynamic interface between the luminal contents of food, commensal and pathogenic bacteria, and the gastrointestinal tract. The role of barrier dysfunction is of significant research interest in the development and targeted treatment of chronic inflammatory gastrointestinal conditions, such as inflammatory bowel disease. This review aims to examine the role of intestinal barrier dysfunction in the development of inflammatory bowel disease, the pathophysiology of increased barrier permeability in inflammatory bowel disease, and to explore potential treatment targets and clinical applications.

Cathepsin L, a lysosomal enzyme, participates in diverse physiological processes. Recombinant Trichinella spiralis cathepsin L domains (rTsCatL2) exhibited natural cysteine protease activity and hydrolyzed host immunoglobulin and extracellular matrix proteins in vitro, but its functions in larval invasion are unknown. The aim of this study was to explore its functions in T. spiralis invasion of the host's intestinal epithelial cells.

RNAi significantly suppressed the expression of TsCatL mRNA and protein with TsCatL specific siRNA-302. T. spiralis larval invasion of Caco-2 cells was reduced by 39.87% and 38.36%, respectively, when anti-TsCatL2 serum and siRNA-302 were used. Mice challenged with siRNA-302-treated muscle larvae (ML) exhibited a substantial reduction in intestinal infective larvae, adult worm, and ML burden compared to the PBS group, with reductions of 44.37%, 47.57%, and 57.06%, respectively. The development and fecundity of the females from the mice infected with siRNA-302-treated ML was significantly inhibited. After incubation of rTsCatL2 with Caco-2 cells, immunofluorescence test showed that the rTsCatL2 gradually entered into the cells, altered the localization of cellular tight junction proteins (claudin 1, occludin and zo-1), adhesion junction protein (e-cadherin) and extracellular matrix protein (laminin), and intercellular junctions were lost. Western blot showed a 58.65% reduction in claudin 1 expression in Caco-2 cells treated with rTsCatL2. Co-IP showed that rTsCatL2 interacted with laminin and collagen I but not with claudin 1, e-cadherin, occludin and fibronectin in Caco-2 cells. Moreover, rTsCatL2 disrupted the intestinal epithelial barrier by inducing cellular autophagy.

rTsCatL2 disrupts the intestinal epithelial barrier and facilitates T. spiralis larval invasion.

Clostridioides difficile toxins TcdA and TcdB are responsible for diarrhea and colitis. Lack of functional studies in organoid models of the gut prompted us to elucidate the toxin's effects on epithelial barrier function and the molecular mechanisms for diarrhea and inflammation.

Human adult colon organoids were cultured on membrane inserts. Tight junction (TJ) proteins and actin cytoskeleton were analyzed for expression via Western blotting and via confocal laser-scanning microscopy for subcellular localization.

Polarized intestinal organoid monolayers were established from stem cell-containing colon organoids to apply toxins from the apical side and to perform functional measurements in the organoid model. The toxins caused a reduction in transepithelial electrical resistance in human colonic organoid monolayers with sublethal concentrations. Concomitantly, we detected increased paracellular permeability fluorescein and FITC-dextran-4000. Human colonic organoid monolayers exposed to the toxins exhibited redistribution of barrier-forming TJ proteins claudin-1, -4 and tricellulin, whereas channel-forming claudin-2 expression was increased. Perijunctional F-actin cytoskeleton organization was affected.

Adult stem cell-derived human colonic organoid monolayers were applicable as a colon infection model for electrophysiological measurements. The TJ changes noted can explain the epithelial barrier dysfunction and diarrhea in patients, as well as increased entry of luminal antigens triggering inflammation.

Cellular senescence is a pivotal factor contributing to aging and the pathophysiology of age-related diseases. Despite the presence of inflammation and abnormal immune system function in both inflammatory bowel diseases (IBD) and senescence, the relationship between the two remains largely unexplored. Therefore, our study aimed to investigate the intricate connection between cellular senescence, telomeres, and IBD. The review highlights the presence of senescence markers, particularly p16 and p21, in IBD patients, suggesting their potential association with disease progression and mucosal inflammation. We emphasize the critical role of macrophages in eliminating senescent cells and how disturbance in effective clearance may contribute to persistent senescence and inflammation in IBD. Additionally, we shed light on the involvement of telomeres in IBD, as their dysfunction impairs enterocyte function and disrupts colonic barrier integrity, potentially exacerbating the pathogenesis of the disease. Targeting senescence and telomere dysfunctions holds promise for the development of innovative therapeutic approaches to mitigate intestinal inflammation and alleviate symptoms in IBD patients. By unraveling the precise role of senescence in IBD, we can pave the way for the discovery of novel therapeutic interventions that effectively address the underlying mechanisms of intestinal inflammation, offering hope for improved management and treatment of IBD patients.

Achieving endoscopic remission is a key therapeutic goal in patients with ulcerative colitis (UC) that is associated with favorable long-term disease outcomes. Here, we prospectively compared the predictive value of endoscopic and/or histologic remission against ileal barrier healing for predicting long-term disease behavior in a large cohort of UC patients in clinical remission.

At baseline, UC patients in clinical remission underwent ileocolonoscopy with assessment of ileal barrier function by confocal endomicroscopy. Endoscopic and histologic disease activity and ileal barrier healing were scored using validated scores. During subsequent follow-up (FU), patients were closely monitored for clinical disease activity and occurrence of major adverse outcomes (MAO) defined as the following: disease relapse; UC-related hospitalization; UC-related surgery; necessity for initiation or dose escalation of systemic steroids, immunosuppressants, small molecules or biological therapy.

Of the 73 UC patients included, 67% experienced MAO during a mean FU of 25 months. The probability of MAO-free survival was significantly higher in UC patients with endoscopic and/or histologic remission compared to patients with endoscopically and/or histologically active disease. Ileal barrier healing on endomicroscopy was highly accurate for predicting the further course of UC and outcompeted endoscopic and histologic remission for predicting MAO-free survival.

Ileal barrier healing in clinically remittent UC patients can accurately predict future MAO development and is superior in its predictive capabilities than endoscopic and histologic remission. Ileal barrier healing therefore represents a novel and superior surrogate parameter for stratification of UC patients according to their risk for development of complicated disease behavior.

https://classic.clinicaltrials.gov/ct2/show/NCT05157750, identifier NCT05157750.