Berberine alleviates ETEC-induced intestinal inflammation and oxidative stress damage by optimizing intestinal microbial composition in a weaned piglet model.

Introduction: Enterotoxigenic Escherichia coli (ETEC) is the main diarrhea-causing pathogen in children and young animals and has become a global health concern. Berberine is a type of "medicine and food homology" and has a long history of use in China, particularly in treating gastrointestinal disorders and bacterial diarrhea. Methods: In this study, we explored the effects of berberine on growth performance, intestinal inflammation, oxidative damage, and intestinal microbiota in a weaned piglet model of ETEC infection. Twenty-four piglets were randomly divided into four groups-a control group (fed a basal diet [BD] and infused with saline), a BD+ETEC group (fed a basal diet and infused with ETEC), a LB+ETEC group (fed a basal diet with 0.05% berberine and infused with ETEC infection), and a HB+ETEC group (fed a basal diet with 0.1% berberine and infused with ETEC). Results: Berberine significantly improved the final body weight (BW), average daily gain (ADG), and average daily feed intake (ADFI) (P<0.05) of piglets, and effectively decreased the incidence of diarrhea among the animals (P<0.05). Additionally, berberine significantly downregulated the expression levels of the genes encoding TNF-α, IL-1ß, IL-6, IL-8, TLR4, MyD88, NF-κB, IKKα, and IKKß in the small intestine of piglets (P<0.05). ETEC infection significantly upregulated the expression of genes coding for Nrf2, CAT, SOD1, GPX1, GST, NQO1, HO-1, GCLC, and GCLM in the small intestine of the animals (P<0.05). Berberine significantly upregulated 12 functional COG categories and 7 KEGG signaling pathways. A correlation analysis showed that berberine significantly increased the relative abundance of beneficial bacteria (Gemmiger, Pediococcus, Levilactobacillus, Clostridium, Lactiplantibacillus, Weissella, Enterococcus, Blautia, and Butyricicoccus) and decreased that of pathogenic bacteria (Prevotella, Streptococcus, Parabacteroides, Flavonifractor, Alloprevotella) known to be closely related to intestinal inflammation and oxidative stress in piglets. In conclusion, ETEC infection disrupted the intestinal microbiota in weaned piglets, upregulating the TLR4/MyD88/NF-κB and Nrf2 signaling pathways, and consequently leading to intestinal inflammation and oxidative stress-induced damage. Discussion: Our data indicated that berberine can optimize intestinal microbiota balance and modulate the TLR4/MyD88/NF-κB and Nrf2 signaling pathways, thus helping to alleviate intestinal inflammation and oxidative damage caused by ETEC infection in weaned piglets.

Bowel Inflammation and Nutrient Supplementation: Effects of a Fixed Combination of Probiotics, Vitamins, and Herbal Extracts in an In Vitro Model of Intestinal Epithelial Barrier Dysfunction.

The gut microbiota is a very important factor in the state of health of an individual, its alteration implies a situation of "dysbiosis," which can be connected to functional gastrointestinal disorders and pathological conditions, such as Inflammatory Bowel Disease (IBD), Irritable Bowel Syndrome (IBS), Ulcerative Colitis (UC) and Crohn's Disease (CD), and Colorectal Cancer (CRC). In this work, we studied the effect of a food supplement called ENTERO-AD containing a mix of probiotics (Lactobacillus acidophilus LA1, L. reuteri LR92, Bifidobacterium breve Bbr8), Matricaria Chamomilla, and B group vitamins (B1, B2, B6) on intestinal inflammation. The in vitro model used for the study is the Caco-2 cell, a culture derived from human intestinal adenocarcinoma; the inflammatory condition was achieved with treatment with Lipopolysaccharide (LPS) and the association between Tumor necrosis factor α/Interferon γ (TNF-α/IFN-γ) [1,2]. The effect of ENTERO-AD was evaluated by cell viability, measures of Transepithelial Electrical Resistance (TEER), paracellular permeability, and immunofluorescence. Results of the study have shown that ENTERO-AD has a favorable effect on Caco-2 cells in inflammatory conditions. It improves the integrity of Occludin and Zonula Occludens-1 (ZO-1) proteins, leading to an improvement in terms of TEER values and a reduction of paracellular permeability. This evidence underlines the protective effect of ENTERO-AD and its components in intestinal inflammation.

Vitamin K2 alleviates dextran sulfate sodium-induced colitis via inflammatory responses, gut barrier integrity, and the gut microbiota in mice.

Vitamin K2 (VK2) has been shown to have potential benefits in improving intestinal integrity, but its potential and mechanisms for alleviating intestinal inflammation are still unclear. The present results showed that VK2 supplementation significantly alleviated the symptoms of colitis and maintained the intestinal barrier integrity. In addition, VK2 significantly down-regulated the mRNA expression levels of pro-inflammatory cytokines including IL-1ß, IL-6, and TNF-α, while up-regulated the mRNA expression level of anti-inflammatory cytokines such as IL-10. Moreover, VK2 significantly alleviated DSS-induced intestinal epithelial barrier dysfunction by maintaining the tight junction function. Furthermore, VK2 also regulated DSS-induced gut microbiota dysbiosis by reshaping the structure of gut microbiota, such as increasing the relative abundance of Firmicutes, Euryarchaeota, Prevotellaceae, and Prevotella and reducing the relative abundance of Proteobacteria, Rikenellaceae, Enterobacteriaceae, Acetatifactor, and Alistioes. In conclusion, these results indicated that VK2 effectively alleviates DSS-induced colitis in mice by modulating the gut microbiota.

Activation of AMPK/SIRT1/FOXO3a signaling by BMS-477118 (saxagliptin) mitigates chronic colitis in rats: uncovering new anti-inflammatory and antifibrotic roles.

Ulcerative colitis (UC) is a debilitating chronic disease marked by persistent inflammation and intestinal fibrosis. Despite the availability of various treatments, many patients fail to achieve long-term remission, underscoring a significant unmet therapeutic need. BMS-477118, a reversible inhibitor of dipeptidyl peptidase 4 (DPP4), has demonstrated anti-inflammatory properties in preclinical and clinical studies with minimal adverse effects compared to other antidiabetic agents. However, the potential benefits of BMS-477118 in chronic UC have not yet been explored. In this study, we aimed to investigate the effects of BMS-477118 in rats subjected to chronic dextran sodium sulfate (DSS) administration. Our findings indicate that BMS-477118 activates the interconnected positive feedback loop involving AMPK, SIRT1, and FOXO3a, improving histological appearance in injured rat colons. BMS-477118 also reduced fibrotic changes associated with the chronic nature of the animal model, alleviated macroscopic damage and disease severity, and improved the colon weight-to-length ratio. Additionally, BMS-477118 prevented DSS-induced weight loss and enhanced tight junction proteins. These effects, in conjunction with reduced oxidative stress and its potential anti-inflammatory, antiapoptotic, and autophagy-inducing properties, fostered prolonged survival in rats with chronic UC. To conclude, BMS-477118 has the potential to activate the AMPK/SIRT1/FOXO3a signaling pathway in inflamed colons. These results suggest that the AMPK/SIRT1/FOXO3a pathway could be a new therapeutic target for UC. Further research is mandatory to explore the therapeutic possibilities of this pathway. Additionally, continued studies on the therapeutic potential of BMS-477118 and other DPP4 inhibitors are promising for creating new treatments for various conditions, including UC in diabetic patients.

Increased Intestinal Inflammation and Permeability in Glaucoma.

Objective: Evidence suggests that dysbiosis of the gut microbiota plays a pivotal role in the development of glaucoma. This dysbiosis is commonly associated with chronic intestinal inflammation and increased intestinal permeability. However, the understanding of intestinal inflammation and permeability in glaucoma remains insufficient. This study aims to investigate the potential relationship between fecal inflammation and permeability markers and glaucoma. Methods: We recruited 114 glaucoma patients and 75 healthy controls. Levels of fecal lactoferrin (Lf) and alpha-1 antitrypsin (AAT) were quantified using enzyme linked immunosorbent assay (ELISA) to compare both biomarkers between groups and across different severity grades of glaucoma. Logistic regression analysis was used to assess the association between these fecal biomarkers and glaucoma. The severity of glaucoma was assessed based on the mean deviation (MD) in the visual field. Results: In this study, we observed elevated levels of fecal Lf and AAT in glaucoma patients. The proportion of glaucoma patients with abnormal fecal Lf levels (≥ 7.25 µg/g) was significantly higher than that of the controls (p = 0.012). A positive correlation was noted between fecal Lf and AAT (rho = 0.20, p = 0.006). After adjusting for age and sex, multivariable logistic regression analysis indicated that both fecal Lf (OR = 1.11, 95% CI: 1.01-1.21, p = 0.026) and AAT (OR = 1.01, 95% CI: 1.01-1.02, p < 0.001) positively correlated with glaucoma. These biomarkers might reflect glaucoma severity, with significant differences in fecal Lf levels observed between moderate and severe stages, but not in the early stage. Furthermore, increasing levels of fecal AAT correlated with greater severity of glaucomatous injury and a larger vertical cup-to-disc ratio (VCDR) (p < 0.05). Conclusion: This study suggests an increase in intestinal inflammation and permeability in glaucoma, further indicating the importance of the 'gut-retina axis' in the pathogenesis of the disease and potentially offering new therapeutic avenues.

Chicory supplementation improves growth performance in juvenile ostriches potentially by attenuating enteritis.

Introduction: Enteritis and dysbiosis are the major causes of high morbidity and mortality of juvenile ostriches. Chicory (CC) has been proven to have excellent antioxidant, anti-inflammatory, and antibacterial activities. However, it's unclear whether CC could improve the survival rate of juvenile ostriches by relieving enteritis and correcting dysbiosis. Materials and methods: South African ostrich hatchlings (Struthio camelus domesticus) were fed with and without a CC-supplemented diet, and the body weight gain and mortality were compared over 4 months of age. Fresh fecal samples of clinically healthy ostriches were collected, and 16S DNAs were analyzed. Moreover, ostrich chicks with LPS-induced enteritis were fed with different dosages (0, 20, 40, and 80 mg/kg) of chicoric acid (CA), a major bioactive component of CC, for five consecutive days. The expression levels of tight junction (TJ)-related proteins and inflammatory mediators in the ilea were detected with western blot and immunofluorescence. Results: The ostrich chicks fed on the CC-supplemented diet began to increase in weight at the 1st month of age and became remarkably heavier at the fourth month (p < 0.01) compared with those fed on the non-CC-supplemented diet. Additionally, the mortality percentage was lower in the chicks fed on the CC-supplemented diet than those fed on the non-CC-supplemented diet (19% vs. 36%, respectively). The diet with the CC supplementation significantly increased the abundance of Phascolactobacteria (linear discriminant analysis; LDA >4) and Bacteroidota (26.7% vs. 17.7%, respectively) as well as decreased the enrichment of Clostridium (5.0% vs. 9.1%, respectively) in the ostrich ilea compared to the diet without CC. The supplementation of CA at a dose of 80 mg/kg significantly increased the expression level of ZO-1 and claudin-3 (p < 0.0001) and suppressed the levels of IL-1ß, IL-6, and TNF-α (p < 0.0001) in ostriches with LPS-induced ileitis. Conclusion: Our results substantiate that CC or CA supplementation in a diet could effectively improve growth performance and reduce mortality in juvenile ostriches via modulating the gut microbiota and attenuating enteritis.

Neutrophil extracellular traps induce barrier dysfunction in DSS-induced ulcerative colitis via the cGAS-STING pathway.

Peptidyl arginine deiminase 4 (PAD4)-mediated neutrophil extracellular traps (NETs) play a crucial role in the pathogenesis of ulcerative colitis (UC). The cGAS-STING intracellular DNA-sensing pathway has been recognized as a pivotal mediator of inflammation. This study aimed to explore how NETs contribute to intestinal inflammation and barrier dysfunction in UC, focusing on the cGAS-STING pathway. We observed a significant increase of STING expression in UC mouse colons, which was mitigated by blocking NET formation through PAD4 genetic knockout. Moreover, NETs were discovered to activate the cGAS-STING pathway in MC38 cells in a dose and time-dependent manner, leading to the secretion of inflammatory cytokines and impaired barrier function. Additionally, STING deficiency ameliorated the clinical colitis index, intestinal inflammation, and barrier dysfunction. These findings underscore the involvement of cGAS-STING in regulating NET-mediated intestinal inflammation, suggesting its potential as a novel therapeutic target for UC.

Huaiyu pill alleviates inflammatory bowel disease in mice blocking toll like receptor 4/ myeloid differentiation primary response gene 88/ nuclear factor kappa B subunit 1 pathway.

OBJECTIVE: To investigate the therapeutic effects of Huaiyu pill (, HYP) on inflammatory bowel disease (IBD) and the underlying mechanisms have not been elucidated. METHODS: To establish the IBD model, mice were administered with dextran sulfate sodium (DSS). Mice were intragastrically pre-treated with sulfasalazine (SASP) and HYP. Disease activity index (DAI) and colon length were monitored, and the colonic tissues were subjected to hematoxylin-eosin staining. Pro-inflammatory factors and vascular inflammation-related proteins were determined using enzyme-linked immunosorbent assay (ELISA). The potential mechanisms of HYP were examined using network pharmacology analysis.The expressions of zona occludens 1 (ZO-1), occludin, toll like receptor 4 (TLR4), myeloid differentiation primary response gene 88 (MYD88), and nuclear factor kappa B p65 subunit (NF-κB p65) in colon tissues were examined using Western blotting or immunohistochemical analyses. RESULTS: Pre-treatment with HYP enhanced the colon length, decreased DAI scores, and mitigated histopathological alterations in DSS-treated mice. HYP alleviated intestinal inflammation by downregulating the levels of interleukin 1 beta (IL-1ß), interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-α) and interleukin 17 (IL-17). Additionally, HYP suppressed the disruption of the gut barrier by upregulating the ZO-1, occludin, and mucin 2 (MUC2) levels and downregulating the endothelin 1 (ET-1) and erythropoietin (EPO) levels. Network pharmacological analysis and experimental results revealed that HYP downregulated the colonic tissue levels of TLR4, MYD88, and NF-κB p65 in DSS-treated mice. CONCLUSION: This study investigated the in vivotherapeutic effects of HYP on IBD and the underlying molecular mechanisms. These findings provide an experimental foundation for the clinical application of HYP.

Selenium deficiency modulates necroptosis-mediated intestinal inflammation in broiler through the lncRNAWSF27/miRNA1696/GPX3 axis.

Deficiency of selenium (Se), an important trace element, causes diarrhea and even death in broilers, thereby affecting the economic development of poultry production. Adding Se is one way to relieve this situation; however, it has not fundamentally resolved intestinal inflammation. Therefore, we sought a new strategy to alleviate intestinal inflammation by studying the specific mechanisms of Se deficiency. By replicating the Se-deficient broiler model and establishing a chicken small intestinal epithelial cell (CSIEC) model, we determined that Se deficiency caused intestinal oxidative stress and necroptotic intestinal inflammation in broilers by decreasing glutathione peroxidase (GPX) 3 expression. Simultaneously, the expression of long non-coding RNA (lncRNA)WSF27 decreased and that of miR-1696 increased in Se-deficient intestines. Recently discovered competing endogenous RNAs (ceRNAs) form novel regulatory networks, which were found that selenoproteins involved in ceRNA regulation. However, the mechanism of action of the non-coding RNA/GPX3 axis in Se-deficient broiler intestinal inflammation remains unclear. This study aimed to explore the mechanism through which Se deficiency regulates intestinal inflammation in broilers through the lncRNAWSF27/miR-1696/GPX3 axis. Our previous studies showed that lncRNAWSF27, miR-1696, and GPX3 have ceRNA-regulatory relationships. To further determine the role of the lncRNAWSF27/miR-1696/GPX3 axis in Se-deficient broiler intestinal inflammation, CSIEC models with GPX3 knockdown/overexpression, lncRNAWSF27 knockdown, or miR-1696 knockdown/overexpression were established to simulate intestinal injury. GPX3 knockdown, as well as lncRNAWSF27 and miR-1696 overexpression, aggravated cell damage. On the contrary, it can alleviate this situation. Our results reveal that mechanism of lncRNAWSF27/miR-1696/GPX3 regulated Se-deficient broiler intestinal inflammation. This conclusion enriches our understanding of the mechanism of intestinal injury caused by Se deficiency, and contributes to the diagnosis of Se-deficient intestinal inflammation and relevant drug development.

ScRNA-seq reveals trained immunity-engaged Th17 cell activation against Edwardsiella piscicida-induced intestinal inflammation in teleost.

Mucosal immunity typically involves innate and adaptive immune cells, while the cellular mechanism of teleost's intestinal immune cells that engages gut homeostasis against bacterial infection remains largely unknown. Taking advantage of the enteric fish pathogen (Edwardsiella piscicida) infection-induced intestinal inflammation in turbot (Scophthalmus maximus), we find that ß-glucan training could mitigate the bacterial infection-induced intestinal inflammation. Through single-cell transcriptome profiling and cellular function analysis, we identify that E. piscicida infection could tune down the activation of intestinal Th17 cells, while ß-glucan-training could preserve the potential to amplify and restore the function of intestinal Th17 cells. Moreover, through pharmacological inhibitor treatment, we identify that Th17 cells are essential for ameliorating bacterial infection-induced intestinal inflammation in teleost. Taken together, these results suggest a new concept of trained immunity activation to regulate the intestinal Th17 cells' function, which might contribute to better developing strategies for maintaining gut homeostasis against bacterial infection.

Protective effects of sodium humate on the intestinal barrier damage of Salmonella Typhimurium-challenged broilers.

Salmonella Typhimurium (S. Typhimurium) infections can lead to severe intestinal damage and reduce growth performance in broilers. Thus, this study examined the potential mitigating impact of sodium humate (HNa) on intestinal barrier damage resulting from S. Typhimurium infection in broilers. A total of 320 1-day-old Arbor Acres broilers were randomly assigned into 5 treatments with 8 replicates. On d 22-24, broilers in the CON group were challenged with 1 ml of PBS, while broilers in the other groups were challenged with 1 ml of 3 × 109 CFU/ml S. Typhimurium, daily. Dietary administration with 4 g/kg of HNa increased (P < 0.05) the final body weight, jejunal secretory immunoglobulin A (sIgA), total antioxidant capacity (T-AOC), total superoxide dismutase (T-SOD), and catalase (CAT) levels as compared with the MOD group broilers. Furthermore, HNa alleviated intestinal barrier damage by increasing villus height (VH), upregulating protein expression of Occludin, Claudin-1, and zonula occludens-1 (ZO-1), inhibiting toll-like receptor 4 (TLR4)/nuclear factor kappa-B (NF-κB) signaling pathway activation, and decreasing the secretion of inflammatory cytokines (P < 0.05). Collectively, the present study showed that HNa mitigated intestinal barrier damage induced by S. Typhimurium infection in broilers.

Indole-3-Carboxaldehyde Alleviates LPS-Induced Intestinal Inflammation by Inhibiting ROS Production and NLRP3 Inflammasome Activation.

Indole-3-carboxaldehyde (IAld) is a tryptophan (Trp) metabolite derived from gut microbiota, which has a potential protective effect on intestinal inflammatory diseases. Abnormal activation of NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is an important cause of intestinal inflammation. However, the effect and mechanism of IAld on NLRP3 inflammasome activation remain unclear. Here, we found that IAld inhibited the activation of the NLRP3 inflammasome in intestinal epithelial cells, and effectively prevented intestinal epithelial barrier injury caused by lipopolysaccharide (LPS) stimulation. Mechanistically, we demonstrated that IAld activated the aryl hydrocarbon receptor (AhR), subsequently prevented reactive oxygen species (ROS) production, maintained mitochondrial membrane potential, and blocked the NF-κB/NLRP3 inflammatory pathway in intestinal epithelial cells. Also, the AhR-specific inhibitor CH-223191 effectively blocked the IAld-induced NLRP3 inhibition and intestinal epithelial barrier repairment. In addition, in vivo results showed that IAld prevented pro-inflammatory mediator production and intestinal inflammatory damage in LPS-induced mice, which is related to AhR activation and NLRP3 inflammasome inhibition. Collectively, our study unveiled that IAld is an effective endogenous antioxidant and suggested the AhR as a potential treatment target for NLRP3-induced intestinal inflammatory diseases.

Activation of GABABR Attenuates Intestinal Inflammation by Reducing Oxidative Stress through Modulating the TLR4/MyD88/NLRP3 Pathway and Gut Microbiota Abundance.

Oxidative stress emerges as a prominent factor in the onset and progression of intestinal inflammation, primarily due to its critical role in damaging cells and tissues. GABAergic signaling is important in the occurrence and development of various intestinal disorders, yet its effect on oxidative stress remains unclear. We attempted to assess whether GABAergic signaling participated in the regulation of oxidative stress during enteritis. The results showed that lipopolysaccharide (LPS) significantly decreased γ-aminobutyric acid (GABA) levels in the ileal tissues of mice. Interestingly, the application of GABA significantly repressed the shedding of intestinal mucosal epithelial cells and inflammatory cell infiltration, inhibited the expressions of proinflammatory factors, including granulocyte colony-stimulating factor and granulocyte-macrophage colony stimulating factor, and enhanced the levels of anti-inflammatory cytokines interleukin (IL)-4 and IL-10, indicating that GABA could alleviate enteritis in mice. This observation was further supported by transcriptome sequencing, revealing a total of 271 differentially expressed genes, which exhibited a marked enrichment of inflammatory and immune-related pathways, alongside a prominent enhancement of GABA B receptor (GABABR) signaling following GABA administration. Effectively, Baclofen pretreatment alleviated intestinal mucosal damage in LPS-induced mice, suppressed proinflammatory cytokines IL-1ß, IL-6, and tumor necrosis factor alpha expressions, and boosted total antioxidant capacity, superoxide dismutase (SOD), and glutathione (GSH) levels. Moreover, Baclofen notably enhanced the viability of LPS-stimulated IPEC-J2 cells, contracted the proinflammatory secretion factors, and reinforced SOD, GSH, and catalase levels, emphasizing the anti-inflammatory and antioxidant effects associated with GABABR activation. Mechanistically, Baclofen restrained the mRNA and protein levels of toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing 3 (NLRP3), and inducible nitric oxide synthase, while elevating nuclear factor erythroid 2-related factor 2 and heme oxygenase-1 in both mice and IPEC-J2 cells, indicating that activating GABABR strengthened antioxidant abilities by interrupting the TLR4/MyD88/NLRP3 pathway. Furthermore, 16S rDNA analysis demonstrated that Baclofen increased the relative abundance of probiotic, particularly Lactobacillus, renowned for its antioxidant properties, while reducing the relative richness of harmful bacteria, predominantly Enterobacteriaceae, suggesting that GABABR signaling may have contributed to reversing intestinal flora imbalances to relieve oxidative stress in LPS-induced mice. Our study identified previously unappreciated roles for GABABR signaling in constricting oxidative stress to attenuate enteritis, thus offering novel insights for the treatment of intestinal inflammation.

The Role of Iron in Intestinal Mucus: Perspectives from Both the Host and Gut Microbiota.

Although research on the role of iron in host immunity has a history spanning decades, it is only relatively recently that attention has been directed toward the biological effects of iron on the intestinal mucus layer, prompted by an evolving understanding of the role of this material in immune defence. The mucus layer, secreted by intestinal goblet cells, covers the intestinal epithelium, and given its unique location, interactions between the host and gut microbiota, as well as among constituent microbiota, occur frequently within the mucus layer. Iron, being an essential nutrient for the vast majority of life forms, regulates immune responses from both the host and microbial perspectives. In this review, we summarize the iron metabolism of both the host and gut microbiota, and describe how iron contributes to intestinal mucosal homeostasis via the intestinal mucus layer with respect to both host and constituent gut microbiota. The findings described herein offer a new perspective on iron-mediated intestinal mucosal barrier function.

Vitamin B12 ameliorates gut epithelial injury via modulating the HIF-1 pathway and gut microbiota.

Inflammatory bowel diseases (IBDs) are immune chronic diseases characterized by recurrent episodes, resulting in continuous intestinal barrier damage and intestinal microbiota dysbiosis. Safe strategies aimed at stabilizing and reducing IBDs recurrence have been vigorously pursued. Here, we constructed a recurrent intestinal injury Drosophila model and found that vitamin B12 (VB12), an essential co-factor for organism physiological functions, could effectively protect the intestine and reduce dextran sulfate sodium-induced intestinal barrier disruption. VB12 also alleviated microbial dysbiosis in the Drosophila model and inhibited the growth of gram-negative bacteria. We demonstrated that VB12 could mitigate intestinal damage by activating the hypoxia-inducible factor-1 signaling pathway in injured conditions, which was achieved by regulating the intestinal oxidation. In addition, we also validated the protective effect of VB12 in a murine acute colitis model. In summary, we offer new insights and implications for the potential supportive role of VB12 in the management of recurrent IBDs flare-ups.

Saponins alleviate intestinal inflammation and regulate intestinal metabolic disorders induced by dextran sulfate sodium: TNF-α protein action.

Intestinal inflammation is a common feature of many digestive diseases, and intestinal metabolic disorders further aggravate the pathological state. The aim of this study was to investigate the regulatory effect of saponins on TNF-α protein and its effect on intestinal metabolism in the model of intestinal inflammation induced by sodium dextran sulfate. Through cell culture and biochemical detection, appropriate cell lines were selected to simulate intestinal inflammatory environment, induce inflammatory response, observe cell morphological changes and growth status, and evaluate the protective effect of TNF-α protein on cells. The level of TNF-α protein was quantitatively determined by biochemical assay, and the effect of saponins on its secretion and activity was investigated. Saponin treatment can restore the expression of intestinal metabolism-related enzymes and improve metabolic disorders. Therefore, by regulating the expression of TNF-α protein and its signaling pathway, saponins show a alleviating effect on intestinal inflammation and help restore intestinal metabolic balance.

Biomarker relationships with small bowel histopathology among malnourished children with environmental enteric dysfunction in a multicountry cohort study.

BACKGROUND: Validated biomarkers could catalyze environmental enteric dysfunction (EED) research. OBJECTIVES: Leveraging an EED histology scoring system, this multicountry analysis examined biomarker associations with duodenal histology features among children with EED. We also examined differences in 2-h compared with 1-h urine collections in the lactulose rhamnose (LR) dual sugar test. METHODS: Three cohorts of undernourished children unresponsive to nutrition intervention underwent esophagogastroduodenoscopy and duodenal biopsies. Histopathology scores were compared to fecal calprotectin (CAL), myeloperoxidase (MPO), neopterin (NEO), and urinary LR ratio and lactulose percentage recovery. Log-transformed biomarkers were used in linear regressions adjusted for age, center, and sample collection-biopsy time interval in multivariable models. RESULTS: Data on >1 biomarker were available for 120 Bangladeshi (CAL, MPO, NEO, and LR), 63 Pakistani (MPO, NEO, and LR), and 63 Zambian children (CAL). Median age at endoscopy was similar (19 mo) across centers. Median sample collection prior to endoscopy was consistent with each center's study design: 2 wk in Bangladesh (urine and stool) and Zambia (stool), and 6 (urine) and 11 (stool) mo in Pakistan. In multivariable models, intraepithelial lymphocytes were associated with CAL (exponentiated [exp.] coefficient: 1.19; 95% confidence interval [CI]: 1, 1.41), intramucosal Brunner's glands with MPO (exp. coefficient: 1.33; 95% CI: 1.05, 1.69) and NEO (exp. coefficient: 1.37; 95% CI: 1.1, 1.7), and chronic inflammation with NEO (exp. coefficient: 1.61; 95% CI: 1.17, 2.17). Intraepithelial lymphocytes were associated with lactulose % recovery (exp. coefficient: 1.22; 95% CI: 1.05, 1.41). LR recovery was substantially lower in 1-h collections than in 2-h collections. CONCLUSIONS: Four commonly used markers of enteric dysfunction were associated with specific histologic features. One-hour urine collection may be insufficient to reflect small bowel permeability in LR testing. While acknowledging the challenges with obtaining relevant tissue, these findings form the basis for further EED biomarker validation research.

Abelmoschus manihot polysaccharide fortifies intestinal mucus barrier to alleviate intestinal inflammation by modulating Akkermansia muciniphila abundance.

The intestinal mucus barrier is an important line of defense against gut pathogens. Damage to this barrier brings bacteria into close contact with the epithelium, leading to intestinal inflammation. Therefore, its restoration is a promising strategy for alleviating intestinal inflammation. This study showed that Abelmoschus manihot polysaccharide (AMP) fortifies the intestinal mucus barrier by increasing mucus production, which plays a crucial role in the AMP-mediated amelioration of colitis. IL-10-deficient mouse models demonstrated that the effect of AMP on mucus production is dependent on IL-10. Moreover, bacterial depletion and replenishment confirmed that the effects of AMP on IL-10 secretion and mucus production were mediated by Akkermansia muciniphila. These findings suggest that plant polysaccharides fortify the intestinal mucus barrier by maintaining homeostasis in the gut microbiota. This demonstrates that targeting mucus barrier is a promising strategy for treating intestinal inflammation.

Enteric glial NLRP3 inflammasome contributes to gut mucosal barrier alterations in a mouse model of diet-induced obesity.

AIM: In the present study, we investigated the involvement of NLRP3 inflammasome in the intestinal epithelial barrier (IEB) changes associated with obesity, and its role in the interplay between enteric glia and intestinal epithelial cells (IECs). METHODS: Wild-type C57BL/6J and NLRP3-KO (-/-) mice were fed with high-fat diet (HFD) or standard diet for 8 weeks. Colonic IEB integrity and inflammasome activation were assessed. Immunolocalization of colonic mucosal GFAP- and NLRP3-positive cells along with in vitro coculture experiments with enteric glial cells (EGCs) and IECs allowed to investigate the potential link between altered IEB, enteric gliosis, and NLRP3 activation. RESULTS: HFD mice showed increased body weight, altered IEB integrity, increased GFAP-positive glial cells, and NLRP3 inflammasome hyperactivation. HFD-NLRP3-/- mice showed a lower increase in body weight, an improvement in IEB integrity and an absence of enteric gliosis. Coculture experiments showed that palmitate and lipopolysaccharide contribute to IEB damage and promote enteric gliosis with consequent hyperactivation of enteric glial NLRP3/caspase-1/IL-1ß signaling. Enteric glial-derived IL-1ß release exacerbates the IEB alterations. Such an effect was abrogated upon incubation with anakinra (IL-1ß receptor antagonist) and with conditioned medium derived from silenced-NLRP3 glial cells. CONCLUSION: HFD intake elicits mucosal enteric gliotic processes characterized by a hyperactivation of NLRP3/caspase-1/IL-1ß signaling pathway, that contributes to further exacerbate the disruption of intestinal mucosal barrier integrity. However, we cannot rule out the contribution of NLRP3 inflammasome activation from other cells, such as immune cells, in IEB alterations associated with obesity. Overall, our results suggest that enteric glial NLRP3 inflammasome might represent an interesting molecular target for the development of novel pharmacological approaches aimed at managing the enteric inflammation and intestinal mucosal dysfunctions associated with obesity.

The role of autophagy in RIP1 mediated cell death and intestinal inflammation.

Autophagy, a highly conserved catabolic process that targets various types of cellular cargoes to lysosomal degradation, is one of the most important biological mechanisms critical for cellular homeostasis. Components of these cellular cargoes can range from individual proteins to invading pathogens, and degrading these materials is important for maintaining organismal health and survival. The process of autophagy is carried out by complex molecular mechanisms, and a growing body of evidence indicates that these mechanisms intersect with those involved in the cell death pathways. In this review, we examine several emerging studies elucidating the role of autophagy in RIP1-mediated cell death signaling, with particular emphasis on impaired autophagy caused by ATG16L1 deficiency. We also discuss how autophagy in RIP1-mediated cell death affects intestinal homeostasis in preclinical models, and the implications of the intersection between RIP1 and autophagy for understanding the intestinal pathologies associated with inflammatory bowel disease (IBD). Finally, we highlight the potential benefits of therapeutic targeting of RIP1 and autophagy proteins, while also proposing areas of research that will likely elucidate new links between autophagy and cell death signaling.