Ameliorative Effects of Larazotide Acetate on Intestinal Permeability and Bacterial Translocation in Acute Pancreatitis Model in Rats.

BACKGROUND: Intestinal barrier dysfunction in acute pancreatitis (AP) may progress to systemic inflammatory response syndrome (SIRS) and multi-organ failures by causing bacterial translocation. Larazotide acetate (LA) is a molecule that acts as a tight junction (TJ) regulator by blocking zonulin (Zo) receptors in the intestine. AIMS: In our study, we aimed to investigate the effects of LA on intestinal barrier dysfunction and bacterial translocation in the AP model in rats. METHODS: Thirty-two male Sprague-Dawley rats were divided into 4 groups; control, larazotide (LAR), AP, and AP + LAR. The AP model was created by administering 250 mg/100 g bm L-Arginine intraperitoneally 2 times with an hour interval. AP + LAR group received prophylactic 0.01 mg/mL LA orally for 7 days before the first dose of L-Arginine. For intestinal permeability analysis, fluorescein isothiocyanate-dextran (FITC-Dextran) was applied to rats by gavage. The positivity of any of the liver, small intestine mesentery, and spleen cultures were defined as bacterial translocation. Histopathologically damage and zonulin immunoreactivity in the intestine were investigated. RESULTS: Compared to the control group, the intestinal damage scores, anti-Zo-1 immunoreactivity H-Score, serum FITC-Dextran levels and bacterial translocation frequency (100% versus 0%) in the AP group were significantly higher (all p < 0.01). Intestinal damage scores, anti-Zo-1 immunoreactivity H-score, serum FITC-Dextran levels, and bacterial translocation frequency (50% versus 100%) were significantly lower in the AP + LAR group compared to the AP group (all p < 0.01). CONCLUSIONS: Our findings show that LA reduces the increased intestinal permeability and intestinal damage by its effect on Zo in the AP model in rats, and decreases the frequency of bacterial translocation as a result of these positive effects.

Magnesium hydride attenuates intestinal barrier injury during hemorrhage shock by regulating neutrophil extracellular trap formation via the ROS/MAPK/PAD4 pathway.

Magnesium hydride (MgH2) is a hydrogen storage material that is known for its high capacity and safety and is capable of releasing hydrogen in a controlled manner when administered orally. This release of hydrogen has been associated with a range of biological effects, including anti-inflammatory properties, antioxidant activity, and protection of the intestinal barrier. Previous research has shown that neutrophil extracellular traps (NETs) play a role in the dysfunction of the intestinal barrier in conditions such as sepsis and critical illnesses. However, it remains unclear as to whether MgH2 can protect the intestinal barrier by inhibiting NET formation, and the underlying mechanisms have yet to be elucidated. A rat model of hemorrhagic shock was created, and pretreatment or posttreatment procedures with MgH2 were performed. After 24 h, samples from the small intestine and blood were collected for analysis. In vitro, human neutrophils were incubated with either phorbol-12-myristate-13-acetate (PMA) or MgH2. Reactive oxygen species generation and the expression of key proteins were assessed. The results demonstrated that MgH2 administration led to a decrease in inflammatory cytokines in the serum and mitigated distant organ dysfunction in rats with HS. Furthermore, MgH2 treatment reversed histopathological damage in the intestines, improved intestinal permeability, and enhanced the expression of tight junction proteins (TJPs) during HS. Additionally, MgH2 treatment was found to suppress NET formation in the intestines. In vitro pretreatment with MgH2 alleviated intestinal monolayer barrier disruption that was induced by NETs. Mechanistically, MgH2 pretreatment reduced ROS production and NET formation, inhibited the activation of ERK and p38, and suppressed the expression of the PAD4 protein. These findings indicated that MgH2 may inhibit NET formation in a ROS/MAPK/PAD4-dependent manner, which reduces NET-related intestinal barrier damage, thus offering a novel protective role in preventing intestinal barrier dysfunction during HS.

Sleep Deprivation Impairs Intestinal Mucosal Barrier by Activating Endoplasmic Reticulum Stress in Goblet Cells.

Sleep deficiency is associated with intestinal inflammatory conditions and is increasingly recognized as a public health concern worldwide. However, the effects of sleep deficiency on intestinal goblet cells (GCs), which play a major role in intestinal barrier formation, remain elusive. Herein, the effects of sleep deprivation on intestinal GCs were determined using a sleep-deprivation mouse model. Sleep deprivation impaired the intestinal mucosal barrier and decreased the expression of tight junction proteins. According to single-cell RNA sequencing and histologic assessments, sleep deprivation significantly reduced GC numbers and mucin protein levels in intestinal tissues. Furthermore, sleep deprivation initiated endoplasmic reticulum stress by activating transcription factor 6 and binding Ig protein. Treatment with melatonin, an endoplasmic reticulum stress regulator, significantly alleviated endoplasmic reticulum stress responses in intestinal GCs. In addition, melatonin increased the villus length, reduced the crypt depth, and restored intestinal barrier function in mice with sleep deprivation. Overall, the findings revealed that sleep deprivation could impair intestinal mucosal barrier integrity and GC function. Targeting endoplasmic reticulum stress could represent an ideal strategy for treating sleep deficiency-induced gastrointestinal disorders.

Wheat peptides inhibit the activation of MAPK and NF-κB inflammatory pathways and maintain epithelial barrier integrity in NSAID-induced intestinal epithelial injury.

The use of non-steroidal anti-inflammatory drugs (NSAIDs) has negative effects on the gastrointestinal tract, but the proton pump inhibitors currently in use only protect against gastrointestinal disease and may even make NSAID-induced enteropathy worse. Therefore, new approaches to treating enteropathy are required. This study aimed to investigate the protective effect of wheat peptides (WPs) against NSAID-induced intestinal damage in mice and their mechanism. Here, an in vivo mouse model was built to investigate the protective and reparative effects of different concentrations of WPs on NSAID-induced intestinal injury. WPs ameliorated NSAID-induced weight loss and small intestinal tissue damage in mice. WP treatment inhibited NSAID-induced injury leading to increased levels of oxidative stress and expression levels of inflammatory factors. WPs protected and repaired the integrity and permeability injury of the intestinal tight junction induced by NSAIDs. An in vitro Caco-2 cell model was built with lipopolysaccharide (LPS). WP pretreatment inhibited LPS-induced changes in the Caco-2 cell permeability and elevated the levels of oxidative stress. WPs inhibited LPS-induced phosphorylation of NF-κB p65 and mitogen-activated protein kinase (MAPK) signaling pathways and reduced the expression of inflammatory factors. In addition, WPs increased tight junction protein expression, which contributed to improved intestinal epithelial dysfunction. Our results suggest that WPs can ameliorate NSAID-induced impairment of intestinal barrier functional integrity by improving intestinal oxidative stress levels and reducing inflammatory factor expression through inhibition of NF-κB p65 and MAPK signaling pathway activation. WPs can therefore be used as potential dietary supplements to reduce NSAID-induced injury of the intestine.

Protective Effect and Mechanism of Aspirin Eugenol Ester on Lipopolysaccharide-Induced Intestinal Barrier Injury.

Intestinal inflammation is a complex and recurrent inflammatory disease. Pharmacological and pharmacodynamic experiments showed that aspirin eugenol ester (AEE) has good anti-inflammatory, antipyretic, and analgesic effects. However, the role of AEE in regulating intestinal inflammation has not been explored. This study aimed to investigate whether AEE could have a protective effect on LPS-induced intestinal inflammation and thus help to alleviate the damage to the intestinal barrier. This was assessed with an inflammation model in Caco-2 cells and in rats induced with LPS. The expression of inflammatory mediators, intestinal epithelial barrier-related proteins, and redox-related signals was analyzed using an enzyme-linked immunosorbent assay (ELISA), Western blotting, immunofluorescence staining, and RT-qPCR. Intestinal damage was assessed by histopathological examination. Changes in rat gut microbiota and their functions were detected by the gut microbial metagenome. AEE significantly reduced LPS-induced pro-inflammatory cytokine levels (p < 0.05) and oxidative stress levels in Caco-2 cells and rats. Compared with the LPS group, AEE could increase the relative expression of Occludin, Claudin-1, and zonula occludens-1 (ZO-1) and decrease the relative expression of kappa-B (NF-κB) and matrix metalloproteinase-9. AEE could significantly improve weight loss, diarrhea, reduced intestinal muscle thickness, and intestinal villi damage in rats. Metagenome results showed that AEE could regulate the homeostasis of the gut flora and alter the relative abundance of Firmicutes and Bacteroidetes. Flora enrichment analysis indicated that the regulation of gut flora with AEE may be related to the regulation of glucose metabolism and energy metabolism. AEE could have positive effects on intestinal inflammation-related diseases.

Fenofibrate reduces glucose-induced barrier dysfunction in feline enteroids.

Diabetes mellitus (DM) is a common chronic metabolic disease in humans and household cats that is characterized by persistent hyperglycemia. DM is associated with dysfunction of the intestinal barrier. This barrier is comprised of an epithelial monolayer that contains a network of tight junctions that adjoin cells and regulate paracellular movement of water and solutes. The mechanisms driving DM-associated barrier dysfunction are multifaceted, and the direct effects of hyperglycemia on the epithelium are poorly understood. Preliminary data suggest that fenofibrate, An FDA-approved peroxisome proliferator-activated receptor-alpha (PPARα) agonist drug attenuates intestinal barrier dysfunction in dogs with experimentally-induced DM. We investigated the effects of hyperglycemia-like conditions and fenofibrate treatment on epithelial barrier function using feline intestinal organoids. We hypothesized that glucose treatment directly increases barrier permeability and alters tight junction morphology, and that fenofibrate administration can ameliorate these deleterious effects. We show that hyperglycemia-like conditions directly increase intestinal epithelial permeability, which is mitigated by fenofibrate. Moreover, increased permeability is caused by disruption of tight junctions, as evident by increased junctional tortuosity. Finally, we found that increased junctional tortuosity and barrier permeability in hyperglycemic conditions were associated with increased protein kinase C-α (PKCα) activity, and that fenofibrate treatment restored PKCα activity to baseline levels. We conclude that hyperglycemia directly induces barrier dysfunction by disrupting tight junction structure, a process that is mitigated by fenofibrate. We further propose that counteracting modulation of PKCα activation by increased intracellular glucose levels and fenofibrate is a key candidate regulatory pathway of tight junction structure and epithelial permeability.

DNase I targeted degradation of neutrophil extracellular traps to reduce the damage on IgAV rat.

BACKGROUND: In the past two years, studies have found a significant increase in neutrophil extracellular traps (NETs) in patients with IgA vasculitis (IgAV), which is correlated with the severity of the disease. NETs have been reported as an intervention target in inflammatory and autoimmune diseases. This study aimed to investigate the effect of targeted degradation of NETs using DNase I in IgAV rat model. METHODS: Twenty-four Sprague-Dawley rats were randomly divided into three groups: the IgAV model group, the DNase I intervention group and the normal control group, with an average of 8 rats in each group. The model group was established by using Indian ink, ovalbumin, and Freund's complete adjuvant. In the intervention group, DNase I was injected through tail vein 3 days before the end of established model. The circulating cell free-DNA (cf-DNA) and myeloperoxidase-DNA (MPO-DNA) were analyzed. The presence of NETs in the kidney, gastric antrum and descending duodenum were detected using multiple fluorescences immunohistochemistry and Western blots. Morphological changes of the tissues were observed. RESULTS: After the intervention of DNase I, there was a significant reduction in cf-DNA and MPO-DNA levels in the intervention group compared to the IgAV model group (all P<0.001). The presence of NETs in renal, gastric, and duodenal tissues of the intervention group exhibited a significant decrease compared to the IgAV model group (P < 0.01). Moreover, the intervention group demonstrated significantly lower levels of renal MPO and citrullinated histone H3 (citH3) protein expression when compared to the IgAV model group (all P < 0.05). The HE staining results of intervention group demonstrated a significant reduction in congestion within glomerular and interstitial capillaries. Moreover, there was a notable improvement in gastric and intestinal mucosa necrosis, congestion and bleeding. Additionally, there was a substantial decrease in inflammatory cells infiltration. CONCLUSION: The degradation of NETs can be targeted by DNase I to mitigate tissue damage in IgAV rat models. Targeted regulation of NETs holds potential as a therapeutic approach for IgAV.

Treatment with S-adenosylmethionine ameliorates irinotecan-induced intestinal barrier dysfunction and intestinal microbial disorder in mice.

This study aimed to investigate the protective effects of S-adenosylmethionine (SAM) on irinotecan-induced intestinal barrier dysfunction and microbial ecological dysregulation in both mice and human colon cell line Caco-2, which is widely used for studying intestinal epithelial barrier function. Specifically, this study utilized Caco-2 monolayers incubated with 7-ethyl-10-hydroxycamptothecin (SN-38) as well as an irinotecan-induced diarrhea model in mice. Our study found that SAM pretreatment significantly reduced body weight loss and diarrhea induced by irinotecan in mice. Furthermore, SAM inhibited the increase of intestinal permeability in irinotecan-treated mice and ameliorated the decrease of Zonula occludens-1(ZO-1), Occludin, and Claudin-1 expression. Additionally, irinotecan treatment increased the relative abundance of Proteobacteria compared to the control group, an effect that was reversed by SAM administration. In Caco-2 monolayers, SAM reduced the expression of reactive oxygen species (ROS) and ameliorated the decrease in transepithelial electrical resistance (TER) and increase in fluorescein isothiocyanate-dextran 4000 Da (FD-4) flux caused by SN-38. Moreover, SAM attenuated changes in the localization and distribution of ZO-1and Occludin in Caco-2 monolayers induced by SN-38 and protected barrier function by inhibiting activation of the p38 MAPK/p65 NF-κB/MLCK/MLC signaling pathway. These findings provide preliminary evidence for the potential use of SAM in treating diarrhea caused by irinotecan.

X-ray radiation-induced intestinal barrier dysfunction in human epithelial Caco-2 cell monolayers.

Radiation therapy and unwanted radiological or nuclear exposure, such as nuclear plant accidents, terrorist attacks, and military conflicts, pose serious health issues to humans. Dysfunction of the intestinal epithelial barrier and the leakage of luminal antigens and bacteria across the barrier have been linked to various human diseases. Intestinal permeability is regulated by intercellular structures, termed tight junctions (TJs), which are disrupted after radiation exposure. In this study, we investigated radiation-induced alterations in TJ-related proteins in an intestinal epithelial cell model. Caco-2 cells were irradiated with 2, 5, and 10 Gy and harvested 1 and 24 h after X-ray exposure. The trypan blue assay revealed that cell viability was reduced in a dose-dependent manner 24 h after X-ray exposure compared to that of non-irradiated cells. However, the WST-8 assay revealed that cell proliferation was significantly reduced only 24 h after radiation exposure to 10 Gy compared to that of non-irradiated cells. In addition, a decreased growth rate and increased doubling time were observed in cells irradiated with X-rays. Intestinal permeability was significantly increased, and transepithelial electrical resistance values were remarkably reduced in Caco-2 cell monolayers irradiated with X-rays compared to non-irradiated cells. X-ray irradiation significantly decreased the mRNA and protein levels of ZO-1, occludin, claudin-3, and claudin-4, with ZO-1 and claudin-3 protein levels decreasing in a dose-dependent manner. Overall, the present study reveals that exposure to X-ray induces dysfunction of the human epithelial intestinal barrier and integrity via the downregulation of TJ-related genes, which may be a key factor contributing to intestinal barrier damage and increased intestinal permeability.

Helminths' therapeutic potential to treat intestinal barrier dysfunction.

The intestinal barrier is a dynamic multi-layered structure which can adapt to environmental changes within the intestinal lumen. It has the complex task of allowing nutrient absorption while limiting entry of harmful microbes and microbial antigens present in the intestinal lumen. Excessive entry of microbial antigens via microbial translocation due to 'intestinal barrier dysfunction' is hypothesised to contribute to the increasing incidence of allergic, autoimmune and metabolic diseases, a concept referred to as the 'epithelial barrier theory'. Helminths reside in the intestinal tract are in intimate contact with the mucosal surfaces and induce a range of local immunological changes which affect the layers of the intestinal barrier. Helminths are proposed to prevent, or even treat, many of the diseases implicated in the epithelial barrier theory. This review will focus on the effect of helminths on intestinal barrier function and explore whether this could explain the proposed health benefits delivered by helminths.

Fecal microbiota transplantation from sodium alginate-dosed mice and normal mice mitigates intestinal barrier injury and gut dysbiosis induced by antibiotics and cyclophosphamide.

This study investigated the protective properties of fecal microbiota derived from mice treated with sodium alginate (SA) and normal mice with both types immunosuppressed by exposure to antibiotics and cyclophosphamide. A dietary intervention using SA obviously increased the diversity and improved the composition of gut microbiota in normal mice. Fecal microbiota transfer (FMT) from both mice treated with sodium alginate and normal mice alleviated spleen tissue damage and improved immune function. FMT alleviated intestinal mucosal injury and reduced intestinal permeability via increasing mucin and tight junction protein expression. In addition, FMT reduced gut inflammation via down-regulating the expression of toll-like receptor 4 protein. Furthermore, FMT treatment improved the disordered gut microbiota via increasing the abundance of Lactobacillus and Lachnospiraceae NK4A136 group whilst decreasing the abundance of Bacteroides. PICRUSt2 function prediction analysis showed that, compared with the model group, FMT treatment significantly down-regulated lipopolysaccharide biosynthesis and the mitogen-activated protein kinase signaling pathway-fly. Collectively, we found that SA can regulate the gut microbiota structure of normal mice and confirms the effectiveness of FMT in alleviating intestinal barrier damage and gut dysbiosis in antibiotic-cyclophosphamide-induced immunosuppressed mice. This work also reveals that SA can potentially alleviate the immunosuppression caused by cyclophosphamide in mice by modulating the intestinal microbiota and exploiting their functional properties.

Biogenic selenium nanoparticles alleviate intestinal epithelial barrier injury by regulating mitochondria-lysosome crosstalk.

The intestinal epithelial barrier plays a fundamental role in human and animal health. Mitochondrial dysfunction can lead to intestinal epithelial barrier damage. The interaction between mitochondria and lysosomes has been proved to regulate each other's dynamics. Our previous studies have demonstrated that biogenic selenium nanoparticles (SeNPs) can alleviate intestinal epithelial barrier injury through regulating mitochondrial autophagy. In this study, we hypothesize that the protective effects of SeNPs against intestinal epithelial barrier dysfunction are associated with mitochondrial-lysosomal crosstalk. The results showed that lipopolysaccharide (LPS) and TBC1D15 siRNA transfection both caused the increase of intestinal epithelial permeability, activation of mitophagy, and mitochondrial and lysosomal dysfunction in porcine jejunal epithelial cells (IPEC-J2). SeNP pretreatment significantly up-regulated the expression levels of TBC1D15 and Fis1, down-regulated Rab7, caspase-3, MCOLN2 and cathepsin B expression levels, reduced cytoplasmic Ca2+ concentration, effectively alleviated mitochondrial and lysosomal dysfunction, and maintained the integrity of the intestinal epithelial barrier in IPEC-J2 cells exposed to LPS. Furthermore, SeNPs obviously reduced cytoplasmic Ca2+ concentration and activated the TBC1D15/Fis/Rab7-mediated signaling pathway, shortened the contact time between mitochondria and lysosomes, inhibited mitophagy, maintained mitochondrial and lysosomal homeostasis, and effectively attenuated intestinal epithelial barrier injury in IPEC-J2 cells transfected with TBC1D15 siRNA. These results indicated that the protective effect of SeNPs on intestinal epithelial barrier injury is closely associated with the TBC1D15/Rab7-mediated mitochondria-lysosome crosstalk signaling pathway.

Hesperetin attenuates sepsis-induced intestinal barrier injury by regulating neutrophil extracellular trap formation via the ROS/autophagy signaling pathway.

Background: Hesperetin (HES), one of the major flavonoids that has various biological activities, such as anti-inflammatory and antioxidant activities, may preserve the intestinal barrier during sepsis. However, the detailed mechanism remains unclear. Our previous studies confirmed that neutrophil extracellular traps (NETs) may jeopardize the intestinal barrier via a reactive oxygen species (ROS)-dependent pathway during sepsis. Therefore, we hypothesized that HES may inhibit NET formation and protect the intestinal barrier function during sepsis. Methods: Mice were pretreated with HES (50 mg kg-1) intraperitoneally for one week, and sepsis models were then induced using lipopolysaccharides (LPS) (10 mg kg-1). The mice were randomly divided into three groups: (1) sham group; (2) LPS group; and (3) HES + LPS group. Twenty-four hours after LPS injection, the serum and terminal ileum specimens were collected for subsequent studies. To detect ROS production and NET formation in vitro, human neutrophils were collected and incubated with phorbol-12-myristate-13-acetate (PMA) and various concentrations of HES. The level of autophagy was measured by an immunofluorescence assay and western blot analysis. TUNEL staining was utilized to analyze cell apoptosis. Results: The outcomes demonstrated that HES decreased inflammatory cytokine and myeloperoxidase (MPO) levels in serum and attenuated distant organ dysfunction in LPS-induced septic mice. Meanwhile, HES treatment reversed intestinal histopathological damage in septic mice, improving intestinal permeability and enhancing tight junction expression. Moreover, we found that neutrophil infiltration and NET formation in the intestine were suppressed during sepsis after HES pretreatment. In vitro, HES treatment reduced PMA-induced ROS production and NET formation, which were reversed by hydrogen peroxide (H2O2) administration. Notably, HES also inhibited NET formation by reducing the microtubule-associated protein light chain 3 (LC3)-II/LC3-I ratio (an indicator of autophagy) in PMA-induced neutrophils, which was reversed by rapamycin. Moreover, when autophagy was suppressed by chloroquine or induced by rapamycin, apoptosis in cells will be switched with autophagy. Conclusion: Taken together, these findings suggest that HES may inhibit NET formation in a ROS/autophagy-dependent manner and switch neutrophil death from NETosis to apoptosis, which reduced NETs-related intestinal barrier damage, providing a novel protective role in intestinal barrier dysfunction during sepsis.

Lutein Prevents Liver Injury and Intestinal Barrier Dysfunction in Rats Subjected to Chronic Alcohol Intake.

Chronic alcohol intake can affect both liver and intestinal barrier function. The goal of this investigation was to evaluate the function and mechanism of lutein administration on the chronic ethanol-induced liver and intestinal barrier damage in rats. During the 14-week experimental cycle, seventy rats were randomly divided into seven groups, with 10 rats in each group: a normal control group (Co), a control group of lutein interventions (24 mg/kg/day), an ethanol model group (Et, 8-12 mL/kg/day of 56% (v/v) ethanol), three intervention groups with lutein (12, 24 and 48 mg/kg/day) and a positive control group (DG). The results showed that liver index, ALT, AST and TG levels were increased, and SOD and GSH-Px levels were reduced in the Et group. Furthermore, alcohol intake over a long time increased the level of pro-inflammatory cytokines TNF-α and IL-1ß, disrupted the intestinal barrier, and stimulated the release of LPS, causing further liver injury. In contrast, lutein interventions prevented alcohol-induced alterations in liver tissue, oxidative stress and inflammation. In addition, the protein expression of Claudin-1 and Occludin in ileal tissues was upregulated by lutein intervention. In conclusion, lutein can improve chronic alcoholic liver injury and intestinal barrier dysfunction in rats.

Inflammation of Mesenteric Adipose Tissue Correlates with Intestinal Injury and Disease Severity in Rats with Severe Acute Pancreatitis.

BACKGROUND: Visceral adipose tissue (VAT) is related to SAP prognosis. As a depot of VAT, mesenteric adipose tissue (MAT) resides between pancreas and gut, which might affect SAP and the secondary intestinal injury. AIMS: To investigate the changes of MAT in SAP. METHODS: 24 SD rats were randomly divided into four groups. 18 rats in SAP group were euthanized in time gradients (6 h, 24 h, and 48 h after modeling) and the others in control group. Blood samples and tissues of pancreas, gut, and MAT were taken for analysis. RESULTS: Compared to the control group, SAP rats appeared MAT inflammation, presenting higher mRNA expression of TNF-α and IL-6 and lower IL-10, and histological changes after 6 h of modeling, which became worse over time. Flow cytometry showed that B lymphocytes increased in MAT after 24 h of SAP modeling and lasted up to 48 h, earlier than the changes of T lymphocytes and macrophages. The intestinal barrier integrity was damaged after 6 h of modeling, presenting lower mRNA and protein expression of ZO-1 and occludin, higher serum levels of LPS and DAO, with pathological changes, which gradually aggravated after 24 h and 48 h. SAP rats had higher serum levels of inflammatory indicators and revealed histological inflammation of pancreas, the severity of which increased with the passage of modeling time. CONCLUSION: MAT appeared inflammation in early-stage SAP, and became worse over time, with the same trend as the intestinal barrier injury and the severity of pancreatitis. B lymphocytes infiltrated early in MAT, which might promote the MAT inflammation.

Berberine-Based Carbon Quantum Dots Improve Intestinal Barrier Injury and Alleviate Oxidative Stress in C57BL/6 Mice with 5-Fluorouracil-Induced Intestinal Mucositis by Enhancing Gut-Derived Short-Chain Fatty Acids Contents.

This study aims to evaluate the effect of berberine-based carbon quantum dots (Ber-CDs) on improving 5-fluorouracil (5-FU)-induced intestinal mucositis in C57BL/6 mice, and explored the mechanisms behind this effect. Thirty-two C57BL/6 mice were divided into four groups: normal control (NC), 5-FU-induced intestinal mucositis model (5-FU), 5-FU + Ber-CDs intervention (Ber-CDs), and 5-FU + native berberine intervention (Con-CDs). The Ber-CDs improved body weight loss in 5-FU-induced mice with intestinal mucositis compared to the 5-FU group. The expressions of IL-1ß and NLRP3 in spleen and serum in Ber-CDs and Con-Ber groups were significantly lower than those in the 5-FU group, and the decrease was more significant in the Ber-CDs group. The expressions of IgA and IL-10 in the Ber-CDs and Con-Ber groups were higher than those in the 5-FU group, but the up-regulation was more significant in the Ber-CDs group. Compared with the 5-FU group, the relative contents of Bifidobacterium, Lactobacillus and the three main SCFAs in the colon contents were significantly increased the Ber-CDs and Con-Ber groups. Compared with the Con-Ber group, the concentrations of the three main short-chain fatty acids in the Ber-CDs group were significantly increased. The expressions of Occludin and ZO-1 in intestinal mucosa in the Ber-CDs and Con-Ber groups were higher than those in the 5-FU group, and the expressions of Occludin and ZO-1 in the Ber-CDs group were more higher than that in the Con-Ber group. In addition, compared with the 5-FU group, the damage of intestinal mucosa tissue in the Ber-CDs and Con-Ber groups were recovered. In conclusion, berberine can attenuate intestinal barrier injury and oxidative stress in mice to mitigate 5-fluorouracil-induced intestinal mucositis, moreover, the above effects of Ber-CDs were more significant than those of native berberine. These results suggest that Ber-CDs may be a highly effective substitute for natural berberine.

ATG16L1 protects from interferon-γ-induced cell death in the small intestinal crypt.

The breakdown of the intestinal mucosal barrier is thought to underlie the progression to Crohn disease (CD), whereby numerous risk factors contribute. For example, a genetic polymorphism of the autophagy gene ATG16L1, associated with an increased risk of developing CD, contributes to the perturbation of the intestinal epithelium. We examined the role of Atg16l1 in protecting the murine small intestinal epithelium from T-cell-mediated damage using the anti-CD3 model of enteropathy. Our work showed that mice specifically deleted for Atg16l1 in intestinal epithelial cells (IECs) (Atg16l1ΔIEC) had exacerbated intestinal damage, characterized by crypt epithelial cell death, heightened inflammation, and decreased survival. Moreover, Atg16l1 deficiency delayed the recovery of the intestinal epithelium, and Atg16l1-deficient IECs were impaired in their proliferative response. Pathology was largely driven by interferon (IFN)-γ signaling in Atg16l1ΔIEC mice. Mechanistically, although survival was rescued by blocking tumor necrosis factor or IFN-γ independently, only anti-IFN-γ treatment abrogated IEC death in Atg16l1ΔIEC mice, thereby decoupling IEC death and survival. In summary, our findings suggest differential roles for IFN-γ and tumor necrosis factor in acute enteropathy and IEC death in the context of autophagy deficiency and suggest that IFN-γ-targeted therapy may be appropriate for patients with CD with variants in ATG16L1.

Baicalein alleviates non-alcoholic fatty liver disease in mice by ameliorating intestinal barrier dysfunction.

Non-alcoholic fatty liver disease (NAFLD) is the main cause of chronic liver disease, and its pathological development is closely related to the gut-liver axis. The intestinal barrier, an important component of the gut-liver axis, can prevent gut microbes and endotoxins from entering the liver. Intestinal barrier function is impaired in patients with NAFLD. Baicalein, which is the main flavonoid in Scutellariae Radix, can improve NAFLD. However, whether baicalein alleviates NAFLD by ameliorating intestinal barrier dysfunction remains unclear. In this study, a methionine-choline deficient (MCD) diet-induced NAFLD mouse model is used. The effects of baicalein on lipid accumulation, inflammation and the intestinal barrier in MCD-fed mice were evaluated by detecting blood lipid levels, lipid accumulation, liver pathological changes, inflammatory factors, inflammatory signaling pathways, the three main short-chain fatty acids (acetate, propionate and butyrate), intestinal permeability and intestinal tight junction protein expression. Compared with the MCD-only group, baicalein intake decreased the serum and liver lipid levels. Moreover, the accumulation of lipid droplets and steatosis in the liver were also alleviated; all these results demonstrated that baicalein could alleviate NAFLD. Meanwhile, the levels of inflammatory cytokines decreased in the baicalein group. Further investigation of the mucosal permeability to 4 kDa fluorescein isothiocyanate-dextran, concentrations of short-chain fatty acids in feces, and the expression of intestinal zonula occluden 1 and claudin-1 indicated that a baicalein diet could decrease the intestinal permeability caused by a MCD diet. Moreover, the protein levels of p-NF-κB p65 and the ratio of p-NF-κB p65/NF-κB p65 increased, and IκB-α and PPARα decreased in NAFLD mice, while the administration of baicalein could alleviate these changes. The above results indicated that the mechanism of baicalein in the alleviation of NAFLD lies in the regulation of the intestinal barrier.

Red raspberry supplementation mitigates alcohol-induced liver injury associated with gut microbiota alteration and intestinal barrier dysfunction in mice.

Alcoholic liver disease (ALD) is still a global health concern. Long-term alcohol intake alters the gut microbiota diversity and metabolic activity, and causes intestinal barrier dysfunction, leading to the development of ALD. This research explored the protective effects and underlying mechanisms of red raspberry (RR) on alcohol-related disorders in mice. Male C57BL/6J mice were fed a standard diet or a standard diet supplemented with 2%, 4%, and 8% weight/weight RR. Meanwhile, mice were administered 35% (v/v) ethanol (EtOH, 10 mL per kg body weight) intragastrically once daily for six weeks, except the control group mice. The results showed that RR supplementation decreased liver injury markers (alanine and aspartate transaminases) in the serum, reduced triglyceride level in the liver and downregulated hepatic cytochrome P450 2E1 mRNA expression in mice administered EtOH. In addition, EtOH-mediated oxidative stress in the liver was attenuated by RR supplementation through decreased hepatic malondialdehyde content and increased antioxidant (glutathione, glutathione peroxidase, and catalase) levels and activities in mice exposed to EtOH. Moreover, RR supplementation reversed EtOH-induced alteration in the cecal microbial composition at the phylum, order, genus, and species levels and improved the intestinal barrier function associated with the inhibition of the NF-κB/MLCK pathway, which was accompanied by upregulation of tight junctions (zonula occludens 1, occludin, claudin-1, and claudin-4) and E-cadherin mRNA and protein expressions. Accordingly, RR supplementation resulted in a decreased level of endotoxins in the serum and attenuation of the inflammatory response in the liver, illustrated by a significant decrease in tumor necrosis factor-alpha, interleukin (IL)-1ß, and IL-6 levels. Overall, RR supplementation alleviated the adverse effects of chronic alcohol intake in C57BL/6J mice and could be a potential supplement for improving ALD.

Marine Fish Protein Peptide Regulating Potassium Oxonate-Induced Intestinal Dysfunction in Hyperuricemia Rats Helps Alleviate Kidney Inflammation.

The metabolic disease hyperuricemia (HUA) is characterized by a disturbance in purine metabolism. Peptides, such as marine fish-derived peptides, have previously been shown to be effective in alleviating HUA. In this study, HUA rats were induced by potassium oxonate with 100 mg/kg (L), 200 mg/kg (M), and 400 mg/kg (H) of marine fish protein peptide (MFPP). The results showed that MFPP could effectively reduce the serum uric acid (SUA) levels compared with the model group rats; kidney histopathology and the levels of inflammatory factors (TNF-α, IL-6, and IL-10) indicated that MFPP attenuated HUA-induced kidney inflammation. Meanwhile, MFPP restored the abundance of beneficial bacteria, including Lactobacillus, Blautia, Colidextribacter, and Intestinimonas. MFPP further repaired the intestinal barrier by recovering the expression of gene Ildr2 encoding the tricellular tight junction protein ILDR2 and the immune-related genes Ccr7 and Nr4a3 and also regulated the expression of Entpd8 and Cyp27b1 to restore kidney function and uric acid metabolism. MFPP was proved to have potential as a therapeutic strategy to be included in dietary intervention to relieve HUA.