BACKGROUND & AIMS:Gut dysbiosis is involved in the pathogenesis of acute pancreatitis (AP), yet therapeutic interventions remain limited. Our previous study found the relative abundance of Blautia is significantly decreased in AP, suggesting its protective role. METHODS:We quantified Blautia coccoides in patients with AP and tested its effects in AP mice. Untargeted metabolomics identified deoxycholic acid. Farnesoid X receptor (FXR) signaling was tested with agonists and antagonists. 16S rRNA sequencing was applied to explore changes of gut microbiota. In vitro co-culture assays verified the microbial interaction. The role of bile salt hydrolase (BSH) was confirmed through experiments involving inhibitor and BSH-engineered E coli. RESULTS:We observed reduced B coccoides in patients with AP that correlated with disease severity. In AP mice, gavage of B coccoides mitigated pancreatic and intestinal injury. Untargeted metabolomics revealed the increased level of deoxycholic acid (DCA), which could reproduce the protective phenotype of B coccoides. We further found that DCA acts primarily within the intestine to activate FXR, which suppressed pro-inflammatory nuclear factor κB (NF-κB) and NLRP3 pathways. FXR activation also induced production of fibroblast growth factor 15 (FGF15), which protected pancreatic acinar cells. 16S rRNA sequencing showed that B coccoides increased the abundance of BSH-producing genera, Parabacteroides and Bacteroides. In vitro, B coccoides supernatant promoted the growth of representative strains from these genera. Inhibition of BSH abrogated the protective effects of B coccoides, whereas administration of BSH-engineered E coli could ameliorate AP. CONCLUSIONS:B coccoides alleviated AP by reshaping gut microbiota composition, enhancing BSH-mediated DCA production, and activating the intestinal FXR-FGF15 signaling to suppress inflammation.

Gut barrier dysfunction is critical in the pathogenesis of acute pancreatitis (AP), yet the underlying mechanisms remain unclear. Mucin 2 (MUC2), the primary component of the intestinal mucus layer, is essential for gut homeostasis and microbial eubiosis. This study aimed to elucidate the protective mechanism of intestinal MUC2 in AP. We reported that intestinal MUC2 expression was decreased in AP patients and correlated with disease severity. Intestinal epithelial-specific Muc2 knockout (Muc2ΔIEC) mice demonstrated exacerbated AP in a gut microbiota-dependent manner. Decreased abundance of Lactobacillus and correlated reduced levels of riboflavin were found in Muc2ΔIEC mice after AP induction. Supplementation with riboflavin effectively ameliorated AP in Muc2ΔIEC mice, whereas administration of an engineered strain deficient in riboflavin synthesis failed to provide a protective effect. MUC2 deficiency aggravated a macrophage-dominant immune imbalance in the pancreas, which was reversed by riboflavin. In vitro experiments revealed that riboflavin suppresses pro-inflammatory macrophage activation by inhibiting the CD40 signaling pathway. This inhibition preserved mitochondrial function and reversed the histone H3 acetylation at pro-inflammatory gene promoters. Our study demonstrates that intestinal MUC2 deficiency is associated with reduced levels of microbiota-derived riboflavin, which could partially suppress pro-inflammatory macrophage activation via the CD40 pathway. Targeting the microbiota-derived riboflavin in AP may help to ameliorate the disease course.

Abstract Background Autoimmune pancreatitis (AIP) is a chronic pancreatic inflammatory disease that is often difficult to differentiate from pancreatic cancer. Some AIP patients may even progress into pancreatic ductal adenocarcinoma (PDAC). We sought to delineate the peripheral immunological landscape of AIP, identify its differences from PDAC and find novel biomarkers for disease differentiation. Methods Single‐cell RNA/BCR sequencing (scRNA/BCR‐seq) was performed on peripheral blood mononuclear cells (PBMCs) from 10 type 1 AIP patients. Public PBMC sequencing data from 13 PDAC patients and 11 healthy volunteers were integrated in the analysis. Fourteen‐colour flow cytometry was conducted in independent cohorts for validation. Results The analyses revealed a significantly higher proportion of IgG4high‐switched memory B cells in patients with AIP than in PDAC. These cells, characterised by high CD23 expression, exhibited enhanced antigen‐presenting capacity and might differentiate into pancreatic plasma cells in AIP. Compared with PDAC, AIP was characterised by an increased frequency of T follicular helper (Tfh) cells with a more pronounced exhaustion‐like phenotype. Coculture experiments demonstrated that IgG4high‐switched memory B cells can promote Tfh cell differentiation through major histocompatibility complex‐mediated antigen presentation. TREM2‐up‐regulated intermediate monocytes were also increased in AIP and showed greater potential to differentiate into macrophages. The Boruta algorithm identified proportional changes in these subsets as useful for disease differentiation, and these findings were validated by multi‐colour flow cytometry. A nomogram was established, with an AUC of .94 in the internal cohort and .88 in the external cohort. As for prognostic prediction, the reduction rate of Tfh cells after steroid therapy was associated with relapse risk. Conclusion By integrating scRNA/BCR‐seq and flow cytometry, we identified three novel immune cell subsets in PBMCs of AIP patients and confirmed their diagnostic and prognostic value. A flow cytometry‐derived nomogram based on these subsets provides a novel tool for differentiating patients with AIP from those with PDAC.

Mucin-2 (MUC2) plays a crucial role in maintaining intestinal homeostasis during acute pancreatitis (AP). We aimed to investigate the role of B3GNT7 (β-1,3-N-acetylglucosamine transferase) in the O-glycosylation of MUC2 in AP. We used two mouse models of AP induced by caerulein/lipopolysaccharide or L-arginine, and observed colonic goblet cells using electron microscopy, noting that Golgi damage was linked to decreased levels of mature MUC2. Golgi stress–associated proteins (reduced GM130 and elevated GOLPH3) were identified using immunofluorescence. Transcriptome analysis revealed the downregulation of B3gnt7, a glycosyltransferase that is highly enriched in the Golgi apparatus of goblet cells in AP mice. B3GNT7 expression was negatively correlated with pancreatic and colonic pathological scores. In patients with AP, intestinal B3GNT7 levels are markedly reduced and correlated with Ranson scores, C-reactive protein levels, and intestinal permeability markers (serum diamine oxidase and D-lactate). Adeno-associated virus (AAV)-mediated knockdown of B3GNT7 reduced O-glycosylated MUC2 levels, exacerbated pancreatic and systemic inflammation, and worsened intestinal permeability and dysbiosis. In vitro, LPS-treated HT-29 cells exhibited Golgi stress (decreased levels of B3GNT7 and O-glycosylated MUC2) that was reversed by L-glutathione (GSH). These findings demonstrate that B3GNT7 downregulation, mediated by Golgi stress, disrupts MUC2 O-glycosylation, exacerbating AP by impairing intestinal homeostasis.

Hypertriglyceridemia(HTG)is a common and significant contributor to acute pancreatitis(AP).Caffeine has been reported to have a protective effect against pancreatic disorders.However,the role of caffeine in hypertriglyceridemia acute pancreatitis(HAP)is still unknown.To investigate a new understanding of the relationship between caffeine and gut microbiota in HAP development.Using multi-omics analysis of 71 HAP and HTG patients,their characteristics of intestinal microecology were detected.HTG mice models were established through either pharmacological induction(P-407 intraperitoneal injection)or genetic ablation of GPIHBP1(GPIHBP1-/-).Genes deferentially expressed in the gut were identified by RNA sequencing and the role of caffeine in reshaping gut microbial networks was investigated.Caffeine levels decreased significantly in HAP patients and were inversely correlated with the severity of HAP.Caffeine maintained the intestinal homeostasis and attenuated HAP through a gut microbiota-dependent manner in the mouse model.Specially,the commensal Faecalibacterium prausnitzii,which contributed most in distinguishing the differences between HTG and HAP patients,has been found to be related to the effect of caffeine on alleviating HAP.RNA sequencing combined with TLR4-/-mice revealed that TLR4/NLRP3 may be the key signaling pathway for caffeine to maintain intestinal homeostasis and alleviating HAP.This study reveals the gut metabolites and microbiota characteristics of HAP and HTG patients,and explores the therapeutic potential of caffeine against HAP from the perspective of gut microbiota.

Aim To develop effective prevention measures, a deep understanding of the evolution patterns and trends of pancreatitis burden is essential. Our study aims to quantify the burden related to pancreatitis in 204 countries and regions from 1990 to 2021. Methods Data related to pancreatitis were derived from the Global Burden of Disease Study in 2021. The burden of pancreatitis was assessed using incidence, disability-adjusted life years (DALYs), deaths and their corresponding age-standardized rates (ASRs), stratified by age, sex, Sociodemographic Index (SDI) and Human Development Index (HDI). The estimated annual percentage change was used to quantify the variation in ASRs. The analysis covered the period from 1990 to 2021. Results In 2021, there were 2,741,736 new cases of pancreatitis (95% UI 2,413,878-3,133,076), leading to 122,416 deaths (95% UI 109,848-141,362), accounting for 0.22% of global deaths, causing a loss of 4,101,154 DALYs (95% UI 3,647,631-4,684,283). The burden of pancreatitis in 2021 and its trends from 1990 to 2021 showed substantial differences based on sex, SDI quintiles and geographical regions. Conclusion Based on our results, the burden of pancreatitis is high and increasing among males and the elderly. Countries with high levels of SDI bear a greater disease burden. Forecast analysis predicts that by 2050, the number of deaths and DALYs related to pancreatitis will continue to rise. Understanding the disease burden and future burden trends associated with pancreatitis is crucial for implementing effective interventions to alleviate the global burden.

BACKGROUNDS:With the change in dietary patterns, the number of patients suffering from hypertriglyceridemia-induced acute pancreatitis (HTG-AP) has been increasing year by year. HTG-AP patients have a higher likelihood of progressing to severe conditions and exhibit a markedly increased risk of recurrence compared to other etiologies. At present, effective prediction models for the recurrence of HTG-AP need to be established and improved urgently, which is of great significance in improving the prognosis of patients. METHODS:A total of 429 HTG-AP patients were included in this study. Variables were selected by LASSO regression to construct a Logistic regression prediction model, and the performance of the model was verified by ROC curve, calibration curve and decision curve analysis (DCA). RESULTS:Elevated Thyroid-stimulating hormone (TSH) and triglyceride (TG) levels, Female and Age >33 years were identified as independent risk factors (P < 0.05). A further dietary retrospective study found that the intake of fat and carbohydrate in the recurrent HTG-AP (RAP) group was significantly higher than that in the primary HTG-AP (OAP) group (P < 0.01), while the salt intake was much lower. CONCLUSION:Elevated TSH was likely to be an independent risk factor for HTG-AP recurrence. In addition, the new nomogram model based on TSH level shows high accuracy in predicting HTG-AP recurrence, which is expected to provide certain help for clinical prevention and treatments.

BACKGROUND:Faecalibacterium prausnitzii plays a crucial role in ulcerative colitis (UC) remission, but its action mechanism is unknown. Here, we aimed to explore the potential mechanisms focusing on the interaction of F. prausnitzii with host immune response and its potential modulation on gut microbiome. METHODS:RNA-seq analysis together with 16S rRNA sequencing and metabolomics were performed in a dextran sodium sulfate (DSS)-induced colitis mouse model followed by F. prausnitzii gavage. To present evidence of sIgA involved in the anti-inflammatory effects of F. prausnitzii, we further applied immunoglobulin A (IgA) knockout mice and secretory IgA (sIgA) depletion mouse models using polymeric immunoglobulin receptor (pIgR) neutralizing antibody. Colonic immune cells were characterized by flow cytometry. The fecal relative abundance of F. prausnitzii, inecalcitol, and colonic IgA expression were assessed in UC patients. RESULTS:F. prausnitzii markedly ameliorated colitis by alleviating intestinal inflammation and barrier dysfunction, with significantly decreased abundance of pro-inflammatory taxa (Enterococcus, Desulfovibrio, Escherichia-Shigella, and Enterorhabdus) and increased abundance of Lachnospiraceae NK4A136_group. Functions related to intestinal immune network for IgA production pathway were up-regulated shown by transcriptomics and KEGG pathway analysis. Increased expression of IgA production associated genes including MHCII-related genes, Aicda, and Tnfrsfl3c were verified, accompanied by up-regulated colonic IgA and pIgR. The IgA knockout mice and sIgA depletion model weakened the anti-inflammation and microbiota-modulation effects of F. prausnitzii, which was further proved by fecal microbiota transplantation (FMT). The shift profile of fecal metabolites after F. prausnitzii supplement was characterized by increased production of inecalcitol, which may account for the enhanced IgA response. In a cohort of UC patients, the relative abundance of F. prausnitzii was decreased and positively correlated with colonic IgA expression and negatively correlated with disease severity. CONCLUSIONS:F. prausnitzii effectively alleviated colonic inflammation and modulated dysbiosis via enhancing colonic IgA response, thus showing promise as a UC treatment.

Fecal microbiota transplantation (FMT) is a promising therapy for inflammatory bowel disease (IBD) via rectifying gut microbiota. The aim of this study was to identify a mechanism of how specific bacteria-associated immune response contributes to alleviated colitis. Forty donors were divided into high (donor H) and low (donor L) groups according to the diversity and the abundance of Bacteroides and Faecalibacterium by 16S rRNA sequencing. FMT was performed on dextran sulfate sodium (DSS)-induced colitis in mice. Mice with colitis showed significant improvement in intestinal injury and immune imbalance after FMT with group donor H (P < 0.05). Bacteroides thetaiotaomicron and Faecalibacterium prausnitzii were identified as targeted strains in donor feces by real-time PCR and droplet digital PCR. Mice with colitis were treated with mono- or dual-bacterial gavage therapy. Dual-bacterial therapy significantly ameliorated intestinal injury compared with mono-bacterial therapy (P < 0.05). Dual-bacterial therapy increased the M2/M1 macrophage polarization and improved the Th17/Treg imbalance and elevated IL-10 production by Tregs compared with the DSS group (P < 0.05). Metabolomics showed increased abundance of lecithin in the glycerophospholipid metabolism pathway. In conclusion, B. thetaiotaomicron and F. prausnitzii, as the key bacteria in donor feces, alleviate colitis in mice. The mechanism may involve increasing lecithin and regulating IL-10 production of intestinal Tregs. NEW & NOTEWORTHY We demonstrate that donors with high abundance of Bacteroides and Faecalibacterium ameliorate dextran sulfate sodium (DSS)-induced colitis in mice by fecal microbiota transplantation (FMT). The combination therapy of Bacteroides thetaiotaomicron and Faecalibacterium prausnitzii is superior to mono-bacterial therapy in ameliorating colitis in mice, of which mechanism may involve promoting lecithin and inducing IL-10 production of intestinal Tregs.

Caffeine, a controversial substance, was once known to be addictive and harmful. In recent years, new effects of caffeine on the human body have been confirmed. Recent research over the past few decades has shown the potential of caffeine in treating pancreas-related diseases. This review aims to analyze the known and possible mechanisms of caffeine on pancreatic diseases and provides an overview of the current research status regarding the correlation between caffeine and pancreatic disease, while enhancing our understanding of their relationship. Caffeine is a common component of coffee, tea, soft drinks and energy drinks. This review summarized the recent studies about its effects on pancreatic diseases and related mechanisms.

Intestinal barrier dysfunction usually occurred in acute pancreatitis (AP) but the mechanism remains unclear. In this study, RNA sequencing of ileum in L-arginine-induced AP mice demonstrated that phosphoenolpyruvate kinase 1 (Pck1) was significantly up-regulated. Increased Pck1 expression in intestinal epithelial cells (IECs) was further validated in ileum of AP mice and duodenum of AP patients. In AP mice, level of Pck1 was positively correlated with pancreatic and ileal histopathological scores, serum amylase activity, and intestinal permeability (serum diamine oxidase (DAO), D-lactate, and endotoxin). In AP patients, level of Pck1 had a positive correlation with Ranson scores, white blood cell count and C-reactive protein. Inhibition of Pck1 by 3-Mercaptopicolinic acid hydrochloride (3-MPA) alleviated pancreatic and ileal injuries in AP mice. AP + 3-MPA mice showed improved intestinal permeability, including less epithelial apoptosis, increased tight junction proteins (TJPs) expression, decreased serum DAO, D-lactate, endotoxin, and FITC-Dextran levels, and reduced bacteria translocation. Lysozyme secreted by Paneth cells and mucin2 (MUC2) secretion in goblet cells were also partly restored in AP + 3-MPA mice. Meanwhile, inhibition of Pck1 improved intestinal immune response during AP, including elevation of M2/M1 macrophages ratio and secretory immunoglobulin A (sIgA) and reduction in neutrophils infiltration. In vitro, administration of 3-MPA dramatically ameliorated inflammation and injuries of epithelial cells in enteroids treated by LPS. In conclusion, inhibition of Pck1 in IECs might alleviate AP via modulating intestinal homeostasis.

Mucin-2 (MUC2) secreted by goblet cells participates in the intestinal barrier, but its mechanism in acute necrotizing pancreatitis (ANP) remains unclear. In acute pancreatitis (AP) patients, the functions of goblet cells (MUC2, FCGBP, CLCA1, and TFF3) decreased, and MUC2 was negatively correlated with AP severity. ANP rats treated with pilocarpine (PILO) (PILO+ANP rats) to deplete MUC2 showed more serious pancreatic and colonic injuries, goblet cell dysfunction, gut dysbiosis, and bacterial translocation than those of ANP rats. GC-MS analysis of feces showed that PILO+ANP rats had lower levels of butyric acid, isobutyric acid, isovaleric acid, and hexanoic acid than those of ANP rats. The expression of MUC2 was associated with colonic injury and gut dysbiosis. All these phenomena could be relieved, and goblet cell functions were also partially reversed by MUC2 supplementation in ANP rats. TNF-alpha-treated colonoids had exacerbated goblet cell dysfunction. MUC2 expression was negatively correlated with the levels of pro-inflammatory cytokines (IL-1 beta and IL-6) (p < .05) and positively related to the expression of tight junction proteins (Claudin 1, Occludin, and ZO1) (p < .05). Downregulating MUC2 by siRNA increased the levels of the pro-inflammatory cytokines in colonoids. MUC2 might maintain intestinal homeostasis to alleviate ANP.

Objective To compare efficacy and safety of fecal microbiota transplantation (FMT) with glucocorticoid as induction therapy in ulcerative colitis (UC). Methods The patients with active mild to moderate UC were recruited into the single-center, prospective cohort study. The patients were treated with either FMT (FMT group) or glucocorticoids (GCs group). Patients received FMT administration for 3 days. The primary outcome was clinical and endoscopic remission at week 12. Inflammatory parameters were assessed by routine blood tests. Safety was assessed by adverse events recorded. The serum levels of TNF-α, IFN-γ, IL-1β, IL-4, IL-5, IL-6, IL-10 IL-8, IL-12p70, IL-13, IL-17A and IL-23 following FMT were measured by Luminex multiplex assay. Results Of the 122 patients, 62 patients were treated with FMT and 60 with glucocorticoids. 34 patients in FMT group (54.8%) and 29 in GCs group (48.3%) reached the primary outcome ( p = 0.30). The incidence of adverse events in GCs group (35/60, 58.3%) was significantly higher than that in FMT group (14/62, 22.6%) and two serious adverse events were observed following GCs. Patients in FMT group were stratified into responders (RE) and non-responders (NR) groups. The level of TNF-α and IL-6 decreased significantly in RE group, while IL-10 decreased significantly in NR group. Conclusion FMT therapy was as effective as glucocorticoids to induce remission in active mild to moderate UC, accompanied by fewer adverse events. The modification of serum TNF-α, IL-6 and IL-10 might be related to the efficacy of FMT in UC. Trial registration This study was registered with ClinicalTrials.gov (NCT02435160). Registered on 6 April, 2015. https://clinicaltrials.gov/ct2/results?cond=&term=NCT02435160&cntry=&state=&city=&dist=

Background: Fecal microbiota transplantation (FMT) may contribute to disease remission in ulcerative colitis (UC). We studied the microbiota change and its regulation on T cells after FMT. Methods: Patients with mild to moderately active UC were included to receive FMT. The intestinal histopathological changes and barrier function were evaluated. The fecal samples of donors and patients were analyzed by 16S rRNA gene-based microbiota analysis, and the colon Th17 and Treg cells were assessed. Results: Fifteen patients completed the 8-week-follow-up. A total of 10 patients (66.7%) were in the responders (RE) group and five in the non-responders (NR) group. The Nancy histological index and fecal calprotectin decreased (p < 0.001, p = 0.06, respectively) and Occludin and Claudin1 increased in the RE group. The abundance of Faecalibaterium increased significantly by 2.3-fold in the RE group at week 8 (p = 0.043), but it was suppressed in the NR group. Fecal calprotectin (r = −0.382, p = 0.003) and Nancy index (r = −0.497, p = 0.006) were correlated inversely with the abundance of Faecalibacterium, respectively. In the RE group the relative mRNA expression of RORγt decreased and Foxp3 increased. Significantly decreased CD4+ RORγt+ Th17 and increased CD4+ Foxp3+ Treg were also observed in the RE group. The relative abundance of Faecalibacterium correlated with CD4+ RORγt+ Th17 (r = −0.430, p = 0.018) and CD4+ Foxp3+ Treg (r = 0.571, p = 0.001). Conclusions: The long-term Faecalibaterium colonization following FMT plays a crucial role in UC remission by alleviating intestinal inflammation. This anti-inflammatory effect of Faecalibacterium may be achieved by regulating the imbalance of Th17/Treg levels in UC.

Toll-like receptor 4 (TLR4) has been identified as a potentially promising therapeutic target in acute pancreatitis (AP). However, the role of intestinal TLR4 in AP and AP-associated gut injury remains unclear. This study aimed to explore the relationship between intestinal TLR4 and gut microbiota during AP. A mouse AP model was establish by intraperitoneal injection of L-arginine. Pancreatic injury and intestinal barrier function were evaluated in wild-type and intestinal epithelial TLR4 knockout (TLR4ΔIEC) mice. Gut microbiota was analyzed by 16S rRNA sequencing. Quadruple antibiotics were applied to induce microbiota-depleted mice. Differentially expressed genes in gut were detected by RNA sequencing. L. reuteri treatment was carried out in vivo and vitro study. Compared with wild-type mice, AP and AP-associated gut injury were exacerbated in TLR4ΔIEC mice in a gut microbiota-dependent manner. The relative abundance of Lactobacillus and number of Paneth cells remarkably decreased in TLR4ΔIEC mice. The KEGG pathway analysis derived from RNA sequencing suggested that genes affected by intestinal TLR4 deletion were related to the activation of nod-like receptor pathway. Furthermore, L. reuteri treatment could significantly improve the pancreatic and intestinal injury in TLR4ΔIEC mice through promoting Paneth cells in a NOD2-dependent manner. Loss of intestinal epithelial TLR4 exacerbated pancreatic and intestinal damage during AP, which might be attributed to the gut microbiota dysbiosis especially the exhausted Lactobacillus. L. reuteri might maintain intestinal homeostasis and alleviate AP via Paneth cells modulation.Abbreviations: AP Acute pancreatitis, TLR4 Toll-like receptor 4, IL-1β Interleukin-1β, IL-6 Interleukin-6, TNF-α Tumor necrosis factor-α, SIRS Systematic inflammatory response syndrome, LPS Lipopolysaccharides, SPF Specific pathogen-free, ZO-1 Zonula occludens-1, CON Control, H&E Hematoxylin and eosin, FISH Fluorescence in situ hybridization, DAPI 4',6-diamidino-2-phenylindole, PCoA Principal co-ordinates analysis, SCFA Short chain fatty acid, LEfSe Linear discriminant analysis Effect Size, ANOVA Analysis of variance, F/B Firmicutes/Bacteroidetes, PCA Principal component analysis, NOD2 Nod-like receptor 2, ABX antibiotics, PCNA proliferating cell nuclear antigen.

We demonstrate that AP patients and experimental AP mice exhibited a dysfunction of Paneth cells. Our in vivo research showed that the severity of AP was exacerbated by the long-term dysfunction of Paneth cells, which was associated with gut microbiota disorder.

Severe acute pancreatitis (SAP) is a severe acute abdominal disease. Recent evidence shows that intestinal homeostasis is essential for the management of acute pancreatitis. Chitosan oligosaccharides (COS) possess antioxidant activity that are effective in treating various inflammatory diseases. In this study we explored the potential therapeutic effects of COS on SAP and underlying mechanisms. Mice were treated with COS (200 mg·kg−1·d−1, po) for 4 weeks, then SAP was induced in the mice by intraperitoneal injection of caerulein. We found that COS administration significantly alleviated the severity of SAP: the serum amylase and lipase levels as well as pancreatic myeloperoxidase activity were significantly reduced. COS administration suppressed the production of proinflammatory cytokines (TNF-α, IL-1β, CXCL2 and MCP1) in the pancreas and ileums. Moreover, COS administration decreased pancreatic inflammatory infiltration and oxidative stress in SAP mice, accompanied by activated Nrf2/HO-1 and inhibited TLR4/NF-κB and MAPK pathways. We further demonstrated that COS administration restored SAP-associated ileal damage and barrier dysfunction. In addition, gut microbiome analyses revealed that the beneficial effect of COS administration was associated with its ability to improve the pancreatitis-associated gut microbiota dysbiosis; in particular, probiotics Akkermansia were markedly increased, while pathogenic bacteria Escherichia–Shigella and Enterococcus were almost eliminated. The study demonstrates that COS administration remarkably attenuates SAP by reducing oxidative stress and restoring intestinal homeostasis, suggesting that COS might be a promising prebiotic agent for the treatment of SAP. Supplementation of chitosan oligosaccharides(COS) could ameliorate severity of pancreatic injury, prevent intestinal barrier disruption and reduce inflammatory and oxidative injury in severe acute pancreatitis (SAP). The protective mechanism partly attributed to the reshaping of gut microbiota and TLR4 and Nrf2/HO-1 pathway.

ObjectiveTo investigate the potential therapeutic role of porous SiO2‐coated ultrasmall selenium particles nanospheres (Se@SiO2 nanospheres) pretreatment in acute pancreatitis (AP) and to investigate the related mechanism.MethodsC57BL/6 mice were randomized to the normal control (CON) group, the AP (induced by cerulein injection) (CAE) group, and AP pretreated with Se@SiO2 nanocomposites at 1 and 2 mg/kg (CAE + 1 or 2 mg/kg Se@SiO2) groups, respectively. Serum levels of amylase and lipase, inflammatory cytokines (interleukin [IL]‐6, IL‐1β and tumor necrosis factor [TNF]‐α), alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen (BUN), and creatinine (Cr) were measured, and histopathology was performed to examine the tissue samples of the pancreas, lungs, kidneys and liver. Immunofluorescence assay of reactive oxygen species (ROS), myeloperoxidase (MPO) and terminal deoxynucleotidyl transferase‐mediated dUTP nick‐end labeling were conducted, and levels of MPO, malondialdehyde, superoxide dismutase and glutathione were evaluated. Finally, Western blot analysis was used to evaluate protein expressions of Nrf2, HO‐1, NQO1, TLR4, MyD88 and p‐p65 in pancreatic tissue.ResultsSe@SiO2 nanospheres alleviated pathological damage to the pancreas, and reduced pancreatic enzymes and inflammatory cytokines. Injury to other organs such as the liver, lungs and kidneys was also alleviated, as indicated by decreased ALT, AST, BUN, and Cr levels as well as improved histopathology. Moreover, Se@SiO2 nanospheres reduced oxidative stress, and ultimately inhibited TLR4/ MyD88/p‐p65 pathway and increased the protein expressions of NQO1, Nrf2, and HO‐1.ConclusionSe@SiO2 nanospheres may alleviate AP by relieving oxidative stress and targeting the TLR4/Myd88/p‐p65 and NQO1/Nrf2/HO‐1 pathways.

To investigate the potential therapeutic role of porous SiO 2 -coated ultrasmall selenium particles nanospheres (Se@SiO 2 nanospheres) pretreatment in acute pancreatitis (AP) and to investigate the related mechanism. C57BL/6 mice were randomized to the normal control (CON) group, the AP (induced by cerulein injection) (CAE) group, and AP pretreated with Se@SiO 2 nanocomposites at 1 and 2 mg/kg (CAE + 1 or 2 mg/kg Se@SiO 2 ) groups, respectively. Serum levels of amylase and lipase, inflammatory cytokines (interleukin [IL]-6, IL-1β and tumor necrosis factor [TNF]-α), alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen (BUN), and creatinine (Cr) were measured, and histopathology was performed to examine the tissue samples of the pancreas, lungs, kidneys and liver. Immunofluorescence assay of reactive oxygen species (ROS), myeloperoxidase (MPO) and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling were conducted, and levels of MPO, malondialdehyde, superoxide dismutase and glutathione were evaluated. Finally, Western blot analysis was used to evaluate protein expressions of Nrf2, HO-1, NQO1, TLR4, MyD88 and p-p65 in pancreatic tissue. Se@SiO 2 nanospheres alleviated pathological damage to the pancreas, and reduced pancreatic enzymes and inflammatory cytokines. Injury to other organs such as the liver, lungs and kidneys was also alleviated, as indicated by decreased ALT, AST, BUN, and Cr levels as well as improved histopathology. Moreover, Se@SiO 2 nanospheres reduced oxidative stress, and ultimately inhibited TLR4/ MyD88/p-p65 pathway and increased the protein expressions of NQO1, Nrf2, and HO-1. Se@SiO 2 nanospheres may alleviate AP by relieving oxidative stress and targeting the TLR4/Myd88/p-p65 and NQO1/Nrf2/HO-1 pathways.