Severe Colitis Research Articles

MZB1-mediated IgA secretion suppresses the development and progression of colorectal cancer triggered by gut inflammation

Colorectal cancer (CRC) ranks among the top causes of mortality globally. Gut inflammation is one crucial risk factor that augments CRC development since patients suffering from inflammatory bowel disease have an increased incidence of CRC. The role of immunoglobulin (Ig)A in maintaining gut homeostasis and preventing inflammation has been well established. Our earlier work demonstrated that the marginal zone and B1 cell-specific protein (MZB1) promotes gut IgA secretion and its absence results in pronounced dextran sulfate sodium salt (DSS)-induced colitis. In the present study, we explored the role of MZB1 in CRC development using the azoxymethane (AOM)/DSS-induced CRC model. We observed an increase in both the number and size of the tumor nodules in Mzb1-/- mice compared with Mzb1+/+ mice. The increase in CRC development and progression in Mzb1-/- mice was associated with reduced intestinal IgA levels, altered gut flora, and more severe gut and systemic inflammation. Oral administration of the monoclonal IgA, W27, alleviated both the gut inflammation and AOM/DSS-induced CRC. Notably, cohousing Mzb1+/+ and Mzb1-/- mice from the 10th day after birth led to similar CRC development. Our findings underscore the pivotal role of MZB1-mediated IgA secretion in suppressing the onset and progression of CRC triggered by gut inflammation. Moreover, our study highlights the profound impact of microbiota composition, modulated by gut IgA levels, on gut inflammation. Nonetheless, establishing a direct correlation between the severity of colitis and subsequent CRC development and the presence or absence of a particular microbiota is challenging.

Cyclosporine A alleviates colitis by inhibiting the formation of neutrophil extracellular traps via the regulating pentose phosphate pathway

BackgroundThe aberrant formation of neutrophil extracellular traps (NETs) has been implicated in ulcerative colitis (UC), a chronic recurrent intestinal inflammation. Cyclosporine A (CsA) is now applied as rescue therapy for acute severe UC. In addition, it has been certained that CsA inhibits the formation of NETs in vitro and the mechanism of which was still vague. The study aimed to explore the mechanism CsA inhibits the NETs formation of colitis in vivo and in vitro.MethodsNETs enrichment in clinical samples was analyzed using databases from Gene Expression Omnibus and verified in our center. Dextran sulfate sodium (DSS)-induced acute colitis mice model was used to investigate the effect of CsA on NETs of colonic tissue expression. To clarify the mechanism, intracellular energy metabolites were examined by Liquid Chromatograph Mass Spectrometer, and reactive oxygen species (ROS) levels were examined by fluorescence intensity in neutrophils treated with CsA after LPS stimulation. The transcriptional level and activity of G6PD of neutrophils were also assessed using qRT-PCR and WST-8. RNA Sequencing was used to detect differentially expressed genes of neutrophils stimulated by LPS with or without CsA. The expression levels of related proteins were detected by western blot.ResultsNETs enrichment was especially elevated in moderate-to-severe UC patients compared to HC. NETs expression in the colon from DSS colitis was decreased after CsA treatment. Compared with neutrophils stimulated by LPS, NETs formation and cellular ROS levels were decreased in LPS + CsA group. Cellular ribulose 5-phosphate and NADPH/NADP + related to the pentose phosphate pathway (PPP) were reduced in LPS + CsA group. In addition, CsA could decrease G6PD activity in neutrophils stimulated with LPS, and the results were further verified by inhibiting G6PD activity. At last, P53 protein was highly expressed in LPS + CsA group compared with the LPS group. Intracellular G6PD activity, ROS level and NETs formation, which were downregulated by CsA, could be reversed by a P53 inhibitor.ConclusionOur results indicated CsA could alleviate the severity of colitis by decreasing the formation of NETs in vivo. In vitro, CsA reduced ROS-dependent NETs release via downregulating PPP and cellular ROS levels by decreasing G6PD activity directly by activating the P53 protein.

C-X-C Motif Chemokine Ligand 1 Promotes Colitis by Modulating the Gut Microbiota

Introduction: C-X-C motif chemokine ligand 1 (CXCL1) is a potent neutrophil chemoattractant that plays a pivotal role in recruiting neutrophils during inflammatory conditions. This study explored the role of CXCL1 in modulating the gut microbiota, influencing neutrophil infiltration, and contributing to the development of colitis. Methods: We employed quantitative PCR to assess CXCL1 expression in colon samples. A mouse model of dextran sulfate sodium (DSS)-induced colitis was utilized to explore the progression of colitis in wild-type (WT) and CXCL1-deficient (CXCL1−/−) mice. Results: Colitis attenuation was evident in CXCL1−/− mice. Significant alterations were observed in the gut microbiome, as revealed by 16S rRNA gene sequencing. Furthermore, CXCL1−/− mice exhibited reduced gut permeability and diminished endotoxin levels in peripheral blood following DSS treatment compared to WT mice. In response to DSS treatment, WT mice showed a clear increase in neutrophil infiltration, while CXCL1−/− mice exhibited lower levels of infiltration. Fecal microbiota transplantation (FMT) using stools from CXCL1−/− mice alleviated DSS-induced colitis. Interestingly, FMT from patients with colitis increased CXCL1 and Ly6G expression in the colons of gut-sterilized mice. Clinical data analysis revealed elevated CXCL1 and CD15 expression in patients with colitis, with a positive correlation between the severity of colitis and the expression of CXCL1 and CD15. Conclusion: These findings shed light on the pivotal role of CXCL1 in promoting colitis by modulating the gut microbiota.

Colitis induced by IL-17A-inhibitors

BackgroundInterleukin (IL)-17A is essential for intestinal mucosal integrity, contributing to the prevention of detrimental immunity such as infectious colitis and inflammatory bowel disease (IBD). Indeed, neutralization of IL-17A has been abandoned as a therapeutic principle in IBD because of increased disease activity. However, it is controversial whether IL-17A inhibitors increase the risk of developing colitis in patients who do not have underlying IBD. Here, we present two cases of different forms of colitis that occurred during treatment with two IL-17A inhibitors, secukinumab and ixekizumab.Case presentationsWe report the case of a 35-year-old female with SAPHO (synovitis–acne–pustulosis–hyperostosis–osteitis) syndrome who was admitted due to severe colitis with bloody diarrhea, fever, abdominal pain and weight loss after receiving secukinumab for 3 months as well as the case of a 41-year-old male with psoriatic arthritis who presented himself to the outpatient clinic with bloody stools, abdominal pain and nausea 5 months after changing his therapy from secukinumab to ixekizumab. In both patients, treatment with IL-17A-inhibitors was stopped and tumor necrosis factor inhibitors were started. Both patients recovered, are clinically stable and show no more signs of active colitis.ConclusionThe role of IL-17A inhibitors in the pathogenesis of infectious colitis and new-onset IBD is not fully understood and requires further research. Patients receiving IL-17A-inhibitor therapy should be carefully screened and notified of the possible side effects.

S101 Myelosuppression Due to the Use of Azathioprine and COVID Infection and Severe Acute Colitis in a Patient With Ulcerative Colitis: Case Report

S101 Myelosuppression Due to the Use of Azathioprine and COVID Infection and Severe Acute Colitis in a Patient With Ulcerative Colitis: Case Report

An Australian study of exclusive enteral nutrition for management of active severe inflammatory bowel disease focusing on efficacy and patient reported perspective

An Australian study of exclusive enteral nutrition for management of active severe inflammatory bowel disease focusing on efficacy and patient reported perspective

Attitude and influencing factors on exercise in patients with moderately to severely active inflammatory bowel disease: a qualitative study

ObjectivesTo explore the attitudes towards exercise, factors influencing exercise and exercise-related needs of patients with moderately to severely active inflammatory bowel disease.DesignA qualitative phenomenological research.SettingThe study was conducted at a...

Comparing the Efficacy and Safety of Adalimumab and Vedolizumab in Treating Moderate to Severe Crohn's Disease and Ulcerative Colitis.

Numerous patients with inflammatory bowel disease (IBD) do not respond to conventional or biological therapy. Adalimumab (ADA) and vedolizumab (VDZ), according to certain research, may be a useful alternative treatment for these people. The purpose of this study was to assess the effectiveness and safety of using ADA and VDZ to treat moderate to severe IBD: Crohn's disease (CD) and ulcerative colitis (UC). We searched PubMed, Medline, Web of Science, Scopus, the Cochrane Library, Embase, Google Scholar, CINAHL, Clinicaltrials.gov, and WHO trials registry (ICTRP). Randomized controlled trials (RCTs) comparing ADA or VDZ with placebo in participants with active CD or UC were included. The primary outcomes were the clinical response and remission at induction and maintenance phases and mucosal healing. The secondary outcome was the incidence of profound negative events. The research used Comprehensive Meta-Analysis version 3 (Biostat Inc., USA). Eighteen RCTs were incorporated, in which 11 studies described the usefulness and safeness of ADA or VDZ in CD patients, and seven studies investigated the efficacy and safety of ADA or VDZ in UC patients. The meta-analysis revealed that both ADA and VDZ treatments were superior to placebo for producing clinical remission and eliciting clinical response at induction and maintenance phases in individuals with moderately to severely active CD or UC. Interestingly, we found that ADA was superior to VDZ as first-line treatment for patients with CD, but not UC. ADA and VDZ are effective and safe in CD and UC patients. However, RCTs of a larger number of patients are still required for better assessing the safety profile of ADA and VDZ.

Claudin-2 protects against colitis-associated cancer by promoting colitis-associated mucosal healing.

Patients with inflammatory bowel disease (IBD) are susceptible to colitis-associated cancer (CAC). Chronic inflammation promotes the risk for CAC. In contrast, mucosal healing predicts improved prognosis in IBD and reduced risk of CAC. However, the molecular integration among colitis, mucosal healing, and CAC remains poorly understood. Claudin-2 (CLDN2) expression is upregulated in IBD; however, its role in CAC is not known. The current study was undertaken to examine the role for CLDN2 in CAC. The AOM/DSS-induced CAC model was used with WT and CLDN2-modified mice. High-throughput expression analyses, murine models of colitis/recovery, chronic colitis, ex vivo crypt culture, and pharmacological manipulations were employed in order to increase our mechanistic understanding. The Cldn2KO mice showed significant inhibition of CAC despite severe colitis compared with WT littermates. Cldn2 loss also resulted in impaired recovery from colitis and increased injury when mice were subjected to intestinal injury by other methods. Mechanistic studies demonstrated a possibly novel role of CLDN2 in promotion of mucosal healing downstream of EGFR signaling and by regulation of Survivin expression. An upregulated CLDN2 expression protected from CAC and associated positively with crypt regeneration and Survivin expression in patients with IBD. We demonstrate a potentially novel role of CLDN2 in promotion of mucosal healing in patients with IBD and thus regulation of vulnerability to colitis severity and CAC, which can be exploited for improved clinical management.

S104 Fatal Presentation of Thrombotic Cutaneous Gangrene Associated With Acute Severe Colitis

S104 Fatal Presentation of Thrombotic Cutaneous Gangrene Associated With Acute Severe Colitis

IL-18-induced HIF-1α in ILC3s ameliorates the inflammation of C. rodentium-induced colitis

Group 3 innate lymphoid cells (ILC3s) are vital for defending tissue barriers from invading pathogens. Hypoxia influences the production of intestinal ILC3-derived cytokines by activating HIF. Yet, the mechanisms governing HIF-1α in ILC3s and other innate RORγt+ cells during invivo infections are poorly understood. Inour study, transgenic mice with specific Hif-1a gene inactivation in innate RORγt+ cells (RAG1KO HIF-1α▵Rorc) exhibit more severe colitis following Citrobacter rodentium infection, primarily due to the inability to upregulate IL-22. We find that HIF-1α▵Rorc mice have impaired IL-22 production in ILC3s, while non-ILC3 innate RORγt+ cells, also capable of producing IL-22, remain unaffected. Furthermore, we show that IL-18, induced by Toll-like receptor 2, selectively triggers IL-22 in ILC3s by transcriptionally upregulating HIF-1α, revealing an oxygen-independent regulatory pathway. Our results highlight that, during late-stage C.rodentium infection, IL-18 induction in the colon promotes IL-22 through HIF-1α in ILC3s, which is crucial for protection against this pathogen.

Risk and management of post-operative infectious complications in inflammatory bowel disease: A systematic review.

Indications for surgery in inflammatory bowel disease (IBD) include treatment-refractory disease or severe complications such as obstruction, severe colitis, dysplasia, or neoplasia. Infectious complications following colorectal surgery in IBD are significant, particularly in high-risk patients. To gather evidence on risk factors associated with increased post-operative infectious complications in IBD and explore management strategies to reduce morbidity and mortality. A systematic review adhering to PRISMA-P guidelines was conducted. MEDLINE (PubMed) and Cochrane Library databases were searched using specific keywords. Inclusion criteria encompassed studies involving patients with IBD undergoing abdominal surgery with infectious complications within 30 d postoperatively. Exclusion criteria included patients under 18 years and non-infectious complications. Selected papers were analyzed to identify factors contributing to post-operative infections. A narrative analysis was performed to provide evidence-based recommendations for management. The data were then extracted and assessed based on the Reference Citation Analysis (https://www.referencecitationanalysis.com/). The initial database search yielded 1800 articles, with 330 articles undergoing full-text review. After excluding duplicates and irrelevant papers, 35 articles were included for analysis. Risk factors for post-operative complications in patients with IBD included hypoalbuminemia, malnutrition, preoperative abscess, and obesity. Perioperative blood transfusion was associated with increased infectious complications. Medications such as 5-aminosalicylates and immunomodulators did not increase post-operative complications. Corticosteroids were associated with an increased risk of complications. Ustekinumab and vedolizumab showed similar rates of infectious complications compared to other treatments. The impact of minimally invasive surgery on post-operative complications varied across studies. In order to reduce post-operative infectious complications in patients with IBD, a comprehensive approach involving multiple disciplines is necessary.

The Role of Platelets and von Willebrand Factor in the Procoagulant Phenotype of Inflammatory Bowel Disease.

Although the risk of thrombosis is well documented for inflammatory bowel disease [IBD] patients, the underlying pathological mechanism seems to be different from other thrombotic conditions. Determining the factors responsible for the increased risk of thrombosis in IBD would help to improve the management of this frequent complication. We studied the interplay between platelets, coagulation, and von Willebrand factor [VWF] in 193 IBD patients and in experimental models [acute and chronic] of colitis in wild-type and VWF-deficient mice. We found a platelet-dependent increase in thrombin generation in IBD patients and in our mouse model of colitis. Agglutinated platelets were present in the blood of patients and mice. Interestingly, we observed not only a significant increase in total VWF antigen, but we were also able to detect the presence of active VWF [VWF in its platelet-binding conformation; 3.2 ± 2.7 μg/mL] in the plasma of 30% of all IBD patients. In healthy controls, active VWF levels were <0.3 μg/mL. This led us to further explore experimental colitis in VWF-deficient mice and we observed that these mice were protected against the procoagulant state triggered by the colitis. Unexpectedly, these mice also showed a significant worsening of colitis severity in both acute and chronic models. Platelets and VWF [including its active form] appear to be central players in the procoagulant phenotype in IBD. We observed that the role of VWF in haemostasis differs from its role in colonic tissue healing, potentially opening new therapeutic avenues for a life-threatening complication in IBD patients.

Correlation between the Eosinophil Colonic Mucosa Density and Severity of Ulcerative Colitis

Background: The inflammatory process of ulcerative colitis (UC) involves eosinophils. Eosinophils are not only related to the severity of UC but also to clinical improvement. The role of eosinophils in colonic mucosa has not been fully understood. This study aims to determine the correlation between the density of eosinophils in the colonic mucosa and the severity of ulcerative colitis.Method: This is a prospective cross-sectional study with consecutive sampling between August 2020 and July 2021. The subjects were UC inpatients/outpatients at Dr. Sardjito Hospital who met the inclusion and exclusion criteria. The number and location of the biopsies are determined based on a colonoscopy performed by a Gastroenterology-Hepatology Consultant. An Anatomic Pathology Specialist examined the eosinophil colonic tissue. The severity of UC was classified using the Truelove Witts score. Data analysis using a computer program with a p-value 0.05 was considered statistically significant.Results: There are 3 UC severity categories according to the Truelove Witts score: 22 mild (45.8%), 9 moderate (18.8%), and 17 severe (35.4%). Seven participants (14.6%) had eosinophilia, with a median eosinophilia score of 203.33 cells/microL (0–1470 cells/microL). Five participants (10.4%) with colonic mucosal eosinophilia, with a median value of 14.13 cells/HPF (0–172 cells/HPF). The density of colonic mucosal eosinophils and the severity of UC had a moderate connection (r = 0.396; p = 0.005).Conclusion: There is a significant correlation between the density of eosinophils in the colonic mucosa and the severity of UC.

Perinatal foodborne titanium dioxide exposure-mediated dysbiosis predisposes mice to develop colitis through life

BackgroundPerinatal exposure to titanium dioxide (TiO2), as a foodborne particle, may influence the intestinal barrier function and the susceptibility to develop inflammatory bowel diseases (IBD) later in life. Here, we investigate the impact of perinatal foodborne TiO2 exposure on the intestinal mucosal function and the susceptibility to develop IBD-associated colitis. Pregnant and lactating mother mice were exposed to TiO2 until pups weaning and the gut microbiota and intestinal barrier function of their offspring was assessed at day 30 post-birth (weaning) and at adult age (50 days). Epigenetic marks was studied by DNA methylation profile measuring the level of 5-methyl-2′-deoxycytosine (5-Me-dC) in DNA from colic epithelial cells. The susceptibility to develop IBD has been monitored using dextran-sulfate sodium (DSS)-induced colitis model. Germ-free mice were used to define whether microbial transfer influence the mucosal homeostasis and subsequent exacerbation of DSS-induced colitis.ResultsIn pregnant and lactating mice, foodborne TiO2 was able to translocate across the host barriers including gut, placenta and mammary gland to reach embryos and pups, respectively. This passage modified the chemical element composition of foetus, and spleen and liver of mothers and their offspring. We showed that perinatal exposure to TiO2 early in life alters the gut microbiota composition, increases the intestinal epithelial permeability and enhances the colonic cytokines and myosin light chain kinase expression. Moreover, perinatal exposure to TiO2 also modifies the abilities of intestinal stem cells to survive, grow and generate a functional epithelium. Maternal TiO2 exposure increases the susceptibility of offspring mice to develop severe DSS-induced colitis later in life. Finally, transfer of TiO2-induced microbiota dysbiosis to pregnant germ-free mice affects the homeostasis of the intestinal mucosal barrier early in life and confers an increased susceptibility to develop colitis in adult offspring.ConclusionsOur findings indicate that foodborne TiO2 consumption during the perinatal period has negative long-lasting consequences on the development of the intestinal mucosal barrier toward higher colitis susceptibility. This demonstrates to which extent environmental factors influence the microbial-host interplay and impact the long-term mucosal homeostasis.

Propionibacterium freudenreichii CIRM-BIA 129 mitigates colitis through S layer protein B-dependent epithelial strengthening.

The growing incidence of human diseases involving inflammation and increased gut permeability makes the quest for protective functional foods more crucial than ever. Propionibacterium freudenreichii (P. freudenreichii) is a beneficial bacterium used in the dairy and probiotic industries. Selected strains exert anti-inflammatory effects, and the present work addresses whether the P. freudenreichii CIRM-BIA129, consumed daily in a preventive way, could protect mice from acute colitis induced by dextran sodium sulfate (DSS), and more precisely, whether it could protect from intestinal epithelial breakdown induced by inflammation. P. freudenreichii CIRM-BIA129 mitigated colitis severity and inhibited DSS-induced permeability. It limited crypt length reduction and promoted the expression of zonula occludens-1 (ZO-1), without reducing interleukin-1β mRNA (il-1β) expression. In vitro, P. freudenreichii CIRM-BIA129 prevented the disruption of a Caco-2 monolayer induced by proinflammatory cytokines. It increased transepithelial electrical resistance (TEER) and inhibited permeability induced by inflammation, along with an increased ZO-1 expression. Extracellular vesicles (EVs) from P. freudenreichii CIRM-BIA129, carrying the surface layer protein (SlpB), reproduced the protective effect of P. freudenreichii CIRM-BIA129. A mutant strain deleted for slpB (ΔslpB), or EVs from this mutant strain, had lost their protective effects and worsened both DSS-induced colitis and inflammation in vivo. These results shown that P. freudenreichii CIRM-BIA129 daily consumption has the potential to greatly alleviate colitis symptoms and, particularly, to counter intestinal epithelial permeability induced by inflammation by restoring ZO-1 expression through mechanisms involving S-layer protein B. They open new avenues for the use of probiotic dairy propionibacteria and/or postbiotic fractions thereof, in the context of gut permeability.NEW & NOTEWORTHY Propionibacterium freudenreichii reduces dextran sodium sulfate (DSS)-induced intestinal permeability in vivo. P. freudenreichii does not inhibit inflammation but damages linked to inflammation. P. freudenreichii inhibits intestinal epithelial breakdown through S-layer protein B. The protective effects of P. freudenreichii depend on S-layer protein B. Extracellular vesicles from P. freudenreichii CB 129 mimic the protective effect of the probiotic.

Minocycline synergizes with corticosteroids in reducing colitis severity in mice via the modulation of pro-inflammatory molecules.

Background: A few studies have highlighted the anti-inflammatory properties of minocycline in reducing colitis severity in mice, but its molecular mechanism is not fully understood. The aim of this study was to determine the anti-inflammatory properties of minocycline and the expression/activity profiles of molecules involved in pro-inflammatory signaling cascades, cytokines, and molecules involved in the apoptotic machinery. The synergistic effect between minocycline and corticosteroids was also evaluated. Methods: The effects of various treatment approaches were determined in mice using the dextran sulfate sodium (DSS) colitis model at gross and microscopic levels. The expression/activity profiles of various pro- or anti-inflammatory molecules were determined using Western blotting and polymerase chain reaction (PCR). Results: Minocycline treatment significantly reduced colitis severity using prophylactic and treatment approaches and produced a synergistic effect with budesonide and methylprednisolone in reducing the active state of colitis. This was mediated in part through reduced colonic expression/activity of pro-inflammatory molecules, cytokines, proteins involved in the apoptotic machinery, and increased expression of the anti-inflammatory cytokine IL-10. Conclusion: Minocycline synergizes with corticosteroids to reduce colitis severity, which could reduce their dose-dependent side effects and treatment cost. The reduction in colitis severity was achieved by modulating the expression/activity profiles of various pro- and anti-inflammatory signaling molecules, cytokines, and molecules involved in the apoptotic machinery.

Drug Clearance in Patients with Inflammatory Bowel Disease Treated with Biologics.

Biological therapy is very effective for treating patients with moderate to severe inflammatory bowel disease (IBD). However, up to 40% can have primary non-response, and up to 50% of the patients can experience a loss of response to anti-tumor necrosis factor therapy. These undesirable outcomes can be attributed to either a mechanistic failure or pharmacokinetic (PK) issues characterized by an inadequate drug exposure and a high drug clearance. There are several factors associated with accelerated clearance of biologics including increased body weight, low serum albumin and immunogenicity. Drug clearance has gained a lot of attention recently as cumulative data suggest that there is an association between drug clearance and therapeutic outcomes in patients with IBD. Moreover, clearance is used by model informed precision dosing (MIDP) tools, or PK dashboards, to adjust the dosing for reaching a target drug concentration threshold towards a more personalized application of TDM. However, the role of drug clearance in clinical practice is yet to be determined. This comprehensive review aims to present data regarding the variables affecting the clearance of specific biologics, the association of clearance with therapeutic outcomes and the role of clearance monitoring and MIPD in patients with IBD.

Prophylactic Coloprotective Effect of Urtica dioica Leaves against Dextran Sulfate Sodium (DSS)-Induced Ulcerative Colitis in Rats.

Background and Objectives: Urtica dioica, a source of bioactive functional compounds, provides nutritional and gastrointestinal therapeutic benefits. This study attempted to investigate the prophylactic coloprotective action of an aqueous extract of Urtica dioica (AEUD) on dextran sulfate sodium (DSS)-induced ulcerative colitis (UC). Materials and Methods: Phenolic compounds, total sugar, and mineral levels were determined in AEUD. Then, AEUD at different doses (50, 100, and 200 mg/kg, BW, p.o.) and mesalazine (MESA) as a standard treatment (100 mg/kg, BW, p.o.) were given orally for 21 days. Acute colitis was induced by administering drinking water with 5% (w/v) DSS for 7 days. Body weight variation, fecal occult blood, and stool consistency were determined daily. The severity of colitis was graded according to colon length, disease activity index (DAI), histological evaluations, and biochemical alterations. Rats orally administered DSS regularly developed clinical and macroscopic signs of colitis. Results: Due to its richness in phenolic and flavonoid compounds (247.65 ± 2.69 mg EAG/g MS and 34.08 ± 0.53 mg EQt/g MS, respectively), AEUD markedly ameliorated DAI, ulcer scores, colon length shortening, colonic histopathological changes, and hematological and biochemical modifications. Taken together, AEUD treatment notably (p < 0.01) suppressed DSS-induced UC by reducing oxidative stress via lowering MDA/H2O2 production and stimulating the effect of enzyme antioxidants as well as attenuating inflammation by decreasing CRP levels by 79.5% between the DSS and DSS + AEUD-50 groups compared to the MESA group (75.6%). Conclusions: AEUD was sufficient to exert a coloprotective effect that might be influenced by its bioactive compounds' anti-inflammatory and antioxidant capabilities.

Deficiency of inflammation-sensing protein neuropilin-2 in myeloid-derived macrophages exacerbates colitis via NF-κB activation.

Neuropilin-2 (NRP2) is a multifunctional protein engaged in the regulation of angiogenesis, lymphangiogenesis, axon guidance, and tumor metastasis, but its function in colitis remains unclear. Here, we found that NRP2 was an inflammation-sensing protein rapidly and dramatically induced in myeloid cells, especially in macrophages, under inflammatory contexts. NRP2 deficiency in myeloid cells exacerbated dextran sulfate sodium salt-induced experimental colitis by promoting polarization of M1 macrophages and colon injury. Mechanistically, NRP2 could be induced via NF-κB activation by TNF-α in macrophages, but exerted an inhibitory effect on NF-κB signaling, forming a negative feedback loop with NF-κB to sense and alleviate inflammation. Deletion of NRP2 in macrophages broke this negative feedback circuit, leading to NF-κB overactivation, inflammatory exacerbation, and more severe colitis. Collectively, these findings reveal inflammation restriction as a role for NRP2 in macrophages under inflammation contexts and suggest that NRP2 in macrophages may relieve inflammation in inflammatory bowel disease. © 2023 The Pathological Society of Great Britain and Ireland.