Acute Colitis Model Research Articles

Harnessing a Safe Novel Lipid Nanoparticle: Targeted Oral Delivery to Colonic Epithelial and Macrophage Cells in a Colitis Mouse Model.

A novel lipid nanoparticle (nLNP), formulated with three essential lipids to mimic ginger-derived exosomal particles, shows strong potential for delivering IL-22 mRNA specifically to the colon, presenting a unique oral drug delivery system for inflammatory bowel disease (IBD). However, its cellular targets and uptake behavior in healthy versus diseased colons remain unclear. Understanding these aspects is crucial for fully elucidating its targeting effectiveness in inflamed colon tissue. This study investigates the nLNP's cellular targets in healthy and diseased mouse colons. Flow cytometry compared nLNP uptake in healthy mice and a DSS-induced acute colitis model. The results revealed efficient internalization of nLNP by colonic epithelial cells in healthy and inflamed mice. In non-inflamed mice, the small number of colonic macrophages resulted in minimal uptake of nLNP by these cells. In inflamed mice, macrophages migrated to the damaged epithelium, where nLNP uptake was significantly increased, highlighting the nLNP's ability to target both epithelial and macrophage cells during inflammation. Additionally, safety assessments showed that the nLNP neither altered in vitro kinase activities nor exhibited immunotoxicity or induced in vivo toxicity at the maximum tolerated oral dose. These findings underscore the nLNP's safety and potential as a promising epithelial/macrophage-targeted drug delivery platform for oral ulcerative colitis (UC) treatment.

Intestinal epithelial Gasdermin C is induced by IL-4R/STAT6 signaling but is dispensable for gut immune homeostasis

Gasdermin C is one of the least studied members of the gasdermin family of proteins, known for their critical involvement in pyroptosis and host defense. Furthermore, evidence for the role of Gasdermin C in the intestine is scarce and partly controversial. Here, we tested the functional role of Gasdermin C in intestinal homeostasis, inflammation and tumorigenesis. : We studied Gasdermin C in response to cytokines in intestinal organoids. We evaluated epithelial differentiation, cell death and immune infiltration under steady state conditions in a new mouse line deficient in Gasdermin C. The role of Gasdermin C was analyzed in acute colitis, infection and colitis-associated cancer. Gasdemin C is highly expressed in the intestinal epithelium and strongly induced by the type 2 cytokines IL-4 and IL-13 in a STAT6-dependent manner. Gasdermin C-deficient mice show no changes in tissue architecture and epithelial homeostasis. Epithelial organoids deficient in Gasdermin C develop normally and show no alterations in proliferation or cell death. No changes were found in models of acute colitis, type 2 intestinal infection and colitis-associated cancer. Gasdermin C genes are upregulated by type 2 immunity, yet appear dispensable for the development of intestinal inflammation, infection and colitis-associated cancer.

The role of PD-1/PD-L1 pathway in ulcerative colitis and changes following tonsil-derived mesenchymal stem cells treatment.

The programmed death 1 (PD-1)/programmed death-ligand 1 (PD-L1) pathway has not been fully evaluated in inflammatory bowel disease. We evaluated PD-1/PD-L1 levels in patients with ulcerative colitis (UC) and their significance in tonsil-derived mesenchymal stem cells (TMSCs) treatment. Using acute and chronic murine colitis model, we measured the PD-1 and PD-L1 levels in inflamed colonic tissues pre- and post-treatment with TMSCs. We also measured PD-1 and PD-L1 levels in colonic tissues from UC patients, compared to normal controls. In the analysis using human colonic tissues, a significant increase in the levels of PD-1 and PD-L1 was observed in the colonic mucosa of patients with UC compared with normal controls (p < 0.001 and p = 0.005, respectively). When comparing the maximal disease extent, PD-L1 levels were highest in patients with proctitis (38.5 ± 46.7), followed by left-side colitis (17.5 ± 23.1) and extensive colitis (5.2 ± 8.2) (p < 0.001). In the chronic colitis model, the level of PD-L1 was decreased (p = 0.040) and the level of PD-1 increased more than in normal controls (p = 0.047). After treatment with TMSC, significant improvements were observed in body weight, disease activity index, and colon length recovery. Additionally, the levels of PD-1 and PD-L1 were recovered; PD-L1 significantly increased (p = 0.031), while the level of PD-1 decreased (p = 0.310). The altered expression of PD-1 and PD-L1 in colonic mucosa may be a possible mechanism of UC, and T-MSC-derived PD-L1 could help suppress colitis.

Glyburide Suppresses Inflammation-Related Colorectal Tumorigenesis Through Inhibition of NLRP3 Inflammasome.

Colorectal cancer represents one of the most serious complications of inflammatory bowel disease. The NLRP3 inflammasome plays a pivotal role in the onset and progression of inflammatory bowel disease and is also implicated in colorectal cancer. This study aimed to investigate whether NLRP3 deficiency or glyburide, a sulfonylurea used for diabetes management and known as an NLRP3 inhibitor, could suppress colitis and its related colorectal tumorigenesis. Mice were divided into three groups: a control group, a glyburide group, and an NLRP3-deficient group. We investigated acute colitis and inflammation-related tumor models using azoxymethane and dextran sodium sulfate. In the colitis model, the colonic inflammation grade was significantly increased in NLRP3-deficient mice but not in mice administered glyburide. In the colorectal carcinogenesis model, fewer colorectal tumors were observed in both NLRP3-deficient and glyburide-treated groups. Additionally, a reduction in the expression levels of inflammatory cytokine genes was detected in the colonic mucosa of the mice of these groups. These findings suggest that NLRP3 deficiency may exacerbate acute colitis, while pharmacological inhibition, as well as deficiency of NLRP3, suppresses colitis-related tumorigenesis, presumably due to the attenuation of chronic inflammation in the colorectum. Glyburide holds promise as a potential chemopreventive agent for colitis-related colorectal cancer.

Benzoylmesaconine mitigates NLRP3 inflammasome-related diseases by reducing intracellular K+ efflux and disrupting NLRP3 inflammasome assembly

BackgroundBenzoylmesaconine (BMA), a major alkaloid derived from the traditional Chinese medicine Aconitum carmichaeli Debx, exhibits potent anti-inflammatory properties. However, the precise mechanism underlying its action remains unclear. PurposeThis study aimed to investigate the inhibitory mechanism of BMA on the NLRP3 inflammasome and assess its therapeutic efficacy in NLRP3-related metabolic diseases. MethodsA classic NLRP3 inflammasome-activated bone marrow-derived macrophage (BMDM) model was established to evaluate BMA's effects on NLRP3 upstream and downstream protein expression, as well as pyroptosis. Two distinct animal disease models, MSU-induced gouty arthritis and DSS-induced colitis, were utilized to validate BMA's anti-inflammatory activity in vivo. ResultsIn vitro findings revealed that BMA can suppress NLRP3 inflammasome activation by inhibiting interleukin-1β (IL-1β) secretion and GSDMD-N protein expression. This mechanism involved blocking intracellular K+ efflux and interfering with the formation of NLRP3 inflammasomes. In vivo studies demonstrated that BMA significantly alleviated inflammatory symptoms in MSU-induced acute gout and DSS-induced colitis models. ConclusionThese findings suggest that BMA effectively inhibits the activation of the NLRP3 signaling pathway through dual mechanisms: reducing intracellular K+ efflux and disrupting NLRP3 inflammasome assembly. This multifaceted action highlights the therapeutic potential of BMA for NLRP3-related diseases.

A derivative of tanshinone IIA and salviadione, 15a, inhibits inflammation and alleviates DSS-induced colitis in mice by direct binding and inhibition of RIPK2.

Inflammatory bowel diseases (IBDs) are chronic inflammatory conditions primarily affecting the gastrointestinal tract. Previous studies established the role of the NF-κB signaling pathway in the development of IBDs, suggesting that anti-inflammatory therapies might offer a viable treatment strategy. Tanshinone IIA and salviadione, both derived from Salviae Miltiorrhizae Radix et Rhizoma, possess anti-inflammatory and anti-oxidative activities. A series of new compounds were synthesized by hybridizing salviadione with tanshinone. Among these compounds, 15a showed beneficial effects in LPS-induced acute lung injury and diabetes-induced renal injury mouse models. The current study explored the therapeutic efficacy of 15a using both acute and chronic colitis models and elucidated the underlying mechanisms. DSS-induced colitis models were established in mice, where acute colitis was treated with compound 15a (5 or 10 mg·kg-1·d-1) for 8 days, while chronic colitis mice received compound 15a (5 or 10 mg·kg-1·d-1, i.g.) during 2.5% DSS administration. The 15a treatment significantly alleviated DSS-induced pathological and inflammatory damages in both acute and chronic colitis mouse models. In mouse intestinal epithelial cell line MODE-K, pretreatment with compound 15a (5 or 10 μM) significantly suppressed LPS + L18-MDP-induced inflammatory responses. The receptor-interacting serine/threonine kinase 2 (RIPK2) was identified as a direct binding target of compound 15a using microarrays and recombinant human proteins. Moreover, 15a could directly bind to and inhibit the phosphorylation of RIPK2, leading to the suppression of the NF-κB and MAPK signaling pathways. Furthermore, LEU153 and VAL32 were identified within the KD domain of RIPK2 as critical amino residues for the binding of 15a. Briefly, the current findings demonstrate that compound 15a holds promise as a therapeutic agent for managing acute and chronic colitis.

N-terminomics profiling of naïve and inflamed murine colon reveals proteolytic signatures of legumain.

Legumain is a cysteine protease broadly associated with inflammation. It has been reported to cleave and activate protease-activated receptor 2 to provoke pain associated with oral cancer. Outside of gastric and colon cancer, little has been reported on the roles of legumain within the gastrointestinal tract. Using a legumain-selective activity-based probe, LE28, we report that legumain is activated within colonocytes and macrophages of the murine colon, and that it is upregulated in models of acute experimental colitis. We demonstrated that loss of legumain activity in colonocytes, either through pharmacological inhibition or gene deletion, had no impact on epithelial permeability in vitro. Moreover, legumain inhibition or deletion had no obvious impacts on symptoms or histological features associated with dextran sulfate sodium-induced colitis, suggesting its proteolytic activity is dispensable for colitis initiation. To gain insight into potential functions of legumain within the colon, we performed field asymmetric waveform ion mobility spectrometry-facilitated quantitative proteomics and N-terminomics analyses on naïve and inflamed colon tissue from wild-type and legumain-deficient mice. We identified 16 altered cleavage sites with an asparaginyl endopeptidase signature that may be direct substrates of legumain and a further 16 cleavage sites that may be indirectly mediated by legumain. We also analyzed changes in protein abundance and proteolytic events broadly associated with colitis in the gut, which permitted comparison to recent analyses on mucosal biopsies from patients with inflammatory bowel disease. Collectively, these results shed light on potential functions of legumain and highlight its potential roles in the transition from inflammation to colorectal cancer.

Synthesis and Anti-Inflammatory Bowel Disease Activity of Pterostilbene Derivatives.

The aberrant activation of NLRP3 inflammasomes is intricately linked to various inflammatory diseases. In this study, we present the discovery and optimization of a series of NLRP3 inflammasome inhibitors based on the pterostilbene skeleton. All compounds underwent screening to evaluate their inhibitory effects on LPS/Nigericin-induced IL-1β secretion and anti-cellular pyroptosis. Most compounds exhibit good biological activity and cellular safety, with compound D20 showing the most prominent activity. Preliminary mechanism studies suggest that compound D20 may affect the assembly of NLRP3 inflammasomes by targeting the NLRP3 protein, thereby inhibiting the activation of NLRP3 inflammasomes. The in vivo anti-inflammatory activity demonstrated significant therapeutic effect of compound D20 on DSS-induced acute colitis model in mice. This work has important reference significance for the development of drugs targeting NLRP3 inflammasomes.

Evaluation of TNF-α and IFN-γ primed conditioned medium of mesenchymal stem cell in acetic acid-induced mouse model of acute colitis

IBD, an autoimmune-inflammatory disorder that affects people who are genetically prone to inflammation. There is a lot of interest in MSC-CM therapy, especially when primed with TNF-α + IFN-γ. Throughout the study, data were collected on the percentage of apoptotic cells, gene expression of ZO-1, Foxp3, GATA3, IDO-1, Muc2, T-bet, Notch1, TNFR2, and ROR-γt, colon weight and length, histopathological analysis, and DAI. TNF-α and IL-10 levels were assessed in addition to the NO level. The results suggest that primed MSC-CM improved DAI, mucosal deterioration, intestinal inflammation and NO concentration. The amount of TNF-α was decreased, but IL-10 and the colon’s percentage of apoptotic cells was increased. The mRNA expression of ZO-1, Foxp3, GATA3, IDO-1, and Muc2 genes increased greatly in the treatment groups, while the expression of T-bet, Notch1, TNFR2, and ROR-γt genes has decreased. These studies suggest that primed MSC-CM may combine with common treatments to improve responsiveness.

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

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

Protective Effect of Rosavin Against Intestinal Epithelial Injury in Colitis Mice and Intestinal Organoids.

Rhodiola species have been utilized as functional foods in Asia and Europe for promoting health. Research has demonstrated that Rhodiola has the potential to alleviate inflammatory bowel disease (IBD) in animal models. However, the specific active components and the underlying mechanism for ameliorating intestinal damage remain unclear. This study aims to explore the relieving effect of Rosavin (Rov), a known active constituent of Rhodiola, in IBD and the regulatory mechanisms. The therapeutic effect of Rov was evaluated using a murine model of acute colitis induced by dextran sulfate sodium salt (DSS). Inflammatory cytokines and neutrophil activation markers were measured by corresponding kits. Immunohistochemistry, immunofluorescence, TUNEL, and EdU assays were applied to investigate the tight conjunction proteins expression, epithelial marker expression, number of apoptotic cells, and epithelial proliferation, respectively. The protection effect of Rov on gut epithelial injury was assessed using TNF-α-induced intestinal organoids. Additinally, RNA sequencing was applied to observe the genetic alteration profile in these intestinal organoids. Oral administration of Rov significantly attenuated weight loss and restored colon length in mice. Notably, Rov treatment led to decreased levels of pro-inflammatory cytokines and neutrophil activation markers while increasing anti-inflammatory factors. Importantly, Rov restored intestinal despair by increasing the number of Lgr5+ stem cells, Lyz1+ Paneth cells and Muc2+ goblet cells in intestines of colitis mice, displaying reduced epithelial apoptosis and recovered barrier function. In TNF-α-induced intestinal organoids, Rov facilitated epithelial cell differentiation and protected against TNF-α-induced damage. RNA sequencing revealed upregulation in the gene expression associated with epithelial cells (including Lgr5+, Lyz1+ and Muc2+ cells) proliferation and defensin secretion, unveiling the protective mechanisms of Rov on the intestinal epithelial barrier. Rov holds potential as a natural prophylactic agent against IBD, with its protective action on the intestinal epithelium being crucial for its therapeutic efficacy.

Bioinspired micro-nano hierarchical delivery system for sequential targeted therapy of inflammatory bowel disease

Inflammatory bowel disease (IBD) constitutes an immense health and economic burden worldwide, highlighting the need for improved therapy. Up to now, various delivery systems have been proposed to enhance IBD treatment. Herein, inspired by cellular communication in nature, we present a novel micro-nano hierarchical microsphere system with the enhanced targeting capability for IBD treatment. The hierarchical microspheres are designed for oral delivery, with astaxanthin nanoparticles in the core and Zein protein shell. Similar to a stepwise process of cellular communication, microscale spheres can escape from the gastric acid due to Zein coating. Once reach into the intestine, mucoadhesive Zein coating and the core could be enzymatically digested, following the targeted release of astaxanthin nanoparticles. Particularly, these astaxanthin nanoparticles are endowed with the mitochondria targeting capability, thereby greatly attenuating pro-inflammatory response of macrophages. Based on these features, practical performances of the hierarchical delivery system have been investigated in both acute and chronic colitis model. Animal experiments have revealed the desired therapeutic effects of the hierarchical microspheres by inhibiting inflammatory responses and modulating gut microbiota. These results suggested the present hierarchical delivery system offers a stepwise strategy for nanodrug delivery to the intestine as well as the effective treatment of IBD.

A hepatocyte-specific transcriptional program driven by Rela and Stat3 exacerbates experimental colitis in mice by modulating bile synthesis.

Hepatic factors secreted by the liver promote homeostasis and are pivotal for maintaining the liver-gut axis. Bile acid metabolism is one such example wherein, bile acid synthesis occurs in the liver and its biotransformation happens in the intestine. Dysfunctional interactions between the liver and the intestine stimulate varied pathological outcomes through its bidirectional portal communication. Indeed, aberrant bile acid metabolism has been reported in inflammatory bowel disease (IBD). However, the molecular mechanisms underlying these crosstalks that perpetuate intestinal permeability and inflammation remain obscure. Here, we identify a novel hepatic gene program regulated by Rela and Stat3 that accentuates the inflammation in an acute experimental colitis model. Hepatocyte-specific ablation of Rela and Stat3 reduces the levels of primary bile acids in both the liver and the gut and shows a restricted colitogenic phenotype. On supplementation of chenodeoxycholic acid (CDCA), knock-out mice exhibit enhanced colitis-induced alterations. This study provides persuasive evidence for the development of multi-organ strategies for treating IBD and identifies a hepatocyte-specific Rela-Stat3 network as a promising therapeutic target.

Eosinophil Depletion as a Potential Therapeutic Strategy in Acute and Chronic Intestinal Inflammation Based on a Dextran Sulfate Sodium Colitis Model.

A role for eosinophils in intestinal inflammation and fibrosis in the context of inflammatory bowel disease has been suggested, yet the precise nature, whether causal or secondary remains debated. Hence, it remains unclear whether targeting eosinophils should be further explored as a treatment option in inflammatory bowel disease. Acute and chronic dextran sulfate sodium colitis was induced in wild-type C57BL/6 mice. Eosinophils were depleted by anti-CCR3 injections before colitis induction in a chronic model and after colitis onset in an acute model in order to investigate the impact of eosinophil depletion on pre-existing colitis. Inflammation was assessed using the disease activity index, macroscopic damage, and histological disease activity score. In the chronic model, fibrosis was assessed by examining colon weight/length ratio, collagen deposition through Martius Scarlet Blue staining, hydroxyproline assay, and COL1A1 expression. Protein and gene expression were assessed using the Meso Scale Discovery platform and real-time quantitative polymerase chain reaction. In the acute and chronic colitis model, eosinophil depletion resulted in reduced disease activity and faster recovery, as observed via the total area under the curve of the disease activity index (P = .004 and P = .02, respectively), macroscopic damage score (P = .009 and P = .08, respectively), and histological disease activity score (P = .09 and P = .002, respectively). In the acute model, the accelerated recovery was accompanied by an increase in interleukin (IL)-10 (P = .03) and a decrease in IL-4 (P = .03) and IL-6 (P = .009). Colon weight/length ratio and collagen deposition were not affected by eosinophil depletion. Eosinophil depletion prevents and decreases intestinal inflammation in a preclinical dextran sulfate sodium model without affecting fibrosis. These results pave the way for exploring eosinophil depletion as a novel treatment modality in addressing intestinal inflammation.

Matrix metalloproteinase-responsive hydrogels with tunable retention for on-demand therapy of inflammatory bowel disease

Therapeutic options for addressing inflammatory bowel disease (IBD) include the administration of an enema to reduce intestinal inflammation and alleviate associated symptoms. However, uncontrollable retention of enemas in the intestinal tract has posed a long-term challenge for improving their therapeutic efficacy and safety. Herein we have developed a protease-labile hydrogel system as an on-demand enema vehicle with tunable degradation and drug release rates in response to varying matrix metalloproteinase-9 (MMP-9) expression. The system, composed of three tailored hydrogel networks, is crosslinked by poly (ethylene glycol) (PEG) with 2-, 4- and 8-arms through dynamic hydrazone bonds to confer injectability and generate varying network connectivity. The retention time of the hydrogels can be tuned from 12 to 36 h in the intestine due to their different degradation behaviors induced by MMP-9. The drug-releasing rate of the hydrogels can be controlled from 0.0003 mg/h to 0.278 mg/h. In addition, injection of such hydrogels in vivo resulted in significant differences in therapeutic effects including MMP-9 consumption, colon tissue repair, reduced collagen deposition, and decreased macrophage cells, for treating a mouse model of acute colitis. Among them, GP-8/5-ASA exhibits the best performance. This study validates the effectiveness of the tailored design of hydrogel architecture in response to pathological microenvironment cues, representing a promising strategy for on-demand therapy of IBD. Statement of significanceThe uncontrollable retention of enemas at the delivery site poses a long-term challenge for improving therapeutic efficacy in IBD patients. MMP-9 is highly expressed in IBD and correlates with disease severity. Therefore, an MMP-9-responsive GP hydrogel system was developed as an enema by linking multi-armed PEG and gelatin through hydrazone bonds. This forms a dynamic hydrogel characterized by in situ gelation, injectability, enhanced bio-adhesion, biocompatibility, controlled retention time, and regulated drug release. GP hydrogels encapsulating 5-ASA significantly improved the intestinal phenotype of acute IBD and demonstrated notable therapeutic differences with increasing PEG arms. This method represents a promising on-demand IBD therapy strategy and provides insights into treating diseases of varying severities using endogenous stimulus-responsive drug delivery systems.

Cryo-Fluorescence Tomography as a Tool for Visualizing Whole-Body Inflammation Using Perfluorocarbon Nanoemulsion Tracers.

We explore the use of intravenously delivered fluorescent perfluorocarbon (PFC) nanoemulsion tracers and multi-spectral cryo-fluorescence tomography (CFT) for whole-body tracer imaging in murine inflammation models. CFT is an emerging technique that provides high-resolution, three-dimensional mapping of probe localization in intact animals and tissue samples, enabling unbiased validation of probe biodistribution and minimizes reliance on laborious histological methods employing discrete tissue panels, where disseminated populations of PFC-labeled cells may be overlooked. This methodology can be used to streamline the development of new generations of non-invasive, cellular-molecular imaging probes for in vivo imaging. Mixtures of nanoemulsions with different fluorescent emission wavelengths were administered intravenously to naïve mice and models of acute inflammation, colitis, and solid tumor. Mice were euthanized 24 h post-injection, frozen en bloc, and imaged at high resolution (~ 50 µm voxels) using CFT at multiple wavelengths. PFC nanoemulsions were visualized using CFT within tissues of the reticuloendothelial system and inflammatory lesions, consistent with immune cell (macrophage) labeling, as previously reported in in vivo magnetic resonance and nuclear imaging studies. The CFT signals show pronounced differences among fluorescence wavelengths and tissues, presumably due to autofluorescence, differential fluorescence quenching, and scattering of incident and emitted light. CFT is an effective and complementary methodology to in vivo imaging for validating PFC nanoemulsion biodistribution at high spatial localization, bridging the resolution gap between in vivo imaging and histology.

4-Octyl itaconate blocks GSDMB-mediated pyroptosis and restricts inflammation by inactivating granzyme A.

GSDMB-mediated pyroptosis facilitates a pro-inflammatory immune microenvironment and needs to be tightly regulated to avoid excessive inflammation. Here, we provide evidence that itaconate and its cell-permeable derivative 4-octyl itaconate (4-OI) can significantly inhibit GSDMB-rendered pyroptotic activity independent of Nrf2. 4-OI interferes proteolytic process of GSDMB by directly modifying Cys54, Cys148 and Ser212 on granzyme A (GrzA), a serine protease that site-specifically cleaves the inter-domain linker of GSDMB, instead of interaction with GSDMB, thereby blocking pyroptosis and exerts anti-inflammatory effects. Moreover, 4-OI alleviates inflammation by suppressing GSDMB-induced pyroptotic cell death during acute colitis models in intestinal epithelial GSDMB conditional transgenic mice. Our data expand the role of 4-OI as a crucial immunometabolic derivative that regulates innate immunity and inflammation through a newly identified posttranslational modification, and targeting of pyroptosis by 4-OI therefore holds potent therapeutic potential for primarily inflammatory and/or autoimmune diseases.

Alginate/silk fibroin/Zn2+ composite microspheres for site-specific delivery for enhanced ulcerative colitis therapy

The limited therapeutic efficacy of oral medications against ulcerative colitis (UC) is attributed to inadequate drug exposure to inflammation site in the colon. To address this challenge, we developed a pH-triggered oral hydrogel microsphere system composed of alginate/silk fibroin (Alg/SF) using zinc ions (Zn2+) as a crosslink agent for colon-targeted delivery. This system, with moderate gelation toughness, can protect the anti-inflammatory drug bornyl acetate (BA) from gastric degradation, ensuring its delivery to the colon. SF effectively shields the microspheres during passage through the small intestine and then facilitates rapid drug release upon reaching the colon. We evaluated the efficacy of this strategy in murine models of both acute and chronic colitis, demonstrating its significant capacity to attenuate pro-inflammatory cytokine secretion, enhance intestinal barrier restitution, and modulate immune cell responses for effective amelioration of colitis-associated symptoms. Upon oral administration of microspheres, their therapeutic efficacy against both acute and chronic UC is demonstrated to be superior to that of a widely used clinical drug, 5-aminosalicylic acid. Overall, the oral hydrogel microspheres offer a promising approach to enhance the therapeutic outcomes of small molecule drug against UC.

Chlorination of epithelial tight junction proteins by neutrophil myeloperoxidase promotes barrier dysfunction and mucosal inflammation.

Neutrophils (polymorphonuclear leukocytes, PMNs) comprise a major component of the immune cell infiltrate during acute mucosal inflammation and have an important role in molding the inflammatory tissue environment. While PMNs are essential to clearance of invading microbes, the major PMN antimicrobial enzyme myeloperoxidase (MPO) can also promote bystander tissue damage. We hypothesized that blocking MPO would attenuate acute colitis and prevent the development of chronic colitis by limiting bystander tissue damage. Using the acute and chronic dextran sodium sulfate model of murine colitis, we demonstrated that MPO-deficient mice experienced less inflammation and more rapidly resolved colitis relative to wild-type controls. Mechanistic studies demonstrated that activated MPO disrupted intestinal epithelial barrier function through the dysregulation of the epithelial tight junction proteins. Our findings revealed that activated MPO chlorinates tyrosine within several tight junction proteins, thereby promoting tight junction mislocalization and dysfunction. These observations in cell models and in murine colitis were validated in human intestinal biopsies from individuals with ulcerative colitis and revealed a strong correlation between disease severity (Mayo score) and tissue chlorinated tyrosine levels. In summary, these findings implicate MPO as a viable therapeutic target to limit bystander tissue damage and preserve mucosal barrier function during inflammation.

Metabolomics reveals the potential metabolic mechanism of infliximab against DSS-induced acute and chronic ulcerative colitis.

Inflammatory bowel disease (IBD) is often accompanied by metabolic imbalance, and infliximab (IFX) can alleviate IBD symptoms, but its metabolic mechanisms remain unclear. To investigate the relationship between IBD, metabolism, and IFX, an acute and chronic ulcerative colitis (UC) model induced by dextran sulfate sodium (DSS) was established. Plasma samples were analyzed using ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry, followed by multivariate statistical analysis. The results showed that IFX could alleviate colonic shortening and reduce colonic pathological damage in acute and chronic mouse colitis, improve acute and chronic UC, and ameliorate metabolic disturbances. Among the 104 elevated metabolites and 170 decreased metabolites, these metabolites mainly belonged to amino acids, glucose, and purines. The changes in these metabolites were mainly associated with drug metabolism-other enzymes, riboflavin metabolism, phenylalanine, tyrosine and tryptophan biosynthesis, phosphonate and phosphinate metabolism, and phenylalanine metabolism. In summary, this study provides a valuable approach to explore the metabolic mechanisms of IFX in treating acute and chronic UC from a metabolomics perspective.