Colitis In Mice Research Articles

Exploring the efficacy of Transcutaneous Auricular Vagus nerve stimulation (taVNS) in modulating local and systemic inflammation in experimental models of colitis

BackgroundCurrent inflammatory bowel disease (IBD) treatments often fail to achieve lasting remission and have adverse effects. Vagus nerve stimulation (VNS) offers a promising therapy due to its anti-inflammatory effects. Its invasive nature, however, has led to the development of non-invasive methods like transcutaneous auricular VNS (taVNS). This study assesses taVNS’s impact on acute colitis progression, inflammatory, anti-inflammatory, and apoptosis-related markers.MethodsMale C57BL/6 mice (11–12 weeks) were used for dextran sulfate sodium (DSS)- and dinitrobenzene sulfonic acid (DNBS)-induced colitis studies. The administration of taVNS or no stimulation (anesthesia without stimulation) for 10 min per mouse began one day before colitis induction and continued daily until sacrifice. Ulcerative colitis (UC)-like colitis was induced by administering 5% DSS in drinking water for 5 days, after which the mice were sacrificed. Crohn’s disease (CD)-like colitis was induced through a single intrarectal injection of DNBS/ethanol, with the mice sacrificed after 3 days. Disease activity index (DAI), macroscopic evaluations, and histological damage were assessed. Colon, spleen, and blood samples were analyzed via qRT-PCR and ELISA. One-way or two-way ANOVA with Bonferroni and Šídák tests were applied.ResultstaVNS improved DAI, macroscopic, and histological scores in DSS colitis mice, but only partially mitigated weight loss and DAI in DNBS colitis mice. In DSS colitis, taVNS locally decreased colonic inflammation by downregulating pro-inflammatory markers (IL-1β, TNF-α, Mip1β, MMP 9, MMP 2, and Nos2) at the mRNA level and upregulating anti-inflammatory TGF-β in non-colitic conditions at both mRNA and protein levels and IL-10 mRNA levels in both non-colitic and colitic conditions. Systemically, taVNS decreased splenic TNF-α in non-colitic mice and increased serum levels of TGF-β in colitic mice and splenic levels in non-colitic and colitic mice. Effects were absent in DNBS-induced colitis. Additionally, taVNS decreased pro-apoptotic markers (Bax, Bak1, and caspase 8) in non-colitic and colitic conditions and increased the pro-survival molecule Bad in non-colitic mice.ConclusionsThis study demonstrates that taVNS has model-dependent local and systemic effects, reducing inflammation and apoptosis in UC-like colitis while offering protective benefits in non-colitic conditions. These findings encourage further research into underlying mechanisms and developing adjunct therapies for UC.

Oral Delivery of miR146a Conjugated to Cerium Oxide Nanoparticles Improves an Established T Cell-Mediated Experimental Colitis in Mice

Background: Dysregulated inflammation and oxidative stress are strongly implicated in the pathogenesis of inflammatory bowel disease. We have developed a novel therapeutic that targets inflammation and oxidative stress. It is comprised of microRNA-146a (miR146a)-loaded cerium oxide nanoparticles (CNPs) (CNP-miR146a). We hypothesized that oral delivery of CNP-miR146a would reduce colonic inflammation in a mouse model of established, chronic, T cell-mediated colitis. Methods: The stability of CNP-miR146a and mucosal delivery was assessed in vitro with simulated gastrointestinal fluid and in vivo after oral gavage by quantitative real-time RT-PCR. The efficacy of orally administered CNP-miR146a was tested in mice with established colitis using the model of adoptive naïve T-cell transfer in recombinant activating gene 2 knockout (Rag2−/−) mice. Measured outcomes included histopathology; CD45+ immune cell infiltration; oxidative DNA damage (tissue 8-hydroxy-2′-deoxyguanosine; 8-OHdG); expression of IL-6 and TNF mRNA and protein, and flow cytometry analysis of lamina propria Th1 and Th17 cell populations. Results: miR146a expression remained stable in simulated gastric and intestinal conditions. miR146a expression increased in the intestines of mice six hours following oral gavage of CNP-miR146a. Oral delivery of CNP-miR146a in mice with colitis was associated with reduced inflammation and oxidative stress in the proximal and distal colons as evidenced by histopathology scoring, reduced immune cell infiltration, reduced IL-6 and TNF expression, and decreased populations of CD4+Tbet+IFNg+ Th1, CD4+RorgT+IL17+ Th17, as well as pathogenic double positive IFNg+IL17+ T cells. Conclusions: CNP-miR146a represents a novel orally available therapeutic with high potential to advance into clinical trials.

The Potential of the Probiotic Isolate Lactobacillus plantarum SS18‐50 to Prevent Colitis in Mice

ABSTRACTThe objective of this study was to investigate the effect of the Lactobacillus plantarum (L. plantarum) SS18‐50 (an isolate with favorable probiotic properties following space traveling) on dextran sulfate sodium (DSS)‐induced colitis in mice. Male ICR mice were randomly assigned to one of six groups: a control group, a model group, and four intervention groups comprising the isolate (SS18‐50‐L and SS18‐50‐H) and the wild type (GS18‐L and GS18‐H) strains. The model group and the intervention groups were administered a 3.5% DSS (w/v) solution to induce acute enteritis. The four intervention groups were administered the corresponding bacterial suspensions, SS18‐50‐L (1.0 × 107 CFU/mL), SS18‐50‐H (1.0 × 109 CFU/mL), GS18‐L (1.0 × 107 CFU/mL), and GS18‐H (1.0 × 109 CFU/mL). The results demonstrated that the disease activity index (DAI) score of the SS18‐50‐H was markedly lower than that of the CON. Subsequently, the colon tissue of mice was analyzed to determine the levels of myeloperoxidase (MPO), superoxide dismutase (SOD), glutathione (GSH), and malondialdehyde (MDA). The results demonstrated that all strains within the intervention groups exhibited good performance to prevent colitis. Particularly, the SS18‐50‐H strain exhibited a pronounced stimulative effect on GSH, an increase in SOD activity, and a decrease in MPO activity and MDA content. The SS18‐50‐H treatment resulted in a notable elevation in serum somatostatin (SS) levels and a concomitant reduction in endothelin (ET) and substance P (SP) levels, which approached normal ranges. The results of the RT‐qPCR analysis demonstrated that the mRNA expression levels of tumor necrosis factor (TNF‐α), cyclooxygenase (COX‐2), interleukin (IL‐10), and interleukin (IL‐6) in the SS18‐50‐H were significantly reduced to levels comparable to those observed in the CON. In conclusion, L. plantarum SS18‐50 has been demonstrated to inhibit the development of colitis in a dose‐dependent manner, thereby establishing it as a high‐quality lactic acid bacterium with a colitis inhibitory effect.

Sulfasalazine-Loaded Copper-Tannic Acid Coordination Nanozyme Enables ROS Scavenging and Immunomodulation for Inflammatory Bowel Disease Therapy.

Inflammatory bowel disease (IBD) is associated with elevated levels of reactive oxygen species (ROS) and an increased expression of proinflammatory cytokines. Anti-inflammatory drugs, monoclonal antibodies, and immunomodulators are commonly employed to control the inflammatory response in the management of IBD. Here, a copper and tannic acid (TA) coordination nanozyme (CuTA) loaded with sulfasalazine (SSZ-CuTA) is synthesized for the treatment of IBD by simultaneous scavenging ROS and immunosuppression. The CuTA exhibits both dismutase-like activity and catalase-like activity, making it efficient at scavenging ROS. These nanozymes can efficiently traverse gastric acid and subsequently exert their effects within the intestinal tract. It is verified that SSZ-CuTA can restore intestinal mucosal and goblet cells to a healthy state by effectively eliminating ROS and reducing the pro-inflammatory factors in a mouse IBD model. Overall, the SSZ-CuTA will offer a promising alternative treatment for patients suffering from IBD where excessive ROS and high inflammation coexist.

Fructo-oligosaccharides Alleviated Ulcerative Colitis via Gut Microbiota-Dependent Tryptophan Metabolism in Association with Aromatic Hydrocarbon Receptor Activation in Mice.

Fructo-oligosaccharide (FOS) is a typical prebiotic with intestinal health-promoting effects. Here, we explored the anticolitis activity of FOS and clarified the underlying mechanisms. Dextran sulfate sodium (DSS)-induced mice were gavaged with FOS (400 mg/kg) for 37 days, and administration of FOS alleviated DSS-induced colitis symptoms. Besides, FOS improved gut microbiota dysbiosis and modulated the intestinal microbiota-controlled tryptophan metabolic pathways. Targeted metabolomic results showed that FOS significantly increased the colonic levels of indole-3-acetic acid (IAA) and indole-3-propionic acid (IPA) and subsequently increased the expressions of aromatic hydrocarbon receptors (AhR) in the colon and further promoted the expressions of interleukin-22 (IL-22) and intestinal tight junction proteins in the colitis mice. These findings for the first time highlight a novel anticolitis mechanism of FOS by alleviating intestinal microbiota dysbiosis and modulating microbial tryptophan metabolism to promote IAA and IPA production for triggering AhR/IL-22 axis activation.

Type 5 Resistant Starch Can Effectively Alleviate Experimentally Induced Colitis in Mice by Modulating Gut Microbiota.

Resistant starch (RS) has been shown to modulate intestinal microbiota in animal models in ways that could reduce the effects of dysbiosis-related diseases. However, the mechanism of how this is achieved is not understood. The present study aimed to reveal the mechanism of how RS mitigates dextran sulfate sodium (DSS)-induced colitis in mice by using a starch-lipid complex (RS type 5), with an RS type 2 from high-amylose maize starch as a comparison. Both RS5 and RS2 induced changes in the diversity and composition of the gut bacteria, leading to the alleviation of the induced colitis symptoms including decreasing the loss in body weight, disease activity index score, and colonic shortening. The levels of inflammatory cytokines were modulated and accompanied by an increase in goblet cell numbers and thickening of the intestinal mucus layer. RS5 was more effective, compared to RS2, in alleviating all of the colitis symptoms, mainly through improving the gut microflora dysbiosis and stimulating the generation of short-chain fatty acids (SCFAs). Our study shows that RS5 could effectively alleviate the symptoms of colitis, highlighting a potential use for RS5, particularly in relieving inflammatory bowel disease.

Therapeutic Efficacy and Underlying Mechanisms of a Mannoglucan from Hirsutella sinensis Mycelium on Dextran Sulfate Sodium-Induced Inflammatory Bowel Disease in Mice: Modulation of the Intestinal Barrier, Oxidative Stress and Gut Microbiota

Hirsutella sinensis (H. sinensis), a non-sexual form of the valuable Chinese medicinal herb, demonstrates various biological activities, such as immune modulation and antioxidative capabilities. Nonetheless, the effects of bioactive polysaccharides derived from H. sinensis on colitis have yet to be investigated. In our prior research, we extracted a mannoglucan (HSWP-1d) from H. sinensis and found that it attenuates TGF-β1-induced epithelial-mesenchymal transition. The present study investigated the protective effects of HSWP-1d against colitis induced by dextran sulfate sodium (DSS) in mice. The results demonstrate that HSWP-1d effectively ameliorates symptoms of colitis and preserves the intestinal barrier’s stability by enhancing the expression of tight junction proteins. The administration of HSWP-1d results in a reduction in oxidative stress through the augmentation of antioxidative enzyme activities, concomitant with the suppression of oxidative product generation. Simultaneously, HSWP-1d reduced the levels of pro-inflammatory cytokines while elevating the levels of anti-inflammatory cytokines, effectively mitigating the inflammatory response. Furthermore, HSWP-1d influences and alters short-chain-fatty-acid (SCFA) levels, thereby enhancing the intestinal microenvironment. In conclusion, HSWP-1d contributes to intestinal well-being and holds potential as both a therapeutic choice and a supplier of essential nutrients for the amelioration of colitis.

Protective effect of Huanglian Pingwei San on DSS-induced ulcerative colitis in mice through amelioration of the inflammatory response and oxidative stress

IntroductionUlcerative colitis (UC) results in the breakdown of the mucosal barrier caused by persistent inflammation and oxidative stress. Huanglian Pingwei San (HLPWS) is a commonly prescribed traditional Chinese medicine for treating colitis, but the precise mechanism remains unclear. The aim of this study was to systematically investigate the protective effect of HLPWS on UC mice and to elucidate the underlying mechanisms involved.MaterialsUC mouse model was established in C57BL/6 mice via 2.25% dextran sulfate sodium (DSS). The chemical composition of HLPWS was examined through UPLC/MS Q-TOF analysis. The efficacy of HLPWS in treating UC was assessed. A TUNEL assay was used to detect apoptotic cells. An ELISA was used to evaluate the levels of inflammatory cytokines in colon tissues and serum. The percentages of Treg and Th17 cells were measured via flow cytometry. The protein expression in the colonic tissue was validated via immunohistochemistry (IHC) and Western blotting.ResultsHLPWS significantly improved UC symptoms and colon tissue histology in mice. The structure and function of the intestinal barrier were restored by HLPWS treatment, as shown by increased DAO content, reduced levels of FITC-dextran, and increased protein expression of ZO-1, occludin, claudin, and MUC2. HLPWS dose-dependently decreased the number of apoptotic cells by inhibiting P53, P21, P27, cleaved caspase 3, and p-H2AX expression. HLPWS also reduced abnormal oxidative stress by reducing Keap1 expression and increasing Nrf2 and HO-1 levels. Furthermore, HLPWS rebalanced the Treg/Th17 ratio to alleviated inflammatory reactions in UC mice.ConclusionThese findings suggest that HLPWS alleviated colonic intestinal barrier dysfunction in UC mice by reducing oxidative stress and restoring immune balance. This study underscores the potential therapeutic benefits of HLPWS and highlights its potential as a future pharmaceutical candidate for UC treatment.

Optimization of a green tea seed oil-loaded double-layer emulsion and its preventive effects on dextran sulfate sodium-induced colitis in mice.

Green tea seed oil (GTSO; Camellia sinensis) is rich in bioactive compounds and has great potential for preventing intestinal inflammation. Conversely, high-fat diets have been shown to promote or aggravate gastrointestinal inflammation, and the bioactive ingredients of GTSO face difficulty passing through the gastrointestinal tract while remaining intact. This study employed whey protein isolate (WPI) and sodium carboxymethyl cellulose (CMC-Na) to prepare a GTSO-loaded double-layer emulsion. The optimal parameters were as follows: WPI (2% w/w) and 35% oil phase for the primary emulsion preparation, CMC-Na (0.8% w/w) for the final emulsion, and 450W of ultrasonic power for homogenization. No significant changes in particle size or coalescence in the emulsions were observed after 30days of storage at 4°C. In addition, in a simulated gastrointestinal digestion system, more than 60% of the encapsulated GTSO was able to remain intact while passing through the gastric and small intestinal environment. In mice with dextran sulfate sodium-induced colitis, pretreatment with the GTSO emulsion significantly prevented the further development of colitis, whereas an empty-carrier-plus-free-GTSO treatment had no such protective effects and even tended to aggravate the disease. The results of the present study suggest that encapsulated GTSO is a reliable alternative approach for colitis prevention. PRACTICAL APPLICATION: The green tea seed oil-loaded double-layer emulsion demonstrates good storage stability when kept at 4°C, exhibits excellent slow-release performance, and achieves superior outcomes in the prevention of colitis. Our current study provides a reliable alternative approach for the prevention of colitis.

Pickled radish alleviates the progression of colitis in mice by reducing inflammation and repairing intestinal barrier

Scope: Pickled radish is a traditional fermented food known for its health benefits, however, evidence supporting its role in regulating gastrointestinal function is limited. This study aimed to investigate the beneficial effect of pickled radish on DSS-induced colitis in mice. Method and Results: Divide the mice into four groups: control, DSS model, low-dose (DSS+ 5 % pickled radish powder), and high-dose (DSS+ 10 % pickled radish powder). Colitis was induced by 3 % DSS administration in drinking water for eight days. Body weight loss, disease activity index (DAI), colon length, histology, and levels of inflammatory markers were measured to evaluate the effects of pickled radish on colitis. The results indicate that pickled radish significantly eased symptoms of colitis in mice induced by DSS, dose-dependently reducing DAI, reversed colon shortening, alleviating pathological damage to colon tissue and inflammatory response. Mechanistic investigation revealed that pickled radish upregulated the expression of tight junction-related genes (Zo-1, E-cadherin) and down-regulated inflammation-related genes (Il-1β, Il-6, TNF-α). Moreover, low-dose pickled radish significantly reversed the imbalance of gut microbiota and increased SCFAs. Conclusion: These findings suggest the potential of pickled radish in functional foods targeting the improvement of gastrointestinal health.

Mare milk and fermented mare milk alleviate DSS-induced ulcerative colitis in mice by reducing inflammation and modulating intestinal flora.

Mare milk (MM) and fermented mare milk (FM) are specialized animal milks with high nutritional value, containing a variety of functionally active substances that are capable of resisting inflammatory responses and oxidative stress. However, researches on the maintenance of intestinal homeostasis have been insufficient. This study aimed to investigate the effects of MM and FM on the prevention of DSS-induced ulcerative colitis in a mouse model and to preliminarily elucidate the underlying mechanisms. The results showed that MM and FM had different degrees of protective effects against the damage of DSS and alleviated ulcerative colitis by inhibiting weight loss, reducing colon length shortening, and restoring intestinal structure. Additionally, MM and FM maintained intestinal tight junction protein levels to repair barrier function, downregulated inflammatory cytokines (e.g., IL-1β, TNF-α, IL-6, and iNOS) and bolstered the body's antioxidant defense system. Moreover, MM and FM regulate the dysregulation of intestinal microenvironment by improving gut microbiota diversity and reshaping its structure, including increasing the proportion of Firmicutes and Bacteroidetes and the relative abundance of beneficial bacterial genera (e.g., Akkermansia). In summary, mare milk and fermented mare milk can serve as a dietary resource for preventing ulcerative colitis and maintaining intestinal homeostasis.

Protective effects of insoluble dietary fiber from cereal bran against DSS-induced chronic colitis in mice: From inflammatory responses, oxidative stress, intestinal barrier, and gut microbiota.

Insoluble dietary fiber (IDF) is a crucial component of cereals, and IDF from cereal bran (IDF-CB) has been reported to have multiple biological activities. However, the effect of IDF-CB on chronic colitis remains underexplored. The study aimed to investigate the impact of IDFs from wheat bran (WBIDF), rice bran (RBIDF), millet bran (MBIDF) and oat bran (OBIDF) on chronic colitis induced by dextran sulfate sodium (DSS). Our findings demonstrated that IDFs-CB supplementation mitigated DSS-induced weight loss and reduced lesions in the colon and spleen. Levels of proinflammatory cytokines (IL-1β, IL-6, IL-8, and TNF-α) and oxidative stress markers (MPO, iNOS and MDA)were decreased, and anti-inflammatory cytokine (IL-10) and T-SOD activity were increased after IDF-CB inclusion. Furthermore, IDFs-CB restored intestinal barrier function by regulating gene expression (up-regulated Muc-2, ZO-1 and Occludin, and down-regulated Claudin-1 and Claudin-4). Additionally, we analyzed the gut microbiota and SCFAs composition. WBIDF, MBIDF and OBIDF inhibited the growth of Muribaculaceae_unclassified, Bacteroides and Parasutterella. Conversely, IDFs-CB promoted the growth of Candidatus_Saccharimonas and norank_f__norank_o__Clostridia_UCG-014. Notably, WBIDF enhanced the abundance of Allobaculum, while MBIDF and OBIDF increased the abundance of Lachnospiraceae_NK4A136. Moreover, supplementation with IDFs-CB significantly elevated certain SCFA concentrations-particularly acetic acid and isohexanoic acid. Our results suggested that IDF-CB effectively alleviated DSS-induced chronic colitis; among them，WBIDF exhibited superior efficacy followed by OBIDF，MBIDF，and RBIDF. This study provides a theoretical foundation for dietary recommendations for patients suffering from inflammatory bowel disease.

Pectin from comfrey roots alleviate DSS-induced ulcerative colitis in mice through modulating the intestinal barrier.

The objective of this study was to investigate whether pectin extracted from comfrey roots (CRPs) could alleviate ulcerative colitis (UC) induced by sodium dextran sulfate (DSS) in mice by improving the intestinal barrier. CRP was able to relieve symptoms associated with weight loss, diarrhea, and colon length in UC mice. CRP inhibited the excessive secretion of TNF-α and IL-6 and increased the level of IL-10 in the serum. After CRP treatment, the mRNA expression levels of ZO-1 and Muc2 increased. The colonic epithelial cells recovered well, and the mucous layer was relatively intact in the CRP group. CRP and 5-aminosalicylic acid (ASA) alleviated UC symptoms in mice by reducing the abundance of Oscillibacter, Alistipes, and Anaeroplasma and increasing the abundance of Lachnospiraceae_UCG-001 to regulate the intestinal microflora. The abundance of Rikenellaceae was positively correlated with the mRNA expression level of ZO-1, and the abundance of Monoglobus was positively correlated with the mRNA expression level of Muc2. These results suggested that CRP could repair the intestinal barrier and mitigate DSS-induced colon damage in mice, indicating that CRP may be a potential functional component in combating UC.

Different polysaccharide-enhanced probiotic and polyphenol dual-functional factor co-encapsulated microcapsules demonstrate acute colitis alleviation efficacy and food fortification

Probiotics and polyphenols have multiple bioactivities, and developing co-encapsulated microcapsules (CM) is a novel strategy to enhance their nutritional diversity. However, the development of CMs is challenged by complicated processing, single types, and unclear in vivo effects and applications. In this study, the co-microencapsulations of polyphenol and probiotic were constructed using pectin, alginate (WGCA@LK), and Fu brick tea polysaccharides (WGCF@LK), respectively, with chitosan-whey isolate proteins by layer-by-layer coacervation reaction, and their protective effects, in vivo effectiveness, and application potential were evaluated. WGCA@LK improved the encapsulation rate of polyphenols (42.41 %), and remained high viability of probiotics after passing through gastric acidic environment (8.79 ± 0.04 log CFU/g) and storage for 4 weeks (4.59 ± 0.06 log CFU/g). WGCF@LK exhibited the highest total antioxidant activity (19.40 ± 0.25 μmol/mL) and its prebiotic activity removed the restriction on probiotic growth. WGCA@LK showed strong in vitro colonic adhesion, but WGCF@LK promoted in vivo retention of probiotics at 48 h. WGCF@LK showed excellent anti-inflammatory effects and alleviated symptoms of acute colitis in mice. These findings provide unique insights into the fortification of probiotic-polyphenol CMs by different polysaccharides and the development of novel health foods with rich functional hierarchies and superior therapeutic effects.

Pimpinellin Mitigates DSS-Induced Ulcerative Colitis in Mice by Reducing Inflammation and Regulating Gut Microbiota

Pimpinellin Mitigates DSS-Induced Ulcerative Colitis in Mice by Reducing Inflammation and Regulating Gut Microbiota

Albumin binding domain fusion improved the therapeutic efficacy of Inhibitor of Differentiation-2 protein in colitis mice

AimsThe human Inhibitor of Differentiation-2 (hID2) protein is a promising candidate for the treatment of colitis. However, its relatively low molecular weight limits its clinical application. To extend the therapeutic half-life, an albumin-binding domain (ABD), known for its high affinity for human serum albumin (HSA), was fused to hID2, resulting in a recombinant ABD-hID2. The anti-colitis bioactivity of ABD-hID2 than that of hID2 was evaluated in this study. Main methodsWestern blotting, size-exclusion high-performance chromatography, HSA binding assay, and pharmacokinetic studies were used to characterise ABD-hID2, which was induced by dextran sulfate sodium salt (DSS), Citrobacter rodentium (CR), and ABD-hID2 and hID2. The Disease Activity Index, histological pathologies, inflammatory response, Alcian blue or tuft cell staining, and tight junction proteins were determined. Alterations in the intestinal microbiota after ABD-hID2 treatment were analysed via 16S rRNA gene sequencing. Key findingsCompared with hID2, ABD-hID2 exhibited a decreased dimer complex, bound to HSA with high affinity, and demonstrated an extended blood retention time in vivo. Consequently, ABD-hID2 exhibited increased therapeutic efficacy in both DSS- and CR-induced colitis mouse models, as evidenced by the alleviation of colitis symptoms, preservation of goblet and tuft cell functions, restoration of the intestinal mucus barrier, and suppression of abnormal immune-inflammatory responses. Additionally, the modulation of the gut microbiota may play a role in the protective effects of ABD-hID2 in mice with CR-induced ulcerative colitis. SignificanceABD-hID2 enhances the bioactivity of hID2 and has the potential for further development as a treatment for colitis.

Epithelial-specific loss of Smad4 alleviates the fibrotic response in an acute colitis mouse model.

Mucosal healing is associated with better clinical outcomes in patients with inflammatory bowel disease. But the epithelial-specific contribution to mucosal healing in vivo is poorly understood. We evaluated mucosal healing in an acute dextran sulfate sodium mouse model that shows an alleviated colitis response after epithelial-specific loss of Smad4. We find that enhanced epithelial wound healing alleviates the fibrotic response. Dextran sulfate sodium caused increased mesenchymal collagen deposition-indicative of fibrosis-within a week in the WT but not in the Smad4 KO colon. The fibrotic response correlated with decreased epithelial proliferation in the WT, whereas uninterrupted proliferation and an expanded zone of proliferation were observed in the Smad4 KO colon epithelium. Furthermore, the Smad4 KO colon showed epithelial extracellular matrix alterations that promote epithelial regeneration. Our data suggest that epithelium is a key determinant of the mucosal healing response in vivo, implicating mucosal healing as a strategy against fibrosis in inflammatory bowel disease patients.

Microbial-derived bile acid reverses inflammation in IBD via GPBAR1 agonism and RORγt inverse agonism

The interplay between the dysbiotic microbiota and bile acids is a critical determinant for development of a dysregulated immune system in inflammatory bowel disease (IBD). Here we have investigated the fecal bile acid metabolome, gut microbiota composition, and immune responses in IBD patients and murine models of colitis and found that IBD associates with an elevated excretion of primary bile acids while secondary, allo- and oxo- bile acids were reduced. These changes correlated with the disease severity, mucosal expression of pro-inflammatory cytokines and chemokines, and reduced inflow of anti-inflammatory macrophages and Treg in the gut. Analysis of bile acids metabolome in the feces allowed the identification of five bile acids: 3-oxo-DCA, 3-oxo-LCA, allo-LCA, iso-allo-LCA and 3-oxo-UDCA, whose excretion was selectively decreased in IBD patients and diseased mice. By transactivation assay and docking calculations all five bile acids were shown to act as GPBAR1 agonists and RORγt inverse agonists, skewing Th17/Treg ratio and macrophage polarization toward an M2 phenotype. In a murine model of colitis, administration of 3-oxo-DCA suffices to reverse colitis development and intestinal dysbiosis in a GPBAR1-dependent manner. In vivo administration of 3-oxo-DCA to colitic mice also reverses disease severity and RORγt activation induced by a RORγt agonist and IL-23, a Th17 inducing cytokine. These results demonstrated that intestinal excretion of 3-oxoDCA, a dual GPBAR1 agonist and RORγt inverse agonist, is reduced in IBD and in models of colitis and its restitution protects against colitis development, highlighting a potential role for this agent in IBD management.

Effect of the arabinogalactan from Ixeris chinensis (Thunb.) Nakai. attenuates DSS-induced colitis and accompanying depression-like behavior.

An arabinogalactan (ICPA) was extracted from the medicinal and edible plant Ixeris chinensis (Thunb.) Nakai., and ICPA exhibited excellent immunomodulatory activity. In this research, the impact of ICPA on DSS-induced ulcerative colitis was investigated. The results indicated that ICPA ameliorated the symptoms of colitis mice including loss of body weight, decrease of disease activity index, shortness of colon length and reduction of spleen index that caused by DSS. After treatment with ICPA, inflammatory cell infiltration and crypt loss were alleviated, and the number of goblet epithelial cells was enriched. ICPA inhibited the overproduction of TNF-α, IL-1β, and NLRP3, and promoted the secretion of IL-10 in colon tissues. Meanwhile, the intestinal barrier integrity was restored through increasing the expression of ZO-1 and occludin. ICPA could also regulate the structure of gut microbiota through elevating the abundance of Turicibacter and Bifidobacterium, and decreasing the ratio of Bacteroidetes/Firmicutes. In addition, ICPA improved the depression-like behavior of UC mice, and reduced the expression of proteins NLRP3, GFAP, and Iba-1 in brain tissues. These results suggested ICPA had an alleviative effect on UC and accompanied depression-like behavior, and could be developed as a dietary supplement for the prevention and treatment of UC.

Intestinal Anti-Inflammatory and Antioxidant Potential of Arthrospira platensis Aqueous Extract on DNBS-Induced Colitis in BALB/c Mice

Background: The most common Inflammatory Bowel Diseases (IBD) affecting the gastrointestinal system are Crohn's disease and ulcerative colitis. However, the usual therapies for them are associated with a multitude of side effects. The blue-green microalgae Arthrospira platensis is known for its safety profile, nutritional, and medicinal properties in the treatment of different inflammatory and gastrointestinal disorders. Objective: The objective of this study was to investigate the potential intestinal anti-inflammatory effects of the aqueous extract derived from Arthrospira platensis (AAP) in a mouse model of DNBS-induced colitis. Methods: GC-MS and FTIR-ATR were used to determine the different types of chemical compounds found in the AAP extract. BALB/c mice that received DNBS intrarectally were treated with three doses (50, 100 and 200 mg/kg) of AAP for three days. The inflammatory status was assessed daily using a Disease Activity Index (DAI). Mice were sacrificed on the third day, and the extent of colonic damage was evaluated through both macroscopic and histological examinations. Finally, biochemical assays of different markers (MDA, NO, and GSH) were performed. Results: The GC-MS analysis revealed the presence of eleven bioactive compounds, including 2- thiophenecarboxylic acid, 2-biphenyl ester, palmitic acid, 2-linoleoyl glycerol, ethyl isoallocholate, and methyl palmitate. In addition, FTIR spectroscopy revealed the presence of amino, hydroxyl, and glucosidic groups. The treatment of colitic mice with AAP decreased the severity of colitis, as demonstrated by the improvement in the clinical score and the reduction of colonic tissue damage, as well as the modulation of the local biochemical marker levels. Conclusion: The AAP effectively improves DNBS-induced colitis, but its short treatment duration and focus on acute colitis highlight the need for further research on long-term and chronic effects.