Colitis In Mice Research Articles

The beneficial impact of ketogenic diets on chemically-induced colitis in mice depends on the diet's lipid composition

Previously, we showed that restrictive diets, including ketogenic diet (KD), have an anti-inflammatory impact on the healthy gastrointestinal tract of mice. Afterward, we found that energy-restricting diets mitigate inflammation in the dextran sodium sulfate (DSS) colitis mouse model. The current study aimed to verify the impact of KD on DSS colitis and assess if the diet's fat composition influences the outcomes of the intervention.Mice with mild chronic colitis were fed control chow, KD composed of long-chain triglycerides (KD LCT) or a KD containing a mix of LCT and medium-chain triglycerides (KD LCT/MCT).KDs did not reverse DSS-enhanced gut permeability and shortening of the colon. Both KDs had a similar impact on liver, cecum, and spleen weight, villi and colon length, the thickness of muscularis externa, and expression of ZO-1 and occludin. On the contrary, body weight, glutathione (GSH) and taurine-GSH levels, GSH-S transferase (GST), and myeloperoxidase (MPO) activity, as well as an abundance of several fecal bacteria, all were differentially affected by the two types of KDs. When compared to the DSS control diet, reduction in colon mucosa cytokines expression was stronger in KD LCT than in the KD LCT/MCT group.We conclude that the outcomes of the KD interventions in terms of potential therapeutical applications depend on lipid composition. KD LCT showed a strong positive impact on gut inflammation. A potential contribution of GSH to KD outcomes and a correlation between MPO activity and microbiota composition was identified.

Dietary Porphyra tenera ameliorated dextran sodium sulfate-induced colitis in mice via modulating gut microbiota dysbiosis

Bioactive components from Porphyra tenera (PT) have been reported to confer various health benefits. The role of PT in inflammatory bowel disease (IBD) has not been fully investigated. This study aimed to explore the anti-inflammatory properties of PT on dextran sodium sulfate (DSS)-treated mice. PT supplementation attenuated the severity of colitis in DSS-treated mice, evidenced by the reduction of disease activity index (DAI), restoration of colonic histological damage and suppression of abnormal inflammatory response. Sequencing analysis indicated that intake of PT alleviated DSS-induced gut microbiota dysbiosis, accompanied by reversing the generation of short-chain fatty acids (SCFAs) and bile acids (BAs). Overall, our findings demonstrated that supplementation of PT attenuated the severity of intestinal inflammation and ameliorated gut microbiota dysbiosis in a murine colitis model, which provided a rationale for further application of edible seaweeds for preventing inflammation-related disorders in humans.

Sensing of Liver-Derived Nicotinamide by Intestinal Group 2 Innate Lymphoid Cells Links Liver Cirrhosis and Ulcerative Colitis Susceptibility.

The correlation between liver disease and the progression of ulcerative colitis (UC) has remained elusive. In this study, it demonstrates that liver injury is intricately linked to the heightened severity of UC in patients, and causes more profound intestinal damage during DSS-induced colitis in mice. Metabolomics analysis of plasma from liver cirrhosis patients shows liver injury compromising nicotinamide supply for NAD+ biosynthesis in the intestine. Subsequent investigation identifies intestinal group 2 innate lymphoid cells (ILC2s) are responsible for liver injury-exacerbated colitis. Reconstitution of ILC2s or the restoration of NAD+ metabolism proves effective in relieving liver injury-aggravated experimental colitis. Mechanistically, the NAD+ salvage pathway regulates gut ILC2s in a cell-intrinsic manner by supporting the generation of succinate, which fuels the electron transport chain to sustaining ILC2s function. This research deepens the understanding of cellular and molecular mechanisms in liver disease-UC interplay, identifying a metabolic target for innovative treatments in liver injury-complicated colitis.

Morin alleviates DSS-induced ulcerative colitis in mice via inhibition of inflammation and modulation of intestinal microbiota

Ulcerative colitis (UC) is a chronic inflammatory condition with recurrent and challenging symptoms. Effective treatments are lacking, making UC management a critical research area. Morin (MO), a flavonoid from the Moraceae family, shows potential as an anti-UC agent, but its mechanisms are not fully understood. Using a dextran sulfate sodium (DSS)-induced UC mouse model, we employed network pharmacology to predict MO’s therapeutic effects. Assessments included changes in body weight, disease activity index (DAI), and colon length. Immunofluorescence, hematoxylin and eosin (H&E), and PAS staining evaluated colon damage. ELISA and western blot analyzed inflammatory factors, tight junction (TJ)-associated proteins (Claudin-3, Occludin, ZO-1), and Mitogen-Activated Protein Kinase (MAPK)/ Nuclear Factor kappa B (NF-κB) pathways. 16S rRNA sequencing assessed gut microbiota diversity, confirmed by MO’s modulation via Fecal Microbial Transplantation (FMT). Early MO intervention reduced UC severity by improving weight, DAI scores, and colon length, increasing goblet cells, enhancing barrier function, and inhibiting MAPK/NF-κB pathways. MO enriched gut microbiota, favoring beneficial bacteria like Muribaculaceae and Erysipelotrichaceae while reducing harmful Erysipelotrichaceae and Muribaculaceae. This study highlights MO’s potential in UC management through inflammation control, mucosal integrity maintenance, and gut flora modulation.

Structure-anti-inflammatory activity relationship of garlic fructans in mice with dextran sulfate sodium-induced colitis: Impact of chain length

The present study identified the protective effects of garlic oligo/poly-saccharides of different chain lengths against dextran sulfate sodium (DSS)-induced colitis in mice and elucidated the structure-function relationships. The results showed that oral intake of garlic oligo/poly-saccharides decreased disease activity index, reduced colon shortening and spleen enlargement, and ameliorated pathological damage in the mouse colon. The dysregulation of colonic pro/anti-inflammatory cytokines was significantly alleviated, accompanied by up-regulated antioxidant enzymes, blocked TLR4-MyD88-NF-κB signaling pathway, enhanced intestinal barrier integrity, and restored SCFA production. Garlic oligo/poly-saccharides also reversed gut microbiota dysbiosis in colitic mice by expanding beneficial bacteria and suppressing the growth of harmful bacteria. High-molecular-weight polysaccharides exhibited stronger alleviating effects on DSS-induced colitic symptoms in mice than low-molecular-weight oligo/poly-saccharides did, probably due to their greater ability to be fermented in the colon. Taken together, this study demonstrated the anti-inflammatory effects of garlic oligo/poly-saccharides and revealed that high-molecular-weight polysaccharide fractions were more effective in alleviating DSS-induced colitis.

Lower fecal microbiota transplantation ameliorates ulcerative colitis by eliminating oral-derived Fusobacterium nucleatum and virulence factor

BackgroundRecently, the oral oncobacterium Fusobacterium nucleatum (F. nucleatum), has been linked with ulcerative colitis (UC). Here, we aim to investigate whether Fecal Microbiota Transplantation (FMT) can alleviate UC by restoring gut microbiota and eliminating oral-derived F. nucleatum and virulence factor fadA.MethodC57BL/6J mice were randomly divided into a healthy control group (HC), Dextran Sulfate Sodium group (DSS), oral inoculation group (OR), upper FMT group (UFMT), and lower FMT group (LFMT). Disease activity index, body weight, survival rate, and histopathological scores were used to measure the severity of colitis. The function of the intestinal mucosal barrier was evaluated by performing immunohistochemical staining of the tight junction protein Occludin. Real-time PCR was used to assess the relative abundance of the nusG gene and the virulence gene fadA. Cytokine levels were detected by ELISA. Full-length sequencing of 16S rRNA was used to analyze the changes and composition of gut microbiota.FindingsOral incubation of F. nucleatum further exacerbated the severity of colitis and gut dysbiosis. Peptostreptococcaceae, Enterococcaceae, and Escherichia coli were significantly enriched in OR mice. However, LFMT mice showed an obvious decrease in disease activity and were more effective in restoring gut microbiota and eliminating F. nucleatum than UFMT mice. Bacteroidota, Lachnospiraceae, and Prevotellaceae were mainly enriched bacteria in LFMT mice. In addition, Genera such as Lactobacillus, Allobaculum, and Bacteroidales were found negative correlation with TNF-α, IL-1β, and IL-6. Genera like Romboutsia, Escherichia Shigella, Enterococcus, and Clostridium were found positively correlated with TNF-α, IL-1β, and IL-6.ConclusionsOral incubation of F. nucleatum further exacerbates the severity and dysbiosis in DSS-induced colitis mice. Besides, lower tract FMT can ameliorate colitis by restoring the gut microbiota diversity and eliminating F. nucleatum and virulence factor fadA.

Paeonol alleviates ulcerative colitis by modulating PPAR-γ and nuclear factor-κB activation

Ulcerative colitis (UC) is a chronic idiopathic inflammatory disease affecting the gastrointestinal tract. Although paeonol has been used for treating UC due to its anti-inflammatory and antioxidant effects, the underlying mechanisms remain unclear. In this study, we investigated the mechanisms of paeonol’s action on UC by conducting in-vitro and in-vivo studies using NCM460 cells and RAW264.7 cells, and the DSS-induced mice colitis model. The in vitro studies demonstrate that paeonol exerts inhibitory effects on the activation of the NF-κB signaling pathway through upregulating PPARγ expression, thereby attenuating pro-inflammatory cytokine production, reducing reactive oxygen species levels, and promoting M2 macrophage polarization. These effects are significantly abrogated upon addition of the PPARγ inhibitor GW9662. Moreover, UC mice treated with paeonol showed increased PPARγ expression, which reduced inflammation and apoptosis to maintain intestinal epithelial barrier integrity. In conclusion, our findings suggest that paeonol inhibits the NF-κB signaling pathway by activating PPARγ, reducing inflammation and oxidative stress and improving Dss-induced colitis. This study provides a new insight into the mechanism of treating UC by paeonol.

A Family of Cyclic Lipopeptides Found in Human Isolates of Bacillus Ameliorates Acute Colitis via Direct Agonism of Toll-Like Receptor 2 in a Murine Model of Inflammatory Bowel Disease

BackgroundThe Bacillus-derived cyclic lipopeptides (surfactin, iturin, and fengycin) form potent Heterogeneous Lipopeptide Micelle (HeLM) complexes. HeLM is a small molecule that has been shown to have immunomodulatory effects. However, how HeLM regulates inflammation is not clear, moreover its application to Inflammatory Bowel Disease (IBD), specifically Ulcerative Colitis (UC), has not been tested before.AimsTo use a murine model of IBD and determine the effects of HeLM and related molecular mechanisms of action.MethodsColitis was induced in mice by administration of 4% Dextran Sodium Sulfate. Three preparations were tested against negative and positive controls: Purified HeLM, the wild-type strain that produces it, and an isogenic mutant that does not produce HeLM. Clinical, biochemical, and histological scoring systems were used to assess the severity of colitis. RT-qPCR and cell cultures were used to determine the levels of molecular signaling. Fecal samples were processed for metagenomic analysis.ResultsPurified HeLM, and the wild-type strain, significantly decreased the severity of colitis as determined by the disease activity index (DAI), mouse colitis histology index (MCHI), fecal calprotectin, and colonic length. This effect was not seen in the mutant. HeLM was found to be an agonist to TLR-2, seemingly activating the Toll-Like Receptor 2/IL-10 pathway, with subsequent downregulation of inflammatory cytokines (TNF-α, IL-1β, and IL-6). At higher concentrations HeLM inhibited lipopolysaccharide ligands from activating TLR-4. The reduction in colitis was not due to microbiome modulation, as had previously been hypothesized.ConclusionOur results indicate that HeLM ameliorates colitis by TLR-2-induced IL-10 production and possibly via the inhibition of lipopolysaccharide.

Immunomodulatory Effects of a Probiotic Mixture: Alleviating Colitis in a Mouse Model through Modulation of Cell Activation Markers and the Gut Microbiota.

Ulcerative colitis (UC) is a persistent inflammatory intestinal disease that consistently affects the colon and rectum. Its exact cause remains unknown. UC causes a considerable challenge in healthcare, prompting research for novel therapeutic strategies. Although probiotics have gained popularity as possible candidates for managing UC, studies are still ongoing to identify the best probiotics or probiotic mixtures for clinical applications. This study aimed to determine the efficacy of a multi-strain probiotic mixture in mitigating intestinal inflammation in a colitis mouse model induced by dextran sulfate sodium. Specifically, a multi-strain probiotic mixture consisting of Tetragenococcus halophilus and Eubacterium rectale was used to study its impact on colitis symptoms. Anti-inflammatory effects were evaluated using ELISA and flow cytometry. The configuration of gut microbial communities was determined using 16S rRNA metagenomic analysis. According to this study, colitis mice treated with the probiotic mixture experienced reduced weight loss and significantly less colonic shortening compared to untreated mice. Additionally, the treated mice exhibited increased levels of forkhead box P3 (Foxp3) and interleukin 10, along with decreased expression of dendritic cell activation markers, such as CD40+, CD80+, and CD83+, in peripheral blood leukocytes and intraepithelial lymphocytes. Furthermore, there was a significant decrease in the frequencies of CD8+N.K1.1+ cells and CD11b+Ly6G+ cells. In terms of the gut microbiota, probiotic-mixture treatment of colitis mice significantly increased the abundance of the phyla Actinobacteria and Verrucomicrobia (p < 0.05). These results provide valuable insights into the therapeutic promise of multi-strain probiotics, shedding light on their potential to alleviate colitis symptoms. This research contributes to the ongoing exploration of effective probiotic interventions for managing inflammatory bowel disease.

Modified Gegen Qinlian Decoction modulated the gut microbiome and bile acid metabolism and restored the function of goblet cells in a mouse model of ulcerative colitis.

Modified Gegen Qinlian Decoction (MGQD) has been shown to effectively relieve ulcerative colitis (UC) without a known pharmacological mechanism. In this study, the anti-colitis efficaciousness of MGQD and its underlying mechanisms in UC were evaluated. Mice with colitis were administered MGQD for 7 days. Following the evaluation of clinical symptoms, gut microbiota in the feces of UC mice was examined using 16S rRNA sequencing and bile acids (BAs) were examined using LC/MS. Gut microbiota consumption and fecal microbiota transplantation (FMT) were used to explore the involvement of gut microbiota in the anti-UC action of MGQD. MGQD relieved colitis as shown by weight loss protection, a lower disease activity index (DAI), restoration of intestinal length reduction, and lower histopathologic scores. MGQD also restored crypt stem cell proliferation and function of colonic goblet cells, and promoted MUC2 protein secretion. Interestingly, investigations using gut bacterial depletion and FMT showed that MGQD attenuated colonic damage in a gut-dependent way. The modulation of the gut microbiota by MGQD might be attributed to a decrease in Odoribacter and an increase in norank_f_Muribaculaceae. In addition, MGQD modulated the metabolism of BAs while restoring the structure of the gut microbiota. MGQD significantly alleviated colitis in mice, which may be associated with the modulation of gut microbiota and BA metabolism and restoration of function of goblet cells. However, factors other than the gut microbiota may also be involved in the amelioration of UC by MGQD.

P-Hydroxy benzaldehyde, a phenolic compound from Nostoc commune, ameliorates DSS-induced colitis against oxidative stress via the Nrf2/HO-1/NQO-1/NF-κB/AP-1 pathway

BackgroundUlcerative colitis (UC), a chronic idiopathic inflammatory bowel disease (IBD), presents with limited current drug treatment options. Consequently, the search for safe and effective drug for UC prevention and treatment is imperative. Our prior studies have demonstrated that the phenolic compound p-Hydroxybenzaldehyde (HD) from Nostoc commune, effectively mitigates intestinal inflammation. However, the mechanisms underlying HD's anti-inflammatory effects remain unclear. PurposeThis study delved into the pharmacodynamics of HD and its underlying anti-inflammation mechanisms. MethodsFor in vivo experiments, dextran sodium sulfate (DSS)-induced colitis mouse model was established. In vitro inflammation model was established using lipopolysaccharide (LPS)-induced RAW264.7 and bone marrow-derived macrophages (BMDMs). The protective effect of HD against colitis was determined by monitoring clinical symptoms and histological morphology in mice. The levels of inflammatory factors and oxidative stress markers were subsequently analyzed with enzyme-linked immunosorbent assay (ELISA) and biochemical kits. Furthermore, western blotting (WB), immunofluorescence (IF), luciferase reporter gene, drug affinity reaction target stability (DARTS) assay, molecular docking, and molecular dynamics (MD) simulation were used to determine the potential target and molecular mechanism of HD. ResultsOur findings indicate that HD significantly alleviated the clinical symptoms and histological morphology of colitis in mice, and curtailed the production of pro-inflammatory cytokines, including TNF-α, IL-6, IFN-γ, COX-2, and iNOS. Furthermore, HD stimulated the production of SOD, CAT, and GSH-px, enhanced total antioxidant capacity (T-AOC), and reduced MDA levels. Mechanically, HD augmented the expression of Nrf2, HO-1, and NQO-1, while concurrently downregulating the phosphorylation of p65, IκBα, c-Jun, and c-Fos. ML385 and siNrf2 largely attenuated the protective effect of HD in enteritis mice and RAW 264.7 cells, as well as the promotion of HO-1 expression levels. ZnPP-mediated HO-1 knockdown reversed HD-induced inhibition of colonic inflammation. Luciferase reporter assay and IF assay confirmed the transcriptional activation of Nrf2 by HD. DARTS analysis, molecular docking, and MD results showed high binding strength, interaction efficiency and remarkable stability between Nrf2 and HD. ConclusionThese outcomes extend our previous research results that HD can combat oxidative stress through the Nrf2/HO-1/NQO-1/NF-κB/AP-1 pathways, effectively alleviating colitis, and propose new targets for HD to protect against intestinal barrier damage.

Colonization of microbiota derived from Macaca fascicularis, Bama miniature pigs, beagle dogs, and C57BL/6J mice alleviates DSS-induced colitis in germ-free mice.

Fecal microbiota transplantation (FMT) is an innovative and promising treatment for inflammatory bowel disease (IBD), which is related to the capability of FMT to supply functional microorganisms to improve recipient gut health. Numerous studies have highlighted considerable variability in the efficacy of FMT interventions for IBD. Several factors, including the composition of the donor microorganisms, significantly affect the efficacy of FMT in the treatment of IBD. Consequently, identifying the functional microorganisms in the donor is crucial for enhancing the efficacy of FMT. To explore potential common anti-inflammatory bacteria with therapeutic implications for IBD, germ-free (GF) BALB/c mice were pre-colonized with fecal microbiota obtained from diverse donors, including Macaca fascicularis (MCC_FMT), Bama miniature pigs (BP_FMT), beagle dogs (BD_FMT), and C57BL/6 J mice (Mice_FMT). Subsequently, mice were treated with dextran sodium sulfate (DSS). As expected, the symptoms of colitis were alleviated by MCC_FMT, BP_FMT, BD_FMT, and Mice_FMT, as demonstrated by the prevention of an elevated disease activity index in mice. Additionally, the utilization of distinct donors protected the intestinal barrier and contributed to the regulation of cytokine homeostasis. Metagenomic sequencing data showed that the microbial community structure and dominant species were significantly different among the four groups, which may be linked to variations in the anti-inflammatory efficacy observed in the respective groups. Notably, Lactobacillus reuteri and Flavonifractor plautii were consistently present in all four groups. L. reuteri exhibited a significant negative correlation with IL-1β, and animal studies further confirmed its efficacy in alleviating IBD, suggesting the presence of common functional bacteria across different donors that exert anti-inflammatory effects. This study provides essential foundational data for the potential clinical applications of FMT.IMPORTANCEDespite variations in efficacy observed among donors, numerous studies have underscored the potential of fecal microbiota transplantation (FMT) for managing inflammatory bowel disease (IBD), indicating the presence of shared anti-IBD bacterial species. In the present study, the collective anti-inflammatory efficacy observed across all four donor groups prompted the identification of two common bacterial species using metagenomics. A significant negative correlation between Lactobacillus reuteri and IL-1β was revealed. Furthermore, mice gavaged with L. reuteri successfully managed the colitis challenge induced by dextran sodium sulfate (DSS), suggesting that L. reuteri may act as an efficacious bacterium mediating shared anti-inflammatory effects among variable donors. This finding highlights the utilization of variable donors to screen FMT core bacteria, which may be a novel strategy for developing FMT applications.

Establishment and Evaluation of a Mouse Model of Experimental Ulcerative Colitis Induced by the Gavage Administration of Dextran Sulfate Sodium.

Given the critical role of dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) mouse models in the appraisal of associated therapeutic drugs, the optimization of the administration method and dosages is of paramount importance. Therefore, UC was induced in mice through the gavage administration of a DSS solution instead of free drinking water. The effects of varying daily dosages (2, 4, 6, and 8 g/kg) and frequencies (once or twice) of administration on the body weight and survival rate of the model mice were evaluated. Concurrently, the inflammatory indicators and tissue sections of the model mice were thoroughly evaluated. The results revealed that when the daily dosage reached 8 g/kg, the dosage exhibited a high level of toxicity, resulting in a high mortality rate among the mice. The DSS administration of 6 g/kg*2 not only elicited conspicuous symptoms, significant weight loss, substantial shortening of the colon, and significant changes in various inflammatory indicators, such as myeloperoxidase (MPO), nitric oxide (NO), reactive oxygen species (ROS), and glutathione (GSH), but it also maintained a high survival rate in the UC mice. The findings from this experiment lay a solid experimental foundation for future research on drugs intended for the treatment of UC.

Identifying polyamine related biomarkers in diagnosis and treatment of ulcerative colitis by integrating bulk and single-cell sequencing data

Ulcerative colitis (UC) is a chronic inflammatory disorder of the colon, and its pathogenesis remains unclear. Polyamine metabolic enzymes play a crucial role in UC. In this study, we aimed to identify pivotal polyamine-related genes (PRGs) and explore the underlying mechanism between PRGs and the disease status and therapeutic response of UC. We analyzed mRNA-sequencing data and clinical information of UC patients from the GEO database and identified NNMT, PTGS2, TRIM22, TGM2, and PPARG as key PRGs associated with active UC using differential expression analysis and weighted gene co-expression network analysis (WCGNA). Receiver operator characteristic curve (ROC) analysis confirmed the accuracy of these key genes in UC and colitis-associated colon cancer (CAC) diagnosis, and we validated their relationship with therapeutic response in external verification sets. Additionally, single-cell analysis revealed that the key PRGs were specific to certain immune cell types, emphasizing the vital role of intestinal tissue stem cells in active UC. The results were validated in vitro and in vivo experiments, including the colitis mice model and CAC mice model. In conclusion, these key PRGs effectively predict the progression of UC patients and could serve as new pharmacological biomarkers for the therapeutic response of UC.

Gastrodin Alleviates DSS-Induced Colitis in Mice through Strengthening Intestinal Barrier and Modulating Gut Microbiota.

Inflammatory bowel diseases (IBDs) are commonly associated with dysfunctional intestinal barriers and disturbed gut microbiota. Gastrodin, a major bioactive ingredient of Gastrodia elata Blume, has been shown to exhibit anti-oxidation and anti-inflammation properties and could mitigate non-alcoholic fatty liver disease, but its role in modulating IBD remains elusive. The aim of this study was to investigate the impact of gastrodin on DSS-induced colitis in mice and explore its potential mechanisms. Gastrodin supplementation alleviated clinical symptoms such as weight loss, a shortened colon, and a high disease activity index. Meanwhile, gastrodin strengthened the intestinal barrier by increasing the 0expression of tight junction proteins and mucin. Furthermore, Gastrodin significantly reduced pro-inflammatory cytokine secretion in mice by downregulating the NF-κB and MAPK pathways. Gut microbiota analysis showed that gastrodin improved the DSS-disrupted microbiota of mice. These findings demonstrate that gastrodin could attenuate DSS-induced colitis by enhancing the intestinal barrier and modulating the gut microbiota, providing support for the development of a gastrodin-based strategy to prevent or combat IBD.

Abstract Tu022: Gut-derived bacterial metabolites promote cardiac inflammation, leading to heart failure in murine model of DSS-induced colitis

Background: Inflammatory Bowel Disease (IBD) affects millions of people all over the world. This has been known to contribute to several other comorbidities. Recently, impaired gut-barrier permeability has been known to contribute to cardiovascular diseases in IBD patients. However, the precise mechanisms remain unclear. In this study, we propose that bacterial metabolites, like peptidoglycan, may play a role in promoting cardiac inflammation and ultimately leading to heart failure in mice following colitis. Methods: We induced colitis in C57 black mice with DSS (dextran sodium sulfate) treatment. Further, we collected fecal sample for 16s rRNA analysis to evaluate microbial flora. Additionally, heart and intestine tissues were collected to determine inflammatory genes expression (qPCR), immune cell infiltration (FACS), and intestinal permeability (WB and immunohistochemistry). Blood was collected to quantify the circulating peptidoglycan (PGN) level. The effect of PGN on NFkB inflammatory pathways was evaluated in macrophages. Results: Echo-data showed cardiac dysfunction in DSS mice. Masson’s trichrome staining showed deteriorated intestinal villi, while western blot data indicated decreased Occludin and increased PV-1 level, suggesting a leaky gut in DSS treated mice. Comparative analysis of 16s rRNA sequencing data showed significantly altered Firmicutes/Bacteroidetes ratio in DSS treated mice as compared to control mice. Moreover, plasma PGN level was significantly increased 3 weeks following DSS treatment. Real-time gene expression data of pro-inflammatory cytokines (TNFα) and fibrosis associated genes (col1α1, fibronectin) were increased in DSS mice heart. Increased CD68 expression in the immunostaining data of DSS mice heart suggests the recruitment of inflammatory macrophages. At the molecular level, CDK9 expression was significantly increased in macrophage following PGN treatment, which ultimately leads to an increase in NFkB signaling. Finally, CDK9 inhibition attenuated PGN-induced NFkB signaling. Conclusion: Together, our study suggests that colitis-induced gut leakage leads to CDK9-mediated NFκB upregulation, contributing to cardiac inflammation. Ongoing research will shed light on the underlying molecular mechanisms of cardiovascular dysfunction.

Clickable nanozyme enhances precise colonization of probiotics for ameliorating inflammatory bowel disease

Convincing evidence suggests that aberrant gut microbiota changes play a critical role in the progression and pathogenesis of inflammatory bowel disease (IBD). Probiotic therapeutic interventions targeting the microbiota may provide alternative avenues to treat IBD, but currently available probiotics often suffer from low intestinal colonization and limited targeting capability. Here, we developed azido (N3)-modified Prussian blue nanozyme (PB@N3) spatio-temporal guidance enhances the targeted colonization of probiotics to alleviate intestinal inflammation. First, clickable PB@N3 targets intestinal inflammation, simultaneously, it scavenges reactive oxygen species (ROS). Subsequently, utilizing “click” chemistry to spatio-temporally guide targeted colonization of dibenzocyclooctyne (DBCO)-modified Lactobacillus reuteri DSM 17938 (LR@DBCO). The “click” reaction between PB@N3 and LR@DBCO has excellent specificity and efficacy both in vivo and in vitro. Despite the complex physiological environment of IBD, “click” reaction can prolong the retention time of probiotics in the intestine. Dextran sulfate sodium (DSS)-induced colitis mice model, demonstrates that the combination of PB@N3 and LR@DBCO effectively mitigates levels of ROS, enhances the colonization of probiotics, modulates intestinal flora composition and function, regulates immune profiles, restores intestinal barrier function, and alleviates intestinal inflammation. Hence, PB@N3 spatio-temporal guidance enhances targeted colonization of LR@DBCO provides a promising medical treatment strategy for IBD.

Expression of MAF bZIP transcription factor B protects against ulcerative colitis through the inhibition of the NF-κB pathway.

The aim of this study was to explore whether MAF bZIP transcription factor B (MAFB) might alleviate ulcerative colitis (UC) in dextran sulfate sodium (DSS)-induced mice and LPS-induced IEC-6 cells. UC in vivo and in vitro model was established by using DSS and LPS, respectively. The mice body weight and disease activity index (DAI) score were recorded daily, and colon length was measured. Moreover, the permeability was evaluated utilizing a fluorescein isothiocyanate dextran (FITC-Dextran) probe. Histopathological changes of DSS-induced colitis mice was assessed utilizing H&E staining. Next, qRT-PCR was performed to detect IL-1β, IL-6, TNF-α, and IL-10 level in in vivo and in vitro. Furthermore, the level of MDA, SOD, CAT, and GSH were evaluated in colon tissues. Besides, the expressions of tight junction proteins and NF-κB pathway relative proteins were examined in colitis mice and IEC-6 cells using western blot, immunohistochemistry and immunofluorescence. MAFB level was downregulated in DSS-induced colitis mice. Moreover, the upregulation of MAFB protected mice from DSS-induced colitis by suppressing DSS-induced inflammation, oxidative stress, and intestinal barrier impairment. We also demonstrated that the upregulation of MAFB inactivated NF-κB pathway in DSS-caused colitis mice. Subsequently, we observed that MAFB upregulation could inhibit LPS-caused epithelial barrier impairment and inflammation in IEC-6 cells. Additionally, MAFB overexpression could suppress the activation of NF-κB pathway in IEC-6 cells. The upregulation of MAFB could protect against UC via the suppression of inflammation and the intestinal barrier impairment through inhibiting the NF-κB pathway.

Genistein alleviates dextran sulfate sodium-induced colitis in mice through modulation of intestinal microbiota and macrophage polarization.

Ulcerative colitis (UC) is a colonic immune system disorder, manifested with long duration and easy relapse. Genistein has been reported to possess various biological activities. However, it remains unclear whether genistein can ameliorate UC by modulating the homeostasis of the intestinal bacterial community. The dextran sodium sulfate (DSS)-induced UC mice were administrated with genistein (20mg/kg/day) or genistein (40mg/kg/day) for ten days. The general physical condition of the mice was monitored. After sacrifice, the changes in colon length and colonic pathological morphology were observed. The expression of intestinal barrier proteins, inflammatory cytokines, and macrophage markers in the colon was detected. The composition and metabolic products of the intestinal microbiota were analyzed. Genistein treatment visibly improved body weight change and disease activity index in DSS-induced mice. Genistein treatment ameliorated colonic pathological alterations and promoted the expression of mucin-2 and tight junction proteins. Genistein administration inhibited myeloperoxidase activity and colonic inflammatory cytokines. Furthermore, genistein administration improved the structure of the intestinal microbial community, promoted the production of short-chain fatty acids, and modulated macrophage polarization. These results revealed that genistein mediated macrophage polarization balance by improving intestinal microbiota and its metabolites, thereby alleviating DSS-induced colitis.

ITGB2 related to immune cell infiltration as a potential therapeutic target of inflammatory bowel disease using bioinformatics and functional research.

Inflammatory bowel disease (IBD) is a chronic systemic inflammatory condition regarded as a major risk factor for colitis-associated cancer. However, the underlying mechanisms of IBD remain unclear. First, five GSE data sets available in GEO were used to perform 'batch correction' and Robust Rank Aggregation (RRA) to identify differentially expressed genes (DEGs). Candidate molecules were identified using CytoHubba, and their diagnostic effectiveness was predicted. The CIBERSORT algorithm evaluated the immune cell infiltration in the intestinal epithelial tissues of patients with IBD and controls. Immune cell infiltration in the IBD and control groups was determined using the least absolute shrinkage selection operator algorithm and Cox regression analysis. Finally, a total of 51 DEGs were screened, and nine hub genes were identified using CytoHubba and Cytoscape. GSE87466 and GSE193677 were used as extra data set to validate the expression of the nine hub genes. CD4-naïve T cells, gamma-delta T cells, M1 macrophages and resting dendritic cells (DCs) are the main immune cell infiltrates in patients with IBD. Signal transducer and activator of transcription 1, CCR5 and integrin subunit beta 2 (ITGB2) were significantly upregulated in the IBD mouse model, and suppression of ITGB2 expression alleviated IBD inflammation in mice. Additionally, the expression of ITGB2 was upregulated in IBD-associated colorectal cancer (CRC). The silence of ITGB2 suppressed cell proliferation and tumour growth invitro and invivo. ITGB2 resting DCs may provide a therapeutic strategy for IBD, and ITGB2 may be a potential diagnostic marker for IBD-associated CRC.