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Background: Inflammatory bowel disease (IBD) is a chronic condition influenced by diet, which affects gut microbiota and immune functions. The rising prevalence of IBD, linked to Western diets in developing countries, highlights the need for dietary interventions. This study aimed to assess the impact of white kidney beans (WKB) on gut inflammation and microbiota changes, focusing on their effects on enteric glial cells (EGCs) and immune activity in colitis., Methods: Male C57BL/6 mice were divided into four groups: normal diet (ND), ND with 2.5% dextran sulfate sodium (DSS) for colitis induction, ND with 20% WKB, and WKB with 2.5% DSS. The dietary intervention lasted 17 weeks, with DSS given in the final week. Colonic inflammation was assessed by body weight, disease activity index, and histopathology. Epithelial barrier integrity was evaluated using immunofluorescence, transmission electron microscopy, and permeability assays. EGCs activity was analyzed via immunofluorescence and quantitative real-time PCR. Immune responses were measured using flow cytometry and cytokine profiling, while gut microbiota changes were examined through metagenomic sequencing., Results: WKB supplementation significantly alleviated DSS-induced colitis in mice, evidenced by reduced weight loss, disease activity, and improved colonic histology. This effect was linked to enhanced mucosal barrier integrity, seen through increased tight junction protein and Muc2 expression, accompanied by favorable ultrastructural changes. WKB modulated EGCs activity via TNF-like cytokine 1 A inhibition, resulting in reduced glial fibrillary acidic protein expression. Immunologically, it downregulated Th1 and Th17 pro-inflammatory cells, increased Treg cells, and altered cytokine profiles (reduced TNF-α, IFN-γ, IL-17; increased IL-10). Metagenomic analysis showed that WKB restored gut microbiota balance, particularly enhancing beneficial bacteria like Akkermansia. KEGG pathway analysis further indicated that WKB supplementation improved key metabolic pathways, notably those related to phenylalanine, tyrosine, and tryptophan biosynthesis, thereby countering DSS-induced metabolic disruptions., Conclusions: WKB shows promise for treating IBD by enhancing mucosal barriers, inhibiting EGCs activity, balancing Th1/Th17/Treg cells, and restoring gut microbiota and metabolic homeostasis, thereby alleviating colitis symptoms., Competing Interests: Declarations. Ethics approval and consent to participate: This animal experiment was supported by Air Force Medical Center according to Laboratory Animal Welfare and Ethical review. Consent for publication: All authors agree to this submission. Competing interests: The authors declare no competing interests. Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Qi Sun and Bai-Rong Li have contributed equally to this work., (© 2025. The Author(s).)

Polysaccharides from Diospyros lotus L. were investigated for their structural characterization and anti-inflammatory activity. Four low polymer dispersity index (PDI) subfractions were obtained: DRP-1 (153.95 kDa), DRP-2 (61.22 kDa), DRP-3 (22.80 kDa), and DRP-4 (8.93 kDa), respectively. DRP-4 contained the highest number of RG-I domains (43.25%), while DRP-1 had the highest degree of methyl esterification (37.5%). Results from the dextran sulfate sodium (DSS) salt-induced ulcerative colitis (UC) mice model indicated that DCP promoted mucosal and tight junction protein (caudin-1 and occludin) expression. Moreover, DCP improved the microbial community composition through selective enrichment of beneficial bacteria such as Lachnospiraceae and Lactobacillaceae . The anti-inflammatory activity of DCP was speculated to be related to its neutral sugar side chain and low esterification degree. These results suggested that DCP could prevent DSS-induced colitis and inhibit colon inflammation by maintaining a balanced gut microbiome and protecting the colon mucosal barrier.

Previous research has consistently shown that high-fat diet (HFD) consumption can lead to the development of colonic inflammation. Neohesperidin (NHP), a naturally occurring flavanone glycoside in citrus fruits, has anti-inflammatory properties. However, the efficacy and mechanism of NHP in countering prolonged HFD-induced inflammation remains unclear. In this study, rats on HFD were intragastrically administered (i.g.) with NHP for 12 consecutive weeks. Results indicate that this natural compound is effective in reducing colorectal inflammation at doses of 40-80 mg/kg body weight (BW) by i.g. administration, with significant decreases in inflammation markers such as TNF-α and IL-1β levels. It also improved intestinal mucosal tissue integrity and reduced HFD-stimulated colorectal inflammation via the JAK2/STAT3 pathway. Furthermore, intestinal microbiota sequencing results show that NHP intervention significantly downregulated the Firmicutes/Bacteroidetes ratio. This ratio is closely related to the preventive role in the context of glycolipid metabolism disorder. Compared with fecal cultures of rats from the HFD group, after 48 h in vitro fermentation, those from the NHP group had distinct microbiota composition and notably higher concentrations of SCFAs. Collectively, these observations suggest that 80 mg/kg BW NHP possesses biological activities in downregulating HFD-induced colorectal inflammation by regulating intestinal flora and promoting SCFAs formation.

Lactobacillus helveticus LZ-R-5 (R-5), a strain with high epithelial adhesion and bioactive exopolysaccharide production, was isolated from Tibetan kefir grains. This study investigated its potential to alleviate intestinal inflammation using a DSS-induced colitis model in BALB/c mice. We integrated microbial diversity and serological analyses to assess changes in gut flora and cytokines following the R-5 treatment. Pathological assessments showed that R-5 reduced crypt distortion in the proximal colon and mitigated hepatic immune challenges by enhancing gut barrier function. The increased relative expression of TGF-β1 and the downregulation of NLRP3-related inflammatory factors were conducive to preventing organ damage in the thymus and spleen of mice with colitis. Additionally, R-5 stimulated GPR43 expression and improved epithelial nutrition, promoting mucin production to prevent enterotoxin leakage. It also modulated the gut microbiota by suppressing Bacteroides and Erysipelatoclostridium, leading to a microbiota composition more akin to that of normal flora.

Background: Immune cell populations in the intestinal muscularis propria during colitis are poorly resolved. Maintaining homeostasis in this niche is critical, highlighted by the poorer prognosis of inflammatory bowel disease associated with muscularis propria inflammation., Methods: This study utilizes single-cell RNA sequencing to survey the immune cell populations within the muscularis propria of normal colon and dextran sodium sulfate-induced colitis. Findings are validated by immunohistochemistry, flow cytometry and cell-lineage tracing in vivo, and in vitro assays with muscularis macrophages (MMφ)., Results: In naïve conditions, transcriptional duality is observed in MMφs with 2 major subpopulations: conventional resident Cx3cr1+ MMφs and Lyve1+ MMφs. The Lyve1+ population is phagocytic and expresses several known MMφ markers in mouse and human, confirming their identity as a bona fide MMφ subset. Single-cell transcriptomics indicate that resident MMφs are retained during colitis and exhibit plasticity toward an inflammatory profile. Lyve1+ MMφs, which express anti-inflammatory marker CD163, are absent during colitis, as confirmed by flow cytometry. In contrast, lineage tracing finds that resident Cx3cr1+ MMφs remain during colitis and are not completely replaced by the inflammatory infiltrating monocytes. In vitro studies provide biological evidence of the plasticity of resident Cx3cr1+ MMφs in response to lipopolysaccharide (LPS), mirroring transcriptional observations in vivo of their inflammatory plasticity. Potential markers for colitic MMφs, validated in animal models and in individuals with ulcerative colitis, are identified., Conclusions: Our findings contribute to the understanding of the immune system in the muscularis propria niche during colitis by resolving the heterogeneity and origins of colitic MMφs., (© The Author(s) 2024. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Aims: Peroxiredoxin3 (Prdx3) is an intracellular antioxidant enzyme that is specifically localized in mitochondria and protects against oxidative stress by removing mitochondrial reactive oxygen species (ROS). The intestinal epithelium provides a physical and biochemical barrier that segregates host tissues from commensal bacteria to maintain intestinal homeostasis. An imbalance between the cellular antioxidant defense system and oxidative stress has been implicated in the pathogenesis of inflammatory bowel disease (IBD). However, the role of Prdx3 in the intestinal epithelium under intestinal inflammation has not been elucidated. To investigate the potential role of Prdx3 in intestinal inflammation, we used intestinal epithelial cell (IEC)-specific Prdx3-knockout mice. Results: IEC-specific Prdx3-deficient mice showed more severe colitis phenotypes with greater degrees of body weight loss, colon shortening, barrier disruption, mitochondrial damage, and ROS generation in IECs. Furthermore, exosomal miR-1260b was dramatically increased in Prdx3-knockdown colonic epithelial cells. Mechanistically, Prdx3 deficiency promoted intestinal barrier disruption and inflammation via P38-mitogen-activated protein kinase/NFκB signaling. Innovation: This is the first study to report the protective role of Prdx3 in acute colitis using IEC-specific conditional knockout mice. Conclusion: Our study sheds light on the role of exosome-loaded miRNAs, particularly miR-1260b, in IBD. Targeting miR-1260b or modulating exosome-mediated intercellular communication may hold promise as potential therapeutic strategies for managing IBD and restoring intestinal barrier integrity. Antioxid. Redox Signal. 42, 133-149.

The incidence of ulcerative colitis (UC) is closely associated with dietary fiber (DF) intake. This study aims to evaluate the ameliorative effects of insoluble dietary fiber from adzuki bean seed coat (AIDF) on dextran sulfate sodium (DSS)-induced UC in mice, both with and without bound polyphenols (BPs). We employed a model based on the "remove/backfill" of components. Compared to dephenolized dietary fiber (AIDF-DF) and AIDF-DF with replaced BPs (AIDF-BP), AIDF was found to effectively reduce the splenic index, alleviate colonic histopathological damage, lower serum levels of inflammatory mediators (TNF-α, IL-1β, IFN-γ, IL-6), decrease activities of LPS, DAO, MPO, and iNOS, regulate intestinal tight junction (TJ) mRNA and protein expression, and restore the integrity of the colonic epithelial cell barrier. AIDF mitigated the inflammatory response in UC by inhibiting the TLR4/NF-κB inflammatory signaling pathway. It increased the abundance of beneficial gut microbiota (e.g., Akkermansia, Verrucomicrobiota) while reducing the abundance of harmful bacteria (e.g., Proteobacteria), thereby alleviating intestinal disturbances in DSS-induced colitis in mice. In conclusion, the presence of BPs in AIDF plays a critical role in attenuating DSS-induced UC in mice., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest in the work., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Lactobacillus acidophilus L. acidophilus Lactobacillus, Bifidobacterium, and Akkermansia, This study aimed to explore the ameliorative effects and underlying mechanisms of oral administration Lactobacillus acidophilus 6074 fermented jujube juice (LAFJ) on dextran sulfate sodium (DSS)-induced colitis in mice. In this study, jujube juice was used as a substrate and fermented by L. acidophilus 6074 to investigate its effects on gut microbiota, intestinal barrier function, oxidative stress, inflammatory factors, and short-chain fatty acids (SCFAs) in mice with colitis and to reveal its potential mechanism for alleviating colitis. The results demonstrated that fermentation caused significant changes in the nutrients and nonnutrients of jujube juice, mainly in organic acids (malic acid, lactic acid, citric acid, and succinic acid) and free amino acids (Thr, Met, Ser, Ile, and Lys). High-dose LAFJ (20 mL/kg/day) significantly reduced the disease activity index (DAI), improved histopathological morphology, and increased colon length in colitis mice. LAFJ alleviated colon damage and preserved the integrity of the colonic mucosal barrier by promoting the expression of colonic tight junction proteins occludin, claudin-1, and zonula occluden-1 (ZO-1). Furthermore, LAFJ inhibited the production of proinflammatory factors and attenuated oxidative stress. Gut microbiota of mice revealed that LAFJ increased beneficial bacteria such as Lactobacillus, Bifidobacterium, and Akkermansia, promoted the production of SCFAs, and inhibited the growth of harmful microorganisms. Overall, LAFJ could reshape and restore gut microbiota imbalance caused by intestinal inflammation and alleviate the development of colitis, which may become a novel dietary intervention., (© 2024 Wiley‐VCH GmbH.)

Butyrate can strengthen the intestinal epithelial barrier. However, the mechanisms by which butyrate affects intestinal epithelial cells (IECs) pyroptosis in Crohn's disease (CD) remain unclear. In this study, we collected colonic biopsy samples from CD patients and healthy controls to assess pyroptosis levels. Our findings indicated elevated expression of pyroptosis markers in CD patients, alongside distinct morphological evidence of pyroptosis in IECs. We further investigated the effects of tributyrin on pyroptosis and the cGAS-STING pathway in a trinitrobenzene sulfonic acid-induced colitis rat model. Tributyrin significantly mitigated intestinal inflammation, reduced pathological progression, and inhibited pyroptosis and cGAS-STING pathway activation in the colitis rat model. Similarly, in an in vitro model of IECs pyroptosis, sodium butyrate inhibited pyroptosis and cGAS-STING pathway activation in HT-29 cells. Co-treatment with a cGAS-STING pathway activator and butyrate demonstrated that the activator reversed the inhibitory effects of butyrate on pyroptosis and cGAS-STING pathway activation in both the colitis rat model and HT-29 cells. Mechanistically, the cGAS-STING pathway was found to interact with NLRP3. Taken together, butyrate may mitigate intestinal inflammation in CD by suppressing cGAS-STING-NLRP3 axis-mediated IECs pyroptosis. These findings offer new insights into potential therapeutic strategies for managing CD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Lipid metabolism disorder is a critical feature of Crohn's disease (CD). Phosphatidylinositol (PI) and its derivative, phosphatidylinositol bisphosphate (PIP2), are associated with CD. The mechanisms underlying such association remain unknown. In this study, we explored the role played by the major PI derivative, phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2], in CD pathogenesis. The relationship between CD activity and PI or PIP2 was analyzed via lipidomics. The mucosal expression of PI(4,5)P2 in patients with CD was measured using immunofluorescence. The function and mechanism of PI(4,5)P2 were examined in dextran sulfate sodium (DSS)-induced colitis mice and lipopolysaccharide (LPS)-induced Caco-2 cell models, along with MeRIP and mRNA sequencing. The results suggested lipid PI and PIP2 were substantially negatively associated with disease activity and high-sensitivity C-reactive protein. PI(4,5)P2 was substantially downregulated in the inflamed mucosa of patients with CD. PI(4,5)P2 alleviated mouse colitis, with improvements in survival rate, colon length, weight, and disease activity index. PI(4,5)P2 also alleviated DSS-induced tissue damage, tight junction loss, and intestinal epithelial cell (IEC) pyroptosis. In the in vitro LPS-induced cell model, PI(4,5)P2 inhibited pyroptosis, as well as NLRP3, and caspase-1 expression, in addition to reducing interleukin (IL)-18, IL-1β, and lactate dehydrogenase (LDH) secretion. PI(4,5)P2 mediated NNMT upregulation in mice and Caco-2 cells and suppressed pyroptosis in IECs. NNMT knockdown restricted the inhibitory effect of PI(4,5)P2 on IEC pyroptosis. NNMT inhibited the stability of RBP4 mRNA via m6A modification, thereby preventing pyroptosis following PI(4,5)P2 treatment. Significant correlations were also observed between PI(4,5)P2 and NNMT, NNMT and RBP4, and RBP4 and GSDMD expression in the intestinal tissues from patients with CD. Our results indicated that PI(4,5)P2 ameliorates colitis by inhibiting IEC pyroptosis via NNMT-mediated RBP4 m6A modification. Thus, PI(4,5)P2 shows potential as a therapeutic target in CD., Competing Interests: Competing interests: The authors declare no competing interests. Ethics approval: All experiments were performed in accordance with the relevant guidelines and regulations. The animal experimental process complied with the regulations on the Management of Experimental Animals, and ethical requirements were approved by the Ethics Committee of the Sixth Affiliated Hospital of Sun Yat-sen University., (© 2024. The Author(s).)

Objectives: To investigate the effects of asperosaponin VI (AVI) on intestinal epithelial cell apoptosis and intestinal barrier function in a mouse model of Crohn's disease (CD)-like colitis and explore its mechanisms., Methods: Male C57BL/6 mice with TNBS-induced CD-like colitis were treated with saline or AVI (daily dose 150 mg/kg) by gavage for 6 days. The changes in body weight, colon length, DAI scores, and colon pathologies of the mice were observed, and the expressions of inflammatory factors and tight injunction proteins were detected using ELISA and RT-qPCR. The effects of AVI on barrier function and apoptosis of mouse intestinal epithelial cells and TNF‑α‑treated Caco-2 cells were analyzed using immunofluorescence staining, TUNEL assay, and Western blotting. Network pharmacology, TUNEL assay, and Western blotting were performed to explore and validate the therapeutic mechanisms of AVI for CD., Results: In the mouse models of CD-like colitis, AVI significantly improved body weight loss, colon shortening and DAI and tissue inflammation scores, alleviated intestinal villi and goblet cell injuries, and lowered the expressions of inflammatory factors. AVI treatment significantly reduced the loss of tight junction proteins and apoptosis in both mouse intestinal epithelial cells and TNF‑α-stimulated Caco-2 cells. KEGG enrichment pathway analysis suggested that the therapeutic effect of AVI on CD was associated with inhibition of PI3K/AKT/NF-κB pathway activation, which was confirmed by lowered expressions of p-PI3K, p-AKT, and p-p65 in AVI-treated mouse models and Caco-2 cells. In Caco-2 cells, Recilisib significantly blocked the inhibitory effect of AVI on the PI3K/AKT/NF-κB pathway and TNF-α-induced apoptosis, and AKT1 knockdown experiment confirmed the role of the PI3K/AKT pathway for mediating the activation of downstream NF-κB signaling., Conclusions: AVI can improve TNBS-induced CD-like colitis in mice by reducing intestinal epithelial cell apoptosis and intestinal barrier damage via inhibiting the PI3K/AKT/NF-κB signaling pathway.

Objective: To study the therapeutic effect of sinomenine hydrochloride (SH) on dextran sodium sulfate (DSS)-induced colitis in mice as an animal model and the changes of Notch signaling pathway in colon tissue of mice after treatment., Methods: Twenty-four mice were randomly divided into control group, model group, SH low-dose group (20 mg/kg) and SH high-dose group (60 mg/kg), with 6 mice in each group. Disease activity index (DAI), colonic mucosal injury index and colonic histopathological score were calculated. The expression levels of related genes, proteins in Notch signaling pathway and inflammatory factors were quantified., Results: SH can significantly reduce the symptoms of colitis mice, and can significantly reduce the DAI score (Model: 3.44 ± 0.27; SH-20: 2.50 ± 0.18; SH-60: 1.89 ± 0.17; P < 0.001) and histopathological injury degree (Model: 7.67 ± 0.52; SH-20: 5.17 ± 0.75, P < 0.01; SH-60: 3.33 ± 0.52, P < 0.001). SH can down-regulate the expression levels of Notch1, NICD1, Jagged1 and Hes1 proteins in colon tissue of colitis mice (Model: 1.92 ± 0.16, 1.83 ± 0.21, 2.23 ± 0.22, 1.91 ± 0.17; SH-20: 1.56 ± 0.12, 1.39 ± 0.13, 1.58 ± 0.12, 1.38 ± 0.11; SH-60: 1.24 ± 0.09, 1.23 ± 0.10, 1.23 ± 0.11, 1.22 ± 0.09; P < 0.01), and reduce the contents of serum pro-inflammatory cytokines TNF-α, IL-1β and IL-6 (Model: 718.53 ± 81.81, 51.62 ± 2.80, 444.07 ± 67.77; SH-20: 544.72 ± 90.03, 34.10 ± 2.90, 345.43 ± 43.40; SH-60: 434.11 ± 71.75, 29.44 ± 3.70, 236.11 ± 29.35; P < 0.001)., Conclusion: The therapeutic effect of SH on DSS-induced colitis in mice may be related to inhibiting the overactivation of Notch signaling pathway., Competing Interests: Declarations. Ethics approval and consent to participate: This study has been approved by the Animal Ethics Committee of Bengbu Medical University (No.2021336). All experiments were conducted in accordance with relevant guidelines and regulations. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: Neuropeptide S receptor 1 (NPSR1) has been implicated in the the onset of inflammatory bowel disease (IBD), though its exact mechanism remains unclear. This study investigates the role of NPSR1 in regulating CD4 + T cell effector function in IBD., Methods: Peripheral blood and colonic mucosal biopsies from IBD patients, as well as dextran sodium sulfate (DSS)-induced mouse colitis models, were analyzed to assess the effects of NPSR1 on colitis and CD4 + T cell-mediated immune responses. NPSR1 knockdown was conducted both in vitro and in vivo to elucidate underlying mechanisms. Expression of NPSR1 and CD4 + T cell-related factors was measured using quantitative real-time PCR, immunoblotting, cytometric bead array, immunofluorescence, and immunohistochemistry. CD4 + T cell effector functions were evaluated through flow cytometry, EdU incorporation assay, Annexin V-FITC/PI staining, and transwell assay., Results: NPSR1 expression was elevated in the intestinal tissues from IBD patients. Its downregulation provided protection in DSS-induced mouse colitis models. NPSR1 correlated positively with CD4 + T cell-mediated inflammation, and its knockdown reduced CD4 + T cell-mediated immune responses and inhibited CD4 + T cell differentiation. Additionally, NPSR1 knockdown decreased CD4 + T cell proliferation, increased apoptosis, and enhanced CCL2-induced migration in vitro, while significantly reducing Th1 cell chemotaxis in vivo., Conclusions: This study demonstrates that NPSR1 promotes chronic colitis by regulating CD4 + T cell effector functions in IBD, offering potential new therapeutic strategies for IBD treatment., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Ulcerative colitis (UC) is a complex, refractory inflammatory bowel disease characterized impared intestinal mucosal barrier and imbalanced M1/M2 macrophage polarization mediating its progression. Formononetin (FN), a bioactive isoflavone with established anti-inflammatory and immunomodulatory properties, shows promise in mitigating UC, yet its therapeutic and underlying mechanisms remain unclear. In this study, colitis was induced in mice by administering 2.5% (w/v) dextran sulfate sodium (DSS) solution for 7 days. Oral (25, 50, and 100 mg/kg) FN for 10 days significantly ameliorated colitis symptoms in a dose-dependent manner, by mitigating body weight loss, reducing disease activity index (DAI), colonic weight, and colonic weight index, while enhancing survival rates and colonic length. Histological analysis revealed FN remarkably suppressed inflammatory damage in colonic tissues. Furthermore, FN modulated the expression of pro- and anti-inflammatory cytokines and enhanced antioxidant capacity. Notably, FN treatment significantly enhanced the expression of tight junction (TJ) proteins (claudin-1, ZO-1, occludin) at both protein and mRNA levels in the colon tissues, suggesting improved intestinal barrier function. Crucially, FN inhibited macrophage infiltration in colonic tissues and rebalanced M1/M2 macrophage polarization. While, macrophage depletion largely abrogated FN's protective effects against colitis, indicating a crucial role for macrophages in mediating FN's therapeutic response. Overall, FN effectively alleviated colitis primarily via modulating inflammatory cytokine expression, enhancing antioxidant capacity, upregulating TJs proteins expression, and remodeling M1/M2 macrophage polarization equilibrium. These findings suggest that FN could be the next candidate to unlocking UC's treatment challenge., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Aims: Although zinc pyrithione (ZPT) has been studied as topical antimicrobial and cosmetic consumer products, little is known about its pharmacological actions in gastrointestinal (GI) health and inflammation. Our aims were to investigate the effects of ZPT on transient receptor potential (TRP) channels and Ca 2+ signaling in intestinal epithelial cells (IECs) and its therapeutic potential for colitis., Main Methods: Digital Ca 2+ imaging and patch-clamp electrophysiology were performed on human colonic epithelial cells (HCoEpiC) and rat small intestinal epithelial cells (IEC-6). The transcription levels of proinflammatory cytokines such as IL-1β were detected by RTq-PCR. Dextran sulfate sodium (DSS) was used to induce colitis in mice., Key Findings: ZPT dose-dependently induced Ca 2+ signaling and membrane currents in IECs, which were attenuated by selective blockers of transient receptor potential ankyrin 1 (TRPA1) and transient receptor potential vanilloid 4 (TRPV4) channels, respectively. Interestingly, Ca 2+ entry via TRPA1 channels inhibited the activity of TRPV4 channels in HCoEpiC, but not vice versa. ZPT significantly promoted migration of IECs by activating TRPA1 and TRPV4 channels. ZPT reversed lipopolysaccharides (LPS)-induced changes in mRNA expression of TRPA1 and TRPV4. Moreover, ZPT decreased mRNA levels of pro-inflammatory factors promoted by LPS in HCoEpiC, which were restored by selective TRPA1 blocker. In whole animal studies in vivo, ZPT significantly ameliorated DSS-induced body weight loss, colon shortening and increases in stool score, serum calprotectin and lactic acid (LD) in mouse model of colitis., Significance: ZPT exerts anti-colitic action likely by anti-inflammation and pro-mucosal healing through TRP channels in IECs. The present study not only expands pharmacology spectrum of ZPT in GI tract, but also repurposes it to a potential drug for colitis therapy., Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interest., (Copyright © 2024. Published by Elsevier Inc.)

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., Competing Interests: Declarations of competing interests None., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

The optimal balance of the intestinal microbiota is considered to be an essential part of the human body that affects many metabolic processes. However, the exact role of the gut microbiota in metabolism is still not fully understood. To investigate the metabolic role of gut microbiota, the content of short-chain fatty acids and tryptophan metabolites was studied in mice with sodium dextran sulfate-induced colitis. It was found that the production of short-chain fatty acids increased on experimental day 14, but by experimental day 60, they completely disappeared. At the same time, indoles of bacterial origin increased on experimental day 60., (© 2025. Springer Science+Business Media, LLC, part of Springer Nature.)

Ulcerative colitis (UC) is a chronic inflammatory disorder with an unsatisfactory cure rate and mucosal healing is a key treatment objective. Christensenellaceae minuta (C. minuta) has emerged as a next-generation of probiotic for maintaining intestinal health. We investigated the therapeutic efficacy of C. minuta in dextran sulfate sodium (DSS)-induced colitis, focusing on mucosal healing and the underlying mechanisms. C. minuta effectively alleviated colitis and promoted the regeneration of intestinal epithelial cells (IECs). Using 16S rRNA sequencing and metabolomics, we found that C. minuta administration increased beneficial bacteria, decreased pathogenic bacteria, and significantly elevated propionic acid levels. Additionally, C. minuta activated the PI3K-AKT pathway by upregulating systemic and local IGF-1 expression. Inhibiting the PI3K-AKT pathway reduced the therapeutic effects of C. minuta and impaired IEC regeneration. Furthermore, C. minuta promoted macrophage differentiation into the M2 phenotype and decreased proinflammatory factors. We propose that C. minuta alleviates colitis by regulating the gut microbiota, modulating macrophage differentiation, and enhancing mucosal healing by activating the PI3K-AKT pathway via IGF-1 secretion induced by short-chain fatty acids. Our findings provide evidence from animal experiments to support future clinical trials and the therapeutic translation of C. minuta., Competing Interests: Declaration of Competing Interest The author(s) declare(s) that there is no conflict of interest regarding the publication of this paper., (Copyright © 2024 The Authors. Published by Elsevier GmbH.. All rights reserved.)

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&#95;unclassified, Bacteroides and Parasutterella. Conversely, IDFs-CB promoted the growth of Candidatus&#95;Saccharimonas and norank&#95;f&#95;&#95;norank&#95;o&#95;&#95;Clostridia&#95;UCG-014. Notably, WBIDF enhanced the abundance of Allobaculum, while MBIDF and OBIDF increased the abundance of Lachnospiraceae&#95;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., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The prevalence and severity of gastrointestinal diseases were increased with age. In this study, the intestinal protective effects of Lactococcus lactis HF08 (HF08) and its derived postbiotic (P-HF08) on D-gal-induced aging mice and D-gal/DSS-induced aging colitis mice were investigated. In D-gal-induced aging mice, both HF08 and P-HF08 alleviated aging-related intestinal barrier dysfunction, inflammatory status, and gut microbiota disorder. The effects of probiotic HF08 were superior to those of postbiotic P-HF08, attributed to ability of HF08 to regulate the gut microbiota. However, in D-gal/DSS-induced aging colitis mice, the effects of P-HF08 on colitis surpassed that of HF08. Specifically, both HF08 and P-HF08 could reduce symptoms of age-related colitis, including reduction of lose weight, the DAI score, colonic shortening, and colon tissue damage. The inhibitory effects of P-HF08 on intestinal inflammation surpassed those of HF08, as evidenced by the levels of colon IL-6, IL-1β, and IL-10. Western blot results demonstrated that the anti-inflammatory effects of P-HF08 were attributed to the downregulation of key proteins in the TLR4/NF-κB pathway. And four potential TLR4 inhibitors were identified from HF08 metabolites (eplerenone, genistein, indoleacrylic acid, and turanose) by molecular docking. Nevertheless, HF08 could better regulate gut microbiota and metabolite in aging-related colitis than P-HF08, which was consistent with the results on aging mice. Overall, our finding revealed that when the intestinal barrier was intact (aging), probiotics showed superior regulation of intestinal microbiota, while postbiotics offered greater safety in case of intestinal barrier damage (aging colitis). This study offered a novel perspective into the applications of probiotics and their derivatives in the aging related gastrointestinal diseases adjuvant therapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Liubao insect tea (LIT) is a traditional tea produced from the excreta of Hydrillodes repugnalis that are fed with Liubao tea. In this study, LIT polyphenols (LITP) were extracted and identified, mainly consisting of brevifolin carboxylic acid, brevifolin, ellagic acid. The study aimed to explore the therapeutic potential of LITP in experimental colitis induced by dextran sulfate sodium in mice. LITP treatment effectively mitigated colitis symptoms, including body weight loss, diarrhoea and haematochezia, etc. Furthermore, LITP treatment significantly increased colon length, attenuated inflammatory cell infiltration and mucosal damage, safeguarded the integrity of the epithelial cell barrier, and reduced proinflammatory cytokines levels. Noteworthy alterations in the abundance of gut microbiota community were also observed, with increases in beneficial bacteria Akkermansia, Clostridia&#95;UCG-014, and decreases in harmful bacteria Turicibacter and Erysipelatoclostridium. In conclusion, LITP exerted alleviative effects on colitis via fortifying intestinal barrier and modulating the intestinal microbiota., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Krüppel-like factor 4 (KLF4), a transcription factor, is involved in various biological processes. However, the role of KLF4 in regulating the intestinal epithelial barrier (IEB) in inflammatory bowel disease (IBD) and its mechanism have not been extensively studied., Methods: KLF4 expression in IBD patients and colitis mice was analyzed using Gene Expression Omnibus(GEO) database, immunohistochemistry (IHC) and Western blot. The roles of KLF4 in IEB and colitis symptoms were verified in dextran sulfate sodium (DSS)-induced and 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis model mice using an adenovirus carrying KLF4 shRNA (shKLF4-Adv). Furthermore, the influence of KLF4 on trans-epithelium electrical resistance (TEER), paracellular permeability, apical junction complex (AJC) protein expression and apoptosis was assessed in vitro and in vivo. MeRIP and RIP assays were used to verify the effects of m6A modification on KLF4 expression., Results: KLF4 expression was significantly decreased in IBD patients and was negatively associated with inflammatory features. KLF4 deletion aggravated colitis symptoms and IEB injuries by reducing AJC protein expression and increasing apoptosis in mice with colitis. Furthermore, KLF4 transcriptionally regulated the expression of AJC proteins and inhibited apoptosis by reducing cellular ROS levels and proinflammatory cytokine expression. Moreover, we observed that METTL3/ALKBH5/YTHDF2-mediated m6A modification led to a decrease in KLF4 expression in Caco-2 cells. In addition, APTO-253, an inducer of KLF4, exhibited a synergistic effect with mesalazine on IEB function., Conclusions: Our study demonstrated that KLF4 is a crucial regulator of IEB, suggesting that targeting KLF4 may be a promising therapeutic alternative for IBD., Competing Interests: Declarations. Conflict of Interest: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Ethics approval and consent to participate: Ethical approval for the study was granted by the Ethics Committee at the First Affiliated Hospital of Soochow University (Suzhou, China. No. 2023532), and informed consent was also obtained from all participants. The Ethics Committee of Soochow University (Suzhou, China) approved all animal experimental procedures (No.202311A0034). Consent for publication: All authors reviewed the results and approved this manuscript for publication., (© 2024. The Author(s).)

Inflammatory bowel disease (IBD) is a chronic gastrointestinal disease with intricate pathogenesis, and clinical treatment is still not ideal. The imbalance of gut microbiota is associated with IBD progression. Various probiotics have been used as functional foods for the prevention and treatment of IBD, but the specific mechanism is still not fully understood. Lactobacillus johnsonii ( L. johnsonii ) is a potential anti-inflammatory bacterium, and compared to other probiotic Lactobacillus species, its colonization in the gut of colitis patients is significantly reduced. In this study, we first found that dietary L. johnsonii exerts strong anti-inflammatory and antioxidant effects in colitis mice, and this beneficial effect is directly related to its derived extracellular vesicles (LJ-EVs). Further experimental results indicate that LJ-EVs effectively prevented colitis symptoms and modulated gut microbiota and metabolic pathways. Meanwhile, we have studied for the first time the protective effect of LJ-EVs on the intestinal barrier from the perspective of reducing oxidative stress. We found that LJ-EVs can be directly taken up by intestinal epithelial cells and activate the Nrf2/HO-1 antioxidant signaling pathway, reducing endotoxin damage to cells and maintaining intestinal barrier homeostasis, which cascades to alleviate intestinal inflammation response. This study reveals the mechanism of L. johnsonii in treating colitis and provides a new approach for the development of oral LJ-EVs for the treatment of colitis.

Inflammatory bowel diseases (IBDs) are chronic, relapsing, and inflammatory disorders of the gastrointestinal tract characterized by abnormal immune responses. Recently, STING has emerged as a promising therapeutic target for various autoinflammatory diseases. However, few STING-selective small molecules have been investigated as novel strategies for IBD. In this study, we sought to examine the effects of PROTAC-based STING degrader SP23 on acute colitis and explore its underlying mechanism. SP23 treatment notably alleviates dextran sulfate sodium (DSS)-induced colitis. Pharmacological degradation of STING significantly reduced the production of inflammatory cytokines, such as TNF-α, IL-1β, and IL-6, and inhibited macrophage polarization towards the M1 type. Furthermore, SP23 administration decreased the loss of tight junction proteins, including ZO-1, occludin, and claudin-1, and downregulated STING and NLRP3 signaling pathways in intestinal inflammation. In vitro, STING activated NLRP3 inflammasome-mediated pyroptosis in intestinal epithelial cells, which could be abrogated by SP23 and STING siRNA intervention. In conclusion, these findings provide new evidence for STING as a novel therapeutic target for IBD, and reveal that hyperactivation of STING could exaggerate colitis by inducing NLRP3/Caspase-1/GSDMD axis mediated intestinal epithelial cells pyroptosis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Intestinal stem cells (ISCs) are necessary to maintain intestinal renewal. Here, we found that the highland barley β-glucan (HBG) alleviated pathological symptoms and promoted the proliferation of intestinal stem cells in colitis mice. Notably, metabolomics studies showed that docosahexaenoic acid (DHA) was significantly increased by the HBG treatment. DHA is a ligand for peroxisome proliferator-activated receptor α (PPARα), which can promote ISC proliferation. Expectedly, HBG facilitated the expression of intestinal PPARα and the proliferation of ISCs in colitis mice. Further experiments verified that DHA significantly facilitated the expression of PPARα and the proliferation of ISCs in intestinal organoids. Intriguingly, the effect of DHA on ISC proliferation was reversed by the PPARα inhibitor. Together, our data indicate that HBG might accelerate PPARα-mediated ISC proliferation through DHA. This provides new insights into the effective application of polysaccharides in maintaining intestinal homeostasis.

Dietary fiber is known to promote the production of short-chain fatty acids (SCFAs) by gut bacteria, which can enhance intestinal epithelial barrier function and ameliorate intestinal inflammation in patients with inflammatory bowel disease (IBD). Interestingly, some IBD patients show reduced expression of solute carrier family member 3 (Slc26a3) in intestinal epithelial cells. The objective of this research was to investigate the interaction between SCFAs and Slc26a3 during colitis and assess how this interaction affects intestinal epithelial barrier function. We showed that butyrate alleviated colonic inflammation in a dose-dependent manner in a dextran sulfate sodium salt (DSS)-induced colitis model. Consistent with this, butyrate increased Slc26a3 and tight junction protein levels. In addition, butyrate inhibited histone deacetylase (HDAC) levels and significantly increased the expression of Slc26a3 by the acetylation of histones in Caco-2BBe cells. The utilization of a pan-HDAC inhibitor or inhibitors specific to certain classes of HDACs revealed that butyrate primarily suppressed HDAC8 to blunt the NF-κB pathways and enhance the expression of Slc26a3. Notably, we demonstrated that HDAC8 activation counteracted the beneficial effect of butyrate in DSS-induced colitis. Therefore, we concluded that butyrate improves the expression of Slc26a3 via inhibition of the HDAC8/NF-κB pathway, leading to increased intestinal epithelial barrier function.

The maintenance of intestinal homeostasis is a fundamental process critical for organismal integrity. Sitting at the interface of the gut microbiome and mucosal immunity, adaptive and innate lymphoid populations regulate the balance between commensal micro-organisms and pathogens. Checkpoint inhibitors, particularly those targeting the CTLA-4 pathway, disrupt this fine balance and can lead to inflammatory bowel disease and immune checkpoint colitis. Here, we show that CTLA-4 is expressed by innate lymphoid cells and that its expression is regulated by ILC subset-specific cytokine cues in a microbiota-dependent manner. Genetic deletion or antibody blockade of CTLA-4 in multiple in vivo models of colitis demonstrates that this pathway plays a key role in intestinal homeostasis. Lastly, we have found that this observation is conserved in human IBD. We propose that this population of CTLA-4-positive ILC may serve as an important target for the treatment of idiopathic and iatrogenic intestinal inflammation., (© 2024. The Author(s).)

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., (© 2024. The Author(s).)

Vitamin K2 (VK2) has been shown to have potential benefits in improving intestinal integrity, but its potential and mechanisms for alleviating intestinal inflammation are still unclear. The present results showed that VK2 supplementation significantly alleviated the symptoms of colitis and maintained the intestinal barrier integrity. In addition, VK2 significantly down-regulated the mRNA expression levels of pro-inflammatory cytokines including IL-1β, IL-6, and TNF-α, while up-regulated the mRNA expression level of anti-inflammatory cytokines such as IL-10. Moreover, VK2 significantly alleviated DSS-induced intestinal epithelial barrier dysfunction by maintaining the tight junction function. Furthermore, VK2 also regulated DSS-induced gut microbiota dysbiosis by reshaping the structure of gut microbiota, such as increasing the relative abundance of Firmicutes, Euryarchaeota, Prevotellaceae, and Prevotella and reducing the relative abundance of Proteobacteria, Rikenellaceae, Enterobacteriaceae, Acetatifactor, and Alistioes. In conclusion, these results indicated that VK2 effectively alleviates DSS-induced colitis in mice by modulating the gut microbiota., Competing Interests: Declaration of competing interest The authors declare they have no competing interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Ulcerative colitis (UC) is a chronic relapsing and progressive inflammatory disease of the colon. TIPE2 is a negative regulator of innate and adaptive immunity that maintains immune homeostasis. We found that TIPE2 was highly expressed in mucosa of mice with colitis. However, the role of TIPE2 in colitis remains unclear. We induced colitis in mice with dextran sulfate sodium (DSS) and treated them with TIPE2, and investigated the inflammatory activity of the colon in vivo by cytokines detection and histopathological analyses. We also measured inflammatory alteration and tight junctions induced by DSS in vitro. The results demonstrated that administration of TIPE2 promoted the severity of colitis in mice and human colon epithelial cells. Furthermore, TIPE2 aggravated intestinal epithelial barrier dysfunction by decreasing the expression of the tight junction proteins Occludin, Claudin-1 and ZO-1. In addition, TIPE2 exacerbated intestinal inflammatory response by inhibiting the expression of SOCS3, remarkably activating JAK2/STAT3 signaling pathway, and increasing the translocation of phosphorylated STAT3 into the nucleus. Silencing of TIPE2 attenuated the DSS-induced activation of JAK2/STAT3, thereby rescuing epithelial inflammatory injury and restoring barrier dysfunction. These results indicate that TIPE2 augments experimental colitis and disrupted the integrity of the intestinal epithelial barrier by activating the JAK2/STAT3/SOCS3 signaling pathway., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The unknown mechanism that controls intestinal barrier dysfunction in individuals with Crohn's disease (CD) plays a crucial role in the onset of intestinal inflammation. Testin, an intercellular linker protein, has the potential to protect epithelial barrier function. This study aimed to analyse the effects of Testin on CD-like colitis and explore the possible underlying mechanism. Colon samples from CD patients and trinitrobenzene-sulfonic acid (TNBS)-treated mice were collected to examine changes in Testin expression. To assess the therapeutic effects of Testin on CD-like colitis in mice, we examined the symptoms of enteritis, performed histological analysis, and evaluated intestinal barrier permeability. The ability of Testin to stabilize tight junction (TJ) proteins was investigated via immunofluorescence and western blotting. We conducted in vivo and in vitro experiments using colonic organoids and blocking techniques to explore how Testin safeguards the integrity of the intestinal barrier. Testin expression was downregulated in the colons of CD patients and TNBS-treated mice. Increasing Testin expression led to amelioration of colitis symptoms and reduced the production of inflammatory cytokines in the colons of TNBS-induced colitis model mice. Furthermore, increased Testin expression resulted in decreased depletion of TJ proteins (ZO-1 and Claudin-1) and promoted the effectiveness of the intestinal barrier in mice with TNBS-induced colon damage and in lipopolysaccharide (LPS)-stimulated colonic organoids. Elevated Testin levels inactivated the JNK/P38 signalling pathway, potentially contributing to the beneficial impact of Testin on the intestinal barrier. Testin can inhibit the loss of TJ proteins in CD mice by inactivating the JNK/P38 pathway. These findings help to clarify how Testin alleviates CD-like colitis in mice by protecting intestinal barrier function. These findings could lead to the use of a new treatment approach for CD in clinical practice., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Inflammatory bowel disease (IBD), including ulcerative colitis and Crohn's disease, manifests as chronic intestinal inflammation with debilitating symptoms, posing a significant burden on global healthcare. Moreover, current therapies primarily targeting inflammation can lead to immunosuppression-related complications. Human amniotic epithelial stem cells (hAESCs), which exhibit low immunogenicity and ethical acceptability, have gained attention as potential therapeutics. In this study, it is demonstrated that their encapsulation in a hydrogel and administration via anal injection enhanced the colonic mucosal barrier repair in a murine colitis model induced by dextran sodium sulfate during the recovery phase. The underlying mechanism involved the release of exosomes from hAESCs enriched with microRNA-23a-3p, which post-transcriptionally reduced tumor necrosis factor receptor 1 expression, suppressing the nuclear factor-κB pathway in colonic epithelial cells, thus played a key role in inflammation. The novel approach shows potential for IBD treatment by restoring intestinal epithelial homeostasis without the immunosuppressive therapy-associated risks. Furthermore, the approach provides an alternative strategy to target the key molecular pathways involved in inflammation and promotes intestinal barrier function using hAESCs and their secreted exosomes. Overall, this study provides key insights to effectively treat IBD, addresses the unmet needs of patients, and reduces related healthcare burden., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Inflammatory bowel disease (IBD) is a common chronic disease with a complex etiology, characterized by body weight loss, intestinal barrier damage, and an imbalance of intestinal flora, posing a significant threat to people's health. In this work, we studied whether safer natural active agaro-oligosaccharides (AOSs) benefit mice with IBD and elucidated their underlying mechanisms. The findings indicated that oral administration of agarobiose (A2), agarotriose (A3), and agarotetraose (A4) contributed to alleviating body weight loss and colon shortening, as well as enhancing IL-10 levels while reducing IL-6, IL-1β, and TNF-α. AOSs improved colon disruption, reduced the number of goblet cells caused by DSS, and enhanced the expression of Muc2, ZO-1, and occludin-1 to repair the intestinal barrier. It is noteworthy that A3 demonstrated superior outcomes in the evaluated AOSs relative to A2 and A4. This was evidenced by an increase in Bacteroidota and reduced Firmicutes at the phylum level, which corrected DSS-induced intestinal dysbiosis and significantly restored disrupted metabolic pathways, including amino acid and lipid metabolism. The differential metabolites between the AOS treatment groups and the model group were mainly enriched in arginine synthesis with co-regulated critical substances N -acetyl-L-citrulline and N2-acetylornithine, which alleviated colitis. This evidence offers a fresh perspective on the potential application of AOSs as functional foods to improve intestinal inflammation and metabolism.

Background: Exosomes derived from endometrial regenerative cells (ERC-Exos) can inherit the immunomodulatory function from ERCs, however, whether ERC-Exos exhibit such effect on inflammatory bowel diseases with mucosal immune dysregulation has not been explored. Insulin-like growth factor-Ⅱ (IGF2) is considered to possess the potential to induce an anti-inflammatory phenotype in immune cells. In this study, the contribution of IGF2 in mediating the protective efficacy of ERC-Exos on colitis was investigated., Methods: Lentiviral transfection was employed to obtain IGF2-specific knockout ERC-Exos (IGF2 -/- -ERC-Exos). Experimental colitis mice induced by dextran sulfate sodium (DSS) were divided into the phosphate-buffered saline (untreated), ERC-Exos-treated and IGF2 -/- -ERC-Exos-treated groups. Colonic histopathological analysis and intestinal barrier function were explored. The infiltration of CD4 + T cells and dendritic cells (DCs) were analyzed by immunofluorescence staining and flow cytometry. The maturation and function of bone marrow-derived dendritic cells (BMDCs) in different exosome administrations were evaluated by flow cytometry, ELISA and the coculture system, respectively., Results: Compared with the untreated group, ERC-Exos treatment significantly attenuated DSS-induced weight loss, bloody stools, shortened colon length, pathological damage, as well as repaired the weakened intestinal mucosal barrier, including promoting the goblet cells retention, restoring the intestinal barrier integrity and enhancing the expression of tight junction proteins, while the protective effect of exosomes was impaired with the knockout of IGF2 in ERC-Exos. Additionally, IGF2-expressing ERC-Exos decreased the proportions of Th1 and Th17, increased the proportions of Treg, as well as attenuated DC infiltration and maturation in mesenteric lymph nodes and lamina propria of the colitis mice. ERC-Exos were also observed to be phagocytosed by BMDCs and IGF2 is responsible for the modulating effect of ERC-Exos on BMDCs in vitro., Conclusions: Exosomes derived from ERCs can exert a therapeutic effect on experimental colitis with remarkable alleviation of the intestinal barrier damage and the abnormal mucosal immune responses. We emphasized that IGF2 plays a critical role for ERC-Exos mediated immunomodulatory function and protection against colitis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Inflammatory bowel diseases (IBD) have a complex, poorly understood pathogenesis and lack long-lasting effective treatments. Recent research suggests that intestinal fungal dysbiosis may play a role in IBD development. This study investigates the effects of the glucocorticoid-induced leucine zipper protein (GILZp)", known for its protective role in gut mucosa, and a yeast extract (Py) with prebiotic properties, either alone or combined, in DSS-induced colitis. Both treatments alleviated symptoms via overlapping or distinct mechanisms. In particular, they reduced the transcription levels of pro-inflammatory cytokines IL-1β and TNF-α, as well as the expression of the tight junction protein Claudin-2. Additionally, GILZp increased MUC2 transcription, while Py reduced IL-12p40 and IL-6 levels. Notably, both treatments were effective in restoring the intestinal burden of clinically important Candida and related species. Intestinal mycobiome analysis revealed that they were able to reduce colitis-associated fungal dysbiosis, and this effect was mainly the result of a decreased abundance of the Meyerozima genus, which was dominant in colitic mice. Overall, our results suggest that combined treatment regimens with GILZp and Py could represent a new strategy for the treatment of IBD by targeting multiple mechanisms, including the fungal dysbiosis.

Experimental evidence suggests that, in the inflamed gut of inflammatory bowel disease (IBD) patients, interleukin-34 (IL-34) triggers detrimental signaling pathways. Factors/mechanisms regulating IL-34 production in IBD remain poorly characterized. Bromodomain-containing 4 (BRD4), a transcriptional and epigenetic regulator, is over-expressed in IBD, and studies in cancer cells suggest that BRD4 might positively control IL-34 expression. This study aimed to assess whether, in IBD, BRD4 regulates IL-34 expression. In IBD, there was an up-regulation of both IL-34 and BRD4 compared to the controls, and the two proteins co-localized in both lamina propria mononuclear cells (LPMCs) and epithelial cells. Flow cytometry analysis of CD45+ LPMCs confirmed that the percentages of IL-34- and BRD4-co-expressing cells were significantly higher in IBD than in the controls and showed that more than 80% of the IL-34-positive CD45-LPMCs expressed BRD4. IL-34 and BRD4 were mainly expressed by T cells and macrophages. IL-34 expression was reduced in IBD LPMCs transfected with BRD4 antisense oligonucleotide and in the colons of mice with dextran sulfate sodium-induced colitis treated with JQ1, a pharmacological inhibitor of BRD4. These data indicate that BRD4 is a positive regulator of IL-34 in IBD, further supporting the pathogenic role of BRD4 in IBD-associated mucosal inflammation.

Impaired intestinal homeostasis is a major pathological feature of inflammatory bowel diseases (IBD). Mannose and selenium (Se) both demonstrate potential anti-inflammatory and anti-oxidative properties. However, most lectin receptors bind free monosaccharide ligands with relatively low affinity and most Se species induce side effects beyond a very narrow range of dosage. This has contributed to a poorly explored therapies for IBD that combine mannose and Se to target intestinal epithelial cells (IECs) for normalization gut homeostasis. Herein, a facile and safe strategy for ulcerative colitis (UC) treatment was developed using optimized, mannose-functionalized Se nanoparticles (M-SeNPs) encapsulated within a colon-targeted hydrogel delivery system containing alginate (SA) and chitosan (CS). This biocompatible nanosystem was efficiently taken up by IECs and led to increased expression of Se-dependent glutathione peroxidases (GPXs), thereby modulating IECs' immune response. Using a mouse model of DSS-induced colitis, (CS/SA)-embedding M-SeNPs (C/S-MSe) were found to mitigate oxidative stress and inflammation through the inhibition of the NF-kB pathway in the colon. This stabilized mucosal homeostasis of IECs and ameliorated colitis-related symptoms, thereby providing a potential new approach for treatment of IBD., (© 2024. The Author(s).)

Background: The incidence of inflammatory bowel disease (IBD) is on the rise in developing countries, and investigating the underlying mechanisms of IBD is essential for the development of targeted therapeutic interventions. Interferon regulatory factor 7 (IRF7) is known to exert pro-inflammatory effects in various autoimmune diseases, yet its precise role in the development of colitis remains unclear., Methods: We analyzed the clinical significance of IRF7 in ulcerative colitis (UC) by searching RNA-Seq databases and collecting tissue samples from clinical UC patients. And, we performed dextran sodium sulfate (DSS)-induced colitis modeling using WT and Irf7 -/- mice to explore the mechanism of IRF7 action on colitis., Results: In this study, we found that IRF7 expression is significantly reduced in patients with UC, and also demonstrated that Irf7 -/- mice display heightened susceptibility to DSS-induced colitis, accompanied by elevated levels of colonic and serum pro-inflammatory cytokines, suggesting that IRF7 is able to inhibit colitis. This increased susceptibility is linked to compromised intestinal barrier integrity and impaired expression of key molecules, including Muc2, E-cadherin, β-catenin, Occludin, and Interleukin-28A (IL-28A), a member of type III interferon (IFN-III), but independent of the deficiency of classic type I interferon (IFN-I) and type II interferon (IFN-II). The stimulation of intestinal epithelial cells by recombinant IL-28A augments the expression of Muc2, E-cadherin, β-catenin, and Occludin. The recombinant IL-28A protein in mice counteracts the heightened susceptibility of Irf7 -/- mice to colitis induced by DSS, while also elevating the expression of Muc2, E-cadherin, β-catenin, and Occludin, thereby promoting the integrity of the intestinal barrier., Conclusion: These findings underscore the pivotal role of IRF7 in preserving intestinal homeostasis and forestalling the onset of colitis., (© 2024. The Author(s).)

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., (© 2024 Hashemi et al.)

Inflammatory bowel diseases (IBD) are often associated with dysregulated gut microbiota and excessive inflammatory microenvironment. Probiotic therapy combined with inflammation management is a promising approach to alleviate IBD, but the efficacy is hindered by the inferior colonization of probiotics in mucus-depleted inflammatory bowel segments. Here, we present modified montmorillonite armed probiotic Escherichia coli Nissle 1917 (MMT-Fe@EcN) with enhanced intestinal colonization and hydrogen sulfide (H 2 S) scavenging for synergistic alleviation of IBD. The montmorillonite layer that can protect EcN against environmental assaults in oral delivery and improve on-site colonization of EcN in the mucus-depleted intestinal segment due to its strong adhesive capability and electronegativity, with a 22.6-fold increase in colonization efficiency compared to EcN. Meanwhile, MMT-Fe@EcN can manage inflammation by scavenging H 2 S, which allows for enhancing probiotic viability and colonization for restoring the gut microbiota. As a result, MMT-Fe@EcN exhibits extraordinary therapeutic effects in the dextran sulfate sodium-induced mouse colitis models, including alleviating intestinal inflammation and restoring disrupted intestinal barrier function, and gut microbiota. These findings provide a promising strategy for clinical IBD treatment and potentially other mucus-depletion-related diseases., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024. Published by Elsevier B.V.)

Scope: Curcumin (Cur), with diverse pharmacological properties, shows anti-obesity, immunomodulatory, and anti-inflammatory effects. Its role in ulcerative colitis complicated by obesity remains unclear., Methods and Results: Here, colitis is induced in obese mice using dextran sulfate sodium (DSS), followed by administration of Cur at a dosage of 100 mg kg -1 for 14 days. Cur effectively alleviates DSS-induced colitis in obese mice, accompanied by an increase in body weight and survival rate, reduction in disease activity index, elongation of the colon, decrease in colonic weight, and improvements in ulcer formation and inflammatory cell infiltration in colonic tissues. Additionally, Cur effectively improves lipid metabolism and the composition of the gut microbiota, and enhances mucosal integrity and boosts anti-oxidative stress capacity in obese mice with colitis. Importantly, Cur is effective in improving the homeostasis of memory T cells in obese mice with colitis. Furthermore, Cur regulates inflammatory cytokines expression and inhibits activation of the JAK2/STAT signaling pathway in colonic tissues of obese mice with colitis., Conclusions: Cur alleviates colitis in obese mice through a comprehensive mechanism that improves lipid metabolism, modulates gut microbiota composition, enhances mucosal integrity and anti-oxidative stress, balances memory T cell populations, regulates inflammatory cytokines, and suppresses the JAK2/STAT signaling pathway., (© 2024 Wiley‐VCH GmbH.)

This study aimed to investigate whether bergapten (BG), a furanocoumarin phytohormone, holds promise for Crohn's disease (CD)-like colitis treatment and to preliminarily explore its potential mechanisms. 2,4,6-Trinitrobenzenesufonic acid (TNBS)-treated mice were applied to establish an in vivo research model, and BG was administered with different concentrations. The status of mice in each group was evaluated by disease activity index (DAI), and the severity was evaluated by pathological sections. The intestinal barrier was assessed by measuring in vivo intestinal permeability, peripheral blood intestinal fatty acid-binding protein (I-FABP) levels, epithelial resistance values, and tight junction protein levels. Markers were then used to assess Th17/Treg levels, mitophagy, and the peroxisome proliferator-activated receptor (PPAR)γ/ nuclear factor kappa B (NF-κB) signaling pathway. BG significantly reduced colon tissue damage in a concentration-dependent manner. DAI scores showed that the loose feces, occult blood, and weight loss of mice in the BG treatment were significantly reduced, and pathological section results revealed reduced inflammatory infiltration and fibrosis. Reduced serum FITC-dextran and I-FABP and increased levels of epithelial resistance and tight junction proteins support that the intestinal barrier was protected upon BG. The proportion of Th17 in mesenteric lymph nodes increased while Treg decreased in the model group. BG treatment effectively reduced the conversion of Treg to Th17. Additionally, BG was found to enhance mitophagy and activate the PPARγ/NF-κB signaling. BG demonstrates promising effects in ameliorating intestinal barrier damage and Th17/Treg imbalance in a murine model of CD-like colitis, while also promoting intracellular mitophagy. The PPARγ/NF-κB signaling pathway may serve as a key mediator of BG's regulatory mechanisms., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Environmental stress is a significant contributor to the development of inflammatory bowel disease (IBD). The involvement of temperature stimulation in the development of IBD remains uncertain. Our preliminary statistical data suggest that the prevalence of IBD is slightly lower in colder regions compared to non-cold regions. The observation indicates that temperature changes may play a key role in the occurrence and progression of IBD. Here, we hypothesized that cold stress has a protective effect on IBD., Methods: The cold exposure model for mice was placed in a constant temperature and humidity chamber, maintained at a temperature of 4 °C. Colitis models were induced in the mice using TNBS or DSS. To promote the detection methods more clinically, fluorescence confocal endoscopy was used to observe the mucosal microcirculation status of the colon in the live model. Changes in the colonic wall of the mice were detected using 9.4 T Magnetic Resonance Imaging (MRI) imaging and in vivo fluorescence imaging. Hematoxylin and eosin (H&E) and Immunofluorescence (IF) staining confirmed the pathological alterations in the colons of sacrificed mice. Molecular changes at the protein level were assessed through Western blotting and Enzyme-Linked Immunosorbent Assay (ELISA) assays. RNA sequencing (RNA-seq) and metabolomics (n = 18) were jointly analyzed to investigate the biological changes in the colon of mice treated by cold exposure., Results: Cold exposure decreased the pathologic and disease activity index scores in a mouse model. Endomicroscopy revealed that cold exposure preserved colonic mucosal microcirculation, and 9.4 T MRI imaging revealed alleviation of intestinal wall thickness. In addition, the expression of the TLR4 and PP65 proteins was downregulated and epithelial cell junctions were strengthened after cold exposure. Intriguingly, we found that cold exposure reversed the decrease in ZO-1 and occludin protein levels in dextran sulfate sodium (DSS)- and trinitrobenzenesulfonic acid-induced colitis mouse models. Multi-omics analysis revealed the biological landscape of DSS-induced colitis under cold exposure and identified that the peroxisome proliferator-activated receptor (PPAR) signaling pathway mediates the effects of cold on colitis. Subsequent administration of rosiglitazone (PPAR agonist) enhanced the protective effect of cold exposure on colitis, whereas GW9662 (PPAR antagonist) administration mitigated these protective effects. Overall, cold exposure ameliorated the progression of mouse colitis through the PPARγ/NF-κB signaling axis and preserved the intestinal mucosal barrier., Conclusion: Our study provides a mechanistic link between intestinal inflammation and cold exposure, providing a theoretical framework for understanding the differences in the prevalence of IBD between the colder regions and non-cold regions, and offering new insights into IBD therapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Maintaining intracellular redox balance is essential for the survival, antibody secretion, and mucosal immune homeostasis of immunoglobulin A (IgA) antibody-secreting cells (ASCs). However, the relationship between mitochondrial metabolic enzymes and the redox balance in ASCs has yet to be comprehensively studied. Our study unveils the pivotal role of mitochondrial enzyme PCK2 in regulating ASCs' redox balance and intestinal homeostasis. We discover that PCK2 loss, whether globally or in B cells, exacerbates dextran sodium sulphate (DSS)-induced colitis due to increased IgA ASC cell death and diminished antibody production. Mechanistically, the absence of PCK2 diverts glutamine into the TCA cycle, leading to heightened TCA flux and excessive mitochondrial reactive oxygen species (mtROS) production. In addition, PCK2 loss reduces glutamine availability for glutathione (GSH) synthesis, resulting in a decrease of total glutathione level. The elevated mtROS and reduced GSH expose ASCs to overwhelming oxidative stress, culminating in cell apoptosis. Crucially, we found that the mitochondria-targeted antioxidant Mitoquinone (Mito-Q) can mitigate the detrimental effects of PCK2 deficiency in IgA ASCs, thereby alleviating colitis in mice. Our findings highlight PCK2 as a key player in IgA ASC survival and provide a potential new target for colitis treatment., (© 2024 John Wiley & Sons Ltd.)

Isoorientin (ISO) is a naturally occurring flavonoid with diverse functional properties that mitigate the risk of diseases stemming from oxidation, inflammation, and cancer cell proliferation. P-glycoprotein (P-gp) is a vital component of the intestinal epithelium and may play a role in the onset of intestinal inflammatory conditions, such as inflammatory bowel disease (IBD). Recent studies have suggested that short-chain fatty acids (SCFAs) and secondary bile acids (SBAs) produced by the gut microbiota stimulate the increase of P-gp expression, alleviating excessive inflammation and thereby preservation of intestinal homeostasis. ISO has been shown to improve colon health and modulate the gut microbiota. In this study, we aimed to explore whether ISO can modulate the microbes and their metabolites to influence P-gp expression to alleviate IBD. First, the impact of ISO on dextran sulfate sodium (DSS)-treated colitis in mice was investigated. Second, 16S rRNA gene sequencing was conducted. The present study indicated that ISO mitigated the symptoms and pathological damage associated with DSS-treated colitis in mice. Western blot analysis revealed ISO upregulated P-gp in colon tissues, suggesting the critical role of P-gp protein in intestinal epithelial cells. 16S microbial diversity sequencing revealed ISO restored the richness and variety of intestinal microorganisms in colitis-bearing mice and enriched SCFA-producing bacteria, such as Lachnospiraceae&#95;NK4A136&#95;group . The experiments also revealed that the ISO fecal microbiota transplantation (FMT) inoculation of DSS-treated mice had similarly beneficial results. FMT mice showed a reduction in colitis symptoms, which was more pronounced in ISO-FMT than in CON-FMT mice. Meanwhile, ISO-FMT expanded the abundance of beneficial microorganisms, increased the expression of metabolites, such as SCFAs and total SBAs, and significantly upregulated the expression of P-gp protein. In addition, Spearman's correlation analysis demonstrated a positive correlation between the production of SCFAs and SBAs and the expression of P-gp. The present study identified that ISO increases the expression of P-gp in the intestinal epithelium by regulating intestinal microorganisms and their metabolites, which maintains colonic homeostasis, improves the integrity of the colonic epithelium, and alleviates colitis.

Purpose: Inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), are chronic gastrointestinal disorders associated with significant morbidity and complications. This study investigates the therapeutic potential of docosahexaenoic acid (DHA) in a trinitrobenzene sulfonic acid (TNBS) induced colitis model, focusing on inflammation, oxidative stress, and intestinal membrane permeability., Methods: Wistar albino rats were divided into Control, Colitis, and Colitis + DHA groups (n = 8-10/group). The Colitis and Colitis + DHA groups received TNBS intrarectally, while the Control group received saline. DHA (600 mg/kg/day) or saline was administered via gavage for six weeks. Macroscopic and microscopic evaluations of colon tissues were conducted. Parameters including occludin and ZO-1 expressions, myeloperoxidase (MPO) activity, malondialdehyde (MDA), glutathione (GSH), total antioxidant status (TAS), total oxidant status (TOS), Interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-α) levels were measured in colon tissues., Results: Colitis induction led to significantly higher macroscopic and microscopic damage scores, elevated TOS levels, reduced occludin and ZO-1 intensity, decreased mucosal thickness, and TAS levels compared to the Control group (p < 0.001). DHA administration significantly ameliorated these parameters (p < 0.001). MPO, MDA, TNF-α, and IL-6 levels were elevated in the Colitis group but significantly reduced in the DHA-treated group (p < 0.001 for MPO, MDA; p < 0.05 for TNF-α and IL-6)., Conclusion: DHA demonstrated antioxidant and anti-inflammatory effects by reducing reactive oxygen species production, enhancing TAS capacity, preserving GSH content, decreasing proinflammatory cytokine levels, preventing neutrophil infiltration, reducing shedding in colon epithelium, and improving gland structure and mucosal membrane integrity. DHA also upregulated the expressions of occludin and ZO-1, critical for barrier function. Thus, DHA administration may offer a therapeutic strategy or supplement to mitigate colitis-induced adverse effects., (© 2024. The Author(s).)

A new polysaccharide fraction (ATP) was obtained from Armillariella tabescens mycelium. Structural analysis suggested that the backbone of ATP was →4)-α-D-Glcp(1 → 2)-α-D-Galp(1 → 2)-α-D-Glcp(1 → 4)-α-D-Glcp(1→, which branched at O-3 of →2)-α-D-Glcp(1 → and terminated with T-α-D-Glcp or T-α-D-Manp. Besides, ATP significantly alleviated ulcerative colitis (UC) symptoms and inhibited the production of pro-inflammation cytokines (IL-1β, IL-6). Meanwhile, ATP could improve colon tissue damage by elevating the expression of MUC2 and tight junction proteins (ZO-1, occludin and claudin-1) levels and enhance intestinal barrier function through inhibiting the activation of MMP12/MLCK/p-MLC2 signaling pathway. Further studies exhibited that ATP could increase the relative abundance of beneficial bacteria such as f. Muribaculacese, g. Muribaculaceae, and g. Alistips, and decrease the relative abundance of g. Desulfovibrio, g. Colidextribacter, g. Ruminococcaceae and g.Oscillibacter, and regulate the level of short-chain fatty acids. Importantly, FMT intervention with ATP-derived microbiome certified that gut microbiota was involved in the protective effects of ATP on UC. The results indicated that ATP was potential to be further developed into promising therapeutic agent for UC., Competing Interests: Declaration of competing interest The authors have no conflict of interest to declare., (Copyright © 2024. Published by Elsevier B.V.)

Tertiary lymphoid tissues (TLTs) are adaptive immune structures that develop during chronic inflammation and may worsen or lessen disease outcomes in a context-specific manner. Immune cell activity governing TLT formation in the intestines is dependent on immune cell aryl hydrocarbon receptor (AhR) activation. Homeostatic immune cell activity in the intestines is further dependent on ligand activation of AhR in intestinal epithelial cells (IECs), yet whether AhR activation and signaling in IECs influences the formation of TLTs in the presence of dietary AhR ligands is not known. To this end, we used IEC-specific AhR deletion coupled with a mouse model of dextran sodium sulfate (DSS)-induced colitis to understand how dietary AhR ligand 3, 3'-diindolylmethane (DIM) influenced TLT formation. DIM consumption increased the size of TLTs and decreased T-cell aggregation to TLT sites in an IEC-specific manner. In DSS-exposed female mice, DIM consumption increased the expression of genes implicated in TLT formation (Interleukin-22, Il-22 ; CXC motif chemokine ligand 13, CXCL13 ) in an IEC AhR-specific manner. Conversely, in female mice without DSS exposure, DIM significantly reduced the expression of Il-22 or CXCL13 in iAhRKO mice, but this effect was not observed in WT animals. Our findings suggest that DIM affects the immunological landscape of TLT formation during DSS-induced colitis in a manner contingent on AhR expression in IECs and biological sex. Further investigations into specific immune cell activity, IEC-specific AhR signaling pathways, and dietary AhR ligand-mediated effects on TLT formation are warranted.

Objective: To investigate the effect and potential mechanisms of α-cyperone (CYP) on Crohn's disease (CD) -like colitis induced by 2, 4, 6-trinitrobenzene sulfonic acid (TNBS) in mice., Methods: The mice were randomly and evenly divided into wild type (WT), TNBS, CYP and 5-aminosalicylic acid (5-ASA) groups, with 10 mice in each group. The symptoms of enteritis, the function and structure of the intestinal barrier, and the expression levels of inflammatory factors, including interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and gamma-interferon (IFN-γ), in the colon were assessed. The lipopolysaccharide (LPS)-induced inflammation model of Caco2 cells was constructed and the cells were divided into Control, LPS and LPS+CYP groups. The expression levels of tight junction protein and inflammatory factors in each group were assessed. Gene Ontology (GO) functional enrichment analysis was conducted to predict the possible pathways of action and potential molecular mechanisms of CYP, and to verify them in vivo and in vitro ., Results: In the in vivo study, compared with those of the TNBS group, the body mass and colon length of mice in the CYP group and the 5-ASA group were significantly increased, while the disease activity scores and histological inflammation scores were significantly decreased ( P <0.05). The level of lucifcein-glucan isothiocyanate and the bacterial translocation rate (in the liver, the spleen, and mesenteric lymph nodes) were significantly decreased, while the transepithelial electric resistance (TEER) value and the expression levels of zonula occluden protein-1 (ZO-1), and claudin-1 were significantly increased ( P <0.05). The expression of inflammatory factors was significantly decreased ( P <0.05). In the in vitro study, compared with those of the LPS group, the TEER value and the expression of ZO-1 and claudin-1 in the Caco2 cells in the LPS+CYP group were significantly increased ( P <0.05). The expression of inflammatory factors was significantly decreased ( P <0.05). Enrichment analysis showed that CYP was correlated with inflammatory response ( P <0.001). Western blot results showed that CYP could significantly reduce the expression of key proteins in toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) signaling pathway in vivo and in vitro ( P <0.05)., Conclusion: CYP may protect the intestinal barrier by antagonizing the inflammatory response of the intestinal mucosa through regulating the expression of the TLR4/NF-κB signaling pathway, thereby alleviating TNBS-induced CD-like colitis in mice., Competing Interests: 利益冲突　所有作者均声明不存在利益冲突, (© 2024《四川大学学报（医学版）》编辑部 版权所有Copyright ©2024 Editorial Office of Journal of Sichuan University (Medical Sciences).)

Objective: To investigate the effect and molecular mechanism of isolongifolene (ISO) on the apoptosis of intestinal epithelial cells and 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced Crohn's disease (CD)-like colitis in mice., Methods: In the animal experiments, mice were randomly assigned to the wild type (WT) group, TNBS group and TNBS+ISO group, with 8 mice in each group. Colitis models of mice were established in the TNBS group and the TNBS+ISO group by rectal injection of TNBS. After modeling, the mice in the TNBS+ISO group were given ISO intervention via intragastric gavage (10 mg/kg), and the other two groups were given the same amount of normal saline via intragastric gavage. The mice were sacrificed on the 7th day. The changes in body mass, disease activity scores (DAI), and the colon length of mice were measured, and transepithelial electrical resistance (TEER) of the colon tissues was determined. The score of colon inflammation was calculated according to HE staining. The levels of intestinal mucosal inflammatory factors, including tumor necrosis factor alpha (TNF-α), interferon (IFN)-γ, interleukin (IL)-1β, and IL-6, were measured by RT-PCR and ELISA. The apoptosis of colon tissue cells was determined by TUNEL assay. The expressions of apoptotic proteins (cleaved caspase-3/caspase-3 and Bax), an anti-apoptotic protein (Bcl-2), and tight junction proteins (ZO-1 and claudin-1) were detected by Western blot and immunofluorescence. In the cell experiment, TNF-α was used to induce intestinal epithelial cell Caco-2 apoptosis model, which was treated with ISO. Then, intervention with the AMPK inhibitor Compound C was given. TUNEL assay, Western blot assay, and immunofluorescence assay were performed to measure apoptosis and the expression of apoptosis proteins in the Caco-2 cells. Gene Ontology (GO) enrichment analysis was performed to predict the biological function of ISO. Then, the mechanism involved was verified by examination of the mice and Caco-2 cells. Western blot was performed to determine the expression levels of p-AMPK/AMPK and p-PGC1α in the colon tissues from the mice of different groups and Caco-2 cells. The apoptosis of the cells was determined by TUNEL assay., Results: According to the results of the animal experiment, ISO could alleviate experimental colitis and intestinal barrier dysfunction, leading to improvements in body mass loss, colon length shortening, DAI score, inflammatory rating, and TEER values (all P <0.05) in mice. Furthermore, ISO decreased the expression of pro-inflammatory factors TNF-α, IFN-γ, IL-1β, and IL-6 and increased the expression of the tight junction proteins ZO-1 and claudin-1 (all P <0.05). In the cell experiment, in a TNF-α-induced intestinal epithelial cell model, ISO was also found to protect intestinal barrier against damage. ISO reduced the proportion of apoptotic intestinal epithelial cells, reduced the expression of cleaved-caspase-3/caspase-3 and Bax, and upregulated the level of Bcl-2 (all P <0.05). GO enrichment predictive analysis showed that the role of ISO in improving CD-like enteritis might be associated with the negative regulation of apoptosis. Verification of the mechanism showed that the expression of p-AMPK and p-PGC1α in the mice colon tissue was significantly upregulated after ISO intervention ( P <0.05). In contrast, the AMPK inhibitor Compound C increased the apoptosis rate of ISO-treated Caco-2 cells and decreased the relative expression levels of ZO-1 and claudin-1 ( P <0.05)., Conclusion: ISO reduces intestinal epithelial cell apoptosis at least in part by activating AMPK/PGC1α signaling pathway, thereby alleviating TNBS-induced intestinal barrier dysfunction and CD-like colitis in mice., Competing Interests: 利益冲突　所有作者均声明不存在利益冲突, (© 2024《四川大学学报（医学版）》编辑部 版权所有Copyright ©2024 Editorial Office of Journal of Sichuan University (Medical Sciences).)