Neohesperidin Attenuates DSS-Induced Ulcerative Colitis by Inhibiting Inflammation, Reducing Intestinal Barrier Damage, and Modulating Intestinal Flora Composition.

Flavonoid natural products are emerging as a promising approach for treating Ulcerative Colitis (UC) due to their natural origin and minimal toxicity. This study investigates the effects of Neohesperidin (NEO), a natural flavonoid, on Dextran Sodium Sulfate (DSS)-induced UC in mice, focusing on the underlying molecular mechanisms. Early intervention with NEO (25 and 50 mg/kg) mitigated colon shortening, restored damaged barrier proteins, and significantly reduced the inflammatory cytokine levels. Moreover, NEO inhibited the MAPK/NF-κB signaling pathway and enhanced the levels of intestinal barrier proteins (Claudin-3 and ZO-1). Additionally, NEO increased beneficial intestinal probiotics (S24-7 and Lactobacillaceae) while reducing harmful bacteria (Erysipelotrichi, Enterobacteriaceae). Fecal microbial transplantation (FMT) results demonstrated that NEO (50 mg/kg) markedly improved UC symptoms. In conclusion, early NEO intervention may alleviate DSS-induced UC by inhibiting inflammatory responses, preserving intestinal barrier integrity and modulating gut microbiota.

Impaired Epithelial CD200L Tolerance Signaling in Irritable Bowel Syndrome Cases With Diarrhea May Be Associated With Recurrent Miscarriages.

PROBLEM: There is a higher incidence of irritable bowel syndrome with miscarriages, and recurrent miscarriages of otherwise normal embryos have been linked to subnormal expression of the immune checkpoint inhibitor CD200L. We sought to determine if alterations in the expression of the CD200 immune checkpoint inhibitor occur in colonic tissue in IBS-D patients. METHOD OF STUDY: Quantitative immunohistochemical staining of biopsies from proximal and distal colon or rectum for the inhibitory CD200L and CD200S molecules was done. CD56 cells were also enumerated as they play a role in recurrent miscarriages and may express CD200S. RESULTS: CD200L was decreased and CD200S was unchanged in epithelium but not stroma of 3 IBS-D cases. One case had an increase in both CD200L and CD200S. CD56 cells were also stained for CD200S. Degranulation was assessed by the percentage of extracellular CD200S that was increased as epithelial CD200L decreased. CONCLUSIONS: This pilot study was promising and warrants a larger sample to determine if a correlation between uterine implantation site CD200L and CD200S expression in normal and failing implantation sites is needed. Colonic epithelial CD200L may then provide useful information about the pathogenesis of the spontaneous miscarriage in individual cases.

Role of gut microbiota in Crohn's disease pathogenesis: Insights from fecal microbiota transplantation in mouse model.

BACKGROUND: Inflammatory bowel disease, particularly Crohn's disease (CD), has been associated with alterations in mesenteric adipose tissue (MAT) and the phenomenon termed "creeping fat". Histopathological evaluations showed that MAT and intestinal tissues were significantly altered in patients with CD, with these tissues characterized by inflammation and fibrosis. AIM: To evaluate the complex interplay among MAT, creeping fat, inflammation, and gut microbiota in CD. METHODS: Intestinal tissue and MAT were collected from 12 patients with CD. Histological manifestations and protein expression levels were analyzed to determine lesion characteristics. Fecal samples were collected from five recently treated CD patients and five control subjects and transplanted into mice. The intestinal and mesenteric lesions in these mice, as well as their systemic inflammatory status, were assessed and compared in mice transplanted with fecal samples from CD patients and control subjects. RESULTS: Pathological examination of MAT showed significant differences between CD-affected and unaffected colons, including significant differences in gut microbiota structure. Fetal microbiota transplantation (FMT) from clinically healthy donors into mice with 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced CD ameliorated CD symptoms, whereas FMT from CD patients into these mice exacerbated CD symptoms. Notably, FMT influenced intestinal permeability, barrier function, and levels of proinflammatory factors and adipokines. Furthermore, FMT from CD patients intensified fibrotic changes in the colon tissues of mice with TNBS-induced CD. CONCLUSION: Gut microbiota play a critical role in the histopathology of CD. Targeting MAT and creeping fat may therefore have potential in the treatment of patients with CD.

Electroacupuncture at Zusanli regulates the pathological phenotype of inflammatory bowel disease by modulating the NLRP3 inflammasome pathway.

BACKGROUND: This study sought to explore the effect of electroacupuncture (EA) intervention at Zusanli (ST36) acupoint on modulating the NLRP3 inflammasome pathway for treating inflammatory bowel disease (IBD). METHODS: C57BL/6 mice were administrated with 3% dextran sulfate sodium (DSS) to construct the IBD model. DSS mice were then administrated with EA (10 Hz, 1.5 mA) at ST36 for 7 days or intragastric administration of sulfasalazine (SASP) each day during the entire course. The control group animals were administered with distilled water. Then, partial least squares discriminant analysis revealed differences in the relative content of metabolites. The pathological changes of colon and spleen tissues were observed by H&E and immunohistochemistry (IHC) staining. qPCR determined the mRNA expression levels, while ELISA and western blot analysis determined the protein expression. RESULTS: Compared with the control groups, DSS-induced decreases of body weight were reversed after EA stimulation at ST36 or SASP treatment. The DAI of DSS mice was significantly higher relative to the control groups, whereas the DAI of DSS mice were decreased after EA stimulation at ST36 or SASP treatment. The intestinal weight/length ratio increased significantly in DSS groups; however, EA at ST36 significantly improved the macroscopic/microscopic characteristics and the weight and length of the colon. EA reversed inflammation and leukocyte infiltration and normalized the elevated levels of IL-1ß, IL-18, and NLRP3. Furthermore, EA improved the expression levels of ZO-1, occludin, and claudin 1, exhibiting normalization of the colon's tight junctions. CONCLUSIONS: EA at Zusanli acupoint of colon tissue significantly improved the pathological phenotype, showing a therapeutic effect on IBD.

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.

l-Theanine Alleviates Ulcerative Colitis by Regulating Colon Immunity via the Gut Microbiota in an MHC-II-Dependent Manner.

Alterations to the gut microbiota are associated with ulcerative colitis (UC), whereas restoration of normobiosis can effectively alleviate UC. l-Theanine has been shown to reshape the gut microbiota and regulate gut immunity. To investigate the mechanisms by which l-theanine alleviates UC, we used l-theanine and l-theanine fecal microbiota solution to treat UC mice. In this study, we used l-theanine and l-theanine fecal microbiota solution to treat UC mice to explore the mechanism by which l-theanine alleviates UC. By reducing inflammation in the colon, we demonstrated that l-theanine alleviates symptoms of UC. Meanwhile, l-theanine can improve the abundance of microbiota related to short-chain fatty acid, bile acid, and tryptophan production. Single-cell sequencing results indicated that l-theanine-mediated suppression of UC was associated with immune cell changes, especially regarding macrophages and T and B cells, and validated the immune cell responses to the gut microbiota. Further, flow cytometry results showed that the ability of dendritic cells, macrophages, and monocytes to present microbiota antigens to colonic T cells in an MHC-II-dependent manner was reduced after treating normal mouse fecal donors with l-theanine. These results demonstrate that l-theanine modulates colon adaptive and innate immunity by regulating the gut microbiota in an MHC-II-dependent manner, thereby alleviating UC.

Proanthocyanidins and ß-Glucan Synergistically Regulate Intestinal Inflammation in Dextran Sulfate Sodium-Induced Colitis Mice.

Proanthocyanidins (PA) have been proven to have an anti-inflammation effect in multiple models by regulating oxidative stress. ß-glucan (BG) could alleviate colitis from the perspectives of intestinal permeability and gut microbiota. In the present study, the synergistic anti-inflammatory function of PA and BG was explored from multiple aspects including immune response, intestinal barrier, gut microbiota, and differential metabolites. The results showed that the supplementation of PA and BG improved the colitis symptoms including atrophy of the colon, body weight loss, and organ index increase. Additionally, inflammatory cytokine levels and oxidative stress status were significantly regulated with the intake of PA and BG. Moreover, PA and BG intervention improved intestinal permeability and promoted the expression of barrier proteins. The microbiome and metabolic profile of cecal contents showed that PA and BG supplementation increased the abundance of anti-inflammatory bacteria and decreased the abundance of pro-inflammatory bacteria. Furthermore, some beneficial metabolites involved in amino acid metabolism, carbohydrate metabolism, and biosynthesis of other secondary metabolite pathways were increased. Overall, these findings have demonstrated the regulation of the inflammatory response and remodel of metabolite profiles by PA and BG complexes, indicating that it may serve as a new strategy for inflammatory bowel disease treatment in the future.

SPH7854, a gut-limited RORγt antagonist, ameliorates TNBS-induced experimental colitis in rat.

Multiple lines of evidence suggest that Retinoic Acid Related Orphan Nuclear Receptor gamma t (RORγt) is a potent therapeutic target for inflammatory bowel disease (IBD). However, systemic blockade of RORγt easily leads to thymic lymphoma and aberrant liver function. Therefore, the development of gut-limited RORγt antagonists may lead to the development of innovative IBD therapeutics that improve safety and retain effectiveness. We discovered SPH7854, a potent and selective RORγt antagonist. The effect of SPH7854 on the differentiation of T helper 1 (Th1)/Th17/regulatory T (Treg) cells was evaluated in mouse and human primary cells. SPH7854 (2-(4-(ethylsulfonyl)phenyl)-N- (6-(2-methyl-2-(pyridin-2-yl) propanoyl)pyridin-3-yl)acetamide) dose-dependently inhibited interleukin-17A (IL-17A) secretion from mouse CD4 + T cells and human peripheral blood mononuclear cells (PBMC). Additionally, SPH7854 strongly suppressed Th17 cell differentiation and considerably promoted Treg cell differentiation while slightly affected Th1 cell differentiation from mouse CD4 + T cells. The pharmacokinetic (PK) studies indicated that SPH7854 was restricted to the gut: the bioavailability and maximal plasma concentration of SPH7854 after oral administration (6 mg/kg) were 1.24 ± 0.33 % and 4.92 ± 11.81 nM, respectively, in rats. Strikingly, oral administration of SPH7854 (5 mg/kg and 15 mg/kg) twice daily significantly alleviated 2, 4, 6-trinitrobenzensulfonic acid (TNBS)-induced colitis in rats. SPH7854, especially at 15 mg/kg, significantly alleviated symptoms and improved macroscopic signs and microscopic structure in rat colitis, with decreased colonic mucosal levels of IL-17A, IL-6, tumor necrosis factor α (TNFα), monocyte chemoattractant protein-1 (MCP-1) and myeloperoxidase (MPO). These evidences indicated that blockade of RORγt activity via a gut-limited antagonist may be an effective and safe therapeutic strategy for IBD treatment.

Gut Microbiota Defines Functional Direction of Colonic Regulatory T Cells with Unique TCR Repertoires.

Intestinal microbiota and selected strains of commensal bacteria influence regulatory T (Treg) cell functionality in the colon. Nevertheless, whether and how microbiota changes the transcriptome profile and TCR specificities of colonic Tregs remain to be precisely defined. In this study, we have employed single-cell RNA sequencing and comparatively analyzed colonic Tregs from specific pathogen-free and germ-free (GF) mice. We found that microbiota shifts the activation trajectory of colonic Tregs toward a distinct phenotypic subset enriched in specific pathogen-free but not in GF mice. Moreover, microbiota induced the expansion of specific Treg clonotypes with shared transcriptional specificities. The microbiota-induced subset of colonic Tregs, identified as PD-1- CXCR3+ Tregs, displayed enhanced suppressive capabilities compared with colonic Tregs derived from GF mice, enhanced production of IL-10, and were the primary regulators of enteric inflammation in dextran sodium sulfate-induced colitis. These findings identify a hitherto unknown gut microbiota and immune cell interaction module that could contribute to the development of a therapeutic modality for intestinal inflammatory diseases.

Anti-inflammation mechanisms of a homogeneous polysaccharide from Phyllanthus emblica L. on DSS induced colitis mice via the gut microbiota and metabolites alteration.

Phyllanthus emblica L. offers promising therapeutic potential for inflammatory diseases. This study revealed the molecular structure of a homogeneous polysaccharide purified from Phyllanthus emblica L. (PEP-1) and evaluated its anti-inflammatory effects on ulcerative colitis (UC) in mice. In the in vivo experiment, administered in varying dosages to dextran sulfate sodium (DSS)-induced UC models, PEP-1 significantly alleviated colonic symptoms, histological damages and reshaped the gut microbiota. Notably, it adjusted the Firmicutes/Bacteroidetes ratio and reduced pro-inflammatory species, closely aligning with shifts in the fecal metabolites and metabolic pathways such as the metabolism of pyrimidine, beta-alanine, and purine. These findings underscore the potential of PEP-1 as a therapeutic agent for UC, providing insights into the mechanisms through gut microbiota and metabolic modulation.

Exploring the immune landscape of disulfidptosis in ulcerative colitis and the role of modified gegen qinlian decoction in mediating disulfidptosis to alleviate colitis in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Ulcerative colitis (UC), a recurrent inflammatory bowel disease, continues to challenge effective pharmacologic management. Disulfidptosis, a recently identified form of cell death, appears implicated in the progression of various diseases. Scientific studies have demonstrated that Modified Gegen Qinlian decoction (MGQD) alleviates UC symptoms. However, the underlying mechanisms remain inadequately elucidated. AIM OF THE STUDY: This study investigated the role of disulfidptosis in UC and explored the potential of MGQD to ameliorate UC by mediating disulfidptosis. METHODS: Microarray data were utilized to identify disulfidptosis-related genes stably expressed in UC, and integrated genomic analyses were conducted to elucidate the landscape of disulfidptosis in UC. Subsequently, C57BL/6J mice were administered 3% dextran sodium sulfate (DSS) to induce experimental colitis and treated with MGQD. Quantitative real-time polymerase chain reaction and immunohistochemical analysis of colonic tissues from colitis mice were performed to validate the microarray data findings. Finally, molecular docking was employed to explore the binding interactions between MGQD components and disulfidptosis biomarkers. RESULTS: Myosin heavy chain 10 (MYH10) and filamin A (FLNA) were identified as stably expressed in UC, demonstrating high diagnostic value for the disease. Correlation analysis indicated that disulfidptosis-related genes are associated with elevated levels of immune cells in UC. Single gene set enrichment analysis further clarified that these genes might be involved in the pathological processes of UC via immune-related pathways. Subsequent animal experiments revealed that MYH10 and FLNA were significantly upregulated in mice with colitis, a condition reversed by MGQD treatment. Molecular docking results showed that MYH10 and FLNA serve as stable binding targets for the primary components of MGQD. CONCLUSIONS: The study identified a connection between the disulfidptosis-related landscape and immune infiltration in UC, suggesting that MGQD may modulate disulfidptosis by inhibiting MYH10 and FLNA, thereby alleviating UC.

Characterization of Eurotium cristatum Fermented Thinned Young Apple and Mechanisms Underlying Its Alleviating Impacts on Experimental Colitis.

A hundred million tons of young apples are thinned and discarded in the orchard per year, aiming to increase the yield and quality of apples. We fermented thinned young apples using a potential probiotic fungus, Eurotium cristatum, which notably disrupted the microstructure of raw samples, as characterized by the scanning electron microscope. Fermentation substantially altered the metabolite profiles of samples, which are predicted to alleviate colitis via regulating inflammatory response and response to lipopolysaccharide by using network pharmacology analysis. In vivo, oral gavage of water extracts of E. cristatum fermented young apples (E.YAP) effectively alleviated DSS-induced colitis, restored the histopathology damage, reduced the levels of inflammatory cytokines, and promoted colonic expressions of tight junction proteins. Moreover, E.YAP ameliorated gut dysbacteriosis by increasing abundances of Lactobacillus,Blautia, Muribaculaceae, and Prevotellaceae_UCG-001 while inhibiting Turicibacter, Alistipes, and Desulfovibrio. Importantly, E.YAP increased colonic bile acids, such as CA, TCA, DCA, TUDCA, and LCA, thereby alleviating colitis via PXR/NF-κB signaling. Furthermore, a synbiotic combination with Limosilactobacillus reuteri WX-94, a probiotic strain isolated from feces of healthy individuals with anti-inflammatory properties, augmented anticolitis capacities of E.YAP. Our findings demonstrate that E.YAP could be a novel, potent, food-based anti-inflammatory prebiotic for relieving inflammatory injuries.

IGF2 contributes to the immunomodulatory effects of exosomes from endometrial regenerative cells on experimental colitis.

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.

Stem-like T cells are associated with the pathogenesis of ulcerative colitis in humans.

To understand the role of T cells in the pathogenesis of ulcerative colitis (UC), we analyzed colonic T cells isolated from patients with UC and controls. Here we identified colonic CD4+ and CD8+ T lymphocyte subsets with gene expression profiles resembling stem-like progenitors, previously reported in several mouse models of autoimmune disease. Stem-like T cells were increased in inflamed areas compared to non-inflamed regions from the same patients. Furthermore, TCR sequence analysis indicated stem-like T cells were clonally related to proinflammatory T cells, suggesting their involvement in sustaining effectors that drive inflammation. Using an adoptive transfer colitis model in mice, we demonstrated that CD4+ T cells deficient in either BCL-6 or TCF1, transcription factors that promote T cell stemness, had decreased colon T cells and diminished pathogenicity. Our results establish a strong association between stem-like T cell populations and UC pathogenesis, highlighting the potential of targeting this population to improve clinical outcomes.

Reciprocal regulation of T follicular helper cells and dendritic cells drives colitis development.

The immunological mechanisms underlying chronic colitis are poorly understood. T follicular helper (TFH) cells are critical in helping B cells during germinal center reactions. In a T cell transfer colitis model, a lymphoid structure composed of mature dendritic cells (DCs) and TFH cells was found within T cell zones of colonic lymphoid follicles. TFH cells were required for mature DC accumulation, the formation of DC-T cell clusters and colitis development. Moreover, DCs promoted TFH cell differentiation, contributing to colitis development. A lineage-tracing analysis showed that, following migration to the lamina propria, TFH cells transdifferentiated into long-lived pathogenic TH1 cells, promoting colitis development. Our findings have therefore demonstrated the reciprocal regulation of TFH cells and DCs in colonic lymphoid follicles, which is critical in chronic colitis pathogenesis.

Remdesivir ameliorates ulcerative colitis-propelled cell inflammation and pyroptosis in acetic acid rats by restoring SIRT6/FoxC1 pathway.

INTRODUCTION: Ulcerative colitis (UC) is a primary culprit of inflammatory bowel disease that entails prompt and effective clinical intervention. Remdesivir (RDV), a broad-spectrum antiviral nucleotide, has been found to exert anti-inflammatory effects in experimental animals. AIM: This study investigates the prospective anti-inflammatory merit of RDV on an experimental model of UC. The role of SIRT6/FoxC1 in regulating colonic cell inflammation and pyroptosis is delineated. METHOD: Rats were challenged with a single intrarectal dose of acetic acid (AA) solution (2 ml; 4 % v/v) to induce colitis. RDV (20 mg/kg, ip) and sulfasalazine (100 mg/kg, po) were administered to rats 14 days before the injection of AA. RESULTS: Administration of RDV ameliorated colonic cell injury and loss as manifested by improvement of severe colon histopathological mutilation and macroscopic damage and disease activity index scores together with restoration of normal colon weight/length ratio. In addition, RDV alleviated colonic inflammatory reactions, thereby curtailing NF-κB activation and the inflammatory cytokines, TNF-α, IL-18, and IL-1ß. Mitigation of colonic oxidative stress and apoptotic reactions were also evident in the setting of RDV treatment. Mechanistically, RDV enhanced the anti-inflammatory cascade, SIRT6/FoxC1, together with curbing the pyroptotic signal, NLRP3/cleaved caspase-1/Gasdermin D-elicited colonic inflammatory cell death. CONCLUSION: This study reveals, for the first time, the anti-inflammatory effect of RDV against experimental UC. Augmenting SIRT6/FoxC1-mediated repression of colonic inflammation and pyroptosis might advocate the colo-protective potential of RDV.

Fut2 deficiency aggravates chronic colitis through 2-oxindole-AHR mediated cGAS-STING pathway.

OBJECTIVE: This study aims to disclose how loss of fucosyltransferase 2 (Fut2) impacts intestinal inflammation through cGAS-STING pathway that is closely associated with gut microbiota, and which microbial metabolite improves colitis in Fut2 deficiency. METHODS: Chronic colitis was induced in intestinal epithelial Fut2 knock out mice (Fut2△IEC), whose intestinal inflammation and activity of cGAS-STING pathway were evaluated. 16S rRNA sequencing and metabolomics were performed using intestinal samples. 2-oxindole was used to treat RAW264.7 cells and Fut2△IEC mice with colitis (Fut2△IEC-DSS) to investigate the effect of 2-oxindole on cGAS-STING response and intestinal inflammation. RESULTS: Fut2 loss exacerbated chronic colitis in mice, manifested by declined body weight, reduced colon length, increased disease activity index (DAI) and more colon injury in Fut2△IEC-DSS mice compared with WT-DSS (wild type mice with colitis). Lack of Fut2 promoted activation of cGAS-STING pathway. Fut2 deficiency had a primary impact on colonic microbiota, as shown by alteration of microbial diversity and structure, as well as decreased Lactobacillus. Metabolic structure and tryptophan metabolism in colonic luminal microbiota were also influenced by Fut2 loss. Fut2 deficiency also led to decreased levels of aryl hydrocarbon receptor (AHR) and its ligand 2-oxindole derived from tryptophan metabolism. 2-oxindole compromised cGAS-STING response through activating AHR in macrophages, and protected against intestinal inflammation and overactive cGAS-STING pathway in Fut2△IEC-DSS mice. CONCLUSION: Fut2 deficiency promotes cGAS-STING pathway through suppressing 2-oxindole-AHR axis, ultimately facilitating the susceptibility to chronic colitis.

Colonic Tuft Cells: The Less-Recognized Therapeutic Targets in Inflammatory Bowel Disease and Colorectal Cancer.

Tuft cells are more than guardian chemosensory elements of the digestive tract. They produce a variety of immunological effector molecules in response to stimulation; moreover, they are essential for defense against protozoa and nematodes. Beyond the description of their characteristics, this review aims to elucidate the potential pathogenic and therapeutic roles of colonic tuft cells in inflammatory bowel disease and colorectal cancer, focusing on their primarily immunomodulatory action. Regarding inflammatory bowel disease, tuft cells are implicated in both maintaining the integrity of the intestinal epithelial barrier and in tissue repair and regeneration processes. In addition to maintaining intestinal homeostasis, they display complex immune-regulatory functions. During the development of colorectal cancer, tuft cells can promote the epithelial-to-mesenchymal transition, alter the gastrointestinal microenvironment, and modulate both the anti-tumor immune response and the tumor microenvironment. A wide variety of their biological functions can be targeted for anti-inflammatory or anti-tumor therapies; however, the adverse side effects of immunomodulatory actions must be strictly considered.

Banana Lectin: A Novel Immunomodulatory Strategy for Mitigating Inflammatory Bowel Disease.

Compared to the general population, patients with inflammatory bowel disease (IBD) are less likely to be vaccinated, putting them at an increased risk of vaccine-preventable illnesses. This risk is further compounded by the immunosuppressive therapies commonly used in IBD management. Therefore, developing new treatments for IBD that maintain immune function is crucial, as successful management can lead to better vaccination outcomes and overall health for these patients. Here, we investigate the potential of recombinant banana lectin (rBanLec) as a supporting therapeutic measure to improve IBD control and possibly increase vaccination rates among IBD patients. By examining the therapeutic efficacy of rBanLec in a murine model of experimental colitis, we aim to lay the foundation for its application in improving vaccination outcomes. After inducing experimental colitis in C57BL/6 and BALB/c mice with 2,4,6-trinitrobenzene sulfonic acid, we treated animals orally with varying doses of rBanLec 0.1-10 µg/mL (0.01-1 µg/dose) during the course of the disease. We assessed the severity of colitis and rBanLec's modulation of the immune response compared to control groups. rBanLec administration resulted in an inverse dose-response reduction in colitis severity (less pronounced weight loss, less shortening of the colon) and an improved recovery profile, highlighting its therapeutic potential. Notably, rBanLec-treated mice exhibited significant modulation of the immune response, favoring anti-inflammatory pathways (primarily reduction in a local [TNFα]/[IL-10]) crucial for effective vaccination. Our findings suggest that rBanLec could mitigate the adverse effects of immunosuppressive therapy on vaccine responsiveness in IBD patients. By improving the underlying immune response, rBanLec may increase the efficacy of vaccinations, offering a dual benefit of disease management and prevention of vaccine-preventable illnesses. Further studies are required to translate these findings into clinical practice.

Novel 5-HT7 receptor antagonists modulate intestinal immune responses and reduce severity of colitis.

Inflammatory bowel disease (IBD) encompasses several debilitating chronic gastrointestinal (GI) inflammatory disorders, including Crohn's disease and ulcerative colitis. In both conditions, mucosal inflammation is a key clinical presentation associated with altered serotonin (5-hydroxytryptamine or 5-HT) signaling. This altered 5-HT signaling is also found across various animal models of colitis. Of the 14 known receptor subtypes, 5-HT receptor type 7 (5-HT7) is one of the most recently discovered. We previously reported that blocking 5-HT signaling with either a selective 5-HT7 receptor antagonist (SB-269970) or genetic ablation alleviated intestinal inflammation in murine experimental models of colitis. Here, we developed novel antagonists, namely, MC-170073 and MC-230078, which target 5-HT7 receptors with high selectivity. We also investigated the in vivo efficacy of these antagonists in experimental colitis by using dextran sulfate sodium (DSS) and the transfer of CD4+CD45RBhigh T cells to induce intestinal inflammation. Inhibition of 5-HT7 receptor signaling with the antagonists, MC-170073 and MC-230078, ameliorated intestinal inflammation in both acute and chronic colitis models, which was accompanied by lower histopathological damage and diminished levels of proinflammatory cytokines compared with vehicle-treated controls. Together, the data reveal that the pharmacological inhibition of 5-HT7 receptors by these selective antagonists ameliorates the severity of colitis across various experimental models and may, in the future, serve as a potential treatment option for patients with IBD. In addition, these findings support that 5-HT7 is a viable therapeutic target for IBD.NEW & NOTEWORTHY This study demonstrates that the novel highly selective 5-HT7 receptor antagonists, MC-170073 and MC-230078, significantly alleviated the severity of colitis across models of experimental colitis. These findings suggest that inhibition of 5-HT7 receptor signaling by these new antagonists may serve as an alternative mode of treatment to diminish symptomology in those with inflammatory bowel disease.