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The composition of the microbial community in the intestine may influence the functions of distant organs such as the brain, lung, and skin. These microbes can promote disease or have beneficial functions, leading to the hypothesis that microbes in the gut explain the co-occurrence of intestinal and skin diseases. Here, we show that the reverse can occur, and that skin directly alters the gut microbiome. Disruption of the dermis by skin wounding or the digestion of dermal hyaluronan results in increased expression in the colon of the host defense genes Reg3 and Muc2, and skin wounding changes the composition and behavior of intestinal bacteria. Enhanced expression Reg3 and Muc2 is induced in vitro by exposure to hyaluronan released by these skin interventions. The change in the colon microbiome after skin wounding is functionally important as these bacteria penetrate the intestinal epithelium and enhance colitis from dextran sodium sulfate (DSS) as seen by the ability to rescue skin associated DSS colitis with oral antibiotics, in germ-free mice, and fecal microbiome transplantation to unwounded mice from mice with skin wounds. These observations provide direct evidence of a skin-gut axis by demonstrating that damage to the skin disrupts homeostasis in intestinal host defense and alters the gut microbiome.

BackgroundMethodsResultsConclusionInterleukin-1 receptor 2 (IL1R2) and C-C motif chemokine receptor 2 (CCR2) as critical mediators of immune modulation and inflammation. This study aims to evaluate their functions in dextran sulfate sodium (DSS)-induced intestinal injury.A DSS-induced intestinal injury model was established in C57BL/6 mice. Pharmacological inhibitors targeting IL1R2 or CCR2 were administered. Adipose-derived mesenchymal stem cell (ADMSC)-derived exosomes were isolated and loaded with IL1R2-siRNA, which were then administered to intestinal epithelial cells (IEC-6) or DSS-challenged mice.IL1R2 and CCR2 were upregulated in DSS-treated colon tissues. Pharmacological inhibition of IL1R2 or CCR2 improved body weight, restored colon length, reduced serum TNF-α and IL-6 levels, and preserved epithelial integrity in mice. miR-128-3p enriched in ADMSC-derived exosomes significantly reduced CCR2 expression in IEC-6 cells. Further loading of an IL1R2 siRNA in these exosomes led to a simultaneous inhibition of IL1R2. These exosomes reduced lipopolysaccharide-induced apoptosis and inflammation in IEC-6 cells and improved histological outcomes in DSS-challenged mice.IL1R2 and CCR2 are key mediators of inflammation in DSS-induced intestinal injury. Dual inhibition of IL1R2 and CCR2 holds great promise for alleviating inflammatory responses and improving histological presentations in inflammatory bowel disease. [ABSTRACT FROM AUTHOR]

Ulcerative colitis (UC) is a multifactorial intestinal disease with a high incidence. In recent years, there has been an urgent need for pleiotropic drugs with a clear biosafety profile. Tacrolimus (TAC) is an immunosuppressant with stronger in vivo effects and better gastrointestinal absorption and is considered a potential treatment for UC. FKBP12 is a mediator of TAC immunosuppression; however, it is unclear whether it can participate in the development of UC in combination with TAC. The purpose of this study is to preliminarily validate the function of FKBP12 by establishing dextran sulfate sodium (DSS)-induced UC model and TAC treatment. The results revealed that TAC was effective in alleviating DSS-induced UC symptoms such as body weight and disease activity index (DAI). TAC significantly protects colonic tissue and attenuates DSS-induced histomorphological changes. In addition, FKBP12 is down-regulated in the intestinal tissue of DSS-induced UC mice and in serum samples of UC patients. In conclusion, our study revealed that FKBP12 may act as a TAC receptor to have anti-inflammatory and protective effects on DSS-induced UC in mice, which will provide a new option for the treatment of UC. [ABSTRACT FROM AUTHOR]

Ulcerative colitis is a chronic idiopathic inflammatory bowel disease (IBD) that seriously impacts human health. So far, little information has been reported on the possible benefits of polysaccharides from Scutellaria baicalensis Georgi (SBGP) in alleviating colitis. Therefore, our study investigated the potential therapeutic effects of SBGP on mice with DSS-induced colitis. Results showed that SBGP administration ameliorated the severity of clinical symptoms and enhanced immunomodulatory effects in dextran sulfate sodium (DSS)-treated mice. Additionally, SBGP was found to regulate the inflammatory response, improve mucosal barrier integrity, and maintain tight junctions in the colonic epithelium. Furthermore, SBGP was found to restrain the activation of Notch and MLCK/MLC signaling pathways, which play important roles in inflammation and epithelial barrier homeostasis. These findings suggest that SBGP may have therapeutic potential for the treatment of colitis and other IBD. [ABSTRACT FROM AUTHOR]

Introduction: Ulcerative colitis (UC) is often characterized by dysbiosis of the colonic microbiota and metabolic disturbances, which can lead to liver damage. Patchoulene epoxide (PAO), a tricyclic sesquiterpene derived from the aged essential oil of Pogostemonis Herba, is known for its anti-inflammatory and ulcer-healing properties. However, its dual protective role against UC and liver injury remains largely unexplored. This study aims to elucidate the protective effect and underlying mechanism of PAO against dextran sulfate sodium (DSS)-induced UC and liver injury in mice. Methods: Colitis and liver injury in mice were induced by adding 3% DSS to their drinking water continuously for 7 days, and PAO at the doses of 20 and 40 mg/kg was administered orally to mice daily from the first day until the experimental endpoint. Stool consistency scores, blood stool scores, and body weights were recorded weekly. Disease activity index (DAI) was determined before necropsy, where colon and liver tissues were collected for biochemical analyses. Additionally, the fecal microbiome and its metabolites of treated mice were characterized using 16S rRNA amplicon sequencing and metabolomics. Results: PAO significantly reduced the disease activity index and mitigated colonic atrophy in UC mice. It also improved colonic and hepatic pathological changes by safeguarding tight and adherens junctions, and suppressing the generation of pro-inflammatory cytokines and lipopolysaccharide. These beneficial effects were attributed to PAO's capability to regulate the colonic microbiota and metabolic processes. PAO was found to enhance the diversity of the colonic microbiota and to shift the microbial balance in UC mice. Specifically, it restored the microbiota from an Akkermansia-dominated state, characteristic of UC, to a healthier Muribaculaceae-dominated composition. Furthermore, PAO corrected the colon metabolic disturbance in UC mice by modulating the purine metabolism, notably increasing the abundance of deoxyadenosine, adenosine and guanine in UC mice. Conclusions: The therapeutic effect of PAO on UC and liver injury was mainly attributed to its regulation of colonic microbiota and purine metabolism. These insights emphasize the overall therapeutic benefits of PAO in treating UC and liver injury. [ABSTRACT FROM AUTHOR]

Systematic bone and muscle loss is a complex metabolic disease, which is frequently linked to gut dysfunction, yet its etiology and treatment remain elusive. While probiotics show promise in managing diseases through microbiome modulation, their therapeutic impact on gut dysfunction-induced bone and muscle loss remains to be elucidated. Employing dextran sulfate sodium (DSS)-induced gut dysfunction model and wide-spectrum antibiotics (ABX)-treated mice model, our study revealed that gut dysfunction instigates muscle and bone loss, accompanied by microbial imbalances. Importantly, Bifidobacterium animalis subsp. lactis A6 (B. lactis A6) administration significantly ameliorated muscle and bone loss by modulating gut microbiota composition and enhancing butyrate-producing bacteria. This intervention effectively restored depleted butyrate levels in serum, muscle, and bone tissues caused by gut dysfunction. Furthermore, butyrate supplementation mitigated musculoskeletal loss by repairing the damaged intestinal barrier and enriching beneficial butyrate-producing bacteria. Importantly, butyrate inhibited the NF-κB pathway activation, and reduced the secretion of corresponding inflammatory factors in T cells. Our study highlights the critical role of dysbiosis in gut dysfunction-induced musculoskeletal loss and underscores the therapeutic potential of B. lactis A6. These discoveries offer new microbiome directions for translational and clinical research, providing promising strategies for preventing and managing musculoskeletal diseases. [ABSTRACT FROM AUTHOR]

Introduction: Inflammatory bowel disease (IBD) is a recurrent gastrointestinal disorder that significantly impacts patients' quality of life globally. This study focuses on the polysaccharides (MP) extracted from Meconopsis integrifolia , to investigate its role in alleviating DSS (dextran sulfate sodium)-induced colitis in mice. Methods: The study commenced with a comprehensive chemical characterization of Meconopsis polysaccharides. Subsequently, the colitis-alleviating activity of MP was validated through in vivo experiments. Results: The results revealed that MP is primarily composed of ten monosaccharides, exhibits good thermal stability, and has a relatively uniform molecular weight distribution. In vivo experiments demonstrated that MP significantly mitigated DSS-induced weight loss, increased DAI, colon shortening, and tissue damage in mice. Furthermore, MP reduced the levels of inflammatory cytokines such as IL-1β, TNF-α, and IL-6 in serum. Mechanistically, MP exerted its anti-inflammatory effects by inhibiting the activation of the PI3K/AKT signaling pathway. Additionally, MP promoted gut microbiota diversity and regulated SCFA concentrations, contributing to an improved intestinal microenvironment and alleviation of colitis symptoms. Discussion: Our findings highlight the superior effectiveness of Meconopsis polysaccharides in alleviating DSS-induced colitis and open new avenues for targeted therapeutic strategies in the treatment of IBD. [ABSTRACT FROM AUTHOR]

Background: The rising incidence of ulcerative colitis (UC) in China poses a noticeable health challenge. This study aimed to assess the pivotal role of USP1-associated factor 1 (UAF1) in colitis. UC was induced in male C57BL/6 mice using 2.0% dextran sulfate sodium (DSS). In an in vitro model, RAW264.7 cells were exposed to 200 ng/ml of LPS + ATP. UAF1 expression level was evaluated in colonic tissues, macrophages, and serum samples using quantitative reverse transcription polymerase chain reaction (RT-qPCR). The study assessed weight, disease activity index (DAI) score, myeloperoxidase (MPO) activity, crypt length, inflammatory factors, and epithelial cell function in a mouse model of colitis treated with a UAF1 inhibitor. Microarray analysis identified potential UAF1 targets. Gene interference investigated NLR family pyrin domain containing 3 (NLRP3) involvement in UAF1-induced colitis inflammation. Immunoprecipitation, ubiquitination, and luciferase assays examined the effects of methyltransferase-like 3 (METTL3) methylation on the expression levels of NLRP3 and UAF1. UAF1 expression level was upregulated in colon tissues, RAW264.7 macrophages, and serum samples of colitis mice (P < 0.01). The UAF1 inhibitor (ML-323) enhanced weight and reduced DAI score in colitis mice (P < 0.01). It also decreased MPO activity and ulcer area, and restored crypt length (P < 0.01). UAF1 inhibitor improved epithelial cell function by suppressing NLRP3 activity (P < 0.01). UAF1 promoted inflammation in RAW264.7 macrophages via NLRP3 inflammasome induction (P < 0.01). UAF1 modulated NLRP3 protein expression, leading to reduced NLRP3 ubiquitination induced by LPS + ATP. The m6A-forming enzyme METTL3 enhanced UAF1 stability (P < 0.01) to facilitate UAF1 expression. The findings suggested that METTL3, as an m6A-forming enzyme, could regulate UAF1 mRNA, promoting inflammation in colitis through NLRP3 induction. Inhibiting UAF1 emerges as a potential therapeutic strategy for colitis. [ABSTRACT FROM AUTHOR]

This study investigated the role of Ninjurin1 (Ninj1), encoding a small transmembrane protein, in colitis‐associated colon tumorigenesis in relation to sex hormones. Male and female wild‐type (WT) and Ninj1 knockout (KO) mice were treated with azoxymethane (AOM) and dextran sulfate sodium (DSS), with or without testosterone propionate (TP). At week 2 (acute colitis stage), Ninj1 KO exhibited an alleviation in the colitis symptoms in both male and female mice. The M2 macrophage population increased and CD8+ T cell population decreased only in the female Ninj1 KO than in the female WT AOM/DSS group. In the female AOM/DSS group, TP treatment exacerbated colon shortening in the Ninj1 KO than in the WT. At week 13 (tumorigenesis stage), male Ninj1 KO mice had fewer tumors, but females showed similar tumors. In the WT AOM/DSS group, females had more M2 macrophages and fewer M1 macrophages than males, but this difference was absent in Ninj1 KO mice. In the Ninj1 KO versus WT group, the expression of pro‐inflammatory mediators and Ho‐1 and CD8+ T cell populations decreased in both female and male Ninj1 KO mice. In the WT group, M2 macrophage populations were increased by AOM/DSS treatment and decreased by TP treatment. However, neither treatment changed the cell populations in the Ninj1 KO group. These results suggest that Ninj1 is involved in colorectal cancer development in a testosterone‐dependent manner, which was different in male and female. This highlights the importance of considering sex disparities in understanding Ninj1's role in cancer pathogenesis. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is one of the most prevalent causes of cancer-related fatalities globally, and its development is closely associated with dietary and microbial factors. The aim of this study was to investigate the potential of ganjang, a traditional fermented soy sauce, in alleviating colitis-associated colorectal cancer (CAC) in a mouse model induced by azoxymethane/dextran sulfate sodium (AOM/DSS). The bacterial composition of ganjang samples from different regions primarily included Lactobacillus spp. and Bacillus spp. Administration of ganjang to AOM/DSS-induced mice significantly improved CAC-related symptoms, including increased body weight, restored colon length, and reduced spleen size. Additionally, ganjang administration led to a decrease in tumor size and number, the modulation of apoptotic and proliferative markers, decreased inflammatory cytokine levels, and the restoration of the intestinal epithelial barrier. Furthermore, ganjang samples altered the gut microbiota composition by increasing the relative abundance of Lactobacillus spp. These findings suggest that ganjang has potential as a functional food for CRC prevention or mitigation, primarily through the modulation of CAC symptoms, tumor growth, inflammatory responses, intestinal epithelial barrier integrity, and gut microbiota composition. [ABSTRACT FROM AUTHOR]

Introduction: Ulcerative colitis (UC) is a global gastrointestinal disease, which is mainly caused by both dysfunctional epithelial barrier and inflammation response. Iron is a critical fundamental element for both the maintenance of homeostasis and the mediation of inflammation in many tissues. However, the role and mechanism of iron in the phase of enteritis and the subsequent repairing phase of intestinal stem cells has not been elucidated. In this study, we aimed to explore whether and how iron depletion would affect the occurrence and outcome of experimental colitis. Methods: Iron depletion was realized by deferoxamine (DFO) at either the early stage or late stage of dextran sulfate sodium (DSS) induced experimental colitis in mice. The gross images of colons, general health, histology, barrier integrity, and qRT-PCR were performed. Meanwhile, cell culture and colonic organoids were used to examine the influence of iron depletion in vitro. Signaling pathway and inflammatory infiltration were investigated by immunostaining. Results: Iron depletion within the early stage of DSS treatment significantly inhibited the onset of the inflammatory response, maintained the integrity of the colonic epithelium, and preserved the activity of intestinal stem cells (ISCs) both in vivo and in vitro. However, both continuous iron depletion by DFO and late DFO treatment aggravated colonic injury and postponed the recovery from colitis. Early DFO-induced iron depletion was able to maintain the p-STAT3 and p-ERK1/2 signaling pathways within the colonic epithelium at the early phase of colitis, but late DFO treatment inhibited the activity of these two pathways. Discussion: Our study demonstrated that the manipulation of iron depletion by DFO might greatly affect the outcomes of experimental colitis in a phase-dependent manner, which suggests that the balance of iron metabolism might be an effective therapeutic target for the clinical treatment of IBD patients. [ABSTRACT FROM AUTHOR]

Stress-protective effects have been reported for M. vaccae NCTC 11659 and M. vaccae ATCC 15483T. However, it remains to be investigated whether also closely related rapidly growing environmental saprophytic non-tuberculous mycobacteria (NTM) species have protective effects against the negative consequences of chronic psychosocial stress. Therefore, the aim of the current study was to assess whether repeated i.g. administrations of a heat-inactivated preparation of Mycobacterium aurum DSM 33539 prior to 19 days of chronic subordinate colony housing (CSC) are able to ameliorate the negative effects of this preclinically validated mouse model for chronic psychosocial stress on subsequent dextran sulfate sodium (DSS) colitis in male C57BL/6N mice. The results of the present study show that repeated i.g. administrations of M. aurum DSM 33539 have stabilizing effects on the composition of the gut microbiome, indicated by the findings that M. aurum DSM 33539 prevented CSC-induced increases in the relative abundances of the colitogenic phyla Desulfobacterota and Deferribacterota. Indeed, the relative abundance of Deferribacterota on day 19 was strongly correlated with histological damage to the colon. In line with the latter, M. aurum DSM 33539 was further protective against the aggravating effects of stress on subsequent DSS colitis. Collectively, our findings confirm and extend previous findings from our group and suggest that the stress-protective effects reported for M. vaccae NCTC 11659 and M. vaccae ATCC 15483T are generalizable also to other NTM species. [ABSTRACT FROM AUTHOR]

Ulcerative colitis (UC) is non-specific inflammatory bowel disease. UC development and progression were closely associated with epigenetic modifications. Nevertheless, the specific relationship between N6-methyladenosine (m6A) modification at RNA transcription levels and UC pathogenesis remains unclear. We established UC cell models and mouse models through dextran sulfate sodium (DSS) induction. The expression levels of METTL14 were analyzed via qRT-PCR and western blot. In vitro functional experiments evaluated the effects of METTL14 overexpression on the viability of DSS-induced NCM460 cells and ferroptosis markers. Use of the m6A methylation detection kit, MeRIP-qPCR, and RNA stability experiments confirmed the molecular mechanism controlled by METTL14. In vivo experiments with inflammatory mice models elucidated the interaction between METTL14 and GPX4. Findings from this study indicated a notable reduction in m6A methyltransferase METTL14 expression in DSS-induced NCM460 cells and DSS-induced mice models. METTL14 overexpression effectively suppressed ferroptosis in DSS-induced NCM460 cells. In addition, METTL14 enhanced GPX4 mRNA stability through mediating m6A modification, and the interplay between METTL14 and GPX4 through m6A modification introduced innovative therapeutic approaches for UC management. [ABSTRACT FROM AUTHOR]

Inflammatory bowel disease (IBD) is a chronic and potentially life-threatening inflammatory disease of gastroenteric tissue characterized by episodes of intestinal inflammation, but the underlying mechanisms remain elusive. Here, we explore the role and precise mechanism of Van-Gogh-like 2 (VANGL2) during the pathogenesis of IBD. VANGL2 decreases in IBD patients and dextran sulfate sodium (DSS)-induced colitis in mice. Myeloid VANGL2 deficiency exacerbates the progression of DSS-induced colitis in mice and specifically enhances the activation of NLRP3 inflammasome in macrophages. NLRP3-specific inhibitor MCC950 effectively alleviates DSS-induced colitis in VANGL2 deficient mice. Mechanistically, VANGL2 interacts with NLRP3 and promotes the autophagic degradation of NLRP3 through enhancing the K27-linked polyubiquitination at lysine 823 of NLRP3 by recruiting E3 ligase MARCH8, leading to optineurin (OPTN)-mediated selective autophagy. Notably, decreased VANGL2 in the peripheral blood mononuclear cells from IBD patients results in overt NLRP3 inflammasome activation and sustained inflammation. Taken together, this study demonstrates that VANGL2 acts as a repressor of IBD progression by inhibiting NLRP3 inflammasome activation and provides insights into the crosstalk between inflammation and autophagy in preventing IBD. Although NLRP3 inflammasome activation and impaired autophagy are linked to inflammatory bowel disease (IBD), the underlying mechanisms remain unclear. This study shows that VANGL2 reduces IBD progression by recruiting the ubiquitin ligase MARCH8 to regulate NLRP3 activation through OPTN-mediated autophagy. [ABSTRACT FROM AUTHOR]

Background/Objectives: Danggui Beimu Kushen pill (DBK) is a traditional Chinese medicine renowned for its efficacy in the treatment of inflammatory conditions. It has been used in the modern clinical treatment of ulcerative colitis (UC). Further research is required to clarify its underlying mechanisms. Methods: DBK compounds were analyzed using UPLC-ESI-MS/MS. A mouse model of Dextran sulfate sodium (DSS)-induced UC was used to assess the efficacy of DBK. Network pharmacology identified DBK targets in UC, which were validated by molecular docking simulations. Cytokine levels were quantified using ELISA. Western blotting, immunofluorescence (IF), and immunohistochemistry (IHC) were employed to explore its underlying molecular mechanisms. Results: DBK treatment enhanced body weight and colon length in mice with DSS-induced colitis. Inflammatory cytokine levels (TNF-α, IL-1β, IL-6, IL-23, and IL-17A) were notably decreased in both serum and colon tissues. Network pharmacology and molecular docking analyses identified the IL-6/IL-6R and IL-17A/IL-17RA signaling pathways as crucial for the DBK treatment of UC. Additional validation using WB, IHC, and IF analyses demonstrated that DBK alleviated UC by suppressing the IL-6/STAT3 and IL-17/TRAF6/NF-κB pathways. Conclusions: DBK mitigates intestinal injury in mice with DSS-induced colitis and exerts therapeutic effects on UC by inhibiting the IL-6/IL-6R and IL-17A/IL-17RA signaling pathways to reduce inflammation. These findings provide significant insights into the mechanism of DBK treatment for UC. [ABSTRACT FROM AUTHOR]

Objective: The study aimed to improve the efficiency of leghorn male hepatoma (LMH) cells for animal virus vaccine production by transitioning from adherent to suspension culture and evaluating the effects of dextran sulfate (DS) on preventing cell aggregation. The goal was to enhance cell growth, viability, and glucose metabolism and to develop efficient suspension-adapted LMH cells for large-scale vaccine production. Methods: LMH cells previously cultured in an adherent state were transferred to 125 mL Erlenmeyer flasks to conduct suspension culture. Cell culture performance, including cell density, viability, and glucose metabolism, during the cultures was measured, along with an assessment of cell aggregation. Additionally, mRNA expression levels of genes associated with cell adhesion and apoptosis were monitored. Results: DS supplementation in suspension culture enhanced cell viability and growth, with higher cell densities and viabilities compared to control media. Additionally, DS supplementation reduced glucose consumption and waste production, indicating improved metabolic efficiency. DS also delayed cell aggregation, possibly by downregulating integrin expression and promoting anti-apoptotic gene expression. However, even after 2 months, cell aggregation persisted in both control and DS-supplemented cultures, suggesting further optimization is needed for LMH cell adaptation to suspension culture. Conclusion: DS supplementation in LMH cell suspension cultures led to notable improvements in cell growth, viability, and glucose metabolism, while also decreasing the cell aggregation. [ABSTRACT FROM AUTHOR]

The list of standard abbreviations for JDS is available at adsa.org/jds-abbreviations-24. Nonstandard abbreviations are available in the Notes. Colorectal cancer (CRC) arises from the accumulation of abnormal mutations in colorectal cells during prolonged inflammation. This study aimed to investigate the potential of probiotic fermented milk containing the probiotic strain, Bifidobacterium animalis ssp. lactis BX-245 (BX-245), in alleviating tumor burden in CRC mice induced by azoxymethane and dextran sodium sulfate. The study monitored changes in tumor size and number, gut microbiota, metabolomics, and inflammation levels before and after the intervention. Our findings indicate that intragastric administration of BX245-fermented milk effectively modulated the intratumor microbiota, as well as the gut microbiota and its metabolism. We also observed a decreased relative abundance of intratumor Akkermansia in the CRC mice, while the intratumor Parabacteroides exhibited a significant positive correlation with tumor number and weight. Moreover, administering BX245-fermented milk significantly reduced gut barrier permeability, alleviated gut barrier damage, and increased serum IL-2 and IFN-γ levels compared with the ordinary fermented milk group. Collectively, our data suggest that administering probiotic fermented milk containing specific functional strains such as BX245 could result in a reduction in tumor burden in CRC mice. Conversely, ordinary fermented milk did not show the same tumor-inhibiting effects. The current results are preliminary, and further confirmation is necessary to establish the causal relationship among probiotic milk, changes in gut microbiota, and disease alleviation. [Display omitted] [ABSTRACT FROM AUTHOR]

A versatile and modular microfluidic system for cell co-culture has been developed. Microfluidic chips, each featuring dual compartments separated by a porous membrane, have been fabricated and assembled within the system to facilitate fluidic interconnection and cell–cell communication through the chip assembly. A set of fluidic valves has been successfully integrated to regulate the flow through the chip assembly. The system allows for chip assembly in various arrangements, including in parallel, in series, and complex connections. Individual chips can be interconnected or disconnected within the system at any time. Moreover, the spatial order and orientation of the chips can be adjusted as needed, enabling the study of different cell–cell arrangements and the impact of the presence or absence of specific cell types. The utility of the system has been evaluated by culturing and interconnecting multi-monolayers of intestinal epithelial cells as a model of the complex cellular system. Epithelial monolayers were grown in multiple chips and interconnected in various configurations. The transepithelial electrical resistance and permeability profiles were investigated in detail for these configurations upon treatment of the cells with dextran sulfate sodium. Immune cells were stimulated through the epithelial layers and the expression of inflammatory cytokines was detected. This miniaturized platform offers controlled conditions for co-culturing key cellular components and assessing potential therapeutic agents in a physiologically relevant setting. [ABSTRACT FROM AUTHOR]

Chondroitin sulphate (CS) is a sulphated glycosaminoglycan (GAG) polysaccharide found on proteoglycans (CSPGs) in extracellular and pericellular matrices. Chondroitinase ABC (CSase ABC) derived from Proteus vulgaris is an enzyme that has gained attention for the capacity to cleave chondroitin sulphate (CS) glycosaminoglycans (GAG) from various proteoglycans such as Aggrecan, Neurocan, Decorin etc. The substrate specificity of CSase ABC is well-known for targeting various structural motifs of CS chains and has gained popularity in the field of neuro-regeneration by selective degradation of CS GAG chains. Within this context, our investigation into the biochemistry of CSase ABC led us to a previously unreported inhibition of CSase ABC activity by Dextran Sulphate (DexS). To understand the inhibitory effects of DexS, we compared its inhibition of CSase ABC to that of other polysaccharides such as Heparan Sulphate, Heparin, Colominic Acid, Fucoidan, and Dextran. This analysis identified key structural factors such as monosaccharide composition and linkage, sulphation degree and overall charge as influencing CSase ABC inhibition. Remarkably, DexS emerged as a unique inhibitor of CSase ABC, with distinctive inhibitory effects that correlate with its chain length. DexS has been used to reliably induce ulcerative colitis in mice, effectively mimicking inflammatory bowel diseases in humans, and has been previously shown to inhibit both RNA polymerase and reverse transcriptase. Our investigation emphasizes the interplay between the properties of DexS and CSase ABC, providing significant insights into the utilization of polysaccharide-based inhibitors for modulating enzyme activity. [ABSTRACT FROM AUTHOR]

Ulcerative colitis (UC) is a prominent category of disease that is associated with bowel inflammation, it can occur at any period of life and is prevalently rising on a global scale. Dextran sulfate sodium (DSS) has been extensively used to develop colitis due to its ability to mimic human UC, providing consistent and reproducible inflammation, ulceration, and disruption of the epithelial barrier in the colon. Chronic inflammation in the gut can lead to alterations in the gut-liver axis, potentially impacting liver function over time, while direct evidence linking diversion colitis to liver damage is limited. Thus, the present study aims to assess the gut and liver damage against DSS and the possible molecular mechanisms. Forty-seven animals were randomly assigned to six groups. Ulcerative colitis was induced using 2.5% w/v DSS in three alternate cycles, each lasting 7 days, with 1-week remission periods in between. SOV (5 and 10 mg/kg, orally) and the standard drug 5-aminosalicylic acid (100 mg/kg, orally) were administered from the start of the 2nd DSS cycle until the end of the experiment. Biochemical parameters, ELISA, histopathological, and immunohistochemical analyses have been conducted to assess damage in the colon and liver. SOV significantly reduced colitis severity by lowering the DAI score, oxidative stress markers (LPS, IL-1β, MPO, nitrite), and restoring liver biomarkers (SGPT, SGOT). Histopathological findings supported these protective benefits in the liver and gut. Moreover, immunohistochemical analysis showed SOV enhanced the expression of the cytoprotective mediator Nrf2/Keap-1 and reduced the expression of inflammatory mediators NF-κB and IL-6. Present findings concluded that SOV demonstrated a dose-dependent effect against UC through anti-inflammatory and antioxidant pathways, with the highest dose of SOV 10 mg/kg having more significant (p < 0.001) results than the low dose of 5 mg/kg. [ABSTRACT FROM AUTHOR]

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The Notch intracellular domain (NICD) regulates gene expression during development and homeostasis in a transcription factor complex that binds DNA either as monomer, or cooperatively as dimers. Mice expressing Notch dimerization-deficient (NDD) alleles of Notch1 and Notch2 have defects in multiple tissues that are sensitized to environmental insults. Here, we report that cardiac phenotypes and DSS (Dextran Sodium Sulfate) sensitivity in NDD mice can be ameliorated by housing mice under hypo-allergenic conditions (food/bedding). However, compound heterozygote NDD mice (N1RA/–; N2RA/–) in hypo-allergenic conditions subsequently develop severe hydrocephalus and hemorrhages. Further analysis revealed multiple vascular phenotypes in NDD mice including leakage, malformations of brain vasculature, and vasodilation in kidneys, leading to demise around P21. This mouse model is thus a hypomorphic allele useful to analyze vascular phenotypes and gene-environment interactions. The possibility of a non-canonical Notch signal regulating barrier formation in the gut, skin, and blood systems is discussed. [ABSTRACT FROM AUTHOR]

Lysosomes are best known for their roles in inflammatory responses by engaging in autophagy to remove inflammasomes. Here, we describe an unrecognized role for the lysosome, showing that it finely controls macrophage inflammatory function by manipulating the lysosomal Fe2+—prolyl hydroxylase domain enzymes (PHDs)—NF-κB—interleukin 1 beta (IL1B) transcription pathway that directly links lysosomes with inflammatory responses. TRPML1, a lysosomal cationic channel, is activated secondarily to ROS elevation upon inflammatory stimuli, which in turn suppresses IL1B transcription, thus limiting the excessive production of IL-1β in macrophages. Mechanistically, the suppression of IL1B transcription caused by TRPML1 activation results from its modulation on the release of lysosomal Fe2+, which subsequently activates PHDs. The activated PHDs then represses transcriptional activity of NF-κB, ultimately resulting in suppressed IL1B transcription. More importantly, in vivo stimulation of TRPML1 ameliorates multiple clinical signs of Dextran sulfate sodium-induced colitis in mice, suggesting TRPML1 has potential in treating inflammatory bowel disease. Lysosomes are best known for their roles in inflammatory responses via autophagy. Here, Xing et al., find that lysosomes regulate macrophage inflammatory responses by finely controlling interleukin-1β production, altering lysosomal Fe2+ release through the TRPML1 channel. [ABSTRACT FROM AUTHOR]

Hyaluronan (HA) levels are dynamically regulated homeostatically through biosynthesis and degradation. HA homeostasis is often perturbed under disease conditions. HA degradation products are thought to contribute to disease pathology. The hyaluronidase CEMIP requires the presence of living cells for its HA depolymerizing activity. CEMIP is overexpressed in a variety of pathological conditions, and the inhibition of its hyaluronidase activity therefore has therapeutic potential. To identify novel inhibitors of the CEMIP hyaluronidase activity, we established here a cell-compatible, medium-throughput assay for CEMIP-dependent HA depolymerization. The assay employs ultrafiltration plates to separate low- from high-molecular-weight HA, followed by quantification of HA fragments using an HA ELISA-like assay. Using this assay, we tested a range of compounds that have been reported to inhibit other hyaluronidases. Thereby, we identified several sulfated hydrocarbon polymers that inhibit CEMIP more potently than other hyaluronidases. One of these is heparin, a sulfated glycosaminoglycan produced by mast cells that constitutes the first described physiological CEMIP inhibitor. The most potent inhibitor (IC50 of 1.8 nM) is dextran sulfate, a synthetic sulfated polysaccharide. Heparin and dextran sulfate are used in numerous established and experimental biomedical applications. Their ability to inhibit CEMIP needs to be taken into account in these contexts. [ABSTRACT FROM AUTHOR]

BACKGROUND: Fecal microbiota transplantation (FMT) of healthy donors improves ulcerative colitis (UC) patients by restoring the balance of the gut microbiota. However, donors vary in microbial diversity and composition, often resulting in weak or even ineffective FMT. Improving the efficacy of FMT through combination treatment has become a promising strategy. Ulva lactuca polysaccharides (ULP) have been found to benefit host health by regulating gut microbiota. The effect of the combination of ULP and FMT in ameliorating UC has not yet been evaluated. RESULTS: The present study found that supplementation with ULP combined with FMT showed better effects in ameliorating UC than supplementation with FMT alone. Results suggested that FMT or ULP combined with FMT alleviated the symptoms of UC in mice, as evidenced by prevention of body weight loss, improvement of disease activity index and protection of the intestinal mucus. Notably, ULP in combination with FMT was more effective than FMT in reducing levels of cytokines and related inflammatory enzymes. In addition, ULP combined with FMT effectively restored the dysbiosis induced by dextran sulfate sodium (DSS) and further enriched probiotics (such as Bifidobacterium). The production of short‐chain fatty acids, especially acetic acid, was also significantly enriched by ULP combined with FMT. CONCLUSION: Supplementation of ULP combined with FMT could significantly ameliorate DSS‐induced colitis in mice by inhibiting inflammation and restoring dysbiosis of gut microbiota. These results suggested that ULP combined with FMT has potential application in ameliorating UC. © 2024 Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

Background: The conversion of primary bile acids to secondary bile acids by the gut microbiota has been implicated in colonic inflammation. This study investigated the role of gut microbiota related bile acid metabolism in colonic inflammation in both patients with inflammatory bowel disease (IBD) and a murine model of dextran sulfate sodium (DSS)-induced colitis. Methods: Bile acids in fecal samples from patients with IBD and DSS-induced colitis mice, with and without antibiotic treatment, were analyzed using ultraperformance liquid chromatography-mass spectrometry (UPLC-MS). The composition of the microbiota in fecal samples from IBD patients and DSS-colitis mice was characterized via Illumina MiSeq sequencing of the bacterial 16S rRNA gene V3-V4 region. Metagenomic profiling further identified metabolism-related gene signatures in stool samples from DSS-colitis mice. Histological analysis, quantitative PCR (qPCR) and Western Blotting were conducted on colonic samples from DSS-induced colitis mice to assess colonic inflammation, mucosal barrier integrity, and associated signaling pathways. The multivariate analysis of bile acids was conducted using Soft Independent Modelling of Class Analogy (SIMCA, Umetrics, Sweden). The relation between the relative abundance of specific phyla/genera and bile acid concentration was assess through Spearman's correlation analyses. Finally, lithocholic acid (LCA), the key bile acid, was administered via gavage to evaluate its effect on colonic inflammation and mucosal barrier integrity. Results: In patients with IBD, the composition of colonic bile acids and gut microbiota was altered. Moreover, changes in the gut microbiota further modulate the composition of bile acids in the intestine. As the gut microbiota continues to shift, the bile acid profile undergoes additional alterations. The aforementioned alterations were also observed in mice with DSS-induced colitis. The study revealed a correlation between dysbiosis of the gut microbiota and modifications in the profile of colonic bile acids, notably LCA observed in both patients with IBD and mice with DSS-induced colitis. Through multivariate analysis, LCA was identified as the key bile acid that significantly affects colonic inflammation and the integrity of mucosal barrier. Subsequent experiments confirmed that LCA supplementation effectively mitigated the inhibitory effects of gut microbiota on colitis progression in mice, primarily through the activation of the sphingosine-1-phosphate receptor 2 (S1PR2)/NF-κB p65 signaling pathway. Analysis of the microbiome and metagenomic data revealed changes in the gut microbiota, notably an increased abundance of an unclassified genus within the family Prevotellaceae in DSS-induced colitis mice. Furthermore, a positive correlation was observed between the relative abundance of Prevotellaceae and bile acid biosynthesis pathways, as well as colonic LCA level. Conclusions: These findings suggest that LCA and its positively correlated gut bacteria, Prevotellaceae, are closely associated with intestinal inflammation. Targeting colonic inflammation may involve inhibiting LCA and members of the Prevotellaceae family as potential therapeutic strategies. [ABSTRACT FROM AUTHOR]

Background: A. muciniphila (AKK) has attracted extensive research interest as a potential next-generation probiotics, but its role in intestinal pathology is remains unclear. Herein, this study was conducted to investigate the effects of A. muciniphila DSM 22,959 on growth performance, intestinal barrier function, microecology and inflammatory response of weaned piglets stimulated by dextran sulfate sodium salt (DSS). Method: Twenty-four Duroc × Landrace × Yorkshire (DLY) weaned piglets used for a 2 × 2 factorial arrangement of treatments were divided into four groups with six piglets in each group. From 1 to 15 d, the CA and DA groups were orally fed with 1.0 × 1011 colony-forming units A. muciniphila per day, while the CON and DCON groups were received gastric infusion of anaerobic sterile saline per day. The pigs were orally challenged (DCON, DA) or not (CON, CA) with DSS from day 9 to the end of the experiment and slaughtered on day 16. Results: Presence of A. muciniphila in DSS-challenged weaned pigs resulted in numerically increased diarrhea rate, blood neutrophilic granulocyte, serum C-reactive protein and immunoglobulin M levels, and numerically reduced final weight, average daily feed intake and average daily gain. The decrease in intestinal villus height, villous height: crypt depth ratio and digestibility was accompanied by lower expression of ZO1, ZO2, Claudin1, DMT1, CAT1, SGLT1 and PBD114 genes, as well as decreased enzyme activities of intestinal alkaline phosphatase, lactase, sucrase and maltase of piglets in DA group compared to piglets in DCON group. The abundance of Bifdobacterium, Lactobacillus, A. muciniphila, Ruminococcus gnavus was numerically higher in digesta of pigs in DA group than those in DCON group. The inflammatory responses of piglets were dramatically changed by the simultaneous presence of A. muciniphila and DSS: expression level of IL17A, IL17F, IL23, RORγt, Stat3 was elevated in DA pigs compared to the other pig groups. Conclusions: Our result showed that the oral A. muciniphila aggravates DSS-induced health damage of weaned piglet, which may attribute to the deteriorating intestinal morphology, dysbiosis of microbiota and inflammatory response disorders. [ABSTRACT FROM AUTHOR]

Inflammation induces tumor formation and plays a crucial role in tumor progression and prognosis. KCNK6, by regulating K(+) efflux to reduce NLRP3 Inflammasome-induced lung injury, relaxes the aorta. This study aims to elucidate the effects and biological mechanism of KCNK6 in inflammation-associated carcinogenesis, which may be essential for colon homeostasis and the defense system. To induce colitis, mice were given 3.0% Dextran Sodium Sulfate (DSS) in their drinking water for 7 days. The Azoxymethane (AOM) +DSS method was used to induce colon cancer in the mice model. Bone marrow-derived macrophages (BMDM) from Kcnk6-/- mice, AW264.7 cells, and human colon cancer HCT116 and Caco2 cells were used as in vitro models. The loss of Kcnk6 prevented spontaneous colitis and restored mucosal integrity and homeostatic molecules. Additionally, the loss of Kcnk6 reduced the severity of AOM/DSS-induced carcinogenesis. Kcnk6 promoted cell viability and proliferation in HCT-116 or Caco-2 cells. The loss of Kcnk6 inhibited the levels of inflammatory factors in BMDM cells. Kcnk6 accelerated potassium channel activity, inducing NLRP3 inflammasome activation. METTL3-mediated m6A modification increased Kcnk6 stability in a YTHDF2-dependent manner. Histone lactylation activated the transcription of YTHDF2/Kcnk6. Our study revealed the important role of Kcnk6 in inflammation-associated carcinogenesis progression. The m6A methyltransferase METTL3 and histone lactylation increased Kcnk6 stability in a YTHDF2-dependent manner, providing a potential strategy for inflammation-associated carcinogenesis or colorectal cancer therapy. PLAIN LANGUAGE SUMMARY: Our study revealed the important role of Kcnk6 senescence in inflammation associated carcinogenesis progression. The m6A methyltransferase METTL3 and histone lactylation increased Kcnk6 stability in YTHDF2- dependent manner, providing a potential strategy for inflammation associated carcinogenesis or colorectal cancer therapy. [ABSTRACT FROM AUTHOR]

[Display omitted] • Two fungus polysaccharides from Dictyophora indusiata (DIP) and Tremella fuciformis (TFP) with distinct glycosidic linkages were extracted and purified. • DIP and TFP ameliorated colitis in mice in a microbiota-dependent manner. • DIP, composed of l,3-β-D-glucan, and β-1,4- and β-1,6-linked glucan as branched chains, exerted better anti-inflammatory activity compared to the TFP. • Glycosidic linkages play a pivotal role in the anti-inflammatory activities of fungus polysaccharides. Over decades, the source-function relationships of bioactive polysaccharides have been progressively investigated, however, it is still unclear how a defined structure may conduce to the bioactivities of polysaccharides. To explore the structure–function relationship of fungus polysaccharides, we employed a dextran sulfate sodium (DSS)‐induced colitis mouse model to compare the anti-inflammatory activity of two fungus polysaccharides from Dictyophora indusiata (DIP) and Tremella fuciformis (TFP), which exhibit distinct glycosidic linkages. The structures of DIP and TFP were characterized through molecular weight detection, molecular morphology analysis, methylation analysis, and NMR analysis. Subsequently, we employed a DSS-induced colitis model to assess the anti-inflammatory efficacy of DIP and TFP. The colitis symptoms, histological morphology, intestinal inflammatory cytokines, and the composition and function of gut microbiota before and after polysaccharides treatment in colitis mice were also investigated. DIP, l,3-β-D-glucan with 1,4-β and 1,6-β-D-Glcp as branched chains, exhibited superior therapeutic effect than that of TFP consisted of a linear 1,3-α-D-mannose backbone with D-xylose and L-fucose in the side chains. Both DIP and TFP relieved DSS-induced colitis in a gut microbiota-dependent manner. Furthermore, metagenomics showed that DIP and TFP could partially reverse the bacterial function in colitis mice. Glycoside Hydrolase 1 (GH1) and GH3 were identified as being involved in hydrolyzing the glucose linkages in DIP, while GH92 and GH29 were predicted to be active in cleaving the α-1,3-linked mannose linkages and the glycosidic bonds of L-fucose residues in TFP. Our findings highlight the pivotal role of glycosidic linkages in anti-inflammatory activities of fungus polysaccharides and would promote the design and discovery of polysaccharides with designated activity to be used as functional foods and/or therapeutics. [ABSTRACT FROM AUTHOR]

Simple Summary: Periplaneta americana is a traditional medicinal insect, and its extracts are valued for their precise clinical efficacy. P. americana concentrated ethanol-extract liquid (PACEL) contains indole analogues, including tryptophan (Trp), tryptamine (Try), and 1,2,3,4-tetrahydrogen-β-carboline-3-carboxylic acid (Thcc), which exhibit notable biological activities. Using a dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) mouse model, we compared the efficacy of PACEL, Trp, Try, and Thcc in mitigating UC symptoms. Transcriptome sequencing was conducted to detect the gene expression in the colon tissues and identify key biological pathways. This study compared the therapeutic effects of PACEL and its three indole analogues in animal experiments and transcriptomic analysis, revealing that Trp, Try, and Thcc in PACEL may exert therapeutic effects by inhibiting NF-κB signaling in the treatment of UC. Ulcerative colitis (UC) is an inflammatory disease of the intestinal mucosa, and its incidence is steadily increasing worldwide. As a traditional Chinese medicinal insect, Periplaneta americana has been broadly utilized in clinical practice to treat wound healing. The tryptophan (Trp), tryptamine (Try), and 1,2,3,4-tetrahydrogen-β-carboline-3-carboxylic acid (Thcc) identified from P. americana concentrated ethanol-extract liquid (PACEL) exhibit significant cell proliferation-promoting and anti-inflammatory effects in the treatment of UC, but the mechanism involved remains obscure. Here, a dextran sulfate sodium (DSS)-induced UC mouse model was used to investigate the efficacy of high/low doses of PACEL, Trp, Try, and Thcc. Transcriptome sequencing was employed to detect the gene expression in the mouse intestine. The results showed that high doses of PACEL, Trp, Try, and Thcc could significantly improve weight loss and diarrhea, notably in the PACEL and Trp groups. Transcriptome analysis indicated that statistically changed genes in four treatment groups were specifically enriched in the immune system. Of these, the integrated analysis identified six hub genes (IL1β, CCL4, CXCL5, CXCR2, LCN2, and MMP9) regulated by NF-κB, which were significantly downregulated. This study investigates the molecular mechanisms underlying the UC treatment properties of indole analogues from PACEL, potentially through the inhibition of the NF-κB signaling pathway. [ABSTRACT FROM AUTHOR]

The innate immune sensor NLRP3 inflammasome overactivation is involved in the pathogenesis of ulcerative colitis. PGAM5 is a mitochondrial phosphatase involved in NLRP3 inflammasome activation in macrophages. However, the role of PGAM5 in ulcerative colitis and the mechanisms underlying PGAM5 regulating NLRP3 activity remain unknown. Here, we show that PGAM5 deficiency ameliorates dextran sodium sulfate (DSS)-induced colitis in mice via suppressing NLRP3 inflammasome activation. By combining APEX2-based proximity labeling focused on PGAM5 with quantitative proteomics, we identify NEK7 as the new binding partner of PGAM5 to promote NLRP3 inflammasome assembly and activation in a PGAM5 phosphatase activity-independent manner upon inflammasome induction. Interfering with PGAM5–NEK7 interaction by punicalagin inhibits the activation of the NLRP3 inflammasome in macrophages and ameliorates DSS-induced colitis in mice. Altogether, our data demonstrate the PGAM5–NEK7 interaction in macrophages for NLRP3 inflammasome activation and further provide a promising therapeutic strategy for ulcerative colitis by blocking the PGAM5–NEK7 interaction. Punicalagin directly binds to PGAM5 and blocks the interaction between PGAM5 and NEK7 to inhibit NLRP3 inflammasome activation in a PGAM5 phosphatase activity-independent manner, resulting in amelioration of ulcerative colitis. [Display omitted] [ABSTRACT FROM AUTHOR]

Artemisia ordosica Krasch, a traditional Chinese herbal medicine, possesses antibacterial, antiviral, and anti-inflammatory properties. The aim of this experiment was to investigate the therapeutic effect of Artemisia ordosica Krasch extraction (AOE) in treating colitis induced by dextran sulfate sodium (DSS) in mice. The in vitro antioxidant activity of AOE was evaluated by assessing its iron reduction capacity and scavenging capacity towards 1,1-diphenyl-2-picrylhydrazyl (DPPH) and hydroxyl radicals (·OH). The protective effect of AOE on colitis in mice was determined by monitoring key indicators such as body weight, colon length, and survival rate in mice, as well as by assessing the expression of colon-related genes and cytokine levels. We evaluated the impact of AOE on intestinal microbiota by measuring the 16s sequencing of cecal contents and bile acid metabolism. The results showed that the iron reduction capacity of AOE was positively correlated with its concentration. The half-maximal inhibitory concentrations (IC50) for scavenging DPPH and hydroxyl radicals were 3.126 mg/mL and 6.139 mg/mL, with a 95% confidence interval of 95%. In vivo studies demonstrated that AOE reduced DSS-induced colitis in mice by increasing the colon length, enhancing antioxidant enzyme activity, inhibiting inflammatory cell infiltration, suppressing the formation of TNF-α and IL-6, and reducing malondialdehyde (MDA) levels. qPCR analysis revealed that AOE reversed the down-regulation of Claudin mRNA expression, and altered the composition of cecal microbiota, thus mitigating DSS-induced colitis. AOE plays a crucial role in alleviating colitis in mice and effectively improves DSS-induced colitis, highlighting its potential as a therapeutic agent for inflammatory bowel diseases. [ABSTRACT FROM AUTHOR]

Introduction: Inflammatory bowel disease (IBD), including ulcerative colitis, is marked by intestinal barrier disruptions, immune system dysregulation, and an imbalance in the gut microbiota. The golden chanterelle mushroom, Cantharellus cibarius Fr., a popular edible mushroom, has shown potential therapeutic benefits. This study examines the therapeutic potential of a crude polysaccharide extract obtained from C. cibarius Fr. (CCP) on intestinal barrier integrity, inflammatory cytokine levels, and gut microbiota composition in a murine model of colitis induced by dextran sulfate sodium (DSS). Methods: To induce colitis BALB/c mice were provided to consume autoclaved water with 3% DSS for 7 days, followed by 14 days of CCP supplementation. To assess the effects of CCP, histological analysis of colon tissue was performed, gene expression, inflammatory responses, tight junction proteins expression, gut barrier integrity, and cytokines levels were measured and analyzed and 16S rRNA sequencing were evaluated. Results and Discussion: CCP treatment alleviates colitis symptoms by improving body weight, and enhancing intestinal integrity through increased mucin-2 and tight junction protein expression. Additionally, CCP administration regulates the altered immune response by mitigating the expression of pro-inflammatory cytokines and upregulating anti-inflammatory cytokines. Furthermore, CCP supplementation effectively modulates DSS-induced dysbiosis as demonstrated by 16S rRNA sequencing results. These findings suggest that crude polysaccharides from the golden chanterelle mushroom, C. cibarius Fr., hold promise for treating colitis, via strengthening the intestinal barrier, regulating inflammatory responses, and reshaping the gut dysbiosis in a DSS-induced colitis model. CCP offers a novel approach for managing colitis, as a chronic inflammatory condition. [ABSTRACT FROM AUTHOR]

BACKGROUND & AIMS: Lacticaseibacillus rhamnosus GG (LGG) is the worlds most consumed probiotic but its mechanism of action on intestinal permeability and differentiation along with its interactions with an essential source of signaling metabolites, dietary tryptophan (trp), are unclear. METHODS: Untargeted metabolomic and transcriptomic analyses were performed in LGG monocolonized germ-free mice fed trp-free or -sufficient diets. LGG-derived metabolites were profiled in vitro under anaerobic and aerobic conditions. Multiomic correlations using a newly developed algorithm discovered novel metabolites tightly linked to tight junction and cell differentiation genes whose abundances were regulated by LGG and dietary trp. Barrier-modulation by these metabolites were functionally tested in Caco2 cells, mouse enteroids, and dextran sulfate sodium experimental colitis. The contribution of these metabolites to barrier protection is delineated at specific tight junction proteins and enterocyte-promoting factors with gain and loss of function approaches. RESULTS: LGG, strictly with dietary trp, promotes the enterocyte program and expression of tight junction genes, particularly Ocln. Functional evaluations of fecal and serum metabolites synergistically stimulated by LGG and trp revealed a novel vitamin B3 metabolism pathway, with methylnicotinamide (MNA) unexpectedly being the most robust barrier-protective metabolite in vitro and in vivo. Reduced serum MNA is significantly associated with increased disease activity in patients with inflammatory bowel disease. Exogenous MNA enhances gut barrier in homeostasis and robustly promotes colonic healing in dextran sulfate sodium colitis. MNA is sufficient to promote intestinal epithelial Ocln and RNF43, a master inhibitor of Wnt. Blocking trp or vitamin B3 absorption abolishes barrier recovery in vivo. CONCLUSIONS: Our study uncovers a novel LGG-regulated dietary trp-dependent production of MNA that protects the gut barrier against colitis.

Introduction: Ulcerative colitis (UC) is a chronic inflammatory condition of the intestinal tract in which mucosal healing is a crucial measure of therapeutic efficacy. Quercetin, a flavonoid prevalent in various foods and traditional Chinese medicines, exhibits notable pharmacological properties, including antioxidant and anti-inflammatory activities. Consequently, it warrants investigation to determine its potential therapeutic effects on UC. The objective of this study was to investigate the effects and underlying mechanisms of quercetin in a murine model of UC. Methods: A comprehensive approach integrating network predictions with transcriptomic analyses was employed to identify the potential targets and enriched pathways associated with quercetin in UC. Subsequently, the effects of quercetin on pathological morphology, inflammatory mediators, and mucosal barrier-associated proteins, as well as the identified potential targets and enriched pathways, were systematically investigated in a murine model of dextran sulfate sodium (DSS)-induced UC. Results: Network analyses identified CXCL8 and its receptors, CXCR1 and CXCR2, as primary target genes for therapeutic intervention in UC. Further validation through transcriptomic analysis and immunofluorescence staining demonstrated significant upregulation of the CXCL8-CXCR1/2 axis in the intestinal tissues of patients with UC. Experimental investigations in animal models have shown that quercetin markedly alleviates DSS-induced symptoms in mice. This effect includes the restoration of colonic crypt architecture, normalization of goblet cell structure and density, reduction of inflammatory cell infiltration, and decreased concentrations of inflammatory mediators. Quercetin enhanced the expression of tight junction (TJ) proteins, including ZO-1, MUC2 (Mucin 2), and occludin, thereby preserving the integrity of the intestinal mucosal barrier. Additionally, it significantly diminished the levels of IL-17A, NF-κB, CXCL8, CXCR1, and CXCR2 in the colonic tissues of mice with UC. Discussion: The ameliorative effects of quercetin on colon tissue damage in DSS-induced UC mice were significant, possibly due to its ability to inhibit the CXCL8-CXCR1/2 signaling axis. These findings provide a solid foundation for the clinical application and pharmaceutical advancement of quercetin. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Inflammatory bowel disease is associated with a high risk of colitis-associated cancer (CAC). We evaluated the role of TLR3 in CAC using a murine model. Wild-type (WT) and TLR3-knockout (TLR3−/−) mice received azoxymethane (AOM) 12.5 mg/kg intraperitoneally on day zero, followed by three cycles of 2% dextran sulfate sodium (DSS) for five days and free water for two weeks. We evaluated clinical indices, such as weight change, colon length, histological severity of colitis, and tumor number. We performed immunofluorescence assays for phospho-IκB kinase and β-catenin in colon tissues. To elucidate the antitumorigenic mechanism of TLR3 signaling, we injected poly(I: C) or phosphate-buffered saline intraperitoneally into an AOM/DSS-induced tumorigenesis model in WT mice. We also evaluate the direct antitumor effect of TLR signaling in AOM-treated WT and TLR3−/− mice without DSS. TLR3 deficiency increased tumor burden and colitis severity in the colon tissue than in the WT mice. β-catenin immunoreactivity was higher in TLR3−/− mice, while phospho-IκB kinase expression was similar. TLR3 activation by poly(I: C) did not reduce tumor burden in WT mice, but long-term AOM administration without DSS significantly increased tumor burden in TLR3−/− mice. TLR3 signaling attenuates CAC development, suggesting it may be a target for preventing CAC in inflammatory bowel disease. [ABSTRACT FROM AUTHOR]

Objective: To investigate effect of mesalazine (MSLZ) on improvement of colonic barrier in mice with ulcerative colitis(UC), and its regulatory mechanism on wingless-type mouse mammary tumor virus integration site1(Wnt1) signaling pathway. Methods: C57BL/6 mice were randomly divided into normal control group(Control), model group(UC), MSLZ group and MSLZ+sh-Wnt1 group. Except for Control group, other groups were treated with sodium dextran sulfate (DSS) to establish UC model. Mice in Control, UC and MSLZ groups were intraperitoneally injected 5×109 pfu/ml NC-shRNA. Mice in MSLZ+sh-Wnt1 group were intraperitoneally injected 5×109 pfu/ml shRNA-Wnt1. Mice in MSLZ group and MSLZ+sh-Wnt1 group were gavaged with 400 mg/kg MSLZ every day, and mice in Control and UC groups were gavaged with sterile distilled water of same dose every day. Colon length of mice in each group was detected. Kit was used to detect contents of D-lactate (D-LA), lipopolysaccharide (LPS) and activity of diamine oxidase (DAO) in serum of mice in each group. TUNEL staining was used to detect apoptosis in colon tissue of mice in each group. Immunohistochemistry was used to detect expressions of mucin 2 (MUC2) and Occludin in colon tissues. Western blot was used to detect expressions of Wnt1, β-catenin, B cell lymphoma-2(Bcl-2) and Bcl-2 associated X protein(Bax). Results: MSLZ could significantly increase length of colon, increase expressions of MUC2, Occludin, Wnt1, β-catenin and Bcl-2 in colon tissue, decrease levels of D-LA, LPS, DAO in serum, cell apoptosis rate and expression of Bax in colon tissue, while MSLZ+sh-Wnt1 could partially reverse protective effect of MSLZ on colon barrier function (all P<0.05). Conclusion: MSLZ can inhibit apoptosis of colon mucosa in UC mice, alleviate pathological damage of colon tissue, and ameliorate barrier function of colon mucosa, which may be related to activation of Wnt1 signaling pathway. [ABSTRACT FROM AUTHOR]

AIM: To investigate the potential of atractylenolide Ⅲ(AⅢ) in mitigating dextran sulfate sodium (DSS)-induced injury in a mouse model of chronic inflammatory bowel disease (IBD), and to explore the mechanisms involved, particularly the modulation of signal transducer and activator of transcription 3 (STAT3) signaling, which plays a crucial role in the homeostasis of T helper 17(Th17) and regulatory T(Treg) cells. METHODS: A mouse model of DSSinduced chronic IBD was established, and the mice were divided into 4 groups: control, model(DSS), high-dose(50 mg/kg) AⅢ, and low-dose (30 mg/kg) AⅢ. The disease activity index (DAI) was utilized to assess disease severity. Histopathological damage in the colons of IBD mice was evaluated by hematoxylin-eosin (HE) staining. The protein levels of phosphorylated STAT3, occludin and zonula occludens-1 (ZO-1) were analyzed using immunohistochemical staining and Western blot. Flow cytometry was employed to examine the differentiation of splenic lymphocytes into Th17/Treg cells. RESULTS: Both DAI assessments and HE staining indicated that AⅢ significantly alleviated inflammatory injury in mice with DSS-induced chronic IBD. Immunohistochemical analysis demonstrated that AⅢ enhanced the expression of ZO-1 and occludin in colonic tissues. Flow cytometry results revealed that AⅢ helped maintain the balance between splenic Th17 and Treg cells. Furthermore, immunohistochemical staining and Western blot showed that AⅢ inhibited the phosphorylation of STAT3. CONCLUSION: Treatment with AⅢ effectively reduced inflammatory injury in a mouse model of chronic IBD by preserving Th17/Treg homeostasis through the inhibition of STAT3 phosphorylation. As a natural compound, AⅢ exhibits significant therapeutic potential for the treatment of chronic IBD. [ABSTRACT FROM AUTHOR]

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

The impaired mucosal barrier is a hallmark of ulcerative colitis (UC), an inflammatory colonic disorder with epidemiological and pathophysiology sex bias. UC Patients overexpress the colonic epithelial cells (CECs)-derived peptide pancreastatin (PST). Pancreastatin inhibitor 8 (PSTi8), an inhibitor of PST, has shown promising anti-inflammatory effects on UC. However, no data exist in the context of CEC barrier function and integrity. We investigated the impact of PSTi8 treatment on CECs in homeostatic and colitic conditions. PSTi8 (2.5 mg/mL/kg, i.r.) or PBS treatment started one day before colitis induction (5% dextran sodium sulfate for five days) in male and female C57BL/6 mice. The disease activity score was assessed daily. Epithelial-associated cytokines, markers specific to differentiation, proliferation, differentiated CECs, stem cells, CECs regulators, and the PSTi8 G-protein coupled receptor 78 (GPR78) signaling pathway, were evaluated using ELISA, immunofluorescence and qRT-PCR. PSTi8 treatment reduced the epithelial-associated cytokines and differentiated CECs while promoting CEC proliferation and self-renewal in females at a steady state through the GRP78 signaling pathway. PSTi8 treatment exacerbated colitis severity and increased CEC differentiation while reducing proliferation in colitic females. Conversely, PSTi8 treatment reduced males' susceptibility to colitis by preserving stem cells and differentiated CECs. PST regulated colonic mucosal maintenance in a sex- and disease-dependent manner. [ABSTRACT FROM AUTHOR]

Microgravity may profoundly impact the cardiovascular system, skeletal muscle system, and immune system of astronauts. At the cellular level, microgravity may also affect cell proliferation, differentiation, and growth, as well as lipid metabolism. In this work, we investigated lipid changes in Caco-2 cells cultured in a clinostat for 24 h under simulated microgravity conditions (SMC). Complex lipids were measured using a UHPLC-QTOF/MS platform, and the data were subjected to multivariate analysis. Under SMC, levels of ceramides Cer 18:0;O2/16:0, Cer 18:1;O2/16:0, Cer 18:1; O2/22:0, Cer 18:1;O2/24:0, and Cer 18:2;O2/24:0 were found to be upregulated, while sphingomyelins SM 16:1;O2/16:0, SM 16:1;O2/18:1, SM 18:1;O2/24:0, and SM 18:2;O2/24:0 were found to be downregulated. On the other hand, considering that sphingolipids are involved in the process of inflammation, we also treated Caco-2 cells with dextran sodium sulfate (DSS) to induce cell inflammation and lipopolysaccharide (LPS) to induce cell immune responses. As a result, we observed similar lipid dysregulation, indicating that SMC may exert a condition similar to inflammation. Our lipidomics strategy provides new insights into the altered metabolic pathway of ceramides and sphingomyelins of Caco-2 cells under SMC. [ABSTRACT FROM AUTHOR]

Background and Aim: Selenium, an essential micronutrient for humans, has been shown to be protective against ulcerative colitis (UC), but the exact mechanism remains unclear. The role of selenium, protecting against ferroptosis of intestinal epithelial cells (IECs) in colitis, was investigated in this current study. Methods: Serum selenium level and ferroptosis‐related gene expression in the colonic mucosa were measured in UC patients and healthy controls. The effects of sodium selenite supplementation on experimental colitis were investigated in dextran sulfate sodium (DSS)‐treated mice. The influence of sodium selenite on IEC ferroptosis was evaluated through assessing cell death rate, intracellular ferrous iron content, lipid reactive oxygen species level, and mitochondrial membrane damage of DSS‐treated Caco‐2 cells. Moreover, glutathione peroxidase 4 (GPX4) and acyl‐CoA synthetase long‐chain family member 4, ferroptosis‐related genes, were detected in Caco‐2 cells and mouse intestines. Results: Serum selenium was decreased in UC patients in comparison with healthy individuals. Additionally, serum selenium level was negatively correlated with disease activity and was associated with clinical inflammation and nutrition indicators. The expression of GPX4 in the mucosa of UC was positively correlated with serum selenium level. The in vivo experiments showed that selenium treatment ameliorated DSS‐induced colitis and inhibited ferroptosis in IECs. The in vitro results suggested that selenium supplementation inhibited DSS‐induced ferroptosis in Caco‐2 cells. GPX4 was upregulated after selenium supplementation both in vivo and in vitro. Conclusions: Serum selenium level was associated with IEC ferroptosis in UC patients. Selenium supplementation alleviates DSS‐induced colitis and inhibits ferroptosis in IECs by upregulating the expression of GPX4. [ABSTRACT FROM AUTHOR]

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

Ulcerative colitis (UC) is an idiopathic, chronic, relapsing inflammatory bowel disease (IBD), characterized by chronic inflammation of the gastrointestinal tract. The pathophysiology of UC is complicated and involves several factors including immune, genetic, and environmental factors. Recently, a huge amount of research has concentrated on the role of interleukins including interleukin-6 (IL-6) in its pathophysiology. Thus, this study aims to examine the colo-protective and immunomodulatory effect of Tocilizumab (TCZ) in an experimental model of dextran sulfate sodium (DSS) induced UC. In the current study, we analyzed the inflammatory, immunomodulatory, apoptotic, autophagy, and endoplasmic reticulum (ER) stress markers and other clinical features including stool consistency, rectal bleeding, and edema markers in rats. Our results showed that induction of colitis caused bloody diarrhea and increased IL-6 levels. Treatment with TCZ significantly ameliorated DSS-induced injury via decreasing inflammatory markers of colon injury (IL-6), signal transducer and activator of transcription-3 (STAT-3), and C-reactive protein (CRP). Furthermore, TCZ attenuated the apoptotic marker (caspase-3), and down-regulated endoplasmic reticulum stress sensor proteins (inositol- requiring transmembrane kinase endonuclease-1 (IRE-1) and activated transcription factor-6 (ATF-6)) and autophagy proteins (autophagy-related 16-like protein 1 (ATG16L1) and nucleotide-binding oligomerization domain-containing protein-2 (NOD2)), as compared to DSS group. Altogether, the current data suggest TCZ to be a promising protective therapy against UC. [ABSTRACT FROM AUTHOR]