Diabetes mellitus is a chronic disease that has become more prevalent worldwide because of lifestyle changes. It leads to serious complications, including increased atherosclerosis, protein glycosylation, endothelial dysfunction, and vascular denervation. These complications impair neovascularization and wound healing, resulting in delayed recovery from injuries and an elevated risk of infections. The present study aimed to investigate the effect of lipoic acid (LA) on the key mediators involved in the wound healing process, specifically CD4 + CD25 + T cell subsets, CD4 + CD25 + Foxp3 + regulatory T (Treg) cells, T-helper-17 (Th17) cells that generate IL-17 A, glucocorticoid-induced tumor necrosis factor receptor (GITR) expressing cells, as well as cytokines such as IL-2, IL-1β, IL-6, and TNF-α and IFN-γ. These mediators play crucial roles in epidermal and dermal proliferation, hypertrophy, and cell migration.

We divided mice into 5 groups: the non-diabetic (normal control; NC), wounded non-diabetic mice (N + W), wounded diabetic mice (D + W), wounded diabetic mice treated with 50 mg/kg lipoic acid (D + W + L50) for 14 days, and wounded diabetic mice treated with 100 mg/kg lipoic acid (D + W + L100) for 14 days.

Flow cytometric analysis indicated that lipoic acid-treated mice exhibited a significant decrease in the frequency of intracellular cytokines (IL-17 A, TNF-α and IFN-γ) in CD4 + T cells, as well as a reduction in the number of GITR-expressing cells. Conversely, a significant upregulation in the number CD4+, CD25+, FOXp3 + and CD4 + CD25 + Foxp3 + regulatory T (Treg) cells was observed in this group compared to both the normal + wounded (N + W) and diabetic + wounded (D + W) groups. Additionally, the mRNA Levels of inflammatory mediators (IL-2, IL-1β, IL-6, and TNF-α) were downregulated in lipoic acid-treated mice compared to other groups. T thereby he histological findings of diabetic skin wounds treated with lipoic acid showed well-healed surgical wounds.

These findings support the beneficial role of lipoic acid in fine-tuning the balance between anti-inflammatory and pro-inflammatory cytokines, influencing both their release and gene expression.

Inflammatory bowel disease (IBD) involves gastrointestinal inflammation, due to intestinal epithelial barrier destruction caused by excessive immune activation. Conventional cell culture systems do not provide a model system that can recapitulate the complex interactions between epithelial cells, immune cells, and intestinal bacteria. To address this, we developed a microfluidic device that mimics the inflammatory response associated with microbial invasion of the intestinal mucosa. The device consisted of two media channels, an upper and a lower channel, and a porous membrane between these channels on which C2BBe1 intestinal epithelial cells were seeded to form a tight junction layer. Each electrode was placed in contact with both channels to continuously monitor the tight junction state. Fresh medium flow allowed bacterial numbers to be controlled and bacterial toxins to be removed, allowing co-culture of mammalian cells and bacteria. In addition, RAW264 macrophage cells were attached to the bottom of the lower channel. By introducing E. coli into the lower channel, the RAW264 cells were activated and produced TNF-α, successfully recapitulating a culture model of inflammation in which the C2BBe1cell tight junction layer was destroyed. The main structure of the device was initially made of polydimethylsiloxane to facilitate its widespread use, but with a view to introducing anaerobic bacteria in the future, a similar phenomenon was successfully reproduced using polystyrene. When TPCA-1, an IκB kinase 2 inhibitor was added into this IBD culture model, the tight junction destruction was significantly suppressed. The results suggest that this IBD culture model also is useful as a screening system for anti-IBD drugs.

Schistosomiasis is one of the most devastating tropical diseases in developing countries and is usually misdiagnosed with colitis because the prevalence of co-occurrence of both diseases is high. Previously, infection of Schistosoma japonicum cercariae has been shown to provide immediate protection against dextran sodium sulphate (DSS)-induced acute colitis in mice models. Studies using synthesised peptides or soluble proteins from parasites also revealed similar protection against colitis. However, most of these studies were done within a short timeframe, which cannot completely represent the actual situation where natural infection of Schistosoma or colitis is usually chronic.

This study aims to investigate how chronic schistosomiasis affects chronic intestinal inflammation.

Mice were infected with Schistosoma mansoni and induced simultaneously with chronic colitis. The symptoms and severity of intestinal inflammation and fibrosis were investigated by disease activity index, histology, enzyme-linked immunosorbent assay (ELISA), and quantitative polymerase chain reaction (qPCR). Furthermore, immune analysis by ELISA and qPCR and microbiome analysis by 16S rDNA sequencing were done to investigate the underlying mechanism.

Concomitant occurrence of chronic schistosomiasis and chronic colitis significantly alleviated colitis symptoms, lessened intestinal inflammation, and reduced egg-induced fibrosis. Further analysis revealed an alternation of the intestinal immunity and gut microbiome community in mice with both diseases, which could be the potential reason for this outcome.

Our results represent a mechanism of how schistosomiasis and chronic intestinal inflammation affect each other.

Inflammatory bowel disease (IBD) is a complex condition linked to the gut microbiota, host metabolism, and the immune system. Edible mushroom polysaccharides (EMPs) are gaining attention for their benefits, particularly as prebiotics that help balance gut microbial, a key factor in IBD. With their scalable production, diverse hydrophilic properties, and demonstrated anti-inflammatory effects in both laboratory and animal studies, EMPs show promise for easing IBD symptoms. By supporting a healthy gut microbiome through various mechanisms, EMPs can play an important role in preventing and managing IBD, ultimately benefiting overall health and opening new treatment avenues. This review examines how EMPs affect IBD, focusing on their role in shaping gut microbiota, restoring gut barriers, regulating immune function, and influencing pathways related to colitis. It also explores their impact on the microbiota-gut-multi organ axis and overall host health, as well as the relationship between EMPs preparation, structure, and bioactivity, along with their potential applications in food and medicine. This investigation provides valuable insights into the intricate connections between the gut, immune system, and systemic inflammation system, highlighting how EMPs are key players in this complex interaction.

Ulcerative colitis (UC) is a chronic inflammatory bowel disorder distinguished by alternating phases of remission and exacerbation. Restoring immune balance through the modulation of M1 macrophage polarization represents a potentially valuable therapeutic strategy for UC. Indoleamine 2,3-dioxygenase-1 (IDO1) has been shown to contribute to macrophage plasticity, but its role in the pathogenesis of UC via regulating M1 macrophage polarization has not been studied yet. For the clinical component, we analyzed IDO1 expression in UC using bioinformatics analysis of Gene Expression Omnibus (GEO) datasets and validated the result using western blotting of colonic tissues from new recruited UC patients. Colitis was induced in mice via dextran sulfate sodium (DSS) treatment and subsequently treated with oral administration of 1-methyl-DL-tryptophan (1-MT), an inhibitor of IDO1 pathway. The results indicated that IDO1 expression was significantly elevated in UC patients and correlated with M1 macrophage polarization observed in both human data and colitis mice. Furthermore, 1-MT markedly ameliorated DSS-induced weight loss, colonic shortening and disease severity via inhibiting IDO1 expression level, downregulating GRP78-XBP1 pathway and reducing M1 proportion. Notably, in vitro study revealed that overexpressing IDO1 in RAW264.7 cells induced macrophage M1 polarization with increased expression levels of GRP78 and XBP1, which was attenuated by 1-MT treatment. Additionally, the catalytic effect exerted by IDO1 overexpression on M1 polarization was neutralized by employing an inhibitor targeting the endoplasmic reticulum (ER) stress pathway. Thus, our findings suggest that IDO1 may promote UC progression by skewing macrophages towards M1 polarization through ER stress-associated GRP78-XBP1 pathway.

Inflammatory bowel diseases (IBD) are chronic, remitting, and relapsing conditions of the gastrointestinal tract with incompletely elucidated etiology. The anti-TNF-α mAbs represent one of aflash nanocomplexation and flash nanoprecipitation process, resulting in particles with a narrow size distribution and tunable release profile, with the longest in vitro release lasting over four months. These mAb-releasing NPs are then incorporated into hyaluronic acid hydrogel microparticles (MPs) to enhance tissue retention, thus extending the duration of mAb release in vivo. A single i.m. injection of the LAI can maintain the serum mAb level above the therapeutically effective concentration for over 100 days in healthy mice. In a 9-week study using a dextran sulfate-induced chronic colitis model, the anti-TNF-α LAI formulation demonstrates substantial therapeutic efficacy and a better safety profile than free mAb injections. This work demonstrates the effectiveness of this LAI system in maintaining a persistent serum mAb level and its potential as a versatile, safer, and effective delivery system for antibody therapeutics.

High-altitude hypoxia can cause gastrointestinal issues and damage the intestinal mucosal barrier, which is crucial for digestion and nutrient absorption. The Notch signaling pathway affects this barrier's integrity. This study explores the Notch pathway's role in hypoxia-induced intestinal injury. C57BL/6 mice were used to model intestinal mucosal barrier injury through dextran sodium sulfate (DSS) and hypobaric hypoxia (simulating 5000 m altitude for 7 days). Mice were treated with Notch inhibitor Dibenzazepine (DBZ) and Mucin2 (MUC2) activator Prostaglandin E2 (PGE2). We evaluated weight, colon length, histology, Zonula occludens 1 (ZO-1) and Claudin-1 levels, MUC2 and Notch1 staining, serum diamine oxidase (DAO) and D-lactate (D-La), inflammatory markers, and Notch pathway proteins. DSS and hypoxia caused weight loss, colon shortening, ulcers, and inflammation, with fewer goblet cells and lower MUC2 levels. Elevated serum DAO, D-La, and inflammatory markers indicated severe intestinal damage. DBZ treatment post-DSS and hypoxia significantly reduced these symptoms. PGE2 activation of MUC2 also alleviated symptoms and mitigated intestinal damage. Hypoxia worsens DSS-induced mucosal barrier disruption by activating the Notch pathway, shifting stem cell differentiation towards absorptive cells instead of goblet cells, reducing MUC2 secretion, and intensifying damage. Targeting the Notch pathway and enhancing MUC2 expression could effectively treat hypoxia-induced intestinal injury.

Clostridioides difficile infects the large intestine and can result in debilitating and potentially fatal colitis. The intestinal microbiota is a major factor influencing the severity of disease following infection. Factors like diet that shape microbiota composition and function may modulate C. difficile colitis. Here, we report that mice fed two distinct standard mouse chows (LabDiet 5010 and LabDiet 5053) exhibited significantly different susceptibility to severe C. difficile infection. Both diets are grain-based with comparable profiles of macro and micronutrient composition. Diet 5010-fed mice had severe morbidity and mortality compared to Diet 5053-fed mice despite no differences in C. difficile colonization or toxin production. Furthermore, Diet 5053 protected mice from toxin-induced epithelial damage. This protection was microbiota-dependent as germ-free mice or mice harboring a reduced diversity microbiota fed Diet 5053 were not protected from severe infection. However, cohousing with mice harboring a complex microbiota restored the protective capacity of Diet 5053 but not Diet 5010. Metabolomic profiling revealed distinct metabolic capacities between Diet 5010- and Diet 5053-fed intestinal microbiotas. Diet 5053-mediated protection extended beyond C. difficile infection as Diet 5053-fed mice displayed less severe dextran sodium sulfate-induced colitis than Diet 5010-fed mice, highlighting a potentially broader capacity for Diet 5053 to limit colitis. These findings demonstrate that standard diet formulations in combination with the host microbiota can drive variability in severity of infectious and non-infectious murine colitis systems, and that diet holds therapeutic potential to limit the severity of C. difficile infection through modulating the functional capacity of the microbiota.IMPORTANCEDiet is a major modulator of the microbiota and intestinal health. This report finds that two different standard mouse diets starkly alter the severity of colitis observed in a pathogen-mediated (Clostridioides difficile) and non-infectious (dextran sodium sulfate) mouse colitis experimental systems. These findings in part explain study-to-study variability using these mouse systems to study disease. Since the gut microbiota plays a key role in intestinal homeostasis, diet-derived modulation of the microbiota is a promising avenue to control disease driven by intestinal inflammation and may represent a potential intervention strategy for at-risk patients.

This study aimed to investigate the therapeutic potential of scopoletin in ulcerative colitis, with a primary focus on its impact on crucial inflammatory pathways and immune responses. A male mouse model of DSS-induced colitis was employed with six distinct groups: a control group, a group subjected to DSS only, three groups treated with varying scopoletin doses, and the final group treated with dexamethasone. The investigation included an assessment of the effects of scopoletin on colitis symptoms, including alterations in body weight, Disease Activity Index (DAI), and histopathological changes in colonic tissue. Furthermore, this study scrutinized the influence of scopoletin on cytokine production, PPARγ and NF-κB expression, NLRP3 inflammasome, and the composition of intestinal bacteria. Scopoletin treatment yielded noteworthy improvements in DSS-induced colitis in mice, as evidenced by reduced weight loss and colonic shortening (p < 0.05, < 0.01, respectively). It effectively diminished TNF-α, IL-1β, and IL-12 cytokine levels (p < 0.01, p < 0.05), attenuated NLRP3 inflammasome activation and the associated cytokine release (p < 0.05, p < 0.01), and modulated the immune response by elevating PPARγ expression while suppressing NF-κB pathway activation (p < 0.05, p < 0.01). Additionally, scopoletin induced alterations in the gut microbiota composition, augmenting beneficial Lactobacillus and Bifidobacteria while reducing E. coli (p < 0.05). It also enhanced tight junction proteins, signifying an improvement in the intestinal barrier integrity (p < 0.05, < 0.01). Scopoletin is a promising therapeutic agent for managing ulcerative colitis, showing benefits that extend beyond mere anti-inflammatory actions to encompass regulatory effects on gut microbiota and restoration of intestinal integrity.

Notch signaling is an evolutionarily conserved, multifunctional pathway involved in cell fate determination and immune modulation and contributes to the pathogenesis of autoinflammatory diseases. Emerging evidence reveals a bidirectional interaction between Notch and the gut microbiota (GM), whereby GM composition is capable of modulating Notch signaling through the binding of microbial elements to Notch receptors, leading to immune modulation. Furthermore, Notch regulates the GM by promoting SCFA-producing bacteria while suppressing proinflammatory strains. Beneficial microbes, such as Lactobacillus and Akkermansia muciniphila, modulate Notch and reduce proinflammatory cytokine production (such as IL-6 and TNF-α). The interaction between GM and Notch can either amplify or attenuate inflammatory pathways in inflammatory bowel diseases (IBDs), Behçet's disease, and PAPA syndrome. Together, these findings provide novel therapeutic perspectives for autoinflammatory diseases by targeting the GM via probiotics or inhibiting Notch signaling. This review focuses on Notch-GM crosstalk and how GM-based and/or Notch-targeted approaches may modulate immune responses and promote better clinical outcomes.

Microencapsulation improves the storage, handling, and administration of probiotics by protecting them from environmental factors and adverse conditions in the gastrointestinal tract. This process facilitates their controlled delivery in the body, which can simplify their use in therapies without compromising their therapeutic efficacy.

This study investigates the microencapsulation of Lactiplantibacillus plantarum LM-20, its probiotic properties, and its effects in a murine model of ulcerative colitis.

Synbiotic microencapsulation was carried out using spray drying with maltodextrin, gum Arabic, and inulin, achieving an encapsulation efficiency of 90.76%. The resulting microcapsules exhibited remarkable resistance to simulated gastrointestinal conditions in vitro, maintaining a survival rate of 90%. The drying process did not compromise the probiotic characteristics of the bacteria, as they demonstrated enhanced auto-aggregation, hydrophobicity, and phenol tolerance. The therapeutic potential of the microencapsulated synbiotic was evaluated in a murine model of dextran sodium sulfate-induced ulcerative colitis. The results revealed that mice treated with microencapsulated Lactiplantibacillus plantarum LM-20 showed an 83.3% reduction in the disease activity index (DAI) compared to the ulcerative colitis control group. Moreover, a significant decrease was observed in pro-inflammatory cytokine levels (IL-1β and TNF-α) and myeloperoxidase activity, with values comparable to those of the healthy control group.

These findings suggest that microencapsulated Lactiplantibacillus plantarum LM-20 could be a promising candidate for therapeutic applications in the prevention and management of ulcerative colitis.

To explore the protective effect and underlying mechanism of Quzhou Aurantii Fructus flavonoids (QAFF) on Ulcerative colitis (UC).

The constituents of QAFF were accurately determined by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). The therapeutic impacts of QAFF were assessed in dextran sulfate sodium (DSS)-induced UC mice, focusing on the changes in body weight, disease activity index (DAI), colon length, histological assessment of colonic tissues, levels of pro-inflammatory cytokines, and expression of tight junction proteins. Western blotting confirmed key regulatory proteins within the differential signaling pathways, guided by transcriptome analysis. Additionally, the influence of QAFF on the gut microbiome was explored through 16S ribosomal RNA (rRNA) sequencing. The alterations in endogenous metabolites were detected by untargeted metabolomics, and their potential correlation with intestinal flora was then examined utilizing Spearman correlation analysis. Subsequently, the regulation of gut microbiome by QAFF was validated by fecal microbiota transplantation (FMT).

Eleven flavonoids, including Naringin and hesperidin, were initially identified from QAFF. In vivo experiments demonstrated that QAFF effectively ameliorated colitis symptoms, reduced IL-6, IL-1β, and TNF-α levels, enhanced intestinal barrier integrity, and downregulated PI3K/AKT pathway activation. Furthermore, QAFF elevated the levels of beneficial bacteria like Lachnospiraceae_NK4A136_group and Alloprevotella and concurrently reduced the pathogenic bacteria such as Escherichia-Shigella, [Eubacterium]_siraeum_group, and Parabacteroides. Metabolomics analysis revealed that 34 endogenous metabolites exhibited significant alterations, predominantly associated with Glycerophospholipid metabolism. These metabolites were significantly correlated with those differential bacteria modulated by QAFF. Lastly, the administration of QAFF via FMT ameliorated the colitis symptoms.

QAFF could ameliorate inflammatory responses and intestinal barrier dysfunction in DSS-induced UC mice probably by modulating the PI3K/AKT signaling pathway and gut microbiome, offering promising evidence for the therapeutic potential of QAFF in UC treatment.

Dietary consumption of green asparagus has been associated with several health benefits. These beneficial properties are attributed to the presence of many bioactive compounds in asparagus, including saponins, phenolics, flavonoids, as well as dietary fiber mostly comprising fructans and inulins, which are prebiotics capable of supporting the growth of beneficial members of gut microbiota. In this study, we used the in vitro Human Gut Simulator system to assess the fermentation of oro-gastro-intestinally digested asparagus powder by the human gut microbiota. Microbial community composition differed between communities grown on the asparagus digest and on the Western diet derived medium. Asparagus supported beneficial Ruminococcus but also hydrogen sulfide producing members of Desulfovibrionaceae. Fermentation of asparagus released more antioxidants into the environment compared to the Western diet medium, and supernatant of asparagus-grown cultures protected cultured human epithelial cells against damage and inflammation. We thus showed that asparagus powder has potential to be used as a functional food, offering protection against intestinal damage and inflammation - effects mediated by the gut microbiota.

Inflammatory bowel disease (IBD) is a complex gastrointestinal disorder attributed to genetic and environmental factors. Microcystin-leucine-arginine (MC-LR) is an environmental toxin that accumulates in the gut and produces intestinal damage. The aim of this study was to investigate the effects of exposure to MC-LR on development and progression of IBD as well examine the underlying mechanisms of microcystin-initiated tissue damage. Male C57BL/6 mice were treated with either MC-LR alone or concurrently with dextran-sulfate sodium (DSS). Mice were divided into 4 groups (1): PBS gavage (control, CT) (2); 200 μg/kg MC-LR gavage (MC-LR) (3); 3% DSS Drinking Water (DSS); and (4) 3% DSS Drinking Water + 200 μg/kg MC-LR gavage (DSS + MC-LR). The mice in each experimental group exhibited reduced body weight, shortened colon length, increased disease activity index (DAI) score, a disrupted intestinal barrier, and elevated levels of proinflammatory cytokines compared to control. Compared to the group treated with MC-LR alone, colitis symptoms were exacerbated following combined exposure to both DSS and MC-LR. Subsequent experiments confirmed that MC-LR or DSS increased protein phosphorylation levels of Janus Kinase1 (JAK1) and Signal Transducer and Activator of Transcription3 (STAT3). Compared to group treated with MC-LR alone, the combined treatment of DSS and MC-LR also significantly upregulated the expression of related proteins. In conclusion, our study indicates that MC-LR-induced colitis involves activation of JAK1/STAT3 signaling pathway and that MC-LR exacerbates DSS-induced colitis through the same pathway.

Inflammatory Bowel Diseases (IDB) are chronic disorders characterized by gut inflammation, mucosal damage, increased epithelial permeability and altered mucus layer. No accurate in vitro model exists to simulate these characteristics. In this context, drug development for IBD or intestinal inflammation requires in vivo evaluations to verify treatments efficacy. A new model with altered mucus layer composition; altered epithelial permeability and pro-inflammatory crosstalk between immune and epithelial cells will be developed to enhance in vitro models for studying IBD treatments. The effects of dextran sulfate sodium and/or lipopolysaccharides on intestinal permeability, cytokines synthesis (IL-6, IL-8, TNF-α and IL-1β), mucins (MUC2, MUC5AC) and tight junction proteins expression (Claudin-1, ZO-1 and Occludin) were investigated in a tri-coculture model combining differentiated Caco-2/HT29-MTX cells and THP-1 cells. Two anti-inflammatory agents were evaluated to assess the model's therapeutic strategy applicability (corticoids and pro-resolving factors). Two in vitro models have been developed. The first model, characterized by increased permeability of the epithelial layer and subsequent secretion of inflammatory cytokines, can reproduce the different phases of inflammation, and enables the evaluation of preventive treatments. The second model simulates the acute phase of inflammation and allows for the assessment of curative treatments. Both models demonstrated reversibility when treated with betamethasone and pro-resolving factors. These in vitro models are valuable for selecting therapeutic agents prior to their application in in vivo models. They enable the assessment of agents' anti-inflammatory effects and their ability to permeate the inflamed epithelial layer and interact with immune cells.

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

Inflammatory bowel disease is a chronic condition characterized by inflammation of the gastrointestinal tract, resulting from an abnormal immune response to normal stimuli, such as food and intestinal flora. Since the etiology of this disease remains largely unknown, murine models induced by the consumption of dextran-sodium sulfate serve as a pivotal tool for studying colon inflammation. In this study, we employed both acute and chronic colitis mouse models induced by varying durations of dextran-sodium sulfate consumption to investigate the pathological and immunologic characteristics throughout the disease course. During the acute phase, activated innate inflammation marked by M1 macrophage infiltration was prominent. In contrast, the chronic phase was characterized by tissue remodeling, with a significant increase in M2 macrophages and lymphocytes. RNA-sequencing revealed genetic changes in acute and chronic colitis, marked by the maintenance of genomic integrity in the acute phase and extracellular matrix dynamics in the chronic phase. These phase-specific alterations reflect the multifaceted physiological processes involved in the initiation and progression of inflammation in the large intestine, underscoring the necessity for distinct experimental approaches for each phase. The findings demonstrate that the factors shaping the large intestinal immune microenvironment change specifically during the acute and chronic phases of experimental inflammatory bowel disease, highlighting the importance of developing therapeutic strategies that align with the disease course.

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.

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.

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.

Lonicerae japonicae flos (LJF), the dried flower bud or newly bloomed flower of Lonicera japonica Thunb., is widely used in Traditional Chinese medicine (TCM), exhibiting anti-inflammatory and immune-enhancing properties. Luteolin (Lut) is a major bioactive component of LJF, demonstrating a regulatory role in immune disorders. However, the specific role of Lut in regulating macrophage-mediated intestinal inflammation and its underlying molecular mechanisms have not yet been fully explored.

This study was designed to explore whether Lut alleviates Ulcerative colitis (UC) in mice and to elucidate its underlying mechanism in intestinal inflammation.

Mice were administered Dextran sodium sulfate (DSS) for 7 d to establish a UC model, followed by oral administration of Lut (12.5, 25, and 50 mg/kg body weight). RNA-sequencing (RNA-Seq) was used to screen signaling pathways. RAW264.7 cells were cultured and treated with Lut (6.25, 12.5, and 25 μM) and lipopolysaccharide (LPS, 1 μg/mL) for 24 h. To examine the role of the AMP-activated protein kinase (AMPK)/Peroxisome proliferator-activated receptor γ (PPARγ) signaling pathway, the cells were treated with compound C (an AMPK inhibitor) and GW9662 (a PPARγ antagonist).

Lut suppressed the inflammation of DSS-induced colitis in vivo, attenuated DSS-induced clinical man-ifestations, reversed colon length reduction, and reduced histological injury. Lut induced a shift in the macrophage phenotype from classical (M1) to alternative (M2) by suppressing M1 marker gene expression and enhancing M2 marker gene expression following DSS or LPS induction. RNA-seq revealed that PPARγ was involved in the regulation of macrophages by Lut. Furthermore, the polarization effect of Lut on macrophages was shown to be mediated through the AMPK-PPARγ signaling pathway.

These findings indicate that Lut effectively ameliorates UC in mice through the activation of the AMPK-PPARγ signaling pathway, leading to the inhibition of macrophage M1 polarization and promotion of M2 polarization. This study provides insight into future research on the utilization of Lut-rich TCM dietary supplements as a prophylactic treatment strategy in the prevention of UC.

Ulcerative colitis (UC) is a chronic and easily recurrent inflammatory bowel disease. The gut microbiota and plasma metabolites play pivotal roles in the development and progression of UC. Therefore, therapeutic strategies targeting the intestinal flora or plasma metabolites offer promising avenues for the treatment of UC. Luteolin (Lut), originating from a variety of vegetables and fruits, has attracted attention for its potent anti-inflammatory properties and potential to modulate intestinal flora.

The therapeutic efficacy of Lut was evaluated in an established dextran sodium sulfate (DSS)-induced colitis mice model. The clinical symptoms were analyzed, and biological samples were collected for microscopic examination and the evaluation of the epithelial barrier function, microbiome, and metabolomics.

The findings revealed that Lut administration at a dose of 25 mg/kg significantly ameliorated systemic UC symptoms in mice, effectively reduced the systemic inflammatory response, and significantly repaired colonic barrier function. Furthermore, Lut supplementation mitigated gut microbiota dysbiosis in a UC murine model, increasing the abundance of Muribaculaceae, Rikenella, and Prevotellaceae while decreasing Escherichia_Shigella and Bacteroides levels. These alterations in gut microbiota also influenced plasma metabolism, significantly increasing phosphatidylcholine (PC), 6'-Deamino- 6'-hydroxyneomycin C, and gamma-L-glutamyl-butyrosine B levels and decreasing Motapizone and Arachidoyl-Ethanolamide (AEA) levels.

This study reveals that Lut supplementation modulates intestinal inflammation by restoring the gut microbiota community structure, thereby altering the synthesis of inflammation-related metabolites. Lut is a potential nutritional supplement with anti-inflammatory properties and offers a novel alternative for UC intervention and mitigation. In addition, further studies are needed to ascertain whether specific microbial communities or metabolites can mediate the recovery from UC.

The incidence of ulcerative colitis (UC) is closely associated with dietary fiber (DF) intake. This study aims to evaluate the ameliorative effects of insoluble dietary fiber from adzuki bean seed coat (AIDF) on dextran sulfate sodium (DSS)-induced UC in mice, both with and without bound polyphenols (BPs). We employed a model based on the "remove/backfill" of components. Compared to dephenolized dietary fiber (AIDF-DF) and AIDF-DF with replaced BPs (AIDF-BP), AIDF was found to effectively reduce the splenic index, alleviate colonic histopathological damage, lower serum levels of inflammatory mediators (TNF-α, IL-1β, IFN-γ, IL-6), decrease activities of LPS, DAO, MPO, and iNOS, regulate intestinal tight junction (TJ) mRNA and protein expression, and restore the integrity of the colonic epithelial cell barrier. AIDF mitigated the inflammatory response in UC by inhibiting the TLR4/NF-κB inflammatory signaling pathway. It increased the abundance of beneficial gut microbiota (e.g., Akkermansia, Verrucomicrobiota) while reducing the abundance of harmful bacteria (e.g., Proteobacteria), thereby alleviating intestinal disturbances in DSS-induced colitis in mice. In conclusion, the presence of BPs in AIDF plays a critical role in attenuating DSS-induced UC in mice.

The potential for mitigating intestinal inflammation through the gut-bone axis in the treatment of osteoporosis is significant. While various gut-derived postbiotics or bacterial metabolites have been created as dietary supplements to prevent or reverse bone loss, their efficacy and safety still need improvement. Herein, a colon-targeted drug delivery system is developed using surface engineering of polyvinyl butyrate nanoparticles by shellac resin to achieve sustained release of postbiotics butyric acid at the colorectal site. These engineered postbiotics nanoparticles can effectively suppress macrophage inflammatory activation, modulate the redox balance, and regulate the composition of the gut microbiota, thereby restoring epithelial barriers, inhibiting bacterial invasion, and down-regulating pro-inflammatory responses. As a result, the remission of systemic inflammation is accompanied by a rebalancing of osteoblast and osteoclast activity, alleviating inflammatory bowel disease-related and post-menopausal bone loss. Specifically, the treatment of engineered postbiotics nanoparticles can also improve the quality and quantity of bone with restoration of deteriorative mechanical properties, which indicating a therapeutic potential on fracture prevention. This study provides valuable insights into the gut-bone axis and establishes a promising and safe therapeutic strategy for osteoporosis.

UC, also known as ulcerative colitis, is an inflammatory bowel disease that is chronic and nonspecific. Palmatine (PAL), a natural alkaloid active ingredient, has demonstrated predominant protective effects on UC. In spite of this, PAL on UC is unclear in terms of its underlying mechanisms. Thus, this study aimed to investigate its effects and mechanism. By inducing rats with 5 % dextran sulfate sodium (DSS), an in vivo model of UC was developed. and then oral PAL administration. In vitro viability of NCM460 cells was measured using Cell Counting Kit-8. An enzyme-linked immunosorbent assay was used to determine the levels of inflammatory factores. The levels of oxidative stress parameters were also assessed, and the expression level of cyclooxygenase-2 (COX-2), acyl-CoA synthetase long-chain family member 4 (ACSL4), glutathione peroxidase 4 (GPX4), NF-E2-related factor 2(Nrf2), phospho-Nrf2, and heme oxygenase-1 (HO-1) was detected by Western blot. An iron kit was employed to measure iron content in cells and colonic tissues. Results indicated that PAL treatment significantly improved UC in rats, as shown by reduced disease activity index scores and increased colon length, which decreased IL-18, IL-1β, IL-6, TNF-α, MDA, NO, and LDH levels, but increased GSH level in DSS-induced rats and NCM460 cells. Further, PAL treatment markedly decreased COX-2, ACSL4, Nrf2, and HO-1 expression levels while increasing that of GPX4 and phospho-Nrf2. Furthermore, PAL inhibited the iron overload in the cells and colonic tissues. PAL may protect against UC by inhibiting the inflammatory response, oxidative stress, iron load, and suppressing ferroptosis pathway.

Ulcerative colitis (UC) is closely associated with disruptions in gut microbiota. Restoring balance to gut microbiota and reducing intestinal inflammation has become a promising therapeutic approach for UC. However, challenges remain, including limited efficacy in some treatments. This study explores the synergistic effects and underlying mechanisms of Hizikia fusiforme polysaccharides (HFP) combined with fecal microbiota transplantation (FMT) to improve UC symptoms. Seven-week-old C57/BL6J mice were induced with UC using dextran sodium sulfate (DSS). Supplementation with either FMT alone or in combination with HFP effectively alleviated UC symptoms, reduced colonic inflammation, and corrected gut microbiota imbalance. Notably, HFP combined with FMT yielded showed better effects in ameliorating DSS-induced UC in mice than did FMT alone. Enrichment of probiotics, such as Bifidobacterium, and upregulation of beneficial metabolites, such as betaine, were identified as potential mechanisms for the enhanced effects of HFP combined with FMT against DSS-induced UC. These findings suggest that the combination of Hizikia fusiforme polysaccharides with FMT has potential applications in rectifying dysbiosis and ameliorating inflammatory bowel diseases.

In this study, a dextran sodium sulfate-induced ulcerative colitis model in C57BL/6 mice was used to explore the effect of acceptable daily intake (ADI) of aspartame on inflammation in colonic tissues. The effects of aspartame on the inflammatory state of the colon in mice were comprehensively evaluated by comparing the body weight, colon length/colon length index, splenic index, disease activity index (DAI) score, histological activity index (HAI) score, the expression levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, claudin-3, and occludin, the infiltration characteristics of macrophage and neutrophil and the composition of the gut microbiota in the control group, aspartame group, ulcerative colitis model group, and aspartame + ulcerative colitis group. We demonstrated that, in a mouse model of dextran sulfate-induced ulcerative colitis, ADI of aspartame caused a significant decrease in body weight, colon length/colon length index, DAI scores, and expression levels of the proteins claudin-3 and occludin. Moreover, ADI of aspartame caused an increase in the splenic index, HAI scores, the levels of proinflammatory factors TNF-α, IL-1β, and IL-6 both in intestinal tissue and serum and infiltration of macrophages and neutrophils in colon tissues. These results showed that ADI of aspartame promoted intestinal pathology and systemic inflammation in a mouse model of colitis.

This study explored Panduratin A's protective effects against DSS-induced colitis in mice, focusing on reducing inflammation and oxidative stress in the colon.

Mice were treated with dextran sodium sulfate (DSS) and Panduratin A (3, 6, 18 mg/kg), and changes in body weight, colon length, Disease Activity Index (DAI), histopathology, inflammation markers including tumor necrosis factor- α (TNF-α), Interleukin-1 β (IL-1β), Myeloperoxidase (MPO), and oxidative stress, Malondialdehyde (MDA) were evaluated.

Panduratin A significantly reversed DSS-induced symptoms, including body weight loss, colonic length shortening, and DAI increase, while reducing histopathological damage. It lowered inflammatory markers and oxidative stress, suppressed NF-κB activation, and enhanced Nrf2 and HO-1 expression.

Panduratin A shows promise as a colitis treatment, warranting further research for broader clinical application.

Fusobacterium nucleatum (F. nucleatum), an anaerobic resident of the oral cavity, is increasingly recognized as a contributing factor to ulcerative colitis (UC). The adhesive properties of F. nucleatum are mediated by its key virulence protein, FadA adhesin. However, further investigations are needed to understand the pathogenic mechanisms of this oral pathogen in UC. The present study aimed to explore the role of the FadA adhesin in the colonization and invasion of oral F. nucleatum in dextran sulphate sodium (DSS)-induced colitis mice via molecular techniques. In this study, we found that oral inoculation of F. nucleatum strain carrying the FadA adhesin further exacerbated DSS-induced colitis, leading to elevated alveolar bone loss, disease severity, and mortality. Additionally, CDH1 gene knockout mice treated with DSS presented increases in body weight and alveolar bone density, as well as a reduction in disease severity. Furthermore, FadA adhesin adhered to its mucosal receptor E-cadherin, leading to the phosphorylation of β-catenin and the degradation of IκBα, the activation of the NF-κB signalling pathway and the upregulation of downstream cytokines. In conclusion, this research revealed that oral inoculation with F. nucleatum facilitates experimental colitis via the secretion of the virulence adhesin FadA. Targeting the oral pathogen F. nucleatum and its virulence factor FadA may represent a promising therapeutic approach for a portion of UC patients.

Resatorvid (TAK-242), a specific inhibitor of Toll-like receptor-4 (TLR4), has attracted attention for its anti-inflammatory properties. Despite this, few studies have evaluated its effects on ulcerative colitis (UC). This study aimed to investigate the effects of TAK-242 on macrophage polarization and T helper cell balance and the mechanism by which it alleviates UC. Our findings indicated that TLR4 expression was elevated in patients with UC, a mouse model of UC, and HT29 cells undergoing an inflammatory response. TAK‑242 treatment reduced apoptosis in TNF-α and LPS-stimulated HT29 cells and alleviated symptoms of dextran sulfate sodium (DSS)‑induced colitis in vivo. TAK‑242 downregulated TLR4 expression and decreased the secretion of pro-inflammatory cytokines TNF-α, IL-6, and IL-1β while enhancing IL-10 production. TAK-242 also reduced M1 macrophage polarization and diminished Th1 and Th17 cell infiltration while increasing Th2 cell infiltration and M2 macrophage polarization both in vitro and in vivo. Mechanistically, TAK-242 inhibited the JAK2/STAT3 signaling pathway, an important regulator of macrophage polarization and T helper cell balance. Furthermore, the in vivo and in vitro effects of TAK-242 were partially negated by the administration of the JAK2/STAT3 antagonist AG490, suggesting that TAK-242 inhibits the JAK2/STAT3 pathway to exert its biological activities. Taken together, this study underscores TAK-242 as a promising anti-UC agent, functioning by modulating macrophage polarization and T helper cell balance via the TLR4/JAK2/STAT3 signaling pathway.

Fibrosis characterized by intestinal strictures is a common complication of Crohn's disease (CD), without specific antifibrotic drugs, which usually relies on surgical intervention. The transcription factor XBP1, a key component of endoplasmic reticulum (ER) stress, is required for degranulation of mast cells and linked to PAR2 activation and fibrosis. Many studies have confirmed that naringin (NAR) can inhibit ER stress and reduce organ fibrosis. We hypothesized that ER stress activated the PAR2-induced epithelial-mesenchymal transition process by stimulating mast cell degranulation to release tryptase and led to intestinal fibrosis in CD patients; NAR might play an antifibrotic role by inhibiting ER stress-induced PAR2 activation. We report that the expression levels of XBP1, mast cell tryptase, and PAR2 are upregulated in fibrotic strictures of CD patients. Molecular docking simulates the interaction of NAR and spliced XBP1. ER stress stimulates degranulation of mast cells to secrete tryptase, activates PAR2-induced epithelial-mesenchymal transition process, and promotes intestinal fibrosis in vitro and vivo experiments, which is inhibited by NAR. Moreover, F2rl1 (the coding gene of PAR2) deletion in intestinal epithelial cells decreases the antifibrotic effect of NAR. Hence, the ER stress-mast cell tryptase-PAR2 axis can promote intestinal fibrosis, and NAR administration can alleviate intestinal fibrosis by inhibiting ER stress-induced PAR2 activation.

Ulcerative colitis has been associated with psychological distress and an aberrant immune response. The immunomodulatory role of systemic cytokines produced during experimental intestinal inflammation in tonic immobility (TI) defensive behavior remains unknown. The present study characterized the TI defensive behavior of guinea pigs subjected to colitis induction at the acute stage and after recovery from intestinal mucosa injury. Moreover, we investigated whether inflammatory mediators (tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-8, IL-10, and prostaglandins) act on the mesencephalic nucleus, periaqueductal gray matter (PAG). Colitis was induced in guinea pigs by intrarectal administration of acetic acid. The TI defensive behavior, histology, cytokine production, and expression of c-FOS, IBA-1, and cyclooxygenase (COX)-2 in PAG were evaluated. Colitis reduced the duration of TI episodes from the first day, persisting throughout the 7-day experimental period. Neuronal c-FOS immunoreactivity was augmented in both columns of the PAG (ventrolateral (vlPAG) and dorsal), but there were no changes in IBA-1 expression. Dexamethasone, infliximab, and parecoxib treatments increased the duration of TI episodes, suggesting a modulatory role of peripheral inflammatory mediators in this behavior. Immunoneutralization of TNF-α, IL-1β, and IL-8 in the vlPAG reversed all effects produced by colitis. In contrast, IL-10 neutralization further reduced the duration of TI episodes. Our results reveal that peripherally produced inflammatory mediators during colitis may modulate neuronal functioning in mesencephalic structures such as vlPAG.

Mammalian milk exosomal miRNAs play an important role in maintaining intestinal immune homeostasis and protecting epithelial barrier function, but the specific miRNAs and whether miRNA-mediated mechanisms are responsible for these benefits remain a matter of investigation. This study isolated sheep milk-derived exosomes (sheep MDEs), identifying the enriched miRNAs in sheep MDEs, oar-miR-148a, and oar-let-7b as key components targeting TLR4 and TRAF1, which was validated by a dual-luciferase reporter assay. In dextran sulfate sodium-induced colitis mice, administration of sheep MDEs alleviated colitis symptoms, reduced colonic inflammation, and systemic oxidative stress, as well as significantly increased colonic oar-miR-148a and oar-let-7b while reducing toll-like receptor 4 (TLR4) and TNF-receptor-associated factor 1 (TRAF1) level. Further characterization in TNF-α-challenged Caco-2 cells showed that overexpression of these miRNAs suppressed the TLR4/TRAF1-IκBα-p65 pathway and reduced IL-6 and IL-12 production. These findings indicate that sheep MDEs exert gastrointestinal anti-inflammatory effects through the miRNA-mediated modulation of TLR4 and TRAF1, highlighting their potential in managing colitis.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD) marked by persistent inflammation of the mucosal lining of the large intestine, leading to debilitating symptoms and reduced quality of life. Emerging evidence suggests that an imbalance of the gut microbiota plays a crucial role in UC pathogenesis, and various signaling pathways are implicated in the dysregulated immune response. Probiotics are live microorganisms that confer health benefits to the host, have attracted significant attention for their potential to restore gut microbial balance and ameliorate inflammation in UC. Recent studies have elucidated the mechanisms by which probiotics modulate these signaling pathways, often by producing anti-inflammatory molecules and promoting regulatory immune cell function. For example, probiotics can inhibit the nuclear factor-κB (NF-κB) pathway by stabilizing Inhibitor of kappa B alpha (IκBα), dampening the production of proinflammatory cytokines. Similarly, probiotics can modulate the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway, suppressing the activation of STAT1 and STAT3 and thus reducing the inflammatory response. A better understanding of the underlying mechanisms of probiotics in modulating pathogenic signaling pathways in UC will pave the way for developing more effective probiotic-based therapies. In this review, we explore the mechanistic role of probiotics in the attenuation of pathogenic signaling pathways, including NF-κB, JAK/STAT, mitogen-activated protein kinases (MAPKs), Wnt/β-catenin, the nucleotide-binding domain (NOD)-, leucine-rich repeat (LRR)- and pyrin domain-containing protein 3 (NLRP3) inflammasome, Toll-like receptors (TLRs), interleukin-23 (IL-23)/IL-17 signaling pathway in UC.

Immune mediators affect multiple biological functions of intestinal epithelial cells (IECs) and, like Paneth and Paneth-like cells, play an important role in intestinal epithelial homeostasis. IFN-γ a prototypical proinflammatory cytokine disrupts intestinal epithelial homeostasis. However, the mechanism underlying the process remains unknown. In this study, using in vivo and in vitro models we demonstrate that IFN-γ is spontaneously secreted in the small intestine. Furthermore, we observed that this cytokine stimulates mitochondrial activity, ROS production, and Paneth and Paneth-like cell secretion. Paneth and Paneth-like secretion downstream of IFN-γ, as identified here, is mTORC1 and necroptosis-dependent. Thus, our findings revealed that the pleiotropic function of IFN-γ also includes the regulation of Paneth cell function in the homeostatic gut.

The perineuronal net (PNN) is a well-described highly specialized extracellular matrix structure found in the central nervous system. Thus far, no reports of its presence or connection to pathological processes have been described in the peripheral nervous system. Our study demonstrates the presence of a PNN in the spinal afferent innervation of the distal colon of mice and characterizes structural and morphological alterations induced in an ulcerative colitis (UC) model. C57Bl/6 mice were given 3% dextran sulfate sodium (DSS) to induce acute or chronic UC. L6/S1 dorsal root ganglia (DRG) were collected. PNNs were labeled using fluorescein-conjugated Wisteria Floribunda (WFA) l lectin, and calcitonin gene-related peptide (CGRP) immunofluorescence was used to detect DRG neurons. Most DRG cell bodies and their extensions toward peripheral nerves were found surrounded by the PNN-like structure (WFA+), labeling neurons' cytoplasm and the pericellular surfaces. The amount of WFA+ neuronal cell bodies was increased in both acute and chronic UC, and the PNN-like structure around cell bodies was thicker in UC groups. In conclusion, a PNN-like structure around DRG neuronal cell bodies was described and found modulated by UC, as changes in quantity, morphology, and expression profile of the PNN were detected, suggesting a potential role in sensory neuron peripheral sensitization, possibly modulating the pain profile of ulcerative colitis.