Regulatory T cells (Tregs) have a key role in the maintenance of immune tolerance and in the prevention of autoimmunity. Recent studies have shown an association between decreased Treg frequency and a deficient suppressive activity with the development of many autoimmune diseases. Although glycosylation, which consists in the addition of glycans to proteins and lipids on the cell surface, is recognized as a critical modification for T cell development and function, the relevance of glycans in Treg biology and activity, as well as their impact in the immunopathogenesis of autoimmune diseases, deserves more attention, as it is far from being fully understood. This review discusses the biological impact of N-glycans in Treg biology, highlighting their potential to uncover novel pathogenic mechanisms in autoimmunity and new targets for promising therapeutic approaches with clinical applications in autoimmune disease patients.

The liver is the human body's largest digestive gland, which can participate in digestion, metabolism, excretion, detoxification and immunity. Chronic liver diseases such as metabolic dysfunction-associated fatty liver disease (MAFLD) or viral hepatitis involve ongoing inflammation and resulting liver fibrosis may ultimately lead to the development of hepatobiliary cancers (HCC). Inflammation is the coordinated reaction of different liver cell types to cell signals and death of inflammation, which are linked to injury pathways within the liver or external agents from the gut-liver axis and the circulation. Regulatory T (Treg) cells play a crucial role in controlling inflammation and are essential for maintaining immune tolerance and balance. In this review, we highlight the recent discoveries related to the function of immune systems in liver inflammation and discuss the role of Treg cells in the different liver diseases (including MAFLD, autoimmune hepatitis and others).

Inflammatory bowel diseases (IBD), including ulcerative colitis and Crohn's disease, arise from various factors such as dietary, genetic, immunological, and microbiological influences. The gut microbiota plays a crucial role in the development and treatment of IBD, though the exact mechanisms remain uncertain. Current research has yet to definitively establish the beneficial effects of the microbiome on IBD. Bacteria and viruses (both prokaryotic and eukaryotic) are key components of the microbiome uniquely related to IBD. Numerous studies suggest that dysbiosis of the microbiota, including bacteria, viruses, and bacteriophages, contributes to IBD pathogenesis. Conversely, some research indicates that bacteria and bacteriophages may positively impact IBD outcomes. Additionally, plant metabolites play a crucial role in alleviating IBD due to their anti-inflammatory and microbiome-modulating properties. This systematic review discusses the role of the microbiome in IBD pathogenesis and evaluates the potential connection between plant metabolites and the microbiome in the context of IBD pathophysiology.

Genome wide association studies (GWAS) identify many risks for Crohn's disease (CD), including a site near the metabolism gene laccase domain containing 1 (LACC1). We previously found this site near LACC1 was associated with decreased LACC1 expression in T lymphocytes, yet the mechanism affecting gene expression and its links to T cell function and inflammatory disease were unknown. Here we identify variants in the promoter region that influence transcription of LACC1. Direct association of disease-risk variants with lower LACC1 pre-mRNA in human CD4+ T cells is confirmed by comparing transcripts from each allele from donors heterozygous for the LACC1 CD-risk allele. Using gene editing, we validate the function of this promoter region in LACC1 expression in T cells. Human CD4+ T cells with LACC1 gene knockdown show altered metabolism, including reduced oxygen consumption rate, and reduced in vitro regulatory T cell differentiation. Therefore, our study provides a mechanism linking these specific LACC1 variants to colitis by attributing promoter region variants to changes in T cell metabolism and function.

Inflammatory bowel diseases (IBDs), encompassing Crohn's disease and ulcerative colitis, are complex chronic disorders characterized by an intricate interplay between genetic predisposition, immune dysregulation, gut microbiota alterations, and environmental exposures. This review aims to synthesize recent advances in IBD pathogenesis, exploring key mechanisms and potential avenues for prevention and personalized therapy. A comprehensive literature search was conducted across major bibliographic databases, selecting the most recent and impactful studies on IBD pathogenesis. The review integrates findings from multi-omics analyses, single-cell transcriptomics, and longitudinal cohort studies, focusing on immune regulation, gut microbiota dynamics, and environmental factors influencing disease onset and progression. Immune dysregulation, including macrophage polarization (M1 vs. M2) and Th17 activation, emerges as a cornerstone of IBD pathogenesis. Dysbiosis, as a result of reduced alpha and beta diversity and overgrowth of harmful taxa, is one of the main contributing factors in causing inflammation in IBD. Environmental factors, including air and water pollutants, maternal smoking, and antibiotic exposure during pregnancy and infancy, significantly modulate IBD risk through epigenetic and microbiota-mediated mechanisms. While recent advances have supported the development of new therapeutic strategies, deeply understanding the complex dynamics of IBD pathogenesis remains challenging. Future efforts should aim to reduce the burden of disease with precise, personalized treatments and lower the incidence of IBD through early-life prevention and targeted interventions addressing modifiable risk factors.

Inflammatory bowel diseases (IBD) are chronic relapsing disorders with increasing prevalence. Knowledge gaps still limit the possibility to develop more specific and effective therapies. Using a dextran sodium sulfate colitis mouse model, we found that inflammation increased the total number and altered the frequencies of leukocytes within colon mesenteric lymph nodes (cMLNs). Although the inflammation reduced the frequency of regulatory T (Treg) cells, their absolute numbers were increased. Increased frequency of colitogenic Th17 cells was also observed. Noteworthy, untreated mice lacking Poly(ADP-ribose)-Polimerase-1 functional gene (PARP-1KO) displayed higher frequency of Treg cells and lower percentage of Th17 cells in cMLNs. In colitic PARP-1KO mice the inflammation driven expansion of the Foxp3 Treg population was more pronounced than in WT mice. Conversely, colitis increased Th17 cells to a lower extent in PARP-1KO mice compared with WT mice, resulting in a more protective Treg/Th17 cell ratio. Consequently PARP-1KO mice developed less severe colitis with reduced expression of inflammatory cytokines. In ex vivo experiments PARP-1KO and WT CD11c dendritic cells (DCs) promoted naïve CD4 T cell differentiation differently, the former sustaining more efficiently the generation of Treg cells, the latter that of Th17 cells. Addition of HMGB1 B box or of dipotassium glycyrrhizate, which sequesters extracellular HMGB1, revealed a role for this alarmin in the regulation exerted by PARP-1 on the stimulating vs. tolerogenic function of DCs during colitis. Moreover, a higher percentage of CD11c DC from PARP-1KO mice expressed CD103, a marker associated with the ability of DC to induce Treg cells, compared with WT DC. Conversely, PARP-1KO DC were including a reduced percentage of CX3CR1+ DC, described to induce Th17 cells. These findings were observed in both splenic and colon lamina propria DC.

Our previous study found that early weaning is associated with decreased growth performance, intestinal barrier impairment, and an imbalance in Th17/Treg in pigeon squabs. Chitosan oligosaccharides (COS) has been substantiated to regulate gut microbiota and restore Th17/Treg equilibrium in mammals, thereby ameliorating growth performance. However, the potential effects of COS in altricial birds remain unclear. Three hundred healthy 7-day-old American king pigeon squabs were selected with similar body weights and randomly divided into 5 groups. The 5 treatment groups were as follows: the control group (CON), fed with artificial pigeon milk; 4 supplementation groups, fed with artificial pigeon milk +100 (COS1), 150 (COS2), 200 (COS3), and 250 (COS4) mg/kg COS, respectively. Results showed that dietary supplementation of COS significantly enhanced the growth performance of weaned squabs. Compared to the CON group, the COS groups exhibited increased villus length and villus area in the jejunum and ileum, accompanied by improvements in morphological structure and mucosal permeability. COS was found to reduce the levels of Th17-associated cytokines and increase the levels of Treg-associated cytokines. COS downregulated the expression of retinoic acid receptor-related orphan receptor C (RORC), a key transcription factor of Th17 cells, while upregulated the expression of Forkhead box protein P3 (FOXP3), a key transcription factor of Treg cells. Dietary COS supplementation increased gut bacterial diversity, altered the relative abundance of several bacteria taxa and enhanced the concentration of short-chain fatty acids (SCFA). Correlation analysis demonstrated a close association between gut microbiota, SCFAs, and indicators related to the Th17/Treg balance. Moreover, we found that SCFAs correlated more strongly with Th17/Treg-related indexes than gut microbiota. These results demonstrated that COS could relieve early weaning stress in pigeon squabs and the optimal dosage of dietary COS supplementation was suggested to be 200 mg/kg. In addition, COS had a protective effect on maintaining intestinal immune balance by modulating microbiota and Th17/Treg related signaling pathways, in which SCFAs might play a crucial role as messengers.

Regulatory T (Treg) cells play a critical regulatory role in the immune system by suppressing excessive immune responses and maintaining immune balance. The effective migration of Treg cells is crucial for controlling the development and progression of inflammatory diseases. However, the mechanisms responsible for directing Treg cells into the inflammatory tissue remain incompletely elucidated. In this study, we identified BAF60b, a subunit of switch/sucrose nonfermentable (SWI/SNF) chromatin remodeling complexes, as a positive regulator of Treg cell migration that inhibits the progression of inflammation in experimental autoimmune encephalomyelitis (EAE) and colitis animal models. Mechanistically, transcriptome and genome-wide chromatin-landscaped analyses demonstrated that BAF60b interacts with the transcription factor RUNX1 to promote the expression of CCR9 on Treg cells, which in turn affects their ability to migrate to inflammatory tissues. Our work provides insights into the essential role of BAF60b in regulating Treg cell migration and its impact on inflammatory diseases.

T-cell immunoglobulin domain and mucin domain-3 (Tim-3) is a versatile immunomodulator that protects against intestinal inflammation. Necroptosis is a type of cell death that regulates intestinal homeostasis and inflammation. The mechanism(s) underlying the protective role of macrophage Tim-3 in intestinal inflammation is unclear; thus, we investigated whether specific Tim-3 knockdown in macrophages drives intestinal inflammation via necroptosis. Tim-3 protein and mRNA expression were assessed via double immunofluorescence staining and single-cell RNA sequencing (sc-RNA seq), respectively, in the colonic tissues of patients with inflammatory bowel disease (IBD) and healthy controls. Macrophage-specific Tim3-knockout (Tim-3M-KO) mice were generated to explore the function and mechanism of Tim-3 in dextran sodium sulfate (DSS)-induced colitis. Necroptosis was blocked by pharmacological inhibitors of receptor-interacting protein kinase (RIP)1, RIP3, and reactive oxygen species (ROS). Additionally, in vitro experiments were performed to assess the mechanisms of neutrophil necroptosis induced by Tim-3 knockdown macrophages. Although Tim-3 is relatively inactive in macrophages during colon homeostasis, it is highly active during colitis. Compared to those in controls, Tim-3M-KO mice showed increased susceptibility to colitis, higher colitis scores, and increased pro-inflammatory mediator expression. Following the administration of RIP1/RIP3 or ROS inhibitors, a significant reduction in intestinal inflammation symptoms was observed in DSS-treated Tim-3M-KO mice. Further analysis indicated the TLR4/NF-κB pathway in Tim-3 knockdown macrophages mediates the TNF-α-induced necroptosis pathway in neutrophils. Macrophage Tim-3 regulates neutrophil necroptosis via intracellular ROS signaling. Tim-3 knockdown macrophages can recruit neutrophils and induce neutrophil necroptosis, thereby damaging the intestinal mucosal barrier and triggering a vicious cycle in the development of colitis. Our results demonstrate a protective role of macrophage Tim-3 in maintaining gut homeostasis by inhibiting neutrophil necroptosis and provide novel insights into the pathogenesis of IBD.

Intestinal microecology is a dominant and complex microecological system in human body. Generally, intestinal microecosystem consists of normal symbiotic flora and its living environment (including intestinal epithelial tissue and intestinal mucosal immune system). Commensal flora is the core component of microecology. Both structures of intestinal mucosa and functions of immune system are essential to maintain homeostasis of intestinal microecosystem. Under normal conditions, intestinal microorganisms and intestinal mucosa coordinate with each other to promote host immunity. When certain factors in the intestine are altered, such as disruption of the intestinal barrier causing dysbiosis of the intestinal flora, the immune system of the host intestinal mucosa makes a series of responses, which leads to the development of intestinal inflammation and promotes colorectal cancer. In this review, to further understand the relationship between intestinal microecology and intestinal diseases, we systematically elaborate the composition of the intestinal mucosal immune system, analyze the relationship between intestinal flora and mucosal immune system, and the role of intestinal flora on intestinal inflammatory diseases and colorectal cancer.

Inflammatory bowel disease (IBD) is a term encompassing a few chronic inflammatory disorders that leads to damage of the intestinal tract. Although much progress has been made in understanding the pathology of IBD, the precise pathogenesis is not completely understood. Circular RNAs (circRNAs) are single-stranded, covalently closed, endogenous molecules in eukaryotes with a variety of biological functions. CircRNAs have been shown to have regulatory effects in many diseases, such as cancer, cardiovascular disease, and neurological disorders. CircRNAs have also been found to play important roles in IBD, and although they are not sufficiently investigated in the context of IBD, a few circRNAs have been identified as potential biomarkers for the diagnosis and prognosis of IBD and as potential therapeutic targets for IBD. Herein, we survey recent progress in understanding the functions and roles of circRNAs in IBD and discuss their potential clinical applications.

Mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) have garnered extensive interest for their immunomodulatory properties in immune-mediated inflammatory diseases. However, the development of EVs as clinical drugs often faces challenges such as low production yield and suboptimal therapeutic efficacy. In this study, we discovered that thermally engineering was able to enhance the yield of MSC-EVs. Moreover, the PD-L1 expression of EVs released from the thermal engineering MSCs was found to be upregulated significantly, and these EVs ameliorated the symptoms and pathological damages in murine dextran sulfate sodium (DSS)-induced colitis model. The therapeutic effect on DSS-induced colitis was mediated through the regulation of the Th17/Treg cell balance, demonstrating the immunomodulatory properties of the thermally engineering MSC-EVs. Overall, our findings suggest that thermal engineering can be utilized as a promising strategy for enhancing EV production and may provide a potential therapeutic approach for clinical treatment of colitis.

Tissue-resident memory T (TRM) cells are a recently discovered subpopulation of memory T cells that reside in non-lymphoid tissues such as the intestine and skin and do not enter the bloodstream. The intestine encounters numerous pathogens daily. Intestinal mucosal immunity requires a balance between immune responses to pathogens and tolerance to food antigens and symbiotic microbiota. Therefore, intestinal TRM cells exhibit unique characteristics. In healthy intestines, TRM cells induce necessary inflammation to strengthen the intestinal barrier and inhibit bacterial translocation. During intestinal infections, TRM cells rapidly eliminate pathogens by proliferating, releasing cytokines, and recruiting other immune cells. Moreover, certain TRM cell subsets may have regulatory functions. The involvement of TRM cells in inflammatory bowel disease (IBD) is increasingly recognized as a critical factor. In IBD, the number of pro-inflammatory TRM cells increases, whereas the number of regulatory subgroups decreases. Additionally, the classic markers, CD69 and CD103, are not ideal for intestinal TRM cells. Here, we review the phenotype, development, maintenance, and function of intestinal TRM cells, as well as the latest findings in the context of IBD. Further understanding of the function of intestinal TRM cells and distinguishing their subgroups is crucial for developing therapeutic strategies to target these cells.

Echinacea purpurea is popularly used as a food supplement or nutritional supplement for its immune regulatory function against various threats. As one of its promising components, Echinacea purpurea (L.) Moench polysaccharide (EPP) has a wide range of biological activities. To evaluate the effect of EPP as a dietary supplement on ulcerative colitis (UC), this study used sodium dextran sulfate (DSS) to induce a UC model, extracted EPP using the ethanol subsiding method, and then supplemented with EPP by gavage for 7 days. Then, we evaluated the efficacy of EPP on DSS rats in terms of immunity, anti-inflammation, and intestinal flora. The result showed that EPP could alleviate colonic shortening and intestinal injury in rats with DSS-induced colitis, decrease the disease activity index (DAI) score, downregulate serum levels of inflammatory cytokines, and contribute to the restoration of the balance between the T helper cells 17 (Th17) and the regulatory T cells (Treg) in the spleen and mesenteric lymph nodes (MLNs). Meanwhile, EPP could downregulate the expression of Toll-like receptors 4 (TLR4), myeloid differentiation factor 88 (MyD88), and nuclear factor kappa-B (NF-κB) in colon tissue. In addition, the results of 16SrRNA sequencing showed that EPP also had a regulatory effect on intestinal flora of UC rats. These results indicate that EPP might achieve a beneficial effect on UC rats as a dietary supplement through restoring Th17/Treg balance, inhibiting the TLR4 signaling pathway and regulating intestinal flora, suggesting its possible application as a potential functional food ingredient alleviating UC.

Inflammatory bowel disease (IBD) is a significant global health concern that can lead to depression in affected patients. Liquiritin apioside (LA) possesses anti-oxidative and anti-inflammatory properties. However, its anti-inflammatory mechanism in IBD has not been extensively studied.

This study elucidates the pivotal role of LA in alleviating inflammation by regulating gut metabiota-derived metabolites and evaluating its regulative effects on promoting a balance of Th17/Treg cells in colitis mice.

To evaluate the effect of LA on IBD,16S rRNA gene sequencing and UPLC-QTOF-MS analysis were used to identify the changes of intestinal bacteria and their metabolites. Cytokines levels were determined by ELISA and qPCR, while immune cell ratios were evaluated via flow cytometry.

Our findings revealed that LA treatment ameliorated general states of DSS-induced colitis mice and their accompanying depressive behaviors. Moreover, LA restricted the expression of pro-inflammatory cytokines and revised the imbalanced Treg/Th17 differentiation, while promoting SCFAs production in inflamed colon tissues. Fecal microbiota transplantation from LA-fed mice also corrected the imbalanced Treg/Th17 differentiation, indicating that LA-mediated restoration of the colonic Treg/Th17 balance mainly depends on the changes in gut metabolites.

These results provide scientific evidence explaining the apparent paradox of low bioavailability and high bioactivity in polyphenols, and suggesting that LA could be used as a potential dietary supplement for the prevention and improvement of IBD.

Inflammatory Bowel Disease (IBD) is characterized by prolonged inflammation of the gastrointestinal tract, which is thought to occur due to dysregulation of the immune system allowing the host's cells to attack the GI tract and cause chronic inflammation. IBD can be caused by numerous factors such as genetics, gut microbiota, and environmental influences. In recent years, emphasis on commensal bacteria as a critical player in IBD has been at the forefront of new research. Each individual harbors a unique bacterial community that is influenced by diet, environment, and sanitary conditions. Importantly, it has been shown that there is a complex relationship among the microbiome, activation of the immune system, and autoimmune disorders. Studies have shown that not only does the microbiome possess pathogenic roles in the progression of IBD, but it can also play a protective role in mediating tissue damage. Therefore, to improve current IBD treatments, understanding not only the role of harmful bacteria but also the beneficial bacteria could lead to attractive new drug targets. Due to the considerable diversity of the microbiome, it has been challenging to characterize how particular microorganisms interact with the host and other microbiota. Fortunately, with the emergence of next-generation sequencing and the increased prevalence of germ-free animal models there has been significant advancement in microbiome studies. By utilizing human IBD studies and IBD mouse models focused on intraepithelial lymphocytes and innate lymphoid cells, this review will explore the multifaceted roles the microbiota plays in influencing the immune system in IBD.

Crohn's disease (CD) is an inflammatory bowel disease that can affect any part of the intestine. There is currently no recognized cure for CD because its cause is unknown. One of the modern approaches that have been suggested for the treatment of CD and other inflammatory-based disorders is cell therapy.

Search terms were stem cell therapy, CD, adipose-derived stem cells, mesenchymal stem cells, and fistula. Of 302 related studies, we removed duplicate and irrelevant papers and identified the ones with proper information related to our scope of the research by reviewing all the abstracts and categorizing each study into the proper section.

Nowadays, stem cell therapy is widely implied in treating CD. Although mesenchymal and adipose-derived tissue stem cells proved to be safe in treating Crohn's-associated fistula, there are still debates on an optimal protocol to use. Additionally, there is still a lack of evidence on the efficacy of stem cell therapy for intestinal involvement of CD. Future investigations should focus on preparing a standard protocol as well as luminal stem cell therapy in patients.

Regulatory T cells (Tregs) play an important immunosuppressive role in inflammatory bowel disease (IBD). However, findings on the quantitative and functional changes of intestinal and circulating Tregs in patients with IBD are rather contradictory. We therefore conducted a meta-analysis on this issue. The pooled effect was assessed using the standardized mean difference (SMD) with a 95% confidence interval (CI), and subgroup analyses were performed to investigate heterogeneity. This analysis included 764 IBD (402 UC and 362 CD) patients and 341 healthy controls (HCs) pooled from 17 eligible studies. The percentage of circulating Tregs was significantly decreased in active IBD patients compared to HCs (SMD = -0.95, p < 0.001) and inactive IBD patients (SMD = -0.80, p < 0.001). There was no difference in the percentage of circulating Tregs between inactive IBD patients and HCs. The suppressive function of circulating Tregs was impaired in active IBD patients according to limited data (SMD = -0.75, p = 0.02). Besides, the percentage of intestinal Tregs was significantly higher in inflamed regions than in non-inflamed regions (SMD = 0.85, p < 0.001). Our study quantitatively summarized the quantitative and functional changes of Tregs and supported the therapeutic potential of Tregs in IBD. Moreover, additional research into the functions and characteristics of intestinal Tregs in IBD is needed.

Rheumatoid arthritis (RA) is a common autoimmune disorder initiated by inflammatory synovitis. Hyperproliferation of destructive synovial fibroblasts (SFs) is one of the pathogenic mechanisms of RA. Abnormalities in regulatory T cells (Tregs) may also play a critical role in this progression. To date, it is unclear whether both natural Tregs (nTregs) and induced Tregs (iTregs) share similar characteristics in RA progression and whether Tregs directly suppress the autoaggressive activities of SFs. In this study, we compared suppressive effects on effector T cells (Teffs) and inflamed SFs between nTregs and iTregs in a collagen-induced arthritis (CIA) model. Our results demonstrated that iTregs but not nTregs maintained a suppressive effect on Teffs after adoptive transfer into CIA mice. Additionally, we discovered that iTregs directly inhibited the destructive activities of CIA-SFs. Thus, this study suggests that administration of the iTreg subset has great potential for treatment of RA in the clinic in the future.

Hypoxia is a feature of inflammatory conditions [e.g., inflammatory bowel disease (IBD)] and can exacerbate tissue damage in these diseases. To counteract hypoxia's deleterious effects, adaptive responses have evolved which protect against hypoxia-associated tissue injury. To date, much attention has focused on hypoxia-activated HIF (hypoxia-inducible factor) transcription factors in these responses. However, recent work has identified epigenetic regulators that are also oxygen-sensitive, but their role in adaptation to hypoxic inflammation is currently unclear. Here, we show that the oxygen-sensing epigenetic regulator UTX is a critical modulator of colitis severity. Unlike HIF transcription factors that act on gut epithelial cells, UTX functions in colitis through its effects on immune cells. Hypoxia results in decreased CD4 + T cell IFN-γ production and increased CD4 + regulatory T cells, and these findings are recapitulated by T cell-specific UTX deficiency. Hypoxia impairs the histone demethylase activity of UTX, and loss of UTX function leads to accumulation of repressive H3K27me3 epigenetic marks at IL12/STAT4 pathway genes ( Il12rb2, Tbx21, and Ifng ). In a colitis mouse model, T cell-specific UTX deletion ameliorates colonic inflammation, protects against weight loss, and increases survival. Together these findings implicate UTX's oxygen-sensitive histone demethylase activity in mediating protective, hypoxia-induced pathways in colitis.

The objective of this study is to investigate potential biomarkers of Crohn's disease (CD) and the pathological importance of infiltration of associated immune cells in disease development using machine learning.

Three publicly accessible CD gene expression profiles were obtained from the GEO database. Inflammatory tissue samples were selected and differentiated between colonic and ileal tissues. To determine the differentially expressed genes (DEGs) between CD and healthy controls, the larger sample size was merged as a training unit. The function of DEGs was comprehended through disease enrichment (DO) and gene set enrichment analysis (GSEA) on DEGs. Promising biomarkers were identified using the support vector machine-recursive feature elimination and lasso regression models. To further clarify the efficacy of potential biomarkers as diagnostic genes, the area under the ROC curve was observed in the validation group. Additionally, using the CIBERSORT approach, immune cell fractions from CD patients were examined and linked with potential biomarkers.

Thirty-four DEGs were identified in colon tissue, of which 26 were up-regulated and 8 were down-regulated. In ileal tissues, 50 up-regulated and 50 down-regulated DEGs were observed. Disease enrichment of colon and ileal DEGs primarily focused on immunity, inflammatory bowel disease, and related pathways. CXCL1, S100A8, REG3A, and DEFA6 in colon tissue and LCN2 and NAT8 in ileum tissue demonstrated excellent diagnostic value and could be employed as CD gene biomarkers using machine learning methods in conjunction with external dataset validation. In comparison to controls, antigen processing and presentation, chemokine signaling pathway, cytokine-cytokine receptor interactions, and natural killer cell-mediated cytotoxicity were activated in colonic tissues. Cytokine-cytokine receptor interactions, NOD-like receptor signaling pathways, and toll-like receptor signaling pathways were activated in ileal tissues. NAT8 was found to be associated with CD8 T cells, while CXCL1, S100A8, REG3A, LCN2, and DEFA6 were associated with neutrophils, indicating that immune cell infiltration in CD is closely connected.

CXCL1, S100A8, REG3A, and DEFA6 in colonic tissue and LCN2 and NAT8 in ileal tissue can be employed as CD biomarkers. Additionally, immune cell infiltration is crucial for CD development.

Inflammatory bowel disease (IBD), which encompasses Crohn's disease and ulcerative colitis, has a complicated etiology that might be brought on by metabolic dysbiosis. Previous metabonomic studies have found a correlation between decreased azelaic acid (AzA) and IBD. Herein, data from the Metabolomics Workbench showed that the content of AzA decreased in IBD patients (PR000639) and dextran sulfate sodium (DSS)-induced mice (PR000837). The effects of AzA on IBD were then examined using a DSS-induced mouse model, and the results demonstrated that AzA alleviated clinical activity, decreased pro-inflammatory cytokine production, and reduced CD4⁺CD25⁺Foxp3⁺Treg percentages in mesenteric lymph nodes. Through network pharmacology analysis, we discovered 99 candidate IBD-associated genes that are potentially regulated by AzA. After the enrichment analysis of the candidate genes, the renin-angiotensin system (RAS) pathway was one of the most substantially enriched pathways. Additionally, AzA reversed the increased expression of important RAS components (ACE, ACE2, and MAS1L) following DSS induction, suggesting that AzA exerts therapeutic effects possibly via the RAS pathway. This study suggests that AzA may be a promising drug for treating IBD.

Advanced therapies have transformed the treatment of inflammatory bowel disease; however, many patients fail to respond, highlighting the need for therapies tailored to the underlying cell and molecular disease drivers. The first-in-class oral molecule ABX464 (obefazimod), which selectively upregulates miR-124, has demonstrated its ability to be a well-tolerated treatment with rapid and sustained efficacy in patients with ulcerative colitis (UC). Here, we provide evidence that ABX464 affects the immune system in vitro , in the murine model of inflammatory bowel disease, and in patients with UC. In vitro , ABX464 treatment upregulated miR-124 and led to decreases in proinflammatory cytokines including interleukin (IL) 17 and IL6, and in the chemokine CCL2. Consistently, miR-124 expression was upregulated in the rectal biopsies and blood samples of patients with UC, and a parallel reduction in Th17 cells and IL17a levels was observed in serum samples. In a mouse model of induced intestinal inflammation with dextran sulfate sodium, ABX464 reversed the increases in multiple proinflammatory cytokines in the colon and the upregulation of IL17a secretion in the mesenteric lymph nodes. By upregulating miR-124, ABX464 acts as "a physiological brake" of inflammation, which may explain the efficacy of ABX464 with a favorable tolerability and safety profile in patients with UC.

Inflammatory bowel disease (IBD) is an inflammatory disease of the gastrointestinal tract, the incidence of which has rapidly increased worldwide, especially in developing and Western countries. Recent research has suggested that genetic factors, the environment, microbiota, and immune responses are involved in the pathogenesis; however, the underlying causes of IBD are unclear. Recently, gut microbiota dysbiosis, especially a decrease in the abundance and diversity of specific genera, has been suggested as a trigger for IBD-initiating events. Improving the gut microbiota and identifying the specific bacterial species in IBD are essential for understanding the pathogenesis and treatment of IBD and autoimmune diseases. Here, we review the different aspects of the role played by gut microbiota in the pathogenesis of IBD and provide a theoretical basis for modulating gut microbiota through probiotics, fecal microbiota transplantation, and microbial metabolites.

Hydrogel is a three-dimensional network polymer material rich in water. It is widely used in the biomedical field because of its unique physical and chemical properties and good biocompatibility. In recent years, the incidence of inflammatory bowel disease (IBD) has gradually increased, and the disadvantages caused by traditional drug treatment of IBD have emerged. Therefore, there is an urgent need for new treatments to alleviate IBD. Hydrogel has become a potential therapeutic platform. However, there is a lack of comprehensive review of functional hydrogels for IBD treatment. This paper first summarizes the pathological changes in IBD sites. Then, the action mechanisms of hydrogels prepared from chitosan, sodium alginate, hyaluronic acid, functionalized polyethylene glycol, cellulose, pectin, and γ-polyglutamic acid on IBD were described from aspects of drug delivery, peptide and protein delivery, biologic therapies, loading probiotics, etc. In addition, the advanced functions of IBD treatment hydrogels were summarized, with emphasis on adhesion, synergistic therapy, pH sensitivity, particle size, and temperature sensitivity. Finally, the future development direction of IBD treatment hydrogels has been prospected.

Tumor necrosis factor-[Formula: see text] inhibitors (TNFi) have been a standard treatment in ulcerative colitis (UC) for nearly 20 years. However, insufficient response rate to TNFi therapies along with concerns around their immunogenicity and inconvenience of drug delivery through injections calls for development of UC drugs targeting alternative proteins. Here, we propose a multi-omic network biology method for prioritization of protein targets for UC treatment. Our method identifies network modules on the Human Interactome-a network of protein-protein interactions in human cells-consisting of genes contributing to the predisposition to UC (Genotype module), genes whose expression needs to be modulated to achieve low disease activity (Response module), and proteins whose perturbation alters expression of the Response module genes to a healthy state (Treatment module). Targets are prioritized based on their topological relevance to the Genotype module and functional similarity to the Treatment module. We demonstrate utility of our method in UC and other complex diseases by efficiently recovering the protein targets associated with compounds in clinical trials and on the market . The proposed method may help to reduce cost and time of drug development by offering a computational screening tool for identification of novel and repurposing therapeutic opportunities in UC and other complex diseases.

Chronic or recurrent immune system activation and inflammation inside the gastrointestinal tract is characterized by inflammatory bowel disease (IBD). Due to the lack of safety and efficacy of traditional medications, the use of food supplements for IBD management is on the rise. Numerous studies reported that, certain food supplements have a variety of therapeutic benefits for IBD. In the present study, a mouse model of IBD was used to the anti-colitis effects of lignin supplementation with Lactobacillus plantarum (L. plantarum) on intestinal inflammation. The animal model was treated with dextran sodium sulphate (DSS), the illness index increased, and colon length and body weight declined, but these effects were reversed when lignin and L. plantarum treated groups. In addition, lignin and L. plantarum supplementation inhibited the DSS induced increase in levels of cytokines TNF-α (250 pg/mL), INF-γ (180 pg/mL), IL-1β (70 pg/mL) and TGF- β (72 pg/mL). Gene and protein expression study revealed that Lignin and L. plantarum supplementation restored the expression of E-cad and suppressed the expression of STAT3 in DSS induced colitis model. Lignin and L. plantarum supplementation also suppressed CD44 expression (1.2 fold) by up regulating the expression of miR199a (1 fold) over DSS induced colitis. Our study suggests that Lactobacillus, lignin, and their synergistic treatments have protective roles against inflammatory bowel disease through changes in inflammatory cytokines, and miR 199a expression in DSS-induced colitis.

Interleukin (IL)-33 is a tissue-derived nuclear cytokine belonging to the IL-1 family. Stimulation-2 (ST2) is the only known IL-33 receptor. ST2 signals mostly on immune cells found within tissues, such as regulatory T cells (Treg cells), CD8+ T cells, and natural killer (NK) cells. Therefore, the IL-33/ST2 signaling pathway is important in the immune system. IL-33 deficiency impairs Treg cell function. ST2 signaling is also increased in active Treg cells, providing a new approach for Treg-related immunotherapy. The IL-33/ST2 signaling pathway regulates multiple immune-related cells by activating various intracellular kinases and factors in the tumor microenvironment (TME). Here, we review the latest studies on the role of the IL-33/ST2 signaling pathway in TME and Treg immunotherapy.

This study aimed to compare the differences between oral administration and intravenous injection of polygalacturonic acid (PGA) in the regulation of immune and intestinal microflora in ulcerative colitis (UC) mice. PGA was administered orally or intravenously. PGA in the high-dose ig group was the most effective in treating UC by increasing colon length and downregulating disease activity index, histopathological score and proinflammatory cytokine levels. In spleen, the efficacy of PGA on restoring Th17/Treg balance in the high-dose iv group was better than that in the high-dose ig group, the opposite was observed in the lamina propria. The level of colonic IL-17A in the high-dose ig group was lower than that in the high-dose iv group, the opposite was observed for that of colonic IL-10. Western blot and immunohistochemistry analysis revealed that PGA in the high-dose ig group decreased the protein expression of RORγt, and increased that of FOXP3. Furthermore, PGA in the high-dose ig group was more effective than that in the high-dose iv group in improving the intestinal microflora structure. Our results suggest that in immune regulation, oral PGA is more effective in the lamina propria and gut microbiota while intravenous PGA is more effective in the spleen.

Dendritic cell immunoreceptor (DCIR; Clec4a2), a member of the C-type lectin receptor family, plays important roles in homeostasis of the immune and bone systems. However, the intestinal role of this molecule is unclear. Here, we show that dextran sodium sulfate (DSS)-induced colitis and azoxymethane-DSS-induced intestinal tumors are reduced in Clec4a2^-/- mice independently of intestinal microbiota. STAT5 phosphorylation and expression of Csf2 and tight junction genes are enhanced, while Il17a and Cxcl2 are suppressed in the Clec4a2^-/- mouse colon, which exhibits reduced infiltration of neutrophils and myeloid-derived suppressor cells. Granulocyte-macrophage colony-stimulating factor (GM-CSF) administration ameliorates DSS colitis associated with reduced Il17a and enhanced tight junction gene expression, whereas anti-GM-CSF exacerbates symptoms. Furthermore, anti-NA2, a ligand for DCIR, ameliorates colitis and prevents colorectal tumors. These observations indicate that blocking DCIR signaling ameliorates colitis and suppresses colonic tumors, suggesting DCIR as a possible target for the treatment of these diseases.

Inflammatory bowel disease (IBD) is a non-specific chronic intestinal inflammatory disease, often presenting with abdominal pain, diarrhea, bloody stool, anorexia, and body loss. It is difficult to cure completely and a promising treatment is urgently needed. Natural compounds can offer promising chemical agents for treatment of diseases. Polydatin is a natural ingredient extracted from the dried rhizome of Polygonum cuspidatum, which has anti-inflammatory, anti-tumor, and dementia protection activities. The purpose of this study was to evaluate the therapeutic effect of polydatin on IBD and explore its possible mechanism. We found that polydatin could effectively suppress the differentiation of Th17 cells in vitro, but had no effect on the differentiation of Treg cells. Polydatin significantly alleviated colitis induced by dextran sulfate sodium (DSS) and 2, 4, 6-trinitrobenzenesulfonic acid (TNBS) in mice, and dramatically decreased the proportion of Th17 cells in spleen and mesenteric lymph nodes. Mechanism investigations revealed that polydatin specifically inhibited signal transducer and activator of transcription 3 (STAT3) phosphorylation by directly binding to STAT3, leading to Th17 cell reduction and thereby alleviating colitis. These findings provide novel insights into the anti-colitis effect of polydatin, which may be a promising drug candidate for the treatment of IBD.

The rising incidence of ulcerative colitis has become a new challenge for public health. Chimonanthus nitens Oliv. leaf granule (COG) is a natural medicine used for the treatment of respiratory diseases, which has excellent anti-inflammatory and antioxidant effects. However, the therapeutic effect of COG in ulcerative colitis (UC) has not been reported. Here, the experimental colitis was treated with dextran sodium sulfate (DSS) and COG. After treatment with high (30 g/kg), medium (15 g/kg), and low (7.5 g/kg) doses of COG for 11 consecutive days, the body weight, disease activity index (DAI) score, colon length, colon weight index, and the pathological score of mice were effectively improved. COG significantly reduced the levels of inflammatory cytokines in UC mice in vitro and in vivo and restored the secretion levels of IL-6 and IL-10 in the colon. Meanwhile, compared to mice with colitis, COG-treated mice showed lower levels of MDA, MPO, NO, and eNOS and higher levels of GSH-Px and MAO, which indicated that oxidative stress damage in colitic mice was alleviated by COG. Moreover, less Th17 and more Tregs were observed in the COG-treated groups. In addition, COG improved the diversity and relative abundance of gut microflora in the colon of colitic mice, and Lachnospiraceae_NK4A136_group and Lachnospiraceae_UCG-006 were obviously regulated at the genus level. In summary, COG has a protective effect on DSS-induced experimental colitis, mainly through inhibition of immune-inflammatory responses and oxidative stress and regulation of mTreg cell responses and intestinal flora composition.

Intestinal mucus forms the first line of defense against bacterial invasion while providing nutrition to support microbial symbiosis. How the host controls mucus barrier integrity and commensalism is unclear. We show that terminal sialylation of glycans on intestinal mucus by ST6GALNAC1 (ST6), the dominant sialyltransferase specifically expressed in goblet cells and induced by microbial pathogen-associated molecular patterns, is essential for mucus integrity and protecting against excessive bacterial proteolytic degradation. Glycoproteomic profiling and biochemical analysis of ST6 mutations identified in patients show that decreased sialylation causes defective mucus proteins and congenital inflammatory bowel disease (IBD). Mice harboring a patient ST6 mutation have compromised mucus barriers, dysbiosis, and susceptibility to intestinal inflammation. Based on our understanding of the ST6 regulatory network, we show that treatment with sialylated mucin or a Foxo3 inhibitor can ameliorate IBD.

As a main digestive organ and an important immune organ, the intestine plays a vital role in resisting the invasion of potential pathogens into the body. Intestinal immune dysfunction remains important pathogenesis of inflammatory bowel disease (IBD). In this review, we explained the interactions among symbiotic flora, intestinal epithelial cells, and the immune system, clarified the operating mechanism of the intestinal immune system, and highlighted the immunological pathogenesis of IBD, with a focus on the development of immunotherapy for IBD. In addition, intestinal fibrosis is a significant complication in patients with long-term IBD, and we reviewed the immunological pathogenesis involved in the development of intestinal fibrogenesis and provided novel antifibrotic immunotherapies for IBD.

This study was conducted to investigate how chito-oligosaccharides (COSs) affect the growth performance and immune stress response and to further explain their mechanisms. A total of 32 boars that were 28 days old and three-way weaned were randomly allotted to four equal groups [CON (basal diet) group, enterotoxigenic Escherichia coli (ETEC) group, COS group, and COS*ETEC group]. The results showed that COS partially reversed the negative changes in the average daily gain and average daily feed intake caused by the ETEC challenge and thereby alleviated the increase in the feed conversion ratio. Dietary COS increased the villus length as compared with the CON group and improved the ileal morphological structure. Additionally, it increased the bacterial diversity and Bacteroidetes abundance and lowered the Firmicutes abundance and Firmicutes-to-Bacteroidetes ratio at the phylum level. COS treatment lowered the abundance of Lactobacillus, Streptococcus, and Anarovovrio in the intestines of piglets, while it increased Muribaculaceae_unclassified and Prevotella at the genus level. COS had a significant inhibitory effect on the increase in the relative expression abundance of STAT3 mRNA caused by ETEC. The IL-10 and FOXP3 mRNAs were found to be significantly lower in the COS, ETEC, and COS*ETEC groups as compared to the CON group. These results demonstrate that COS could be beneficial for improving the growth performance and attenuating ETEC-challenged intestinal inflammation via regulating microbiota and Th17/Treg balance-related immune signaling pathways.

Accumulating evidence suggests that the adoptive transfer of ex vivo expanded regulatory T cells (Treg) may overcome colitogenic immune responses in patients with inflammatory bowel diseases. The objective of the ER-TREG 01 trial is to assess safety and tolerability of a single infusion of autologous ex vivo expanded Treg in adults with ulcerative colitis.

The study is designed as a single-arm, fast-track dose-escalation trial. The study will include 10 patients with ulcerative colitis. The study intervention consists of (1) a baseline visit; (2) a second visit that includes a leukapheresis to generate the investigational medicinal product, (3) a third visit to infuse the investigational medicinal product and (4) five subsequent follow-up visits within the next 26 weeks to assess safety and tolerability. Patients will intravenously receive a single dose of 0.5×10⁶, 1×10⁶, 2×10⁶, 5×10⁶ or 10×10⁶ autologous Treg/kg body weight. The primary objective is to define the maximum tolerable dose of a single infusion of autologous ex vivo expanded Treg. Secondary objectives include the evaluation of safety of one single infusion of autologous ex vivo expanded Treg, efficacy assessment and accompanying immunomonitoring to measure Treg function in the peripheral blood and intestinal mucosa.

The study protocol was approved by the Ethics Committee of the Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany (number 417_19 Az). In addition, the study was approved by the Paul-Ehrlich Institute, Federal Institute for Vaccines and Biomedicines, Langen, Germany (number 3652/01). The study is funded by the German Research Foundation (DFG, KFO 257 project 08 and SFB/TransRegio 241 project C04). The trial will be conducted in compliance with this study protocol, the Declaration of Helsinki, Good Clinical Practice and Good Manufacturing Practice. The results will be published in peer-reviewed scientific journals and disseminated in scientific conferences and media.

NCT04691232.