Diabetic stroke-associated acute intestinal injury is characterized by high mortality, disability, and poor prognosis due to the lack of effective therapies. Our prior research demonstrated that administration of 300 mg/kg sodium butyrate (NaB) can improve neurological outcomes post-diabetic stroke. Nonetheless, whether the effect of NaB is related to intestinal regulation, along with its underlying mechanisms, remains uncertain. This study aims to investigate the effects and mechanistic pathways of NaB on diabetic stroke-associated acute intestinal injury. A middle cerebral artery occlusion/reperfusion model was established in mice with streptozotocin-induced diabetes. The results demonstrated that NaB alleviated colonic injury 24 h after reperfusion in diabetic stroke. Pyroptosis-related protein levels in colonic tissues were significantly elevated following diabetic stroke but were markedly reduced with NaB treatment. NaB also improved gut barrier integrity and reduced inflammation, promoting epithelial barrier self-repair. In the NaB combined with lipopolysaccharide group, lipopolysaccharide administration induced a significant inflammatory response in the colonic tissue. Conversely, treatment with NaB and VX-765 (an inhibitor for Caspase-1) led to a notable alleviation in intestinal inflammation. These findings suggest that NaB mitigates colonic injury and enhances barrier function following diabetic stroke, potentially through the Caspase-1/Gasdermin D pyroptosis pathway. This study may provide a novel strategy and direction for intestinal rehabilitation in diabetic stroke patients.

There is an urgent need to identify biomarkers of tumorigenesis for colitis-associated cancer (CAC) as early cancer detection remains crucial for patients with inflammatory bowel disease (IBD). This in silico study examines the relationship between IBD and CAC, with particular regard to differentially-expressed genes (DEGs).

Integrated bioinformatics tools and public databases were employed. Data from GEO (GSE102133, GSE48958, GSE9348, GSE83687, GSE138202) were processed using GEOexplorer. DEGs were then functionally annotated with DAVID, SRplot, and integrated analysis via Metascape. Validation used Oncopression and Human Protein Atlas. Survival analysis employed GEPIA2. miRNA interactions were studied via miRTargetLink 2.0. Immune infiltration was analyzed with TIMER 2.0. COL1A1 expression and mutations were examined using cBioPortal, Kaplan-Meier plotter, and DNA methylation was analyzed using MethSurv. Correlation of COL1A1 gene promoter methylation with tissue type and clinical data was performed using the UALCAN database. The ROC analysis of COL1A1 was conducted in the R environment.

Our analysis identified three potential hub genes (ICAM1, LAMC1, and COL1A1), which are overexpressed in IBD and cancer tissues compared to normal tissue, and hence may play a role in CAC. Furthermore, patients with lower COL1A1 expression had longer disease-free survival (p = 0.01) than those with higher expression. Therefore, this gene was chosen for further analysis and identified as the most crucial.

COL1A1 reveals significant immunohistochemistry, mutations, and methylation data. Further studies involving machine learning and clinical data are required to validate the results.

Intestinal fibrosis is a serious complication of Crohn's disease (CD), often resulting from chronic inflammation. However, the precise mechanisms through which inflammation induces intestinal fibrosis remain inadequately elucidated.

A comprehensive single-cell atlas of full-thickness CD, provided by Dr. Florian Rieder, was subjected to reanalysis. Our study used a DSS-induced chronic colitis model in both wild-type (WT) and Areg-/- mice. Additionally, a CD45RBhi CD4+ T cell adoptive transfer model involving WT and Areg-/- Treg cells (Tregs) was used. The expressions of AREG in CD with or without intestinal fibrosis, Tregs and human intestinal myofibroblasts (MFs) were determined. The effect of AREG on proliferation/migration/activation in human intestinal MFs was determined.

Several types of cells were differentially expressed between stricture and non-stricture CD. Among T cells, Tregs accounted for a larger proportion and were significantly increased in stenotic tissues of stricture CD. Although DSS-induced colitis was more severe in Areg-/- mice, which developed less severe intestinal fibrosis compared with WT mice. The transfer of Areg-/- Tregs resulted in less severe fibrosis in Rag-/- mice than WT Tregs. Moreover, TGF-β stimulated AREG expression in Tregs and human intestinal MFs via activation of Smad3.

These findings demonstrated that AREG derived from Tregs and human intestinal MFs, induced by TGF-β, amplifies intestinal fibrotic reactions in experimental colitis as well as in human CD patients. Thus, the TGF-β-Smad3-AREG pathway could be a potential therapeutic target for treating fibrosis in CD.

We utilized patient samples from the large, phase 2b/3 SELECTION trial to identify circulating biomarkers of ulcerative colitis (UC) and potential early mediators of filgotinib treatment effects.

Samples were collected at baseline and during the induction phase of the SELECTION trial. Evaluated biomarkers comprised serum and stool proteins (measured by enzyme-linked immunosorbent assay), whole-blood cell counts, and whole-blood RNA-seq-derived gene-expression factors identified via exploratory factor analysis. Biomarker levels were assessed by baseline disease severity (endoscopy/bleeding/stool and Mayo Clinic Score) and biologic status (naive vs experienced). Effects of filgotinib on biomarker levels, including week 4 biomarker changes that may mediate week 10 clinical improvements, were assessed.

The biomarker analysis set included 598 biologic-naive patients and 592 biologic-experienced patients. Systemic inflammatory biomarkers (C-reactive protein [CRP], interleukin-6 [IL-6], serum amyloid A [SAA], and platelet cell counts) had the strongest positive correlations with baseline UC disease severity. CRP, IL-6, SAA, and neutrophil activation biomarkers (including neutrophil gelatinase-associated lipocalin [NGAL], tumor necrosis factor ɑ, and oncostatin M [OSM]), as well as platelet, neutrophil, and monocyte cell counts were increased in biologic-experienced versus biologic-naive patients. Gene-expression-derived plasmablast and cell proliferation factors were positively correlated with disease severity; B cell, T-cell activation, and plasmacytoid dendritic cell factors were negatively correlated. Filgotinib reduced nearly all proinflammatory biomarkers correlated with baseline UC disease activity; reduced SAA, CRP, IL-6, NGAL, and OSM at week 4 were identified as mediators of improved week 10 clinical scores.

Filgotinib significantly impacted circulating biomarkers related to UC pathology. Several proinflammatory and neutrophil activation biomarkers may be early mediators of filgotinib treatment effects.

NCT02914522.

Blood orange peel flour (BO-pf)-a by-product of the citrus supply chain-still contains bioactive molecules with known health benefits, such as antiradical scavenging activity or an antiproliferative activity regarding tumors. In vitro studies have demonstrated that orange polyphenols showed potential involvement in necroptosis. In addition to previous research, we tested BO-pf on two colorectal cancer cell lines. Using HT29 and Caco2 cells, our experiments confirmed the regulation of inflammasome expression. They provided valuable insights into how BO-pf influences the cancer cell features (i.e., viability, proliferation, and pro- and anti-inflammatory activity). Notably, BO-pf extract is a rich source of polyphenolic compounds with antioxidant properties. Western blot and real-time PCR analyses showed that treatment with BO-pf extract demonstrated beneficial effects by influencing the expression of both pro-inflammatory cytokines (IL-1β, IL-6) through the modulation of the TLR4/NF-kB/NLRP3 inflammasome signaling. Moreover, the results of this study demonstrate that BO-pf extracts can enhance the expression of anti-inflammatory cytokines, such as IL-10 and TGFβ, suggesting that BO-pf extracts may represent a promising functional ingredient to counteract the intestinal inflammatory responses involved in IBD.

Colorectal cancer (CRC) is considered as an age-related disease, and cellular senescence (CS) plays a crucial role in cancer development and progression. Previous studies have shown the role of epigenetic changes in aging and cancer development, but the role of RNA pseudouridine (Ψ) modification in aging and cancer remains to be explored.

Using bulk RNA sequencing, CRC cells with low Ψ writers expression levels have higher CS levels. We developed the Psi Score for assessing the transcriptomic profile of RNA Ψ modification regulation and found that the Psi Score correlates with CS. Furthermore, Psi-related senescence may be mediated by mTOR, TGF-β, TNF-α, and inflammatory response signaling pathways. Meanwhile, Psi Score could predict the anti-cancer treatment outcomes of anti-aging interventions and could be used to predict the response to immunotherapy.

Overall, these findings reveal that RNA Ψ modification connected aging and cancer and provided novel insights into biomarker-guided cancer regimens.

The effects of combustible cigarettes (CCs) and electronic nicotine delivery systems (ENDS) on immune cell-driven colon inflammation and intestinal healing of patients with ulcerative colitis (UC) are still unknown and, therefore, were examined in this study.

Intracellular staining and flow cytometry analysis of immune cells isolated from UC patients who used ENDS (UCENDS), CCs (UCCC) and who were nonsmokers (UCAIR) were performed to elucidate cellular mechanisms which were responsible for CCs and ENDS-dependent modulation of immune response during UC progression. Additionally, dextran sulfate sodium (DSS)-colitis was induced in ENDS/CC/air-exposed mice (DSSENDS/ DSSCC/DSSAIR groups) to support clinical findings.

Significantly increased number of immunosuppressive, IL-10, TGF-β, and IL-35-producing, FoxP3-expressing CD3 + CD4 + T regulatory cells (Tregs) was observed in the blood of UCENDS patients while the reduced presence of inflammatory, TNF-α and IFN-γ-producing, Tbx21-expressing CD3 + CD4 + Th1, IL-4-producing Gata3-expresing Th2 and IL-17, IL-22-producing, RORγT, IL-23R-expressing Th17 cells were noticed in the blood of UCCC patients. Exposure to either CCs or ENDS was associated with enhanced mucosal healing, ameliorated spontaneous recovery, and improved survival of DSS-treated mice. An expansion of immunosuppressive cells (IL-10-producing tolerogenic CD11c + dendritic cells, alternatively activated CD206, Arginase 1-expressing, IL-10-producing F4/80 + macrophages, IL-10-producing FoxP3-expressing Tregs) was noticed in the colons of DSSENDS-treated mice, while reduced number of inflammatory, IL-17- and IL-4-producing T lymphocytes was observed in the colons of DSSCC-compared to DSSAIR-treated mice.

Despite different mechanisms of action, both ENDS and CCs attenuated ongoing colon inflammation, enhanced healing, and ameliorated recovery of injured intestines of DSS-treated mice and UC patients.

This is the first study that compared the effects of CCs and ENDS on immune cells of patients suffering from UC, providing new information about molecular and cellular mechanisms which were responsible for ENDS and CCs-dependent modulation of immune cell-driven colon injury and inflammation. Obtained results showed that both ENDS and CCs had the capacity to attenuate detrimental immune response, enhance healing, and ameliorate recovery of injured intestines.

TGM6 is a natural antagonist of mammalian TGF-β signaling produced by the murine helminth parasite Heligmosomoides polygyrus. It differs from the previously described agonist, TGM1 (TGF-β Mimic-1), in that it lacks domains 1/2 that bind TGFBR1. It nonetheless retains TGFBR2 binding through domain 3 and potently inhibits TGF-β signaling in fibroblasts and epithelial cells, but does not inhibit TGF-β signaling in T cells, consistent with divergent domains 4/5 and an altered co-receptor binding preference. The crystal structure of TGM6 bound to TGFBR2 reveals an interface remarkably similar to that of TGF-β with TGFBR2. Thus, TGM6 has adapted its structure to mimic TGF-β, while engaging a distinct co-receptor to direct antagonism to fibroblasts and epithelial cells. The co-expression of TGM6, along with immunosuppressive TGMs that activate the TGF-β pathway, may minimize fibrotic damage to the host as the parasite progresses through its life cycle from the intestinal lumen to submucosa and back again. The co-receptor-dependent targeting of TGFBR2 by the parasite provides a template for the development of therapies for targeting the cancer- and fibrosis-promoting activities of the TGF-βs in humans.

Long non-coding RNAs (lncRNAs) are a class of RNA molecules that exceed 200 nucleotides in length and lack the capacity to encode proteins. In recent years, there has been a surge of interest in lncRNA research, leading to the discovery of their diverse structures and functions. This review focused on elucidating the regulatory roles of lncRNA erythroid differentiation regulatory 1 (Erdr1) within immune cells and its involvement in related disorders. By synthesizing findings from recent studies sourced from PubMed, this paper examined the biological functions and underlying mechanisms by which lncRNA Erdr1 influences immune cells and contributes to various diseases. Emerging research highlights that lncRNA Erdr1 exerts significant effects on the functionality of immune cells, particularly T lymphocytes (T cells), natural killer (NK) cells, and macrophages. Furthermore, Erdr1 has been implicated in the mitigation of several diseases, including acne, wound healing, osteoarthritis, melanoma, gastric cancer, obesity, and autism. Given its complex biological functions and mechanisms, Erdr1 presents itself as a promising biomarker and a potential therapeutic target for a range of immune cell-related disorders.

Intestinal fibrosis, a severe complication of Crohn's disease (CD), is linked to chronic inflammation, but the precise mechanism by which immune-driven intestinal inflammation leads to fibrosis development is not fully understood. This study investigates the role of myeloid-derived suppressor cells (MDSCs) in intestinal fibrosis in CD patients and a 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced mouse model. Elevated MDSCs are observed in inflamed intestinal tissues prior to fibrosis and their sustained presence in fibrotic tissues of both CD patients and murine models. Depletion of MDSCs significantly reduces fibrosis, highlighting their key role in the fibrotic process. Mechanistically, MDSC-derived mCCL6 activates fibroblasts via the CCR1-MAPK signaling, and interventions targeting this axis, including neutralizing antibodies, a CCR1 antagonist, or fibroblast-specific Ccr1 knockout mice reduce fibrosis. In CD patients with stenosis, human CCL15, analogous to mCCL6, is found to be elevated in MDSCs and activated fibroblasts. Additionally, CXCR2 and CCR2 ligands are identified as key mediators of MDSC recruitment in intestinal fibrosis. Blocking MDSC recruitment with CXCR2 and CCR2 antagonists alleviates intestinal fibrosis. These findings suggest that strategies targeting MDSC recruitment and mCCL6/hCCL15 signaling could offer therapeutic benefits for intestinal fibrosis.

Crohn's disease (CD) is a chronic, complex inflammatory disorder of the gastrointestinal tract that presents significant therapeutic challenges. Despite the availability of a wide range of treatments, many patients experience primary non-response, secondary loss of response, or adverse events, limiting the overall effectiveness of current therapies. Clinical trials often report response rates below 60%, partly due to stringent inclusion criteria. Emerging therapies that target novel pathways offer promise in overcoming these limitations. This review explores the latest investigational drugs in phases I, II, and III clinical trials for treating both luminal and perianal CD. We highlight promising therapies that target known mechanisms, including selective Janus kinase inhibitors, anti-adhesion molecules, tumor necrosis factor inhibitors, and IL-23 selective inhibitors. In addition, we delve into novel therapeutic strategies such as sphingosine-1-phosphate receptor modulators, miR-124 upregulators, anti-fractalkine (CX3CL1), anti-TL1A, peroxisome proliferator-activated receptor gamma agonists, TGFBRI/ALK5 inhibitors, anti-CCR9 agents, and other innovative small molecules, as well as combination therapies. These emerging approaches, by addressing new pathways and mechanisms of action, have the potential to surpass the limitations of existing treatments and significantly improve CD management. However, the path to developing new therapies for inflammatory bowel disease (IBD) is fraught with challenges, including complex trial designs, ethical concerns regarding placebo use, recruitment difficulties, and escalating costs. The landscape of IBD clinical trials is shifting toward greater inclusivity, improved patient diversity, and innovative trial designs, such as adaptive and Bayesian approaches, to address these challenges. By overcoming these obstacles, the drug development pipeline can advance more effective, accessible, and timely treatments for CD.

Atopic dermatitis (AD), a prevalent allergic skin condition in children, has been closely associated with imbalances in the gut microbiome. To investigate these microbial alterations and their functional implications, we investigated protein expression, functions and interactions of the gut bacteriome and mycobiome as well as the human proteome in Thai infants with AD using integrative metaproteomic and host interaction analysis. As we observed, probiotic species, such as Lactobacillus acidophilus and Bacteroides salyersiae, were reduced in abundance in the AD group while key pathogenic bacteria and fungi, such as Streptococcus constellatus and Penicillium chrysogenum, increased in abundance. Additionally, the functional analysis of expressed proteins was enriched in response to stress and DNA repair in the bacteriome and ribosome biogenesis-related processes in the mycobiome of the AD group, potentially associated to increased reactive oxygen species (ROS), intestinal inflammation, fungal growth and microbial dysbiosis. Further, a protein-protein interactions (PPIs) network analysis incorporating the human proteome revealed 10 signature proteins related to stress and immune system processes associated with AD. Our findings propose the interactions of the key species and signature protein functions between the gut microbes and the human host in response to AD in Thai infants. To our knowledge, this study serves as the first framework for monitoring bacteriome-mycobiome-human gut studies associated with AD and other allergic diseases in infants.

The intestinal barrier integrity was substantially collapsed when colitis flaring up, accompanying by the hallmark of pathological oxidative stress. Bone morphogenetic protein 7 (BMP 7), an endogenous growth factor in gut had the potential to repair the damaged mucosa. Herein, a smart hydrogel (HDP) had been developed by the boronate-ester crosslinked hyaluronic acid to deliver BMP 7. Hydrogel loading BMP 7 (HDP-BMP 7) presented the comparable mechanical strength with that of the naïve gut mucus. HDP-BMP 7 as artificial mucus could specifically adhere to the inflamed colonic mucosa of colitis mice. Importantly, it could apperceive reactive oxygen species at diseased colon to adapt its intrinsic network, enabling the feedback release of BMP 7 on the pathological oxidative stress. Moreover, in vivo animal experiments showed that the disease symptoms of colitis mice were alleviated by HDP-BMP 7. Importantly, both the mucus barrier and the epithelial barriers were obviously recovered by HDP-BMP 7 treatment, which substantially attenuated the immune-inflammation response of colitis mice. Besides, HDP-BMP 7 enriched the diversity of gut flora, increasing the relative abundance of Lactobacillus and decreasing the ratio of Firmicutes/Bacteroidetes. Its therapeutic mechanism was associated with activating TGF-β/Smad signals. Conclusively, this smart hydrogel might potentiate the repairing effect of growth factors on the gut epithelial integrity.

Eimeria is an intracellular obligate apicomplexan parasite that parasitizes the intestinal epithelial cells of livestock and poultry, exhibiting strong host and tissue tropism. Parasite-host interactions involve complex networks and vary as the parasites develop in the host. However, understanding the underlying mechanisms remains a challenge. Acknowledging the lack of studies on Eimeria invasion mechanism, we described the possible invasion process through comparative analysis with other apicomplexan parasites and explored the fact that parasite-host interactions serve as a prerequisite for successful recognition, penetration of the intestinal mechanical barrier, and completion of the invasion. Although it is recognized that microbiota can enhance the host immune capacity to resist Eimeria invasion, changes in the microenvironment can, in turn, contribute to Eimeria invasion and may be associated with reduced immune capacity. We also discuss the immune evasion strategies of Eimeria, emphasizing that the host employs sophisticated immune regulatory mechanisms to suppress immune evasion by parasites, thereby sustaining a balanced immune response. This review aims to deepen our understanding of Eimeria-host interactions, providing a theoretical basis for the study of the pathogenicity of Eimeria and the development of novel anticoccidial drugs.

Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have emerged as key regulators of intercellular communication, orchestrating essential biological processes by delivering bioactive cargoes to target cells. Available evidence suggests that MSC-EVs can mimic the functions of their parental cells, exhibiting immunomodulatory, pro-regenerative, anti-apoptotic, and antifibrotic properties. Consequently, MSC-EVs represent a cell-free therapeutic option for patients with inflammatory bowel disease (IBD), overcoming the limitations associated with cell replacement therapy, including their non-immunogenic nature, lower risk of tumourigenicity, cargo specificity and ease of manipulation and storage.

This review aims to provide a comprehensive examination of the therapeutic efficacy of MSC-EVs in IBD, with a focus on their mechanisms of action and potential impact on treatment outcomes. We examine the advantages of MSC-EVs over traditional therapies, discuss methods for their isolation and characterisation, and present mechanistic insights into their therapeutic effects through transcriptomic, proteomic and lipidomic analyses of MSC-EV cargoes. We also discuss available preclinical studies demonstrating that MSC-EVs reduce inflammation, promote tissue repair and restore intestinal homeostasis in IBD models, and compare these findings with those of clinical trials.

Finally, we highlight the potential of MSC-EVs as a novel therapy for IBD and identify challenges and opportunities associated with their translation into clinical practice.

The source of mesenchymal stem cells (MSCs) strongly influences the composition and function of MSC-derived extracellular vesicles (EVs), affecting their therapeutic potential. Adipose-derived MSC-EVs, known for their immunoregulatory properties and ease of isolation, show promise as a treatment for inflammatory bowel disease (IBD). MicroRNAs are consistently present in MSC-EVs across cell types and are involved in pathways that are dysregulated in IBD, making them potential therapeutic agents. For example, miR-let-7a is associated with inhibition of apoptosis, miR-100 supports cell survival, miR-125b helps suppress pro-inflammatory cytokines and miR-20 promotes anti-inflammatory M2 macrophage polarisation. Preclinical studies in IBD models have shown that MSC-EVs reduce intestinal inflammation by suppressing pro-inflammatory mediators (e.g., TNF-α, IL-1β, IL-6) and increasing anti-inflammatory factors (e.g., IL-4, IL-10). They also promote mucosal healing and strengthen the integrity of the gut barrier, suggesting their potential to address IBD pathology.

Due to the availability, scalability, and low immunogenicity, bovine milk-derived extracellular vesicles (MEVs) are increasingly considered to be a promising carrier of nanomedicines for future therapy. However, considering that extracellular vesicles (EVs) are of biological origin, different sources of EVs, including the host origin and the specific cells that produce the EVs, may have different effects on the structure and function of EVs. Additionally, MEVs play an important role in immune regulation, due to their evolutionary conserved cargo, such as cytokines and miRNAs. Their potential effects on different organs, as well as their accumulation in the human body, should not be overlooked. In this review, we have summarized current impacts and research progress brought about by utilizing MEVs as nano-drug carriers. Nevertheless, we also aim to explore the possible connections between the molecules involved in cellular immunity, cytokines and miRNAs of MEVs produced under different health conditions, and autoimmune diseases.

Crohn's disease [CD] is characterised by the expansion of mesenteric adipose tissue [MAT], named creeping fat [CF], which seems to be directly related to disease activity. Adipose-stem cells [ASCs] isolated from the CF of patients with CD are extremely pro-inflammatory, which persists during disease remission. We hypothesised that the dysfunctional ASCs in CD accumulate epigenetic modifications triggered by the inflammatory environment, that could serve as molecular markers.

Genome-wide DNA methylome and transcriptome profiling were performed in ASCs isolated from MAT biopsies of patients with active and inactive disease and from non-Crohn's disease patients [non-CD]. A validation cohort was used to test the main candidate genes via quantitative polymerase chain reaction in other fat depots and immune cells.

We found differences in DNA methylation and gene expression between ASCs isolated from patients with CD and from non-CD subjects, but we found no differences related to disease activity. Pathway enrichment analysis revealed that oxidative stress and immune response were significantly enriched in active CD, and integration analysis identified MAB21L2, a cell fate-determining gene, as the most affected gene in CD. Validation analysis confirmed the elevated gene expression of MAB21L2 in MAT and in adipose tissue macrophages in active CD. We also found a strong association between expression of the calcium channel subunit gene CACNA1H and disease remission, as CACNA1H expression was higher in ASCs and MAT from patients with inactive CD, and correlates negatively with C-reactive protein in peripheral blood mononuclear cells.

We identified a potential gene signature of CD in ASCs obtained from MAT. Integration analysis highlighted two novel genes demonstrating a negative correlation between promoter DNA methylation and transcription: one linked to ASCs in CD [MAB21L2] and the other [CACNA1H] related to disease remission.

Over the past decade, there has been a rapid increase in the incidence of inflammatory bowel disease. It has been suggested that multifactorial interactions of environmental factors, genetic factors, immune response and intestinal microbiota are involved in the pathogenesis of inflammatory bowel disease. It is widely recognized that the intestinal microbiota are essential for human metabolism, the immune system and pathogen resistance, and are integral to human health. Therefore, the dysbiosis of the microbiota is a critical step leading to intestinal mucosal damage and a key factor in the pathogenesis of inflammatory bowel disease. Regulating the microbiota through interventions such as enteral nutrition, fecal microbiota transplantation, and probiotic supplementation has the potential to prevent or even reverse intestinal dysbiosis, opening up new perspectives for the treatment of inflammatory bowel disease.

This study was to investigate the effects of the polysaccharides (PPM60-III) and sulfated polysaccharides (SPPM60-III) of pine pollen on the Th17/Treg balance, inflammatory cytokines, intestinal microbiota, and metabolite distribution in 3% DSS drinking water-induced UC mice. First of all, the physiological results showed that PPM60-III and SPPM60-III could alleviate UC, which was shown by the reduction in liver Treg cells, the rebalance of Th17/Treg, and the modulation of inflammatory cytokines. In addition, the 16S rRNA results showed that PPM60-III and SPPM60-III could decrease Beijerinck and Bifidobacterium, and increase Akkermansia, Escherichia coli, and Fidobacteria. Finally, the metabonomics results showed that PPM60-III and SPPM60-III also restored purine and glycerolipid metabolism, up-regulated nicotinate and nicotinamide metabolism and caffeine metabolism to inhibit inflammation. In conclusion, PPM60-III and SPPM60-III could inhibit UC by regulating gut bacteria composition and metabolite distribution; SPPM60-III showed better anti-colitis activity.

Intestinal stem cells at the crypt divide and give rise to progenitor cells that proliferate and differentiate into various mature cell types in the transit-amplifying (TA) zone. Here, we showed that the transcription factor ARID3A regulates intestinal epithelial cell proliferation and differentiation at the TA progenitors. ARID3A forms an expression gradient from the villus tip to the upper crypt mediated by TGF-β and WNT. Intestinal-specific deletion of Arid3a reduces crypt proliferation, predominantly in TA cells. Bulk and single-cell transcriptomic analysis shows increased enterocyte and reduced secretory differentiation in the Arid3a cKO intestine, accompanied by enriched upper-villus gene signatures of both cell lineages. We find that the enhanced epithelial differentiation in the Arid3a-deficient intestine is caused by increased binding and transcription of HNF1 and HNF4. Finally, we show that loss of Arid3a impairs irradiation-induced regeneration with sustained cell death and reprogramming. Our findings imply that Arid3a functions to fine-tune the proliferation-differentiation dynamics at the TA progenitors, which are essential for injury-induced regeneration.

Lactobacillus delbrueckii CIDCA 133 is a promising health-promoting bacterium shown to alleviate intestinal inflammation. However, the specific bacterial components responsible for these effects remain largely unknown. Here, we demonstrated that consuming extractable proteins from the CIDCA 133 strain effectively relieved acute ulcerative colitis in mice. This postbiotic protein fraction reduced the disease activity index and prevented colon shortening in mice. Furthermore, histological analysis revealed colitis prevention with reduced inflammatory cell infiltration into the colon mucosa. Postbiotic consumption also induced an immunomodulatory profile in colitic mice, as evidenced by both mRNA transcript levels (Tlr2, Nfkb1, Nlpr3, Tnf, and Il6) and cytokines concentration (IL1β, TGFβ, and IL10). Additionally, it enhanced the levels of secretory IgA, upregulated the transcript levels of tight junction proteins (Hp and F11r), and improved paracellular intestinal permeability. More interestingly, the consumption of postbiotic proteins modulated the gut microbiota (Bacteroides, Arkkemansia, Dorea, and Oscillospira). Pearson correlation analysis indicated that IL10 and IL1β levels were positively associated with Bacteroides and Arkkemansia_Lactobacillus abundance. Our study reveals that CIDCA 133-derived proteins possess anti-inflammatory properties in colonic inflammation.

Aberrant TGF-β signaling pathway can lead to invasive phenotype of colorectal cancer (CRC), resulting in poor prognosis. It is pivotal to develop an effective prognostic factor on the basis of TGF-β-related genes to accurately identify risk of CRC patients.

We performed differential analysis of TGF-β-related genes in CRC patients from databases and previous literature to obtain TGF-β-related differentially expressed genes (TRDEGs). LASSO-Cox regression was utilized to build a CRC prognostic feature model based on TRDEGs. The model was validated using two GEO validation sets. Wilcoxon rank-sum test was utilized to test correlation of model with clinical factors. ESTIMATE algorithm and ssGSEA and tumor mutation burden (TMB) analysis were used to analyze immune landscape and mutation burden of high-risk (HR) and low-risk (LR) groups. CellMiner database was utilized to identify therapeutic drugs with high sensitivity to the feature genes.

We established a six-gene risk prognostic model with good predictive accuracy, which independently predicted CRC patients' prognoses. The HR group was more likely to experience immunotherapy benefits due to higher immune infiltration and TMB. The feature gene TGFB2 could inhibit the efficacy of drugs such as XAV-939, Staurosporine, and Dasatinib, but promote the efficacy of drugs such as CUDC-305 and by-product of CUDC-305. Similarly, RBL1 could inhibit the drug action of Fluphenazine and Imiquimod but promote that of Irofulven.

A CRC risk prognostic signature was developed on basis of TGF-β-related genes, which provides a reference for risk and further therapeutic selection of CRC patients.

The proper differentiation and reorganization of the intestinal epithelial cell population is critical to mucosal regeneration post injury. Label retaining cells (LRCs) expressing SRY-box transcription factor 9 (SOX9) promote epithelial repair by replenishing LGR5+ intestinal stem cells (ISCs). While, LRCs are also considered precursor cells for enteroendocrine cells (EECs) which exacerbate mucosal damage in inflammatory bowel disease (IBD). The factors that determine LRC-EEC differentiation and the effect of intervening in LRC-EEC differentiation on IBD remain unclear. In this study, we investigated the effects of a natural anthraquinone called aloe emodin (derived from the Chinese herb rhubarb) on mucosal healing in IBD models. Our findings demonstrated that aloe emodin effectively interfered with the differentiation to EECs and preserved a higher number of SOX9+ LRCs, thereby promoting mucosal healing. Furthermore, we discovered that aloe emodin acted as an antagonist of free fatty acid receptors (FFAR1), suppressing the FFAR1-mediated Gβγ/serine/threonine-protein kinase (AKT) pathway and promoting the translocation of forkhead box protein O1 (FOXO1) into the nucleus, ultimately resulting in the intervention of differentiation fate. These findings reveal the effect of free fatty acid accessibility on EEC differentiation and introduce a strategy for promoting mucosal healing in IBD by regulating the FFAR1/AKT/FOXO1 signaling pathway.

Inflammatory bowel disease (IBD), a condition of the digestive tract and one of the autoimmune diseases, is becoming a disease of significant global public health concern and substantial clinical burden. Various signaling pathways have been documented to modulate IBD, but the exact activation and regulatory mechanisms have not been fully clarified; thus, a need for constant exploration of the molecules and pathways that play key roles in the development of IBD. In recent years, several protein post-translational modification pathways, such as ubiquitination, phosphorylation, methylation, acetylation, and glycolysis, have been implicated in IBD. An aberrant ubiquitination in IBD is often associated with dysregulated immune responses and inflammation. Mesenchymal stem cells (MSCs) play a crucial role in regulating ubiquitination modifications through the ubiquitin-proteasome system, a cellular machinery responsible for protein degradation. Specifically, MSCs have been shown to influence the ubiquitination of key signaling molecules involved in inflammatory pathways. This paper reviews the recent research progress in MSC-regulated ubiquitination in IBD, highlighting their therapeutic potential in treating IBD and offering a promising avenue for developing targeted interventions to modulate the immune system and alleviate inflammatory conditions.

Treatments of colitis, inflammation of the intestine, rely on induction of immune suppression associated with systemic adverse events, including recurrent infections. This treatment strategy is specifically problematic in the increasing population of patients with cancer with immune checkpoint inhibitor (ICI)-induced colitis, as immune suppression also interferes with the ICI-treatment response. Thus, there is a need for local-acting treatments that reduce inflammation and enhance intestinal healing. Here, we investigated the effect and safety of bacterial delivery of short-lived immunomodulating chemokines to the inflamed intestine in mice with colitis. Colitis was induced by dextran sulfate sodium (DSS) alone or in combination with ICI (anti-PD1 and anti-CTLA-4), and Limosilactobacillus reuteri R2LC (L. reuteri R2LC) genetically modified to express the chemokine CXCL12-1α (R2LC_CXCL12, emilimogene sigulactibac) was given perorally. In addition, the pharmacology and safety of the formulated drug candidate, ILP100-Oral, were evaluated in rabbits. Peroral CXCL12-producing L. reuteri R2LC significantly improved colitis symptoms already after 2 days in mice with overt DSS and ICI-induced colitis, which in benchmarking experiments was demonstrated to be superior to treatments with anti-TNF-α, anti-α4β7, and corticosteroids. The mechanism of action involved chemokine delivery to Peyer's patches (PPs), confirmed by local CXCR4 signaling, and increased numbers of colonic, regulatory immune cells expressing IL-10 and TGF-β1. No systemic exposure or engraftment could be detected in mice, and product feasibility, pharmacology, and safety were confirmed in rabbits. In conclusion, peroral CXCL12-producing L. reuteri R2LC efficiently ameliorates colitis, enhances mucosal healing, and has a favorable safety profile.NEW & NOTEWORTHY Colitis symptoms are efficiently reduced by peroral administration of probiotic bacteria genetically modified to deliver CXCL12 locally to the inflamed intestine in several mouse models.

The gut microbiome is a significant factor in the pathophysiology of ulcerative colitis (UC), prompting investigations into the use of probiotic therapies to counter gastrointestinal inflammation. However, while much attention has been given to the therapeutic potential of microbes at the species and strain level, the discovery and application of their metabolic products may offer more precise and controlled solutions in battling disease. In this work, we examined the therapeutic potential of indole lactic acid (ILA) to alleviate inflammation in a murine model of colitis. A previously constructed ILA-producing Escherichia coli Nissle 1917 strain (EcN aldh) and its isogenic non-ILA producing counterpart (EcN) were studied in a murine model of Dextran Sodium Sulfate (DSS) induced colitis. The colitic animals suffered from severe colitic symptoms, with no differentiation between the groups in body weight loss and disease activity index. However, three days after cessation of DSS treatment the EcN aldh-treated mice showed signs of reduced intestinal inflammation, as manifested by lower concentrations of fecal lipocalin-2. Additionally, expression analysis of the inflamed tissue revealed distinct effects of the EcN aldh strain on proteins associated with intestinal health, such as TFF3, occludin and IL-1β expression. These results show no impact of EcN or EcN aldh on acute DSS-induced colitis, but suggest that in particular EcN aldh may assist recovery from intestinal inflammation.

The term "inflammatory bowel disease" (IBD) describes a class of relapse-remitting conditions that affect the gastrointestinal (GI) tract. Among these, Crohn's disease (CD) and ulcerative colitis (UC) are two of the most globally prevalent and debilitating conditions. Several articles have brought attention to the significant role that inflammation and oxidative stress cooperatively play in the development of IBD, offering a different viewpoint both on its etiopathogenesis and on strategies for the effective treatment of these conditions. Marine ecosystems may be a significant source of physiologically active substances, supporting the search for new potential clinical therapeutics. Based on this evidence, this review aims to comprehensively evaluate the activity of marine algae and deriving biomolecules in decreasing pathological features of CD and UC. To match this purpose, a deep search of the literature on PubMed (MEDLINE) and Google Scholar was performed to highlight primary biological mechanisms, the modulation of inflammatory and oxidative stress biochemical parameters, and potential clinical benefits deriving from marine species. From our findings, both macroalgae and microalgae have shown potential as therapeutic solutions for IBD due to their bioactive compounds and their anti-inflammatory and antioxidant activities which are capable of modulating markers such as cytokines, the NF-κB pathway, reactive oxidative and nitrosative species (ROS and RNS), trefoil factor 3 (TFF3), lactoferrin, SIRT1, etc. However, while we found promising preclinical evidence, more extensive and long-term clinical studies are necessary to establish the efficacy and safety of marine algae for IBD treatment.

PTPRK is a receptor tyrosine phosphatase that is linked to the regulation of growth factor signalling and tumour suppression. It is stabilized at the plasma membrane by trans homophilic interactions upon cell-cell contact. PTPRK regulates cell-cell adhesion but is also reported to regulate numerous cancer-associated signalling pathways. However, the signalling mechanism of PTPRK remains to be determined. Here, we find that PTPRK regulates cell adhesion signalling, suppresses invasion and promotes collective, directed migration in colorectal cancer cells. In vivo, PTPRK supports recovery from inflammation-induced colitis. In addition, we confirm that PTPRK functions as a tumour suppressor in the mouse colon and in colorectal cancer xenografts. PTPRK regulates growth factor and adhesion signalling, and suppresses epithelial to mesenchymal transition (EMT). Contrary to the prevailing notion that PTPRK directly dephosphorylates EGFR, we find that PTPRK regulation of both EGFR and EMT is independent of its catalytic function. This suggests that additional adaptor and scaffold functions are important features of PTPRK signalling.

Inflammatory bowel disease (IBD) is a complex disease that develops through a sequence of molecular events that are still poorly defined. This process is driven by a multitude of context-dependent genes that play different roles based on their environment. The complexity and multi-faceted nature of these genes make it difficult to study the genetic basis of IBD. The goal of this article is to review the key genes in the pathophysiology of IBD and highlight new technology that can be used in further research. This paper examines Nanostring RNA probe technology, which uses tissue analyzed without the use of enzymes, transcription, or amplification. Nanostring offers several panels of genes to test, including an inflammation panel of 234 genes. This article analyzes this panel and reviews the literature for each gene's effect in IBD for use as a framework to review the pathophysiology of the disease. The panel was narrowed to 26 genes with significant evidence of mechanistic potential in IBD, which were then categorized into specific areas of pathogenesis. These include gut barrier breakdown, inappropriate recognition of commensal bacteria, immune cell activation, proinflammatory cytokine release, and subsequent impairment of the anti-inflammatory response. The eventual goal of this paper is the creation of a customized panel of IBD genes that can be used to better understand the genetic mechanism of IBD and aid in the development of future therapies in IBD.

Intestinal fibrosis is a prevalent complication of IBD that that can frequently be triggered by prolonged inflammation. Fibrosis in the gut can cause a number of issues, which continue as an ongoing challenge to healthcare systems worldwide. The primary causes of intestinal fibrosis are soluble molecules, G protein-coupled receptors, epithelial-to-mesenchymal or endothelial-to-mesenchymal transition, and the gut microbiota. Fresh perspectives coming from in vivo and in vitro experimental models demonstrate that fibrogenic pathways might be different, at least to some extent, independent of the ones that influence inflammation. Understanding the distinctive procedures of intestinal fibrogenesis should provide a realistic foundation for targeting and blocking specific fibrogenic pathways, estimating the risk of fibrotic consequences, detecting early fibrotic alterations, and eventually allowing therapy development. Here, we first summarize the inflammatory and non-inflammatory components of fibrosis, and then we elaborate on the underlying mechanism associated with multiple cytokines in fibrosis, providing the framework for future clinical practice. Following that, we discuss the relationship between modernization and disease, as well as the shortcomings of current studies. We outline fibrosis diagnosis and therapy, as well as our recommendations for the future treatment of intestinal fibrosis. We anticipate that the global review will provides a wealth of fresh knowledge and suggestions for future fibrosis clinical practice.

Probiotic-containing fermented dairy foods have the potential to benefit human health, but the importance of the dairy matrix for efficacy remains unclear. We investigated the capacity of Lacticaseibacillus paracasei BL23 in phosphate-buffered saline (BL23-PBS), BL23-fermented milk (BL23-milk), and milk to modify intestinal and behavioral responses in a dextran sodium sulfate (DSS, 3% wt/vol) mouse model of colitis. Significant sex-dependent differences were found such that female mice exhibited more severe colitis, greater weight loss, and higher mortality rates. Sex differences were also found for ion transport ex vivo, colonic cytokine and tight junction gene expression, and fecal microbiota composition. Measurements of milk and BL23 effects showed BL23-PBS consumption improved weight recovery in females, whereas milk resulted in better body weight recovery in males. Occludin and Claudin-2 gene transcript levels indicated barrier function was impaired in males, but BL23-milk was still found to improve colonic ion transport in those mice. Proinflammatory and anti-inflammatory gene expression levels were increased in both male and female mice fed BL23, and to a more variable extent, milk, compared with controls. The female mouse fecal microbiota contained high proportions of Akkermansia (average of 18.1%) at baseline, and females exhibited more changes in gut microbiota composition following BL23 and milk intake. Male fecal microbiota harbored significantly more Parasutterella and less Blautia and Roseburia after DSS treatment, independent of BL23 or milk consumption. These findings show the complex interplay between dietary components and sex-dependent responses in mitigating inflammation in the digestive tract.NEW & NOTEWORTHY Sex-dependent responses to probiotic Lacticaseibacillus paracasei and milk and the potential of the dairy matrix to enhance probiotic protection against colitis in this context have not been previously explored. Female mice were more sensitive than males to colonic injury, and neither treatment effectively alleviated inflammation in both sexes. These sex-dependent responses may result from differences in the higher baseline proportions of Akkermansia in the gut microbiome of female mice.

Endometriosis (EMT) is a common disease in reproductive-age woman and Crohn disease (CD) is a chronic inflammatory disorder in gastrointestinal tract. Previous studies reported that patients with EMT had an increased risk of CD. However, the linkage between EMT and CD remains unclear. In this study, we aimed to investigate the potential molecular mechanism of EMT and CD.

The microarray data of EMT and CD were downloaded from Gene Expression Omnibus. Common genes of EMT and CD were obtained to perform the Gene Ontology and Kyoto Encyclopedia of Gene Genomes enrichments. The protein-protein interaction network was constructed by Cytoscape software and the hub genes were identified by CytoHubba plug-in. Finally we predicted the transcription factors (TFs) of hub genes and constructed a TFs-hub genes regulation network.

A total of 50 common genes were identified. Kyoto Encyclopedia of Gene Genomes enrichment showed that the common genes mainly enriched in MAPK pathway, VEGF pathway, Wnt pathway, TGF-beta pathway, and Ras pathway. Fifteen hub genes were collected from the protein-protein interaction network, including FMOD, FRZB, CPE, SST, ISG15, EFEMP1, KDR, ADRA2A, FZD7, AQP1, IGFBP5, NAMPT, PLUA, FGF9, and FHL2. Among them, FGF9, FZD7, IGFBP5, KDR, and NAMPT were both validated in the other 2 datasets. Finally TFs-hub genes regulation network were constructed.

Our findings firstly revealed the linkage between EMT and CD, including inflammation, angiogenesis, immune regulation, and cell behaviors, which may lead to the risk of CD in EMT. FGF9, FZD7, IGFBP5, KDR, and NAMPT may closely relate to the linkage.

Numerous studies have demonstrated that bacteriophages (phages) can effectively treat intestinal bacterial infections. However, research on the impact of phages on overall body health once they enter the intestine is limited. This study utilized weaned piglets as subjects to evaluate the systemic effects of an orally administered phage cocktail on their health. Twelve 21-day-old weaned piglets were divided into control (CON) and phage gavage (Phages) groups. The phage cocktail consisted of five lytic phages, targeting Salmonella enterica serovar Choleraesuis (S. choleraesuis), Enteropathogenic Escherichia coli (EPEC), and Shiga tox-in-producing Escherichia coli (STEC). The phages group received 10 mL of phage cocktail orally for 20 consecutive days. The results show that the phage gavage did not affect the piglets' growth performance, serum biochemical indices, or most organ indices, except for the pancreas. However, the impact on the intestine was complex. Firstly, although the pancreatic index decreased, it did not affect the secretion of digestive enzymes in the intestine. Secondly, phages increased the pH of jejunum chyme and relative weight of the ileum, and enhanced intestinal barrier function without affecting the morphology of the intestine. Thirdly, phages did not proliferate in the intestine, but altered the intestinal microbiota structure and increased concentrations of microbial metabolites isobutyric acid and isovaleric acid in the colonic chyme. In addition, phages impacted the immune status, significantly increasing serum IgA, IgG, and IgM, as well as serum and intestinal mucosal IFN-γ, IL-1β, IL-17, and TGF-β, and decreasing IL-4 and IL-10. They also activated toll-like receptors TLR-4 and TLR-9. Apart from an increase in basophil numbers, the counts of other immune cells in the blood did not change. This study indicates that the impact of phages on body health is complex, especially regarding immune status, warranting further attention. Short-term phage gavage did not have significant negative effects on health but could enhance intestinal barrier function.