Pathogenesis Of Inflammatory Bowel Disease Research Articles

Maximizing Treatment Options for IBD through Drug Repurposing.

Chronic inflammation characterizes Inflammatory Bowel Disease (IBD), encompassing Crohn's Disease (CD) and Ulcerative Colitis (UC). Despite modest activity of disease in most UC patients, exacerbations occur, especially in those with severe symptoms, necessitating interventions, like colectomy. Current treatments for IBD, predominantly small molecule therapies, impose significant economic burdens. Drug repurposing offers a cost-effective alternative, leveraging existing drugs for novel therapeutic applications. This approach capitalizes on shared molecular pathways across diseases, accelerating therapeutic discovery while minimizing costs and risks. This article provides an overview of IBD and explores drug repurposing as a promising avenue for more effective and affordable treatments. Through computational and animal studies, potential drug candidates are categorized, offering insights into IBD pathogenesis and treatment strategies.

Anti-IL23/12 agents and JAK inhibitors for inflammatory bowel disease

IBD (inflammatory bowel disease) is a chronic inflammatory disease of the gastrointestinal tract with increasing incidence worldwide. Multiple factors, such as genetic background, environmental and luminal factors, and mucosal immune dysregulation, have been implicated in the cause of IBD, although the cause of the disease remains unknown. IL-12 and IL-23 and their downstream signaling pathways participate in the pathogenesis of inflammatory bowel disease. Early and aggressive treatment with biologic therapies or novel small molecules is needed to decrease complications and the need for hospitalization and surgery. The landscape of inflammatory bowel disease (IBD) treatment has tremendously improved with the development of biologics and small molecule drugs. Several novel biologics and small molecule drugs targeting IL-12 and IL-23 and their downstream targets have shown positive efficacy and safety data in clinical trials, and several drugs have been approved for the treatment of IBD. In the future, numerous potential emerging therapeutic options for IBD treatment are believed to come to the fore, achieving disease cure.

The Effect of Protein Nutritional Support on Inflammatory Bowel Disease and Its Potential Mechanisms

Inflammatory bowel disease (IBD), a complex chronic inflammatory bowel disorder that includes Crohn’s disease (CD) and Ulcerative Colitis (UC), has become a globally increasing health concern. Nutrition, as an important factor influencing the occurrence and development of IBD, has attracted more and more attention. As the most important nutrient, protein can not only provide energy and nutrition required by patients, but also help repair damaged intestinal tissue, enhance immunity, and thus alleviate inflammation. Numerous studies have shown that protein nutritional support plays a significant role in the treatment and remission of IBD. This article presents a comprehensive review of the pathogenesis of IBD and analyzes and summarizes the potential mechanisms of protein nutritional support in IBD. Additionally, it provides an overview of the clinical effects of protein nutritional support in IBD and its impact on clinical complications. Research findings reveal that protein nutritional support demonstrates significant benefits in improving clinical symptoms, reducing the risk of complications, and improving quality of life in IBD patients. Therefore, protein nutritional support is expected to provide a new approach for the treatment of IBD.

Lactobacillus acidophilus inhibits the TNF-α-induced increase in intestinal epithelial tight junction permeability via a TLR-2 and PI3K-dependent inhibition of NF-κB activation

BackgroundDefective intestinal epithelial tight junction (TJ), characterized by an increase in intestinal TJ permeability, has been shown to play a critical role in the pathogenesis of inflammatory bowel disease (IBD). Tumor necrosis factor-α (TNF-α) is a key pro-inflammatory cytokine involved in the immunopathology of IBD and has been shown to cause an increase in intestinal epithelial TJ permeability. Although TNF-α antibodies and other biologics have been advanced for use in IBD treatment, these therapies are associated with severe side effects and have limited efficacy, and there is an urgent need for therapies with benign profiles and high therapeutic efficacy. Probiotic bacteria have beneficial effects and are generally safe and represent an important class of potential therapeutic agents in IBD. Lactobacillus acidophilus (LA) is one of the most used probiotics for wide-ranging health benefits, including in gastrointestinal, metabolic, and inflammatory disorders. A specific strain of LA, LA1, was recently demonstrated to have protective and therapeutic effects on the intestinal epithelial TJ barrier. However, the mechanisms of actions of LA1 remain largely unknown.MethodsThe primary aim of this study was to investigate microbial-epithelial interactions and novel signaling pathways that regulate the effect of LA1 on TNF-α-induced increase in intestinal epithelial TJ permeability, using cell culture and animal model systems.Results and ConclusionPre-treatment of filter-grown Caco-2 monolayers with LA1 prevented the TNF-α-induced increase in intestinal epithelial TJ permeability by inhibiting TNF-α-induced activation of NF-κB p50/p65 and myosin light chain kinase (MLCK) gene and kinase activity in a TLR-2-dependent manner. LA1 produced a TLR-2- and MyD88-dependent activation of NF-κB p50/p65 in immune cells; however, LA1, in intestinal cells, inhibited the NF-κB p50/p65 activation in a TLR-2-dependent but MyD88-independent manner. In addition, LA1 inhibition of NF-κB p50/p65 and MLCK gene was mediated by TLR-2 pathway activation of phosphatidylinositol 3-kinase (PI3K) and IKK-α phosphorylation. Our results demonstrated novel intracellular signaling pathways by which LA1/TLR-2 suppresses the TNF-α pathway activation of NF-κB p50/p65 in intestinal epithelial cells and protects against the TNF-α-induced increase in intestinal epithelial TJ permeability.

Integrating plasma proteomics with genome-wide association data to identify novel drug targets for inflammatory bowel disease

Inflammatory bowel disease (IBD) is a chronic disease that includes Crohn’s disease (CD) and ulcerative colitis (UC). Although genome-wide association studies (GWASs) have identified many relevant genetic risk loci, the impact of these loci on protein abundance and their potential utility as clinical therapeutic targets remain uncertain. Therefore, this study aimed to investigate the pathogenesis of IBD and identify effective therapeutic targets through a comprehensive and integrated analysis. We systematically integrated GWAS data related to IBD, UC and CD (N = 25,305) by the study of de Lange KM with the human blood proteome (N = 7213) by the Atherosclerosis Risk in Communities (ARIC) study. Proteome-wide association study (PWAS), mendelian randomisation (MR) and Bayesian colocalisation analysis were used to identify proteins contributing to the risk of IBD. Integrative analysis revealed that genetic variations in IBD, UC and CD affected the abundance of five (ERAP2, RIPK2, TALDO1, CADM2 and RHOC), three (VSIR, HGFAC and CADM2) and two (MST1 and FLRT3) cis-regulated plasma proteins, respectively (P < 0.05). Among the proteins identified via Bayesian colocalisation analysis, CADM2 was found to be an important common protein between IBD and UC. A drug and five druggable target genes were identified from DGIdb after Bayesian colocalisation analysis. Our study's findings from genetic and proteomic approaches have identified compelling proteins that may serve as important leads for future functional studies and potential drug targets for IBD (UC and CD).

Eosinophils, Eosinophilic Gastrointestinal Diseases, and Inflammatory Bowel Disease: A Critical Review

Background/Objectives: Inflammatory bowel disease (IBD) and eosinophilic gastrointestinal diseases (EGIDs) are complex, multifactorial chronic inflammatory disorders affecting the gastrointestinal tract. Their epidemiology, particularly for eosinophilic esophagitis (EoE), is increasing worldwide, with a rise in the co-diagnosis of IBD and EGIDs. Both disorders share common risk factors, such as early exposure to antibiotics or specific dietary habits. Moreover, from a molecular perspective, eosinophilic infiltration is crucial in the diagnosis of eosinophilic disorders, and it also plays a pivotal role in IBD histological diagnosis. Indeed, recent evidence highlights the significant role of eosinophils in the health of the intestinal mucosal barrier and as mediators between innate and acquired immunity, even indicating a potential role in IBD pathogenesis. This narrative review aims to summarize the current evidence regarding the common clinical and molecular aspects of EGIDs and IBD and the current state of knowledge regarding overlap conditions and their pathogenesis. Methods: Pubmed was searched until May 2023 to assess relevant studies describing the epidemiology, pathophysiology, and therapy of EGIDs in IBD. Results: The immune pathways and mechanisms underlying both EGIDs and IBD remain partially known. An improved understanding of the role of eosinophils in overlapping conditions could lead to enhanced diagnostic precision, the development of more effective future therapeutic strategies, and a more accurate prediction of patient response. Consequently, the identification of red flags indicative of an eosinophilic disorder in IBD patients is of paramount importance and must be evaluated on a case-by-case basis.

Fibroblast growth factor receptor 4 deficiency in macrophages aggravates experimental colitis by promoting M1-polarization.

Compelling evidence indicates that dysregulated macrophages may play a key role in driving inflammation in inflammatory bowel disease (IBD). Fibroblast growth factor (FGF)-19, which is secreted by ileal enterocytes in response to bile acids, has been found to be significantly lower in IBD patients compared to healthy individuals, and is negatively correlated with the severity of diarrhea. This study aims to explore the potential impact of FGF19 signaling on macrophage polarization and its involvement in the pathogenesis of IBD. The dextran sulfate sodium (DSS)-induced mouse colitis model was utilized to replicate the pathology of human IBD. Mice were created with a conditional knockout of FGFR4 (a specific receptor of FGF19) in myeloid cells, as well as mice that overexpressing FGF19 specifically in the liver. The severity of colitis was measured using the disease activity index (DAI) and histopathological staining. Various techniques such as Western Blotting, quantitative PCR, flow cytometry, and ELISA were employed to assess polarization and the expression of inflammatory genes. Myeloid-specific FGFR4 deficiency exacerbated colitis in the DSS mouse model. Deletion or inhibition of FGFR4 in bone marrow-derived macrophages (BMDMs) skewed macrophages towards M1 polarization. Analysis of transcriptome sequencing data revealed that FGFR4 deletion in macrophages significantly increased the activity of the complement pathway, leading to an enhanced inflammatory response triggered by LPS. Mechanistically, FGFR4-knockout in macrophages promoted complement activation and inflammatory response by upregulating the nuclear factor-κB (NF-κB)-pentraxin3 (PTX3) pathway. Additionally, FGF19 suppressed these pathways and reduced inflammatory response by activating FGFR4 in inflammatory macrophages. Liver-specific overexpression of FGF19 also mitigated inflammatory responses induced by DSS in vivo. Our study highlights the significance of FGF19-FGFR4 signaling in macrophage polarization and the pathogenesis of IBD, offering a potential new therapeutic target for IBD.

Fibroblast growth factor receptor 4 deficiency in macrophages aggravates experimental colitis by promoting M1-polarization.

Compelling evidence indicates that dysregulated macrophages may play a key role in driving inflammation in inflammatory bowel disease (IBD). Fibroblast growth factor (FGF)-19, which is secreted by ileal enterocytes in response to bile acids, has been found to be significantly lower in IBD patients compared to healthy individuals, and is negatively correlated with the severity of diarrhea. This study aims to explore the potential impact of FGF19 signaling on macrophage polarization and its involvement in the pathogenesis of IBD. The dextran sulfate sodium (DSS)-induced mouse colitis model was utilized to replicate the pathology of human IBD. Mice were created with a conditional knockout of FGFR4 (a specific receptor of FGF19) in myeloid cells, as well as mice that overexpressing FGF19 specifically in the liver. The severity of colitis was measured using the disease activity index (DAI) and histopathological staining. Various techniques such as Western Blotting, quantitative PCR, flow cytometry, and ELISA were employed to assess polarization and the expression of inflammatory genes. Myeloid-specific FGFR4 deficiency exacerbated colitis in the DSS mouse model. Deletion or inhibition of FGFR4 in bone marrow-derived macrophages (BMDMs) skewed macrophages towards M1 polarization. Analysis of transcriptome sequencing data revealed that FGFR4 deletion in macrophages significantly increased the activity of the complement pathway, leading to an enhanced inflammatory response triggered by LPS. Mechanistically, FGFR4-knockout in macrophages promoted complement activation and inflammatory response by upregulating the nuclear factor-κB (NF-κB)-pentraxin3 (PTX3) pathway. Additionally, FGF19 suppressed these pathways and reduced inflammatory response by activating FGFR4 in inflammatory macrophages. Liver-specific overexpression of FGF19 also mitigated inflammatory responses induced by DSS in vivo. Our study highlights the significance of FGF19-FGFR4 signaling in macrophage polarization and the pathogenesis of IBD, offering a potential new therapeutic target for IBD.

CircHIPK2 Contributes Cell Growth in Intestinal Epithelial of Colitis and Colorectal Cancer through Promoting TAZ Translation.

Colorectal cancer (CRC) and inflammatory bowel disease (IBD) are escalating global health concerns. Despite their distinct clinical presentations, both disorders share intricate genetic and molecular interactions. The Hippo signaling pathway plays a crucial role in regulating cell processes and is implicated in the pathogenesis of IBD and CRC. Circular RNAs (circRNAs) have gained attention for their roles in various diseases, including IBD and CRC. However, a comprehensive understanding of specific circRNAs involved in both IBD and CRC, and their functional roles is lacking. Here, it is found that circHIPK2 (hsa_circRNA_104507) is a bona fide circRNA consistently upregulated in both IBD and CRC suggesting its potential as a biomarker. Furthermore, silencing of circHIPK2 suppressed the growth of CRC cells in vitro and in vivo. Interestingly, decreased circHipk2 potentiated dextran sulfate sodium (DSS)-induced colitis but alleviated colitis-associated tumorigenesis. Most significantly, mechanistic investigations further unveil that circHIPK2, mediated by FUS, interacting with EIF4A3 to promote the translation of TAZ, ultimately increasing the transcription of downstream target genes CCN1 and CCN2. Taken together, circHIPK2 emerges as a key player in the shared mechanisms of IBD and CRC, modulating the Hippo signaling pathway. CircHIPK2-EIF4A3 axis contributes to cell growth in intestinal epithelial of colitis and CRC by enhancing TAZ translation.

The role of the fecal microbiota in inflammatory bowel disease.

The understanding of the potential role of the microbiota in the pathogenesis of inflammatory bowel disease (IBD) is ever-evolving. Traditionally, the management of IBD has involved medical therapy and/or surgical intervention. IBD can be characterized by gut microbiome alterations through various pathological processes. Various studies delve into nontraditional methods such as probiotics and fecal microbiota transplant and their potential therapeutic effects. Fecal microbiota transplant involves the delivery of a balanced composition of gut microorganisms into an affected patient via multiple possible routes and methods, while probiotics consist of live microorganisms given via the oral route. At present, neither method is considered first-line treatment, however, fecal microbiota transplant has shown potential success in inducing and maintaining remission in ulcerative colitis. In a study by Kruis and colleagues, Escherichia coli Nissle 1917 was considered to be equivalent to mesalamine in mild ulcerative colitis. Alteration of the microbiome in the management of Crohn's disease is less well defined. Furthermore, variation in the clinical usefulness of 5-aminosalicylic acid medication has been attributed, in part, to its acetylation and inactivation by gut microbes. In summary, our understanding of the microbiome's role is continually advancing, with the possibility of paving the way for personalized medicine based on the microbiome.

N,N,N′,N′-Tetrakis(2-pyridylmethyl)ethylenediamine induces endothelium-dependent hyperpolarization-mediated vasorelaxation via store-operated calcium entry mechanism in healthy and intestinal inflammatory mice

Although the store-operated Ca2+ entry (SOCE) plays a critical role in maintaining Ca2+ homeostasis in vascular endothelial cells (VECs), its role in regulating endothelium-dependent hyperpolarization (EDH)-mediated vasorelaxation is largely unknown. Inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) are the most common gastrointestinal disorders with no effective cures. The present study applied N,N,N′,N′-tetrakis (2-pyridylmethyl)ethylenediamine (TPEN) as a Ca2+ chelator in the endoplasmic reticulum (ER) to study the SOCE/EDH-mediated vasorelaxation of micro-arteries and their involvements in the pathogenesis of IBD and IBS. Human submucosal arterioles and the second-order branch of 6–8 weeks male C57BL/6 mouse mesenteric arterioles were used, and TPEN-induced vasorelaxation was recorded by Danish DMT520A microvascular measuring system. The mice were fed water with 2.5 % dextran sulfate sodium for 7 days to induce mouse model of ulcerative colitis, and water avoidance stress was used to induce mouse model of IBS. The statistical significance of differences in the means of experimental groups was determined using a t-test for two groups or one-way ANOVA for more than two groups. TPEN concentration-dependently induced vasorelaxation of human colonic submucosal arterioles and the second-order branch of murine mesenteric arteries in endothelium-dependent manner. TPEN-induced vasorelaxation was much greater in the arteries pre-constricted by noradrenaline than those by high K+. While TPEN-induced vasorelaxation was unaffected by inhibitors of NO and PGI2, it was significantly inhibited by the selective inhibitors of IKCa and SKCa channels but was potentiated by their activator. Moreover, TPEN-induced vasorelaxation was attenuated by selective inhibitors of NCX, NKA, SOCE, STIM translocation and Orai transportation. Finally, TPEN-induced vasorelaxation via SOCE/EDH was impaired in colitic mice but remained intact in IBS mice. Interestingly, TPEN could rescue vagus neurotransmitter ACh-induced vasorelaxation that was impaired in IBS mice. Therefore, since TPEN-induced SOCE/EDH-mediated vasorelaxation of mesenteric arteries is well-preserved to be able to rescue ACh-induced vasorelaxation impaired in IBS, TPEN has therapeutic potentials for IBS.

Peroxiredoxin 3 deficiency exacerbates DSS-induced acute colitis via exosomal miR-1260b-mediated barrier disruption and pro-inflammatory signaling.

Peroxiredoxin3 (Prdx3) is an intracellular antioxidant enzyme that is specifically localized in mitochondria and protects against oxidative stress by removing mitochondrial reactive oxygen species (ROS). The intestinal epithelium provides a physical and biochemical barrier that segregates host tissues from commensal bacteria to maintain intestinal homeostasis. An imbalance between the cellular antioxidant defense system and oxidative stress has been implicated in the pathogenesis of inflammatory bowel disease (IBD). However, the role of Prdx3 in the intestinal epithelium under intestinal inflammation has not been elucidated. To investigate the potential role of Prdx3 in intestinal inflammation, we used intestinal epithelial cell (IEC)-specific Prdx3-knockout mice. IEC-specific Prdx3-deficient mice showed more severe colitis phenotypes with greater degrees of body weight loss, colon shortening, barrier disruption, mitochondrial damage, and ROS generation in IECs. Furthermore, exosomal miR-1260b was dramatically increased in Prdx3-knockdown colonic epithelial cells. Mechanistically, Prdx3 deficiency promoted intestinal barrier disruption and inflammation via P38-MAPK/NFκB signaling. this is the first study to report the protective role of Prdx3 in acute colitis using IEC-specific conditional knockout mice. our study sheds light on the role of exosome-loaded miRNAs, particularly miR-1260b, in IBD. targeting miR-1260b or modulating exosome-mediated intercellular communication may hold promise as potential therapeutic strategies for managing IBD and restoring intestinal barrier integrity.

Intestinal epithelial Cldn-7 regulates intestinal inflammation by altering the gut microbiota

Background and aimTight junctions maintain gut homeostasis by forming a physical barrier that protects the gut from invasion by microbiota. Cldn-7 is an important component involved in this protection, but the relationship between Cldn-7, intestinal inflammation, and gut microbiota has not been clarified. Here, we hypothesize that Cldn-7 depletion affects intestinal inflammation by altering the gut microbiota. MethodsBased on the induced intestinal condition of Cldn-7 knockout mice (Cldn7fl/fl;villin-CreaERT2), we established the intestinal flora depletion model and colitis model by antibiotic drinking and feeding with dextran sodium sulfate (DSS). The environment of Cldn-7 gene deletion mice was changed by co-housing experiment. AB-PAS staining and Muc2 were used to detect the effect of co-housing and Cldn-7 deficiency on the mucus layer after flora depletion. qRT-PCR was used to detect the expression of intestinal inflammatory factors and AMPs in mice. Feces were collected and proportions of microbiota were analyzed by 16 S rRNA amplicon sequencing. ResultsMice in the co-housing experiment had altered intestinal microbiota, including diversity, composition, and functional prediction, compared to controls. Intestinal inflammation was restored to some extent following altered intestinal microbiota. The intestinal inflammation caused by Cldn-7 deficiency and susceptibility to DSS could be reduced after antibiotic administration compared to controls, in terms of phenotype, pathological changes, inflammatory factors, mucus barrier, and expression of AMPs. ConclusionsIn analyses of intestinal tissues, colitis induction, and gut microbiota in mice with intestinal disruption of Cldn-7, we found this protein to prevent intestinal inflammation by regulating the gut microbiota. Cldn-7might therefore be an important mediator of host–microbiome interactions. Our research has revealed that Cldn-7 plays an indispensable role in maintaining intestinal homeostasis by regulating the gut microbiota and impacting intestinal inflammation. These findings provide new insights into the pathogenesis of ulcerative colitis.

Association of selected adipokines with vitamin D deficiency in children with inflammatory bowel disease

BackgroundAdipose tissue is significantly involved in inflammatory bowel disease (IBD). Vitamin D can affect both adipogenesis and inflammation. The aim of this study was to compare the production of selected adipokines, potentially involved in the pathogenesis of IBD - adiponectin, resistin, retinol binding protein 4 (RBP-4), adipocyte fatty acid binding protein and nesfatin-1 in children with IBD according to the presence of 25-hydroxyvitamin D (25(OH)D) deficiency.MethodsThe study was conducted as a case-control study in pediatric patients with IBD and healthy children of the same sex and age. In addition to adipokines and 25(OH)D, anthropometric parameters, markers of inflammation and disease activity were assessed in all participants.ResultsChildren with IBD had significantly higher resistin levels regardless of 25(OH)D levels. IBD patients with 25(OH)D deficiency only had significantly lower RBP-4 compared to healthy controls and also compared to IBD patients without 25(OH)D deficiency. No other significant differences in adipokines were found in children with IBD with or without 25(OH)D deficiency. 25(OH)D levels in IBD patients corelated with RBP-4 only, and did not correlate with other adipokines.ConclusionsWhether the lower RBP-4 levels in the 25(OH)D-deficient group of IBD patients directly reflect vitamin D deficiency remains uncertain. The production of other adipokines does not appear to be directly related to vitamin D deficiency.

The role of selenium in the pathogenesis and therapy of inflammatory bowel diseases

In recent decades, Russia, as well as around the world, has recorded a steady increase in the incidence of inflammatory bowel diseases, which include ulcerative colitis and Crohn’s disease. The incidence of inflammatory bowel diseases in Russia accounts for 4.1 per 100 thousand of the population for ulcerative colitis and 0.8 per 100 thousand – for Crohn’s disease. The prevalence of inflammatory bowel diseases in Russia is 19.3–29.8 cases per 100 thousand of the population for ulcerative colitis and 3.0–4.5 per 100 thousand – for Crohn’s disease. In recent years, selenium has attracted the attention of researchers due to its anti-inflammatory and antioxidant properties as well as its ability to influence the intestinal flora. There is evidence that inflammatory bowel diseases has deficiency of trace elements, which is more often detected during active period of the disease than during remission. The purpose of the review is to summarize and analyze current literature data on the relationship between selenium and inflammatory bowel diseases, with special emphasis on the mechanism and function of selenium in intestinal inflammation as well as to discuss the possible therapeutic use of selenium in inflammatory bowel diseases. The authors conducted a search for publications in the electronic databases PubMed and eLibrary. After the selection procedure, 87 studies were included in the review. Due to its anti-inflammatory and antioxidant properties, the concentration of selenium can be crucial in the occurrence and development of inflammatory bowel diseases. Dietary recommendations with the inclusion of selenium gradually improve the quality of life of patients with inflammatory bowel diseases. The development and use of selenium drugs have also provided new therapy strategies. In the future, a large number of experimental and clinical studies are still needed to confirm the relationship between selenium and inflammatory bowel diseases, which, in turn, will mark a new turn in the prevention and treatment of these severe chronic diseases.

Current and future microbiome-based therapies in inflammatory bowel disease.

The role of the microbiome and dysbiosis is increasingly recognized in the pathogenesis of inflammatory bowel disease (IBD). Intestinal microbiota transplant (IMT), previously termed fecal microbiota transplant has demonstrated efficacy in restoring a healthy microbiome and promoting gut health in recurrent Clostridioides difficile infection. Several randomized trials (RCTs) highlighted IMT's potential in treating ulcerative colitis, while smaller studies reported on its application in managing Crohn's disease and pouchitis. This review delves into the current understanding of dysbiosis in IBD, highlighting the distinctions in the microbiota of patients with IBD compared to healthy controls. It explores the mechanisms by which IMT can restore a healthy microbiome and provides a focused analysis of recent RCTs using IMT for inducing and maintaining remission in IBD. Lastly, we discuss the current knowledge gaps that limit its widespread use. The body of evidence supporting the use of IMT in IBD is growing. The lack of a standardized protocol impedes its application beyond clinical trials. Further research is needed to identify patient profile and disease phenotypes that benefit from IMT, to delineate key donor characteristics, optimize the delivery route, dosage, and frequency.

Rapamycin promotes the intestinal barrier repair in ulcerative colitis via the mTOR/PBLD/AMOT signaling pathway

Intestinal barrier dysfunction characterized by the functional loss of the intestinal epithelium's tight junction (TJ) barrier is a key factor in the pathogenesis of ulcerative colitis (UC). Although rapamycin, an mTOR (mechanistic target of rapamycin) inhibitor, has shown promise in inducing clinical remission and mucosal healing in inflammatory bowel disease, its underlying mechanism remains elusive. Thus, this study investigated the role of the mTOR pathway in regulating the intestinal barrier. To investigate the molecular mechanism regulating the intestinal barrier, specific intestinal epithelial phenazine biosynthesis-like domain-containing protein (PBLD)-deficient (PBLDIEC−/−) mice and control wild-type (WT) mice were intraperitoneally injected with rapamycin or MHY1485. To determine the relevance of the findings for UC, we analyzed transcriptome data and single-cell expression profiles from public databases and intestinal mucosal tissues obtained from patients with active UC or colon cancer. We observed that mTOR activation in the intestinal epithelium of patients with active UC. Moreover, in vivo, rapamycin markedly increased the expressions of PBLD and TJ proteins and reduced intestinal inflammation in mice with dextran sulfate sodium-induced enteritis. However, the therapeutic efficacy of rapamycin was notably reduced in PBLDIEC−/− mice. In vitro, rapamycin influenced PBLD expression by modulating the nuclear transcription of transcription factor EB (TFEB). Angiomotin (AMOT) could directly bind to PBLD, and rapamycin could not effectively increase the expression of TJ proteins after the knockdown of PBLD or AMOT. In summary, the administration of rapamycin is a potential treatment for UC, and targeting the mTOR/PBLD/AMOT axis is a potential novel approach for UC treatment.

Active Inflammatory Bowel Disease Is Associated with Short Sleep Duration via Objective Measures.

Poor sleep quality has been associated with inflammatory bowel disease (IBD) activity, although studies incorporating actigraphy suggest that the perception of sleep differs rather than objective difference in sleep quality. Short sleep duration has been associated with increased pro-inflammatory cytokines that have been implicated in the pathogenesis of IBD. An observational study incorporated home-based polysomnography that was conducted within twelve weeks of an objective assessment of IBD activity such as calprotectin, colonoscopy, or MRI. Participants completed a survey on subjective measures of sleep quality, clinical IBD activity, depression, and anxiety. Polysomnography results were normalized by standardized results for a healthy population matched by gender and age. Twenty participants were included in the final analysis. Those with objective evidence of active IBD had shorter stage 2 sleep duration, leading to shorter NREM sleep and total sleep time. Sleep latency was also longer in those with active IBD, leading to worse sleep efficiency-despite no difference in time available for sleep between the two groups. These changes persisted after normalization of polysomnography results by health population age and gender matched norms. Depression scores correlated with sleep latency and stage 2 sleep duration and were associated with objectively active IBD. Objectively confirmed active IBD was associated with shorter sleep duration. Observed sleep changes may, in part, relate to coexistent depression. Further research should consider the utility of changes in sleep duration and quality as a means of longitudinally assessing objective IBD activity.

Advances in Inflammatory Bowel Disease Diagnostics: Machine Learning and Genomic Profiling Reveal Key Biomarkers for Early Detection.

This study, utilizing high-throughput technologies and Machine Learning (ML), has identified gene biomarkers and molecular signatures in Inflammatory Bowel Disease (IBD). We could identify significant upregulated or downregulated genes in IBD patients by comparing gene expression levels in colonic specimens from 172 IBD patients and 22 healthy individuals using the GSE75214 microarray dataset. Our ML techniques and feature selection methods revealed six Differentially Expressed Gene (DEG) biomarkers (VWF, IL1RL1, DENND2B, MMP14, NAAA, and PANK1) with strong diagnostic potential for IBD. The Random Forest (RF) model demonstrated exceptional performance, with accuracy, F1-score, and AUC values exceeding 0.98. Our findings were rigorously validated with independent datasets (GSE36807 and GSE10616), further bolstering their credibility and showing favorable performance metrics (accuracy: 0.841, F1-score: 0.734, AUC: 0.887). Our functional annotation and pathway enrichment analysis provided insights into crucial pathways associated with these dysregulated genes. DENND2B and PANK1 were identified as novel IBD biomarkers, advancing our understanding of the disease. The validation in independent cohorts enhances the reliability of these findings and underscores their potential for early detection and personalized treatment of IBD. Further exploration of these genes is necessary to fully comprehend their roles in IBD pathogenesis and develop improved diagnostic tools and therapies. This study significantly contributes to IBD research with valuable insights, potentially greatly enhancing patient care.

Targeting the Interleukin 23 Pathway in Inflammatory Bowel Disease.

Interleukin (IL) 23, a member of the IL12 family of cytokines, maintains intestinal homeostasis, but is also implicated in the pathogenesis of inflammatory bowel diseases (IBDs). The IL23 receptor is a heterodimer composed of disulfide-linked p19 and p23 subunits. Humanized monoclonal antibodies selectively targeting the p19 subunit of IL23 are poised to become prominent drugs in IBDs. In this review, we discuss the pharmacodynamic and pharmacokinetic properties of the currently available IL23p19 inhibitors and discuss the mechanistic underpinnings of their therapeutic effects, including the mechanism of action, epitope affinity, potency, and downstream signaling. Furthermore, we address available data on the efficacy, safety, and tolerability of IL23-specific p19 inhibitors in the treatment of IBDs and discuss important studies performed in other immune-mediated inflammatory diseases. Finally, we evaluate the potential for combining classes of biological therapies and provide future directions on the development of precision medicine-guided positioning of IL23p19 inhibitors in IBD.