Characterization of faecal microbiota and serum inflammatory markers in dogs diagnosed with chronic enteropathy or small-cell lymphoma: a pilot study.

Dogs diagnosed with chronic enteropathy (CE) or small-cell lymphoma (SCL) exhibit marked differences in faecal microbiota and organic acid profiles compared with healthy dogs, as well as immune abnormalities in intestinal mucosal tissue. However, few studies have analysed trace organic acids, such as succinic acid, which have been suggested to be associated with IBD in humans. Therefore, in this study, we compared the faecal microbiota and organic acid profiles as well as serum inflammatory markers between dogs with disease (n = 11; 6 with CE and 5 with SCL) and healthy controls (n = 16). We also performed machine learning and correlation analysis to obtain more detailed insights into the characteristics of affected dogs. These results revealed that dogs with CE and SCL had lower levels of Erysipelotrichaceae (e.g. Turicibacter and Allobaculum), exhibited abnormalities in the succinic acid metabolism (i.e. succinic acid accumulation and decreased levels of Phascolarctobacterium as succinic acid-utilising bacteria) and increased levels of pathobiont bacteria such as Escherichia-Shigella. Additionally, the presence of Dubosiella was significantly negatively correlated with Canine Inflammatory Bowel Disease Activity Index scores. These findings are expected to aid the development of microbiome-based medications and/or supplements, although further verification is needed.

Sialylation in the gut: From mucosal protection to disease pathogenesis.

Sialylation, a crucial post-translational modification of glycoconjugates, entails the attachment of sialic acid (SA) to the terminal glycans of glycoproteins and glycolipids through a tightly regulated enzymatic process involving various enzymes. This review offers a comprehensive exploration of sialylation within the gut, encompassing its involvement in mucosal protection and its impact on disease progression. The sialylation of mucins and epithelial glycoproteins contributes to the integrity of the intestinal mucosal barrier. Furthermore, sialylation regulates immune responses in the gut, shaping interactions among immune cells, as well as their activation and tolerance. Additionally, the gut microbiota and gut-brain axis communication are involved in the role of sialylation in intestinal health. Altered sialylation patterns have been implicated in various intestinal diseases, including inflammatory bowel disease (IBD), colorectal cancer (CRC), and other intestinal disorders. Emerging research underscores sialylation as a promising avenue for diagnostic, prognostic, and therapeutic interventions in intestinal diseases. Potential strategies such as sialic acid supplementation, inhibition of sialidases, immunotherapy targeting sialylated antigens, and modulation of sialyltransferases have been utilized in the treatment of intestinal diseases. Future research directions will focus on elucidating the molecular mechanisms underlying sialylation alterations, identifying sialylation-based biomarkers, and developing targeted interventions for precision medicine approaches.

Evaluating the causal effect of circulating proteome on the risk of inflammatory bowel disease-related traits using Mendelian randomization.

Objective: This study sought to identify circulating proteins causally linked to Inflammatory Bowel Disease (IBD) traits through a Mendelian Randomization (MR) analytical framework. Methods: Using a large-scale, two-sample MR approach, we estimated the genetic links of numerous plasma proteins with IBD and its subtypes, leveraging information from the Inflammatory Bowel Disease Genetics Consortium. To assess the robustness of MR findings, methods like Bayesian colocalization, and Steiger filtering analysis, evaluation of protein-altering variants. Further insights into IBD's underlying mechanisms and therapeutic targets were gleaned from single-cell sequencing analyses, protein-protein interaction assessments, pathway enrichment analyses, and evaluation of drug targets. Results: By cis-only MR analysis, we identified 83 protein-phenotype associations involving 27 different proteins associated with at least one IBD subtype. Among these proteins, DAG1, IL10, IL12B, IL23R, MST1, STAT3 and TNFRSF6B showed overlapping positive or negative associations in all IBD phenotypes. Extending to cis + trans MR analysis, we further identified 117 protein-feature associations, including 44 unique proteins, most of which were not detected in the cis-only analysis. In addition, by performing co-localization analysis and Steiger filtering analysis on the prioritized associations, we further confirmed the causal relationship between these proteins and the IBD phenotype and verified the exact causal direction from the protein to the IBD-related feature. Conclusion: MR analysis facilitated the identification of numerous circulating proteins associated with IBD traits, unveiling protein-mediated mechanisms and promising therapeutic targets.

[Old and New Biologics and Small Molecules in Inflammatory Bowel Disease: Anti Integrins].

Recently, novel biologics or small molecular drugs have been introduced for overcoming the unmet needs associated with anti-tumor necrosis factor α agents for inflammtory bowel disease (IBD) treatment. Among these novel drugs, anti integrin agents block leukocyte trafficking to the intestine by blocking the interaction between integrin and cell adhesion molecules. Vedolizumab (anti-α4ß7) is most widely used anti-integrin approved in both ulcerative colitis and Crohn's disease .It has been shown to be effective in both induction and maintenance therapy with a favorable safety profile due to gut selectivity. Several models incorporating clinical, genetic, immune and gut microbial markers to predict response to vedolizumab in IBD have been developed. Etrolizumab (anti-ß7) blocks leukocyte trafficking via α4ß7 and cell adhesion via αEß7 integrins. In addition, the introduction of subcutaneous vedolizumab showed similar efficacy and safety with improved patients' convenience. Other investigational anti-integrin therapies include abrilumab (anti-α4ß7 IgG2), PN-943 (orally administered and gut-restricted α4ß7 antagonist peptide), AJM300 (orally active small molecule inhibitor of α4), and ontamalimab (anti-MAdCAM-1 IgG).

[Small Molecule Therapy for Inflammatory Bowel Disease: JAK Inhibitors and S1PR Modulators].

Small molecules, including Janus kinase (JAK) inhibitors and sphingosine-1-phosphate receptor modulators (S1PRMs), are promising new treatments for inflammatory bowel disease (IBD). Small molecules exhibit more predictable pharmacokinetics than biologics, are less likely to induce immune responses, and can be administered orally. JAK inhibitors function by blocking the activity of JAK enzymes, which prevents the subsequent phosphorylation and activation of signal transducer and activator of transcription (STAT) proteins. Tofacitinib and filgotinib are approved for treating ulcerative colitis (UC), while upadacitinib is approved for UC and Crohn's disease. Nevertheless, JAK inhibitors can increase the risk of herpes zoster, cancer, major adverse cardiovascular events, and venous thromboembolism. S1PRMs bind to S1PRs, particularly S1PR1, on lymphocytes. This interaction inhibits lymphocytes from exiting the lymph nodes and migrating to the gut, thereby reducing inflammation and the immune response in the intestinal mucosa. Ozanimod and etrasimod are S1PRMs approved for the treatment of UC, but they can cause side effects such as bradycardia, conduction disorder, and macular edema. Overall, JAK inhibitors and S1PRMs offer significant benefits in managing IBD, although their potential side effects require careful monitoring.

[Old and New Biologics and Small Molecules in Inflammatory Bowel Disease: Anti-interleukins].

Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, is a chronic inflammatory disease of the gastrointestinal tract. The introduction of biologics, particularly anti-interleukin (IL) agents, has revolutionized IBD treatment. This review summarizes the role of ILs in IBD pathophysiology and describes the efficacy and positioning of anti-IL therapies. We discuss the functions of key ILs in IBD and their potential as therapeutic targets. The review then discusses anti-IL therapies, focusing primarily on ustekinumab (anti-IL-12/23), risankizumab (anti-IL-23), and mirikizumab (anti-IL-23). Clinical trial data demonstrate their efficacy in inducing and maintaining remission in Crohn's disease and ulcerative colitis. The safety profiles of these agents are generally favorable. However, long-term safety data for newer agents are still limited. The review also briefly discusses emerging therapies such as guselkumab and brazikumab. Network meta-analyses suggest that anti-IL therapies perform well compared to other biological agents. These agents may be considered first- or second-line therapies for many patients, especially those with comorbidities or safety concerns. Anti-IL therapies represent a significant advancement in IBD treatment, offering effective and relatively safe options for patients with moderate to severe disease.

[Old and New Biologics and Small Molecules in Inflammatory Bowel Disease: Anti-Tumor Necrosis Factors].

Inflammatory bowel disease (IBD), which includes ulcerative colitis and Crohn's disease, is a chronic condition characterized by relapsing and remitting inflammation of the gastrointestinal tract. The pathogenesis involves a complex interplay of genetic, environmental, and immune factors. Treatment paradigms have evolved significantly over the past few decades, with the introduction of biologics, particularly anti-TNF (tumor necrosis factor) agents, marking a significant advancement. Anti-TNF therapies, including infliximab, adalimumab, golimumab, and certolizumab pegol, have efficacy in inducing and maintaining remission, promoting mucosal healing, and improving the quality of life in moderate to severe IBD patients. The early and appropriate use of these agents can mitigate disease progression and reduce the dependency on corticosteroids, enhancing long-term patient outcomes. Nevertheless, these therapies are expensive and are associated with potential adverse effects, including increased risk of infections and malignancies. This review discusses the mechanisms, clinical efficacy, safety profiles, and therapeutic positioning of anti-TNF agents in IBD management, integrating current Korean treatment guidelines.

Unravelling the role of beta-CGRP in inflammatory bowel disease and its potential role in gastrointestinal homeostasis.

BACKGROUND: The role of beta calcitonin gene-related peptide (beta-CGRP) in gastrointestinal tract is obscure, but experimental models suggest an effect on the homeostasis of the intestinal mucosa. We measured beta-CGRP circulating levels in a large series of subjects with a recent diagnosis of inflammatory bowel disease (IBD), in order to assess the potential role of this neuropeptide in IBD pathogenesis. METHODS: Morning serum beta-CGRP levels were measured by ELISA (CUSABIO, China) in 96 patients recently diagnosed of IBD and compared with those belonging from 50 matched healthy controls (HC) and 50 chronic migraine (CM) patients. RESULTS: Beta-CGRP levels were lower in patients with IBD (3.1 ± 1.9 pg/mL; 2.9 [2.4-3.4] pg/mL) as compared to HC (4.7 ± 2.6; 4.9 [4.0-5.8] pg/mL; p < 0.001) and to CM patients (4.6 ± 2.6; 4.7 [3.3-6.2] pg/mL; p < 0.001). Beta-CGRP levels in CM were not significantly different to those of HC (p = 0.92). Regarding IBD diagnostic subtypes, beta-CGRP levels for ulcerative colitis (3.0 ± 1.9pg/mL; 2.5 [2.1-3.4] pg/mL) and Crohn's disease (3.3 ± 2.0 pg/mL; 3.2 [2.4-3.9] pg/mL) were significantly lower to those of HC (p < 0.01 and p < 0.05, respectively) and CM (p < 0.01 and p < 0.05, respectively). CONCLUSIONS: We have found a significant reduction in serum beta-CGRP levels in patients with a recent diagnosis of all kinds of IBD as compared to two control groups without active intestinal disease, HC and CM, which may suggest a role for this neuropeptide in the pathophysiology of IBD. Our data indicate a protective role of beta-CGRP in the homeostasis of the alimentary tract.

Targeting microbial pathogenic mechanisms as a novel therapeutic strategy in IBD.

BACKGROUND: Current therapy for patients suffering from inflammatory bowel diseases (IBD) is focused on inflammatory mechanisms exclusively and not the dysbiotic microbiota, despite growing evidence implicating a role for intestinal microbes in disease. MAIN BODY: Ongoing research into the intestinal microbiota of IBD patients, using new technologies and/or deeper application of existing ones, has identified a number of microorganisms whose properties and behaviors warrant consideration as causative factors in disease. Such studies have implicated both bacteria and fungi in the pathogenesis of disease. Some of these organisms manifest mechanisms that should be amenable to therapeutic intervention via either conventional or novel drug discovery platforms. Of particular note is a deeper characterization of microbial derived proteases and their destructive potential. CONCLUSION: Given the steady progress on the mechanistic role of the microbiota in inflammatory diseases, it is reasonable to anticipate a future in which therapeutics targeting microbial derived pathogenic factors play an important role in improving the lives of IBD patients.

Evaluating the role of large language models in inflammatory bowel disease patient information.

This letter evaluates the article by Gravina et al on ChatGPT's potential in providing medical information for inflammatory bowel disease patients. While promising, it highlights the need for advanced techniques like reasoning + action and retrieval-augmented generation to improve accuracy and reliability. Emphasizing that simple question and answer testing is insufficient, it calls for more nuanced evaluation methods to truly gauge large language models' capabilities in clinical applications.

Chronic binge drinking-induced susceptibility to colonic inflammation is microbiome-dependent.

Alterations in intestinal permeability and the gut microbiome caused by alcohol abuse are associated with alcoholic liver disease and with worsening of inflammatory bowel diseases (IBD) symptoms. To resolve the direct effects of chronic ethanol consumption on the colon and its microbiome in the absence of acute or chronic alcohol-induced liver disease, we developed a mouse model of chronic binge drinking that uncovers how alcohol may enhance susceptibility to colitis via the microbiota. Employing daily ethanol gavage, we recapitulate key features of binge ethanol consumption. We found that binge ethanol drinking worsens intestinal infection, colonic injury and inflammation, and this effect persists beyond the drinking period. Using gnotobiotics, we showed that alcohol-driven susceptibility to colitis is microbiota-dependent and transferable to ethanol-naïve mice by microbiome transplantation. Allobaculum spp. expanded in binge drinking mice, and administration of Allobaculum fili was sufficient to enhance colitis in non-drinking mice. Our study provides a model to study binge drinking-microbiota interactions and their effects on host disease and reinforces the pathogenic function of Allobaculum spp. as colitogenic bacteria. Our findings illustrate how chronic binge drinking-induced alterations of the microbiome may affect susceptibility to IBD onset or flares.

Roseburia intestinalis-derived extracellular vesicles ameliorate colitis by modulating intestinal barrier, microbiome, and inflammatory responses.

Inflammatory bowel disease (IBD) is a chronic disorder characterized by recurrent gastrointestinal inflammation, lacking a precise aetiology and definitive cure. The gut microbiome is vital in preventing and treating IBD due to its various physiological functions. In the interplay between the gut microbiome and human health, extracellular vesicles secreted by gut bacteria (BEVs) are key mediators. Herein, we explore the role of Roseburia intestinalis (R)-derived EVs (R-EVs) as potent anti-inflammatory mediators in treating dextran sulfate sodium-induced colitis. R was selected as an optimal BEV producer for IBD treatment through ANCOM analysis. R-EVs with a 76 nm diameter were isolated from R using a tangential flow filtration system. Orally administered R-EVs effectively accumulated in inflamed colonic tissues and increased the abundance of Bifidobacterium on microbial changes, inhibiting colonic inflammation and prompting intestinal recovery. Due to the presence of Ile-Pro-Ile in the vesicular structure, R-EVs reduced the DPP4 activity in inflamed colonic tissue and increased the active GLP-1, thereby downregulating the NFκB and STAT3 via the PI3K pathway. Our results shed light on the impact of BEVs on intestinal recovery and gut microbiome alteration in treating IBD.

Deciphering internal and external factors influencing intestinal junctional complexes.

The intestinal barrier, an indispensable guardian of gastrointestinal health, mediates the intricate exchange between internal and external environments. Anchored by evolutionarily conserved junctional complexes, this barrier meticulously regulates paracellular permeability in essentially all living organisms. Disruptions in intestinal junctional complexes, prevalent in inflammatory bowel diseases and irritable bowel syndrome, compromise barrier integrity and often lead to the notorious "leaky gut" syndrome. Critical to the maintenance of the intestinal barrier is a finely orchestrated network of intrinsic and extrinsic factors that modulate the expression, composition, and functionality of junctional complexes. This review navigates through the composition of key junctional complex components and the common methods used to assess intestinal permeability. It also explores the critical intracellular signaling pathways that modulate these junctional components. Lastly, we delve into the complex dynamics between the junctional complexes, microbial communities, and environmental chemicals in shaping the intestinal barrier function. Comprehending this intricate interplay holds paramount importance in unraveling the pathophysiology of gastrointestinal disorders. Furthermore, it lays the foundation for the development of precise therapeutic interventions targeting barrier dysfunction.

Toxicity and therapeutic property of dioxopiperidin derivative SKT40 demonstrated in-vivo zebrafish model due to inflammatory bowel disease.

Inflammatory bowel disease (IBD) encompasses chronic disorders that cause severe inflammation in the digestive tract. This study evaluates (E)-3-(3,4-dichlorophenyl)-N-(2,6-dioxopiperidin-3-yl) acrylamide (named SKT40), a derivative of dioxopiperidinamide, as a potential novel treatment for IBD. The pharmacological activity of SKT40 indicated positive interactions using network pharmacology and molecular docking in silico. In vivo, adult and larval zebrafish were tested to evaluate the effectiveness of SKT40 at different concentrations (7.5 µM, 10 µM, 15 µM) in preventing dextran sulfate sodium (DSS)-induced intestinal inflammation. The administration of SKT40 resulted in positive effects by reducing reactive oxygen species (ROS), lipid peroxidation, and cell apoptosis in zebrafish larvae. SKT40 demonstrated a significant reduction in intestinal damage in adult zebrafish by increasing antioxidant enzymes that combat the causes of IBD, such as superoxide dismutase (SOD), catalase (CAT), glutathione-S-transferase (GST), and glutathione peroxidase (GPx). It also reduces cellular damage and inflammation, as indicated by decreased levels of lactate dehydrogenase (LDH) and malondialdehyde (MDA). Gene expression analysis identified downregulation in gene expression of inflammatory mediators such as TNF-α, IL-1ß, COX-2, and IL-6. Histopathological analysis showed tissue repair from DSS-induced damage and indicated reduced hyperplasia of goblet cells. These findings suggest that SKT40 effectively treats intestinal damage, highlighting its potential as a promising candidate for IBD therapy.

Nanomedicine for colon-targeted drug delivery: strategies focusing on inflammatory bowel disease and colon cancer.

The nanostructured drug-delivery systems for colon-targeted drug delivery are a promising field of research for localized diseases particularly influencing the colonic region, in other words, ulcerative colitis, Crohn's disease, and colorectal cancer. There are various drug-delivery approaches designed for effective colonic disease treatment, including stimulus-based formulations (enzyme-triggered systems, pH-sensitive systems) and magnetically driven drug-delivery systems. In addition, targeted drug delivery by means of overexpressed receptors also offers site specificity and reduces drug resistance. It also covers GI tract-triggered emulsifying systems, nontoxic plant-derived nanoformulations as advanced drug-delivery techniques as well as nanotechnology-based clinical trials toward colonic diseases. This review gives insight into advancements in colon-targeted drug delivery to meet site specificity or targeted drug-delivery requirements.

[Box: see text].

Higher alpha diversity and Lactobacillus blooms are associated with better engraftment after fecal microbiota transplant in inflammatory bowel disease.

Fecal Microbiota Transplant (FMT) has shown some success in treating inflammatory bowel diseases (IBD). There is emerging evidence that host engraftment of donor taxa is a tenet of successful FMT. We undertook a double-blind, randomized, placebo-controlled pilot study to characterize the response to FMT in children and young adults with mild to moderate active Crohn's disease (CD) and ulcerative colitis (UC). Subjects with CD or UC were randomized to receive antibiotics and weekly FMT or placebo in addition to baseline medications. We enrolled 15 subjects aged 14-29 years. Four subjects had CD, and 11 had UC. Subjects exhibited a wide range of microbial diversity and donor engraftment. Specifically, engraftment ranged from 26 to 90% at week 2 and 3-92% at 2 months. Consistent with the current literature, increases over time of both alpha diversity (p < 0.05) and donor engraftment (p < 0.05) correlated with improved clinical response. We discovered that the post-antibiotic but pre-FMT time point was rich in microbial correlates of eventual engraftment. Greater residual alpha diversity after antibiotic treatment was positively correlated with engraftment and subsequent clinical response. Interestingly, a transient rise in the relative abundance of Lactobacillus was also positively correlated with engraftment, a finding that we recapitulated with our analysis of another FMT trial.

Oral enzyme-responsive nanoprobes for targeted theranostics of inflammatory bowel disease.

BACKGROUND: Inflammatory bowel disease (IBD) is a progressive and debilitating inflammatory disease of the gastrointestinal tract (GIT). Despite recent advances, precise treatment and noninvasive monitoring remain challenging. METHODS: Herein, we developed orally-administered, colitis-targeting and hyaluronic acid (HA)-modified, core-shell curcumin (Cur)- and cerium oxide (CeO2)-loaded nanoprobes (Cur@PC-HA/CeO2 NPs) for computed tomography (CT) imaging-guided treatment and monitoring of IBD in living mice. RESULTS: Following oral administration, high-molecular-weight HA maintains integrity with little absorption in the upper GIT, and then actively accumulates at local colitis sites owing to its colitis-targeting ability, leading to specific CT enhancement lasting for 24 h. The retained NPs are further degraded by hyaluronidase in the colon to release Cur and CeO2, thereby exerting anti-inflammatory and antioxidant effects. Combined with the ability of NPs to regulate intestinal flora, the oral NPs result in substantial relief in symptoms. Following multiple treatments, the gradually decreasing range of the colon with high CT attenuation correlates with the change in the clinical biomarkers, indicating the feasibility of treatment response and remission. CONCLUSION: This study provides a proof-of-concept for the design of a novel theranostic integration strategy for concomitant IBD treatment and the real-time monitoring of treatment responses.

Clostridium tyrobutyricum in Combination with Chito-oligosaccharides Modulate Inflammation and Gut Microbiota for Inflammatory Bowel Disease Treatment.

Synbiotics, the combination of probiotics and prebiotics, are thought to be a pragmatic approach for the treatment of various diseases, including inflammatory bowel disease (IBD). The synergistic therapeutic effects of probiotics and prebiotics remain underexplored. Clostridium tyrobutyricum, a short-chain fatty acid (SCFA) producer, has been recognized as a promising probiotic candidate that can offer health benefits. In this study, the treatment effects of synbiotics containing C. tyrobutyricum and chitooligosaccharides (COSs) on IBD were evaluated. The results indicated that the synbiotic supplement effectively relieved inflammation and restored intestinal barrier function. Additionally, the synbiotic supplement could contribute to the elimination of reactive oxygen species (ROS) and improve the production of SCFAs through the SCFAs-producer of C. tyrobutyricum. Furthermore, such the synbiotic could also regulate the composition of gut microbiota. These findings underscore the potential of C. tyrobutyricum and COSs as valuable living biotherapeutics for the treatment of intestinal-related diseases.

Engineering a Novel Probiotic Toolkit in Escherichia coli Nissle 1917 for Sensing and Mitigating Gut Inflammatory Diseases.

Inflammatory bowel disease (IBD) is characterized by chronic intestinal inflammation with no cure and limited treatment options that often have systemic side effects. In this study, we developed a target-specific system to potentially treat IBD by engineering the probiotic bacterium Escherichia coli Nissle 1917 (EcN). Our modular system comprises three components: a transcription factor-based sensor (NorR) capable of detecting the inflammation biomarker nitric oxide (NO), a type 1 hemolysin secretion system, and a therapeutic cargo consisting of a library of humanized anti-TNFα nanobodies. Despite a reduction in sensitivity, our system demonstrated a concentration-dependent response to NO, successfully secreting functional nanobodies with binding affinities comparable to the commonly used drug Adalimumab, as confirmed by enzyme-linked immunosorbent assay and in vitro assays. This newly validated nanobody library expands EcN therapeutic capabilities. The adopted secretion system, also characterized for the first time in EcN, can be further adapted as a platform for screening and purifying proteins of interest. Additionally, we provided a mathematical framework to assess critical parameters in engineering probiotic systems, including the production and diffusion of relevant molecules, bacterial colonization rates, and particle interactions. This integrated approach expands the synthetic biology toolbox for EcN-based therapies, providing novel parts, circuits, and a model for tunable responses at inflammatory hotspots.