Inflammatory bowel disease (IBD), including ulcerative colitis (UC), is a chronic inflammatory disorder with a rising incidence in pediatric populations. Immune factors play important roles in the pathogenesis of UC. This study aimed to explore the relationships of intestinal immune molecules CD27, CD20 and myeloperoxidase (MPO) with pediatric UC and their diagnostic values. In this study, gene expression data of 206 new-onset UC children and 20 non-IBD controls obtained from the NCBI Gene Expression Omnibus public database and immunohistochemistry analysis were used to evaluate CD27, CD20 and MPO expression in diseased intestinal tissues of UC children. And the diagnostic potentials of them for UC were analyzed using receiver operating characteristic curve and area under the curve (AUC). We found that CD27, CD20 and MPO mRNA and protein expressions were increased in the diseased intestinal tissues of UC children. CD27, CD20 and MPO showed good diagnostic potential for UC in children, with an AUC of 0.95 for CD27, 0.79 for CD20 and 0.92 for MPO, and combination of them had better diagnostic performance with an AUC of 0.98. Besides, they were associated with immune-related biological processes and pathways, and correlated with genes related to immune factors, intestinal epithelial barrier function, and intestinal fibrosis. In conclusion, our findings demonstrated that CD27, CD20 and MPO were increased in diseased intestinal tissues of UC children, and had good diagnostic performance for UC in children.

Parkinson's Disease (PD) is a multisystem disorder in which dysregulated neuroimmune crosstalk and inflammatory relay via the gut-blood-brain axis have been implicated in PD pathogenesis. Although alterations in circulating inflammatory cytokines and reactive oxygen species (ROS) have been associated with PD, no biomarkers have been identified that predict clinical progression or disease outcome. Gastrointestinal (GI) dysfunction, which involves perturbation of the underlying immune system, is an early and often-overlooked symptom that affects up to 80 % of individuals living with PD. Interestingly, 50-70 % of individuals with inflammatory bowel disease (IBD), a GI condition that has been epidemiologically linked to PD, display chronic illness-induced anemia - which drives toxic accumulation of iron in the gut. Ferroptotic (or iron loaded) cells have small and dysmorphic mitochondria-suggesting that mitochondrial dysfunction is a consequence of iron accumulation. In pro-inflammatory environments, iron accumulates in immune cells, suggesting a possible connection and/or synergy between iron dysregulation and immune cell dysfunction. Peripheral blood mononuclear cells (PBMCs) recapitulate certain PD-associated neuropathological and inflammatory signatures and can act as communicating messengers in the gut-brain axis. Additionally, this communication can be modulated by several environmental factors; specifically, our data further support existing literature demonstrating a role for non-steroidal anti-inflammatory drugs (NSAIDs) in modulating immune transcriptional states in inflamed individuals. A mechanism linking chronic gut inflammation to iron dysregulation and mitochondrial function within peripheral immune cells has yet to be identified in conferring risk for PD. To that end, we isolated PBMCs and simultaneously evaluated their directed transcriptome and bioenergetic status, to investigate if iron dysregulation and mitochondrial sensitization are linked in individuals living with PD or IBD because of chronic underlying remittent immune activation. We have identified shared features of peripheral inflammation and immunometabolism in individuals living with IBD or PD that may contribute to the epidemiological association reported between IBD and risk for PD.

Inflammatory bowel disease (IBD) is a chronic immune-mediated condition linked to gut microbiota dysbiosis and altered production of bacterial metabolites, including succinate, which is also a key intermediate in human mitochondrial energy metabolism in human cells. Succinate levels in the gut are influenced by microbial community dynamics and cross-feeding interactions, highlighting its dual metabolic and ecological importance. Extracellular succinate acts as a key signaling metabolite linking microbial metabolism to host physiology, with transient rises supporting metabolic regulation but chronic elevations contributing to metabolic disorders and disease progression. Succinate signals through its cognate receptor SUCNR1, which mediates adaptive metabolic responses under normal conditions but drives inflammation and fibrosis when dysregulated. IBD patients display a dysbiotic gut microbiota characterized by an increased prevalence of succinate-producing bacteria, contributing to elevated succinate levels in the gut and circulation. This imbalance drives inflammation, worsens IBD severity, and contributes to complications like Clostridioides difficile infection and fibrosis. Emerging evidence highlights the potential of intestinal and systemic succinate levels as indicators of microbial dysbiosis, with a bidirectional relationship between microbial composition and succinate metabolism. Understanding the factors influencing succinate levels and their interaction with dysbiosis shows promise in the development of therapeutic strategies to restore microbial balance. Approaches such as dietary fiber enrichment, prebiotics, and probiotics to enhance succinate-consuming bacteria, combined with targeted modulation of succinate pathways (e.g. SDH inhibitors, SUCNR1 antagonists), hold promise for mitigating inflammation and improving gut health in IBD.

Inflammatory bowel disease (IBD) represents a significant disease burden marked by chronic inflammation and complications that adversely affect patients' quality of life. Effective diagnostic strategies involve clinical assessments, endoscopic evaluations, imaging studies, and biomarker testing, where early diagnosis is essential for effective management and prevention of long-term complications, highlighting the need for continual advancements in diagnostic methods. The intricate interplay between genetic factors and the outcomes of biological therapy is of critical importance. Unraveling the genetic determinants that influence responses and failures to biological therapy holds significant promise for optimizing treatment strategies for patients with IBD on biologics. Through an in-depth examination of current literature, this review article synthesizes critical genetic markers associated with therapeutic efficacy and resistance in IBD. Understanding these genetic actors paves the way for personalized approaches, informing clinicians on predicting, tailoring, and enhancing the effectiveness of biological therapies for improved outcomes in patients with IBD.

Vascular cell adhesion molecule (VCAM)-1 has garnered significant research attention due to its potential as a disease biomarker and drug target across several inflammatory pathologies-including atherosclerosis, asthma, rheumatoid arthritis, and inflammatory bowel disease (IBD). The VCAM-1 protein has also been noted for its functional involvement in cancer metastasis and drug resistance to conventional chemotherapeutics. Although the anti-inflammatory and anti-cancer facets of VCAM-1 antagonisation have been examined separately, there is yet to be a review that explicitly addresses the functional interrelationship between these mechanisms. Furthermore, the pleiotropic mechanisms of anti-VCAM-1 therapies may present a useful paradigm for designing drug candidates with synergistic anti-inflammatory and anti-tumorigenic effects. The pathological overlap between inflammatory bowel disease (IBD) and colitis-associated colorectal cancer (CRC) serves as the quintessential disease model to observe this therapeutic duality. This review thereby details the adhesive mechanisms of VCAM-1 in colorectal disease-specifically, driving immune cell infiltration during IBD and tumour cell metastasis in CRC-and posits the potential of this receptor as a common drug target for both diseases. To explore this hypothesis, the current progress of novel VCAM-1-directed drug candidates in experimental models of IBD and CRC is also discussed.

Discovered in 1996, PCSK7 is the seventh of the 9-membered proprotein convertase subtilisin-kexin (PCSK) family. This article reviews the various aspects of the multifaceted biology of PCSK7 and what makes it an exciting new target for metabolic dysfunction-associated steatotic liver disease (MASLD), affecting ∼30% of the population globally, dyslipidemia, cardiovascular disease, and likely cancer/metastasis. We will systematically review and discuss all the available epidemiological data, and structural, cell biology, and in vivo evidence that eventually led to the discovery of PCSK7 as a novel post-translational regulator of apolipoprotein B. Interestingly, PCSK7 is the only convertase, other than PCSK9, that exhibits noncanonical/nonenzymatic functions, which will be amply described in this review. The data so far have suggested that PCSK7 is a potential safe target in MASLD treatment. This was based on human epidemiological data, as well as mouse Pcsk7 knockout and mRNA translation inhibition using hepatocyte-targeted antisense oligonucleotides following a diet-induced MASLD. Additionally, of all the 9 convertases only the gene deletion of Pcsk7 and/or Pcsk9 in mice leads to healthy and fertile animals with no apparent deleterious consequences, suggesting that their pharmacological targeting is likely safe. Accordingly, the synergistic effects of inhibiting both PCSK7 and PCSK9 in a clinical setting may represent a novel therapy for various diseases. We believe that the current surge in oligonucleotide therapy, with many Food and Drug Administration-approved oligonucleotide-based drugs now available in clinics, and the urgent need for novel MASLD therapeutics present an opportune moment for this timely review article.

Inflammatory bowel disease (IBD) has become a global healthcare issue, with its incidence continuing to rise, but currently there is no complete cure. Xylitol is a widely used sweetener in various foods and beverages, but there is limited research on the effects of xylitol on IBD symptoms.

Study on the effect of oral xylitol in improving intestinal inflammation and damage in IBD mice, further explore the mechanism of xylitol in alleviating IBD symptoms using intestinal microbiota and non-targeted metabolomics techniques.

An IBD mouse model was induced using sodium dextran sulfate (DSS). After 30 days of oral administration of xylitol, we assessed the disease activity index (DAI) scores of mice in each group. The expression levels of inflammatory factors in the colon tissues were measured using qPCR. Additionally, we examined the damage to the intestinal mucosa and tight junction structures through HE staining and immunohistochemical staining. Finally, the alterations in the gut microbiota of the mice were analyzed using 16S rDNA sequencing technology.The production of three main short-chain fatty acids (SCFAs, including acetate, propionic acid and butyric acid) in feces and the changes of serum metabolomics were measured by non-targeted metabolomics techniques.

The findings indicated that xylitol effectively mitigated weight loss and improved the DAI score in mice with IBD. Moreover, xylitol reduced the expressions of Caspase-1, IL-1β, and TNF-α in the colon tissue of the mice, and increased the expressions of ZO-1 and occludin in intestinal mucosal. Xylitol could enhance the variety of intestinal bacteria in IBD mice and influenced the abundance of different bacterial species. Additionally, metabolomic analysis revealed that oral xylitol increased the levels of three main SCFAs in the feces of IBD mice, while also impacting serum metabolites.

Our findings suggest that xylitol can help improve IBD symptoms. Xylitol can improve the intestinal flora of IBD mice and increase the production of SCFAs to play an anti-inflammatory role and protect the mucosal tight junction barrier. These discoveries present a fresh prophylactic treatment of IBD.

Not applicable.

Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs), especially, exosomes are considered to have diverse therapeutic effects for various significant diseases. MSC-derived exosomes (MSCex) offer substantial advantages over MSCs due to their long-term preservation, stability, absence of nuclei and fewer adverse effects such as infusion toxicity, thereby paving the way towards regenerative medicine and cell-free therapeutics. These exosomes harbor several cellular contents such as DNA, RNA, lipids, metabolites, and proteins, facilitating drug delivery and intercellular communication. MSCex have the ability to immunomodulate and trigger the anti-inflammatory process hence, playing a key role in alleviating inflammation and enhancing tissue regeneration. In this review, we addressed the anti-inflammatory effects of MSCex and the underlying immunomodulatory pathways. Moreover, we discussed the recent updates on MSCex in treating specific inflammatory diseases, including arthritis, inflammatory bowel disease, inflammatory eye diseases, and respiratory diseases such as asthma and acute respiratory distress syndrome (ARDS), as well as neurodegenerative and cardiac diseases. Finally, we highlighted the challenges in using MSCex as the successful therapeutic tool and discussed future perspectives.

Pyroptosis is a unique form of programmed cell death characterized by intense inflammation. It involves the activation of Gasdermin proteins, which form membrane pores, leading to rapid cell rupture and the release of inflammatory molecules. Unlike other types of cell death, pyroptosis has distinct activation mechanisms and plays a complex role in chronic intestinal diseases, including inflammatory bowel disease, intestinal fibrosis, chronic infectious enteritis, and colorectal cancer. This review comprehensively examines how pyroptosis influences disease development and progression while exploring the therapeutic potential of targeting pyroptosis-related pathways. Moreover, the complex interplay between gut microbiota and pyroptosis is summarized, highlighting its critical role in the pathogenesis of chronic intestinal disorders. A deeper understanding of pyroptosis-related mechanisms in these diseases may provide valuable insights for future research and contribute to the development of innovative therapeutic strategies in gastroenterology.

Inflammatory bowel diseases (IBD) are polygenic, with many genetic variants contributing to disease risk. Knowing the genotype of specific variants or calculating a combined genetic risk score benefits translational and functional research. To address this, we developed MIP4IBD, a flexible and cost-effective genotyping-by-sequencing assay using molecular inversion probes (MIPs).

The assay targets 463 IBD risk variants, and 77 additional relevant variants. Molecular inversion probes capture and library preparation were optimized using 15 IBD DNA samples, comparing genotypes with immunochip. A custom GitHub pipeline was created for data processing, performance testing, and genotype calling. The final design was validated on a larger scale (149 IBD patients, 104 non-IBD controls, and 3 external cell lines), incorporating post hoc quality control criteria.

The assay achieved a 3.5-day turnaround time at €15 per sample with optimal sample throughput, demonstrating a 92.6% success rate in variant capture and genotype concordance rates of 99.3% and 99.6% with Infinium Global Screening Array24 BeadChip and WGS, respectively. A downstream application involved the calculation of a weighted IBD polygenic risk score (PRS), which was significantly higher in IBD patients than controls (mean 0.42 vs -0.49, P = 1.95E-11). Individuals in the highest PRS quartile had a 15.7-fold (95% CI: 6.5-38.3) risk of developing IBD and an earlier age of onset (26 vs 37 years, P = 0.02), compared to the lowest quartile.

MIP4IBD is a validated, scalable genotyping assay targeting IBD risk loci, with an integrated bioinformatics pipeline from sequencing data to genotypes and PRS calculation. Its cost-effectiveness and flexibility for additional variants make it particularly appealing for translational and clinical applications.

Image 1.

Inflammatory bowel disease (IBD) is a multifactorial disease, and patients frequently experience extraintestinal manifestations affecting multiple sites. Causes of systemic inflammation remain poorly understood, but molecules originating from the intestine likely play a role, with microbial and host small molecules polarizing host immune cells towards a pro- or anti-inflammatory phenotype. Using the dextran sodium sulfate (DSS) mouse model, which mimics the disrupted barrier function, microbial dysbiosis, and immune cell dysregulation of IBD, we investigated metabolomic and phenotypic changes at intestinal and systemic sites. Using spatial biology approaches, we mapped the distribution and relative abundance of molecules and cell types across a range of tissues, revealing significant changes in DSS-treated mice. Molecules identified as contributing to the statistical separation of treated from control mice were spatially localized within organs to determine their effects on cellular phenotypes through imaging mass cytometry. This spatial approach identified both intestinal and systemic molecular drivers of inflammation, including several not previously implicated in inflammation linked to IBD or the systemic effects of intestinal inflammation. Metabolic and inflammatory pathway interplay underpins systemic disease, and determining drivers at the molecular level may aid the development of new targeted therapies.

Inflammatory bowel disease (IBD), comprising Crohn's disease (CD) and ulcerative colitis (UC), lacks a known etiology. Although clinical symptoms, imaging, and colonoscopy are common diagnostic tools, fecal calprotectin (FC) serves as a widely used biomarker to track disease activity. Metabolomics, within the omics sciences, holds promise for identifying disease progression biomarkers. This approach involves studying metabolites in biological media to uncover pathological factors.

The purpose of this study was to explore fecal metabolomics in IBD patients, evaluate its potential in differentiating subtypes, and assess disease activity using FC.

Cross-sectional study including IBD patients, clinical data, and FC measurements (=200 μg/g as an indicator of active disease).

Fecal metabolomics utilized chromatography mass spectrometry/solid phase microextraction with MetaboAnalyst 5.0 software for analysis. Of 52 patients (29 UC, 23 CD), 36 (69.2%) exhibited inflammatory activity. We identified 56 fecal metabolites, with hexadecanoic acid, squalene, and octadecanoic acid notably distinguishing CD from UC. For UC, octadecanoic and hexadecanoic acids correlated with disease activity, whereas octadecanoic acid was most relevant in CD.

These findings highlight the potential of metabolomics as a noninvasive complement for evaluating IBD, aiding diagnosis, and assessing disease activity.

Maintenance of remission is essential in inflammatory bowel disease (IBD) in terms of disease course and long-term prognosis. The thiopurines azathioprine and 6-mercaptopurine have longstanding merit in ulcerative colitis, but more therapeutic options have been developed. This review is an update and extension of a review last published in 2016.

To assess the effectiveness and safety of azathioprine and 6-mercaptopurine in monotherapy or combined therapy regimens compared to placebo or active controls for the maintenance of remission in ulcerative colitis.

We searched Cochrane Central Register of Controlled Trials (until May 2023), ClinicalTrials.gov (until May 2023), Embase (until August 2022), MEDLINE (until May 2023), and WHO ICTRP (until May 2023). We checked reference lists of the included studies and, if needed, contacted the authors to request more data or information.

Randomized controlled trials (RCTs) of at least 24 weeks' duration comparing azathioprine or 6-mercaptopurine with placebo or any other medication, or comparing different treatment modalities of azathioprine or 6-mercaptopurine, in persons of any age with quiescent ulcerative colitis were eligible. We only considered studies with mixed IBD populations or with a preceding induction period if separate results on participants with ulcerative colitis in remission were available or could be calculated. The primary outcome was failure to maintain clinical or endoscopic remission (relapse). Secondary outcomes included change in disease activity, quality of life, hospitalization, need for surgery, days off work, adverse events, and withdrawal due to adverse events.

Two authors independently extracted data using standard forms, resolved any disagreements by consensus, and assessed study quality using the Cochrane risk of bias tool (RoB 2). We conducted separate analyses by type of control, calculated pooled risk ratios (RRs) or risk differences (RDs) using the fixed-effect model unless heterogeneity was likely, and assessed the certainty of evidence using the GRADE approach.

We included 10 studies in the review, including 468 adult participants with ulcerative colitis. The risk of bias across these was low for most outcomes, but we considered some outcomes to have some concerns or high risk of bias due to insufficient information on concealment of allocation and outcome measurement. Based on five placebo-controlled studies, azathioprine or 6-mercaptopurine may reduce the risk of failing to maintain remission. In the thiopurine group, 45% (64/143) of participants failed to maintain remission compared to 67% (96/143) of participants receiving placebo (RR 0.66, 95% confidence interval (CI) 0.54 to 0.82; 5 studies, 286 participants; low-certainty evidence). Three studies reported withdrawals due to adverse events. Among participants on azathioprine, 4% (3/80) withdrew due to adverse events compared to 0% (0/82) of placebo participants (RD 0.04, 95% CI -0.02 to 0.09; 3 studies, 162 participants; low-certainty evidence). The evidence is of low certainty when comparing 6-mercaptopurine to 5-aminosalicylate. Based on one three-armed trial, 27% (3/11) of 6-mercaptopurine participants failed to maintain remission compared to 100% (2/2) of 5-aminosalicylate participants (RR 0.35, 95% CI 0.13 to 0.97; 1 study, 13 participants; low-certainty evidence). This trial also involved an induction phase; we only included the results for participants in remission. The single trial comparing 6-mercaptopurine to 5-aminosalicylate did not report separate data on adverse events and withdrawals due to adverse events for the subgroup with successful induction of remission, so we could not analyze these outcomes for this comparison.

Low-certainty evidence suggests that azathioprine or 6-mercaptopurine therapy may be more effective than placebo for the maintenance of remission in ulcerative colitis. More research is needed to evaluate the value of therapeutic drug monitoring and the effects of various treatment modalities on long-term safety.

Inflammation is a protective mechanism that also starts the healing process. However, inflammatory reaction may cause severe tissue damage. The increased influx of phagocytic leukocytes may produce excessive amount of reactive oxygen species, which leads to additional cell injury. Inflammatory response activates the leukocytes and thus induces tissue damage and prolongs inflammation. The inflammation-induced activation of the complement system may also contribute to cell injury. Non-steroidal anti-inflammatory drugs (NSAIDs) and glucocorticoids are chief agents for treating inflammation associated with the diseases. However, the unwanted side effects of NSAIDs (e.g., gastrointestinal disturbances, skin reactions, adverse renal effects, cardiovascular side effects) and glucocorticoids (e.g., suppression of immune system, Cushing's syndrome, osteoporosis, hyperglycemia) limit their use in patients. Natural herbs are important sources of anti-inflammatory drugs. The ingredients extracted from natural herbs display anti-inflammatory effects to work through multiple pathways with lower risk of adverse reaction. At present, the main anti-inflammatory natural agents include saponins, flavonoids, alkaloids, polysaccharides, and so on. The present article will review the anti-inflammatory effects of saponins including escin, ginsenosides, glycyrrhizin, astragaloside, Panax notoginseng saponins, saikosaponin, platycodin, timosaponin, ophiopogonin D, dioscin, senegenin.

Current studies suggest a potential link between inflammatory bowel disease (IBD), comprising Crohn's disease (CD) and ulcerative colitis (UC), and cardiovascular diseases, such as stroke. This study aimed to assess the risk of stroke in IBD patients compared to general population.

Systematic search was done in PubMed, Embase, CENTRAL, Scopus, and CINAHL databases for studies published till September 2023. Using a random-effects model, the hazard ratios (HRs) with 95% confidence intervals (CIs) for stroke occurrence were calculated. Subgroup analyses were done to estimate pooled HR with 95%CI for CD, UC, and overall IBD cases separately. Publication bias assessment was done by Begg's and Egger's tests.

Thirteen studies with 2,802,955 participants were included. IBD patients in general had significantly higher risk of stroke, with HR of 1.30 [95% CI 1.21-1.39]. Subgroup analysis demonstrated an HR of 1.35 [95% CI 1.22-1.49] for CD and 1.15 [95% CI 1.09-1.22] for UC. Substantial heterogeneity was detected across studies, with no substantial publication bias. Sensitivity analyses affirmed the stability of findings.

IBD in general, and Crohn's disease in particular are associated with significantly higher risk of stroke. Our findings further emphasize the importance of cardiovascular risk assessment and management strategies in IBD care.

PROSPERO, CRD42023470602.

Objectives: This bibliometric analysis investigates recent research trends in biologics and small molecules for treating inflammatory bowel disease (IBD) based on literature from the past decade. Methods: This cross-sectional study involved analyzing data retrieved from the Web of Science Core Collection (WoSCC) database to examine the evolution and thematic trends of biological agents and small-molecular drugs for IBD conducted between 1 January 2014, and 20 September 2024. VOSviewer software was utilized to assess co-authorship, co-occurrence, co-citation, and network visualization, followed by a further discussion on significant sub-themes. Results: From 2014 to 20 September 2024, the annual number of global publications increased by 23%, reflecting an acceleration in research activity. The journal "Inflammatory Bowel Diseases" published the highest number of manuscripts (579 publications) and garnered the most citations (13,632 citations), followed by the "Journal of Crohn's & Colitis" (480 publications) and "Alimentary Pharmacology & Therapeutics" (250 publications). The United States led in productivity with 1943 publications and 66,320 citations, with UC San Diego (291) and authors Sandborn and Vermeire (180) topping the list. The co-occurrence cluster analysis of the top 100 keywords resulted in the formation of six distinct clusters: Disease Mechanisms, Drug Development, Surgical Interventions, Therapeutic Drug Monitoring (TDM), Immunological Targets, and Emerging Therapies. Burst terms (TNF-α inhibitors, JAK inhibitors, and trough-level optimization) highlight trends toward personalized biologics and small-molecule regimens. Conclusions: The bibliometric analysis indicates that IBD therapeutic research and clinical applications focus on biologics and small molecules, with research trends leaning toward precise therapy conversion or the combination in non-responders. Future work will assess monotherapy, the combination, and conversion therapies and investigate new drugs targeting inflammatory pathways.

The monolayer of intestinal epithelial cells (IECs) plays a crucial role in controlling intestinal homeostasis, also by its interaction with the immune system, via paracrine cytokine production, thus driving innate responses by tissue-resident immune cells. Here, using a co-culture model, we investigated the interactions between differentiated Caco-2 cells in monolayer and macrophages, by mimicking the cross-talk between enterocytes and immune cells during gastrointestinal (GI) tract inflammation.

Caco-2 mature monolayers grown on Transwell membranes were challenged with apical or basolateral LPS. After stimulations, the enterocyte-like monolayers were transferred in co-culture with THP-1 derived macrophages. The functional impact of treatments was evaluated in terms of monolayer's permeability, expression of mRNAs related to inflammation and immune responses and analysis of immune soluble factors present in the co-culture media.

LPS effectively affected monolayer's permeability and induced a pro-inflammatory transcriptional program in Caco-2 monolayers. Remarkably, THP-1 derived macrophages differentially responded based on the diverse directional source of LPS, previously administered to the Caco-2 monolayers. Basolateral sensing of LPS, by Caco-2 monolayers, induced specific increase of several pro-inflammatory factors such as NF-kB1, IL-6 and IL-8, at transcript level, in macrophages, while apical sensing triggering targeted increase of IL-1β expression. Significantly, the analysis of immune factors secreted in the co-culture media suggested that paracrine interactions between enterocyte-like monolayers and macrophages are differently driven based on the basolateral vs. apical inflammation, previously triggered by LPS against the epithelial monolayer, and thus involving different immune gene networks.

Taken together, our results suggest a framework of interactions between IECs and macrophages, depending upon the "polarized" inflammatory dysregulation.

Medicinal plants represent promising sources for the treatment of gastrointestinal disorders because of their abundance in bioactive compounds with therapeutic properties. Throughout history, various plant species have been used to alleviate digestive ailments, and studies have revealed the presence of metabolites with anti-inflammatory, antibacterial, antiviral, antiparasitic, antidiarrheal, antioxidant, and anticancer activities. The secondary metabolites responsible for these properties include alkaloids, terpenoids, and phenolic compounds, with the latter, particularly flavonoids, being the most associated with their bioactivities. Gastrointestinal diseases, such as gastritis, peptic ulcers, gastroesophageal reflux disease, inflammatory bowel disease, irritable bowel syndrome, and gastrointestinal cancer, are caused primarily by bacteria, parasites, viruses, and the consumption of raw or undercooked foods. These conditions significantly impact human health, necessitating the development of safer and more effective therapeutic alternatives. After an extensive literature review, several plant species with widespread use in the treatment of these disorders were identified, including Matricaria chamomilla, Mentha spicata, Melissa officinalis, Artemisia ludoviciana, Flourensia cernua, Phoradendron californicum, and Turnera difusa. This study revealed that the analyzed plants are rich in bioactive compounds, which confer their medicinal properties. However, many other plants commonly used to treat digestive disorders have been scarcely studied, highlighting the need for further research.

Hydrogen sulfide (H 2 S) is a gaseous gut metabolite with disputed effects on gastrointestinal health. Monitoring H 2 S concentration in the gut would provide insight into its role in disease, but is complicated by sulfide's reactivity and volatility. Here we develop a transcriptional sulfide biosensor in E. coli . The sensor relies on enzymatic oxidation of sulfide catalyzed by a sulfide:quinone reductase (Sqr) to polysulfides, which bind to the repressor SqrR, triggering unbinding from the promoter and transcription of the reporter. Through promoter engineering and improving soluble SqrR expression, we optimized the system to provide an operational range of 50 µM - 750 µM and dynamic range of 18 aerobically. To enable sensing in anaerobic environments, we identified an Sqr from Wolinella succinogenes that uses menaquinone, facilitating reoxidation through the anaerobic electron transport chain by fumarate or nitrate. Use of this homolog resulted in an anaerobic H 2 S response up to 750 µM. This sensor could ultimately enable spatially and temporally resolved measurements of H 2 S in the gastrointestinal tract to elucidate the role of this metabolite in disease, and potentially as a non-invasive diagnostic.

Efferocytosis is the process by which various phagocytes clear apoptotic cells. In recent years, an increasing body of evidence has emphasized the importance of efferocytosis in maintaining internal homeostasis. Intestinal macrophages play a crucial role in modulating intestinal inflammation and promoting tissue repair. Inflammatory bowel disease (IBD) is a chronic, progressive, and relapsing condition, primarily marked by the presence of ulcers in the digestive tract. The exact mechanisms underlying IBD are not yet fully understood, and current treatment approaches mainly aim at repairing the damaged intestinal mucosa and reducing inflammatory responses to ease symptoms.This article provides new perspectives on IBD treatment and clinical management by examining the expression of macrophage efferocytosis-related molecules, the effects of efferocytosis on IBD development, the various roles of macrophage efferocytosis in IBD, and treatment strategies for IBD that focus on efferocytosis.

Inflammatory bowel diseases (IBDs) comprise a group of chronic gastrointestinal disorders characterized by periods of relapse and remission. The mainstay of treatment is medical, involving medications such as steroids, immune modulators, monoclonal antibodies (categorized as biologics), and small molecules. These medications can provide profound therapeutic benefits, but they can also cause severe and irreversible toxicities. Clinicians may utilize laboratory tests in the diagnosis and management of IBD including assessment of disease activity, monitoring medication response or toxicity, surveillance of infectious complications, and detection of nutritional deficiencies. Routine use of laboratory tests may help clinicians avoid reactivation of life-threatening infections such as tuberculosis or hepatitis B virus upon initiation of immune suppressive therapy. They can also be used to detect vitamin deficiencies such as B12 deficiency, which has the potential to cause irreversible neurologic damage. While some laboratory tests constitute established practices, the utility of newer tests such therapeutic drug monitoring (TDM) in the era of biologics is an evolving topic. Although clinical assessment with imaging, endoscopic, and histopathological examination is standard practice, laboratory tests serve as valuable adjuncts. We aim to explore the broad range of laboratory tests available to clinicians and to summarize their application in the current management of IBD in daily clinical practice, with special attention to updates in therapeutic drug monitoring.

Inflammatory Bowel Disease (IBD), Crohn's disease (CD) and ulcerative colitis (UC), requires a combination of procedures and tests in diagnosis and discrimination. This study aimed to delineate specific serum metabolomic biomarkers that diagnose IBD and differentiate IBD subgroups. Serum samples and clinical metadata of the participants, IBD patients and Normal Controls (NC), were collected. Untargeted and targeted metabolomic analyses by high-resolution mass spectrometry and multivariate statistical approaches were applied. Further, Receiver Operating Characteristic (ROC) curves, pathways, and network analyses were conducted. Distinct clustering separated IBD patients from the NC, although the CD and UC subgroups overlapped in the non-targeted profiling. Targeted metabolomics revealed elevated tryptophan and indole-3-acetic acid levels and reduced primary-to-secondary bile acid ratios in both CD and UC patients. The differences in specific tryptophan metabolites between CD and UC were identified. The ROC analysis underscored the discriminatory power of the biomarkers (AUC values: NC vs. CD = 0.9738; NC vs. UC = 0.9887; UC vs. CD = 0.7140). Pathway analysis revealed alterations in glycerolipid metabolism, markedly differentiating UC from CD. Network analysis correlated metabolomic markers with the clinical phenotypes of IBD. Serum metabolomic biomarkers can precisely identify IBD, discriminate IBD subtypes, and further reveal the phenotypes of IBD.

Background: Parkinson's disease (PD) is intricately linked to gastrointestinal inflammation and the presence of neurotoxins in the gut, integrating α-syn pathologic alterations and subsequent neurodegeneration into the brain. Objectives: This study aimed to explore the enduring impact of dextran sodium sulfate (DSS)-mediated colitis on the vulnerability of central dopaminergic neurons to subsequent rotenone exposure. Methods: To induce chronic colitis, 10-month-old C57BL/6 mice were pre-exposed to 3 cycles of 1 week of 1% (w/v) DSS administration in drinking water followed by 2 weeks of regular drinking water. After colitis induction, animals received a low dose of intragastric rotenone for the next 8 weeks, followed by testing for Parkinsonian behavior and GI phenotypes of inflammation. At the end of the 17th week, colon, brain stem, and midbrain tissue were isolated and analyzed for α-syn, inflammatory markers, and dopaminergic neuronal loss. Gut microbial composition was assessed by 16S rRNA sequencing analysis. Results: We found that chronic rotenone administration in the presence of preexisting colitis led to a further increase in colonic pro-inflammatory mediator expressions, α-syn expression, and reduced colonic tight junction protein expressions. We also found early impairment of GI functions and worsened grip strength in rotenone-exposed colitic mice. Furthermore, α-syn pathology specific to the colitic mice exposed to rotenone showed dopaminergic neurons degeneration and astroglial activation in substantia nigra and striatum, including regions of the brain stem, i.e., dorsal motor of the vagus and locus coeruleus. Finally, the result of 16S rRNA gene sequencing analysis indicated that colitic mice, after being exposed to rotenone, exhibited a discernible trend in their microbiota composition (Catenibacterium, Turicibactor, and clostridium sensue stricto 1), linking it to the development of PD. Conclusions: These findings indicate that prolonged low-dose rotenone exposure, combined with an early inflammatory intestinal milieu, provides a preconditioning effect on α-syn pathology and exerts neurodegeneration in the intragastric rotenone PD mouse model.

Taking into account the global spread of microplastic (MP) pollution, the problem of the MP impact on human health is relevant. MP enters the organism predominantly with water and food, and is mostly detected in the large intestine. Therefore, the connection between MP pollution and the increase in colitis is an important question. In order to assess the toxic and pathogenetic effects of MP, experimental studies were actively conducted during recent years, mainly on laboratory mice.

The aim of our review was to summarize and systematize the data on the MP effect on mice colon under normal conditions and during colitis in order to assess the role of MP in the development of intestinal diseases. This manuscript could be relevant for ecologists, experimental biologists, and physicians dealing with problems related to anthropogenic environmental changes and inflammatory bowel diseases.

The search was conducted based on PubMed data about original experimental studies of the MP effects on the colon of healthy mice and mice with colitis.

In healthy mice colon, MP can cause oxidative stress, increased permeability, immune cell infiltration, production of proinflammatory factors, and decreased mucus production. MP affects proliferation, apoptosis, and differentiation of epithelial cells, expression of tight junction components and glycocalyx, membrane transport, signaling pathways, metabolome, and intestinal microflora composition. In mice with acute and chronic experimental colitis, MP consumption leads to a more pronounced pathological process course.

MP may be one of the factors contributing to the development of colitis in humans. However, further research is needed.

Apical periodontitis (AP) is the local inflammation of periapical tissues originating from the dental pulp disease. Cumulative evidence suggests a link between oral and gastro-intestinal systems in both health and disease. In this context, the relationship between AP and inflammatory bowel diseases (IBDs) has not yet been elucidated. The aims of this systematic review and meta-analysis were to describe the prevalence of AP in patients with IBDs and evaluate the potential association between AP and IBDs. Electronic (Embase, PubMed, Scopus, Web of Science) and manual literature searches were conducted from inception to 31 October, 2023 (updated in August, 2024). Strict inclusion criteria were applied to identify observational and experimental clinical studies on AP in IBDs patients. The bias risk was assessed using the Joanna Briggs Institute critical appraisal tools and a biases' report selected from the Oxford Centre for Evidence Based Medicine Catalogue of Bias. A meta-analysis was performed to determine the pooled prevalence and risk of AP at individual and tooth level and the quality of evidence was assessed by the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach. The search strategy identified 82 articles with 5 studies included (657 subjects, 7,142 teeth). The overall proportion of AP was 58% at patient level (95% CI = 37%-78%, I 2 = 95.3%) and 7% at tooth level (95% CI = 2%-15%; I 2 = 99.2%). AP was prevalent in IBDs subjects than in healthy controls, both at patient and tooth level. The pooled OR was 1.57 (95% CI = 1.04-2.35; P = 0.038; I 2 = 20%) at patient level, and 1.91 (95% CI = 1.16-3.15; P = 0.011; I 2 = 82%) at tooth level. A potential association between AP and IBDs is plausible, although the quality evidence was low to very low. Longitudinal and experimental studies should be conducted to better understand the relationship between these two conditions and explore any potential causative factors.

https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=411038, PROSPERO (CRD42023411038).

Inflammatory bowel disease (IBD) is a common chronic intestinal inflammatory disease. High oxidative stress is a treatment target for IBD. Cerium oxide (CeO2) nanomaterials as nanozymes with antioxidant activity are potential drugs for the treatment of colitis.

To synthesize hollow cerium (H-CeO2) nanoparticles by one-step method and to validate the therapeutic efficacy of H-CeO2 in IBD.

H-CeO2 was synthesized by one-step method and examined its characterization and nanoenzymatic activity. Subsequently, we constructed dextran sulfate sodium (DSS)-induced colitis in mice to observe the effects of H-CeO2 on colonic inflammation. The effects of H-CeO2 on colon inflammation and reactive oxygen species (ROS) levels in IBD mice were detected by hematoxylin and eosin staining and dichlorofluorescein diacetate staining, respectively. Finally, the biological safety of H-CeO2 on mice was evaluated by hematoxylin and eosin staining, blood routine, and blood biochemistry.

H-CeO2 nanoparticles prepared by the one-step method were uniform, monodisperse and hollow. H-CeO2 had a good ability to scavenge ROS, ∙OH and ∙OOH. H-CeO2 reduced DSS-induced decreases in body weight and colon length, colonic epithelial damage, inflammatory infiltration, and ROS accumulation. H-CeO2 administration reduced the disease activity index of DSS-induced animals from about 8 to 5. H-CeO2 had no significant effect on body weight, total platelet count, hemoglobin, white blood cell, and red blood cell counts in healthy mice. No significant damage to major organs was observed in healthy mice following H-CeO2 administration.

The one-step synthesis of H-CeO2 nanomaterials had good antioxidant activity, biosafety, and inhibited development of DSS-induced IBD in mice by scavenging ROS.

Inflammatory bowel disease remains a significant challenge in clinical settings. This study investigated the therapeutic potential of sea cucumber ovum hydrolysates (SCH) in a dextran sulfate sodium (DSS)-induced colitis mouse model. SCH, defined by its elevated stability and solubility, with a molecular weight below 1000 Da, significantly alleviated DSS-induced colitis, as evidenced by enhanced splenic index, reduced colonic damage, and diminished serum pro-inflammatory cytokines. Furthermore, macrogenomic analysis demonstrated that SCH increased beneficial gut microbes and decreased pro-inflammatory bacteria. Furthermore, metabolomic analysis of colonic tissues identified elevated levels of anti-inflammatory metabolites, such as Phenyllactate, 2-Hydroxyglutarate, and L-Aspartic acid, in colitis mice after oral administration of SCH. In conclusion, SCH represents a promising candidate for the treatment of colitis.

We conducted a retrospective study to identify incidence rates and potential risk factors of major adverse cardiac events (MACE) in Japanese patients with ulcerative colitis (UC), as existing data are scarce, inconsistent, and provide limited representation of the real-world situation of MACE in Japan.

We utilized administrative claims data, collected between January 2013 and December 2022, from Medical Data Vision, Japan. Patients (aged ≥ 20 years) diagnosed with UC within ± 1 month of the prescription date during the study period were included in the incident cohort. Exclusions comprised patients diagnosed with UC in the first 365 days or with myocardial infarction, heart failure, stroke, or other ischemic heart diseases within 30 days pre-index. The cumulative incidence rate of MACE was calculated using the Kaplan-Meier method. Multivariate Cox regression models were used to calculate hazard ratios (HRs) for all relevant potential risk factors.

Of 11 407 patients in the incident cohort, 91 (0.8%) experienced incident MACE. Over 120 months, the cumulative incidence rate of MACE was 2.86% (95% confidence interval [CI]: 1.89-4.32). Significant HRs (95% CI) were found for age category (≥ 65 years) (4.557 [2.786-7.452]), diabetes (1.709 [1.030-2.835]), and atrial fibrillation (AF) (2.759 [1.188-6.405]) (all p < 0.05). Patients with a history of stroke showed numerically increased risk (1.871 [0.508-6.886]) of MACE.

The cumulative incidence rate of MACE was 2.86% over 120 months. Age, comorbidities of diabetes and AF, and history of stroke were the major risk factors for MACE in Japanese UC patients.

Infliximab is a first-line biologic agent for the treatment of Crohn's disease (CD), in which loss of response (LOR) remains a challenge in the treatment of patients with CD. The study aimed to explore the association between body composition parameters and LOR to infliximab in CD patients.

118 patients with CD admitted to the First Affiliated Hospital of Wenzhou Medical University and treated with infliximab from June 2015 to December 2021 were retrospectively enrolled. The body composition of patients was analyzed by computed tomography (CT). The primary outcome measure was the one-year LOR. Patients were divided into the Remission group and the LOR group to analyze the association between body composition parameters and the LOR to infliximab.

The rate of sarcopenia in the LOR group was higher than in the Remission group (83.7% vs. 60.0%, P=0.008). Multivariate analysis showed that females had a lower risk of sarcopenia than males (OR=0.30, 95% CI 0.11-0.81, P =0.017); BMI was significantly associated with sarcopenia (OR=0.68, 95% CI 0.56-0.83, P <0.001); L1 CD and L2 CD had a lower risk of sarcopenia than L3 CD (OR=0.29, 95% CI 0.10-0.83, P =0.021; OR=0.25, 95% CI 0.07-0.87, P=0.028).

Sarcopenia was identified as a risk factor for developing LOR in infliximab-treated patients.

Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gastrointestinal tract (GI) with a high incidence rate globally, and IBD patients are often accompanied by zinc deficiency. This review aims to summarize the potential therapeutic value of zinc supplementation in IBD clinical patients and animal models. Zinc supplementation can relieve the severity of IBD especially in patients with zinc deficiency. The clinical severity of IBD were mainly evaluated through some scoring methods involving clinical performance, endoscopic observation, blood biochemistry, and pathologic biopsy. Through conducting animal experiments, it has been found that zinc plays an important role in alleviating clinical symptoms and improving pathological lesions. In both clinical observation and animal experiment of IBD, the therapeutic mechanisms of zinc interventions have been found to be related to immunomodulation, intestinal epithelial repair, and gut microbiota's balance. Furthermore, the antioxidant activity of zinc was clarified in animal experiment. Appropriate zinc supplementation is beneficial for IBD therapy, and the present evidence highlights that alleviating zinc-deficient status can effectively improve the severity of clinical symptoms in IBD patients and animal models.

Inflammatory bowel diseases (IBD) are chronic, incurable pathologies with unknown causes, affecting millions of people. Pediatric-onset IBD, starting before the age of 18 years, are increasing, with more aggressive and extensive features than adult-onset IBD. These differences remain largely unexplained. Intestinal mucosal damage, cell death, DNA release from nuclear, mitochondrial, or microbiota sources, and DNA-sensing activating the cGAS-STING pathway may contribute to disease evolution. Increased colonic cGAS and STING are increasingly reported in experimental and human IBD. However, limited knowledge of the mechanisms involved hinders the development of new therapeutic options. Here, we discuss recent advances and unresolved questions regarding DNA release, DNA sensor activation, and the role and therapeutic potential of the cGAS-STING pathway in inflammatory colitis.

Global production and widespread use of plastics are increasing dramatically. With current limited recycling and recovery options, microplastics and nanoplastics (MNPs) persist in the natural environment. Due to their ubiquity, human exposure to MNPs is inevitable. In addition to their inherent toxic effects, MNPs can adsorb harmful contaminants and act as vectors for microorganisms, compounding toxicological effects. After entering the body, bioaccumulation occurs in several tissues and organs, including the liver and the gastrointestinal (GI) tract. Proposed clinical effects of MNP absorption include endocrine disruption, alteration of the GI microbiome, and promotion of chronic inflammatory conditions. MNPs can also influence energy metabolism, activate inflammatory pathways, and increase oxidative stress leading to apoptosis. The GI tract is a major site of bioaccumulation for the MNPs in animals and humans. In this editorial, the current understanding of how MNPs are processed is discussed. Discussion on MNP effects on internal microflora, and their proposed role in developing inflammatory bowel diseases, MNP toxicokinetics, and their significance in health and disease are also reviewed. There is a need to understand the impact of MNP exposure on gut health and gut microbiota and identify current research gaps.

The inflammatory bowel disease (IBD), comprising Crohn's disease (CD) and ulcerative colitis (UC) is a complex disease with multifactorial etiology. The intestinal dysbiosis have been investigated to play an important role in IBD pathogenesis and disease activity. The aim of our study was to analyze the intestinal microbiota composition in IBD across different severity levels and the impact of biologic therapy on microbiota modulation.

In this study, 27 IBD patients were recruited, including 14 patients undergoing biologic therapy for moderate to severe disease activity and 13 controls with inactive disease. The gut microbial composition was determined by 16 S ribosomal RNA gene sequencing of stool samples.

Biologic therapy led to significant clinical improvement in IBD disease activity after 48 weeks. About species richness, community alpha diversity was significant lower in active CD patients and enriched gradually after biologic therapy. The beta-diversity regard to the difference of bacterial community composition showed significant difference between patients in biologic and control group. A decrease in Firmicutes and increase in Bacteroidetes abundance were observed in patients with active disease, both in CD and UC. Biologic treatment induced shifts in gut microbiota, with increased Firmicutes and decreased Bacteroidetes, as well as improved F/B ratio gradually after treatment, correlating with disease activity.

Our study suggested that gut microbiota differences changed after biologic therapies among IBD with different disease activity, and a rising Firmicutes/Bacteroidetes ratio could be a potential predictor for disease activity and treatment response monitoring.

Berberine (BBR) has been reported to mitigate epileptic seizures. However, the potential mechanism of its anti-seizure effect remains uncharacterized.

This study aimed to investigate the protective effect of BBR on acute epileptic seizures induced by kainic acid (KA) in mice and further explore its mechanism of action in the aspect of analysis of gut microbiota.

The protective effect of BBR against acute epileptic seizures was assessed via Racine score and Nissl training. Alterations of gut microbiota and metabolites in seizure mice after BBR treatment were analyzed through 16S sequencing and lipidomics, respectively.

Our results showed that the BBR remarkably alleviated acute epileptic seizures and hippocampal neuron damage in KA-induced mice. The analysis of gut microbiota indicated that BBR reduced the acute epileptic seizures in KA-induced mice by increasing the abundance of Bacteroidetes and Alloprevotella, regulating short-chain fatty acids (SCFAs). Results of lipidomics also identified 21 candidate metabolites in the colon and hippocampus possibly involved in the protective effect of BBR against acute seizures.

These findings suggest that BBR exerts neuroprotection against KA-induced epileptic seizures through remodeling gut microbiota-associated lipid metabolism in the colon and hippocampus. BBR may serve as a valuable candidate drug for curing patients with epilepsy.

Background/Objectives: Inflammatory bowel diseases (IBDs), which include Crohn's disease (CD) and ulcerative colitis (UC), are chronic conditions requiring long-term therapy to maintain remission and improve quality of life. Despite the approval of numerous drugs, IBD continues to present treatment challenges. This review aims to summarize novel therapeutic target agents in phases II and III of development, including sphingosine-1-phosphate receptor modulators (S1P), anti-interleukin-23 (IL-23), and other small molecules and monoclonal antibodies currently under investigation (e.g., anti-TL1A, obefazimod, NX-13, RIPK-inhibitors). Methods: A comprehensive literature search was conducted up to December 2024 to identify relevant articles published in English over the past three-five years, focusing on phase II/III studies for UC and CD. The search included databases such as PubMed, Google Scholar, and the ClinicalTrials.gov portal. Results: Clinical trials underline the potential of novel immunomodulators, including anti-TL1A, obefazimod, NX-13, RIPK inhibitors, and anti-IL-23p19 agents, as promising therapeutic options for IBD. Anti-IL23p19 therapies, such as risankizumab and mirikizumab, alongside guselkumab, exemplify this class's growing clinical relevance. While some are already in clinical use, others are nearing approval. Conclusions: Ongoing research into long-term safety and the development of personalized treatment strategies remains pivotal to enhance outcomes. Patient stratification and the strategic positioning of these therapies within the expanding treatment landscape are critical for optimizing their clinical impact.

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