Dual-targeted therapy (DTT) may offer a promising approach for treating refractory inflammatory bowel disease (IBD). The aim of this case series was to evaluate the safety and clinical response of DTT in clinical practice.

We retrospectively analyzed data from refractory inflammatory bowel disease (IBD) patients receiving dual-target therapy (DTT) across several Chinese IBD centers. The treatment combinations included biologic agents (infliximab (IFX), adalimumab (ADA), vedolizumab (VDZ), and ustekinumab (UST) and oral small molecule tofacitinib (TOF). We collected baseline characteristics, clinical and endoscopic activity indices, inflammatory markers (C-reactive protein and albumin), and adverse events to evaluate the clinical effectiveness, endoscopic response, biochemical remission, and safety profile of DTT.

A total of 8 patients with ulcerative colitis (UC) and 10 with Crohn's disease (CD) underwent DTT at three tertiary hospitals in China. All corticosteroids initiated at baseline (six cases) were completely discontinued within 3 months. Clinical response rates were 88.23% (15/17), 91.67% (11/12), and 100% (7/7) at 3, 6, and 9 months, respectively. Endoscopic response was achieved in 88.89% (8/9) of patients who were evaluated at 9 months. Adverse events included ustekinumab-associated arthralgia and alopecia in one UC patient and tofacitinib-related allergic purpura in another, both of which were subsequently transitioned to monotherapy. Two CD patients developed infections (Clostridium difficile and bacterial intestinal infection) at 3 months, were treated with oral antibiotics, and successfully continued their original DTT regimens.

Our findings suggest that dual-target therapy demonstrates promising efficacy and an acceptable safety profile in refractory IBD patients. DTT may represent a valuable therapeutic option for patients who have not responded to conventional monotherapies.

The role of the intestinal microbiome in Crohn's disease (CD) treatment remains poorly understood. This study investigates microbe-host interactions in CD patients undergoing ustekinumab (UST) therapy. Fecal metagenome, metabolome, and host transcriptome data from 85 CD patients were analyzed using multi-omics integration and mediation analysis. Our findings reveal significant microbiome-metabolite-host interactions. Specifically, Faecalibacterium prausnitzii was linked to altered L-ornithine biosynthesis, resulting in higher L-ornithine levels in patients before UST therapy. In vivo and in vitro studies demonstrated that microbiome-derived L-ornithine enhances UST treatment sensitivity in CD by disrupting the host IL-23 receptor signaling and inhibiting Th17 cell stabilization through the IL-12RB1/TYK2/STAT3 axis. L-ornithine significantly enhances the therapeutic efficacy of UST in CD patients, as demonstrated in a prospective clinical trial. These findings suggest that targeting specific microbe-host metabolic pathways may improve the efficacy of inflammatory bowel disease (IBD) treatments.

Inflammatory bowel diseases (IBD) are chronic, remitting, and relapsing conditions of the gastrointestinal tract with incompletely elucidated etiology. The anti-TNF-α mAbs represent one of aflash nanocomplexation and flash nanoprecipitation process, resulting in particles with a narrow size distribution and tunable release profile, with the longest in vitro release lasting over four months. These mAb-releasing NPs are then incorporated into hyaluronic acid hydrogel microparticles (MPs) to enhance tissue retention, thus extending the duration of mAb release in vivo. A single i.m. injection of the LAI can maintain the serum mAb level above the therapeutically effective concentration for over 100 days in healthy mice. In a 9-week study using a dextran sulfate-induced chronic colitis model, the anti-TNF-α LAI formulation demonstrates substantial therapeutic efficacy and a better safety profile than free mAb injections. This work demonstrates the effectiveness of this LAI system in maintaining a persistent serum mAb level and its potential as a versatile, safer, and effective delivery system for antibody therapeutics.

Ulcerative colitis is chronic inflammatory condition affecting the colon, necessitating remission inducing therapeutic interventions. With the emergence of newer more advanced options, their relative effectiveness remains unclear. This network meta-analysis (NMA) will compare the effectiveness of presently available biologics and small molecules in achieving and maintaining remission among patients of moderate-to-severe ulcerative colitis as part of induction and maintenance therapy.

A systematic search was conducted up to 21st February 2025, including only phase 2b/3 or 3 randomized controlled trials. The primary outcome was induction and maintenance of clinical remission (Full Mayo Score (FMS) ≤ 2, with no individual subscore > 1). Secondary outcomes assessed were clinical response, endoscopic improvement (Mayo Endoscopic Score (MES) ≤ 1 either with or without friability) and steroid free remission.

Across 22 studies (7,683 patients), upadacitinib had the highest likelihood of inducing clinical remission (99.08%), clinical response (97.44%) and endoscopic improvement (99.32%), followed by Infliximab and guselkumab following close by for specific outcomes. In maintenance of clinical remission and endoscopic improvement upadacitinib again ranked highest (95.60%) and (99.46%). Tofacitinib (92.43%) has the highest probability with upadacitinib (87.73%) following behind in achieving steroid free remission.

Upadacitinib displayed high efficacy across multiple outcomes in both induction and maintenance therapy with Infliximab, guselkumab, and filgotinib following closely behind. For achieving steroid free remission tofacitinib has the highest probability of doing so. Overall small molecules and selective IL-23 inhibitors seems promising alternative to older biologics though additional head-to-head trial are warranted along with more real-world data.

Clinically heterogeneous spectrum and molecular phenotypes of inflammatory bowel disease (IBD) remain to be comprehensively elucidated. This exploratory multi-omics study investigated the serum molecular profiles of Crohn's disease (CD) and ulcerative colitis (UC), in association with elevated fecal calprotectin and disease activity states. The serum proteome, metabolome, and lipidome of 75 treated IBD patients were profiled. Single- and multi-omic data analysis was performed to determine differential analytes and integrative biosignatures for biological interpretations. We found that chronic inflammation, phosphatidylcholines and bile acid homeostasis disturbances underlined the differences between CD and UC. Besides, elevated calprotectin was associated with higher levels of inflammatory proteins and sphingomyelins (SM) and lower levels of bile acids, amino acids, and triacylglycerols (TG). Relative to the remission disease state, the active form was characterized by decreased abundances of SMs and increased abundances of inflammatory proteins and TGs. We also observed that molecular changes upon treatment escalation were putatively related to altered levels of inflammatory response proteins, amino acids, and TGs. ISM1, ANGPTL4, chenodeoxycholate, Cer(18:1;2 O/24:1), and TG were identified as candidates subject to further investigation. Altogether, our study revealed that disturbances in immune response, bile acid homeostasis, amino acids, and lipids potentially underlie the clinically heterogeneous spectrum of IBD.

We aimed to identify changes in surgical indications in patients with ulcerative colitis (UC) in the biologics era in a single tertiary center.

In this retrospective observational study, 108 patients with UC who underwent abdominal surgery for UC at Seoul National University Hospital from 2000 to 2021 were included. We compared the total number of patients undergoing UC before and after the introduction of biologic therapy.

Of the 108 patients with UC (male, 59 and female, 49; mean age, 46.8 years), 30 (27.8%) underwent surgery for neoplasms and 78 (72.2%) for medical intractability without neoplasms. The duration between diagnosis and surgery varied significantly (126.00 months vs. 60.50 months, P = 0.001). A significant difference was also noted in the surgical indications according to time (P = 0.02). Between 2000 and 2010, 12 patients (19.4%) underwent surgery for UC with neoplasms and 50 (80.6%) for UC without neoplasms, while between 2011 and 2021, 18 (39.1%) and 28 patients (60.9%) underwent surgery for UC with and without neoplasms, respectively.

Since 2011, when biological agents were covered by insurance in South Korea, there has been a relative increase in the incidence of surgical indications for neoplasia cases. Focusing on closely monitoring individuals with long-term UC for neoplasms is necessary.

This study examined inflammatory bowel disease (IBD) trends over the last 10 years, including their nationwide patterns, and the outcomes of the utilization of total parental nutrition (TPN). Nationwide inpatient sample (NIS) database from 2010 to 2020, was used to identify IBD hospitalization and discharges and investigate outcomes, including in-hospital mortality and hospital resource utilization. The hospitalizations for IBD combining both Crohn's disease (CD) and ulcerative colitis (UC) initially noted a rising trend until 2016 followed by a decreasing trend with statistical significance (p < 0.001). A decreasing trend in TPN utilization in CD dropped from 6.2 to 5.4% (p = 0.07). The prevalence of malnutrition in CD cases significantly increased from 11.6 to 16.6% (p < 0.001), and the use of TPN in malnutrition cases decreased from 25.0 to 20.0% with statistical significance (p = 0.002). TPN in UC cases also exhibited a downward trend, declining from 5.3 to 3.1% with statistical significance (p < 0.001). However, there was a noteworthy increase in malnutrition rates, rising from 13.5 to 17.3% (p = 0.087). Similarly, the utilization of TPN in malnutrition cases among UC cases displayed a significant decrease from 19.9 to 11.3% (p < 0.001). The combined use of TPN in IBD showed a decreased trend from 5.9 to 4.3% with statistical significance (p < 0.001). There is a decline in the trend in TPN usage in both CD and UC. The hospital costs and malnutrition trend has increased, while the inpatient mortality, length of stay, and TPN use decreased over the year.

Background/Objectives: Inflammatory bowel diseases (IBDs) are chronic intestinal disorders with an unpredictable course. In parallel with the advent of new biologic therapies targeting specific interleukin pathways, end-point targets have become more stringent, aiming for mucosal and even histologic healing. Methods: We conducted a prospective study assessing immunohistochemical (IHC) parameters in 46 IBD patients treated with biologic therapy. A similar IHC analysis was performed for comparison with a cohort of 10 "non-IBD" patients. Results: The highest integrated optical density (IOD) of TNF-α was observed in patients with dysplasia, abscesses, mucin depletion and basal plasmacytosis. Non-responders had higher pre- and post-treatment TNF-α expression in both UC and CD compared to responders. On the contrary, the same analysis conducted in the subpopulation treated with anti-TNF-α therapy (Infliximab and Adalimumab) did not reveal a substantial difference in TNF-α expression between responders and non-responders. High pre-treatment interleukin-10 expression was associated with biologic therapy failure, histological inflammatory activity and longer disease duration. Conclusions: Pre-treatment assessment of IL-10 might be a useful tool for identifying a high-risk subset of IBD patients and determining a more aggressive therapy and intensive monitoring strategy.

Despite the success of biological therapies in treating inflammatory bowel disease, managing patients remains challenging due to the absence of reliable predictors of therapy response.

In this study, we prospectively sampled 2 cohorts of patients with inflammatory bowel disease receiving the anti-integrin α4β7 antibody vedolizumab. Samples were subjected to mass cytometry; single-cell RNA sequencing; single-cell B and T cell receptor sequencing (BCR/TCR-seq); serum proteomics; and multiparametric flow cytometry to comprehensively assess vedolizumab-induced immunologic changes in the peripheral blood and their potential associations with treatment response.

Vedolizumab treatment led to substantial alterations in the abundance of circulating immune cell lineages and modified the T-cell receptor diversity of gut-homing CD4+ memory T cells. Through integration of multimodal parameters and machine learning, we identified a significant increase in proliferating CD4+ memory T cells among nonresponders before treatment compared with responders. This predictive T-cell signature demonstrated an activated T-helper 1/T-helper 17 cell phenotype and exhibited elevated levels of integrin α4β1, potentially making these cells less susceptible to direct targeting by vedolizumab.

These findings provide a reliable predictive classifier with significant implications for personalized inflammatory bowel disease management.

Budesonide (BUD) is a BCS class II medication with poor water solubility and limited oral bioavailability. In this study, innovative solid self-microemulsifying drug delivery systems (BUD-SMEDDS) were developed for effective local management of distal ulcerative colitis (UC).

Based on solubility and emulsification tests, the components of the self-microemulsifying drug delivery system (SMEDDS) were Capryol™ 90, Tween 80, and Transcutol HP. The impacts of BUD-SMEDDS ingredients (as inputs) on the average globule size (AGS), polydispersity index (PDI), and self-emulsification time (SET) as responses were investigated using the Box-Behnken design methodology. Solid rectal systems were then fabricated using the optimized values of SMEDDS components in Lutrol® bases. The developed systems were evaluated for in vitro characteristics and in vivo efficacy using a rat colitis model.

For all responses, the greatest impact was attributed to the oil content of SMEDDS. An optimized BUD-SMEDDS with AGS of 33 ± 2.9 nm, PDI of 0.29 ± 0.03 and SET of 25 ± 2.5 s) was selected for rectal formulations. The developed formulations demonstrated acceptable physical characteristics and mucoadhesive abilities. Differential scanning calorimetric (DSC) analysis revealed the absence of BUD crystallinity in the SMEDDS formulations. The drug release patterns could be regulated by selecting the grade and composition of the incorporated Lutrols. Clinical and histopathological assessments revealed considerable improvements in animals treated with BUD-SMEDDS formulations.

Overall findings confirmed the superior capability of solid SMEDDS as BUD carriers to manage distal colitis in tested animals.

Regulatory T (Treg) cells is required to dampen immune responses against intestinal microbiota, which aid in a healthy body to promise that the resident gut microbiota should not attract the attention of the immune system. Inflammation and inflammatory bowel disease (IBD) can be induced if the immune system fails to ignore the resident gut microbiota and targets them instead. D-mannose, a common monosaccharide in nature, has been shown to ameliorate multiple autoimmune diseases. This study aimed to investigate the therapeutic effect of D-mannose on mice ulcerative colitis (UC) induced by 2,4,6-trinitrobenzene sulfonic acid (TNBS), and elucidate its underlying mechanisms.

To simulate human IBD, we constructed a mouse model of UC by injecting TNBS into the colon.

Our results demonstrated that D-mannose treatment effectively alleviated TNBS-induced UC in mice, as evidenced by the amelioration of UC symptoms. D-mannose treatment significantly reduced inflammation by decreasing the expression of proinflammatory cytokines and inflammation mediators. D-mannose treatment also significantly inhibited oxidative stress, promoted the expression of GSH and SOD, decreased the expression of MDA. Mechanistically, D-mannose upregulated the proportion of both CD4(+) Tregs and CD8(+) Tregs.

In summary, our study provides the first evidence of the therapeutic effect of D-mannose on mice with UC, which is likely mediated by upregulating Treg proportions.

The gastrointestinal tract harbors diverse microorganisms in the lumen. Epithelial cells segregate the luminal microorganisms from immune cells in the lamina propria by constructing chemical and physical barriers through the production of various factors to prevent excessive immune responses against microbes. Therefore, perturbations of epithelial integrity are linked to the development of gastrointestinal disorders. Several mesenchymal stromal cell populations, including fibroblasts, myofibroblasts, pericytes, and myocytes, contribute to the establishment and maintenance of epithelial homeostasis in the gut through regulation of the self-renewal, proliferation, and differentiation of intestinal stem cells. Recent studies have revealed alterations in the composition of intestinal mesenchymal stromal cells in patients with inflammatory bowel disease and colorectal cancer. A better understanding of the interplay between mesenchymal stromal cells and epithelial cells associated with intestinal health and diseases will facilitate identification of novel biomarkers and therapeutic targets for gastrointestinal disorders. This review summarizes the key findings obtained to date on the mechanisms by which functionally distinct mesenchymal stromal cells regulate epithelial integrity in intestinal health and diseases at different developmental stages.

The Veterans Health Administration (VHA) listed the infliximab (IFX) biosimilar, IFX-dyyb (Inflectra), on the Veterans Affairs National Formulary (VANF) in May 2017. In September 2018, biosimilar IFX-abda (Renflexis) became the VANF IFX product. The recommended formulary changes from one IFX biosimilar to another provided a unique opportunity to study IFX utilization patterns in IFX-naïve Veterans with Inflammatory Bowel Disease (IBD). This study aimed to describe IFX and healthcare utilization during the 365 days after initiation with IFX reference product (RP) or biosimilars IFX-dyyb and IFX-adba. This descriptive study was performed using the VHA Corporate Data Warehouse. All Veterans initiated on IFX-RP (Remicade) or biosimilars IFX-dyyb and IFX-adba between September 1, 2016 and December 30, 2019 were included and followed for 365 days. Veterans enrolled in the VHA for at least 365 days with no evidence of IFX before their index date were considered IFX-naïve. Continuous data on IFX use, laboratory measurements, and healthcare utilization were reported with means, 95% confidence interval (CI), medians, and interquartile ranges. Frequency, proportions, and 95% CIs were presented for categorical variables. Statistical tests included ANOVA and Kruskal-Wallis for continuous outcomes, Poisson regression for count-based outcomes (i.e., healthcare utilization visits), and Chi-square for dichotomous outcomes. The study identified 1763 IFX-naïve patients with IBD, and 785, 441, and 537 was indexed to RP, IFX-dyyb, and IFX-adba, respectively. Statistical differences were observed in IFX utilization measures related to dosing, adherence, and persistence. The proportion of days covered (PDC) during the 365-day follow-up period varied among the IFX groups: IFX-RP at 66%, IFX-dyyb at 60%, and IFX-abda at 69% (P value < .001). Persistence with the index IFX product during the 365-day follow-up period also varied: IFX-RP at 43%, IFX-dyyb at 32%, and IFX-abda at 51% (P value < .001). Healthcare utilization and laboratory findings were similar among the IFX groups. IFX utilization and laboratory patterns were clinically similar among the IFX biosimilars and RP groups, suggesting that providers did not modify their practice with biosimilars. Statistically significant differences in IFX utilization patterns are explained by formulary dynamics when the VANF product switched from IFX-dyyb to IFX-abda.

The infliximab biosimilar CT-P13 was the first biosimilar drug targeting tumor necrosis factor-α. However, its efficacy and safety in real-world clinical situations have remained insufficient. Therefore, we aimed to verify the efficacy and safety of CT-P13 in bio-naïve patients with Crohn's disease.

This retrospective multicenter study compared the remission rate at week 54 between patients with Crohn's disease who were treated with originator infliximab or CT-P13. Endoscopic and laboratory findings were assessed in both groups. A total of 184 (156 originator and 28 CT-P13) patients were analyzed. Of these, 138 originator users and 19 biosimilar users completed 54-week administration.

The clinical remission rates in patients taking originator infliximab of CT-P13 at week 54 were 92.5 % and 100 %, respectively. The endoscopic scores of each group significantly decreased from baseline at week 54 in both groups, and the mucosal healing rate at week 54 was 53 % and 64 %, respectively. Laboratory data including C-reactive protein, serum albumin, and hemoglobin significantly improved from baseline to week 14 and 54 in both groups. Adverse events were observed more frequently in the CT-P13 group (25 % vs. 4.5 %, p = 0.0015), but severe adverse events were rare in both groups.

The efficacy and safety of CT-P13 were comparable with those of originator infliximab in bio-naïve patients with Crohn's disease evaluated by clinical, endoscopic, and laboratory findings. This study establishes the needed groundwork for the development of a strategy for treatment with biologics in patients with Crohn's disease.

This study, conducted between 4 October 2013, and 30 November 2018, tested the hypothesis that triple antimicrobial therapy, targeting Mycobacterium avium subspecies paratuberculosis (MAP), long considered a putative cause, would favorably affect Crohn's disease. A double-blind multicenter study of adults with active Crohn's disease, (i.e., Crohn's Disease Activity Index [CDAI] 220-450 plus C-reactive protein ≥ 1.0 mg/dL, fecal calprotectin (FCP) >162.9 µg/g stool, or recent endoscopic or radiographic confirmation of active disease) receiving concomitant standard-of-care Crohn's disease treatment (Clinicaltrials.gov: NCT01951326) were stratified by anti-tumor necrosis factor use and randomized (1:1) to anti-MAP RHB-104 (clarithromycin 95 mg, rifabutin 45 mg, and clofazimine 10 mg per capsule) (n = 166), resulting in clarithromycin 950 mg/day, rifabutin 450 mg/day, and clofazimine 100 mg/day, or placebo (n = 165) for up to 52 weeks. A greater proportion of RHB-104 versus placebo-treated patients met the primary endpoint-remission (i.e., CDAI < 150)-at week 26 (36.7% [61/166] vs. 22.4% [37/165], respectively; 95% CI for difference: 4.6, 24.0, p = 0.0048; chi-square test). Clinical response (reduction of CDAI by ≥100 points from baseline) at week 26 (first secondary endpoint) was also higher among the patients treated with RHB-104 (73/166 [44.0%]) compared with placebo (50/165 [30.3%]; 95% CI for difference: 3.4, 24.0, p = 0.0116), and it remained higher at week 52 among the patients treated with RHB-104 (59/166 [35.5%] vs. (35/165 [21.2%] for placebo; 95% CI for difference: 4.7, 23.9, p = 0.0042). A statistically significantly greater decline in FCP (another prospective efficacy endpoint) was also observed in RHB-104-treated patients, compared with placebo, at weeks 12, 26, and 52. The rates of serious adverse events were similar between groups (RHB-104: 18.7%; placebo: 18.8%). No patient died during the study. Antimicrobial therapy directed against MAP resulted in significantly greater improvement in clinical and laboratory (FCP) measures of active Crohn's disease.

Inflammatory bowel disease (IBD) is a chronic and relapsing inflammatory disorder of the gastrointestinal tract for which treatment options remain limited. In this study, we used a dual-luciferase-based screening of an FDA-approved drug library, identifying Bazedoxifene (BZA) as an inhibitor of the NF-κB pathway. We further investigated its therapeutic effects in a dextran sodium sulfate (DSS)-induced colitis model and explored its impact on gut microbiota regulation and the underlying molecular mechanisms. Our results showed that BZA significantly reduced DSS-induced colitis symptoms in mice, evidenced by decreased colon length shortening, lower histological scores, and increased expression of intestinal mucosal barrier-associated proteins, such as Claudin 1, Occludin, Zo-1, Mucin 2 (Muc2), and E-cadherin. Used independently, BZA showed therapeutic effects comparable to those of infliximab (IFX). In addition, BZA modulated the abundance of gut microbiota especially Bifidobacterium pseudolongum, and influenced microbial metabolite production. Crucially, BZA's alleviation of DSS-induced colitis in mice was linked to change in gut microbiota composition, as evidenced by in vivo gut microbiota depletion and fecal microbiota transplantation (FMT) mice model. Molecularly, BZA inhibited STAT3 and NF-κB activation in DSS-induced colitis in mice. In general, BZA significantly reduced DSS-induced colitis in mice through modulating the gut microbiota and inhibiting STAT3 and NF-κB activation, and its independent use demonstrated a therapeutic potential comparable to IFX. This study highlights gut microbiota's role in IBD drug development, offering insights for BZA's future development and its clinical applications.

Current therapies primarily targeting inflammation often fail to address the root relationship between intestinal mucosal integrity and the resulting dysregulated cell death and ensuing inflammation in ulcerative colitis (UC). First, UC tissues from human and mice models in this article both emphasize the crucial role of Gasdermin E (GSDME)-mediated pyroptosis in intestinal epithelial cells (IECs) as it contributes to colitis by releasing proinflammatory cytokines, thereby compromising the intestinal barrier. Then, 4-octyl-itaconate (4-OI), exhibiting potential for anti-inflammatory activity in inhibiting pyroptosis, was encapsulated by butyrate-modified liposome (4-OI/BLipo) to target delivery for IECs. In brief, 4-OI/BLipo exhibited preferential accumulation in inflamed colonic epithelium, attributed to over 95% of butyrate being produced and absorbed in the colon. As expected, epithelium barriers were restored significantly by alleviating GSDME-mediated pyroptosis in colitis. Accordingly, the permeability of IECs was restored, and the resulting inflammation, mucosal epithelium, and balance of gut flora were reprogrammed, which offers a hopeful approach to the effective management of UC.

C-X-C motif chemokine receptor 3 (CXCR3, CD183) is a G-protein-coupled receptor for CXCL9, CXCL10, and CXCL11. CXCR3 induces chemotaxis of immune cells and promotes inflammation. Various mouse models have been developed to mimic the pathogenesis of diseases and used in the evaluation of therapeutics for these diseases. Although CXCR3 is an attractive target to suppress inflammation, anti-CXCR3 therapeutic agents have not been approved. In this study, we established a novel anti-mouse CXCR3 (mCXCR3) monoclonal antibody, Cx3Mab-4 (rat IgG1, kappa), using the Cell-Based Immunization and Screening method. Flow cytometric analysis demonstrated that Cx3Mab-4 bound to mCXCR3-overexpressed Chinese hamster ovary-K1 (CHO/mCXCR3) cells, but did not react to parental CHO-K1 cells. The dissociation constant of Cx3Mab-4 was determined as 1.3 × 10-9 M, indicating that Cx3Mab-4 possesses a high affinity to mCXCR3-expressing cells. Cx3Mab-4 could be useful for targeting CXCR3-expressing cells in preclinical mouse models.

Taurine (Tau) is a semiessential amino acid in mammals with preventive and therapeutic effects on several intestinal disorders. However, the exact function of taurine in ulcerative colitis (UC) is still largely unclear. In this study, we used two taurine-deficient mouse models (CSAD-/- and TauT-/- mice) to explore the influence of taurine on the progression of UC in both dextran sulfate sodium (DSS)-induced colitis and LPS-stimulated Caco-2 cells. We found that cysteine sulfinic acid decarboxylase (CSAD) and taurine transporter (TauT) expressions and taurine levels were markedly reduced in colonic tissues of mice treated with DSS. The CSAD and TauT knockouts exacerbated DSS-induced clinical symptoms and pathological damage and aggravated the intestinal barrier dysfunction and the colonic mucosal inflammatory response. Conversely, taurine pretreatment enhanced the intestinal barrier functions by increasing goblet cells and upregulating tight junction protein expression. Importantly, taurine bound with TLR4 and inhibited the TLR4/NF-κB pathway, ultimately reducing proinflammatory factors (TNF-α and IL-6) and oxidative stress. Our findings highlight the essential role of taurine in maintaining the intestinal barrier integrity and inhibiting intestinal inflammation, indicating that taurine is a promising supplement for colitis treatment.

Evidence-based research has confirmed the role of gastrointestinal microbiota in regulating intestinal inflammation. These data have generated interest in developing microbiota-based therapies for the prevention and management of inflammatory bowel disease (IBD). Despite in-depth understanding of the etiology of IBD, it currently lacks a cure and requires ongoing management. Accumulating data suggest that an aberrant gastrointestinal microbiome, often referred to as dysbiosis, is a significant environmental instigator of IBD. Novel microbiome-targeted interventions including prebiotics, probiotics, fecal microbiota transplant, and small molecule microbiome modulators are being evaluated as therapeutic interventions to attenuate intestinal inflammation by restoring a healthy microbiota composition and function. In this review, the effectiveness and challenges of microbiome-centered interventions that have the potential to alleviate intestinal inflammation and improve clinical outcomes of IBD are explored.

To assess the accuracy of Magnetic Resonance Index of Activity (MaRIA) in evaluating therapeutic efficacy in Crohn's disease (CD) patients with different activity levels using ileocolonoscopy as the reference standard.

Forty-eight patients underwent magnetic resonance enterography (MRE) and ileocolonoscopy at baseline, week 26, and week 52, along with the Simple Endoscopic Score for Crohn's Disease (SES-CD) and MaRIA scores. According to the SES-CD score at baseline, all patients were subdivided into mild, moderate, and severe activity subgroups. The identification of endoscopic mucosal healing (MH) was explored primarily. Moreover, the Crohn's Disease Activity Index (CDAI), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), procalcitonin (PCT), and interleukin-6 (IL-6) levels were collected and analysed.

MaRIA correlated significantly with SES-CD and CRP at baseline, week 26, and week 52. The discrepancies in MaRIA and SES-CD were statistically significant before and after treatment. MaRIA = 24.43 and ΔMaRIA = 12.77 as the cut-off points were found to have high diagnostic accuracy for predicting MH. MaRIA (p<0.001), SES-CD (p<0.001), CRP (p<0.05), ESR (p<0.05), and CDAI score (p<0.05) in patients with MH were considerably decreased compared to those in patients without MH.

MRE has good application value in evaluating the therapeutic response of CD patients treated with biological agents. MaRIA is a reliable indicator in the follow-up of CD patients, which is strongly correlated with SES-CD, and it has high accuracy in predicting endoscopic MH.

Inflammatory bowel diseases (IBDs) are characterized by a multifactorial clinical picture, in which age-related physical, functional and psychological symptoms may coexist. The accurate evaluation and identification of such symptomatology acquires considerable importance in the context of older adults, since those core factors typical of IBD may also expose older patients to an increased risk for age-related negative outcomes, such as frailty and disability. The purpose of the present review was to provide an updated overview on the evaluation and management of IBD in the elderly population, with regard to fatigue, sarcopenia, and frailty. The assessment of fatigue might contribute to the identification of early symptoms of IBD, such as pain and mood disorders, which should be treated timely to offer elderly patient a better quality of life. Similarly, an accurate evaluation of sarcopenia might represent a useful Prognostic Index to identify those patients at risk of developing physical frailty. Frailty in IBD should be evaluated not only in relation to the occurrence of negative outcomes, but also should be considered itself as an outcome itself in IBD. A recommendation for future research on this topic might be the implementation of randomized trials, which include older adults and evaluate fatigue, sarcopenia, and frailty. Similarly, the development of tailored intervention programs, based on both physical and psychological outcomes, with the purpose of improving patients' adaptation to the disease, and monitoring the evolution of symptoms and the response to therapies over time, should be encouraged.

The link between chronic inflammation and cancer development is well acknowledged. Inflammatory bowel disease including ulcerative colitis and Crohn's disease frequently promotes colon cancer development. Thus, control of intestinal inflammation is a therapeutic strategy to prevent and manage colitis-associated colorectal cancer (CRC). Recently, gut mucosal damage-associated molecular patterns S100A8 and S100A9, acting via interactions with their pattern recognition receptors (PRRs), especially TLR4 and RAGE, have emerged as key players in the pathogenesis of colonic inflammation. We found elevated serum levels of S100A8 and S100A9 in both colitis and colitis-associated CRC mouse models along with significant increases in their binding with PRR, TLR4, and RAGE. In this study we developed a dual PRR-inhibiting peptide system (rCT-S100A8/A9) that consisted of TLR4- and RAGE-inhibiting motifs derived from S100A8 and S100A9, and conjugated with a CT peptide (TWYKIAFQRNRK) for colon-specific delivery. In human monocyte THP-1 and mouse BMDMs, S100A8/A9-derived peptide comprising TLR4- and RAGE-interacting motif (0.01, 0.1, 1 μM) dose-dependently inhibited the binding of S100 to TLR4 or RAGE, and effectively inhibited NLRP3 inflammasome activation. We demonstrated that rCT-S100A8/A9 had appropriate drug-like properties including in vitro stabilities and PK properties as well as pharmacological activities. In mouse models of DSS-induced acute and chronic colitis, injection of rCT-S100A8/A9 (50 μg·kg-1·d-1, i.p. for certain consecutive days) significantly increased the survival rates and alleviated the pathological injuries of the colon. In AOM/DSS-induced colitis-associated colorectal cancer (CAC) mouse model, injection of rCT-S100A8/A9 (50 μg·kg-1·d-1, i.p.) increased the body weight, decreased tumor burden in the distal colon, and significantly alleviated histological colonic damage. In mice bearing oxaliplatin-resistant CRC xenografts, injection of rCT-S100A8/A9 (20 μg/kg, i.p., every 3 days for 24-30 days) significantly inhibited the tumor growth with reduced EMT-associated markers in tumor tissues. Our results demonstrate that targeting the S100-PRR axis improves colonic inflammation and thus highlight this axis as a potential therapeutic target for colitis and CRC.

Several advanced imaging techniques are now available for endoscopists managing inflammatory bowel disease (IBD) patients. These tools, including dye-based and virtual chromoendoscopy, probe-based confocal laser endomicroscopy and endocytoscopy, are increasingly innovative applications in clinical practice. They allow for a more in-depth and refined evaluation of the mucosal and vascular bowel surface, getting closer to histology. They have demonstrated a remarkable ability in assessing intestinal inflammation, histologic remission, and predicting relapse and favorable long-term outcomes. In addition, the future application of molecular endoscopy to predict biological drug responses has yielded preliminary but encouraging results. Furthermore, these techniques are crucial in detecting and characterizing IBD-related dysplasia, assisting endoscopic mucosal resection and submucosal dissection towards a surgery-sparing approach. Artificial intelligence (AI) holds great potential in this promising landscape, as it can provide an objective and reproducible assessment of inflammation and dysplasia. Moreover, it can improve the prediction of outcomes and aid in subsequent therapeutic decision-making. This review aims to summarize the promising role of state-of-the-art advanced endoscopic techniques and related AI-enabled models for managing IBD, paving the way for precision medicine.

The landscape of ulcerative colitis has changed in the last two decades. Advancements in pharmacotherapeutics have heralded the introduction of new treatment options, with many agents in development. Better clinical outcomes are seen with tighter disease control, made possible with greater understanding of inflammatory pathways and their blockade with drugs. There has been a resultant shift in treatment targets, beyond symptoms to endoscopic and histological healing. Controlling the burden of disease activity also lowers the risk of developing colorectal cancer. Colorectal cancer screening now requires the use of dye-based agents and high-definition colonoscopy to improve the detection of colonic neoplasms.

Both infliximab (IFX) and fecal microbiota transplantation (FMT) have shown the efficacy for inflammatory bowel disease (IBD). However, there has no head-to-head study on the cost-value of the such treatments on IBD. This study aimed to compare the medical costs using IFX and the new method of FMT (washed microbiota transplantation [WMT]) in the long-term management for IBD under the current health economic condition in China.

Patients with IBD who underwent initial WMT via upper gastrointestinal endoscopy, mid-gut tube, or colonic transendoscopic enteral tubing at a university hospital between April 2013 and August 2021 and achieved the long-term sustainment with WMT or WMT combined with mesalazine until August 2022 were recruited in the real-world. The costs and hospitalizations were analyzed among two therapies mentioned above and IFX standard therapy. The charge of WMT was stable in the long term at our center, and the charge of IFX came from virtual statistics publicized by China Healthcare Security.

Sixty eligible patients with IBD were included in the study. The long-term costs of patients using WMT monotherapy annually or per hospitalization were lower than those on WMT combined with mesalazine, respectively ( p < 0.001, respectively). The cumulative costs of IFX at the time of 0.52 and 0.85 years exceeded that of the above WMT, respectively ( p < 0.001, respectively). Besides, patients on WMT monotherapy paid 51.1 k CNY annually in the nonsustain phase but cut down the costs by 7.2 k CNY and duration of hospitalization by 5.1 days per hospitalization when reaching the goal of sustainment.

This study demonstrated that WMT could dramatically reduce the cost and duration of hospitalizations in the long-term sustainment in the current Chinese IBD cohort. Compared with IFX, WMT could be a good way for the patients with IBD achieving long-term sustainment and saving medical costs.

Inflammatory bowel diseases (IBDs) like Crohn's disease and ulcerative colitis involve chronic gastrointestinal inflammation. The pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-α) drives IBD pathogenesis. Anti-TNF-α therapies using monoclonal antibodies (mAbs) like infliximab (INF) help treat IBD but have limitations. We developed inflammation-targeting polyphenol-poloxamer nanoparticles loaded with the anti-inflammatory mAb INF (INF@PPNP) as a novel IBD therapy. Characterization showed that INF@PPNP had favorable stability and purity. Radiolabeling INF@PPNP with 89Zr enabled tracking localization with positron emission tomography (PET) imaging. Rectal administration of 89Zr-INF@PPNP led to colon delivery with remarkably reduced systemic exposure versus intravenous INF revealed by non-invasive PET imaging. 89Zr-INF@PPNP retention at inflamed foci indicated prolonged INF@PPNP action. INF@PPNP rectally achieved similar anti-inflammatory effects as intravenously injected INF, demonstrating the high therapeutic potential. Our findings support the use of nanoparticle-based rectal administration for localized drug delivery, prolonging drug activity and minimizing systemic exposure, ultimately offering an effective approach for treating IBD.

SB5 is an EMA-approved adalimumab biosimilar, having demonstrated bioequivalence, equivalent efficacy, and similar safety and immunogenicity to the reference product.

Describe patient training and satisfaction using patient-reported outcome measures (PROMs) and assess their impact on 12-month persistence on SB5.

The observational PERFUSE study included 318 Crohn's disease (CD) patients and 88 ulcerative colitis (UC) patients in 27 sites across France between October 2018 and December 2020. PROMs were collected at 1-month post-baseline using an online questionnaire (ePRO) designed with patient associations. Treatment persistence was collected during routine visits (up to 15 months post-initiation). Results are presented by prior experience with subcutaneous biologics and training in proper use of the injection device.

57.1% (n = 145) and 44.1% (n = 67) of naïve and pre-treated patients, respectively, answered the ePRO. Naïve patients were offered training more often (86.9% vs 31.3% respectively, p < 0.05), with disparities between sites. All subgroups' satisfaction scores were high. 12-month persistence on SB5 was significantly higher for respondents than for non-respondents (68.0% [60.9; 74.1] vs 52.3% [44.5; 59.6]; p < 0.05) and in patients with a better perception of their illness (OR=1.02, [1.0; 1.05]; p < 0.05).

Early patient questionnaires may be useful to identify patients at higher risk of treatment discontinuation.

Janus kinase inhibitors (JAKi) are oral small molecules used in the treatment of a broad spectrum of autoimmune and myeloproliferative diseases. JAKi exhibit significant intra- and inter-individual pharmacokinetic variabilities, due to fluctuations in compliance with oral treatments and their metabolism essentially driven by cytochrome P450 enzymes. Intrinsically, JAKi have dose-response relationship and narrow therapeutic index: therapeutic drug monitoring (TDM) is expected to optimize and adapt their dosage regimen in order to resolve problems of efficacy and tolerance linked to dose and safety. A sensitive analytical method using multiplex high-performance liquid-chromatography coupled to tandem mass spectrometry (HPLC-MS/MS) was developed and validated for the simultaneous quantification in plasma of the 6 major currently used JAKi, namely abrocitinib, baricitinib, fedratinib, ruxolitinib, tofacitinib, and upadacitinib. Plasma samples are subjected to protein precipitation with MeOH, using stable isotopically labelled internal standards. The separation of JAKi in supernatants diluted 1:1 with ultrapure H2O was performed using a C18 column Xselect HSS T3 2.5 µm, 2.1x150 mm using a mobile phase composed of formic acid (FA) 0.2% and acetonitrile (+FA 0.1%) in gradient mode. The analytical run time for the multiplex assay was 7 min. JAKi drugs were monitored by electrospray ionization in the positive mode followed by triple-stage quadrupole MS/MS analysis. The method was validated according to SFSTP and ICH guidelines over the clinically relevant concentration ranges (0.5-200 ng/mL for abrocitinib, baricitinib and upadacitinib; 1-400 ng/mL for tofacitinib; 0.5-400 ng/mL for ruxolitinib, and 10-800 ng/mL for fedratinib). This multiplex HPLC-MS/MS assay achieved good performances in term of trueness (91.1-113.5%), repeatability (3.0-9.9%), and intermediate precision (4.5-11.3%). We developed and validated a highly sensitive method for the multiplex quantification of the JAKi abrocitinib, baricitinib, fedratinib, ruxolitinib, tofacitinib, and upadacitinib in human plasma. The method will be applied for prospective clinical pharmacokinetic studies to determine whether TDM programs for JAKi based on residual drug concentrations can be recommended using disease-specific therapeutic ranges.

Vaccine-elicited immune responses are impaired in patients with inflammatory bowel disease (IBD) treated with anti-TNF biologics.

To assess vaccination efficacy against the novel omicron sublineages BQ.1.1 and XBB.1.5 in immunosuppressed patients with IBD.

This prospective multicentre case-control study included 98 biologic-treated patients with IBD and 48 healthy controls. Anti-spike IgG concentrations and surrogate neutralisation against SARS-CoV-2 wild-type, BA.1, BA.5, BQ.1.1, and XBB.1.5 were measured at two different time points (2-16 weeks and 22-40 weeks) following third dose vaccination. Surrogate neutralisation was based on antibody-mediated blockage of ACE2-spike protein-protein interaction. Primary outcome was surrogate neutralisation against tested SARS-CoV-2 sublineages. Secondary outcomes were proportions of participants with insufficient surrogate neutralisation, impact of breakthrough infection, and correlation of surrogate neutralisation with anti-spike IgG concentration.

Surrogate neutralisation against all tested sublineages was reduced in patients with IBD who were treated with anti-TNF biologics compared to patients treated with non-anti-TNF biologics and healthy controls (each p ≤ 0.001) at visit 1. Anti-TNF therapy (odds ratio 0.29 [95% CI 0.19-0.46]) and time since vaccination (0.85 [0.72-1.00]) were associated with low, and mRNA-1273 vaccination (1.86 [1.12-3.08]) with high wild-type surrogate neutralisation in a β-regression model. Accordingly, higher proportions of patients treated with anti-TNF biologics had insufficient surrogate neutralisation against omicron sublineages at visit 1 compared to patients treated with non-anti-TNF biologics and healthy controls (each p ≤ 0.015). Surrogate neutralisation against all tested sublineages decreased over time but was increased by breakthrough infection. Anti-spike IgG concentrations correlated with surrogate neutralisation.

Patients with IBD who are treated with anti-TNF biologics show impaired neutralisation against novel omicron sublineages BQ.1.1 and XBB.1.5 and may benefit from prioritisation for future variant-adapted vaccines.

There are concerns about the serological responses to Coronavirus disease 2019 (COVID-19) vaccines in inflammatory bowel disease (IBD) patients, particularly those receiving anti-TNF therapy. This study aimed to systematically evaluate the efficacy of COVID-19 vaccines in IBD patients receiving anti-TNF therapy.

Electronic databases were searched to identify relevant studies. We calculated pooled seroconversion rate after COVID-19 vaccination and subgroup analysis for vaccine types and different treatments were performed. Additionally, we estimated pooled rate of T cell response, neutralization response, and breakthrough infections in this population.

32 studies were included in the meta-analysis. IBD patients receiving anti-TNF therapy had relatively high overall seroconversion rate after complete vaccination, with no statistical difference in antibody responses associated with different drug treatments. The pooled positivity rate of T cell response was 0.85 in IBD patients receiving anti-TNF therapy. Compared with healthy controls, the positivity of neutralization assays was significantly lower in IBD patients receiving anti-TNF therapy. The pooled rate of breakthrough infections in IBD patients receiving anti-TNF therapy was 0.04.

COVID-19 vaccines have shown good efficacy in IBD patients receiving anti-TNF therapy. However, IBD patients receiving anti-TNF have a relatively high rate of breakthrough infections and a low level of neutralization response.

Inflammatory bowel diseases (IBDs) treatments have shifted from small-molecular therapeutics to the oncoming biologics. The first-line biologics against the moderate-to-severe IBDs are mainly involved in antibodies against integrins, cytokines and cell adhesion molecules. Besides, other biologics including growth factors, antioxidative enzyme, anti-inflammatory peptides, nucleic acids, stem cells and probiotics have also been explored at preclinical or clinical studies. Biologics with variety of origins have their unique potentials in attenuating immune inflammation or gut mucosa healing. Great advances in use of biologics for IBDs treatments have been archived in recent years. But delivering issues for biologic have also been confronted due to their liable nature. In this review, we will focus on biologics for IBDs treatments in the recent publications; summarize the current landscapes of biologics and their promise to control disease progress. Alternatively, the confronted challenges for delivering biologics will also be analyzed. To combat these drawbacks, some new delivering strategies are provided: firstly, designing the functional materials with high affinity toward biologics; secondly, the delivering vehicle systems to encapsulate the liable biologics; thirdly, the topical adhering delivery systems as enema. To our knowledge, this review is the first study to summarize the updated usage of the oncoming biologics for IBDs, their confronted challenges in term of delivery and the potential combating strategies.