Agents In Inflammatory Bowel Disease Research Articles

Echinococcus multilocularis serpin regulates macrophage polarization and reduces gut dysbiosis in colitis.

Helminths serve as principal regulators in modulating host immune responses, and their excretory-secretory proteins are recognized as potential therapeutic agents for inflammatory bowel disease. Nevertheless, our comprehension of the mechanisms underlying immunoregulation remains restricted. This investigation delves into the immunomodulatory role of a secretory protein serpin (Emu-serpin), within the larval stage of Echinococcus multilocularis. Our observations indicate that Emu-serpin effectively alleviates dextran sulfate sodium-induced colitis, yielding a substantial reduction in immunopathology and an augmentation of anti-inflammatory cytokines. Furthermore, this suppressive regulatory effect is concomitant with the reduction of gut microbiota dysbiosis linked to colitis, as evidenced by a marked impediment to the expansion of the pathobiont taxa Enterobacteriaceae. In vivo experiments demonstrate that Emu-serpin facilitates the expansion of M2 phenotype macrophages while concurrently diminishing M1 phenotype macrophages, alongside an elevation in anti-inflammatory cytokine levels. Subsequent in vitro investigations involving RAW264.7 and bone marrow macrophages reveal that Emu-serpin induces a conversion of M2 macrophage populations from a pro-inflammatory to an anti-inflammatory phenotype through direct inhibition. Adoptive transfer experiments reveal the peritoneal macrophages induced by Emu-serpin alleviate colitis and gut microbiota dysbiosis. In summary, these findings propose that Emu-serpin holds the potential to regulate macrophage polarization and maintain gut microbiota homeostasis in colitis, establishing it as a promising candidate for developing helminth therapy for preventing inflammatory diseases.

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

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

Gastroenterology/Hepatology: What You May Have Missed in 2023.

This article summarizes clinically important gastroenterology developments from 2023 for internal medicine specialists. In colorectal cancer screening, a new RNA fecal screening test is on the horizon, as well as a new analysis on the benefits of using artificial intelligence in screening colonoscopy to detect more polyps. There is new evidence for management of gastrointestinal bleeding, a new drug for treatment of recurrent small-intestinal angiodysplasia, and a new endoscopic treatment method in patients with gastrointestinal tumor bleeding. The authors feature a randomized trial about amitriptyline as treatment for patients with irritable bowel syndrome by primary care providers and bring you news about new biologic agents for inflammatory bowel disease and eosinophilic esophagitis. Finally, they review 2 important articles on new terminology and management of metabolic dysfunction-associated fatty liver disease.

Ginsenoside CK Alleviates DSS-Induced IBD in Mice by Regulating Tryptophan Metabolism and Activating Aryl Hydrocarbon Receptor via Gut Microbiota Modulation.

Dysbiosis of gut microbiota is believed to be associated with inflammatory bowel disease (IBD). Ginsenoside compound K (CK), the main metabolite of Panax ginseng ginsenoside, has proven effective as an anti-inflammatory agent in IBD. However, the mechanisms by which CK modulates gut microbiota to ameliorate IBD remain poorly understood. Herein, CK demonstrated the potential to suppress the release of proinflammatory cytokines by gut microbiota modulation. Notably, supplementation with CK promoted the restoration of a harmonious balance in gut microbiota, primarily by enhancing the populations of Lactobacillus and Akkermansia. Furthermore, CK considerably elevated the concentrations of tryptophan metabolites derived from Lactobacillus that could activate the aryl hydrocarbon receptor. Overall, the promising alleviative efficacy of CK primarily stemmed from the promotion of Lactobacillus growth and production of tryptophan metabolites, suggesting that CK should be regarded as a prospective prebiotic agent for IBD in the future.

Development of Ac2-26 Mesoporous Microparticle System as a Potential Therapeutic Agent for Inflammatory Bowel Diseases.

Inflammatory bowel diseases (IBDs) disrupt the intestinal epithelium, leading to severe chronic inflammation. Current therapies cause adverse effects and are expensive, invasive, and ineffective for most patients. Annexin A1 (AnxA1) is a pivotal endogenous anti-inflammatory and tissue repair protein in IBD. Nanostructured compounds loading AnxA1 or its active N-terminal mimetic peptides improve IBD symptomatology. To further explore their potential as a therapeutic candidate, the AnxA1 N-terminal mimetic peptide Ac2-26 was incorporated into SBA-15 ordered mesoporous silica and covered with EL30D-55 to deliver it by oral treatment into the inflamed gut. The systems SBA-Ac2-26 developed measurements revealed self-assembled rod-shaped particles, likely on the external surface of SBA-15, and 88% of peptide incorporation. SBA-15 carried the peptide Ac2-26 into cultured Raw 264.7 macrophages and Caco-2 epithelial cells. Moreover, oral administration of Eudragit-SBA-15-Ac2-26 (200 μg; once a day; for 4 days) reduced colitis clinical symptoms, inflammation, and improved epithelium recovery in mice under dextran-sodium sulfate-induced colitis. The absorption of SBA-15 in gut epithelial cells is typically low; however, the permeable inflamed barrier can enable microparticles to cross, being phagocyted by macrophages. These findings suggest that Ac2-26 is successfully delivered and binds to its receptors in both epithelial and immune cells, aligning with the clinical results. Our findings demonstrate a simple and cost-effective approach to delivering Ac2-26 orally into the inflamed gut, highlighting its potential as non-invasive IBD therapy.

Sophocarpine alleviates intestinal fibrosis via inhibition of inflammation and fibroblast into myofibroblast transition by targeting the Sirt1/p65 signaling axis

In this study, we used alkaloids from Sophora flavescens to inhibit the SASP, leading to fibroblast-into-myofibroblast transition (FMT) to maintain intestinal mucosal homeostasis in vitro and in vivo. We used western blotting (WB) and immunofluorescence staining (IF) to assess whether five kinds of alkaloids inhibit the major inflammatory pathways and chose the most effective compound (sophocarpine; SPC) to ameliorate colorectal inflammation in a dextran sulfate sodium (DSS)-induced UC mouse model. IF, Immunohistochemistry staining (IHC), WB, disease activity index (DAI), and enzyme-linked immunosorbent assay (ELISA) were conducted to investigate the mechanism of action of this compound. Next, we detected the pharmacological activity of SPC on the senescence-associated secretory phenotypes (SASP) and FMT in interleukin 6 (IL-6)–induced senescence-like fibroblasts and discussed the mucosal protection ability of SPC on a fibroblast–epithelium/organoid coculture system and organ-on-chip system. Taken together, our results provide evidence that SPC alleviates the inflammatory response, improves intestinal fibrosis and maintains intestinal mucosal homeostasis in vivo. Meanwhile, SPC was able to prevent IL-6–induced SASP and FMT in fibroblasts, maintain the expression of TJ proteins, and inhibit inflammation and genomic stability of colonic mucosal epithelial cells by activating SIRT1 in vitro. In conclusion, SPC treatment attenuates intestinal fibrosis by regulating SIRT1/NF-κB p65 signaling, and it might be a promising therapeutic agent for inflammatory bowel disease.

P824 Association between visceral adipose tissue and disease duration, clinical activity, and response to various biological agents in inflammatory bowel disease

Abstract Background The relationship between body fat composition and inflammatory bowel disease (IBD) progression, medical response, and prognosis is widely acknowledged. Visceral adipose tissue (VAT) has been shown to be profoundly responsible of most of the obesity-associated metabolic derangements, however it is also related to severity of inflammation. Although VAT can be estimated using computerized tomography, abdominal bioimpedance is a new and reliable technique without expense and radiation exposure. We investigated whether VAT is linked to the disease activity in severe IBD and the short-term response to biological therapies. Methods We prospectively evaluated 65 IBD patients, (n=26 with ulcerative colitis (UC) and n=39 with Crohn’s disease (CD) who had moderate-severe disease activity) at baseline before the initiation of biological therapy. We quantified VAT using abdominal bioimpedance (ViScan). VAT and other body fat metric measures (BMI, total and free fat mass, abdominal fat mass) were also analyzed. The response to biological agents was assessed by clinical (Mayo and CDAI) and endoscopical (mucosal healing) scores at 3 months. Results Out of the 65 patients, 22 individuals (33.8%) exhibited clinical and/or endoscopic response after 3 months. Among responders and non-responders, there was a comparable approximation of disease location (p=0.321) and behavior (p=0.239). Patients with CD had slightly lower levels of VAT, BMI, and free fat mass compared to those with UC. In non-responders with UC, VAT levels were lower than in responders, whereas in non-responders with CD, VAT levels were higher than in responders. No distinction was observed in the VAT response among other classes of biologics, including anti-TNF, ustekinumab, and vedolizumab. Conclusion In summary, VAT parameters using bioimpedance (ViScan) were found to be correlated with the disease activity and reliably identified IBD patients who responded well to various biological treatment in the short-term. Therefore, human fat indices might be novel biomarkers for disease severity and response to therapy.

P688 Comparative Effectiveness of Ustekinumab Versus Vedolizumab in Treating Crohn’s Disease After Failure of Anti-TNF Agents: Real-World Evidence

Abstract Background Despite effective anti-TNF agents in treating Crohn’s disease (CD), some recipients experience primary or secondary non-responses, requiring alternative options. Ustekinumab and vedolizumab have not been compared in randomized controlled trials (RCTs) among CD population. Thus, we used real-world data to compare ustekinumab and vedolizumab at 12 weeks after failure of TNF inhibitors. Methods A retrospective study was conducted at a tertiary hospital in Dammam, Saudi Arabia. Patients with CD who had not responded to anti-TNF agents and had never been exposed to vedolizumab and/or ustekinumab were included. Children ≤ 18 years of age, naïve CD patients, CD patients using only anti-TNF agents, and patients who lost follow up were excluded. Primary endpoints were clinical improvements, which were measured by Harvey-Bradshaw Index scores at 12 weeks, and clinical remission, which was measured as an ordinal outcome. Remission clinically, biochemically, and endoscopically; clinical response; cumulative steroid dose; and corticosteroid-free days were secondary endpoints. Using probabilistic Bayesian models and proportional odds models, we analyzed outcomes, and the posterior distribution was used to calculate the probability of treatment effectiveness. A national institutional review board approved the study. Results Five hundred forty-six patients received biological agents for inflammatory bowel disease, of whom 101 received biological agents for CD; 71 patients received ustekinumab, and 30 patients received vedolizumab. The baseline characteristics were similar except for perianal disease, which was frequently reported in ustekinumab arm (P = 0.006). Most of the patients were male (54.5%), with a median age of 32 (IQR: 26.0-38.0). Most patients (51.5%) had stricturing disease in the Ileocolonic site (70.3%). For ustekinumab, the median HBI score was 5 (IQR: 3.0 -8.0) whereas for vedolizumab, it was 5 (IQR: 4.0 -7.0). In table 1, a Bayesian multivariable proportional odds model revealed a 40% reduction in median HBI scores at 12 weeks favoring ustekinumab, with an aOR of 0.60 (95% CI: 0.25 to 1.31) and a probability of effectiveness of 75% for ustekinumab. At 12 weeks, the ordinal outcome scale was 39% lower for ustekinumab arm, with an aOR of 0.61 (95% CI: 0.26 to 1.35) and a probability of effectiveness of 73% for ustekinumab arm. Secondary endpoints showed favorable results for ustekinumab reaching up to a 90% probability of effectiveness. Conclusion Among CD patients who failed anti-TNF therapies, ustekinumab was more effective than vedolizumab. To validate these results and determine these treatments’ relative efficacy in managing CD, further investigations, including prospective studies and RCTs, are essential.

Immunological relationship between Helicobacter pylori and anti-tumor necrosis factor α agents in inflammatory bowel disease.

Inflammatory bowel disease (IBD) is a group of diseases characterized by refractory and chronic inflammation of the bowel, which can be treated with biologics in clinical practice. Anti-tumor necrosis factor α (TNF-α) agents, which are among the most widely used biologics, alleviate the inflammatory activity in a variety of ways. Helicobacter pylori is a Gram-negative bacterium that colonizes the gastric mucosa, which could cause chronic inflammation and even induce gastric cancer. However, it has been suggested that H. pylori has a potential protective role in IBD patients. Yet there has been limited research on the mechanisms of the effect of H. pylori infection in IBD patients, and whether there is an interaction between H. pylori and anti-TNF-α agents. This review aims to summarize the possible mechanisms of H. pylori and anti-TNF-α agents in the development and treatment of IBD, and to explore the possible interaction between H. pylori infection and anti-TNF-α agents.

The significance of long non-coding RNAs in the pathogenesis, diagnosis and treatment of inflammatory bowel disease.

Inflammatory bowel diseases (IBD) are a group of chronic relapsing gastrointestinal inflammatory diseases with significant global incidence. Although the pathomechanism of IBD has been extensively investigated, several aspects of its pathogenesis remain unclear. Long non-coding RNAs (lncRNAs) are transcripts with more than 200 nucleotides in length that have potential protein-coding functions. LncRNAs play important roles in biological processes such as epigenetic modification, transcriptional regulation and post-transcriptional regulation. In this review, we summarize recent advances in research on IBD-related lncRNAs from the perspective of the overall intestinal microenvironment, as well as their potential roles as immune regulators, diagnostic biomarkers and therapeutic targets or agents for IBD.

Activity of axial spondyloarthritis after one year of anti-tumor necrosis factor therapy among patients with inflammatory bowel diseases.

The disease activity of axSpA after initiating anti-TNF agents for inflammatory bowel diseases (IBD) is poorly understood. We sought to examine the disease activity of axial spondyloarthritis (axSpA) after initiation of anti-tumor necrosis factor (TNF) agents among patients with IBD. This retrospective cohort study included adults with IBD and axSpA who initiated anti-TNF agents between 1/1/2012-10/1/2021 at a large academic center. The primary outcome was symptom resolution (SR) of axSpA at 12 months ("0/10 pain" or "no pain" or "controlled pain" with no morning stiffness and no use of daily NSAIDs). The secondary outcome was clinical remission (CR) of IBD at 12 months (simple clinical colitis activity index <3, Harvey-Bradshaw Index <5, or provider assessment with no use of oral/IV steroids for 30 days). Associations between baseline characteristics and SR of axSpA were examined using logistic regression. 82 patients with axSpA and IBD initiated anti-TNF agents. At 12 months, 52% and 74% achieved SR of axSpA and CR of IBD, respectively. IBD duration <5 years (OR 3.0, 95% CI 1.2-7.5) and adalimumab use (reference: all other anti-TNFs; OR 2.7, 95% CI 1.002-7.1) were associated with SR of axSpA at 12 months. 52% of patients with axSpA and IBD achieved SR of axSpA at 12 months after initiating anti-TNF therapy. Shorter disease duration and adalimumab use may be associated with higher odds of SR. Larger studies are needed to confirm these findings, examine additional clinical predictors of SR, and identify more effective therapeutics for this population.

Lipids, lipid-lowering agents, and inflammatory bowel disease: a Mendelian randomization study.

To assess the causal role of lipid traits and lipid-lowering agents in inflammatory bowel disease (IBD). Univariable mendelian randomization (MR) and multivariable MR (MVMR) analyses were conducted to evaluate the causal association between low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C) and IBD. Drug-targeted MR analyzed the effects of lipid-lowering drugs on IBD, and network MR was used to analyze potential mediation effects. The levels of HDL-C had an inverse relationship with the risk of Crohn's disease (CD, OR: 0.85, 95% CI: 0.73-0.98, P = 0.024). In MVMR, the inverse relationships were found in all three outcomes. Drug-targeted MR analyses showed that with one-SD LDL-C decrease predicted by variants at or near proprotein convertase subtilisin/kexin type 9 (PCSK9), the OR values of people diagnosed with IBD, ulcerative colitis (UC) and CD were 1.75 (95%CI: 1.13-2.69, P = 0.011), 2.1 (95%CI: 1.28-3.42, P = 0.003) and 2.24 (95%CI: 1.11-4.5, P = 0.024), respectively. With one-SD LDL-C decrease predicted by variants at or near cholesteryl ester transfer protein (CETP), the OR value of people diagnosed with CD was 0.12 (95%CI: 0.03-0.51, P = 0.004). Network-MR showed that HDL-C mediated the causal pathway from variants at or near CETP to CD. Our study suggested a causal association between HDL-C and IBD, UC and CD. Genetically proxied inhibition of PCSK9 increased the risk of IBD, UC and CD, while inhibition of CETP decreased the risk of CD. Further studies are needed to clarify the long-term effect of lipid-lowering drugs on the gastrointestinal disorders.

Syringic Acid Alleviates Dextran Sulfate Sodium-Induced Colitis in Mice by Modulating Gut Microbiota.

Inflammatory bowel disease is known to be associated with alterations in gut microbiota. The bioactive compound syringic acid has been shown to alleviate inflammatory bowel disease, but its interaction with gut microbiota and mechanism of action remain unclear. To address this, we conducted a study in which we investigated the potential benefits of syringic acid in a mouse model of dextran sulfate sodium-induced colitis through gut microbiota modulation. Our results show that oral administration of syringic acid effectively reduced symptoms of colitis, as indicated by reduced disease activity index, and histopathology scores. Moreover, syringic acid administration enriched the abundance of Alistipes and norank_f__norank_o__Gastranaerophilales in mice, suggesting a restoration of impaired gut microbiota. Notably, we found that the effects of syringic acid were similar to those of fecal microbiota transplantation in dextran sulfate sodium-induced mice. Further analysis revealed that syringic acid inhibited the NLRP3-Cas-1-GSDMD-IL-1β inflammatory vesicle signaling pathway, leading to amelioration of colonic inflammation in a gut microbiota-dependent manner. Our findings demonstrate the potential of syringic acid as a preventive and therapeutic agent for inflammatory bowel disease.

Association of Antibiotic Use with Durability of Biologic Agents in Inflammatory Bowel Disease: a report from the epi-IIRN.

Different antibiotic classes were reported to have variable effects on immunogenicity towards anti-TNF agents. However, the impact of antibiotic administration on biologic treatment durability was not investigated. We aimed to assess the association between antibiotic treatment and persistence of different classes of biologic therapy in inflammatory bowel disease (IBD) patients. Data from the epi-IIRN, a nationwide registry of all Israeli IBD patients was analyzed. All patients who filled a prescription of either infliximab, adalimumab, vedolizumab, or ustekinumab, were included. Treatment cessation was defined as drug discontinuation of at least 6 months. Macrolides, cephalosporins, fluoroquinolones and penicillins with beta-lacatamase inhibitors were selected as primary exposure variables. Survival analysis was performed using marginal structural models for each drug separately. 13,513 IBD patients with a total of 39,600 patient years were included. Significant differences of overall treatment persistence were demonstrated, with highest persistence rates for ustekinumab and the lowest for infliximab treatment. Macrolides were found to be significantly associated with reduced risk of infliximab cessation (aHR 0.72, 95% CI 0.62-0.89). Flouroquinolones and cephalosporins were associated with an elevated risk of adalimumab treatment cessation (aHR 1.33, 95% CI 1.22-1.46; and aHR 1.20, 95% CI 1.08-1.34, respectively). No significant effects of the studied antibiotics were observed in ustekinumab and vedolizumab users. Specific antibiotic classes are associated with duration of anti-TNF treatment, but not with durability of vedolizumab, or ustekinumab treatments. Further research is required to study the effect of specific antibiotics on response to biologics.

Dihydroartemisinin-ursodeoxycholic acid conjugate is a potential treatment agent for inflammatory bowel disease.

A novel artemisinin derivative, dihydroartemisinin-ursodeoxycholic acid conjugate (4), was found to exhibit strong immunosuppressive activity. Various methods were used to evaluate the immunosuppressive activity and mechanism of action of the compound to explore its potential applications. T cell proliferation, mixed lymphocyte reaction (MLR), and Th1/Th17 differentiation assays were used to evaluate the immunosuppressive activity of the compound. Differentially expressed genes from RNA sequencing were analysed with Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, while enriched signalling pathways were further validated by western blotting (WB). In vivo efficacy was validated with delayed-type hypersensitivity (DTH) mouse models and dextran sodium sulphate (DSS)-induced inflammatory bowel disease (IBD) mouse model. Compound 4 inhibited concanavalin A -induced mouse splenic T cell proliferation (IC50=15nM) and anti-CD3/CD28-induced human primary T cell proliferation (IC50=30nM) while also reducing the secretion of hIFN-γ. Compound 4 exhibited similar inhibitory activity in MLR assay. Compound 4 dose-dependently inhibited human Th1/Th17 differentiation. The KEGG pathway enrichment analysis indicated that the genes related to T cell activation signalling pathways PI3K-AKT, MAPK, and NF-κB were significantly enriched. WB confirmed that compound 4 inhibited the AKT/MAPK and NF-κB signalling pathways. Compound 4 dose-dependently inhibited ear and foot pad swelling in DTH mouse models. In the DSS-induced IBD mouse model, compound 4 significantly decreased the disease activity index and colon density, and inhibited splenomegaly of the mice. The in vitro and in vivo results indicated that compound 4 has the potential to be developed into an anti-IBD drug.

Serum albumin is the strongest predictor of anti-tumor necrosis factor nonresponse in inflammatory bowel disease in resource-constrained regions lacking therapeutic drug monitoring.

Evidence on predictors of primary nonresponse (PNR), and secondary loss of response (SLR) to anti-tumor necrosis factor (anti-TNF) agents in inflammatory bowel disease is scarce from Asia. We evaluated clinical/biochemical/molecular markers of PNR/SLR in ulcerative colitis (UC) and Crohn's disease (CD). Inflammatory bowel disease patients treated with anti-TNF agents (January 2005-October 2020) were ambispectively included. Data concerning clinical and biochemical predictors was retrieved from a prospectively maintained database. Immunohistochemistry for expression of oncostatin M (OSM), OSM receptor (OSM-R), and interleukin-7 receptor (IL-7R) were done on pre anti-TNF initiation mucosal biopsies. One-hundred eighty-six patients (118 CD, 68 UC: mean age, 34.1±13.7 years; median disease duration at anti-TNF initiation, 60 months; interquartile range, 28-100.5 months) were included. PNR was seen in 17% and 26.5% and SLR in 47% and 28% CD and UC patients, respectively. In CD, predictors of PNR were low albumin (P<0.001), postoperative recurrence (P=0.001) and high IL-7R expression (P<0.027) on univariate; and low albumin alone (hazard ratio [HR], 0.09; 95% confidence interval [CI], 0.03-0.28; P<0.001) on multivariate analysis respectively. Low albumin (HR, 0.31; 95% CI, 0.15-0.62; P=0.001) also predicted SLR. In UC, predictors of PNR were low albumin (P<0.001), and high C-reactive protein (P<0.001), OSM (P<0.04) and OSM-R (P=0.07) stromal expression on univariate; and low albumin alone (HR, 0.11; 95% CI, 0.03-0.39; P=0.001) on multivariate analysis respectively. Low serum albumin at baseline significantly predicted PNR in UC and PNR/SLR in CD patients. Mucosal markers of PNR were high stromal OSM/OSM-R in UC and high IL-7R in CD patients.

Has the therapeutical ceiling been reached in Crohn's disease randomized controlled trials? A systematic review and meta-analysis.

The availability of biological agents for inflammatory bowel disease has increased over the past years. In this systematic review and meta-analysis, we aimed to explore time trends in clinical response and clinical remission rates in Crohn's disease (CD) patients treated with biologics while discussing the need for new strategies. MEDLINE, Cochrane, and ISI Web of Science databases were searched for randomized placebo-controlled trials with biological agents in moderate-to-severe CD patients. Sub-group and meta-regression analyses compared treatment and placebo by calculating the pooled odds ratios of clinical remission and clinical response, across time categories and publication year. We also estimated the proportion of patients achieving clinical remission and clinical response by comparing both groups according to the publication year. Twenty-five trials were included in the systematic review, which enrolled 8879 patients between 1997 and 2022. The clinical remission and clinical response odds, in induction and maintenance, have been constant over time, as no statistically significant differences were found between time categories (interaction p-values: clinical remission [induction, p=0.19; maintenance, p=0.24]; clinical response [induction, p=0.43; maintenance, p=0.59]). In meta-regression analyses, publication year did not influence these outcomes (clinical remission [induction, OR 1.01{95% CI 0.97-1.05}, p=0.72; clinical response [induction, OR 1.01{95% CI 0.97-1.04]; p=0.63; maintenance, OR 1.03{95% CI 0.98-1.07}; p=0.21]), with the exception of clinical remission in maintenance studies, which presented a decreased effect (odds ratio 0.97{95% CI 0.94-1.00}, p=0.03]). Our review highlights that the odds of clinical outcomes in CD patients receiving biological treatment relative to placebo have been stable in the last decades.

Targeting FTO by Dac51 contributes to attenuating DSS-induced colitis

BackgroundsDextran Sulphate Sodium (DSS)-induced colitis in mice is used to mimic human Ulcerative colitis (UC) and has been used to explore the pathogenesis of UC and also to evaluate the effectiveness of the therapeutic agent. Various epigenetic pathways have been shown to play important regulatory roles in UC. Reversible N6-methyladenosine (m6A) methylation represented a new layer of post-transcriptional gene regulation that affected a variety of biological processes. Since UC patients may present the up-regulation of FTO-mediated-the reduced total m6A level, our aim was to determine the effects of Dac51, which is an inhibitor of FTO, in DSS induced colitis in mice. MethodsAcute colitis was induced by 3 % DSS in drinking water for 7 days and Dac51 treatment was administered to intraperitoneal injection from days 4–10. Clinical symptoms were analyzed, and biological samples were further collected for histological analysis and the analysis of m6A, respectively. ResultsDac51 treatment attenuated the colitis of DSS treated mice, characterized by the reduced colon shorting and histological damage. The colitis development was due to the reduced m6A level since the increased FTO expression resulted in the colitis phenotype. Dac51 treatment notably attenuated the colitis development. The inhibition of FTO activity in mice by Dac51 treatment was further confirmed by qPCR and western blotting analysis of colon tissues. ConclusionsThese results indicated that Dac51 improved DSS-induced colitis through suppression of FTO expression and provided a preclinical testing of therapeutic agents for inflammatory bowel disease.

P591 Negative impact of high body mass index on the efficacy of anti-TNFα agents in patients with Inflammatory Bowel Disease

Abstract Background Anti-tumor necrosis factor (TNF)-α agents are a therapy of choice in the induction and maintenance treatment of inflammatory bowel disease (IBD). Unfortunately, their efficacy varies. Some IBD patients are primary non-responders and many will experience a secondary loss of response. However, we do not yet have good predictors of their efficacy. Obesity, which prevalence increases worldwide, is also increasingly found in IBD population. Some studies suggest an association between obesity and poorer response to anti-TNFα therapy in IBD patients, although with conflicting results. The aim of this study is to assess the impact of patients’ body mass index (BMI) on the efficacy of anti-TNFα agents in IBD and if there is difference according to the route of administration (intravenous (IV) vs subcutaneous (SC)) or the type of disease (Crohn’s disease (CD) vs ulcerative colitis (UC)). Methods We retrospectively collected data from 188 patients with IBD, aged ≥ 18 years, treated with a first anti-TNFα agent started in our center between January 2002 and December 2020 to avoid missing data. A lack or loss of response to anti-TNFα therapy was defined by the need to optimize or change the treatment or by the initiation of any intercurrent treatment (steroid therapy, hospitalization, or surgery). Frequency of the event and time to its occurrence were analyzed and compared according to BMI using uni- and multivariate logistic regression models and survival curves (Kaplan-Meier), represented by BMI categories (&amp;lt;18.5; 18.5-25; 25-30 and ≥ 30 kg/m²). Results In this cohort of 188 patients (143 CD, 43 UC, 2 Indeterminate Colitis), 8% were obese. We observed that the higher the patient’s BMI, the earlier the risk of optimization or change of treatment (HR=1.043, p=0.045). Association was even stronger for obese patients (HR=2.13, p=0.018). After adjustment for IBD type and administration route, association with obesity persisted. Two other characteristics - female gender (HR=1.56, p=0.012) and higher CRP (HR=1.14, p=0.021) – were associated with earlier optimization or treatment change. Similarly, analysis of survival curves showed a significant difference in time to optimization or change of treatment between BMI categories in patients with CD (p=0.02) but not in those with UC (p=0.87). No association was found between BMI and need for intercurrent treatment. Conclusion This study confirms an association between higher BMI – specifically obesity - and an earlier loss of efficacy of a first anti-TNFα treatment, regardless of IBD type or route of drug administration. Prospective studies with analysis of trough levels are required for a better understanding of the mechanisms involved in the response to anti-TNFα therapy in IBD obese patient.

P744 Safety of live vaccines in children exposed to biological agents for inflammatory bowel disease (IBD) in utero or during breastfeeding

Abstract Background Biological drugs used for IBD are detected in breast milk at a concentration below 10% of the maternal serum concentration and have therefore been considered as permitted drugs. However, warnings have recently been published regarding vaccination with live agents in children whose mothers receive infliximab during breastfeeding. Aim To assess the risk of serious adverse events related to the administration of live vaccines in children exposed to biological drugs in utero or whose mothers were receiving biological agents during breastfeeding. Methods Children born to IBD mothers from DUMBO registry of GETECCU were included. DUMBO is a prospective, observational and multicentre registry, which enrolls pregnant women with IBD over 5 years in 70 centres in Spain. Data on treatment during gestation, type of lactation, breastfeeding, end-date of breastfeeding, maternal treatments during breastfeeding and serious adverse events in children from birth are being prospectively included contacting with the mothers every-3-months. Following the Spanish immunization calendar, rotavirus vaccine is (voluntarily) administered at 2, 4 and 6 (3rd dose only with Rotateq®) months; measles, mumps and rubella (MMR) at 12 months and 3-4 years of age; and varicella at 15 months and 3-4 years of age. Results 526 newborns were included in the registry at the time of data analysis. A total of 205 (39%) had been exposed to biologics during pregnancy or breastfeeding (table 1): 80 (42%) during pregnancy, 7 (2%) during breastfeeding, and 109 (57%) during both. Newborn’s demographics and exposure to drugs during breastfeeding are summarized in table 2. Mean follow-up was 12 months; proportion of children breastfed during follow-up is shown in table 3a. The percentage of children who had been vaccinated according to the recommended schedule was above 95% at all visits (table 3b). Live vaccines administered to children exposed in utero to biologics during the 3rd trimester of gestation are shown in table 4a. From birth, 71% of infants were breastfed (52% exclusively breastfed). Live vaccines administered to children breastfed at least until month 6, until month 12 and until month 15 are summarized in table 4b. No serious adverse event related to live vaccine was reported in our cohort. Conclusion Administration of live virus vaccines from 12 months of age in children born to IBD mothers and exposed to biological drugs in utero or during breastfeeding seems safe and should not be recommended against vaccination or breastfeeding. Rotavirus vaccine (under 6 months of age) appears to be equally safe in these children.