Strategy For Inflammatory Bowel Disease Research Articles

HucMSC-Ex alleviates inflammatory bowel disease in mice by enhancing M2-type macrophage polarization via the METTL3-Slc37a2-YTHDF1 axis

Human umbilical cord mesenchymal stem cell-derived exosomes (hucMSC-Ex) have emerged as a new treatment strategy for inflammatory bowel disease (IBD) due to their immunoregulatory function. N6-methyladenosine (m6A) plays a crucial role in regulating intestinal immunity, especially in IBD where macrophages play an important role, although its mechanism is not yet fully understood. From this perspective, this research aimed to evaluate the effect of hucMSC-Ex on m6A modification of macrophages in IBD. In the process of alleviating inflammation, hucMSC-Ex promotes macrophage polarization toward the M2 type and regulates intracellular m6A levels by upregulating the expression of m6A “Writer” METTL3 and “Reader” YTHDF1. Solute Carrier Family 37 Member 2 (Slc37a2) was identified by Methylation RNA immunoprecipitation sequencing as the target molecule of the hucMSC-Ex. Mechanically, hucMSC-Ex promoted the binding of METTL3 to the Slc37a2 mRNA complex, and enhanced the binding of Slc37a2 to YTHDF1 to upregulate the intracellular expression of Slc37a2, thereby attenuating the pro-inflammatory function of macrophage. This study confirms the modulatory role of hucMSC-Ex on the m6A modification of macrophages in IBD, providing a new scientific basis for the treatment of IBD with hucMSC-Ex.

Alzheimer’s disease-related presenilins are key to intestinal epithelial cell function and gut immune homoeostasis

ObjectiveMutations in presenilin genes are the major cause of Alzheimer’s disease. However, little is known about their expression and function in the gut. In this study, we identify the presenilins...

Biomimetic Supramolecular Assembly with IGF-1C Delivery Ameliorates Inflammatory Bowel Disease (IBD) by Restoring Intestinal Barrier Integrity.

The management of dysfunctional intestinal epithelium by promoting mucosal healing and modulating the gut microbiota represents a novel therapeutic strategy for inflammatory bowel disease (IBD). As a convenient and well-tolerated method of drug delivery, intrarectal administration may represent a viable alternative to oral administration for the treatment of IBD. Here, a biomimetic supramolecular assembly of hyaluronic acid (HA) and β-cyclodextrin (HA-β-CD) for the delivery of the C domain peptide of insulin-like growth factor-1 (IGF-1C), which gradually releases IGF-1C, is developed. It is identified that the supramolecular assembly of HA-β-CD enhances the stability and prolongs the release of IGF-1C. Furthermore, this biomimetic supramolecular assembly potently inhibits the inflammatory response, thereby restoring intestinal barrier integrity. Following HA-β-CD-IGF-1C administration, 16S rDNA sequencing reveals a significant increase in the abundance of the probiotic Akkermansia, suggesting enhanced intestinal microbiome homeostasis. In conclusion, the findings demonstrate the promise of the HA-based mimicking peptide delivery platform as a therapeutic approach for IBD. This biomimetic supramolecular assembly effectively ameliorates intestinal barrier function and intestinal microbiome homeostasis, suggesting its potential for treating IBD.

When Perfect Is the Enemy of Good: Results of a RAND Appropriateness Panel on Treat to Target in Asymptomatic Inflammatory Bowel Disease.

A treat-to-target strategy for inflammatory bowel disease (IBD) recommends iterative treatment adjustments to achieve clinical and endoscopic remission. In asymptomatic patients with ongoing endoscopic activity, the risk/benefit balance of this approach is unclear, particularly with prior exposure to advanced therapies. Using the RAND/University of California Los Angeles Appropriateness Method, 9 IBD specialists rated appropriateness of changing therapy in 126 scenarios of asymptomatic patients with ulcerative colitis and Crohn's disease and active endoscopic disease. Disease extent and behavior, prior treatment, prior complications, and recent disease progression were considered, as were factors that might influence decision-making, including age and pregnancy. Ratings were collected through anonymous survey, discussed at an in-person meeting, and finalized in a second anonymous survey. Panelists rated change in therapy as appropriate (i.e., expected benefit sufficiently outweighs potential harms from continuing therapy) in 96/126 scenarios, generally in patients with progressive, complicated, and/or extensive disease, while changing therapy was rated uncertain in 27 scenarios of mild and/or stable disease. Changing therapy was rated inappropriate in ulcerative colitis patients with mild and stable disease previously exposed to ≥3 therapies or with improved endoscopic activity, and in Crohn's disease patients with only scattered aphthous ulcers. The validated threshold for disagreement was not crossed for any scenario. Patient age older than 65 years and a plan for pregnancy in the next year might influence decision-making in some settings. Appropriateness ratings can help guide clinical decision-making about changing therapy to achieve endoscopic remission in asymptomatic patients with IBD until data from ongoing randomized studies are available.

Dihydroartemisinin Modulates Enteric Glial Cell Heterogeneity to Alleviate Colitis.

The precise mechanism underlying the therapeutic effects of dihydroartemisinin (DHA) in alleviating colitis remains incompletely understood. A strong correlation existed between the elevation of glial fibrillary acidic protein (GFAP)+/S100 calcium binding protein B (S100β)+ enteric glial cells (EGCs) in inflamed colonic tissues and the disruption of the intestinal epithelial barrier (IEB) and gut vascular barrier (GVB) observed in chronic colitis. DHA demonstrated efficacy in restoring the functionality of the dual gut barrier while concurrently attenuating intestinal inflammation. Mechanistically, DHA inhibited the transformation of GFAP+ EGCs into GFAP+/S100β+ EGCs while promoting the differentiation of GFAP+/S100β+ EGCs back into GFAP+ EGCs. Furthermore, DHA induced apoptosis in GFAP+/S100β+ EGCs by inducing cell cycle arrest at the G0/G1 phase. The initial mechanismis further validated that DHA regulates EGC heterogeneity by improving dysbiosis in colitis. These findings underscore the multifaceted therapeutic potential of DHA in ameliorating colitis by improving dysbiosis, modulating EGC heterogeneity, and preserving gut barrier integrity, thus offering promising avenues for novel therapeutic strategies for inflammatory bowel diseases.

The need for affordable, pragmatic, investigator-led clinical trials of treatment strategies in inflammatory bowel disease

The need for affordable, pragmatic, investigator-led clinical trials of treatment strategies in inflammatory bowel disease

Systematic Review with Meta-analysis: Efficacy and Safety of Upadacitinib in Managing Moderate-to-Severe Crohn's Disease and Ulcerative Colitis.

In the panorama of therapeutic strategies for inflammatory bowel diseases, oral upadacitinib stands out for its potential to improve short-term and long-term patient outcomes. This meta-analysis aspires to collate and assess the available evidence regarding the efficacy and safety of upadacitinib in managing moderate-to-severe Crohn's disease and ulcerative colitis. A meta-analysis was conducted using studies sourced from MEDLINE/PubMed, Cochrane Library, Scopus, and Embase, published from January 2010 to March 2024. Peer-reviewed articles that reported data on the effects of upadacitinib in adult patients with Crohn's disease and ulcerative colitis were included based on established inclusion and exclusion criteria. Eight studies, encompassing a total of 2818 patients treated with upadacitinib, were included. In primary outcomes, for patients with Crohn's disease who were using upadacitinib, the weighted pooled clinical remission rate was found to be 45.8% (95% confidence interval [CI] 0.39-0.52), while for patients with ulcerative colitis who were using upadacitinib, the rate was 25.4% (95% CI 0.17-0.36). The pooled clinical response rate for Crohn's disease was 53.6% (95% CI 0.50-0.57), and for ulcerative colitis it was 72.6% (95% CI 0.69-0.76). The pooled serious adverse event rate was 6.0% (95% CI 0.07-0.09). Upadacitinib demonstrates significant efficacy in achieving clinical remission and response in patients with moderate-to-severe Crohn's disease and ulcerative colitis, as shown by clinical remission rates of 44.9% and 36.0%, respectively. The treatment also maintains a favorable safety profile with a serious adverse event rate of 7.8%, making it an effective option for those resistant or intolerant to traditional immunosuppressants or tumor necrosis factor antagonists.

Amino acid HPLC-FLD analysis of spirulina and its protective mechanism against the combination of obesity and colitis in wistar rats

ObjectiveThe cafeteria diet (CD), designed as an experimental diet mimicking the obesogenic diet, may contribute to the pathogenesis of inflammatory bowel diseases (IBD). This study delves into the influence of spirulina (SP) on obesity associated with colitis in Wistar rats. MethodsThe amino acids composition of SP was analyzed using HPLC-FLD. Animals were equally separated into eight groups, each containing seven animals and treated daily for eight weeks as follows: Control diet (SD), cafeteria diet (CD) group, CD + SP (500 mg/kg) and SD + SP. Ulcerative colitis was provoked by rectal injection of acetic acid (AA) (3 % v/v, 5 ml/kg b.w.) on the last day of treatment in the following groups: SD + AA, SD + AA + SP, CD + AA, and CD + AA + SP. ResultsFindings revealed that UC and/or CD increased the abdominal fat, weights gain, and colons. Moreover, severe colonic alteration, perturbations in the serum metabolic parameters associated with an oxidative stress state in the colonic mucosa, defined by overproduction of reactive oxygen species (ROS) and increased levels of plasma scavenging activity (PSA). Additionally, obesity exacerbated the severity of AA-induced UC promoting inflammation marked by the overexpression of pro-inflammatory cytokines. Significantly, treatment with SP provided notable protection against inflammation severity, reduced histopathological alterations, attenuated lipid peroxidation (MDA), and enhanced antioxidant enzyme activities (CAT, SOD, and GPX) along with non-enzymatic antioxidants (GSH and SH-G). ConclusionsThus, the antioxidant effects and anti-inflammatory proprieties of SP could be attributed to its richness in amino acids, which could potentially mitigate inflammation severity in obese subjects suffering from ulcerative colitis. These results imply that SP hold promise as a therapeutic agent for managing of UC, particularly in individuals with concomitant obesity. Understanding SP's mechanisms of action may lead novel treatment strategies for inflammatory bowel diseases and hyperlipidemia in medical research.

A Comprehensive Exploration of Therapeutic Strategies in Inflammatory Bowel Diseases: Insights from Human and Animal Studies.

Inflammatory bowel disease (IBD) is a collective term for a group of chronic inflammatory enteropathies which are characterized by intestinal inflammation and persistent or frequent gastrointestinal signs. This disease affects more than 3.5 million humans worldwide and presents some similarities between animal species, in particular, dogs and cats. Although the underlying mechanism that triggers the disease is not yet well understood, the evidence suggests a multifactorial etiology implicating genetic causes, environmental factors, microbiota imbalance, and mucosa immune defects, both in humans and in dogs and cats. Conventional immunomodulatory drug therapies, such as glucocorticoids or immunosuppressants, are related with numerous adverse effects that limit its long-term use, creating the need to develop new therapeutic strategies. Mesenchymal stromal cells (MSCs) emerge as a promising alternative that attenuates intestinal inflammation by modulating inflammatory cytokines in inflamed tissues, and also due to their pro-angiogenic, anti-apoptotic, anti-fibrotic, regenerative, anti-tumor, and anti-microbial potential. However, this therapeutic approach may have important limitations regarding the lack of studies, namely in veterinary medicine, lack of standardized protocols, and high economic cost. This review summarizes the main differences and similarities between human, canine, and feline IBD, as well as the potential treatment and future prospects of MSCs.

The relationship among vedolizumab drug concentrations, biomarkers of inflammation, and clinical outcomes in a Canadian real-world study.

Therapeutic drug monitoring is used to optimize anti-tumour necrosis factor biologic effectiveness in inflammatory bowel disease, but its role with other biological classes is unclear. This study explores relationships between post-induction vedolizumab trough concentrations and biochemical outcomes in a real-world study of individuals with inflammatory bowel disease. This retrospective analysis of data from a national patient support program between 2018 and 2020, included 436 individuals with Crohn's disease or ulcerative colitis receiving vedolizumab. Optimal vedolizumab concentration thresholds (at weeks 6 and 14) were determined based on their ability to predict biochemical normalization (week 30 faecal calprotectin [<250 µg/g], C-reactive protein [<5 mg/l]). Thresholds best associated with each outcome were evaluated in multivariate analyses. Among patients with Crohn's disease, week 6 serum vedolizumab concentrations (>41.65 µg/ml) predicted normalization defined by C-reactive protein: Spearman correlation coefficient [ρ] = -0.26, P = 0.002 and multivariate analysis (MVA)-OR: 3.22, 95% CI: 1.32-7.87, P = 0.01, and at week 14 (>22.25 µg/ml): ρ = -0.38, P < 0.0001, and MVA-OR: 3.21, 95% CI: 1.26-8.17 but not faecal calprotectin. Similarly, among patients with ulcerative colitis, week 6 vedolizumab concentrations (>39.65 g/ml) predicted normalization defined by C-reactive protein: ρ = -0.26, P = 0.005 and MVA-OR: 4.03, 95% CI: 1.30-12.52, P = 0.016, and at week 14 (>17.35 µg/ml): ρ = -0.39, P = 0.0001 and MVA-OR: 6.95, 95% CI: 1.81-26.77, P = 0.005, but not faecal calprotectin. Induction and post-induction serum vedolizumab were not consistently associated with biochemical normalization. As such, proactive therapeutic drug monitoring for vedolizumab should not be routinely incorporated in a treat to target strategy for inflammatory bowel disease. NCT04567628.

The Effect of Polymorphisms and Other Biomarkers on Infliximab Exposure in Paediatric Inflammatory Bowel Disease: Development of a Population Pharmacokinetic Model.

Therapeutic drug monitoring (TDM) of infliximab has been shown to be a effective strategy for inflammatory bowel disease (IBD). Population pharmacokinetic (PopPK) modeling can predict trough concentrations for individualized dosing. The aim of this study was to develop a PopPK model of infliximab in a paediatric population with IBD, assessing the effect of single nucleotide polymorphisms (SNPs) and other biomarkers on infliximab clearance. This observational and ambispective single-centre study was conducted in paediatric patients with IBD treated with infliximab between July 2016 and July 2022 in the Paediatric Gastroenterology Service of the Hospital Universitari Vall d'Hebron (HUVH) (Spain). Demographic, clinical, and analytical variables were collected. Twenty SNPs potentially associated with variations in the response to infliximab plasma concentrations were analysed. infliximab serum concentrations and antibodies to infliximab (ATI) were determined by ELISA. PopPK modelling was performed using nonlinear mixed-effects analysis (NONMEM). Thirty patients (21 males) were included. The median age (range) at the start of infliximab treatment was 13 years (16 months to 16 years). A total of 190 samples were obtained for model development (49 [25.8%] during the induction phase). The pharmacokinetics (PK) of infliximab were described using a two-compartment model. Weight, erythrocyte sedimentation rate (ESR), faecal calprotectin (FC), and the SNP rs1048610 (ADAM17) showed statistical significance for clearance (CL), and albumin for inter-compartmental clearance (Q). Estimates of CL1 (genotype 1-AA), CL2 (genotype 2-AG), CL3 (genotype 3-GG), Q, Vc, and Vp (central and peripheral distribution volumes) were 0.0066L/h/46.4kg, 0.0055L/h/46.4kg, 0.0081L/h/46.4kg, 0.0029L/h/46.4kg, 0.6750L/46.4kg, and 1.19L/46.4kg, respectively. The interindividual variability (IIV) estimates for clearance, Vc, and Vp were 19.33, 16.42, and 36.02%, respectively. A popPK model utilising weight, albumin, FC, ESR, and the SNP rs1048610 accurately predicted infliximab trough concentrations in children with IBD.

CHANGING THERAPY TO ACHIEVE ENDOSCOPIC HEALING IN ASYMPTOMATIC PATIENTS WITH IBD: WHEN IS PERFECT THE ENEMY OF GOOD?

Abstract INTRODUCTION The treat-to-target strategy for inflammatory bowel disease (IBD) recommends optimizing or changing therapy in patients who have not achieved clinical remission and endoscopic healing. In asymptomatic patients, the potential benefit of changing therapy to achieve endoscopic healing is less clear, particularly since &amp;lt;40% typically achieve endoscopic healing with current therapy. We sought to define appropriateness of changing therapy in asymptomatic IBD patients with active endoscopic inflammation. METHODS Using the RAND/UCLA Appropriateness Method, a panel of 9 IBD specialists considered appropriateness of changing therapy in 16 scenarios of patients with ulcerative colitis (UC) and 96 scenarios of Crohn’s disease (CD), rating them on a 9-point Likert scale as inappropriate (1-3), uncertain (4-6), or appropriate (7-9). Patients in all scenarios were asymptomatic with active endoscopic disease; variables included disease extent, behavior, prior treatment, recent disease progression, and prior disease complications. Current therapy was assumed to be optimized, so the only options were changing therapy or continuing current therapy. An additional 14 scenarios explored whether age &amp;gt;65 years and the possibility of pregnancy within the next year influenced treatment decision-making. Initial ratings were collected via online anonymous survey, discussed at an in-person meeting, and collected as final ratings in a second anonymous survey using a modified Delphi approach. Disagreement was assessed using a validated index. RESULTS Panelists rated it appropriate to change therapy (i.e., expected benefit sufficiently exceeds expected negative consequences) in 96/126 scenarios, generally those with progressive, complicated, and/or extensive disease; 27 scenarios of patients with mild and/or stable disease were rated uncertain, particularly in those with prior exposure to ≥3 drug classes (Table). Changing therapy in asymptomatic patients was rated inappropriate in three scenarios: in patients with UC Mayo 1 disease previously treated with ≥3 therapy classes with no endoscopic progression in the last year; in any patient who showed endoscopic improvement over the last year; and in any patient with CD who had only scattered aphthous ulcers. Patient age &amp;gt;65 years influenced a decision to change therapy specifically for anti-TNFs and JAK inhibitors; the possibility of pregnancy also influenced decision-making. Despite variability in ratings, the threshold for disagreement was not crossed for any scenario. CONCLUSIONS Our panel of IBD specialists rated appropriateness of changing therapy to achieve endoscopic healing in asymptomatic patients with UC and CD in a variety of scenarios. Our findings can be used to help guide clinical decision-making in this population until data from ongoing randomized studies are available (NCT05230173).

PATTERNS AND ASSOCIATED FACTORS OF OBJECTIVE INFLAMMATION ASSESSMENT TO TREAT-TO-TARGET: DATA FROM THE IBD QORUS COLLABORATIVE

Abstract BACKGROUND A Treat-to-Target (T2T) strategy for inflammatory bowel disease (IBD) improves clinical outcomes. The cornerstone of T2T is the routine assessment of objective markers of inflammation to determine treatment efficacy. Despite this, objective testing is often delayed or not performed. This study aims to describe patterns and associated factors of intended assessment of objective markers of inflammation for patients with IBD within the multicenter quality improvement collaborative, IBD Qorus. METHODS Patient and provider survey data from IBD Qorus were prospectively collected from 6/2021 to 10/2022 across 35 academic and community practices during routine clinical care visits. Patients with unknown status of mucosal healing were excluded. The primary outcome of "timely assessment" was defined as provider-reported intent to obtain fecal calprotectin (FC), imaging, or endoscopy within 12 months. Factors associated with the primary outcome were assessed using univariate and multivariate logistic regression, adjusting for age, gender, IBD type, and clinical factors. RESULTS 4,831 encounter-level surveys from the study period were included for analysis. In 73.9% of encounters, providers reported an intent to assess inflammation within the next 6 months. Of these, 77.1% planned to use FC and 57.7% imaging or endoscopy. 89.3% of visits noted an intent to assess inflammation within 12 months. Providers reported in 29.8% of encounters that patients declined FC and in 8.3% that imaging or endoscopy were declined. In the primary univariate analysis, intent for timely assessment was associated with ulcerative colitis (UC), recent emergency department visit or hospitalization, lack of clinical remission, mild Provider Global Assessment, current steroid use, lack of immunomodulator use, lack of steroid-free mucosal healing, care at an academic site, and intent to change therapy. On multivariate analyses, UC (OR 1.38, 95% CI 1.11-1.71), steroid use (OR 2.1, 95% CI 1.1-4.6), and plans to change therapy (OR 1.84, 95% CI 1.2-2.9) remained significantly associated with higher odds of timely assessment. In contrast, steroid-free mucosal healing (OR 0.52, 95% CI 0.41-0.66) and care in community practice (OR 0.63, 95% CI 0.51-0.77) remained significantly associated with lower odds of timely assessment. CONCLUSION In IBD Qorus, there is a strong intent to assess objective markers of inflammation. However, lower odds of intended assessment were found among patients with Crohn’s, patients in steroid-free mucosal healing, and those receiving care in community practice, revealing potential care gaps. Interestingly, providers frequently reported that patients declined FC testing, and declined this at higher rates than that for endoscopy or imaging. This study identifies potential areas to improve testing for inflammation under a T2T strategy.

P978 Changing therapy to achieve endoscopic healing in asymptomatic patients with IBD: When is perfect the enemy of good?

Abstract Background The treat-to-target strategy for inflammatory bowel disease (IBD) recommends optimising or changing therapy in patients who have not achieved clinical remission and endoscopic healing. In asymptomatic patients, the potential benefit of changing therapy to achieve endoscopic healing is less clear, particularly since &amp;lt;40% typically achieve endoscopic healing with current therapy. We sought to define appropriateness of changing therapy in asymptomatic IBD patients with active endoscopic inflammation. Methods Using the RAND/UCLA Appropriateness Method, a panel of 9 IBD specialists considered appropriateness of changing therapy in 16 scenarios of patients with ulcerative colitis (UC) and 96 scenarios of Crohn’s disease (CD), rated on a 9-point Likert scale as inappropriate (1-3), uncertain (4-6), or appropriate (7-9). Patients in all scenarios were asymptomatic with active endoscopic disease; variables included disease extent, behaviour, prior treatment, recent disease progression, and prior disease complications. Current therapy was assumed to be optimised, so the only options were changing therapy or continuing current therapy. An additional 14 scenarios explored patient factors that might influence treatment decision-making. Ratings were collected via online anonymous survey, discussed at an in-person meeting, then finalised in a second anonymous survey using a modified Delphi approach. Disagreement was assessed using a validated index. Results Panelists rated it appropriate to change therapy (i.e., expected benefit sufficiently exceeds expected negative consequences) in 96/126 scenarios, generally those with progressive, complicated, and/or extensive disease; 27 scenarios of mild and/or stable disease were rated uncertain, particularly with prior exposure to ≥3 drug classes. Changing therapy in asymptomatic patients was rated inappropriate in 3 scenarios: in Mayo 1 UC previously treated with ≥3 therapy classes with no endoscopic progression in the last year; in any patient who showed endoscopic improvement over the last year; and in any patient with CD who had only scattered aphthous ulcers. Patient age &amp;gt;65 years influenced a decision to change therapy specifically for anti-TNFs and JAK inhibitors; the possibility of pregnancy also influenced decision-making. Despite variability in ratings, the threshold for disagreement was not crossed for any scenario. Conclusion Our panel of IBD specialists rated appropriateness of changing therapy to achieve endoscopic healing in asymptomatic patients with UC and CD in a variety of scenarios. Our findings can be used to help guide clinical decision-making in this population until data from ongoing randomised studies are available (NCT05230173).

P835 Acceptability, feasibility, and adherence of an emulsifier-free diet in healthy volunteers

Abstract Background Emulsifiers are associated with intestinal inflammation and therefore excluded in new dietary strategies in inflammatory bowel diseases (IBD). We aimed to investigate the feasibility, acceptability, and adherence of an emulsifier-free diet (EFD) in healthy volunteers as part of the FOod Additives on the Mucosal barrier (FOAM) study. Methods We recruited 60 healthy volunteers to a 7-week interventional trial. After 1 baseline week of their habitual diet, participants followed an EFD for 6 weeks. Participants were instructed on how to follow an EFD yet were not advised on ultra-processed food (UPF) reduction. Every 2 weeks after starting the EFD (week 2, 4, and 6), subjects were asked about their experience on a 12-item questionnaire, including 5-point Likert scales, open-ended and multiple answer-type questions. Food logs were kept in the smartphone application 'Fatsecret', including photographs to capture brand names. Manual calculation of all days with plausible energy intakes (800-4200 kcals per day for men and 600-3500 kcals for women) for at least 79.5% of the time was performed to exclude incomplete reporting. Emulsifier intake was measured as number of servings of emulsifier-containing foods. Adherence rate was calculated as a percentage of mistake-free days. Results Of the 60 healthy volunteers, 2 were excluded due to NSAID use. Median (IQR) age was 25.5 years (23.0-33.0), median BMI was 22.7 kg/m2 (21.2-25.6) and 19.0% were male. Median percentage of plausible food logs was 100% (98.0-100%), and 1 subject was excluded due to inadequate dietary reporting. During the EFD, emulsifier intake significantly decreased (baseline vs week 1; p=2.3x10-9, vs week 6; p=5.3x10-9, Figure 1A), as well as UPF consumption according to the NOVA classification (baseline vs week 1; p=5.6x10-7, vs week 6; p=1.6x10-7, Friedman test with post-hoc paired Wilcoxon, Figure 1B). The adherence rate to the EFD was very high (median 88.1%, IQR 76.2-95.2%). Median number of mistakes during the EFD was 6 (2-14), for a median number of 3 selected food items (1-5). Most mistakes were made in the categories of dairy-like products, meat products, and bakery goods. The top 3 reported challenges included restricted food choices, checking food labels, and longer shopping times (Table 1). At week 6, For 70.7% the EFD was tasty to very tasty and for 72.4% it was acceptable to very acceptable. Hot meals and snacks were the most challenging meal types. Conclusion In this 7-week interventional trial in 60 healthy volunteers, adhering to an EFD was feasible and acceptable. While following the EFD, an inadvertent and stable decrease in UPF intake was noted. These finding represent important considerations when designing future dietary trials in IBD.

DOP86 FOod Additives on the Mucosal barrier study (FOAM): Effect of five emulsifiers on inflammation, intestinal permeability, and the microbiome: preliminary results

Abstract Background Common emulsifiers are associated with intestinal inflammation and are therefore excluded in new dietary therapeutic strategies in inflammatory bowel disease. Human data are scarce and involve a limited number of emulsifiers. We aimed to investigate the effect of five different emulsifiers on systemic and intestinal inflammation, intestinal permeability, and the gut microbiome. Methods We recruited 60 healthy volunteers to a 7-week double-blind placebo controlled randomized trial. After 1 week of recording their habitual diet (baseline), participants followed an emulsifier-free diet (EFD) for 6 weeks, starting at baseline. After 2 weeks, participants combined the EFD with 3 daily brownies that contained either 2.75 g carboxymethyl cellulose, 1.350 mg polysorbate-80, 380 mg carrageenan, 3.55 g soy lecithin, or 8.72 g native rice starch, or no additives (placebo) for a period of 4 weeks. Anthropometric measurements and bio samples were taken at baseline, week 2 and week 6. Blood samples were collected for routine tests, LPS-binding ELISAs, and serum proteomics using the Olink Target 96 Inflammation and Cardiometabolic panels. Stool samples were collected for analysis of the microbiota (16S rRNA sequencing), short chain fatty acids (Gas Chromatography – Mass Spectrometry (GC-MS)), and faecal calprotectin (FC) analysis. Urine samples were collected following the 2-hour lactulose mannitol ratio protocol to measure intestinal permeability (using GC-MS). Results Of the 60 healthy volunteers, 2 were excluded due to NSAID use. Median (IQR) age was 25.5 years (23.0-33.0), median BMI was 22.7 kg/m2 (21.2-25.6) and 19.0% were male. There was a median weight loss of 0.1 kg (p=7.6*10-4, paired Wilcoxon, unadjusted p-value). At week 6 and week 2, FC decreased significantly compared to baseline (p= 4.69*10-4, and p=2.81*10-4 respectively, paired Wilcoxon, unadjusted p-value, Table 1 and Figure 1A). No significant increase in FC was noted after consumption of any emulsifier during the trial. In the placebo arm, faecal acetic acid concentration was increased at week 2 (p=0.04). Compared to baseline, there was an increase in both acetic acid and propionic acid concentration (p=0.006 and p=0.04 respectively, paired Wilcoxon, unadjusted p-value, Figure 1B) in the same arm at week 6. Conclusion In this double-blind placebo controlled randomized trial faecal acetic and propionic acid increased in the placebo arm, but did not after consumption of any of the emulsifiers. FC did not increase after consumption of any emulsifier. Pending analysis will shed light on the effect of an EFD and distinct emulsifiers on the serum proteome, intestinal permeability and gut microbial changes.

P668 Dashboard-guided anti-TNF induction as an effective proactive strategy in Inflammatory Bowel Disease's treatment

Abstract Background Infliximab (IFX) and Adalimumab (ADA) are effective treatments for managing Inflammatory Bowel Disease (IBD) but treatment failure is common. Therapeutic drug monitoring (TDM) of trough serum drug concentrations (C Trough) has been used to optimize treatment induction, mitigate immunogenicity, and ensure appropriate drug exposure. HLA DQA1*05 genotype variants have been identified as predictors of immunogenicity. This study aimed to investigate the impact of dashboard-guided optimized induction dosing strategy on clinical and pharmacokinetics outcomes of anti-TNF, with the goal of analysing the HLA DQA1*05 effect. Methods We conducted a retrospective single-centre cohort analysis of IBD patients, Crohn’s disease (CD) and Ulcerative Colitis (UC), who initiated treatment with IFX or ADA between January 2020 and March 2023, using a pharmacokinetic dashboard-guided induction, protocolized with the Pharmacy Department. C Trough measurements were taken at week 2, 6 and 14, first drug intervention based on the model was in week 4. Targeted C Trough levels during induction were set at 10-15 mcg/mL for ADA and &amp;gt; 17 mcg/mL for IFX. Primary objective was to assess clinical remission (CR). Secondary outcomes included treatment failure (TF) and endoscopic remission (ER). We performed a descriptive analysis and generated Kaplan Meier curves to assess drug survival Results We enrolled 147 patients, 92 having CD (74 treated with ADA and 18 with IFX) and 55 having UC (36 treated with ADA and 19 CU with IFX). HLA DQA1*05 genotype variant was present in 44,14% of patients. Combined treatment with thiopurine was used in 45,58% and 11,54% had been previously received biologic treatment. After 24 weeks, 91,83% (135/147) of patients achieved CR and 65,81% (77/117) at week 56. ER was observed in 59,84% (76/127) after a year. Anti-TNF drug survival probability was 85% after a year, meanwhile ADA drug survival in UC patients was 75%. A 77,7% of patients were prescribed an accelerated dose in the first year, which was associated with improved drug durability. Only a patient out of 147 developed antibodies to ADA. The HLA DQA1*05 variant was not a statistically significant predictor of adverse treatment or pharmacokinetic outcomes. Conclusion Optimizing anti-TNF induction with a Dashboard-guide dosing strategy proves to be a valuable approach to enhance clinical remission and durability rates in IBD patients. The role of HLADQA1*05 variant in immunogenicity appears to be mitigated by the model.

P160 Integrative transcriptional analysis to identify predictive biomarkers for IBD severity and subtyping

Abstract Background Conventional diagnostic strategies for Inflammatory Bowel Diseases (IBD) heavily rely on invasive biopsy procedures and subjective questionnaires, thereby introducing intrinsic limitations in the context of precision medicine. By understanding the molecular mechanisms behind IBD disease biology, we aim to identify certain signalling pathways relevant for epithelial tissue regeneration under chronic inflammation conditions. Methods To address these limitations, we compared gene expression in a large cohort of IBD patients, utilizing the IBD Plexus database (Crohn’s &amp; Colitis Foundation, US) as well as other publicly available datasets. We further validated our results derived from the transcriptional programs by using patient derived advanced 3D-organoid models (Hospital of Nottingham, UK). These models, derived from ulcerated and normal tissue regions of IBD patients, serve as a sophisticated platform for robust validation, bridging the gap between molecular insights and clinical applications. Results Our primary objective was to discern putative biomarkers that are capable of effectively stratifying IBD subtypes. We further identified the genes that were upregulated exclusively in each subtypes and the gene signature that is elevated in inflamed samples compared to non-inflamed samples. We found that either the chemokine and interleukin (IL-17) signalling pathways which have known roles in recruitment of immune cells thereby perpetuating chronic inflammation and several key chemokines influence the integrity of the epithelial barrier function and regeneration. We are also analysing non-invasive biomarkers by using samples such as blood, plasma and stool and employ machine learning methods to correlate with established clinical indicators such as sCDAI, PRO2, PRO3, and MAYO categories. Conclusion Hence, in identifying specific targets we can introduce novel therapeutic strategies to mitigate inflammation and restore integrity of the gut epithelial barrier. With this research we aim to improve the current IBD diagnostics landscape as well propels it towards precision medicine by offering precise subtyping and predictive markers for disease severity, ultimately contributing to more personalised and effective therapeutics interventions.

P830 The potential role of artificial intelligence in selecting the modality of biological therapy in patients with inflammatory bowel disease

Abstract Background Selecting an appropriate treatment strategy for inflammatory bowel disease (IBD) is an important task that can significantly alter the clinical course of the disease. Advanced artificial intelligence language models, such as ChatGPT, represent a potential future option that can assist practitioners. ChatGPT can help search the internet for medical facts by summarizing information from medical sources and providing concise explanations, simplifying the process of accessing and understanding medical information. Methods A ChatGPT-guided analysis of 89 IBD patients treated at the Clinical Department of Gastroenterology and Hepatology at University Medical Center "Zvezdara", Belgrade was conducted, considering further treatment with some biological drugs. A treatment modality proposal was obtained through communication with the interactive software ChatGPT (OpenAI, CA USA) and providing complete clinical and laboratory data. The alignment of decisions was analyzed, along with an assessment of treatment success in the group with matching and differing choices. Results In 72 patients (81%), there was concordance in the choice of therapy between ChatGPT and the medical consultation, while in 17 patients, ideas about the treatment approach differed. The most common difference in the choice of therapeutic modality related to the software's selection of ustekinumab compared to our choice of vedolizumab in patients with Crohn's disease who were not biologically naive, affecting seven patients with these characteristics. In 4 patients with severe ulcerative colitis, ChatGPT recommended using cyclosporine in combination with vedolizumab, contrary to the medical consultation's decision to use Anti-TNFα therapy. The group of patients in whom the artificial intelligence advice differed from the medical consultation was in a clinically more severe stage of the disease (CRP 10.4 vs. 9.1, p=0.0293), with worse endoscopic findings (proportion of severe endoscopic disease SES CD≥33/Mayo score&amp;gt;2, 53% vs. 24%, p=0.019). Taking into account the baseline differences in these patient groups, multiple analyses of covariance did not reveal a significant difference in the ultimate treatment outcome - proportions of endoscopic (p=0.773) and clinical remission (p=0.296) between patient groups. Conclusion The integration of advanced artificial intelligence language models may represent a future tactic with the potential to assist practitioners in making decisions about the treatment modality for IBD patients, but clinical experience should be considered.

Grape seed proanthocyanidin extract alleviates inflammation in experimental colitis mice by inhibiting NF-κB signaling pathway.

Ulcerative colitis (UC) is a complex inflammatory disease of colorectum that induces abnormal immune responses and severely affects the quality of life of the patients. Grape seed proanthocyanidin extract (GSPE) exerts anti-inflammatory and antioxidant functions in many inflammatory diseases. The objective of this study was to investigate the potential therapeutic effects and underlying mechanisms of GSPE in UC using a dextran sodium sulfate (DSS)-induced mouse UC model and a lipopolysaccharide (LPS)-stimulated RAW264.7 macrophage model. In this study, we found that the GSPE markedly prevented DSS-induced weight loss and colon length shortening in UC mice. Further investigations showed that GSPE significantly attenuated the expression of pro-inflammatory cytokines TNF-α, IL-6, and IL-1β, and elevated the expression of anti-inflammatory cytokine IL-10 in the colon tissues and serum of DSS-induced colitis mice by suppressing NF-κB signaling pathway. Furthermore, LPS-induced inflammation in RAW264.7 cells was also reversed by GSPE. Taken together, our results confirm that GSPE can ameliorate inflammatory response in experimental colitis via inhibiting NF-κB signaling pathway. This study advances the research progress on a potentially effective therapeutic strategy for inflammatory bowel diseases.