Introduction

Maintaining intestinal homeostasis relies on the interplay between individuals and their unique gut microbiota. Disruptions may result in chronic inflammation and Inflammatory Bowel Disease (IBD) [1]. This study delves into this interplay, emphasizing the characterization of diet-derived microbiome-associated metabolites and prioritizing them based on their effects on epithelial barrier integrity and inflammatory status.

Aims & Methods

Diet-derived microbiome-associated metabolites – epigallocatechin-gallate, gallic acid (GA), protocatechuic acid (PCA), ellagic acid (EA), and urolithins (Uro-A, B, C, D) – were selected through extensive literature research. In the commercial colon cell model (Caco-2) and 3D epithelial organoids from primary adult intestinal-epithelial stem cells, inflammation was induced with TNF-alpha and IFN-gamma (25ng/ml and each) to mimic IBD conditions. The expression of inflammatory cytokines genes (TNF-alpha, CXCL-9, MCP-1, IL-8) and epithelial barrier integrity markers (ZO-1 and OCLN) were evaluated by qRT-PCR. Epithelial barrier integrity was visualized using FITC-dextran assay.

Results

The induction of inflammation significantly increased in key inflammatory markers by an average 7.5-fold change (±1.8SD) in Caco-2 and 3D IBD organoid models. Metabolite analysis in Caco-2 cells showed that GA exhibited a 1.24-fold increase in TNF-alpha (p=0.036) and a -7.22-fold decrease in MCP-1 (p=0.049) gene expressions. EA decreased the expression of TNF-alpha and MCP-1 genes by -1.59-fold (p=0.045) and -3.59-fold (p=0.036) respectively, whereas IL-8 was reduced by -7.62-fold (p=0.01). Uro-A uniquely decreased MCP-1 gene expression by -7.16-fold (p=0.004) but increased IL-8 by 8-fold (p=0.01). PCA demonstrated a statistically significant decrease in all tested inflammatory markers (p<0.05). Analysis of 3D IBD organoids highlighted unique effects in restoring the epithelial barrier and expression of inflammatory marker genes.

Conclusion

Our findings demonstrate the anti-inflammatory properties of gallic acid, ellagic acid, protocatechuic acid, and urolithin-A in both Caco-2 and 3D organoid models. This research elucidates the complex interrelationships within the nutrition-microbiome-metabolome axis and its consequential impact on gut health.

References

1. Zheng, D., Liwinski, T. & Elinav, E. Interaction between microbiota and immunity in health and disease. Cell Res 30, 492–506 (2020). https://doi.org/10.1038/s41422-020-0332-7

Disclosure

No conflict of interest to declare.

Introduction

Mucosa protective effects can be mediated by physical as well as by anti-inflammatory mechanisms of action. For the root extract of marshmallow (Althaea officinalis L., REAo), known to cure mild irritation of stomach/gut mucosa [1], only a physical action had been considered. Recent studies have shown that it also induces regeneration of irritated mucosa [2,3]. Mucosal wound healing depends on the recruitment of several cell types, e.g., endothelial cells, fibroblasts, and macrophages (MΦ). Reactive oxygen species (ROS)-induced damage is associated with mucosal infiltration of activated leukocytes, such as MΦ, which produce excessive ROS and pro-inflammatory cytokines that may overwhelm the antioxidant and immune defenses of the cells and exacerbate mucosal inflammation. Additionally, fibroblasts exhibit a metabolic adaptation to control inflammation-related oxidative stress.

Aims & Methods

We aimed to investigate whether REAo has, on top of its physical effects, also anti-inflammatory/-oxidative properties in human dermal fibroblasts (NHDF), human umbilical vein endothelial cells (HUVEC), and human acute monocytic leukemia (THP-1) differentiated MΦ, critical cellular components of the gastrointestinal and oral mucosa.

The cells were pre-treated with REAo or its final formulation STW 42, containing REAo and selected excipients, followed by incubation with H₂O (pro-oxidative) or lipopolysaccharide (LPS, pro-inflammatory). Intracellular ROS were quantified with DCFDA. The releases of IL-6 and TNF-α were determined by ELISA. THP-1 cells were differentiated into MΦ with 0.1 μg/ml phorbol-12-myristate-13-acetatefor 3–5 days.

Results

Pre-treatment (24 h) of HUVEC, NHDF or THP-1-MΦ with STW 42 or REAo (100-1000 μg/ml) significantly inhibited the H₂O-induced intracellular ROS production by 30.0% to 58.7%. Whereas 24h(HUVEC, NHDF) or 48 h (THP-1-MΦ) pre-treatment with STW 42 or REAo (100-1000 μg/ml) inhibited the LPS-activated IL6 release by 25.0-67.0%. Additionally, 48 h pre-treatment of THP-1-MΦ with 50-500 μg/ml STW 42 or REAo significantly inhibited LPS-induced TNF-α release by 21.5% (50 μg/ml) to 52.0% (500 μg/ml), in comparison with LPS-treated MΦ. The observed effects of STW 42 or REAo were similar to 25-100 μM Diclofenac, which was used as an anti-inflammatory control.

Conclusion

These anti-inflammatory and antioxidant properties may support the benefit of STW 42 and its constituent REAo in patients with mucosal irritation with subsequent irritative cough or gastric complaints due to its protective/reparative effects on the mucosa.

References

1. HMPC of EMA 2016. European Union herbal monograph on Althaea officinalis L., radix. EMA/HMPC/436679/2015
2. Deters A, Zippel J, Hellenbrand N, Pappai D, Possemeyer C, Hensel A. 2010. Aqueous extracts and polysaccharides from Marshmallow roots (Althea officinalis L.): Cellular internalisation and stimulation of cell physiology of human epithelial cells in vitro. J Ethnopharmacol. 127: 62-9. doi: 10.1016/j.jep.2009.09.050.
3. Bonaterra GA, Schmitt J, Schneider K, Schwarzbach H, Aziz-Kalbhenn H, Kelber O, Müller J, Kinscherf R. Phytohustil^® and root extract of Althaea officinalis L. exert anti-inflammatory and anti-oxidative properties and improve the migratory capacity of endothelial cells in vitro. Front Pharmacol. 2022 Dec 8;13:948248.
   

Disclosure

JS and NS have nothing to disclose. GAB and RK received project support from Steigerwald Arzneimittelwerk GmbH, Darmstadt, Germany. OK, HAK and KB are employees of Steigerwald Arzneimittelwerk GmbH, Darmstadt, Germany.

Introduction

Upadacitinib, a selective JAK inhibitor, has demonstrated efficacy in clinical trials for ulcerative colitis (UC), but real-world data in refractory populations remain limited. This study evaluates its effectiveness, safety, and differential response based on prior advanced therapy failures in a real-world cohort.

Aims & Methods

Ambispective analysis of 80 UC patients initiating upadacitinib across 13 centers. Clinical remission (CR: partial Mayo score <3), clinical-biochemical remission (CBR: Mayo <3 + CRP <5 mg/L + calprotectin <250 μg/g), and steroid-free remission (SFR) were assessed at weeks 8, 16, and 6 months. Subgroup analyses compared outcomes by prior biologic/small molecule exposure.

Results

A total of 80 patients with ulcerative colitis were included, with a mean age of 38 years (range 17–69) and a predominance of males (62.5%). Most patients had extensive colitis (57%), and the average disease duration was 9 years. Extraintestinal manifestations were present in 26.6% (mainly articular). The cohort was highly refractory, with a mean of 2.3 prior advanced therapies; 84.6% had previously received infliximab, 37.2% ustekinumab, and nearly one-third had tried tofacitinib. At induction, 54.5% received upadacitinib 45 mg for 8 weeks, and at 6 months, 69.7% were maintained on 30 mg, while 24.2% required 45 mg.
At week 8, a rapid improvement in disease activity was observed, with the mean partial Mayo score dropping from 5.8 at baseline to 2.0. Clinical remission was achieved in 62.3% of patients at this timepoint, and 23.2% reached combined clinical-biochemical remission. These benefits were largely maintained over time: at 6 months, 51.3% of patients remained in clinical remission, 23.1% in combined remission, and 28.2% achieved steroid-free remission. Inflammatory markers also improved, with CRP decreasing from 15.0 mg/L at baseline to 4.8 mg/L at 6 months, and calprotectin showing a downward trend. (Table 1)
When analyzing effectiveness by prior treatment exposure, patients with only one previous advanced therapy achieved higher rates of clinical remission at 6 months (64.3%) compared to those with two or more prior biologic failures (44.0%). A similar pattern was seen for steroid-free remission (35.7% vs. 24.0%). Nonetheless, even among multi-refractory patients, a substantial proportion achieved and maintained remission with upadacitinib.
Treatment was generally well tolerated. Ten patients (12.6%) discontinued upadacitinib before 6 months, mainly due to primary non-response. Adverse events were reported in 23.8% of patients, most commonly mild (acne, herpes zoster, mild infections). Only three discontinuations were attributed to adverse events (herpes zoster, pneumonia, and acne), and no serious safety signals were identified.

Table 1: Effectiveness Outcomes

Conclusion

Upadacitinib demonstrates rapid and sustained effectiveness in refractory UC, even in multi-refractory patients. While response rates diminish with prior treatment failures, clinically meaningful benefits persist, supporting its use in advanced therapy-experienced populations. The safety profile aligns with clinical trial data, with manageable adverse events.

Introduction

Ulcerative colitis (UC) is associated with debilitating symptoms that impair the quality of life (QoL) of patients; restoration of QoL is an important long-term treatment goal.¹ Upadacitinib (UPA), an oral, reversible Janus kinase inhibitor approved for the treatment of UC, improves health-related QoL (HRQoL) and patient-reported outcomes (PROs) with 1 year (yr) of maintenance therapy.^2-4 This post hoc analysis of the U-ACTIVATE long-term extension (LTE) study evaluated the long-term efficacy of UPA in sustaining PROs and HRQoL outcomes in patients who had received up to a total of 4 years (yrs) of UPA maintenance therapy.

Aims & Methods

This analysis included patients who completed 1 yr (52 weeks [wks]) in the U-ACHIEVE maintenance study and received UPA15 mg once-daily (QD) (UPA15) or UPA 30 mg QD (UPA30) maintenance treatment in the U-ACTIVATE LTE study. Patients receiving UPA15 or UPA30 who achieved clinical remission per Adapted Mayo score at maintenance wk 52 continued their double-blind treatment upon entering the LTE study. Nonremitters receiving UPA15 were escalated to UPA30, those receiving UPA30 continued UPA30, and those assigned to PBO were escalated to UPA15, all in a blinded manner. The UPA UC program was not designed to compare UPA15 and UPA30 doses. Efficacy was assessed at LTE wks 0, 96, and 144 (data cutoff date: 30 June 2024) and included the percentage of patients who achieved absence of abdominal pain, absence of bowel urgency, Inflammatory Bowel Disease Questionnaire (IBDQ) response, IBDQ remission, and a meaningful within-person change (MWPC) in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue; Short-Form Health Survey-36 version 2 Mental Component Score (SF-36v2 MCS), and SF-36v2 Physical Component Score (PCS). Data were reported using as-observed (AO) and modified nonresponder imputation (mNRI) methods (shown in Table). Safety was reported previously.²

Results

This analysis included 369 patients treated with UPA15 or UPA30 at wk 0 of LTE trial. In the AO analysis, patients treated with UPA15 or UPA30 achieved sustained improvements from LTE wk 0 to wk 144 in PROs and HRQoL assessments (Table), including the absence of abdominal pain, absence of bowel urgency, IBDQ response, IBDQ remission; and achieved MWPC in FACIT-Fatigue, SF-36v2 PCS, and SF-36v2 MCS. Similar results were observed for all endpoints with the more conservative mNRI analysis (Table).

Conclusion

Patients with UC who responded to induction therapy and received long-term UPA maintenance therapy showed a sustained absence of symptoms and improvements in HRQoL, suggesting that UPA maintains long-term improvements in patient-reported outcomes.

References

1. Turner D, Ricciuto A, Lewis A, D’Amico F, Dhaliwal J, et al. Gastroenterology. 2021;160:1570–83.
2. Panaccione R, et al. J Crohn’s Colitis. 2025;19(S1):i84-i86 [abstract].
3. AbbVie Inc. RINVOQ (Upadacitinib) [package insert] U.S. Food and Drug Administration website. https://www.rxabbvie.com/pdf/rinvoq_pi.pdf. Revised May 2023. Accessed 25 Feb 2025.
4. AbbVie DG& CoK. RINVOQ. Summary of Product Characteristics. European Medicine Agency website. https://www.ema.europa.eu/en/documents/product-information/rinvoq-epar-product-information_en.pdf. Revised Feb 2025. Accessed 25 Feb 2025.

Disclosure

Funding: AbbVie funded this study (U-ACTIVATE; NCT03006068) and participated in the study design, research, analysis, data collection, interpretation of data, reviewing, and approval of the publication. All authors had access to relevant data and participated in the drafting, review, and approval of this publication. No honoraria or payments were made for authorship.

Acknowledgments: AbbVie and the authors thank the participants, study sites, and investigators who participated in this clinical trial. Paulette A. Krishack, PhD, of AbbVie, provided medical writing support; Angela T. Hadsell, BA, of AbbVie, provided editorial support.

Joana Torres has received grant funding/speaker fees from and/or has participated in advisory boards for AbbVie, Lilly, Takeda, Janssen, and Pfizer.

Corey A Siegel has served as a consultant, advisor, and/or speaker for CME activities and/or received grant funding from AbbVie, BMS, Celltrion, Fresenius, Janssen, Lilly, Napo, Pfizer, Prometheus, Prometheus Labs, Roivant, and Takeda.

Julian Panés received consultancy fees/honorarium from AbbVie, Alimentiv, Athos, Atomwise, Boehringer Ingelheim, Celsius, Ferring, Galapagos, Genentech/Roche, GlaxoSmithKline, Janssen, Mirum, Nimbus, Pfizer, Progenity, Prometheus, Protagonist, Revolo, Sanofi, Sorriso, Surrozen, Takeda, and Wasserman, and has served on a data safety monitoring board for Alimentiv, Mirum, Sorriso, Sanofi, and Surrozen.

Edward V. Loftus Jr. has served as a consultant for AbbVie, Abivax, Amgen, Astellas, Avalo, Biocon, Boehringer Ingelheim, Bristol Myers Squibb, Celltrion, Eli Lilly, Fresenius Kabi, Genentech, Gilead, Iota Biosciences, Iterative Health, Janssen, Morphic Therapeutics, Ono Pharma, Takeda, and TR1X Bio; has received research grants from AbbVie, Genentech, Gilead, Janssen, Merck, and Takeda; and is a share owner of Exact Sciences and Moderna.

Remo Panaccione has received consulting fees, speaker fees, and research support from Abbott, AbbVie, Abbivax, Alimentiv Amgen, AnaptysBio, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene Corporation, Celltrion, Cosmos Pharmaceuticals, Eisai, Elan, Eli Lilly, Ferring Pharmaceuticals, Galapagos, Fresenius Kabi, Genentech, Gilead Sciences, GlaxoSmithKline, JAMP Bio, Janssen Pharmaceuticals, Merck, Mylan, Novartis, Oppilan Pharma, Organon, Pandion Pharma, Pendopharm, Pfizer, Progenity, Prometheus Biosciences, Protagonist Therapeutics, Roche, Sandoz, Sanofi, Satisfai Health, Sublimity Therapeutics, Takeda Pharmaceuticals, Theravance Biopharma, Trellus, Viatris, Ventyx, and UCB.

Si Xuan, Nidhi Shukla, Ari Stromberg, Sina Ogholikhan, Leah Rizzo, and Dolly Sharma, are employees of AbbVie and may own stock options.

Gareth Parkesreports personal payments, honoraria, speaker fees, travel grants and/or fellowships from AbbVie, Allergan, Bristol Myers Squibb, Celltrion, Ferring, Galapagos, Janssen, Napp, Takeda, and Tillotts, and directorship and shareholding with Ampersand Health. TR reports personal grants from AbbVie; personal consulting fees from AbbVie, Arena, Aslan, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly, Ferring, Galapagos, Gilead, GSK, Heptares, LabGenius, Janssen, MonteRosa, Mylan, MSD, Novartis, Numab, Pfizer, Roche, Sandoz, Takeda, UCB and XAP; membership of the ECCO Scientific Committee, and membership in the UEG Scientific Committee; director of Endoread.

Introduction

Type 1 diabetes is a disease of the endocrine pancreas, but it also affects the exocrine part, especially the ductal cells. Several studies have shown that secretin-induced ductal HCO₃^- secretion is reduced in diabetes, however, the underlying mechanism and the effect of diabetes on basal secretion is less known.

Aims & Methods

Our aim is to investigate the effect of diabetes on pancreatic exocrine function. Diabetes was induced in wild type and cystic fibrosis transmembrane conductance regulator (CFTR) knock out mice by i.p. administration of streptozotocin and disease development was confirmed by fasting blood glucose level measurement. Pancreatic ductal fluid and HCO₃^- secretion were measured by fluid secretion measurements and fluorescence microscopy, respectively. Expression of ion transporters were investigated by real-time PCR and immunohistochemistry, whereas TEM was used for the morphological characterization of the pancreas.

Results

​Basal fluid and HCO₃^- secretion are significantly elevated in diabetes. Acute or chronic glucose treatment did not affect HCO₃^- secretion, but inhibition of CFTR significantly reduced it in both normal and diabetic mice. Cl^- efflux and the expression of CFTR, ANO1, NHE-1 and AQP1 increased in diabetes. Secretin-stimulated fluid secretion was also significantly higher in diabetic mice.

Conclusion

Our results show that diabetes increases fluid and HCO₃^- secretion in ductal cells both under basal and stimulated conditions in which the increased function of ion and water transporters, especially CFTR, plays central role.
This study was supported by the National Research, Development and Innovation Office Grant (SNN134497 to VV) and the CFRD-SRC Grant (No.: SRC 007).

Introduction

During and following the COVID-19 pandemic, there has been a major expansion of self-administered subcutaneous biologics for the management of inflammatory bowel disease. These agents are more difficult to monitor since patients do not need to attend the Biologics infusion unit and there is no audit trail to confirm administration of the drug at the scheduled time points.

Aims & Methods

Following a successful NHS D&I bid for funding, a pilot proof of concept project to assess the feasibility and uptake of a digital technology (Health Beacon Digital Sharps Box®) to record and monitor subcutaneous injectable pen use was implemented in 50 consecutive IBD patients who were being treated with subcutaneous infliximab (Remsima®), Adalimumab (Amgevita®) or Vedolizumab (Entyvio®), on a 2-weekly schedule. The Health Beacon ICMS is comprised of a Smart Sharps Bin, pre-programmed with a patient’s individual treatment schedule. The bin electronically captures each time a used injection is disposed of, to create a time-stamped record as a proxy for medication adherence. This is accompanied by Health Beacon’s Companion App and Care Team support. Patients were also sent electronic dose reminders if they failed to dispose of a scheduled injection within certain time periods. Adherence data from the HealthBeacon ICMS, as well as patient satisfaction, transmission reports of data to

Results

Of 50 patients invited to join the programme, 45 registered patients had complete record of 6 months follow up; 4 patients deactivated recruitment and 1 left the programme. 21 patients were on Vedolizumab, 18 on Adalimumab and 8 on Infliximab, all 2-weekly SC injection. 45% patients were in the 36-50year age group, with the remaining spread between 18-75 years. M: F=21:24. Of 418 scheduled drops, 360 were made, with overall adherence being 86%. On time adherence was 76%. The study showed that up to 24% pts on SC Biologics at home delay their scheduled drug administration. Patient satisfaction was high. Reasons for delay in administration included forgetting, being away from home and being busy. Reminders were acknowledged.

Conclusion

This is the first study to our knowledge exploring adherence to subcutaneous biologics at home for IBD. It showed that a digital injection monitoring and support system is useful and acceptable to track adherence. Of the patients involved in the study there is an overall adherence of 90%, with up to 24% patients delaying their scheduled administration. Further studies are needed to analyse patient behaviour and impact on disease course.

Disclosure

Anjan Dhar has been paid an honorarium as a Speaker for presenting this abstract the a Health Beacon Meeting

Introduction

Current IBD therapy regimens are still frequently inefficient, can exert severe side effects, and loss of treatment response is common. Thus, the development of novel therapeutic approaches is an unmet clinical need – especially for patients featuring a primary non-response, refractory disease and/or severe side effects. Here we assessed novel small molecule inhibitors targeting a4b7 integrin or IRAK4 regarding their efficacy to relieve colitis in a model of spontaneous intestinal inflammation either as a stand-alone treatment or in combination.

Aims & Methods

IL-10 knockout (IL-10KO) mice, which develop spontaneous immune-driven intestinal inflammation resembling human IBD, were used for all studies. Mice with established disease were fed for three weeks ad libitum with control chow or chow containing the inhibitors at two previously defined concentrations: a higher concentration intended to induce optimal treatment response or a lower, sub-optimal concentration that did not induce therapeutic effect as stand-alone therapy.

Results

When administered as stand-alone treatment at the higher dose, a4b7 and IRAK4 inhibitors both significantly reduced colitis severity (reduced endoscopic and histological colitis scores [p<0.001 and p<0.01], reduced disease activity index scores [p<0.001]). This effect was accompanied by a normalization of immune cell populations in the colonic lamina propria. Particularly, we found reduced numbers of granulocytes, Th1, Th17, and cytotoxic T cell sin a4b7 and IRAK4 treated mice. Furthermore, mRNA and protein levels of inflammatory cytokines (IFNg, IL17, TNFa and IL-1b) were normalized in intestinal tissue of a4b7 and IRAK4 inhibitor-treated mice (p<0.01, each). When administered in lower concentrations, however, the a4b7 and IRAK4 inhibitors were not able to reduce disease activity as a stand-alone treatment. Of note, a combination of the low doses of the a4b7 inhibitor and the IRAK4 inhibitor significantly reduced the disease severity as evidenced by reduced endoscopic and histologic colitis scores [p<0.001, each], reduced disease activity scores [p<0.01] and a normalization of immune cell infiltrates (reduced levels of granulocytes [p<0.001], Th1 cells [p<0.001], Th17 cells [p<0.001] and less IFNg+ CD8 T cells [p<0.001]). Furthermore, while low doses of anti-IL12/23 p40 antibody were not able to reduce disease severity as a stand-alone treatment, combination of low-dose anti-IL12/23 p40 with the low dose of the a4b7 inhibitor resulted in amelioration of colitis (normalized endoscopic [p<0.001] and histologic [p<0.01] colitis scores, reduced infiltration of granulocytes, Th1, Th17 and IFNg+ CD8 T cells [p<0.01, each], normalization of IFNg, TNFa and IL-1b protein and mRNA levels in the intestine).

Conclusion

Our results demonstrate that small molecule inhibitors for a4b7 and IRAK4 were efficient in reducing colitis in a model of spontaneous immune-cell driven intestinal inflammation. Combination of the a4b7 inhibitor with low doses of the IRAK4 inhibitor or sub-optimal doses of an anti-IL12/IL23 antibody was effective to relieve the disease in the IL-10-KO model. This indicates that combination treatment of a4b7 inhibition with other immune-modulatory drugs, such as IL12/23 neutralization or IRAK4 inhibition might be a promising approach for patients that do not respond to single therapies. Furthermore, our results indicate that combination therapy is able to induce significant disease-relieving effects when the drugs are administered in low concentrations what could minimize side effects without interfering with treatment response.