Introduction

Tryptophan metabolism is severely disrupted in IBD. Pro-inflammatory cytokines activate the first rate-limiting enzyme IDO1 leading to tryptophan degradation through the kynurenine pathway. Although Trp degradation typically support de novo NAD synthesis via KP activation, evidence suggests a metabolic block at the downstream enzyme QPRT in IBD. STING has been described as inducing the secretion of type I interferons and other inflammatory cytokines, suggesting its important role in regulating intestinal homeostasis. Several studies have reported an association between STING-mediated IDO1 activity and its role in promoting tumour immune evasion. However, the relationship between STING pathway and tryptophan metabolism in intestine has not be understood. This study aims to investigate the effect of STING signalling on tryptophan degradation and explore how the metabolic blockage in tryptophan-NAD axis may influence STING-mediated immune response.

Aims & Methods

To investigate the STING pathway's role in tryptophan metabolism within the intestinal microenvironment, we utilized human colonic fibroblast cell line CCD-18co. Quantitative RT-PCR and Western blot were employed to measure mRNA and protein expression. Tryptophan metabolism was quantified via LC-MS. QPRT knockdown was achieved using siRNA transfection. Transcriptomic changes were analysed by RNA sequencing. Intracellular NAD level were assessed by NAD-Glo assay. Seahorse assay was conducted to evaluate mitochondrial function.

Results

We screened a range of established IDO1-inducing cytokines (IFNγ, TNFα, etc.) and compared their effects on IDO1 expression with STING agonists diABZI, dsDNA and 2'3'cGAMP. STING agonists induced significantly higher IDO1 expression than any of the cytokines tested. While cultivation of in presence of Anifrolumab (type I IFN receptor antagonist) and Tofacitinib (pan-JAK inhibitor) strongly inhibited STING-induced IDO1 upregulation. LC-MS showed upregulation of IDO1 drive tryptophan into kynurenine pathway, which was again inhibited by Anifrolumab and Tofacitinib.
To mimic the reduced QPRT expression in IBD, we performed QPRT knockdown followed by RNA sequencing. Loss of QPRT resulted in spontaneous activation of type I interferon signature, which was further amplified upon stimulation with STING agonists, leading to a pronounced inflammatory transcriptional response. Mechanistically, QPRT-deficient cells exhibited reduced intracellular NAD levels and signs of mitochondrial dysfunction, including opening of the mitochondrial permeability transition pore (mPTP), release of mitochondrial DNA and RNA into the cytosol, and subsequent activation of the cGAS-STING and RIG-I/MAVS pathways, respectively. These events collectively led to a pronounced induction of type I interferons and pro-inflammatory cytokines. Notably, supplementation with nicotinamide riboside (NR) restored intracellular NAD levels and significantly attenuated the heightened inflammatory response induced by QPRT knockdown.

Conclusion

Our findings reveal a novel mechanism by which STING activation in intestinal fibroblasts promotes tryptophan metabolism via kynurenine pathway. Furthermore, QPRT deficiency-induced metabolic disruption amplifies STING-mediated pro-inflammatory responses via the release of mitochondrial nucleic acids, a process that can be effectively attenuated by supplementation with NAD precursors.

Introduction

Dutch society has witnessed significant societal and demographic changes over the decades. With 28% of the Dutch population having a migration background in 2023, understanding diversity within the gastroenterology workforce is imperative. This study examines the evolution of sex, ethnic, and socio-economic diversity among Dutch gastroenterologists from 2005-2023.

Aims & Methods

This repeated cross-sectional study utilized pseudonymized data from the BIG-register, paired with demographic variables from Statistics Netherlands (CBS), covering the years 2005, 2010, 2015, 2020, and 2023. The total population sample in each year consisted of all individuals registered as gastroenterologists for at least one day in a respective year. Variables such as sex, migration background, year of birth, and parental socio-economic status indicators were analyzed to assess trends and identify factors associated with being a
gastroenterologist. Descriptive and logistic regression analyses were employed to explore these trends and compare generational differences.

Results

The study revealed a narrowing sex gap with an increase in female gastroenterologists (28% to 43% from 2005-2023), particularly among the younger cohort (60% female). However, ethnic diversity has not kept pace, with a decline in the representation of gastroenterologists from migration backgrounds among younger professionals (27% to 18% for gastroenterologists < 1979 and ≥ 1980, respectively). Socio-economic analysis indicated that approximately 75% of gastroenterologists have parents from top-20% assets category.

Conclusion

The gastroenterology field in the Netherlands shows significant advancements in gender diversity, but lags in ethnic and socio-economic diversity. The increasing trend of gastroenterologists from medical families highlights the need for policy adjustments, to ensure access to candidates from more diverse socio-economic backgrounds. Policies should focus much more on promoting comprehensive diversity to enhance healthcare outcomes and reflect the demographic changes within society.

References

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2. Gomez LE, Bernet P. Diversity improves performance and outcomes. J Natl Med
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3. Juch A. 100 jaar Maag-Darm-Leverarts in Nederland 1913-20132013. 336 p.
4. Brach C, Fraser I. Reducing disparities through culturally competent health care: an
analysis of the business case. Qual Manag Health Care. 2002;10(4):15-28.
5. Moberly T. Men outnumber women three to one in some specialties. Bmj.
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6. Subramaniam M, Azad N, Wasan SK, Long MT. Equal Opportunity: Women
Representation on Editorial Boards and Authorship of Editorials in Gastroenterology and
Hepatology Journals. Am J Gastroenterol. 2021;116(3):613-6.
7. Dossa F, Baxter NN. The place of women in gastrointestinal medicine and surgery:
the need for progress. Lancet Gastroenterol Hepatol. 2023;8(11):965-6.
8. Kesavarapu K, Schwartz J, Ikonomi E, Ahmad A. What's holding women back? A
review of gender inequality in gastroenterology in the USA. Lancet Gastroenterol Hepatol.
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9. Esposito I, Simsek C, Nowak A, Tiniakos D, Equality UEG, Diversity G. United
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Disclosure

OKB, ABB, PK and LM have no conflict of interests, CJJM is consultant for Douglas (New Zealand) and HLW (The Netherlands). All outside submitted work.

Introduction

EoE is a debilitating disease with physical, behavioral, and psychosocial impacts, resulting in substantial impairment in quality of life for patients and caregivers. Children with EoE can present with nonspecific symptoms such as food refusal or feeding difficulties, gastroesophageal reflux disease (GERD), nausea, and vomiting. Dupilumab is approved in the USA and EU for patients with EoE aged ≥1 year, weighing ≥15 kg. In the phase 3 randomized placebo-controlled EoE KIDS study (NCT04394351), in children aged 1 to 11 years, dupilumab significantly improved symptoms of EoE vs placebo, as measured by the Pediatric Eosinophilic Esophagitis Symptom Score version 2.0 (caregiver version; PEESSv2.0) after 16 weeks of treatment.

Aims & Methods

In this post-hoc analysis of the EoE KIDS study, we evaluated the effects of long-term dupilumab treatment on PEESSv2.0 scores during the Part C open-label extension. PEESSv2.0 is a validated observer-reported outcome measure that assesses the frequency and severity of EoE symptoms and adaptive behaviors, divided into four domains: GERD, dysphagia, pain, and nausea; each is scored 0–100, with higher scores indicating a greater symptom domain severity. Patients who completed Week 52 in Part B of EoE KIDS were eligible for Part C, where all patients received open-label dupilumab, using the weight-tiered regimen later approved by the FDA (similar to the Part A and B higher-exposure regimen). In patients who received placebo or dupilumab higher exposure during Parts A and B, changes from baseline of the EoE KIDS study (Part A baseline) in the PEESSv2.0 total, frequency, severity, and domain scores were assessed at Week 52 (Part C baseline), Week 76, and Week 100.

Results

At Week 52, the mean change from baseline (95% confidence interval) in PEESSv2.0 total score was –23.8 (–32.1, –15.6; Table), with further reductions observed at Week 100 (–31.5 [–41.5, –21.4]). Mean changes from baseline in PEESSv2.0 frequency and severity scores were further reduced from Week 52 (–25.1 [–34.2, –16.1] and –22.2 [–30.3, –14.1], respectively), to Week 100 (–33.8 [–44.9, –22.7] and –28.6 [–38.3, –19.0]). Similar patterns of reduction were observed for individual primary domain scores, namely, GERD, dysphagia, pain, and nausea. During the Part C open-label extension, dupilumab safety was consistent with the known dupilumab safety profile.

Conclusion

Children with EoE, treated with long-term dupilumab, experienced sustained improvements in the frequency and severity of symptoms of EoE up to Week 100, assessed by the PEESSv2.0. Reductions in GERD, dysphagia, pain, and nausea domain scores were also maintained or in some cases further improved, although interpretation of Part C symptom data is limited due to the open-label study design. Future studies should consider the correlation of symptoms with trends in both endoscopic and histologic outcomes.

Disclosure

Oliva S: Celgene/Receptos/Bristol Myers Squibb, Medtronic, Ocean Pharma, Sanofi/Regeneron Pharmaceuticals Inc – advisory board/consulting fees. Medtronic, Sanofi/Regeneron Pharmaceuticals Inc. – speaker fees.
Gold B: Diasorin Molecular, IQVIA/AstraZeneca, Ironwood Pharmaceuticals, Johnson&Johnson, Mead Johnson/Reckitt, Nutricia, Pfizer Inc, Sanofi/Regeneron Pharmaceuticals – advisory board/consultancy fees.
Ashok D: Alexion Pharma, LaunchitDTx, Mirum Pharma – advisory board/consulting fees. Sanofi – speaker fees.
Parrish C: Sanofi/Regeneron, Takeda – advisory board/consulting. Regeneron Pharmaceuticals Inc., Sanofi – speaker fees. DBV technologies, NIH/NIAID – research support.
Xia C, Raphael BP, Radwan A, Thomas RB: Regeneron Pharmaceuticals Inc. – employees and may hold stock or shares.
Cazeau C, Almansa C, Tilton ST: Sanofi – employees and may hold stock or shares.

Introduction

The correlation between fecal calprotectin (FC) levels and small bowel (SB) inflammation in patients with Crohn's Disease (CD) remains a subject of debate.

Aims & Methods

This study aims to investigate the relationship between FC levels and SB inflammatory activity in patients diagnosed with SB CD.
We conducted a retrospective cohort study involving patients with SB CD who underwent small bowel capsule endoscopy (SBCE) and FC testing. Patients with colon inflammation were excluded. Participants were categorized into four groups based on their SB inflammatory status: no inflammation (all three SB tertiles showed Lewis Score (LS) <135); proximal SB inflammation (first and/or second SB tertiles had LS ≥ 135, with no inflammation in the third SB tertile); distal SB inflammation (third SB tertile had LS ≥ 135, with no inflammation in the proximal SB); pan-SB inflammation (both proximal and distal SB with inflammation).

Results

A total of 87 patients were included in the study, with a median age of 35 years, 75.9% being female. The distribution of inflammation among the patients was as follows: no inflammation in 21.8%; proximal inflammation in 4.6%; distal inflammation in 33.3%; pan-SB inflammation in 40.4%.
FC median values exhibited an ascending trend along the SB axis: no inflammation 58 µg/g (33-180); proximal SB inflammation 65 µg/g (30-128); distal SB inflammation 122 µg/g (42-507); pan-SB inflammation 400 µg/g (205-852).
Statistically significant differences in FC levels were observed between pan-SB inflammation vs. isolated proximal inflammation (p = 0.014), and isolated distal inflammation (p = 0.012).
Additionally, FC showed a positive correlation with LS in the second (r = 0.464, p<0.001) and third tertiles (r = 0.435, p<0.001), but no correlation was noted in the first tertile.
FC demonstrated good predictive capacity for identifying inflammation in the distal SB and pan-SB vs. no inflammation and proximal inflammation, with an area under the curve of 0.790 (p < 0.001) and an optimal cutoff value of 228 µg/g.

Conclusion

FC levels correlate positively with the presence of SB lesions in the second and third tertiles of the small bowel. However, it is not a reliable marker for detecting inflammation in the first tertile, highlighting the importance of conducting a SBCE in these patients.

Introduction

The Pisa EoE Adaptation Questionnaire (PiEAQ) on adaptive behaviors at mealtime significantly improves the correlation between dysphagia scores and histological disease activity (HDA) in eosinophilic esophagitis (EoE) [Reference 1].

Aims & Methods

Whether longitudinal variations of PiEAQ scores (∆PiEAQ) can capture HDA trends following pharmacological treatment of EoE has not been investigated. Consecutive adults (>18 years) with histologically active EoE (i.e., ≥15 eos/high-power field) were prospectively enrolled. Clinical characteristics, HDA, a recall-modified dysphagia symptom questionnaire (mDSQ), esophageal hypervigilance and anxiety scale (EHAS), and PiEAQ (drinking water to push the bolus, lubricating food, chewing for long, and blending food) were recorded longitudinally at baseline (T0) and 12 weeks post-treatment using a 30-day recall period (T1). ROC curve analysis with DeLong test was used to calculate the diagnostic accuracy (AUC) of clinical scores for predicting HDA following treatment. Significance threshold was p<0.05.

Results

Thirty-seven histologically active EoE patients were included (Table 1). The mDSQ, PiEAQ, and EHAS score at baseline were 2.97 (IQR, 2-5), 2.00 (IQR, 1-3), and 21 (IQR, 14– 25), respectively. Following treatment with budesonide orodispersible tablets (72.2%), PPIs (19.6%), dupilumab (5.5%), or milk-free diet (2.7%), histological remission was achieved in 78.4% of patients, while 21.6% remained histologically active. Post-treatment (T1), mDSQ, PiEAQ, and EHAS scores decreased significantly only in patients who achieved histological remission (Table 2 and Figure1). ROC curve analysis showed that a post-treatment reduction of at least 2 adaptive behaviors compared to baseline (∆PiEAQ=-2) had AUC of 85.0%, with 100% specificity and 64% sensitivity for the identification of patients achieving histological remission following treatment. Similarly, a post-treatment reduction of at least 3 points in mDSQ scores compared to baseline (∆mDSQ=-3) had AUC of 81.1% with 100% specificity and 57.7% sensitivity. The non-inferiority analysis showed that the ∆PiEAQ had similar performance to ∆DSQ (DeLong p-value= 0.46). A combined score integrating both ∆PiEAQ and ∆DSQ scores increased the AUC of clinical scores for capturing variations of HDA post-treatment to 90%, with 100% specificity and 73.1% sensitivity for detecting patients achieving histological remission post-treatment (Figure 2).

Conclusion

The PiEAQ is the first questionnaire investigating adaptive behaviors as a standalone domain in EoE. We demonstrated that longitudinal variations in PiEAQ scores are sensitive to HDA variations over time and can monitor histological disease activity trends after treatment. This study confirms that, similar to dysphagia, adaptive behaviors contribute to disease burden in EoE and improve with treatment.

References

1. Visaggi P, Del Corso G, Solinas I, Ovidi F, Adamo G, Dulmin I, Baiano Svizzero F, Bellini M, Savarino EV, de Bortoli N. Adaptive Behaviors, Esophageal Anxiety, and Hypervigilance Modify the Association Between Dysphagia Perception and Histological Disease Activity in Eosinophilic Esophagitis. Am J Gastroenterol. 2024 Dec 30. doi: 10.14309/ajg.0000000000003272. Epub ahead of print. PMID: 39787341.

Disclosure

Speaker or Consultancy for Apogee Therapeutics, Dr Falk Pharma, Malesci, JB Pharmaceuticals, Sanofi, Alfasigma

Clinical Case Summary

A 53-year-old woman was diagnosed with a severe eosinophilic esophagitis showing poor response to multiple therapies, such as high dose of proton pump inhibitors, oral, topical (swallowed fluticasone) and systemic steroids. She was paucisintomatic for reflux disease or dysphagia.
She had history of multiple immune diseases, including Sjogren syndome, autoimmune gastritis, HCV related hepatitis treated with DAA, Hashimoto's thyroiditis, cutaneus and oral lichen planus and multiple allergies.
After 4 years of follow up histopatological findings shifted to a lichenoid esophagitis pattern and all the following endoscopies confirmed the diagnosis of lichen planus esophagitis (LPE).
Endoscopic examinations of the esophagus revealed lacy white papules, rings, desquamation and high bleeding tendency leading to a difficult mucosal evaluation and accurate biopsy sampling.
This condition was refractory to the treatment mentioned above and evolved in stenosing esophagitis (off therapy) associated with solid food dysphagia.
She was then treated with high dose of oral viscous budesonide showing a remission of the stricture with a persistence of endoscopical and histopatological acute inflammatory activity.
Treatment was shifted to Budesonide orodispersible tablets (BOT), showing a dramatic improvement of endoscopical appearance and bleeding tendency, allowing an accurate sampling with a complete histologycal response of LEP after an year of therapy (1 mg BD for 6 months then 0.5 mg BD for 6 months).
After reducing BOT doses to 0.5 mg once daily for 6 month endoscopy showed a recurrence of LEP.
Lichen planus is a subacute to chronic inflammatory disease. Esophageal involvement (LPE) is frequently an underrecognized condition but bears important therapeutic implications, due to its chronic and relapsing tendency, and may have malignant potential[1].
Endoscopy and tailored long term therapy remain crucial. We suggest BOT as a viable treatment option for LPE.

References

Image captions:
1) Endoscopic appearence of acute lichen planus esophagitis (LPE)
2) Stenosing LPE
3) Lichenoid histologic appearence of esophageal mucosa
4) Post treatment esophageal mucosa appearence
5) Post treatment histologic appearence of esophageal mucosa
References: [1] Annegrit Decker et Al "Esophageal lichen planus: Current knowledge, challenges and future perspectives" World J Gastroenterol. 2022 Nov 7;28(41):5893–5909. doi: 10.3748/wjg.v28.i41.5893

Introduction

The Mayo Endoscopic Subscore (MES) is widely used in clinical trials and daily practice to assess disease activity and response to treatment in UC.

Aims & Methods

The objective of this study was to identify any nuances in patients with MES > 1 treated with non-TNF biologics and targeted oral therapies. The Ipsos UC Therapy Monitor, a multi-centre online medical chart review study of patients with UC, was conducted between July and September 2024 among gastroenterologists practicing across hospital and private practices in the UK, France, Germany, Italy, and Spain. Physicians were screened for practice duration and patient volume. Charts of patients prescribed advanced therapy were included in the analysis.

Results

205 sampled physicians collectively reported 820 UC patients. Of the reported patients with MES > 1, 62 were treated with non-TNF biologics and 62 were treated with novel oral therapies. Among the patients treated with non-TNF biologics, a higher proportion were female vs those receiving oral therapy (48% vs 31%); they were also older in age (mean years: 43 vs 38).
The patients treated with non-TNF biologics had a higher prevalence of comorbidities, including depression/anxiety (24% vs 19%), cardiovascular disease (8% vs 0%), and dyslipidemia/hyperlipidemia/hypercholesterolemia (11% vs 7%), compared to those treated with novel oral therapy.
Mean CRP levels were higher in the oral therapy group (10.2 mg/L vs 9.1 mg/L), while mean Mayo scores were slightly lower (4.7 vs 5.2). Fecal calprotectin levels were elevated in patients treated with non-TNF biologics vs oral therapy group (441 µg/g vs 503 µg/g).
When analysing reasons for prescribing selected advanced therapy between the two patient groups, a greater proportion of patients treated with non-TNF biologics had safety reasons specified more frequently by the sampled physicians.

Table 1: % of reported UC patients receiving advanced therapy for specific cited reasons

Conclusion

This study highlights key differences in patient characteristics and treatment considerations among UC patients with MES > 1 treated with non-TNF biologics compared to those treated with targeted oral therapies. Patients on non-TNF biologics tend to be older, more often female, and have a higher prevalence of comorbidities. Physicians prescribing non-TNF biologics prioritize safety, while those prescribing oral therapies focus on rapid symptom control. These findings highlight the importance of considering patient characteristics and treatment goals when selecting advanced therapies for UC patients with MES > 1. Further investigation using comparator cohort is warranted.