Introduction

Fatigue represents one of the largest unmet clinical needs in inflammatory bowel disease (IBD), both during active and quiescent disease (1, 2). Tryptophan (Trp) metabolites play an important role in mediating mood regulation, intestinal homeostasis and immune responses (3, 4). Dietary Trp is metabolized in the intestines by three different pathways (i.e. kynurenine, serotonin and indole cascade). Previous studies have shown the importance of tryptophan/serotonin balance in fatigue and altered tryptophan serum levels have been reported in IBD patients (5, 6).

Aims & Methods

We aimed to explore changes in Trp metabolite plasma levels in fatigued IBD patients. In total, 40 IBD patients (22 Crohn’s disease (CD) and 18 ulcerative colitis (UC) patients) in clinical and biochemical remission (21 females, HBI <5, SCCAI ≤2, CRP <5mg/l and/or fecal calprotectin <250µg/g) and 25 patients (15 CD and 10 UC) with active disease (18 females; HBI >5, SSCAI >2, CRP >5mg/l and/or fecal calprotectin >250µg/g) were included. Patients were classified as fatigued (and further classified as active vs remission: 17 vs 15 females, 6 vs 18 males) or non-fatigued (active vs remission: 1 vs 6 females, 1 vs 1 males) based on their Multidimensional Fatigue Inventory score (cut-off for fatigue: ≥ 40). Targeted quantitative analysis of 21 Trp metabolites was performed in plasma samples utilizing liquid chromatography coupled with quadrupole mass spectrometry. Receiving Operator Characteristic (ROC) curve and random forest analysis were used to assess the biomarker power of Trp metabolites for fatigue. Data were analyzed according to sex and fatigue status.

Results

5-OH-Tryptophan (5-HTP) plasma concentrations, the direct precursor of serotonin, were significantly higher in fatigued compared to non-fatigued female IBD patients who were in remission (p= 0.02), and this was not observed in male patients, independent of disease status nor in female patients with active disease. ROC analysis (area under the curve (AUC)=0.82) and Random Forest analysis showed that 5-HTP could distinguish between fatigue and no fatigue in females with quiescent IBD, as well as the 3-OH-Kynurenine/Indole-3-Aldehyde ratio (AUC=0.89).

Conclusion

5-HTP might represent a novel biomarker for fatigue in female patients with quiescent IBD, but it should be acknowledged that the sample size of male patients and female patients with active disease was limited. The impaired balance between the kynurenine and serotonin pathway suggests a potential role for Trp metabolism in fatigued IBD patients. These results warrant a larger-scale, longitudinal study in male and female IBD patients, both with active and quiescent disease.

References

1. Nocerino, et al. Fatigue in Inflammatory Bowel Diseases: Etiologies and Management. Adv Ther. 2020;37(1):97-112.
2. Truyens, et al. Effect of 5-Hydroxytryptophan on Fatigue in Quiescent Inflammatory Bowel Disease: A Randomized Controlled Trial. Gastroenterology. 2022;163(5):1294-305.e3.
3. Ghiboub, et al. Sustained Diet-Induced Remission in Pediatric Crohn's Disease Is Associated With Kynurenine and Serotonin Pathways. Inflamm Bowel Dis. 2023;29(5):684-94.
4. Ghiboub, et al. Nutritional Therapy to Modulate Tryptophan Metabolism and Aryl Hydrocarbon-Receptor Signaling Activation in Human Diseases. Nutrients. 2020;12(9).
5. Yamashita. Potential Role of Neuroactive Tryptophan Metabolites in Central Fatigue: Establishment of the Fatigue Circuit. International Journal of Tryptophan Research. 2020;13.
6. Borren, et al. Alterations in Fecal Microbiomes and Serum Metabolomes of Fatigued Patients with Quiescent Inflammatory Bowel Diseases. Clin Gastroenterol Hepatol. 2021;19(3):519-527.e5.

Disclosure

No conflict of interest

Introduction

Intestinal ultrasound (IUS), in particular bowel wall thickness (BWT), is accurate in determining endoscopic disease activity in ulcerative colitis (UC). Reduction of BWT six weeks into advanced anti-inflammatory treatment predicted endoscopic response and clinical remission. Filgotinib is a preferential JAK1-inhibitor effective in UC. Currently, there is no data on IUS-kinetics or early prediction of treatment response with filgotinib.

Aims & Methods

In this study, we aimed to identify early IUS predictors of treatment response to filgotinib in patients with moderate to severe UC. This prospective observational study included UC patients with active endoscopic disease (i.e. endoscopic MAYO score (EMS) ≥2) starting with filgotinib. Clinical scores (UCEIS, Lichtiger), biochemical parameters and IUS parameters of the sigmoid were assessed at baseline, after 4 weeks (W4) and at the time of the second endoscopy (between W8 and W23). Endoscopic remission (i.e. EMS=0), endoscopic response (i.e. decrease in EMS ≥1 compared to baseline) and clinical remission (SCCAI ≤2 or Lichtiger score ≤3) were assessed. IUS response (i.e. defined as a reduction in BWT of >25% or >2.0 mm, or >1.0 mm and one colour Doppler signal) was assessed at week 4. All normally distributed data were reported in mean ± standard deviation [SD] and non-normally distributed in median and interquartile range [IQR]. Mann–Whitney U tests were used to compare continuous non-parametric variables, chi square tests for dichotomous variables.

Results

A total of 20 patients were included. 13 patients underwent second endoscopy, 2 refused a follow-up endoscopy and 5 patients were still in follow-up. At baseline, 9 patients (9/20, 45%) had received ≥2 biologicals, 16 patients (16/20, 80%) had previous anti-TNF exposure, and no patients were exposed to other JAK-inhibitors. 8 patients (8/20, 40%) had severe endoscopic disease at baseline (i.e. EMS=3). 5 patients (5/13, 38%) were endoscopic responders at W8-23, and no patient reached endoscopic remission. BWT was significantly lower in the sigmoid colon from W4 onwards for patients reaching endoscopic response (Table 1). Decrease in BWT compared to baseline was statistically greater in endoscopic responders from W4 onwards (Table 1). IUS response was seen at W4 in 6 patients, of which 5 were endoscopic responders (83%, p=0.002). Decrease in BWT from W4 onwards was statistically greater in patients reaching clinical remission at W8-23 (-45% (-55% to -36.6%) vs -9% (-25% to +8%), p=0.014).

Conclusion

On IUS, UC patients treated with filgotinib have significantly lower BWT from week 4 onwards compared to baseline, which could predict endoscopic response.

Disclosure

MP received speakers fees from Janssen and Tillotts
CT received speakers fees from Tillotts
FV received speaker or honoraria fees from AbbVie, Janssen and Tillotts
ML received consultancy/lecturefees from Abbvie, Bristol Myers Squibb , Eli Lilly, Galapagos, Janssen-Cilag, Johnson & Johnson, Medtronic, Pfizer, Takeda and Tillotts.
RG Received speakers fee from Janssen and Tillotts
GD has served as a consultant and/or received speaker’s fees from AbbVie, Alimentiv, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Celltrion Healthcare, Cytoki Pharma, Eli Lilly, Ferring, Galapagos, Glaxo SmithKline, Gossamer Bio, Immunic, InDex Pharmaceuticals, Janssen, Johnson & Johnson, Kaleido, Pfizer, Progenity, Prometheus Biosciences, Prometheus Laboratories, Protagonist Therapeutics, Takeda, Tillotts, Ventyx Biosciences.
KG has received grants from Pfizer Inc, Celltrion and Galapagos; consultancy fees from AbbVie, Arena Pharmaceuticals, Galapagos, Gilead, Immunic Therapeutics, Janssen Pharmaceuticals, Novartis, Pfizer Inc., Samsung Bioepis and Takeda and speaker’s honoraria from Abbvie, Celltrion, Ferring, Janssen Pharmaceuticals, Novartis, Pfizer Inc, Samsung Bioepis, Takeda and Tillotts.

Introduction

The most common among surgical antireflux methods for the treatment of hiatal hernias (HH) are Nissen, Toupet, or Dor surgery. Among the disadvantages of these interventions, the greatest importance is the destruction of the physiological cardia, which is accompanied by the recurrence of HH, dysphagia, gas-bloat syndrome and heartburn recovery. Despite the advances in HH surgery, the performance of antireflux operations remains debatable.

Aims & Methods

To improve methods of diagnosis and treatment of complications of insufficiency of the physiological cardia in HH.In 2017-2022, 78 patients with HH were diagnosed and treated surgically in the digestive surgery department of the institute.
The type and degree of HH were determined during X-ray examination. An endoscopic examination was performed to determine the condition of the mucous membrane of the esophagus and the degree of violations of the physiological cardia. Endoscopic balloon manometry was used to study pressure in the lower esophageal sphincter (LES) and monitor the effectiveness of antireflux surgery.

Results

Axial HH (I type) was diagnosed during X-ray examination – in 60 (77.0%); paraesophageal (II type) – in 9 (11.5%); mixed (III type) – in 9 (11.5%) patients. Depending on the amount of penetration of organs into the chest cavity, HH of the 1st degree was established – in 42 (53.8%), 2nd degree – in 27 (34.6%) and 3rd degree – in 9 (11.5%) patients.
Changes in the mucous membrane of the esophagus – in 40 (51.3%) patients with type I and III HH: non-erosive reflux esophagitis – in 9 (11.5%), erosive reflux esophagitis – in 16 (20.5%), esophageal ulcer – in 6 (7.7%), peptic stricture of the esophagus on the background of esophagitis – in 3 (3.8%), Barrett's esophagus - in 6 (7.7%) patients.
During endoscopic balloon manometry, the pressure in the LES is reduced: axial HH – (11.39±2.44) mmHg, paraesophageal – (13.54±3.32) mmHg, mixed – (8.06±3, 64) mm Hg (the norm is 14-21 mm Hg). The first stage of treatment for patients with reflux esophagitis was conservative therapy, for peptic stricture of the esophagus – endoscopic balloon hydrodilatation, for Barrett's esophagus – argon plasma ablation. As a second stage, 78 patients underwent standard laparoscopic antireflux operations according to Nissen – in 32 (41.1%), Toupet – in 7 (8.9%), Dor – in 5 (6.4%), and in 34 (43.6%) patients, according to the proposed method, which preserves the connections of the diaphragm, esophagus, and stomach, and performing cardiocrurorrhaphy, fundocruroesophagorraphy, cardiogastroplication with gastrodiaphragmopexy restores the antireflux function of the physiological cardia.In the long term, from 6 months to 4 years, significantly more complications were diagnosed after standard antireflux operations compared to the proposed method - gas bloat-syndrome (X²=4.65, p=0.031) pylorospasm (X²=4.03, p=0.045), dysphagia (X²=4.30, p=0.038) and recurrence of HH – 11 (25.0%) vs 3 (8.8%) cases (p<0.05).

Conclusion

The proposed two-stage method of surgical treatment of patients with HH is highly effective. The application of the proposed method ensures the elimination of pathological changes in the mucous membrane of the esophagus, the restoration of the physiological cardia, the preservation of the anatomical relationships of the diaphragm and the zone of the esophageal-gastric transition. In the postoperative period, the proposed method reduces the frequency of recurrence of HH, occurrence of gas bloat-syndrome, pylorospasm, and dysphagia.