Introduction

Crohn's disease (CD) is associated with a high risk of complications, stenosis and fistula frequently requiring surgery.
The aim of our work is to study the epidemiological profile of patients operated on for CD, to compare operated and non-operated patient and to determine the predictive factors for recourse to surgery.

Aims & Methods

This is a retrospective descriptive, comparative and analytical monocentric study over 40 years from January 1983 to april 2023 in a gastroenterology department including all patients followed for CD and operated on. Data was collected from patient registers.
We compared the operated and non-operated group, then we studied the factors associated with surgery in univariate and then multivariate analysis.

Results

Of 1103 patients followed for CD, 31.82%(351) were operated, including 86%(302) operated once, 12%(43) operated twice and 1.4%(5) operated 3 times. The median age of diagnosis was 31[22.5-40]years and the sex-ratio F/M=1.1.
A history of appendectomy was found in 17.2%(60) of patients. Smoking is found in 26.9%(94) of patients.
Patients operated on have an ileocolic location in 68.5%(237), colonic in 14.7%(52), ileal in 12.7%(44) of cases, and upper location in 3.8%(13).
The stenosing phenotype is observed in 38.4%(131) of patients, fistulizing in 35.2%(120) and inflammatory in 26.4%(90). Anoperineal manifestations were associated in 38.8%(122).
Recourse to corticosteroid is observed in 44.2%(155) of operated patients, 40.5%(142) who received immunosuppressive treatment and 26.6%(93) who had benefited from biotherapy.
19.9% (70%) were operated on following a complication of their disease, including 11.4%(8) of those operated on for severe acute colitis, 51.4%(36) for an occlusion, 22.8%(16) for an intestinal perforation, 17.1% (12) for a deep abscess and 4.2% (3) following degeneration.
By comparing the group of operated and non-operated patients, the diagnosis age <40 years was found at a higher rate in the operated p <0.001. In these patients, there is a higher frequency of ileocolic localization, fistulizing and stenosing forms and associated MAP (p<0.001/0.009). We noted a higher rate of patients who were under immunosuppressant p<0.001 and under biotherapy p=0.03 in operated patients.
In multivariate analysis, a history of appendectomy is associated with a high risk of surgery (OR=1.8, 95%CI:0.06-1.2, p=0.02) as well as the fistulizing phenotype (OR=6.5, 95%CI:1.4-2.3 , P<0.001) and the stenosing phenotype (OR=5.3, 95% CI:1.2-2, P<0.001). The occurrence of a complication (OR=9, IC95%=1.5-2.8, p<0.001) as well as the use of immunosuppressants (OR=1.6, IC95%: 0.1-0.8, p=0.001) are associated with a risk surgery high.
The use of corticosteroid therapy is associated with a lower risk of surgery (OR=0.6, 95%CI: -0.8;-0.1, p=0.006).
Other factors such as sex, smoking, location, anoperineal manifestations and biotherapy are not factors associated with surgery.

Conclusion

Despite the revolution in medical treatment, surgery remains a fundamental treatment in the management of CD. In our series, the history of appendectomy, the fistulizing and stenosing character of the disease, the treatment with immunosuppressant and the occurrence of complications are associated with an increased risk of recourse to surgery.
Corticosteroid therapy is associated with a low risk of surgery.
Sex, smoking, location and anoperineal manifestations are not associated with the risk of surgery.

Introduction

Due to the daily rhythm of insulin level, an increase of the morning fasting blood sugar value was known in prediabetes statements. ECG heart rate variability (HRV) parameters like low-frequency (LF) and high-frequency (HF) also have a circadian pattern. The ratio of LF/HF can show the activity of the autonomic nervous system.
The evaluation of the epidemiological and metabolic aspects of lifestyle (effects of missing meals, high carbohydrate intake, night shift etc.) could help find a more accurate pathophysiological knowledge to improve overweight in therapy-resistant patients and clearing the risk of it.

Aims & Methods

Our aim was to compare the results of the mother-child group described in our reference abstract and the group performing physical work during night shift. Searching long-term effects of regular night shift physical work and staying awake, such as anaerobic exercise. Could more objective effects on weight loss or on cardiovascular risk be identified than mentioned in other night shift studies?
17 mothers (M) and 24 children (Ch) consecutively, and 24 night shift employees (NS) were examined in the morning after their night shift. The epidemiological parameters were evaluated, then the oral loading test with orally intake of 75 g of glucose was performed. We checked the venous blood gas parameters to follow mitochondrial function indirectly. The function of the autonomic nervous system was determined by a 2-minute resting HRV and LF/HF values.

Results

Our groups (mean+SD): age were M=48.8 +/- 5.1 vs. Ch=23.5+/-5.4, vs. NS=45.7+/-10.0. The averages of BMI were M=28.59 vs. Ch=31.65 vs. NS=31.56.
The 0-minute insulin: M=5.4 +/- 3.43 vs. Ch=9.0+/-4.13, vs. NS=10.17+/-5.06 which is significant according to Student's t-test, p(M-Ch)=0.003. p(M-NS)= 0.001. The lifestyle differences were irregularity and skipping of the breakfast in the NS group.
The venous lactate was after 120 minutes of the glucose intake (mean +/- SD) M=1.37 +/-0.52 vs. Ch=1.56 +/-0.43, vs. NS=1.51 +/-0.19. Lactate reference value (Siemens Epoc Reader) <0.75 mmol/l, p (M-Ch)=0.005, vs. p(M-NS)=0.003. The 0-minute lactate values were M=1.03+/-0.44 vs. Ch = 1.02 +/- 0.31, vs. NS = 1.17 +/- 0.48. p>0.05. HRV LF/HF values (mean+/- SD) were M= 1.2+/-0.54, vs. Ch=1.05 +/-0.59 vs. NS=0.74+/-0.23, p(M-NS) =0.025, p(M-Ch)>0.05. The venosus partial pressure of oxygen (average +/- SD) were M=28.2 +/- 7.22 vs. Ch=29.8+/-7.26, vs. NS=26.8+/-6.55. p(M-NS)>0,05.

Conclusion

The higher basal insulin and lactate level and lower venosus partial pressure of oxygen in the NS group could be explained by a relative tissue hypoxia which a factor of anaerobic metabolism and could increase the consumption of glucose in the muscles by GLUT4 transporters and elevating the level of circulating glucose.
The vagus tone helped in the dynamic autonomic regulation and it was responsible for cardiovascular health. Its decreasing correlates with the lower LF/HF ratio, which could be a marker for physical overload of the NS group.
Unsuccessful weight loss could be explained with the proportionally higher insulin level in NS group, which causes a feeling of hunger and helps the fat storage. On the other hand, the lower effectiveness of calorie-restricted diets should be improved with regular meals during night shift.
We presented a possible clinically measurable sign of the pathophysiological features of the adipose tissue hypoxygenisation as in hypoxia inducible factor 1-alpha studies presented.
We were planning a long-term health risk study to demonstrate the effectiveness of these parameters.

References

UEG 2023 Abstract 642 and 1400

Introduction

Transcriptomic analysis has potential to evaluate the molecular basis and pathophysiology of inflammatory bowel disease (IBD), discover therapeutic targets, and identify biomarkers. However, the value of this technology in clinical trials is limited by substantial methodological heterogeneity, which confounds interpretation, generalisability, and comparison of data across studies.

Aims & Methods

We conducted a 2-part study that aimed to develop recommendations for standardising transcriptomic analysis in multicentre IBD clinical trials. First, 3 public databases were searched from inception to May 2021 to identify clinical trials that included patients with IBD and transcriptomic analyses. Studies that collected blood or intestinal samples and utilised microarray, RNA sequencing, or other global RNA analysis methods were eligible. Data on study design and methodological approaches to transcriptomic research ranging from biopsy location to data analysis and reporting were extracted by 2 independent reviewers. The results of the systematic review (SR) informed the second part of the study, in which a panel of 16 IBD translational researchers participated in a modified Research and Development/University of California Los Angeles appropriateness methodology (RAM) process. A list of statements focused on topics with substantial methodological heterogeneity (Table) was developed based on the SR and panel opinion and formed the basis for creation of a formal survey. Panellists rated the appropriateness of survey statements in 2 rounds, with panel input and survey modification between rounds.

Table. Overview of RAM survey topics

Results

The SR identified 37 reports (22 abstracts; 15 manuscripts) of 22 clinical trials (13 ulcerative colitis [UC]; 6 Crohn’s disease [CD]; 3 UC and CD) that included transcriptomic analyses. The earliest report was published in 2009, with most (>75%) reports published between 2017 and 2021. Most (59%) analyses were conducted at phase 1b or 2 of clinical development. The appropriateness of 416 statements were rated by 15 panellists in the first survey. The final survey included 305 statements, of which 14 panellists rated 75% appropriate, 1% inappropriate, and 24% uncertain. In general, transcriptomic analysis for multiple research objectives using either mucosal biopsy or blood samples was considered appropriate at all phases of clinical development in patients with active disease. Validation of results with external datasets and/or orthogonal methods was considered appropriate, as was the complete reporting of individual patient metadata (ex, patient demographics, disease/treatment history, sample location, and local disease activity); the latter of which was viewed as a critical component for further analysis and utility of transcriptomic data.

Conclusion

Although inclusion of transcriptomic analysis in IBD clinical trials has increased over the past decade, persistence of existing methodologic heterogeneity will continue to limit the interpretation and generalisability of the results of this important research. This study provides an initial framework for expert recommendations to address and overcome these discrepancies and increase the value of this research in clinical development.

Disclosure

BL, EC, MIS, LS: employees of Alimentiv Inc
AS: research grants from Roche-Genentech, Abbvie, GSK, Scipher Medicine, Alimentiv Inc, Boehringer Ingelheim and Agomab (Origo Biopharma); consulting fees from Genentech, GSK, Pfizer, HotSpot Therapeutics, Alimentiv, Origo Biopharma, Thabor Therapeutics, Goodgut and Boxer Capital
BS: employee of Lilly
BV: research support from from AbbVie, Biora Therapeutics, Landos, Pfizer, Sossei Heptares and Takeda; speaker’s fees from Abbvie, Biogen, Bristol Myers Squibb, Celltrion, Chiesi, Falk, Ferring, Galapagos, Janssen, MSD, Pfizer, R-Biopharm, Takeda, Truvion and Viatris; consulting fees from Abbvie, Alimentiv, Applied Strategic, Atheneum, Biora Therapeutics, Bristol Myers Squibb, Galapagos, Guidepont, Mylan, Inotrem, Ipsos, Janssen, Pfizer, Progenity, Sandoz, Sosei Heptares, Takeda, Tillots Pharma and Viatris
DM: consulting fees from Prometheus Biosciences, Takeda, Pfizer and Prometheus Laboratories; owns stock in Prometheus Biosciences.
FR: consulting fees from Adiso, Adnovate, Agomab, Allergan, AbbVie, Arena,Astra Zeneca, Boehringer-Ingelheim, Celgene/BMS, CDISC,Celsius, Cowen,Ferring,Galapagos,Galmed,Genentech,Gilead,Gossamer,Granite,Guidepoint,Helmsley,Horizon Therapeutics,Image Analysis Limited, Index Pharma, Landos,Jannsen, Koutif, Mestag,Metacrine,Mopac,Morphic,Organovo,Origo,Pfizer,Pliant,Prometheus Biosciences,Receptos, RedX,Roche,Samsung,Sanofi,Surmodics,Surrozen,Takeda,Techlab,Teva,Theravance,Thetis,UCB,Ysios,89Bio
KA: grant support from Janssen, consulting fees from Johnson & Johnson/Janssen, Lilly, Takeda
MA: speaker/consultation fees or grants from Abbvie, Amgen, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion, Ferring, Genentech, Gilead, IQVIA, Janssen, Lilly, MSD, Novartis, Pfizer, Roche, Takeda, and Tillots
RA: speaker/consultation fees or grants from AbbVie, Amgen, Arena Pharmaceuticals, Biogen, Boehringer Ingelheim, Celltrion, Dr Falk Pharma, Ferring, Galapagos, Gilead, InDex Pharmaceuticals, Janssen-Cilag, Kliniksa Pharmaceuticals, MSD Sharp & Dohme, Novartis, Pfizer, Roche Pharma, Samsung Bioepsis, Takeda, and Tillotts Pharma
SS: scientific advisory board fees from Pfizer, Pandion, Celgene, Lilly, Takeda, Cosmo Pharmaceuticals, Merck, Sonoma Biotherapeutics, and EcoR1; grant support from Pfizer, Amgen Takeda, and Novartis; consulting fees from Amgen, Kyverna, BMS, Merck, Third Rock, 89bio, GentiBio and Apple Tree Life Sciences
TR: research grants and/or speaker/consultation fees from Abbvie, Arena, Aslan, AstraZeneca, Boehringer-Ingelheim, BMS, Celgene, Ferring, Galapagos, Gilead, GSK, Heptares, LabGenius, Janssen, Mylan, MSD, Novartis, Pfizer, Roche, Sandoz, Takeda, UCB and XAP therapeutics
BFG: grant/research support from AbbVie, Amgen, AstraZeneca/MedImmune, Atlantic Pharmaceuticals, Boehringer Ingelheim, Celgene, Celltech, Genentech/Hoffmann-La Roche, Gilead Sciences, GlaxoSmithKline, Janssen Research & Development, Pfizer, Receptos/Celgene International, Sanofi, Santarus, Takeda Development Center Americas, Tillotts Pharma AG, and UCB Pharma; consulting fees from Abbott/AbbVie, Akebia Therapeutics, Allergan, Amgen, Applied Molecular Transport, Aptevo Therapeutics, AstraZeneca, Atlantic Pharmaceuticals, Avir Pharma, Biogen Idec, BiomX Israel, Boehringer Ingelheim, Bristol Myers Squibb, Calypso Biotech, Celgene, Elan/Biogen, EnGene, Ferring, Roche/Genentech, Galapagos, GiCare Pharma, Gilead, Gossamer Pharma, GlaxoSmithKline, Inception IBD, Johnson & Johnson/Janssen, Kyowa Hakko Kirin, Lexicon, Lilly, Lycera BioTech, Merck, Mesoblast Pharma, Millennium, Nestle, Nextbiotix, Novo Nordisk, Pfizer, Prometheus Therapeutics and Diagnostics, Progenity, Protagonist, Receptos, Salix Pharmaceuticals, Shire, Sienna Biologics, Sigmoid Pharma, Sterna Biologicals, Synergy Pharma, Takeda, Teva Pharmaceuticals, TiGenix, Tillotts Pharma AG, UCB Pharma, Vertex Pharmaceuticals, Vivelix Pharmaceuticals, VHsquared, and Zyngenia; speakers bureau fees from Abbott/AbbVie, Johnson&Johnson/Janssen, Lilly, Takeda, Tillotts Pharma AG, and UCB Pharma; is a scientific advisory board member for Abbott/AbbVie, Allergan, Amgen, AstraZeneca, Atlantic Pharmaceuticals, Avaxia Biologics, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Centocor, Elan/Biogen, Galapagos, Genentech/Roche, Johnson & Johnson/Janssen, Merck, Nestle, Novartis, Novo Nordisk, Pfizer, Prometheus Laboratories, Protagonist, Salix Pharmaceuticals, Sterna Biologicals, Takeda, Teva, TiGenix, Tillotts Pharma AG, and UCB Pharma; Senior Scientific Officer of Alimentiv.
VJ: consulting/advisory board fees from AbbVie, Alimentiv Inc, Arena Pharmaceuticals, Asahi Kasei Pharma, Asieris, Astra Zeneca, Bristol Myers Squibb, Celltrion, Eli Lilly, Ferring, Flagship Pioneering, Fresenius Kabi, Galapagos, GlaxoSmithKline, Genentech, Gilead, Janssen, Merck, Metacrine, Mylan, Pandion, Pendopharm, Pfizer, Protagonist, Prometheus, Reistone Biopharma, Roche, Sandoz, Second Genome, Sorriso Pharmaceuticals, Takeda, Teva, Topivert, Ventyx, and Vividion; speaker’s fees from, Abbvie, Ferring, Bristol Myers Squibb, Galapagos, Janssen, Pfizer, Shire, Takeda, and Fresenius Kabi.
NVC: grant from R-Biopharm; personal fees from AcelaBio, Alimentiv, Pfizer, ProciseDX, Ventyx.
DA, DC, FU, LM, MN, VA, YH: none

Introduction

Inflammatory bowel disease (IBD) is a complex multi-factorial disease characterized by chronic inflammation of the gastrointestinal tract. Despite significant efforts to understand the pathogenetic mechanisms of IBD, the elucidation of its etiopathology and progression is far from fully understood. The direct analysis of the intestinal tissue from the endoscopy which lead to IBD diagnosis (before starting any treatment) would the ideal samples to elucidate IBD pathogenesis.

Aims & Methods

High-throughput mass-spectrometry-based quantitative proteomic analysis was performed using formalin-fixed paraffin-embedded human intestinal samples from newly diagnosed patients to elucidate the potential mechanisms responsible for gut inflammation in Crohn´s disease (CD) and ulcerative colitis (UC). For this purpose, 193 formalin-fixed paraffin-embedded samples from 40 active UC patients, 67 active CD patients and 46 normal biopsies from healthy controls (HC) were analyzed. Proteins with p-value < 0.05 were considered as significantly dysregulated. Moreover, we used Ingenuity Pathway Analysis (IPA) to analyze the pathways and functions in different locations of the gut (ileum or left colon) that could be related to IBD pathogenesis.

Results

A total of 2,903 proteins were identified, of which 1,010 were differentially expressed between left colon from CD patients and HC. 1,242 proteins were differentially expressed between left colon from UC patients and HC, and 952 differential proteins discriminated between left colon from CD and UC patients. In the comparative study of ileum biopsies from Crohn's disease patients and healthy controls, 956 proteins were differentially expressed. IPA revealed multiple canonical pathways, including EIF2 signaling, regulation of eIF4 and P7056K signaling, mitochondrial dysfunction, and oxidative phosphorylation altered in ileum biopsies from CD patients compared to HC. Regarding the proteomic study in left colon samples, the main canonical pathways enrichment in the comparison of UC and CD with HC were the following: neutrophil extracellular trap signaling pathways, fatty acid oxidation, sitruin signaling pathway, tRNA charging, and mitochondrial dysfunction.

Conclusion

The proteomic results revealed dysregulated proteins and pathways in ileum and left colon biopsies from patients with active CD and UC compared to HC that may unravel key mechanisms contributing to the pathogenesis of these diseases. The results of the study serve as a starting point for hypotheses to understand the pathogenesis and search for therapeutic targets.