Introduction

The Rutgeerts score, developed three decades ago, is used to assess postoperative endoscopic recurrence in patients with Crohn’s disease (CD) following ileocolonic resection with an end-to-end anastomosis.¹ However, contemporary surgical techniques have introduced new anatomical locations – the ileal body and ileal inlet – which were not accounted for in the original Rutgeerts score.² Additionally, the original Rutgeerts score has demonstrated limited inter-observer reliability.³ To address these limitations, an updated Rutgeerts score, incorporating new anatomical sites, has been proposed. According to the updated Rutgeerts score lesions restricted to the ileal inlet, or the ileal body can no longer be scored as i2a.² While the updated Rutgeerts score offers improved assessment of inflammation after an ileocolonic resection, its reproducibility has not yet been validated.

Aims & Methods

The aim of our study was to evaluate the inter- and intra-observer reliability of the updated Rutgeerts score.
We conducted a retrospective analysis of 183 patients with CD (48% male, median age 36.8 years) who underwent video-recorded ileocolonoscopy within 14 months of resection with ileocolonic anastomosis. An expert reader MF selected and scored videos of ileocolonoscopies, which were then used as the gold standard. After receiving a two-hour training with a set of ten videos eight expert gastroenterologists reviewed and scored the videos. Each reader assessed 92 videos, including 23 videos that were re-scored after at least one month. Based on the gold standard, inter- and intra-rater agreement was calculated across all score levels and for each score level. Inter-rater reliability was assessed using Fleiss' kappa, and intra-rater reliability using Cohen’s kappa, both with and without application of linear weights.

Results

The probability of perfect agreement between two readers across all scores was 0.604 (95% CI: 0.559-0.649). The chance-corrected inter-observer agreement based on Fleiss’ kappa with linear weights across all scores was 0.619 (95% CI: 0.562-0.676). The strongest inter-observer agreement was observed for the i2a score, with a value of 0.736 (95% CI: 0.647-0.826), while the weakest was seen for the i1 score (0.357, 95%CI: 0.225-0.489).
Intra-rater reliability with a Cohen’s kappa was 0.688 (0.609-0.767), and with weighted kappa was 0.831 (0.758-0.868). The overall agreement rate was 76.0% (69.1%-82.0%).

	Categorical		Ordinal
	Estimate	95%CI	Estimate	95%CI
All levels	0.604	(0.559;0.649)	0.882	(0.866;0.897)
i0	0.633	(0.467;0.800)	0.884	(0.824;0.945)
i1	0.357	(0.225;0.489)	0.829	(0.758;0.899)
i2a	0.736	(0.647;0.826)	0.925	(0.896;0.954)
i2b	0.502	(0.439;0.566)	0.856	(0.834;0.877)
i3	0.487	(0.351;0.623)	0.859	(0.798;0.920)
i4	0.715	(0.606;0.824)	0.894	(0.854;0.934)

Table 1. Summary of agreement across score levels: Agreement for all scores and by individual score levels, based on the gold standard (defined as the scores given by an expert reader MF). Categorical agreement reflects only perfect agreement. Ordinal agreement applies linear weights, assigning less weight to minor disagreements and more to larger ones.

Conclusion

The updated Rutgeerts score demonstrates good agreement and substantial inter- and intra-rater reliability in assessing postoperative endoscopic recurrence in CD, supporting its potential for broader adaptation in both clinical practice and research settings.

References

1. Rutgeerts P, Geboes K, Vantrappen G, Beyls J, Kerremans R, Hiele M. Predictability of the postoperative course of Crohn’s disease. Gastroenterology. 1990;99(4):956-963. doi:10.1016/0016-5085(90)90613-6
2. Rivière P, Bislenghi G, Vermeire S, et al. Postoperative Crohn’s Disease Recurrence: Time to Adapt Endoscopic Recurrence Scores to the Leading Surgical Techniques. Clin Gastroenterol Hepatol. 2022;20(6):1201-1204. doi:10.1016/j.cgh.2022.02.025
3. Marteau P, Laharie D, Colombel JF, et al. Interobserver Variation Study of the Rutgeerts Score to Assess Endoscopic Recurrence after Surgery for Crohn’s Disease. Journal of Crohn’s and Colitis. 2016;10(9):1001-1005. doi:10.1093/ecco-jcc/jjw082

Introduction

Mirikizumab is an anti-IL-23p19 monoclonal antibody, a key mediator in the pathogenesis of inflammatory bowel diseases. We evaluated the induction efficacy and safety of mirikizumab in the LUCENT-1 (NCT03518086) Chinese subpopulation.

Aims & Methods

In this Phase 3, multi-center, randomized, parallel-arm, double-blind, placebo-controlled trial, conventional-failed or biologic/tofacitinib-failed Chinese adult patients (N=184) with moderately to severely active ulcerative colitis (UC, Modified Mayo Score 4-9, endoscopic subscore ≧2) were randomized in a 3:1 ratio to 300 mg mirikizumab (intravenous) or placebo every 4 weeks for 12 weeks. Randomization was stratified by biologic/tofacitinib failure status, baseline corticosteroid use and baseline disease activity (Modified Mayo Score). The primary objective was to test the hypothesis that mirikizumab was superior to placebo in inducing clinical remission at Week 12 (W12). Key secondary endpoints included alternate clinical remission, clinical response, clinical response in biologic-failed patients, symptomatic remission, endoscopic remission, histologic-endoscopic mucosal and bowel-movement urgency improvement. Analyses in Chinese subpopulation were descriptive. Missing data was imputed as non-responders for the categorical endpoints. Bowel urgency change from baseline data was reported based on Mixed Model Repeated Measured.

Results

Baseline characteristics were balanced across groups. A greater proportion of mirikizumab-treated patients achieved clinical remission (18.6% vs. 7.0%; Δ=11.5 [95%CI: 1.7, 21.3]) and alternate clinical remission at W12 (21.4% vs. 7.0%; Δ=14.3 [95%CI: 4.4, 24.2]). Mirikizumab also improved key secondary endpoints at W12. The frequencies of treatment-emergent adverse events were similar between groups (mirikizumab [60.0%] vs. placebo [62.8%]). There were fewer serious adverse events (10 [7.1%] vs. 7 [16.3%]) and discontinuations due to adverse events (2 [1.4%] vs. 3 [7.0%]) in mirikizumab-treated patients compared to placebo. There was 1 adenocarcinoma of colon (mirikizumab group) and no deaths during the treatment period.

Table 1: Primary and key secondary outcomes of LUCENT-1 in Chinese population	Placebo IV N=43	Miri 300 mg IV N=140
Clinical Remission at Week 12, n (%) Common risk difference vs placebo	3 (7.0)	26 (18.6) 11.5
Alternate Clinical Remission at Week 12, n (%) Common risk difference vs placebo	3 (7.0)	30 (21.4) 14.3
Clinical Response at Week 12, n (%) Common risk difference vs placebo Clinical Response (biologic-failed) at Week 12, n (%) Common risk difference vs placebo	13 (30.2) 3 (13.0)	76 (54.3) 23.2 32 (45.1) 32.0
Endoscopic remission at Week 12, n (%) Common risk difference vs placebo	5 (11.6)	44 (31.4) 19.0
HEMI at Week 12, n (%) Common risk difference vs placebo	2 (4.7)	24 (17.1) 12.6
Symptomatic remission at Week 4, n (%) Common risk difference vs placebo	5 (11.6)	15 (10.7) -1.6
Symptomatic remission at Week 12, n (%) Common risk difference vs placebo	8 (18.6)	49 (35.0) 16.2
Urgency Numeric Rating Scale (NRS), LSM (SE) LSM difference vs placebo	-1.6 (0.4)	-2.0 (0.2) -0.39
CI = confidence interval; IV = intravenous; LSM = least squares mean; Miri = mirikizumab; SE = standard error. Modified Intent-to-Treat population. Number of biologic-failed patients in placebo and Miri groups were 23 and 71, separately. Clinical remission: Stool frequency (SF) subscore = 0 or 1 with a ≥1-point decrease from baseline, and Rectal bleeding (RB) subscore = 0, and Endoscopic subscore (ES) = 0 or 1 (excluding friability) Alternate clinical remission: SF subscore = 0 or 1, RB subscore = 0, and ES = 0 or 1 (excluding friability) Clinical response: decrease in the modified Mayo score of ≥2 points and ≥30% decrease from baseline, and decrease of ≥1 point in the RB subscore from baseline or an RB score of 0 or 1 Clinical response (bio-failed): clinical response in patients who had previously failed biologic or tofacitinib therapy Endoscopic remission: ES = 0 or 1 (excluding friability) HEMI (histologic-endoscopic mucosal improvement): Histologic improvement, defined using Geboes scoring system with neutrophil infiltration in <5% of crypts, no crypt destruction, and no erosions, ulcerations, or granulation tissue; and endoscopic remission Symptomatic remission: SF = 0, or SF = 1 with a ≥1-point decrease from baseline and RB = 0 Urgency NRS (numeric rating scale) ∆ baseline: least square mean change in urgency NRS from baseline Mixed Model for Repeated Measures (MMRM) was used to compare the treatment groups for bowel movement urgency improvement; for all other endpoints, the Cochran-Mantel-Haenszel (CMH) test with missing data imputed as nonresponse, was used to compare the treatment groups while adjusting for the stratification factors. All analyses in Chinese subpopulation were for descriptive purpose, and multiplicity adjustment was not applied.

Conclusion

Efficacy and safety profiles were consistent with LUCENT-1 overall population, supporting benefits of mirikizumab treatment in the Chinese UC patients.

Disclosure

No conflict of interest to disclose

Introduction

Inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), are complex conditions characterized by significant clinical, immunological, molecular, genetic, and microbiological heterogeneity. Current therapeutic strategies, particularly biologics and Janus kinase (JAK) inhibitors, are effective for inducing clinical remission and controlling inflammation. However, one-third of patients fail to respond to these treatments, highlighting the need for predictive biomarkers to better tailor therapy and improve outcomes.

Aims & Methods

In this study, we conducted a multi-omic approach, integrating transcriptomics, proteomics, metabolomics, and metagenomics to identify biomarkers of treatment response in IBD. A cohort of 57 active CD and 70 active UC patients was analyzed before and after 14 weeks of treatment with anti-TNF, ustekinumab, vedolizumab, or tofacitinib. Response was evaluated using endoscopic criteria, categorizing patients as responders or non-responders. Biological samples [serum, urine, serum extracellular vesicles (EVs), intestinal biopsies, and stool] were analysed using RNA sequencing, liquid chromatography-mass spectrometry, nuclear magnetic resonance, and 16S rRNA gene sequencing to assess molecular and microbial profiles.

Results

Our results identified multiple mRNAs, proteins and metabolites associated with treatment response. Gene expression analysis in intestinal tissue showed significant differences between UC patients responders and non-responders to vedolizumab. Proteomic analysis of serum EVs and intestinal tissue samples revealed differentially expressed proteins between different study groups. Metabolomic analysis identified deregulation of 24 serum lipoproteins from CD responders to ustekinumab compared to non-responders. Pathway analysis highlighted significant enrichment in ketone and butyrate metabolism, mitochondrial electron transport chain activity, carnitine synthesis, and fatty acid oxidation pathways. Metagenomic analysis revealed microbial differences in UC patients responders to anti-TNF therapy compared to non-responders.

Conclusion

This multi-omics analysis uncovers promising biomarkers that could serve as predictive indicators of therapeutic response to biologics and JAK inhibitors. Nevertheless, further studies are crucial to confirm these findings and evaluate their clinical relevance in identifying patients most likely to respond to tailored therapeutic interventions. One of the challenges is integrating results from different omics approaches to create a more holistic understanding of the disease, potentially opening doors for more precise/early detection through multipanel biomarkers.

Introduction

Faecal microbiota transplantation (FMT) is an emerging therapy in inflammatory bowel disease (IBD), supported by evidence for improved clinical and endoscopic outcomes. Decontamination of the recipient gastrointestinal tract using antibiotics or colonic lavage has been proposed to improve FMT efficacy by reducing microbial load and creating a niche for donor organism colonisation. The aim of this study was to assess the effects of antibiotic pre-treatment and colonic lavage on clinical and endoscopic outcomes of FMT in IBD.

Aims & Methods

A systematic review of the literature was conducted by searching PubMed, MEDLINE and Scopus from inception to July 2024. Prospective studies examining FMT in IBD with or without antibiotic pre-treatment and/or colonic lavage were included. Outcomes included clinical response, clinical remission, endoscopic response and endoscopic remission. A random-effects model was used to calculate pooled proportions with 95% confidence intervals (CI).

Results

Forty-one studies (n=1185) were included, of which 7 (17.1%) incorporated antibiotic pre-treatment and 29 (70.7%) incorporated colonic lavage prior to FMT therapy. Eight studies (19.5%) were in Crohn’s disease, 32 (78%) were in ulceratice colitis and one study incorporated any IBD. Antibiotic pre-conditioning courses varied in terms of antibiotics used, treatment duration and washout period prior to FMT. Polyethylene glycol was the most used lavage preparation (23 studies, 79.3%). Antibiotic pre-treatment was associated with numerically higher rates of clinical response (64% vs. 56%), clinical remission (47% vs. 39%), endoscopic response (59% vs. 45%) and endoscopic remission (47% vs. 21%) than no antibiotics, but these differences did not reach statistical significance. Colonic lavage was associated with significantly lower clinical response (52% vs. 71%) compared to no lavage. Clinical remission rates were numerically lower in the lavage group (37% vs. 46%), but again, not statistically significant. Endoscopic response and remission rates were similar. Risk of bias was high or moderate in most studies.

Outcome (%; 95% CI)	Antibiotics	No antibiotics	Lavage	No lavage
Clinical response	64% (52-76%)	56% (48-64%)	52% (43-60%)	71% (62-80%)
Clinical remission	47% (30-63%)	39% (31-47%)	37% (28-47%)	46% (29-63%)
Endoscopic response	59% (44-74%)	45% (24-66%)	51% (30-71%)	45% (16-74%)
Endoscopic remission	47% (25-70%)*	21% (11-31%)	22% (10-33%)	22% (10-35%)

*Single study in antibiotic group. Bold = statistically significant difference.

Conclusion

The results of this review suggest while antibiotics may improve FMT outcomes in IBD, the evidence remains inconclusive, and further adequately powered studies are needed before changing clinical practice. Colonic lavage appears to reduce clinical response to FMT and should be avoided where feasible. FMT delivery methods that avoid the need for bowel preparation, such as capsules, enemas or upper gastrointestinal administration should be considered preferable.

Disclosure

RV Bryant, SP Costello and E Tucker are shareholders in BiomeBank.

Introduction

Microscopic colitis (MC) is an inflammatory bowel disease (IBD) that causes chronic non-bloody watery diarrhea and abdominal pain that significantly reduces the quality of life¹. MC can be subdivided into collagenous colitis (CC) and lymphocytic colitis (LC), which are clinically indistinguishable but differ histologically². The activation of immune responses and the alteration of the intestinal epithelial barrier via water channel aquaporin downregulation and crypt hyperproliferation are characteristic features of MC³, often shared by other gastrointestinal disorders, such as “classical” IBD (Crohn’s disease and ulcerative colitis, UC), or irritable bowel syndrome (IBS). Enteric glial cells (EGC) are key regulators of gut homeostasis and epithelial permeability, that respond to inflammation by entering a reactive state, potentially driving epithelial dysfunction. Whether EGC promote resolution or perpetuate inflammation remains unclear.⁴

Aims & Methods

MC is poorly understood and EGC role in MC is still unknown. Therefore, our aim is to investigate the involvement of EGC – due to their neuroimmune functions and involvement in intestinal dysmotility – in patients with MC. In addition, mast cells will be investigated since altered interactions with EGC have been demonstrated during IBS⁵.
Paraffin-embedded colonic biopsies from patients with active CC, LC, UC, IBS-diarrhea (D) and healthy controls (HC) were collected (n=13-26 per cohort). In addition, a subset of CC patients was also sampled during successful treatment with glucocorticosteroid 9mg budesonide (n=13). The amount of EGC was quantified using glial fibrillary acidic protein (GFAP) and S100 calcium-binding protein B (S100β). Mast cells were quantified using tryptase.

Results

Immunofluorescence analysis of EGC revealed an increased amount of EGC^GFAP+ in CC compared to HC (p<0.001). Of note, CC EGC^GFAP+ levels were comparable to those shown by biopsies from patients suffering from IBS-D and UC. Among the 13 CC patients with paired samples before and under budesonide treatment, we observed a trend toward reduced EGC^GFAP+ levels during treatment (p = 0.08). In contrast, LC patients displayed similar EGC^GFAP+ levels as to HC, but lower than those observed in biopsies from patients with CC, IBS-D, and UC (p<0.001). On the other hand, EGC^S100β+ were increased only in active CC (p<0.0001). Yet, UC patients displayed the highest level of EGC^S100β+ (p<0.0001). Mast cells analysis showed an increased counts for tryptase in CC before and under treatment compared to HC (p<0.01).

Conclusion

Our findings indicate that EGC and mast cells are involved in CC pathogenesis due to an increased reactivity of EGC and mast cells in the colonic mucosa. CC patients exhibit signs of EGC^GFAP+ levels comparable to those observed in UC and IBS-D. Oppositely, LC seems to be independent of neuroinflammation as EGC and mast cells presence was comparable to HC. These preliminary findings support the theory that CC and LC are distinct disease entities. Future work will include RNA sequencing of EGC-related genes, counts of eosinophils as well as in situ analysis of mast cells and eosinophils degranulation, and assessment of budesonide effects on EGC in vitro.

References

1. Nyhlin N, Wickbom A, Montgomery SM, et al. Long-term prognosis of clinical symptoms and health-related quality of life in microscopic colitis: a case-control study. Aliment Pharmacol Ther 2014; 39: 963-972. 20140311. DOI: 10.1111/apt.12685.
2. Carrasco A, Esteve M, Salas A, et al. Immunological Differences between Lymphocytic and Collagenous Colitis. J Crohns Colitis 2016; 10: 1055-1066. 20160229. DOI: 10.1093/ecco-jcc/jjw058.
3. Escudero-Hernandez C, Munch A, Ostvik AE, et al. The Water Channel Aquaporin 8 is a Critical Regulator of Intestinal Fluid Homeostasis in Collagenous Colitis. J Crohns Colitis 2020; 14: 962-973. DOI: 10.1093/ecco-jcc/jjaa020.
4. Gonzales J and Gulbransen BD. The Physiology of Enteric Glia. Annu Rev Physiol 2024 20241115. DOI: 10.1146/annurev-physiol-022724-105016.
5. Meira de-Faria F, Casado-Bedmar M, Marten Lindqvist C, et al. Altered interaction between enteric glial cells and mast cells in the colon of women with irritable bowel syndrome. Neurogastroenterol Motil 2021; 33: e14130. 20210402. DOI: 10.1111/nmo.14130.

Introduction

Dysregulated activation of myeloid cells, including monocytes and macrophages, contributes to intestinal inflammation in Inflammatory Bowel Disease (IBD) through excessive release of pro-inflammatory cytokines. Microbial-derived short-chain fatty acids (SCFAs) modulate the inflammatory and metabolic nature of these cells through activation of a wide-range of cellular signalling pathways. Several of these pathways—including targeting Free-fatty acid receptors (FFA1, FFA2, FFA3) and other metabolic pathways (Glycolysis and Oxidative phosphorylation) have exhibited potential by influencing the polarisation from inflammatory to regulatory macrophages. In this study, we aim to unravel these mechanisms and explore the interplay between myeloid cells and SCFAs in IBD.

Aims & Methods

We first investigated the immunomodulatory effects of SCFA on THP-1 and monocyte-derived macrophage (MDM) models of inflammation. These cells were polarised toward an M1-like phenotype (LPS+ IFN-γ) in the presence of SCFAs or pharmacological agonist of FFA3 (AR420626). We analysed how these treatments impacted cytokine secretion and markers of polarisation using ELISA and RT-qPCR. To gain insight with a disease context, CD14+ monocytes from the peripheral blood of IBD patients (n=6), were exposed to M1 polarising stimuli (LPS+IFN-γ), in the presence of SCFAs or AR420626. To explore potential disease-specific responses, monocytes from actively inflamed IBD patients (n=7) and healthy controls (HC) (n=3) were cultured in presence of butyrate (1mM) in the absence of inflammatory stimulus. In both instances, RT-qPCR and ELISA were conducted to assess secretion of pro-inflammatory cytokines and activation of metabolic pathways.

Results

In THP-1 and MDM models, treatment with butyrate (4 mM) markedly suppressed IL-6 secretion, an effect that was mimicked by the FFA3 agonist AR420626 (50 µM). These responses extended to IBD patient-derived monocytes, where strong induction of IL-6 and TNF-α were repressed by both butyrate and propionate (vs M1; p< 0.001). FFA3, which plays an important role in mediating responses to SCFAs, was also upregulated in M1 polarised patient monocytes (vs Unt; p< 0.05). However, this elevated expression was abrogated in monocytes that were exposed to butyrate (1mM), giving insight toward how butyrate can regulate SCFA sensing mechanisms under inflammatory conditions. Interestingly, this pro-inflammatory monocyte phenotype was accompanied by raised expression of the glycolysis markers HK2 and GLUT1 —which, again, were repressed by butyrate (vs Unt; p< 0.05). In untreated monocytes derived from IBD patients, we observed an elevated inflammatory state relative to HCs, suggesting prior disease-associated activation. While these cells displayed heightened baseline expression of HK2 than HC monocytes, this was attenuated by exposure to butyrate (vs Unt; p< 0.05), and cells were rescued from this hyper-inflammatory phenotype.

Conclusion

Taken together, these results highlight that butyrate helps to counteract inflammation in IBD monocytes —possibly stemming from an influence on glycolysis. This work demonstrates that monocyte metabolic activity and SCFA-sensing pathways are dysregulated under inflammatory conditions. These findings provide new insight into the altered immune-metabolic state of monocytes in IBD and highlight the important role of microbial-derived SCFAs to restoring immunometabolic balance.