Introduction

Etrasimod is an investigational, oral, once-daily, selective sphingosine 1‑phosphate (S1P)_1,4,5 receptor modulator in development for the treatment of moderately to severely active ulcerative colitis (UC).

Aims & Methods

The study design for phase 3 ELEVATE UC 52 (NCT03945188) and ELEVATE UC 12 (NCT03996369) trials has been described previously.¹ ELEVATE UC 52 comprised a 12‑week (wk) induction period followed by a 40‑wk maintenance period with a treat-through design. ELEVATE UC 12 comprised a 12‑wk induction period. Patients (pts) had a documented history of inadequate response/loss of response/intolerance to ≥ 1 treatment for UC. This subgroup analysis evaluated the efficacy and safety of etrasimod 2 mg once daily vs placebo (PBO) in adults with UC by prior exposure to advanced (biologic/Janus kinase inhibitor [bio/JAKi]) therapy. We present subgroup efficacy analyses of the primary and select secondary endpoints at Wk 12 and Wk 52 in ELEVATE UC 52 and Wk 12 in ELEVATE UC 12 in pts naïve to, or with prior exposure to, ≥ 1 bio/JAKi therapy. Additional symptomatic endpoints were analysed by study visit to Wk 12 (pooled ELEVATE UC 52 and ELEVATE UC 12).

Results

In ELEVATE UC 52 and ELEVATE UC 12, respectively, 274 and 222 pts with a baseline modified Mayo score 5–9 were treated with etrasimod, and 135 and 112 pts with PBO. Pts treated with etrasimod vs PBO, in both bio/JAKi‑naïve and -exposed subgroups, achieved statistically significant improvements in clinical remission, clinical response and endoscopic improvement at Wks 12 and 52 in ELEVATE UC 52 (Table). In ELEVATE UC 12, bio/JAKi-naïve pts achieved statistically significant improvements in all endpoints, while pts in both subgroups achieved statistically significant improvements in clinical response (Table). In bio/JAKi‑naïve and -exposed pts, respectively, pooled data showed the earliest significant improvements were during Wks 2 and 12 for symptomatic response and Wks 4 and 2 for symptomatic remission (Table).

Table. Subgroup analysis of the proportion of patients achieving the primary and select secondary efficacy and symptomatic endpoints in the ELEVATE UC 52 and ELEVATE UC 12 trials stratified by prior bio/JAKi exposurea
	ELEVATE UC 52, Wk 12			ELEVATE UC 52, Wk 52			ELEVATE UC 12, Wk 12
Endpoint, n/N (%)b by prior bio/JAKi exposure	PBO (N=135)	Etrasimod 2 mg once daily (N=274)	% difference (95% CI) p valuec	PBO (N=135)	Etrasimod 2 mg once daily (N=274)	% difference (95% CI) p valuec	PBO (N=112)	Etrasimod 2 mg once daily (N=222)	% difference (95% CI) p valuec
Clinical remissiond, e Naïve Exposed	9/93 (9.7) 1/42 (2.4)	60/194 (30.9) 14/80 (17.5)	21.5 (12.67, 30.30) <0.001 14.7 (4.82, 24.62) 0.004	7/93 (7.5) 2/42 (4.8)	71/194 (36.6) 17/80 (21.3)	28.8 (19.89, 37.67) <0.001 14.6 (3.36, 25.82) 0.011	12/74 (16.2) 5/38 (13.2)	41/148 (27.7) 14/74 (18.9)	11.9 (0.98, 22.73) 0.033 6.6 (-7.18, 20.29) 0.349
Clinical responsef Naïve Exposed	35/93 (37.6) 11/42 (26.2)	132/194 (68.0) 39/80 (48.8)	29.6 (17.77, 41.45) <0.001 19.9 (2.95, 36.92) 0.021	25/93 (26.9) 6/42 (14.3)	103/194 (53.1) 29/80 (36.3)	26.1 (14.65, 37.58) <0.001 19.7 (5.32, 34.07) 0.007	32/74 (43.2) 14/38 (36.8)	97/148 (65.5) 41/74 (55.4)	22.3 (8.63, 35.89) 0.001 20.1 (1.14, 39.12) 0.038
Endoscopic improvementg Naïve Exposed	17/93 (18.3) 2/42 (4.8)	76/194 (39.2) 20/80 (25.0)	21.2 (11.07, 31.36) <0.001 19.1 (7.20, 30.95) 0.002	12/93 (12.9) 2/42 (4.8)	78/194 (40.2) 24/80 (30.0)	28.1 (18.60, 37.60) <0.001 23.1 (10.77, 35.32) <0.001	14/74 (18.9) 7/38 (18.4)	51/148 (34.5) 17/74 (23.0)	16.2 (4.90, 27.40) 0.005 5.5 (-10.00, 20.97) 0.487
Endpoint, n/N (%)b by prior bio/JAKi exposure	Pooled ELEVATE UC 52 and ELEVATE UC 12, up to Wk 12 PBO			Pooled ELEVATE UC 52 and ELEVATE UC 12, up to Wk 12 Etrasimod 2 mg once daily			Pooled ELEVATE UC 52 and ELEVATE UC 12, up to Wk 12 % difference (95% CI) p valuec
Symptomatic responseh at the earliest visit with significant difference Naïve (Wk 2) Exposed (Wk 12)	49/167 (29.3) 31/80 (38.8)			141/342 (41.2) 85/154 (55.2)			12.1 (3.47, 20.69) 0.0060 16.0 (2.79, 29.19) 0.0176
Symptomatic remissioni at the earliest visit with significant difference Naïve (Wk 4) Exposed (Wk 2)	24/167 (14.4) 7/80 (8.8)			105/342 (30.7) 28/154 (18.2)			16.7 (9.67, 23.79) <0.0001 9.0 (0.54, 17.54) 0.0371
aThis is a subgroup analysis of the full analysis set; therefore, only patients with a baseline MMS score between 5 and 9 were included. Patients with a baseline MMS of 4 were excluded bPatients missing an assessment at the specified analysis visit were considered nonresponders cDifference (%) is for etrasimod minus PBO and is based on estimated common risk difference using Mantel–Haenszel weights, stratified by baseline corticosteroid use (Yes/No) and baseline disease activity (MMS: ≤ 6 or ≥ 7). The 2-sided nominal p value is to test the hypothesis of the common risk difference being 0; p<0.05 is considered statistically significant dSFS = 0 (or = 1 with ≥ 1-point decrease from baseline), RBS = 0 and ES ≤ 1 (excluding friability) ePatients in clinical remission at Wk 52 were also in clinical remission without corticosteroids if they had not been receiving corticosteroids for at least 12 wks immediately prior to Wk 52 fA ≥ 2-point and ≥ 30% decrease from baseline in MMS, and a ≥ 1-point decrease from baseline in RBS or an absolute RBS of ≤ 1 gES of ≤ 1 (excluding friability) hDecrease from baseline ≥ 30% in composite RBS and SFS iSFS = 0 (or = 1 with ≥ 1-point decrease from baseline), RBS = 0 bio, biologic; CI, confidence interval; ES, endoscopic subscore; JAKi, Janus kinase inhibitor; MMS, modified Mayo score; PBO, placebo; n, the number of unique patients achieving each endpoint; N, the number of patients in the subgroup in the analysis set by treatment; RBS, rectal bleeding subscore; SFS, stool frequency subscore; UC, ulcerative colitis; Wk, week

Conclusion

In ELEVATE UC 52, both bio/JAKi-naïve and -exposed pts treated with etrasimod showed statistically significant improvements in induction and maintenance efficacy endpoints vs PBO. In ELEVATE UC 12, etrasimod demonstrated statistically significant improvements vs PBO in induction in bio/JAKi-naïve pts. For symptomatic response in the pooled analysis, a significant treatment difference occurred later for bio/JAKi-exposed than -naïve pts.

References

1. Sandborn WJ et al. Lancet 2023; 401: 1159–1171

Disclosure

SV: research: AbbVie, MSD, Pfizer, Galapagos, Takeda; consultancy/advisory: AbbVie, AbolerIS, Alimentiv, Arena, AstraZeneca, Avaxia, BMS, Boehringer Ingelheim, Celgene, CVasThera, Dr. Falk, Eli Lilly, Ferring, Galapagos, Genentech/Roche, Gilead, Hospira, Imidomics, Janssen, J&J, MateriaPrima, MiroBio, Morphic, MrMHealth, MSD, Mundipharma, Pfizer, Prodigest, Progenity, Prometheus, Robarts Clinical Trials, Second Genome, Shire, Surrozen, Takeda, Theravance, Tillotts, Zealand; speaker: AbbVie, Dr. Falk, Ferring, Hospira, MSD, Takeda, Tillotts.
BES: research: Arena, Janssen. Speaker: BMS, Janssen, Lilly, Pfizer, Takeda. consultancy/advisory: AbbVie, Alimentiv, Amgen, Arena, AstraZeneca, Boehringer-Ingelheim, BMS, Celltrion, Fresenius Kabi, Genentech, GSK, Janssen, Lilly, Merck, Pfizer, Prometheus, Sun, Takeda, Teva. Stock: Ventyx. Non-financial: Janssen, Lilly, Pfizer, Takeda.
LPB: research: Takeda, Fresenius Kabi, Celltrion; consultancy: AbbVie, Alimentiv, Alma Bio, Amgen, AppliedMolecular Transport, Arena, Biogen, BMS, Celltrion, CONNECT Biopharm, Cytoki, Enthera, Ferring, Fresenius Kabi, Galapagos, Genentech, Gilead, Gossamer, GSK, HAC, IAG Image Analysis, Index, Inotrem, Janssen, Eli Lilly, Medac, Mopac, Morphic, MSD, Norgine, Novartis, OM, ONO, OSE, Pandion, Par'Immune, Pfizer, Prometheus, Protagonist, Roche, Sandoz, Takeda, Theravance, Thermo Fisher, TiGenix, Tillotts, Viatris, Vifor, Ysopia, Abivax; speaker: Galapagos, AbbVie, Janssen, Genentech, Ferring, Tillotts, Celltrion, Takeda, Pfizer, Sandoz, Biogen, MSD, Amgen, Vifor, Arena, Eli Lilly, Gilead, Viatris, Medac, Sanofi; stock: CTMA.
GD’H: advisor: AbbVie, AstraZeneca, Alimentiv, BMS, Boehringer Ingelheim, Celltrion, Cosmo, Eli Lilly, Galapagos, GSK, J&J, Takeda, Pfizer, Polpharma, Prometheus, Tillotts, Ventyx; speaker: AbbVie, Boehringer Ingelheim, Celltrion, J&J, Takeda, Pfizer, Tillotts.
JP: personal: AbbVie, Arena, Athos, Atomwise, Boehringer Ingelheim, Celgene, Celltrion, Ferring, Galapagos, Genentech/Roche, GSK, Immunic, Janssen, Mirum, Morphic, Nestlé, Origo, Pandion, Pfizer, Progenity, Revolo, Takeda, Theravance, Wassermann; grants: AbbVie, Pfizer.
AJY: consultancy: Pfizer, Arena, Takeda, BMS; speaker: BMS.
DW: research grants: AbbVie, Arena, BMS, Janssen, Pfizer, Takeda, Ventyx; speaker: AbbVie, BMS, Janssen, Pfizer, Takeda; consultant: AbbVie, Arena, BMS, Janssen, Pfizer, Takeda.
TR: speaker: Takeda, Janssen, Pfizer, BMS, AbbVie, Lilly; Data Adjudication: Ferring/Rebiotix; Advisory boards: AbbVie, Ardelyx, Arena, Boehringer Ingelheim, BMS/Celgene, Ferring, Genentech/Roche, Gilead, Intercept, Iterative Scopes (shareholder), Janssen, Lilly, Pfizer, Prometheus, Sanofi, Takeda, Nestle/Seres
SS: speaker: AbbVie, Arena, Biogen, BMS, Celgene, Celltrion, Dr. Falk, Fresenius, Janssen, MSD, Pfizer, Takeda; consultancy/advisory: AbbVie, Arena, Biogen, BMS, Celgene, Celltrion, Dr. Falk, Fresenius, Gilead, IMAB, Janssen, MSD, Mylan, Pfizer, Protagonist, Provention, Takeda, Theravance.
KS, CJR: employees & shareholders of Pfizer.
MVC: grants: Pfizer, Janssen, Novartis, BMS; consultancy: AbbVie, Arena, BMS, Medtronic, Pfizer, Prometheus, Eli Lilly, Janssen, Takeda; speaker: AbbVie, Janssen, Medtronic, Pfizer, BMS, Takeda.
FB: research: AbbVie, Amgen, Janssen, Takeda; speaker: AbbVie, Arena, Celltrion, Ferring, Galapagos, Janssen, MSD, Pfizer, Takeda; consultancy: AbbVie, Amgen, Arena, Celgene, Celltrion, Ferring, Fresenius Kabi, Janssen, MSD, Pfizer, Sandoz.
MCD: research: Janssen; consultancy: AbbVie, Arena, BMS, Celgene, Eli Lilly, Galapagos, Genentech, Gilead, Janssen, Pfizer, Prometheus, Takeda, Trellus Health, UCB; stock: Trellus; directorship/ownership interests: Trellus.
MG: employee & shareholder of Pfizer AG.
SD: consultancy/advisory: AbbVie, Allergan, Amgen, AstraZeneca, Biogen, Boehringer Ingelheim, Celgene, Celltrion, Ferring, Gilead, Hospira, Janssen, J&J, MSD, Mundipharma, Pfizer, Roche, Sandoz, Takeda, TiGenix, UCB, Vifor; speaker: AbbVie, Amgen, Ferring, Gilead, Janssen, Mylan, Pfizer, Takeda; directorship/ownership interests: Gastroenterology and Endoscopy.
BGF: consultant/advisory board: AbbVie, AbolerIS, AgomAB, AllianThera, Amgen, AnaptysBio, AppliedMolecular Transport, Arena, Avoro Capital, Atomwise, BIOJAMP, Biora, Boehringer Ingelheim, Boxer, Celsius, Celgene/BMS, Connect, Cytoki, Disc Medicine, Duality, EcoR1, Eli Lilly, Equillium, Ermium, First Wave, FirstWord, Galapagos, Galen Atlantica, Genentech/Roche, Gilead, Gossamer, GSK, Hinge, HotSpot, InDex, Imhotex, Immunic, JAK, Janssen, Japan Tobacco, Kaleido, Landos, Leadiant, L.E.K., Lenczner Slaght, LifeSci, Lument AB, Millennium, MiroBio, Morgan Lewis, Morphic, Mylan, OM, Origo, Orphagen, Pandion, Pendopharm, Pfizer, Prometheus, Diagnostics, Play to Know AG, Progenity, Protagonist, PTM, Q32, Rebiotix, REDX, Roche, Sandoz, Sanofi, Seres, Silverback, Surrozen, Takeda, Teva, Thelium, TiGenix, Tillotts, Ventyx, VHSquared, Viatris, Ysios, YSOPIA, Zealand; speaker: AbbVie, Janssen, Takeda; Alimentiv Senior Scientific Director (central reading services; not a company employee, no equity); shareholder: Gossamer

Introduction

The role of the gut microbiota in inflammatory bowel disease (IBD) pathogenesis is widely acknowledged, with numerous bacteria identified as contributing factors. Little however is known about the part viruses play – a likely major component in the structuring and functioning of the gut microbiota. Understanding how viruses interact with the gut microbiota and host cells in the context of IBD could facilitate innovative treatment approaches and personalized interventions.

Aims & Methods

We explore the colonic and upper intestinal virome in patients with IBD compared with general population (GP) controls. Faecal (colonic) and effluent (upper intestinal) derived shotgun metaviromes of 100 IBD individuals (UC = 50, CD = 50) and 50 IBD individuals with an ileostomy, respectively were compared to faecal derived metaviromes of 50 GP individuals. Metaviromes were generated using a combination of shotgun methods and viral particle enrichment, allowing for identification of both eukaryotic and prokaryotic, dsDNA, ssDNA and RNA viruses. Viral diversity, composition and prevalence were compared by calculating Shannon diversity, Bray-Curtis distances and performing logistic regression analyses. P-values were adjusted using false discovery rate (FDR) to correct for multiple testing, where relevant; FDR<0.05 was considered significant.

Results

Similar to bacterial diversity in IBD versus GP samples, we see a significantly lower viral diversity in CD and UC colonic samples compared with the GP, and an even lower diversity when comparing upper intestinal samples to colonic samples (FDR<0.05). Comparing viral populations between groups, we observe that, whilst there is evident interindividual variability within groups, distinct clustering between colonic and upper intestinal samples can be seen, with colonic IBD samples clustering slightly more towards upper intestinal samples. When comparing viral group prevalences between GP and IBD colonic samples, 83 out of 260 viral groups present in IBD-UC samples are absent in the GP samples and 125 out of 302 viral groups present in the GP were absent in IBD-UC. For IBD-CD samples these numbers are 79 out of 248 and 133 out of 302, respectively. The top 3 viral groups that positively associated with IBD-UC samples are: one unknown phage group (predicted bacterial host: Parasutterella spp.), a group containing Lactobacillus phages (bacterial host: Lactobacillus spp.) and a group containing Lactococcus phages (bacterial host: primarily Lactococcus spp). The top 3 viral groups that positively associated with IBD-CD samples are: the same unknown phage group as for IBD-UC, and two other unknown phage groups (predicted bacterial hosts: primarily Enterocloster & Bacteroides spp, respectively).

Conclusion

This first comprehensive description of the gut virome across multiple gastrointestinal sites shows specific alterations in IBD. Many viral groups differentially present in the IBD intestine infect bacteria often associated with gut health and significantly reduced in IBD patients. Dysregulated bile acid signaling has also been implicated in the pathogenesis of IBD, with bacterial dysbiosis being linked to its cause. In IBD populations, we observe phages with the host E.bolteae – a bacteria increased in dysbiosis due to their potential to metabolise bile acids. We speculate that alterations in the gut virome composition are key events that disrupt the equilibrium between gut microbiota and host, promoting a pro-inflammatory state and driving IBD pathogenesis. The next steps will be to investigate the mechanisms underlying these complex interactions.

Disclosure

RKW unrestricted grants: Takeda, Johnson and Johnson, Tramedico, Ferring. Consultant: Takeda

Introduction

The 52-week, phase 3 True North (TN) study (NCT02435992) demonstrated the efficacy and safety of ozanimod (OZA), a highly selective sphingosine 1-phosphate receptor 1 and 5 modulator, in patients (pts) with moderately to severely active ulcerative colitis (UC). A prior analysis reported the long-term safety of OZA up to ~4 y from TN baseline through Week (W) 142 of the ongoing TN open-label extension (OLE; NCT02531126).

Aims & Methods

This analysis assessed the cumulative long-term safety of OZA with an additional year of exposure (pt disposition available until OLE W190 [up to ~5 y of OZA]). All pts who entered the OLE from TN (ie, clinical nonresponders at W10 and those who lost response during maintenance or completed maintenance at W52) were included in this analysis. Treatment-emergent adverse events (TEAEs) were monitored from the first dose of OZA in TN or the OLE through data cutoff; exposure-adjusted incidence rates (EAIRs) per 100 patient-years (PY) are presented. Lab abnormalities, including absolute lymphocyte count (ALC) reductions, were assessed during the OLE through data cutoff.

Results

A total of 823 pts entered the TN OLE. At data cutoff, 43.0% of pts had completed OLE W190 and total OZA exposure was 2681 PY. Overall, the cumulative safety assessments did not meaningfully change with an additional year of OZA exposure (Table). EAIRs of TEAEs, serious TEAEs, and TEAEs leading to treatment discontinuation remained consistent, and there were no new cases of malignancy, bradycardia, third-degree atrioventricular (AV) block, myocardial ischemia, ischemic stroke, pulmonary embolism, deep vein thrombosis, or macular edema with an additional year of OZA exposure. Three pts newly developed infections; however, only 1 pt had a serious infection (keratouveitis), which was not related to treatment. Two additional pts experienced mild hypertension. Reductions in ALC <500 cells/µl were common in the OLE (57.2%), but few pts had ALC <200 cells/µl(6.6%). Occurrence of ALC <200 cells/µl was not temporally associated with serious or opportunistic infections. Most alanine aminotransferase and aspartate aminotransferase elevations were transient and resolved without treatment interruption, and no serious hepatic events occurred.

Table. Cumulative safety assessments during TN and the TN OLE in all pts who entered the OLE	Up to ~4 y of OZA exposurea (n=823) Total PYc = 2536 n (%) EAIRd		Up to ~5 y of OZA exposureb (n=823) Total PYc = 2681 n (%)e n (%)			Up to ~4 y of OZA exposurea (n=823) Total PYc = 2536 n (%) EAIRd		Up to ~5 y of OZA exposureb (n=823) Total PYc = 2681 n (%)e n (%)
TEAEs	685 (83.2)	85.5	687 (83.5)	85.1	Third-degree AV block	1 (0.1)	0.04	1 (0.1)	0.04
Serious TEAEs	158 (19.2)	7.0	163 (19.8)f	6.8	Hypertension	55 (6.7)	2.3	56 (6.8)	2.2
TEAEs leading to treatment discontinuation	64 (7.8)	2.5	66 (8.0)	2.5	Myocardial ischemia	3 (0.4)	0.12	3 (0.4)	0.11
Infection	378 (45.9)	22.7	381 (46.3)	22.1	Ischemic stroke	3 (0.4)	0.12	3 (0.4)	0.11
Herpes zoster	30 (3.6)	1.2	31 (3.8)	1.2	Pulmonary embolism	3 (0.4)	0.12	3 (0.4)	0.11
COVID-19	103 (12.5)	4.3	103 (12.5)	4.1	Deep vein thrombosis	3 (0.4)	0.12	3 (0.4)	0.11
Serious infection	44 (5.3)	1.8	45 (5.5)	1.7	Macular edema	3 (0.4)	0.12	3 (0.4)	0.11
Malignancy	18 (2.2)	0.71	17 (2.1)	0.63	Cystoid macular edema	3 (0.4)	0.12	3 (0.4)	0.11
Bradycardia	3 (0.4)	0.12	3 (0.4)	0.11

^aData cutoff of June 30, 2023. ^bData cutoff of January 10, 2024. ^cTotal PY was calculated as the sum of the number of years on study contributed by each pt from time of first dose to last date on study. ^dEAIRs were calculated as number of pts/PY × 100. ^eTN OLE is an ongoing study. Individual TEAE terms may not add up as harmonization of final data is pending. ^fFor the 5 pts who newly reported a serious TEAE, events included 1 pt each with UC exacerbation, colitis, pancreatitis, and umbilical hernia, and 1 pt with ulcerative keratitis and keratouveitis.

Conclusion

The ongoing safety profile of OZA is consistent with previous analyses, with no new safety concerns identified. Long-term OZA use representing 2681 PY of exposure continues to be well tolerated in pts with moderately to severely active UC.

Disclosure

Acknowledgment: This study was sponsored by Bristol Myers Squibb. Writing and editorial assistance was provided by Traci Stuve, MA, and Alexandra Stafford, PhD, of Peloton Advantage, LLC, an OPEN Health company, and was funded by Bristol Myers Squibb.

JT: received grants from AbbVie and Janssen; received advisory board or speaker fees from AbbVie, Bristol Myers Squibb, Janssen, Pfizer, and Sandoz.
RL: consulted for Bristol Myers Squibb and Pfizer.
KK: received lecture honoraria from Gore.
SL: consulted for AbbVie, Bristol Myers Squibb, Eli Lilly, and Janssen.
TK: served as an advisory board member, consultant, or speaker for AbbVie, Alfresa Pharma, Alimentiv, Astellas, Bristol Myers Squibb, Celltrion, Covidien, EA Pharma, Eli Lilly, Ferring, Galapagos, Gilead Sciences, Janssen, JIMRO, JMDC, Kissei Pharmaceutical, Kyorin Pharmaceutical, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, Nippon Kayaku, Pfizer, Takeda, ThermoFisher Scientific, and Zeria Pharmaceutical; received research funding from AbbVie, Alfresa Pharma, EA Pharma, Gilead, Kyorin Pharmaceutical, Mochida Pharmaceutical, Nippon Kayaku, Otsuka Holdings, Pfizer, Sekisui Medical, Takeda, ThermoFisher Scientific, and Zeria Pharmaceutical.
DB: served as advisory board member or consultant for AbbVie, Amgen, Arena, Atheneum, BNG Service GmbH, Bristol Myers Squibb, CED Service GmbH, Celltrion, DGVS, Diaplan, Doctorflix, Eli Lilly, Else Kröner-Fresenius-Stiftung, Falk Foundation, Ferring, Galapagos, Gastroenterology Today, GlaxoSmithKline, Guidepoint, Impulze, Janssen-Cilag, Medical Tribune, MedTrix, MSD, Mylan, Onkowissen, Pfizer, Pharmacosmos, Roche, Sandoz, Streamed Up, Takeda, Tetrameros, Thieme, Tillotts, UCB, Viatris, and Vifor Pharma.
LK: reported no conflicts of interest.
DM, NRS, AP, MD, HW, DW, MTO, and AJ: employees and/or shareholders of Bristol Myers Squibb.
BPA: consulted for AbbVie, Bristol Myers Squibb, Celltrion, Eli Lilly, Janssen, Medtronic, Pfizer, Prometheus, Samsung Bioepis, and Takeda; lectured for AbbVie, Bristol Myers Squibb, Eli Lilly, Janssen, Pfizer, and Takeda.

Introduction

Microscopic colitis (MC) refers to two pathologies – Collagenous colitis (CC) and Lymphocytic colitis (LC) that cause chronic watery diarrhoea, urgency, incontinence leading to significantly decreased quality of life¹. It is thought that MC develops due to a pathological immune response to intestinal luminal antigens in genetically predisposed individuals, with microbiota playing an important role^{2, 3}. However, the pathogenesis of MC is still unclear.

Aims & Methods

The aim of this study was to identify and characterize changes in bacterial composition of MC patients in terminal ileum and different colonic segments and determine its relation to the clinical course of disease. Biopsies from terminal ileum and six segments of the colon were collected during diagnostic colonoscopies. DNA extraction was performed using AllPrep DNA/RNA Micro Kit (Qiagen) following the manufacturer’s instructions. To determine bacterial composition, sequencing of the 16S rRNA variable region V3-V4 was conducted using the 27F and 338R polymerase chain reaction primers and sequenced on a MiSeq (2×250 bp; Illumina, Hayward, CA). Bioinformatic analysis was performed using DADA2, and taxonomic classification was carried out with the RDP classifier.

Results

Biopsy samples from 20 active CC patients, 20 active LC patients, and 50 controls demonstrated distinct microbial profiles across different intestinal segments, as revealed by beta-diversity and differential compositional analyses. Compared with controls, CC patients had consistent alterations in three bacterial families throughout the entire colon, with Erysipelatoclostridiaceae and Coriobacteriaceae decreased and Pasteurellaceae increased. Additionally, 35 families had segment-specific changes, and 25 families displayed altered abundance in the terminal ileum.
LC patients exhibited a consistent increase in Erisypelotrichaceae across the entire colon, with 38 other families showing segmental changes, and 12 families displaying altered abundance in the terminal ileum. Comparing LC and CC revealed a significantly different bacterial profile. LC showed lower abundance across many families, particularly in the right colon and terminal ileum. After sample collection, 15 CC patients and 12 LC patients received budesonide, with 3 CC and 2 LC patients having incomplete response. Beta diversity analysis revealed significant differences in the ascending colon and left side of the colon of CC patients based on response to budesonide. Patients with incomplete response to budesonide had an increased abundance of the genus Paucibacter. Similar tendencies were not observed in LC.
1 CC patient exhibited a quiescent disease course, 6 reached a sustained remission after treatment, 7 had a relapsing and 6 had a chronic active disease. Significant differences in beta diversity were observed in transverse, descending colon and rectum. Beta diversity of the descending colon had a medium correlation with disease behaviour. In the LC group 6 patients had a quiescent disease, 8 had a sustained remission after treatment, 3 exhibited a relapsing and 4 had a chronic active disease. No significant correlation between microbiota and disease behaviour was observed in LC.

Conclusion

This study showed significant differences in bacterial composition between CC, LC and controls in the terminal ileum and colon. In both CC and LC, bacterial alterations were not consistent throughout the entire colon but varied between different colonic segments. Microbiome differences based on response to budesonide and disease behaviour were observed in CC, but not LC.

References

1. Verhaegh BPM, Münch A, Guagnozzi D, et al. Course of Disease in Patients with Microscopic Colitis: A European Prospective Incident Cohort Study. J Crohns Colitis. 2021;15(7):1174-1183.
2. Miehlke S, Guagnozzi D, Zabana Y, et al. European guidelines on microscopic colitis: United European Gastroenterology (UEG) and European Microscopic Colitis Group (EMCG) statements and recommendations. United European Gastroenterol J. Published online 2020.
3. Burke KE, D’Amato M, Ng SC, Pardi DS, Ludvigsson JF, Khalili H. Microscopic colitis. Nat Rev Dis Primers. 2021;7(1).