Introduction

Colorectal cancer (CRC) often develops from precancerous lesions such as tubular adenomas (TA) and sessile serrated lesions (SSL). The gut microbiome has been implicated in colorectal carcinogenesis, but specific microbial signatures associated with different adenoma subtypes remain incompletely characterized. This study aimed to identify microbial biomarkers associated with TA and SSL, and explore their correlations with dietary macronutrients.

Aims & Methods

Stool samples were collected from 801 patients prior to colonoscopy from National University Hospital and Tan Tock Seng Hospital, Singapore. After colonoscopy, the patients were classified as having TA (n=315), SSL (n=24), both (n=8), or neither (controls, n=454). Shotgun metagenomic sequencing was performed using Novaseq6000, and microbial taxonomy was annotated with MetaPhlAn4. Multivariate linear regression adjusted for age, gender, and BMI was used to identify species associated with polyp subtypes. A subset of 172 participants completed a validated food frequency questionnaire (FFQ) assessing 19 macronutrients, enabling correlation analysis between diet and adenoma-associated microbes.

Results

Patients with TA were older (mean age 64.0±7.8 vs 62.3±7.5 years in controls, p=0.02) and more likely to be male (69.5% vs 52.4%, p<0.01). After adjustment for confounders, we identified 38 microbial species significantly associated with polyp subtypes; 20 were associated with SSL and 18 with TA, with minimal overlap between the two polyp subtypes. Only two species showed associations with both polyp types: Holdemanella biformis and GGB3277_SGB4327, with the latter showing opposing directional relationships (negative for TA, positive for SSL). Of note, SSL were associated with increased abundance of Faecalibacterium SGB15346 and Bifidobacterium adolescentis. In the dietary analysis, we identified significant correlations between SSL-associated microbes and sugar intake, particularly Faecalibacterium SGB15346 (r=0.170, p=0.03) and Clostridium sp_AM49_4BH (r=0.156, p=0.04). E. hominis, positively associated with SSL, showed the strongest dietary associations overall, correlating positively with carbohydrate intake (r=0.243, p<0.01) and starch consumption (r=0.246, p<0.01).

Conclusion

Our study identified distinct microbial signatures associated with TA and SSL, with minimal overlap, suggesting separate host-microbial biological pathways in their development. The positive correlation between SSL-associated microbes and sugar intake provides a potential mechanistic link between dietary habits and SSL formation, which may be particularly relevant given the increasing incidence of early-onset colorectal neoplasia. These findings offer potential microbial biomarkers for early detection of colorectal polyps and suggest targeted dietary interventions as a strategy for precision chemoprevention.

Introduction

Etrasimod is an oral, once-daily, selective sphingosine 1-phosphate (S1P)_1,4,5 receptor modulator for the treatment of moderately to severely active ulcerative colitis (UC), with demonstrated efficacy in patients (pts) with baseline modified Mayo Score (MMS) 4–9.¹ No prior clinical trials of advanced therapies in UC have studied efficacy only in pts with baseline MMS ≤6.

Aims & Methods

GLADIATOR (NCT04607837) was a proof-of-concept, global, randomised, double-blind, placebo-controlled trial to evaluate the efficacy and safety of etrasimod in adults with mildly to moderately active UC (MMS 4–6; endoscopic subscore ≥2; rectal bleeding subscore ≥1) and inadequate response, loss of response or intolerance to ≥1 UC therapy. Pts were randomised 2:1 to etrasimod 2 mg or placebo once daily, stratified by previous biologic/Janus kinase inhibitor exposure and baseline corticosteroid use. GLADIATOR used a treat-through design (12-week [wk] induction period followed by a 40‑wk maintenance period). From Wk 12, pts whose disease had worsened or not improved vs baseline may have been eligible to enrol in an open-label extension trial (NCT03950232). The primary efficacy endpoint was the proportion of pts achieving clinical remission at Wk 52; additional endpoints are shown in the Table. Safety was monitored throughout the study.

Results

In the primary analysis set for efficacy, 127 and 60 pts received etrasimod and placebo, respectively. At Wk 52, 26.0% and 18.3% of pts receiving etrasimod and placebo, respectively, were in clinical remission (p=0.2524; Table). At Wk 12, a greater proportion of pts receiving etrasimod achieved clinical remission, endoscopic improvement (EI) and endoscopic improvement-histologic remission (EIHR) vs placebo (p<0.05; Table). Pts receiving etrasimod were more likely to achieve sustained clinical remission vs placebo (p=0.0104; Table). Etrasimod was generally well tolerated and findings were consistent with the known safety profile.

Conclusion

In pts with mildly to moderately active UC, etrasimod demonstrated higher rates of clinical remission, EI and EIHR at Wk 12, as well as sustained clinical remission at Wk 52, vs placebo. However, the primary endpoint of clinical remission at Wk 52 was not met. Etrasimod demonstrated efficacy in pts with UC with an MMS 4–9, including those with an MMS 4–6, in the ELEVATE UC clinical programme.¹ The proof-of-concept GLADIATOR trial further supports etrasimod’s efficacy in active UC and provides important insights on studying pts with mildly to moderately active UC.

References

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

Disclosure

SD: Lecture fees: AbbVie, Amgen, Ferring Pharmaceuticals Inc, Gilead, Janssen, Mylan, Pfizer Inc, Takeda; Consultancy fees: AbbVie, Allergan, Amgen, AstraZeneca, Biogen, Boehringer Ingelheim, Celgene, Celltrion, Ferring, Gilead Sciences, Hospira, Janssen, Johnson&Johnson, MSD, Mundipharma, Pfizer Inc, Roche, Sandoz, Takeda, TiGenix, UCB, Vifor; Directorship: Gastroenterology and Endoscopy.
MG, KL: Employees of Pfizer AG; shareholders of Pfizer Inc.
LPB: Consultancy fees: AbbVie, Abivax, Alimentiv, Alma Bio Therapeutics, Amgen, Applied Molecular Transport, Arena, Biogen, BMS, Celltrion, CONNECT Biopharm, Cytoki Pharma, Enthera, Ferring, Fresenius Kabi, Galapagos, Genentech, Gilead, Gossamer Bio, GlaxoSmithKline, HAC-Pharma, IAG Image Analysis, Index Pharmaceuticals, Inotrem, Janssen, Lilly, Medac, Mopac, Morphic, MSD, Norgine, Novartis, OM Pharma, ONO Pharma, OSE Immunotherapeutics, Pandion Therapeutics, Par’Immune, Pfizer Inc, Prometheus, Protagonist, Roche, Roivant, Samsung, Sandoz, Sanofi, Takeda, Theravance, Thermo Fisher, Tigenix, Tillotts, Viatris, Vifor, Vectivbio, Ventyx, Ysopia; Grants: Takeda, Fresenius Kabi, Celltrion; Lectures: AbbVie, Amgen, Arena, Biogen, Celltrion, Ferring, Galapagos, Genetech, Gilead, Janssen, Lilly, Medac, MSD, Pfizer Inc, Sandoz, Takeda, Tillotts, Viatris, Vifor.
AJY: Consultancy fees: AbbVie, Arena, BMS, Celltrion, Pfizer Inc, Takeda; Lectures: AbbVie, BMS.
MCD: Consultancy fees: AbbVie, Abivax, Arena Pharmaceuticals, AstraZeneca, BMS, Eli Lilly, Galapagos, Genentech, Gilead Sciences, Janssen Pharmaceuticals, Johnson&Johnson, Merck, Pfizer Inc, Prometheus Laboratories, Prometheus Biosciences, Sanofi, Sphyre, Takeda, UCB; Shareholder: Trellus Health; Directorship: Trellus Health.
DTR: Consultancy fees: AbbVie, Abivax SA, Altrubio, Avalo Therapeutics, Bausch Health, Bristol Myers Squibb, Buhlmann Diagnostics Corp, Celltrion, ClostraBio, Connect BioPharma, Douglas Pharmaceuticals, Eli Lilly & Co., Foresee, Genentech, Image Analysis Group, InDex Pharmaceuticals, Iterative Health, Janssen Pharmaceuticals, Odyssey Therapeutics, Pfizer Inc, Sanofi, Takeda Pharmaceuticals, Throne, Vedanta; Grants: Takeda.
BGF: Senior Scientific Director of Alimentiv Inc, which provides central reading services. He is not a company employee and has no equity stake in the organisation, which is owned by a medical trust; Speaker fees: AbbVie, Janssen, Takeda; Consultancy fees: AbbVie, AbolerIS, AgomAB Therapeutics, Allianthera, Amgen, AnaptysBio, Applied Molecular Transport Inc, Arena Pharma, Avoro Capital Advisors, Atomwise, BioJamp, Biora Therapeutics, Boehringer Ingelheim, Boxer, Celsius Therapeutics,Celgene/BMS, Connect BioPharma, Cytoki, Disc Medicine, Duality, EcoR1, Eli Lilly, Equillium, Ermium, First Wave, First Word Group, Galapagos, Galen Atlantica, Genentech, Gilead, Gossamer Pharma, GSK, Hinge Bio, Hot Spot Therapeutics, Index Pharma, Imhotex, Immunic Therapeutics, JAKAcademy, Janssen, Japan Tobacco Inc, Kaleido Biosciences, Landos Biopharma, Leadiant, L.E.K. Consulting, Lenczner Slaght, LifeSci Capital, Lument AB, Millennium, MiroBio, Morgan Lewis, Morphic Therapeutics, Mylan, OM Pharma, Origo BioPharma, Orphagen, Pandion Therapeutics, Pendopharm, Pfizer Inc, Prometheus Therapeutics and Diagnostics, Play to Know AG, Progenity, Protagonist, PTM Therapeutics, Q32 Bio, Rebiotix, REDX, Roche, Sandoz, Sanofi, Seres Therapeutics, Silverback Therapeutics, Surrozen Inc, Takeda, Teva, Thelium, Tigenix, Tillotts, Ventyx Biosciences, VHSquared Ltd, Viatris, Ysios, Ysopia, Zealand Pharma; Shareholder: Gossamer Pharma.
GRDH: Advisory fees: AbbVie, AstraZeneca, Alimentiv, BMS, Boehringer Ingelheim, Celltrion, Cosmo, Eli Lilly, Galapagos, GSK, Johnson&Johnson, Takeda, Pfizer Inc, Polpharma, Prometheus Biosciences, Tillotts, Ventyx; Speaker fees: AbbVie, Boehringer Ingelheim, Celltrion, Eli Lilly, Johnson&Johnson, Takeda, Pfizer Inc, Tillotts.
FB: Research/grants: AbbVie, Amgen, Eurogenerics, Janssen, Takeda; Lectures: AbbVie, Arena Pharmaceuticals, Celltrion, Ferring, Galapagos, Janssen, Merck Sharp & Dohme, Pfizer Inc, Takeda; Consultancy fees: AbbVie, Abivax, Amgen, Arena Pharmaceuticals, Celgene, Celltrion, Ferring, Fresenius Kabi, Janssen, Merck Sharp & Dohme, Pfizer Inc, Sandoz.
GG, JY, NL, CZ, WW, SM, EHL, IM, SS, WN: Employees/shareholders of Pfizer Inc.
SV: Lectures: AbbVie, Dr. Falk Pharma, Ferring, Galapagos, Hospira, Janssen, MSD, Takeda, Tillotts; Consultancy fees: AbbVie, AbolerIS Pharma, Alimentiv, Arena, AstraZeneca, Avaxia, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, CVasThera, Dr Falk Pharma, Eli Lilly, Ferring, Galapagos, Genentech/Roche, Gilead, Hospira, Imidomics, Janssen, Johnson&Johnson, Materia Prima, MiroBio, Morphic, MrMHealth, MSD, Mundipharma, Pfizer Inc, Prodigest, Progenity, Prometheus, Robarts Clinical Trials, Second Genome, Shire, Surrozen, Takeda, Theravance Biopharma, Tillotts Pharma AG, Zealand Pharma; Grants: AbbVie, MSD, Pfizer Inc, Galapagos, Janssen, Takeda.