Abstract

Background and Aims Alterations in immunoglobulin G (IgG) N-glycosylation are implicated in inflammatory bowel disease (IBD); however, the robustness of IgG glycan signatures across IBD cohorts with diverse demographics and geographic origins remains underexplored. We aimed to determine whether compositional data analysis (CoDA) and machine learning (ML) can identify IBD-related IgG N-glycan signatures and whether these signatures capture disease-associated acceleration of biological aging.

Methods We analyzed the IgG glycome profiles of 1,367 plasma samples collected from healthy controls (HC), symptomatic controls (SC), and people with newly diagnosed Crohn’s (CD), and ulcerative colitis (UC) across four cohorts (UK, Italy, United States, and Netherlands). IgG glycosylation was analyzed by ultra-high-performance liquid chromatography, yielding 24 total-area-normalized glycan peaks (GPs). Analyses were performed using cross-sectional data obtained at baseline. CoDA-powered association analyses were used to identify disease-related effects on GPs while controlling for demographic covariates. ML models were trained and evaluated to assess generalizability to unseen cohorts and demographic subgroups, with a focus on discrimination and reliability.

Results Across all cohorts, people with IBD demonstrated accelerated biological aging as quantified by the GlycanAge index. This was accompanied by consistent reductions in IgG galactosylation, with effects partially modulated by age. Classification models trained on glycomics and demographics achieved robust discrimination (AUROC≈0.80) between non-IBD (HC+SC) and IBD across cohorts.

Conclusion These findings reveal accelerated biological aging in people with IBD and support the translational potential of IgG glycans as biomarkers and a novel route toward clinically interpretable personalized risk estimates.

Competing Interest Statement

GL is the founder and owner of Genos Ltd., a private research organization specializing in high-throughput glycomic analysis and holding several patents in this field. IT-A, FV, MĆV, JŠ, JK, AM are employees of Genos Ltd. GL is also the founder and owner of Genos Glycoscience Ltd., a spin-off company of Genos Ltd. that commercializes its scientific discoveries, and a co-founder and Chief Scientific Officer of GlycanAge Ltd., which markets the GlycanAge biological age test. DPBM is a consultant for Mirador Therapeutics and holds patents for anti-TL1A therapy in IBD. JS has received grant funding from the EC, CCUK, and the Helmsley Trust for biomarker studies in IBD at the University of Oxford, and from the EC for IBD-BIOM and IBD-CHARACTER at the University of Edinburgh. NV, RK, AL, NM, DL, NAK, VA, KF, DG, JSL, and CK have nothing to disclose.

Funding Statement

This work was supported by the European Union's Horizon 2020 Research and Innovation Programme through the SynHealth project (grant no. 101159018), and by the European Union's Seventh Framework Programme through the IBD-BIOM project (grant no. 305479).

Author Declarations

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Tayside Committee on Medical Ethics B gave ethical approval for this work (LREC 06/S1101/16, LREC 2000/4/192); all patients and controls provided written informed consent.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

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Footnotes

↵* shared first authors

↵** shared last authors

AbbreviationsADCCantibody-dependent cellular cytotoxicityAUROCarea under the receiver operating characteristic curveBAAbiological age accelerationCDCcomplement-dependent cytotoxicityCDCrohn’s diseaseCLRcentered log-ratioCMDSclassical multidimensional scalingCoDAcompositional data analysisCRPc-reactive proteinCVcross-validationFccrystallizable fragmentFCPfecal calprotectinFDRfalse discovery rateGPglycan peakGlyCmpGlyCompare-derived glycomotif feature representationGWASgenome-wide association studiesHChealthy controlsIBDinflammatory bowel diseaseIBSirritable bowel syndromeITItalian cohortLOCOleave-one-cohort-outLRlogistic regressionMLmachine learningNLNetherlands cohortOLSordinary least squaresPCAprincipal component analysisSCsymptomatic controlsUCulcerative colitisUHPLCultra-high-performance liquid chromatographyUKUnited Kingdom cohortUSUnited States cohortXBXGBoost