Investigating Multi-Omic Signatures of Ethnicity and Dysglycaemia in Asian Chinese and European Caucasian Adults: Cross-Sectional Analysis of the TOFI_Asia Study at 4-Year Follow-Up

<b>Background:</b> Type 2 diabetes (T2D) is a global health epidemic with rising prevalence within Asian populations, particularly amongst individuals with high visceral adiposity and ectopic organ fat, the so-called Thin-Outside, Fat-Inside phenotype. Metabolomic and microbiome shifts may herald T2D onset, presenting potential biomarkers and mechanistic insight into metabolic dysregulation. However, multi-omics datasets across ethnicities remain limited. <b>Methods:</b> We performed cross-sectional multi-omics analyses on 171 adults (99 Asian Chinese, 72 European Caucasian) from the New Zealand-based TOFI_Asia cohort at 4-years follow-up. Paired plasma and faecal samples were analysed using untargeted metabolomic profiling (polar/lipid fractions) and shotgun metagenomic sequencing, respectively. Sparse multi-block partial least squares regression and discriminant analysis (DIABLO) unveiled signatures associated with ethnicity, glycaemic status, and sex. <b>Results:</b> Ethnicity-based DIABLO modelling achieved a balanced error rate of 0.22, correctly classifying 76.54% of test samples. Polar metabolites had the highest discriminatory power (AUC = 0.96), with trigonelline enriched in European Caucasians and carnitine in Asian Chinese. Lipid profiles highlighted ethnicity-specific signatures: Asian Chinese showed enrichment of polyunsaturated triglycerides (TG.16:0_18:2_22:6, TG.18:1_18:2_22:6) and ether-linked phospholipids, while European Caucasians exhibited higher levels of saturated species (TG.16:0_16:0_14:1, TG.15:0_15:0_17:1). The bacteria <i>Bifidobacterium pseudocatenulatum</i>, <i>Erysipelatoclostridium ramosum,</i> and <i>Enterocloster bolteae</i> characterised Asian Chinese participants, while <i>Oscillibacter</i> sp. and <i>Clostridium innocuum</i> characterised European Caucasians. Cross-omic correlations highlighted negative correlations of <i>Phocaeicola vulgatus</i> with amino acids (r = -0.84 to -0.76), while <i>E. ramosum</i> and <i>C. innocuum</i> positively correlated with long-chain triglycerides (r = 0.55-0.62). <b>Conclusions</b>: Ethnicity drove robust multi-omic differentiation, revealing distinctive metabolic and microbial profiles potentially underlying the differential T2D risk between Asian Chinese and European Caucasians.