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Background: The human gut microbiome is linked to obesity (OB) and cardiometabolic disease (CD). As these conditions are often confounded, uncovering CD and OB-specific relationships remains a challenge. Comparison of study outcomes is hindered by differences in study design and the covariates used. Our goals are twofold: 1) to describe features of microbiome diversity and function associated independently with CD or OB in a deeply phenotyped cohort of Colombian adults, and 2) to test for the replication of associations previously reported for microbiome and OB/CD. Methods: We generated shotgun gut metagenomes for 408 Colombian adults phenotyped for anthropometric and blood biochemistry data. We measured OB using body mass index, waist circumference and body fat percentage. For CD we used glucose metabolism, serum lipids, inflammation and blood pressure. Based on published meta-analyses of microbiome associations, we selected 136 metabolic modules consistently linked to OB, cardiovascular disease or diabetes. Metagenome richness was measured using Nonpareil sequence diversity; functional profile β diversity was calculated from module abundances. Association of modules with CD and OB was tested using linear models adjusted for city, sex and age. Results: In our cohort, sequence diversity negatively correlated with OB, and subjects with CD had lower diversity than healthy subjects with similar OB levels. OB explained a higher proportion of variance for metagenome richness and functional β-diversity than CD. We detected 48 modules uniquely associated with OB but only 3 with CD. OB was positively correlated with modules of transport of simple sugars, while negatively correlated with methanogenesis, glycolysis, and vitamin and amino acid synthesis. Modules unique to CD were involved in osmoprotection and sulfur metabolism. Disease-linked modules had a lower prevalence and mean abundance than health-related ones. Conclusion: The use of a well phenotyped population allowed us to discriminate between microbiome associations with OB controlling for CD. From the previously reported modules, 38% were associated with either CD or OB alone, with far more associated with OB than CD. OB was related to lower functional diversity, evidenced by a loss of beneficial modules. This indicates that OB drives the microbiome associations with CD when both are present. Our results show a relatively poor replication of associations seen in other cohorts, yet the loss of beneficial functions and diversity previously reported is validated in this population.
