Multi-cohort analysis of metagenome for type 2 diabetes identified universal gut microbiota signatures across populations

Abstract

Background: Several studies have investigated the association between the gut microbiota and type 2 diabetes mellitus (T2D) in various populations. Nonetheless, noises specific to individual cohorts might distort the microbial dysbiosis characteristics and result in inconsistent findings across studies. Thus, we aimed to identify the universal features of perturbed gut microbiota across diverse populations. Methods: A total of 433 fecal shotgun metagenomic sequences were analyzed to profile and compare the gut microbiome shifts between patients with T2D and healthy controls from cohorts in Europe and Asia. Results: Based on cross-cohort integrative analysis, patients with T2D showed significantly higher microbial alpha diversity, and distinctive microbial structures compared to healthy individuals. By excluding bacteria exhibiting divergent directional changes, consistent characteristics with ten T2D-enriched bacteria, such as Clostridium bolteae and Clostridium citroniae and eight T2D-depleted bacteria, including Streptococcus thermophiles and Haemophilus parainfluenzae were revealed across populations. Particularly, these reliable bacterial markers, which were robust against demographic variation, distinguished patients with T2D from healthy controls with high accuracy (AUCs > 0.8) in both European and Asian cohorts. Correlation analysis demonstrated that T2D-enriched and T2D-depleted bacteria, respectively, formed their own mutualistic networks that were negatively linked to each other. Moreover, T2D-enriched bacteria were dramatically positively associated with fasting blood glucose and glycated hemoglobin. Functionally, 10 KEGG pathways with consistent directional changes across European, Asian, and combined cohorts were identified. Specifically, the Nucleotide excision repair pathway was markedly downregulated in patients with T2D, while the AGE-RAGE signaling pathway in diabetic complications was consistently enriched in patients with T2D across cohorts. Conclusions: Our results elucidated reproducible profiles of gut commensal bacteria in patients with T2D, which are robust across populations. Identifying the universal gut microbiome signatures of T2D in heterogeneous cohorts offers valuable insights for understanding disease development and is crucial for prevention and diagnosis across diverse populations.