Systems analysis of holobiome for Type 2 Diabetes: in-depth shotgun metagenome with multi-omics revealed key microbiome factors of T2D pathogenesis

Abstract

Recently, many studies have been conducted on the potential role of the intestinal microbiome in humans in metabolic disorders such as type 2 diabetes(T2D). However, microbiome studies on type 2 diabetes have many inconsistent results with large differences between studies, and there is a limitation in the lack of performance of integrated analysis of clinical data, microbiome data, and serum metabolome. In this study, I conducted shotgun metagenome-sequencing based MWAS (Metagenomic wide association studies) on 40 control groups, 40 T2D groups,30 pre-diabetes (Pre-DM) groups. And focusing on the functional module of intestinal microbes, a study on the association between targeted serum metabolites and diabetes clinical traits was conducted. Through the integration of shotgun metagenome, serum metabolome, and clinical metadata analysis, I found that Clostridium spp. and Bacteroides spp. were enriched in T2D patients, including Clostridium perfrigens and Clostridium paraputrificum, which were known to act as pathobionts, possibly promoting T2D pathogenesis. In addition, we found a decrease in methane metabolism when comparing diabetic and Control groups. Methanogenesis modules belonging to methane metabolism negatively correlated with HbA1c, a marker of type 2 diabetes, and lipid metabolites. I propose the possibility of methanogenic microbe deficiency as a biomarker by performing a key-driver analysis on methanogenesis-related modules of gut microbes in type 2 diabetes.