GUT MICROBIOTA IN OBESITY, TYPE 2 DIABETES AND CORONARY HEART DISEASE IN 12,200 SWEDES

BACKGROUND: Despite evidence supporting a role for the gut microbiome in obesity, type 2 diabetes (T2D) and cardiovascular disease (CVD), causal- and mechanistic evidence in humans is limited, and prospective studies are lacking. The gut bacterial composition can be modified by probiotics, dietary changes, and by bacterial viruses, bacteriophages (phages).

Therefore, it is important to understand how dietary factors and phages regulate the gut bacterial equilibrium and their metabolites and are connected to cardiometabolic risk.

OBJECTIVES: We challenge the question of interrelationships between bacteria and phages in human fecal samples and investigate their connection to dietary intakes and the future risk of T2D and CVD. For this purpose, we will integrate clinical phenotype data with multi-omics data of human (genomic, metabolomic, proteomic) and gut (taxonomic, pathways) origin to clarify connections between dietary patterns/intakes, host genetic factors, circulating metabolites and inflammatory proteins and gut microbiota composition, diversity and functional capacity, and how such connections relate to risk of T2D and CVD.

WORKPLAN: In three large population cohorts of in total 12,200 participants, the SCAPIS-Malmö and -Uppsala (N=10,045) and Malmö Offspring Study (N=2,200), we investigate how the gut microbiome composition, diversity and functional capacity are related to diet and associate with cardiometabolic risk traits and incidence of T2D and CVD. We perform novel type of shotgun metagenomic analysis with precision and coverage far beyond the classical reference-based approaches, enabling detection and quantification of all bacterial species to strain level, and phages.

By Mendelian Randomization we study causal connections and directions between gut microbiota, metabolites and risk of T2D and CVD. By integrative Deep Learning we elucidate hidden connections and hierarchies in the multi-omic data.

SIGNIFICANCE: This large study will determine interrelationships between gut bacteria and phages and provide prospective evidence for the role of the gut bacteria and their virus in cardiometabolic diseases. Further, we expect to identify bacterial species and phages that via diet are related to risk of T2D and CVD. Our study will identify risk groups for future interventions, and has the capacity to detect potential new probiotic bacterial strains and evaluate the potential of phages in future cardiometabolic disease preventive strategies.