Microbiome and Metabolome in Ischaemic Heart Disease

Numerous epidemiological studies have combined gut metagenomics with metabolomics to explore pathophysiology and pathogenesis of human non-communicable diseases. However, scant attention was paid to major confounders of study outcomes, such as common pre-morbid conditions or polypharmacy. In the context of ischaemic heart disease (IHD), a leading cause of mortality in the Western world, here we used a unique study design to recapitulate disease initiation, escalation, worsening and response to treatment over time, mimicking a longitudinal study otherwise difficult given the protacted IHD pathogenesis. For this, we recruited 1,241 middle-aged Europeans including healthy controls, controls with dysmetabolic pre-morbidities (obesity and type 2 diabetes) but lacking overt IHD diagnosis, and finally IHD cases at three different stages; acute coronary syndrome, chronic IHD and heart failure. We characterized their phenome, gut metagenome and metabolome. We show that about 75% of microbiome and metabolome features that distinguish IHD cases from healthy controls after adjustment for effects of medication and lifestyle are present already in individuals exhibiting dysmetabolism, suggesting that major alterations of the gut microbiome and metabolome begin long before clinical onset of IHD. In addition, with the applied adjustments for polypharmacy and premorbidites we developed a novel classification approach, which reveals multiple microbiome and metabolome pathophysiological signatures related to prodromal dysmetabolism, specific to IHD and disease subgroups or related to escalation and de-escalation of IHD and its subtypes.