Targeting the gut-heart axis

We have recently shown that the gut microbial profile in patients with chronic heart failure differs from that of healthy individuals, that by-products of microbial metabolism may be relevant for clinical outcome and initiated a proof-of-concept trial targeting the gut microbiota to improve cardiac function. In the present project, we aim to more firmly establish the concept of gut microbiota-directed interventions in cardiovascular disease, by identification of altered microbial functions as novel potential treatment targets. The Project will be organized in 5 work packages (WP): WP1. Increase the resolution and functional information of microbiota-alterations in heart failure, through unbiased metagenomics, parallel analyses of circulating metabolomics and multi-level bioinformatics, specifically searching for potential novel pathways with relevance clinical outcome. WP2. We will characterize the gut microbiota profile and its association to systemic inflammatory and metabolic pathways in acute coronary syndromes, applying the same Methods as in WP1. WP3. Characterize functional microbiota-related effects of targeting the gut microbiome in chronic heart failure, in the recently published GutHeart study (NCT02637167, www.clinicaltrials.gov). In this trial, oral antibiotics and probiotics have been applied to target the gut microbes by different strategies. WP4. Lay the foundation for future studies targeting the gut microbiota in order to reduce inflammation and myocardial damage in acute coronary syndromes. Details on WP4 will be planned after data from WP2 and WP3 have been analyzed. WP5. Investigate direct relationships between the gut microbiota composition and circulating metabolites and inflammatory markers, applying multi level bioinformatics on data generated in WP1-WP4. We intend to identify novel pathways linking gut microbes, plasma metabolites and potentially cardiac function.

We have recently shown that the gut microbial profile in patients with chronic heart failure (HF) differs from that of healthy individuals, that by-products of microbial metabolism may be relevant for clinical outcome and initiated a proof-of-concept trial (Gutheart) targeting the gut microbiota to improve cardiac function in patients with HF. In the present project proposal, we aim to more firmly establish the concept of gut microbiota-directed interventions in cardiovascular disease, by identification of altered microbial functions as novel potential treatment targets. We will characterize the compositional and functional aspects of the gut microbes and related metabolites in two distinct but related clinical settings, acute coronary syndromes (ACS) and chronic HF. Apart from cross sectional studies (WP1 and WP2), we will take advantage of interventional trials targeting the gut microbiome to gain more insight in pathogenic mechanisms. In addition to the ongoing GutHeart-trial in HF (WP3), we plan for intervention in ACS (WP4). WP4 was originally planned as a RCT with oral antibiotics in ACS. However, a recent study reported markedy increased myocardial rupture rate and mortality after oral antibiotics in an animal model (Tang TWH, Circulation 2019 January 29;139(5):647-59). Given these new data, WP4 will need to be adjusted, and the choice and timing of intervention in ACS needs to be selected based on data from the GutHeart study and gut microbiota signatures identified in the cross sectional study of ACS. Although the timeline has been slightly changed in the revised application, the budget remains the same as a full RCT will need additional funding. Data generated from WP1-WP4 will be characterized by full metagenomic analyses of stored stool samples, in parallell with unbiased metabolomic and proteomic analyses of plasma samples. Finally, multi level bioinformatics will be applied to identify novel functional pathways between the gut and the heart.