Periodic Reporting for period 4 - GUTSY (The gut microbiota and its systemic effects on metabolism and atherosclerotic disease)
Reporting period: 2023-07-01 to 2023-12-31
Atherosclerotic cardiovascular disease is the worldwide leading cause of death. Identification and interventions against modifiable cardiovascular risk factors have contributed to a stark reduction in the incidence. However, the proportion of patients with myocardial infarction and stroke without known risk factors is increasing and accounts for 15–30% of patients in studies from Australia and Sweden. We now need to identify the remaining underlying causal risk factors to be able to provide new effective preventive strategies. Atherosclerotic plaque starts forming already in childhood on the inside of artery walls by a build-up of lipids, fibrous elements, calcium, and inflammatory molecules. With age, plaques that are prone to rupture become more common. When a plaque ruptures, it exposes its inner parts to the blood flow, leading to blood clot formation and potentially to myocardial infarction or stroke. The mechanisms driving atherosclerosis formation and progression are partly unknown, and the theory of a microbial contribution was proposed at the beginning of the last century. Even in a healthy state, humans carry a large number of commensal microbes on all mucosal surfaces - the microbiome - that could play a role in atherogenesis. The overall aim of this project was to identify gut bacterial species or products that accelerates or hampers the development of atherosclerotic disease and to provide easily accessible blood biomarkers for an atherosclerosis-enhancing gut microbiota. The field of microbiota research is of great attention, but the field lacks smart study designs that assess true causal effects of gut dysbiosis. Our research is anticipated to lead to identification of atherosclerosis-enhancing gut microbiota characteristics and their associated biomarkers that may open up new avenues for effective population-wide long-term prevention of atherosclerotic disease.
Our studies were based on data from 8973 participants from the Swedish CArdioPulmonary bioImage Study (SCAPIS) without previous cardiovascular disease. Here we searched for gut microbes linked to the early stages of atherosclerosis. We identified 64 gut bacterial species associated with subclinical coronary atherosclerosis measured with computed tomography. The associations were independent of standard risk factors with the strongest evidence for increased atherosclerotic burden in carriers of the bacteria Streptococcus anginosus and Streptococcus oralis subsp. oralis. The abundance of these species was linked to increased circulating cardiovascular inflammatory risk markers and lower levels of the microbial metabolite indole-3-propionate, a metabolite that has been found to reduce the progression of atherosclerosis in mice as well as with increased levels of the diabetes-linked metabolite imidazole propionate. These bacteria normally live in the mouth and in the throat. The results were in general enriched for streptococci and other oral species. These results were presented at the International Human Microbiome Consortium Congress, where it won the clinical oral presentation award in collaboration with the publisher Nature, and was later published in the leading journal Circulation (2023). The publication was accompanied by a joint press release from Lund University and Uppsala University, and was highlighted on Swedish radio on August 7, 2023 (the science broadcast Vetenskapsradion) and the study was featured in the Swedish newspaper UNT on July 25, 2023. The Altmetric score is 478 and the study has been downloaded more than 10,000 times.
Our studies have further shown that the gut microbiome composition is tightly linked to plasma levels of small molecules - metabolites. The studies underlying these results were based on analyses of both fecal and blood samples from 8583 participants in the SCAPIS where we assessed the association of 1300 metabolites with the microbiota and found that some metabolites e.g. the uremic toxin p-cresol have a very strong relationship with certain gut bacteria. Several of these metabolites have also been linked to atherosclerosis. These data have been presented at the International Human Microbiome Consortium Congress and published in Nature Communications in September 2022 and was accompanied by a press release. The results have further been made freely available to the research community through an online atlas: https://gutsyatlas.serve.scilifelab.se/app/gutsyatlas(opens in new window). The paper has yielded a lot of interest from the scientific community with more than 35,000 downloads, and Altmetric score of 461. It was among the top 25 Health Sciences Articles of 2022 in Nature Communications and has already 51 citations from various fields. As a result of this paper, the PI was invited to several international meetings to present and discuss the results.
We have also studied the host genetics of microbiome composition and the first results will be presented during 2024. Future research needs to address what the pathways are for the effects of the microbiome on atherosclerosis. Our new hypothesis based on the results from GUTSY is that oral bacteria play a role in atherosclerosis and that they might be propagated in the gut. Some of the effect is likely mediated by bacterial metabolites. See attached Figure.
Our studies have further shown that the gut microbiome composition is tightly linked to plasma levels of small molecules - metabolites. The studies underlying these results were based on analyses of both fecal and blood samples from 8583 participants in the SCAPIS where we assessed the association of 1300 metabolites with the microbiota and found that some metabolites e.g. the uremic toxin p-cresol have a very strong relationship with certain gut bacteria. Several of these metabolites have also been linked to atherosclerosis. These data have been presented at the International Human Microbiome Consortium Congress and published in Nature Communications in September 2022 and was accompanied by a press release. The results have further been made freely available to the research community through an online atlas: https://gutsyatlas.serve.scilifelab.se/app/gutsyatlas(opens in new window). The paper has yielded a lot of interest from the scientific community with more than 35,000 downloads, and Altmetric score of 461. It was among the top 25 Health Sciences Articles of 2022 in Nature Communications and has already 51 citations from various fields. As a result of this paper, the PI was invited to several international meetings to present and discuss the results.
We have also studied the host genetics of microbiome composition and the first results will be presented during 2024. Future research needs to address what the pathways are for the effects of the microbiome on atherosclerosis. Our new hypothesis based on the results from GUTSY is that oral bacteria play a role in atherosclerosis and that they might be propagated in the gut. Some of the effect is likely mediated by bacterial metabolites. See attached Figure.
These studies constitute the largest studies so far in the field. Our work has not only generated new knowledge regarding the links between the microbiome and human health, it has also provided a roadmap for epidemiological studies on the microbiome. We hope that our analysis pipeline can act as a blueprint for future studies in the field. The generated data will be re-used to answer other important medical research questions.