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Microbe-derived uremic solutes enhance thrombosis potential in the host
Ina Nemet1,2, Masanori Funabashi3,4,5, Xinmin S Li1,2
1Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland, Ohio, USA.
Mbio
|November 10, 2023
Summary
Gut microbes produce toxins linked to cardiovascular disease. We identified specific microbial genes that generate these toxins, demonstrating their role in disease risk and a pro-thrombotic state in vivo.
Area of Science:
- Microbiology
- Cardiovascular Disease Research
- Metabolomics
Background:
- Gut microbial metabolites are increasingly recognized for their role in host health and disease.
- Elevated levels of certain microbial products, such as p-cresol sulfate and indoxyl sulfate, are associated with increased cardiovascular disease (CVD) risk.
- Understanding the specific microbial pathways that generate these harmful molecules is crucial for developing targeted therapies.
Purpose of the Study:
- To link blood levels of microbial products to cardiovascular disease risks using clinical data.
- To identify the specific gut microbes and enzymes responsible for producing detrimental uremic toxins.
- To establish a causal link between microbial genes, toxin production, and adverse host phenotypes in vivo.
Main Methods:
- Large-scale clinical data analysis to correlate microbial product levels with CVD risk and mortality.
- Metagenomic and enzymatic analysis to identify microbes and genes involved in p-cresol and indole production.
- Germ-free mouse models colonized with specific microbial genes to assess in vivo toxin formation and pro-thrombotic effects.
Main Results:
- Clinical observations linked specific microbial products to significant 5-year mortality risks in cardiovascular patients.
- Identified key microbial genes responsible for generating p-cresol and indole, precursors to p-cresol sulfate and indoxyl sulfate.
- Demonstrated that these microbial genes are sufficient to cause the formation of these uremic toxins and induce a pro-thrombotic phenotype in vivo.
Conclusions:
- Gut microbial pathways producing p-cresol and indole are directly implicated in cardiovascular disease risk.
- The identified microbial genes and bioengineered tools provide a foundation for targeting these pathways therapeutically.
- This study establishes a critical link between gut microbial metabolism, uremic toxin production, and cardiovascular pathophysiology.
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