Focus on the gut microbiota
Alterations in the gut microbiota have been linked to many diseases. Identifying the microbial pathways responsible for the production of precursors to uraemic toxinsToxic, nitrogen-containing urinary substances responsible for uraemia and kidney damage.... that adversely affect the host is an important first step in the development of potential therapeutic interventions. Intestinal microbiota are capable of producing indole and p-cresol from the essential amino acids tryptophan and tyrosine, respectively, which serve as precursors of the uraemic toxins indoxyl sulfate and p-cresyl sulfate. Both uraemic toxins are not only harmful to the kidneys (see Uraemic Toxins), but also contribute to the risk of thrombosis and cardiovascular disease.
Recent studies suggest that the metabolic end-products of gut bacteria, which result from the breakdown of essential amino acids, may have a negative impact on cardiovascular health. As these diseases are the leading cause of death in humans, knowledge of these metabolites and the potential to influence their formation is a new approach to heart health.
The role of uraemic toxins in cardiovascular health
The uraemic toxins indoxyl sulfate and p-cresyl sulfate have long been suspected of causing adverse health effects in patients with kidney disease. These two uraemic toxins have pro-inflammatory properties and may also contribute to vascular disease, which, in addition to the risk of thrombosis, is also associated with the risk of cardiovascular disease in patients with kidney disease. For example, elevated levels of indoxyl sulfate and p-cresyl sulfate are associated with a higher risk of death in patients with kidney disease. However, this increased risk of death associated with elevated blood levels of indoxyl sulfate and p-cresyl sulfate also occurs in the absence of kidney disease or cardiovascular risk. Independently of each other, both toxins increase the risk of death.
It is therefore of interest to find out to what extent the precursors indole and p-cresol are produced by the bacteria in the intestine and whether it is possible to influence this production.
Microbial synergies
A study by Nemet and colleagues (2023) showed that a link between microbial pathways and the host may also play a role in the development of the precursors (indole, p-cresol) of the above-mentioned uraemic toxins. They discovered that the formation of p-cresol from the amino acid tyrosine represents a collaboration between (two) different gut bacteria. The first bacterial species forms a metabolic end product from tyrosine, which the second bacterial species then converts into p-cresol. In their studies, the researchers used only two bacterial species that produce specific enzymes for the conversion to p-cresol, which are also found in other intestinal bacteria. This results in an interaction between the metabolites of different bacterial species and the metabolites of other bacteria in the gut.
The research sheds light on the involvement of specific members of the gut microbiota in the synthesis of the precursors of indoxyl sulfate and p-cresyl sulfate, and adds to the existing understanding of the production of these metabolites by the host. In the liver, indole and p-cresol are then converted into the actual uraemic toxins. This requires specific liver enzymes.
Research impulses and outlook
The results of the first studies prompted the above-mentioned authors to carry out further studies using a genetically modified bacterium to investigate the effects of the production of each of the uraemic toxin precursors (indole or p-cresol) or both precursors (indole and p-cresol) on the risk of thrombosis. The results show that each of the two aforementioned uraemic toxins plays an independent role in the development of thrombosis and that each can increase the tendency to thrombosis. The uraemic toxins indoxyl sulfate and p-cresyl sulfate are also involved in the development of atherosclerotic cardiovascular disease.
In conclusion, Nemet et al (2023) are the first to demonstrate the mechanism by which the gut microbiota and the host co-operate in the production of the essential amino acid-derived metabolites indoxyl sulfate and p-cresyl sulfate, and the role of these metabolites in the development of thrombosis and cardiovascular disease, not only in patients with renal disease.
Bibliography:
- Machado Ribeiro, T. R., Brito, C. B., & Byndloss, M. X. (2024). Can our microbiomeAll microbes on or within an animal’s tissues, for instance in the intestines (intenstinal flora = the totality of all microorganisms that colonise the intestine). It includes bacteria, protozoa, fungi and viruses.... break our hearts? Collaborative production of p -cresol sulfate and indoxyl sulfate by commensal microbes increases susceptibility to thrombosis. MBio. https://doi.org/10.1128/mbio.02692-23
- Nemet, I., Funabashi, M., Li, X. S., Dwidar, M., Sangwan, N., Skye, S. M., Romano, K. A., Cajka, T., Needham, B. D., Mazmanian, S. K., Hajjar, A. M., Rey, F. E., Fiehn, O., Tang, W. H. W., Fischbach, M. A., & Hazen, S. L. (2023). Microbe-derived uremic solutes enhance thrombosis potential in the host. MBio, 14(6). https://doi.org/10.1128/mbio.01331-23
