Determining how microbiota-derived tryptophan metabolites regulate lymphocyte function in hypertension

Project: Research

Investigators

  • Brett M Mitchell (PI)

Description

The number of people in the US with hypertension is increasing and now almost 1 in 2 adults have the #1 contributor to cardiovascular-renal disease. Hypertension in both humans and animals are characterized by activated immune cells including various T cells. The microbiota plays a key role in a number of complex diseases including cardiovascular disease. While others have reported that the gut microbiota plays an additional role in blood pressure regulation, the connection between specific gut microbiota metabolites, immune cells, and hypertension has not been examined previously. The Principal Investigator and Physiologist, Dr. Brett Mitchell, has reported that various pro-inflammatory T cells directly cause hypertension through a variety of mechanisms. Co-Investigator and Immunologist Dr. Robert C. Alaniz has determined that the gut microbiota tryptophan metabolite indole binds the aryl hydrocarbon receptor and polarizes T cells into anti-inflammatory regulatory T cells and inhibits pro-inflammatory Th17 cells. However, under certain conditions the 5-hydroxy form of indole predominates and binds the aryl hydrocarbon receptor and leads to decreased regulatory T cells and increased pro-inflammatory T cells. We believe that tryptophan metabolites are key microbiota metabolite s that determine T cell fates in hypertension. Although unknown, we hypothesize that pro-hypertensive stimuli such as a high salt diet or high angiotensin II levels lead to increased formation of detrimental tryptophan metabolites in the gut leading to pro-inflammatory T cell polarization and hypertension, and that the restoration of beneficial tryptophan metabolite levels by direct administration or microbiota manipulation can potentially become an anti-hypertensive therapeutic. Our long-term goal is to develop a safe and effective therapeutic for hypertension that targets gut microbiota tryptophan metabolites. The innovation lies in the idea that manipulating specific microbiota tryptophan metabolites will drastically alter immune cell activation and reduce blood pressure.
Award amount$200,000.00
Award date07/01/2019
Program typeInnovative Project Award
Award ID19IPLOI34760721
Effective start/end date07/01/201906/30/2021
StatusActive