The gut and two cell regulators may pave the way to better high blood pressure drugs.
Monash University researchers have revealed how the gut – and what we eat – regulates high blood pressure, opening the door to more specialised potential new drugs.
The groundbreaking project involved multiple researchers from Australia, China and Singapore, and was led by the Hypertension Research Laboratory at Monash University’s School of Biological Sciences, headed by Professor Francine Marques.
The findings are highly significant for the estimated one in three Australians who have hypertension, which is a leading cause of stroke, heart disease and kidney disease.
“We had evidence that dietary fibre, via the production of gut microbial substances called short-chain fatty acids, reduces blood pressure,” said Professor Marques. “But we didn't understand how this gut-to-host communication took place.”
The key is in two protein receptors in intestinal cells which can be switched on by short-chain fatty acids. These receptors are called GPR41 and GPR43.
“They are what we call ‘G-protein coupled receptors’, part of the largest group of receptors on cell membranes that activate signalling from the surface to the inside of cells,” Professor Marques said.
“They are highly present in immune cells and cells of the lining of the intestinal wall. Once they are activated, they are known to trigger anti-inflammatory mechanisms.
“What is exciting about them is that the molecules that bind to and activate them are produced by the gut when we ingest fibre in our diet.”
Dietary fibre works by being fermented in the gut by microbes, which produce short-chain fatty acids. Dietary fibre comes from legumes, fruit, vegetables, whole grains, nuts, resistant starches such as oats and potatoes, and seeds. A major issue, the researchers said, is that most Australians do not eat enough fibre.
The team’s findings are now published in Circulation Research with a strong focus on gut permeability, or how much it leaks, based on pre-clinical lab work.
“Our study shows that the lack of activation of the receptors, copying a situation when we don’t have enough fibre in our diet, leads to increased gut permeability, allowing microbial components into the circulation,” said lead author Dr Rikeish R Muralitharan, a research fellow in the School of Biological Sciences.
“This activates inflammation in key organs such as the kidney, which regulate blood pressure, and which leads to hypertension. What is exciting here is that this systemic increased inflammation we observe in diseases such as hypertension may start in the gut, and we demonstrate that GPR41 and 43 are, at least partially, responsible for the blood pressure-lowering and cardio-protective effects of a high fibre diet.”
The researchers also show through genetic data from around 300,000 people that some genetic variants mean lower rates of hypertension.
Professor Marques’s Lab is now running a human clinical trial to better understand gut permeability in hypertension, and is starting in vitro tests of potential new drugs to bind to the receptors.
“We have partnered with computational drug discovery and G-protein coupled receptor specialists to design and test new drugs to activate these receptors, opening opportunities for new treatments that reduce blood pressure via the gut,” she said.
To view the Marques Lab, please visit www.marqueslab.com/gut
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