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Understanding the mechanisms behind how dietary fibre lowers blood pressure via GPR41 and GPR43 signaling

Writer's picture: Francine MarquesFrancine Marques

The question

 

High blood pressure is the leading cause of death globally. Innovative ways to prevent hypertension or lower blood pressure are crucial for better blood pressure control.

 

A high-fibre diet results in the production of beneficial by-products called short-chain fatty acids (SCFA) in the gut because of bacterial fermentation. Our group and others and have shown that SCFA supplementation can reduce blood pressure (BP) in animals and, more recently, in human hypertension.1-3

 

SCFAs can be detected by receptors present in the membrane of the host cells called G-protein coupled receptors GPR41 and GPR43. These receptors are present in many host cell-types particularly immune cells and cells lining the colon.4 These receptors also work on similar pathways, so deleting both receptors is important to truly determine their function.

 

In the study published in Circulation Research in January 2024, we aimed to understand whether host GPR41 and GPR43 play a role in hypertension via fibre/SCFA-sensing and the mechanisms involved remained unknown.5 This is important because understanding how the gut communicates with the host is crucial to pinpoint mechanisms that could be targeted for disease treatment.

 

The discovery

 

To answer our question, we first studied mice where we deleted the receptors GPR41 and GPR43, generating a GPR41/43 double knockout mouse model (GPR41/43KO). When GPR41/43KO mice were made hypertensive with a substance called angiotensin II (a common model of hypertension6), they had a more severe hypertensive phenotype compared to wildtype mice.5

 

The hypertensive GPR41/43KO mice also had higher gut permeability (aka ‘leaky gut’), which allows inflammatory substances into the circulation – such as lipopolysaccharides (LPS) from bacteria. A challenge in this study was measuring LPS, because its levels are usually very low. So, instead, we measure and then blocked its receptor, TLR4. When LPS/TLR4 signalling was blocked, there was no difference between hypertensive GPR41/43KO and wildtype mice. This suggests that the increase in gut leakiness and inflammatory bacterial LPS is linked to the worsened hypertensive phenotype we observed in the GPR41/43KO mice.5

 

To determine whether immune cells are responsible for the worsened phenotype in the GPR41/43KO mice, we transferred immune cells from GPR41/43KO to wildtype mice and vice-versa. We found that wildtype mice with GPR41/43KO immune cells had higher blood pressure compared to GPR41/43KO mice with wildtype immune cells. This confirms that expression of GPR41/43 in immune cells were protective in a hypertension setting.5

 

Finally, using data from ~300,000 people, we discovered that participants with genetic variants associated with higher expression of both GPR41 and GPR43 had lower prevalence of hypertension.5

 

The implications

 

Our findings suggest that host SCFA receptors are associated with hypertension and represent a gene-to-environment interaction that regulates blood pressure. In the past, we have focused only on manipulating the gut microbiome and SCFAs to lower blood pressure. We now have evidence that manipulating host receptors to gut microbial by products may be another option for hypertension treatment. This could be achieved by increasing activation of GPR41 and GPR43 using agonists (i.e., drugs that bind to and activate these receptors) and could represent a new class of medications for treatment of hypertension and other cardiovascular diseases.

 

Dr Rikeish R. Muralitharan and Prof Francine Marques


Monash University, Australia

Twitter: @rikeishm, @FZMarques

 

References:

1.            Marques, F. Z. et al. High-Fiber Diet and Acetate Supplementation Change the Gut Microbiota and Prevent the Development of Hypertension and Heart Failure in Hypertensive Mice. Circulation 135, 964-977 (2017).

2.            Kaye, D. M. et al. Deficiency of Prebiotic Fibre and Insufficient Signalling Through Gut Metabolite Sensing Receptors Leads to Cardiovascular Disease. Circulation 141, 1393-1403 (2020).

3.            Jama, H. A. et al. Prebiotic intervention with HAMSAB in untreated essential hypertensive patients assessed in a phase II randomized trial. Nature Cardiovascular Research 2, 35-43 (2023).

4.            R Muralitharan, R. & Marques, F. Z. Diet-related gut microbial metabolites and sensing in hypertension. J Hum Hypertens 35, 162-169 (2021).

5.            R. Muralitharan, R. et al. Gut Microbiota Metabolites Sensed by Host GPR41/43 Protect Against Hypertension. Circ Res (2025).

6.            Jama, H. A. et al. Rodent models of hypertension. Br J Pharmacol (2021).

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