GPR41/43 regulates blood pressure by improving gut epithelial barrier integrity to prevent TLR4 activation and renal inflammation

Abstract

Fermentation of dietary fibre by the gut microbiota leads to the production of metabolites called short-chain fatty acids (SCFAs), which have emerged as potent regulators of immune, metabolic, and tissue barrier functions. More recently, a high fibre diet and SCFA supplementation were shown to lower blood pressure and be cardio-protective. SCFAs activate host signalling responses via the receptors GPR41 and GPR43, which have redundancy in their signalling pathways. Whether these receptors play a role in hypertension or mediate the cardio-protective effects of fibre remains unknown. Using an experimental model that lacks both GPR41 and GPR43, we show that lack of signalling via these receptors increases risk to high blood pressure and leads to cardiorenal fibrosis and hypertrophy. Moreover, we demonstrate that GPR41/43 signalling is essential in maintaining gut epithelial barrier, which prevents the translocation of the bacterial toxins lipopolysaccharides (LPS) from entering the peripheral circulation. In the absence of GPR41/43, this is accompanied by macrophage infiltration to the kidneys, resulting in pro-inflammatory cytokine production. Using an antagonist against the LPS receptor, TLR4, a potent pro-inflammatory signalling pathway, we were able to rescue the cardiovascular phenotype in GPR41/43 knockout mice. We also demonstrate that GPR41/43 are, at least partially, responsible for the blood pressure-lowering and cardio-protective effects of a high fibre diet; however, improvements of gut barrier integrity and macrophages in the kidney were independent of GPR41/43 signalling. Finally, using the UK Biobank, we provide translational evidence that variants associated with lower expression of both GPR41/43 are more prevalent in hypertensive patients. Our findings highlight that lack of SCFA-receptor signalling via both GPR41/43 increases risk of high blood pressure, suggesting these receptors could be targeted as a new treatment.

Prospects for Leveraging the Microbiota as Medicine for Hypertension

“…88 Indeed, blockage of TLR4 reduces BP in the SHR and in the angiotensin II model, including in knockout mice that lack receptors to sense SCFAs, which are fundamental for maintaining the gut epithelial barrier intact. 28,90 Studies in experimental models of hypertension suggest that the intestinal barrier is disrupted, with higher passage of fluorescein isothiocyanate dextran from the gut to the host's circulation and lower levels of tight junction proteins that maintain epithelial cells together and reduce the passage of lipopolysaccharide, as observed in the SHR relative to WKY (Wistar Kyoto) rats, but only after hypertension is established. 91 Studies in human hypertension remain less conclusive, as only biomarkers (eg, zonulin and lipopolysaccharide) have been measured, and recent literature points to doubts about their accuracy.…”