Biology subjects

Peh, A.

Publications and source records attributed to Peh, A..

3 recordsLinked to original sources

bioRxiv2023

Dietary fibre reverses adverse post-stroke outcomes in mice via short-chain fatty acids and its sensing receptors GPR41, GPR43 and GPR109A

Dietary fibre intake is associated with fewer cases of ischaemic stroke. This is likely via the microbiota-gut-brain axis, where fibre is fermented by the gut microbiota, releasing short-chain fatty acids (SCFAs). However, whether fibre or SCFAs can reverse adverse post-stroke outcomes remains unknown. Here, we demonstrated that a low fibre diet exacerbates post-stroke outcomes in mice. This was reversed by a high fibre diet or direct supplementation with SCFAs (delivered either in the water or a high SCFA-releasing diet) immediately after stroke. These modulated the gut microbiome and improved the gut epithelial barrier integrity, which was associated with fewer activated neutrophils and more neuroblast cells in the brain. We then investigated the SCFA-receptors GPR41/43/109A using a triple knockout mouse model, which exhibited poorer stroke outcomes and recovery. These results show that post-stroke interventions using dietary fibre and/or SCFA supplementation, acting via GPR41/43/109A signalling, may represent new therapeutic strategies for stroke-induced brain injury.

neuroscience↗

bioRxiv2023

Gut bacteria translocation to the brain after ischaemic stroke occurs via the sympathetic nervous system

We provide evidence that stroke-induced gut breakdown results in bacteria translocation to the ischaemic mouse brain. Inhibition of sympathetic tone reduced bacterial load in the post-stroke brain and reduced functional deficits without altering cerebral apoptosis, neuroinflammation or infarct volume. These findings indicate that the activation of the sympathetic nervous system after stroke promotes gut-derived bacteria to enter to the brain, and this process worsens motor function in mice. Abstract Figure O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=106 SRC="FIGDIR/small/535309v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@1e78ca0org.highwire.dtl.DTLVardef@c1886forg.highwire.dtl.DTLVardef@1e45ae1org.highwire.dtl.DTLVardef@10aa224_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2022

Dietary fibre controls blood pressure and cardiovascular risk by lowering large intestinal pH and activating the proton-sensing receptor GPR65

High blood pressure (BP) is the most common cause of death globally, due to increasing the risk of cardiovascular diseases. Dietary fiber regulates BP through gut microbial production of acidic metabolites known as short-chain fatty acids (SCFAs). The specific mechanisms of how SCFAs regulate BP are still emerging. In a phenome-wide association study, we identified that the proton-sensing G-protein-coupled receptor GPR65 gene is associated with hypertension and its associated end-organ damage phenotypes. We hypothesized that acidic metabolites produced from the gut microbiota may activate GPR65, thus conferring BP regulating effects. We found that dietary fiber levels determined the luminal and interstitial tissue pH in the large intestine through production of SCFAs by the gut microbiota. We identified that low pH produced by high fiber intake, acting via GPR65 signaling, increased cAMP production and phosphorylation of CREB, and restricted the production of hypertension-promoting inflammatory cytokines by CD8+ T cells. Gpr65-/- mice spontaneously developed higher BP, cardiac and renal hypertrophy and fibrosis. We showed that the benefits of a diet high in fiber, which prevented hypertension and associated end-organ damage, were decreased in Gpr65-/- mice. Finally, adoptive transfers revealed that GPR65 deficiency in CD8+ T cells causally explained this phenotype. In conclusion, we showed that pH sensing by GPR65 in CD8+ T cells mediates much of the cardiovascular benefits of dietary fiber. pH sensing represents a novel gene-by-environment interaction of gut microbiota-to-host biological effects and may form the basis for new therapeutic strategies for hypertension.

molecular biology↗