Cross-talk between microbiota-gut-brain axis and blood pressure regulation

Abstract

Hypertension, or high blood pressure (BP), is a widespread condition affecting one in three adults globally. Despite the availability of treatment options, 50% of hypertensive patients in countries such as Australia fail to achieve adequate BP control, often due to a lack of response to current therapies. Diet plays a crucial role in BP regulation. A high-fibre diet reduces BP through the gut microbiome and the production of microbial metabolites known as short-chain fatty acids (SCFAs). However, the mechanisms of BP regulation by SCFAs remained still unclear. A novel hypothesis we explore in this review is that these microbial metabolites may regulate BP via the activation of central mechanisms, a phenomenon called the gut-brain axis. While substantial evidence in animal models and humans supports the protective role of SCFAs in hypertension, the precise mechanisms remain unclear. SCFA stimulates the release of neurotransmitters and hormones such as serotonin, cholecystokinin, glucagon-like peptide 1 and peptide YY by enteroendocrine cells, a rare population of cells lining the gastrointestinal tract. These hormones bind to their receptors on the peripheral nervous system nerves, such as the vagus and spinal nerves, conveying information to the brain. The mechanisms by which information is relayed from the gut microbiome to the brain likely involve the immune system and gut-derived neurotransmitters and hormones. A deeper understanding of these pathways and mechanisms will facilitate the development of novel therapeutics for hypertension and other cardiovascular diseases.

Keywords: enteroendocrine cells; hypertension; microbiome; short-chain fatty acids; sympathetic nervous system; vagus nerve.

Figure 1. Multi-system interaction involved in gut–brain communication.

The pathways illustrated include neuroendocrine (blue), immune (yellow) and sympathetic nervous system (pink) pathways. In the outer mucosal layer of proximal colon, the digestion of dietary fibres by microbes lead to the production of the microbial metabolite short-chain fatty acids (SCFAs). SCFAs bind to receptors on enteroendocrine cells (EECs) in the gastrointestinal epithelium, resulting in the release of neurotransmitters stored in cytoplasmic granules in EECs. In the neuroendocrine pathway, neurotransmitters bind to their receptors on vagal and spinal afferents, allowing for transmission of signals to the brain. In the sympathetic nervous system pathway, the neurotransmitters are also released into the peripheral circulation. The increase in neurotransmitter signalling to the brain activates the paraventricular nucleus (PVN). The increase in PVN activity increases SNS signalling, thereby shifting the microbial environment and again stimulating the release of neurotransmitter via EECs. Immune cells such as T cells and B cells facilitate both the neuroendocrine and sympathetic nervous system pathway by acting as an intermediary cell in relaying signals from neurohormones released by EECs and enterochromaffin cells to vagus and spinal afferents and the blood circulation, respectively. Created with BioRender.com.

Figure 2. Future directions to delineate mechanisms by which SCFAs influence the gut–brain axis in hypertension.

This figure outlines proposed future research exploring the interactions between various receptors and cell types within the enteroendocrine, immune, and sympathetic nervous system pathways, with a focus on their role in hypertension. Targeted genetic manipulations, such as conditional knockout of specific cells in the gastrointestinal tract, will provide insights into the distinct contributions of these cells and their associated receptors in regulating food intake, blood pressure and immune function. As highlighted in this review, serotonin produced by enterochromaffin cells plays a key role in the gut–brain axis. Investigating how serotonin signalling through the 5HT3 receptor affects appetite and immune function – by using antagonists to inhibit serotonin production or knocking out serotonin receptors on immune cells – represents an important research direction. Additionally, examining the regulation of appetite and blood pressure will be critical for developing improved treatments for obesity and eating disorders. Denervation of the vagus and spinal nerves could help elucidate how neural signalling influences appetite regulation and metabolic processes. Moreover, cell-specific knockouts of receptors on these neural pathways will further reveal the importance of these receptors and their role in modulating gut-brain communication and hypertension. Created with BioRender.com