Figure 5.

Illustration of the possible routes via which short-chain fatty acids (SCFAs) can influence brain function. These acids are taken up by colonocytes and other cells using either H±dependent or sodium-dependent monocarboxylate transporters, or by binding to G protein-coupled receptors. Once inside cells, SCFAs can either inhibit histone deacetylases, leading to more active chromatin and gene expression, or boost histone acetyltransferase activity, resulting in histone acetylation and gene expression. SCFAs affect the gut-brain axis and brain function through diverse pathways including humoral, immune, endocrine, and vagal routes. Through the humoral path, SCFAs can traverse the BBB using monocarboxylate transporters on endothelial cells, influencing the barrier’s integrity by increasing tight junction protein expression. Immunologically, SCFAs impact gut mucosal immunity by activating FFARs or hindering histone deacetylation. They strengthen intestinal barrier integrity by upregulating tight junction proteins and increasing transepithelial electrical resistance. SCFAs also regulate immune cells such as neutrophils, dendritic cells, macrophages, monocytes, and T cells, maintaining bodily balance. Endocrinologically, SCFAs interact with receptors on enteroendocrine cells, triggering the release of hormones like GLP1 and PYY, which signal the brain indirectly via systemic circulation or vagal pathways. They also directly signal the brain through the vagal route. Created with BioRender.com