Mechanisms of Short-Chain Fatty Acids Derived from Gut Microbiota in Alzheimer's Disease

Abstract

Short-chain fatty acids (SCFAs) are important metabolites derived from the gut microbiota through fermentation of dietary fiber. SCFAs participate a number of physiological and pathological processes in the human body, such as host metabolism, immune regulation, appetite regulation. Recent studies on gut-brain interaction have shown that SCFAs are important mediators of gut-brain interactions and are involved in the occurrence and development of many neurodegenerative diseases, including Alzheimer's disease. This review summarizes the current research on the potential roles and mechanisms of SCFAs in AD. First, we introduce the metabolic distribution, specific receptors and signaling pathways of SCFAs in human body. The concentration levels of SCFAs in AD patient/animal models are then summarized. In addition, we illustrate the effects and mechanisms of SCFAs on the cognitive level, pathological features (Aβ and tau) and neuroinflammation in AD. Finally, we analyze the translational value of SCFAs as potential therapeutic targets for the treatment of AD.

Keywords: Alzheimer's disease; gut microbiota; short-chain fatty acids.

Figure 1.

An integral view of the cellular signal transduction pathway of SCFAs. Short-chain fatty acids (SCFAs) affect biological functions through two main pathways. They can bind G protein-coupled receptors on the surface of cell membranes (including GPR41, GPR43, and GPR109) to activate downstream NF-κB, MAPKs, and other signaling pathways. They can also enter cells through MCTs on the cell surface and participate in inhibiting HDACs or promoting HATs to regulate gene transcription. GPR, G protein-coupled receptor; NF-κB, nuclear factor-κB; MAPKs, mitogen-activated protein kinases; MCTs, monocarboxylate transporters; HDACs, histone deacetylases; HATs, histone acetyltransferases

Figure 2.

Overview of the effects of SCFAs in Alzheimer's disease. SCFAs from the gut microbiota enter the CNS by crossing the blood-brain barrier. They act on neurons to promote neuronal repair and regeneration through upregulation of the CREB/BDNF signaling pathway and expression of memory-consolidation genes. In addition, the secretion of inflammatory factors is reduced by inhibiting the MAPK, NF-κB, and other pathways in disease-related microglia and astrocytes with proinflammatory effects. SCFAs also participate in the pathological regulation of Aβ and tau proteins, ultimately ameliorating cognitive impairment in AD. CREB, cyclic-AMP response element binding protein; BDNF, brain-derived neurotrophic factor; NF-κB, nuclear factor-κB; MAPK, mitogen-activated protein kinase