Gut Metabolites Acting on the Gut-Brain Axis: Regulating the Functional State of Microglia

Abstract

The gut-brain axis is a communication channel that mediates a complex interplay of intestinal flora with the neural, endocrine, and immune systems, linking gut and brain functions. Gut metabolites, a group of small molecules produced or consumed by biochemical processes in the gut, are involved in central nervous system regulation via the highly interconnected gut-brain axis affecting microglia indirectly by influencing the structure of the gut-brain axis or directly affecting microglia function and activity. Accordingly, pathological changes in the central nervous system are connected with changes in intestinal metabolite levels as well as altered microglia function and activity, which may contribute to the pathological process of each neuroinflammatory condition. Here, we discuss the mechanisms by which gut metabolites, for instance, the bile acids, short-chain fatty acids, and tryptophan metabolites, regulate the structure of each component of the gut-brain axis, and explore the important roles of gut metabolites in the central nervous system from the perspective of microglia. At the same time, we highlight the roles of gut metabolites affecting microglia in the pathogenesis of neurodegenerative diseases and neurodevelopmental disorders. Understanding the relationship between microglia, gut microbiota, neuroinflammation, and neurodevelopmental disorders will help us identify new strategies for treating neuropsychiatric disorders.

Figure 1.

Gut metabolites regulate the permeability and integrity of the GBB. GBB is thought to be a significant link in the gut-brain axis, which controls metabolites from the gut via the blood to the brain. Some intestinal metabolites regulate the status of microglia indirectly by changing the integrity and permeability of the GBB, thereby affecting the communication between the gut and the brain. Abbreviation: SCFAs, short-chain fatty acid. LPS, lipopolysaccharide. (Figure created with Biorender.com).

Figure 2.

Gut metabolites regulate the permeability and integrity of the BBB. The BBB inhibits the passage of most molecules produced by microbes from circulation into the CNS. Metabolites can alter the integrity of the BBB, thereby increasing translocation and permeability, making the barrier function of the BBB decrease. At the same time, changing the integrity and permeability of the blood-brain barrier will affect the function of microglia. (Figure created with Biorender.com).

Figure 3.

Gut metabolites regulate vagus function and state. The VN is a crucial part of the gut-brain axis, connecting the enteric nervous system with the CNS. Communication between the gut and the brain is closely connected with the function and signaling of the VN. In the gut, many bacterial metabolites can act as signaling molecules to directly regulate vagal nerve activity or indirectly affect vagal nerve function. Ultimately, the phenotype of microglia is altered Abbreviation: SCFAs, short-chain fatty acid. 5-HT, 5-hydroxytryptamine. GABA, γ-aminobutyric acid. H2S, Hydrogen sulfide. (Figure created with Biorender.com).