Genetic Approaches Using Zebrafish to Study the Microbiota-Gut-Brain Axis in Neurological Disorders

Abstract

The microbiota-gut-brain axis (MGBA) is a bidirectional signaling pathway mediating the interaction of the microbiota, the intestine, and the central nervous system. While the MGBA plays a pivotal role in normal development and physiology of the nervous and gastrointestinal system of the host, its dysfunction has been strongly implicated in neurological disorders, where intestinal dysbiosis and derived metabolites cause barrier permeability defects and elicit local inflammation of the gastrointestinal tract, concomitant with increased pro-inflammatory cytokines, mobilization and infiltration of immune cells into the brain, and the dysregulated activation of the vagus nerve, culminating in neuroinflammation and neuronal dysfunction of the brain and behavioral abnormalities. In this topical review, we summarize recent findings in human and animal models regarding the roles of the MGBA in physiological and neuropathological conditions, and discuss the molecular, genetic, and neurobehavioral characteristics of zebrafish as an animal model to study the MGBA. The exploitation of zebrafish as an amenable genetic model combined with in vivo imaging capabilities and gnotobiotic approaches at the whole organism level may reveal novel mechanistic insights into microbiota-gut-brain interactions, especially in the context of neurological disorders such as autism spectrum disorder and Alzheimer's disease.

Keywords: genetic approach; gnotobiotic; gut–brain axis; in vivo imaging; microbiota; zebrafish.

Figure 1

The bidirectional pathways of the microbiota–gut–brain axis (MGBA) involving the microbiota, the intestine, and the brain. Intestinal dysbiosis and derived metabolites in neuropathological conditions induce the barrier permeability defects and local inflammation with increased pro-inflammatory cytokines, MAMPs (e.g., LPS), and activation of immune cells in the gastrointestinal tract. These signaling mediators as well as microbial metabolites (e.g., SCFAs and Trp derivatives) and hormones (e.g., GLP-1, PYY) can distantly affect the brain function via the humoral pathway. In addition, dysregulated regulation of the vagus nerve can also directly modulate the brain function. Together, these MGBA pathways culminate in regulating neuroinflammation and neuronal defects of the brain and behavioral abnormalities. Refer to the text for details. 5-HT; 5-hydroxyltryptamine; LPS, lipopolysaccharides; MAMPs, microbe-associated molecular patterns; SCFAs, short chain fatty acids; Trp; tryptophan.

Figure 2

Key advantages of the zebrafish model for studying the MGBA. Refer to the text for details.