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.

Host tp53 mutation induces gut dysbiosis eliciting inflammation through disturbed sialic acid metabolism

“…Another important factor implicated in both intestinal inflammation and CRC is the commensal microbiota that colonizes the intestine [ 17 ]. The commensal microbiota is known to play an essential role not only in the development, metabolism, and immunity of the host under physiological conditions but is also involved in a variety of inflammatory, metabolic, and neurological diseases when microbiota symbiosis is disrupted, known as microbiota dysbiosis [ 18 – 22 ]. In particular, such intestinal dysbiosis has been strongly implicated in the pathogenesis of IBD in both human and mouse models [ 23 – 25 ] and in CRC, including CAC [ 26 – 32 ].…”

The microbiota promotes social behavior by modulating microglial remodeling of forebrain neurons

“…The neurodevelopmental processes that build social behavior across taxa are poorly understood. Our study reveals microbial modulation of social behavior in a model vertebrate well-suited to simultaneous study of the microbiota, brain, and immune system [93], and provides the first in-depth look at how interactions among these components modulate circuit formation and maintenance, and behavior.…”

The microbiota‐gut‐brain axis and epilepsy from a multidisciplinary perspective: Clinical evidence and technological solutions for improvement of in vitro preclinical models

“…In an extensive review focused on the Zebrafish use to study the MGB axis, three key advantages have been highlighted: (1) the possibility to perform genetic manipulation with zebrafish model being an ideal system to apply recent genome‐editing technology; (2) the suitability for live in vivo imaging of host–bacteria interactions to monitor the spatial and temporal activities of immune‐signaling components by exploiting the optical transparency of the transgenic zebrafish embryo throughout its development; (3) the existence of well‐established protocols for germ‐free experiments 64 . Moreover, Zebrafish and human microbiomes are known to have similar abundances of functional pathways despite substantial disparities in taxonomic composition 65 .…”