1. Introduction
A considerable number of studies have suggested the existence of
so-called Gut-Brain Axis (GBA), indicating that the gut environment
could affect the neurocognitive functions of the brain
(Dinan & Cryan, 2017;
Iannone et al., 2019). For example, an
increase in intestinal permeability may induce systemic immune
dysregulation, resulting in neuroinflammation
(Gorecki, Dunlop, Rodger, & Anderton,
2020), or changes in the dietary pattern contribute to psychiatric
conditions by altering the gut microbiota composition
(Sandhu et al., 2017). These responses
can be mediated by microbiome-produced molecules entering systemic
circulation across the gut, yet it remains unclear whether these
molecules reach brain sites directly or only induce central responses
via long-distance neural signaling
(Martin, Osadchiy, Kalani, & Mayer,
2018).
Due to its complexity, studies on GBA have mainly relied on in
vivo animal models (Raimondi et al.,
2020). They require experienced animal handling
(Maheshwari et al., 2018), feature poor
experimental reproducibility (Voelkl et
al., 2020), and real-time sensing of responses is difficult
(Zhang, Korolj, Lai, & Radisic, 2018).
Moreover, extrapolation of animal data to humans could be problematic,
leading to an increased need for in vitro experimental model for GBA
research. Recent advances in organ-on-a-chip technologies could be a
solution for such problems (Ma, Peng, Li,
& Chen, 2020; Wang et al., 2020).
Organ-on-a-chip is a technology that can simulate the physiological
environment and functionality of human organs on a chip to mimic the key
organotypic cellular architecture and functionality, 3D extracellular
matrix, biochemical factors, and biophysical cues at a smaller scale
(S. H. Lee & J. H. Sung, 2018;
Sung et al., 2018).
It is thought that the gut and the brain communicate via multiple
pathways, and one of the routes is based on the passage of soluble
microbial-derived products from the microbiota across the gut epithelium
and the blood-brain barrier (BBB) to reach the brain cells,
(Raimondi et al., 2020). The gut
epithelium protects the systemic circulation from harmful xenobiotic
compounds, and the BBB plays a vital role in maintaining the physical
and chemical homeostasis of the brain and protects the brain from
harmful molecules and pathogens in the blood
(Jiang, Li, Zheng, Li, & Huang, 2019;
Sharma et al., 2019;
Shimizu, Nishihara, & Kanda, 2018). Some
gut environment-originated substrates or membrane vesicles such as
exosomes may travel via the bloodstream to the BBB, and eventually exert
an influence on the brain (Fig. 1)
(Evrensel & Ceylan, 2015;
Haas-Neill & Forsythe, 2020;
Lauritzen et al., 2014;
McAllister et al., 2001;
Parker, Fonseca, & Carding, 2020).
In present work, we developed a modular GBA chip based on our previous
Gut-Liver chips (Lee, Ha, Choi, & Sung,
2017; S. Y. Lee & J. H. Sung, 2018).
This microfluidic device consists of two parts which are gut barrier
module (upper part) and BBB module (bottom part) (Fig. 2). We observed
of changes in barriers via measurement of trans-endothelial/epithelial
electrical resistance (TEER) and examined the delivery of exosomes
across the gut barrier to the BBB. As there is a lack of in vitro models
for the investigation of inter-organ communication of gut and brain
(Wang et al., 2020), our device could
give a chance to understand this complex system.