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.