34,35 An improvement to the 2D in vitro modeling has been 3D organoids, which leverage the differentiation and self-organization ability of stem cells to construct organ-mimicking tissues. 34,35 These models, however, have shown poor correlation to real tissue physiology due to their planar geometry. 32,33 The conventional form of in vitro models has been 2D models such as well-plates and Petri dishes, whereby host cells and bacteria are cocultured on a planar surface. 28,31Īlternative to in vivo approaches has been in vitro strategies that have been developed to build organ mimicries that can be conveniently investigated in the lab in cheaper and more accessible manners. 27–30 Most importantly, animals differ from humans in various physiological aspects such as their microbiome composition. 26 Animal models benefit from less strict experimentation protocols compared to humans, but they have major disadvantages due to their high cost, ethical issues, and the lack of high-quality real-time visualization capabilities. 22–25 Moreover, fecal samples provide little information about the spatial variation of microbiota across the intestine. 19–21 Analyzing the human microbiome has been conducted by sequencing fecal samples, but these are not representative of the entire gut microbial population, as many bacteria live in hardly accessible zones in the form of surface-attached communities, termed biofilms, inside the intestine. 18 Among various methods, direct experimentation on human subjects has been proven to be difficult due to the inaccessibility of the GI tract, and imaging techniques such as colonoscopy have been invasive and lacked cellular-level resolution. The eminent role of the gut in health and diseases has aroused tremendous interest among the scientific community in deciphering the gut's physiological complexities over the past decades however, one of the major stumbling blocks in these attempts has been the limitations of conventional experimental techniques. 8,9 The disruption of the gut barrier has been linked to various diseases, including gastrointestinal (GI) diseases, such as inflammatory bowel disease (IBD) and colorectal cancer, 10,11 in addition to non-GI diseases as versatile as cancer, diabetes, obesity, asthma, cardiovascular diseases, and respiratory infections such as COVID-19. 7 A notable example of such roles is microbial and epithelial barrier functions, which are essential for maintaining homeostasis, establishing a bidirectional relationship with immune cells, and protecting the body against pathogenic attacks. 6 In addition to food digestion, the gut and its microbiome have broad roles in health regulation and disease prevention. 2 Being equipped with special enzymatic capacity, intestinal enterocytes are able to digest a variety of compounds such as amino acids, peptides, polysaccharides, and xenobiotics, 3–5 and benefiting from a unique metabolic diversity, the microbiome maximizes the digestion by breaking down complex carbohydrates and vitamins. 1 The most well-known function of the gut is the digestion of food and absorption of nutrients. The human gut is one of the critical organs with important biological functions orchestrated by human intestinal cells and a rich microbial consortium, known as the gut microbiome. We then elaborate on different approaches that have been adopted to model key physiochemical stimuli and explore how these models have been beneficial to understanding gut pathophysiology and testing therapeutic interventions. In this review, we outline various gut-on-a-chip designs, particularly focusing on different configurations used to coculture the microbiome and various human intestinal cells. Accordingly, the excellent organ mimicry offered by gut-on-a-chips has fueled numerous investigations on the clinical and industrial applications of these devices in recent years. A myriad of studies has demonstrated that gut-on-a-chip models reinforce a prolonged coculture of microbiota and human cells with genotypic and phenotypic responses that closely mimic the in vivo data. This research has led to innovative approaches to model fluid flow, mechanical forces, and oxygen gradients, which are all important developmental cues of the gut physiological system. Among these attempts, an important research front has focused on simulating the physiology of the gut, an organ with a distinct cellular composition featuring a plethora of microbial and human cells that mutually mediate critical body functions. ![]() Microfluidic technologies have been extensively investigated in recent years for developing organ-on-a-chip-devices as robust in vitro models aiming to recapitulate organ 3D topography and its physicochemical cues.
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