Intestinal Models for Personalized Medicine: from Conventional Models to Microfluidic Primary Intestine-on-a-chip

Abstract

Intestinal dysfunction is frequently driven by abnormalities of specific genes, microbiota, or microenvironmental factors, which usually differ across individuals, as do intestinal physiology and pathology. Therefore, it’s necessary to develop personalized therapeutic strategies, which are currently limited by the lack of a simulated intestine model. The mature human intestinal mucosa is covered by a single layer of columnar epithelial cells that are derived from intestinal stem cells (ISCs). The complexity of the organ dramatically increases the difficulty of faithfully mimicking in vivo microenvironments. However, a simulated intestine model will serve as an indispensable foundation for personalized drug screening. In this article, we review the advantages and disadvantages of conventional 2-dimensional models, intestinal organoid models, and current microfluidic intestine-on-a-chip (IOAC) models. The main technological strategies are summarized, and an advanced microfluidic primary IOAC model is proposed for personalized intestinal medicine. In this model, primary ISCs and the microbiome are isolated from individuals and co-cultured in a multi-channel microfluidic chip to establish a microengineered intestine device. The device can faithfully simulate in vivo fluidic flow, peristalsis-like motions, host-microbe crosstalk, and multi-cell type interactions. Moreover, the ISCs can be genetically edited before seeding, and monitoring sensors and post-analysis abilities can also be incorporated into the device to achieve high-throughput and rapid pharmaceutical studies. We also discuss the potential future applications and challenges of the microfluidic platform. The development of cell biology, biomaterials, and tissue engineering will drive the advancement of the simulated intestine, making a significant contribution to personalized medicine in the future. Graphical abstract The intestine is a primary organ for digestion, absorption, and metabolism, as well as a major site for the host-commensal microbiota interaction and mucosal immunity. The complexity of the organ dramatically increases the difficulty of faithfully mimicking in vivo microenvironments, though physiological 3-dimensional of the native small intestinal epithelial tissue has been well documented. An intestinal stem cells-based microfluidic intestine-on-a-chip model that faithfully simulate in vivo fluidic flow, peristalsis-like motions, host-microbe crosstalk, and multi-cell type interactions will make a significant contribution.

Role of Intestinal Microbes in Chronic Liver Diseases

“…The human intestine as well as liver organoids and their incorporation into more complex organoids-on-a-chip setups were developed [ 139 , 140 ]. Although the technology is still at a nascent stage, the field has already yielded some pivotal discoveries on the ways in which microbes contribute to health and disease [ 139 , 140 , 141 ]. Consequently, the combination of organoids and microbes will open new avenues for host-microbes co-metabolism research and can effectively address the major problems we have described above, such as highly variable microbes, unclear targets of metabolites, and unstable and prolonged clinical treatment of probiotics.…”

Gut-on-a-chip for disease models

“… 34 The epithelium incorporates enterocytes, goblet cells, enteroendocrine cells, tuft cells, Paneth cells and intestinal stem cells ( Figure 1 ). 14 , 35 Enterocytes are primarily responsible for nutrient absorption. Enteroendocrine cells secrete various gastrointestinal hormones.…”

“…The intestine is a complex ecosystem that contains a wide variety of microorganisms under anaerobic conditions. The human intestine contains approximately 10 14 microbial cells, including bacteria (the vast majority), viruses (5.8%), archaea (0.8%) and eukaryotes (0.5%). 43 The composition of the intestinal microbiota is influenced by host genetics, diet and environmental factors.…”

Toward Xeno-Free Differentiation of Human Induced Pluripotent Stem Cell-Derived Small Intestinal Epithelial Cells

“…Proper functionality of small intestinal epithelium is important in nutrition, but also in drug absorption and metabolism. Cell-based intestinal models, an alternative to animal models, have been widely utilized to investigate human small intestine functionality and in drug screening studies [1,2]. From among the currently used models, Caco-2, a colonic adenocarcinoma-derived immortal cell line, has been the gold standard for intestinal research for decades [3,4].…”