Duodenum Intestine-Chip for preclinical drug assessment in a human relevant model

Abstract

Induction of intestinal drug metabolizing enzymes can complicate the development of new drugs, owing to the potential to cause drug-drug interactions (DDIs) leading to changes in pharmacokinetics, safety and efficacy. The development of a human-relevant model of the adult intestine that accurately predicts CYP450 induction could help address this challenge as species differences preclude extrapolation from animals. Here, we combined organoids and Organs-on-Chips technology to create a human Duodenum Intestine-Chip that emulates intestinal tissue architecture and functions, that are relevant for the study of drug transport, metabolism, and DDI. Duodenum Intestine-Chip demonstrates the polarized cell architecture, intestinal barrier function, presence of specialized cell subpopulations, and in vivo relevant expression, localization, and function of major intestinal drug transporters. Notably, in comparison to Caco-2, it displays improved CYP3A4 expression and induction capability. This model could enable improved in vitro to in vivo extrapolation for better predictions of human pharmacokinetics and risk of DDIs.

Is it Time for Reviewer 3 to Request Human Organ Chip Experiments Instead of Animal Validation Studies?

“…Small Intestine Chips lined by cells isolated from patientderived organoids have been used to study induction of CYP450 metabolizing enzymes that can complicate the development of new drugs, and provide insight into the molecular and cellular basis of drug-drug interactions that can cause changes in drug PK, safety, and efficacy. [28] Relative to animal models, Small Intestine Chips better mimic infection by enteric viruses [29] and intestinal injuries induced by acute exposure to -radiation (including dosage sensitivities and responses to countermeasure therapies) exhibited by humans as well. [30] Additional Small Intestine Chip studies showed that probiotic and antibiotic therapies can prevent villus injury induced by pathogenic bacteria, and this led to identification of four proin-flammatory cytokines (IL-8, IL-6, IL-1 , TNF-) elicited by LPS endotoxin and human immune cells that are necessary and sufficient to compromise intestinal barrier function.…”

“…[30] Additional Small Intestine Chip studies showed that probiotic and antibiotic therapies can prevent villus injury induced by pathogenic bacteria, and this led to identification of four proin-flammatory cytokines (IL-8, IL-6, IL-1 , TNF-) elicited by LPS endotoxin and human immune cells that are necessary and sufficient to compromise intestinal barrier function. [25] Interestingly, use of mechanically active Organ Chips also revealed that cessation of mechanical peristalsis-like motions stimulates overgrowth of bacteria, [26][27][28] as seen in patients with ileus and inflammatory bowel disease (IBD). Moreover, similar results were obtained using a human Colon Chip, which showed that peristalsis-like mechanical deformations influence infection by the human pathogen Shigella.…”

Effects of Human Milk Oligosaccharides on the Adult Gut Microbiota and Barrier Function

“…Organoid-derived primary epithelial cells are cultured on top of an extracellular matrix protein-coated porous membrane, and primary intestinal microvascular endothelial cells are cultured in the vascular channel. Cyclic stretch is applied to the membrane, recreating in vivo relevant mechanical forces that emulate intestinal tissue functions and architecture [49]. A tight epithelial monolayer was established in the Colon Intestine Chips, on day 2 post seeding, as indicated by the apparent permeability of FD4 (<0.5 × 10 −6 cm/s) [50] ( Figure S8A,B).…”

Robust Formation of an Epithelial Layer of Human Intestinal Organoids in a Polydimethylsiloxane-Based Gut-on-a-Chip Microdevice

“…Indeed, it has been observed that the commercially available intestinal cell lines are robust enough to adhere, after a simple pretreatment of the hydrophobic PDMS surface (5,7,8,36), compared to the organoid-derived epithelial cells ( Table 1). While some reports demonstrated the microfluidic cultures of the intestinal organoid-derived epithelium (17)(18)(19)(20)(21)(22)(23), it has been elusive to define a reliable and reproducible protocol for robust surface activation of a PDMS microchannel because of the limited quantitative information from the published works. Thus, a systematic optimization of the method that allows a robust surface activation, stable ECM coating, and strong attachment of the organoid-derived intestinal epithelium is an unmet need for holistic applications to various PDMS-based MPS models that deploy organoid-derived cells.…”