Organoids to Study Intestinal Nutrient Transport, Drug Uptake and Metabolism – Update to the Human Model and Expansion of Applications

Abstract

Intestinal transport and sensing processes and their interconnection to metabolism are relevant to pathologies such as malabsorption syndromes, inflammatory diseases, obesity and type 2 diabetes. Constituting a highly selective barrier, intestinal epithelial cells absorb, metabolize, and release nutrients into the circulation, hence serving as gatekeeper of nutrient availability and metabolic health for the whole organism. Next to nutrient transport and sensing functions, intestinal transporters including peptide transporter 1 (PEPT1) are involved in the absorption of drugs and prodrugs, including certain inhibitors of angiotensin-converting enzyme, protease inhibitors, antivirals, and peptidomimetics like β-lactam antibiotics. Here, we verify the applicability of 3D organoids for in vitro investigation of intestinal biochemical processes related to transport and metabolism of nutrients and drugs. Establishing a variety of methodologies including illustration of transporter-mediated nutrient and drug uptake and metabolomics approaches, we highlight intestinal organoids as robust and reliable tool in this field of research. Currently used in vitro models to study intestinal nutrient absorption, drug transport and enterocyte metabolism, such as Caco-2 cells or rodent explant models are of limited value due to their cancer and non-human origin, respectively. Particularly species differences result in poorly correlative data and findings obtained in these models cannot be extrapolated reliably to humans, as indicated by high failure rates in drug development pipelines. In contrast, human intestinal organoids represent a superior model of the intestinal epithelium and might help to implement the 3Rs (Reduction, Refinement and Replacement) principle in basic science as well as the preclinical and regulatory setup.

Organoids: a promising new in vitro platform in livestock and veterinary research

“…They found that the set of genes expressed in the organoids closely resembled that of the tissue of origin, including small intestine-specific genes, most of which were not expressed in the IPEC-J2 cells. Regarding nutrient uptake studies, mouse and human organoid models have been validated in a qualitative sense as valuable tool [ 117 ]. In a quantitative sense, studies would be needed to compare both expression of transporter proteins and actual nutrient transport kinetics with uptake kinetics of intestinal tissue measured in Ussing chambers [ 118 ] or with uptake kinetics measured in live (farm) animals [ 119 ].…”

Cerebral Organoids Derived from a Parkinson’s Patient Exhibit Unique Pathogenesis from Chikungunya Virus Infection When Compared to a Non-Parkinson’s Patient

“…Non-PD organoids had down-regulation of C3, which has been reported in patients with hepatitis C infection [ 93 ]. Functional expression of C3 is necessary to neutralize West Nile and other viruses which cause acute neurological infections and death [ 94 , 95 ]. This poses an important question to be addressed in future research: could a reduction in C3 leave patients with CHIKV disease primed for neurological sequalae?…”

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“…The past decade has seen rapid advances in bioengineering and the emergence of a new field of research focused on the development and application of MPSs, in vitro platforms of complex cell models in a microenvironment that mimics biochemical, electrical, and mechanical responses to model organ-level function. [3] , [4] , [5] These systems include organ-on-a-chip, organoid, and bioreactor models, with multiple human cell types under physical forces, such as fluid flow, interacting to create complex structures and reproduce biological activities, such as barrier function, [6] membrane transport, [7] neuronal network signaling, [8] , [9] thrombosis, [10] and metabolism. [11] , [12] …”