Emulating the gut–liver axis: Dissecting the microbiome's effect on drug metabolism using multiorgan-on-chip models

Lucchetti, Mara; Kaminska, Mathilda; Aina, Kehinde Oluwasegun; Mosig, Alexander S.; Wilmes, Paul

doi:10.1016/j.coemr.2021.03.003

Cited by 19 publications

(10 citation statements)

References 57 publications

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“…Organon-chip models offer a way to circumvent some of the limitations of conventional organoid cultures. In most of the models, a porous membrane serves as a functionable cell culture substrate this is separating two channels and supporting cell growth by providing a scaffold for perfusion with cell culture medium and removal of cellular waste products [173][174][175][176][177].…”

Section: State-of-the-art Models To Study the Effects Of Scfasmentioning

confidence: 99%

Short chain fatty acids: key regulators of the local and systemic immune response in inflammatory diseases and infections

et al. 2023

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The human intestinal microbiome substantially affects human health and resistance to infections in its dynamic composition and varying release of microbial-derived metabolites. Short-chain fatty acids (SCFA) produced by commensal bacteria through fermentation of indigestible fibres are considered key regulators in orchestrating the host immune response to microbial colonization by regulating phagocytosis, chemokine and central signalling pathways of cell growth and apoptosis, thereby shaping the composition and functionality of the intestinal epithelial barrier. Although research of the last decades provided valuable insight into the pleiotropic functions of SCFAs and their capability to maintain human health, mechanistic details on how SCFAs act across different cell types and other organs are not fully understood. In this review, we provide an overview of the various functions of SCFAs in regulating cellular metabolism, emphasizing the orchestration of the immune response along the gut–brain, the gut–lung and the gut–liver axes. We discuss their potential pharmacological use in inflammatory diseases and infections and highlight new options of relevant human three-dimensional organ models to investigate and validate their biological functions in more detail.

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Section: State-of-the-art Models To Study the Effects Of Scfasmentioning

confidence: 99%

Short chain fatty acids: key regulators of the local and systemic immune response in inflammatory diseases and infections

et al. 2023

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“… 137 An example composite device is the gut-liver-on-a-chip, which, owing to the central role of the gut and liver in metabolism, has been proposed as a testing platform for drug toxicities and disease studies. 138,139 Other multi-organ devices involve the gut combination with the kidney, brain, and skin ( Table II lists example studies using these devices). Both single- and multi-organ-on-a-chip devices are envisioned to become game changers in the future, yet much work remains to be done in standardization and validation of the platform against benchmark methods.…”

Section: Applications Of Gut-on-a-chip Devicesmentioning

confidence: 99%

Gut-on-a-chip models for dissecting the gut microbiology and physiology

2023

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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. 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. 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. 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. 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. 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. 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.

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“…The intestinal epithelium is composed of specialized cells that are tightly connected to each other to form a permeable barrier 10 . Through the tightness of the intestinal epithelium the passage of harmful substances and microorganisms are blocked while essential nutrients can be absorped 11 . This barrier also plays a crucial role in the prevention of various diseases 12 .…”

Section: Introductionmentioning

confidence: 99%

Integration of multiple flexible electrodes for real-time detection of barrier formation with spatial resolution in a gut-on-chip system

Lucchetti,

Werr,

Johansson

et al. 2024

Microsyst Nanoeng

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In healthy individuals, the intestinal epithelium forms a tight barrier to prevent gut bacteria from reaching blood circulation. To study the effect of probiotics, dietary compounds and drugs on gut barrier formation and disruption, human gut epithelial and bacterial cells can be cocultured in an in vitro model called the human microbial crosstalk (HuMiX) gut-on-a-chip system. Here, we present the design, fabrication and integration of thin-film electrodes into the HuMiX platform to measure transepithelial electrical resistance (TEER) as a direct readout on barrier tightness in real-time. As various aspects of the HuMiX platform have already been set in their design, such as multiple compressible layers, uneven surfaces and nontransparent materials, a novel fabrication method was developed whereby thin-film metal electrodes were first deposited on flexible substrates and sequentially integrated with the HuMiX system via a transfer-tape approach. Moreover, to measure localized TEER along the cell culture chamber, we integrated multiple electrodes that were connected to an impedance analyzer via a multiplexer. We further developed a dynamic normalization method because the active measurement area depends on the measured TEER levels. The fabrication process and system setup can be applicable to other barrier-on-chip systems. As a proof-of-concept, we measured the barrier formation of a cancerous Caco-2 cell line in real-time, which was mapped at four spatially separated positions along the HuMiX culture area.

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Emulating the gut–liver axis: Dissecting the microbiome's effect on drug metabolism using multiorgan-on-chip models

Cited by 19 publications

References 57 publications

Short chain fatty acids: key regulators of the local and systemic immune response in inflammatory diseases and infections

Short chain fatty acids: key regulators of the local and systemic immune response in inflammatory diseases and infections

Gut-on-a-chip models for dissecting the gut microbiology and physiology

Integration of multiple flexible electrodes for real-time detection of barrier formation with spatial resolution in a gut-on-chip system

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