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      Recent advances in biofabricated gut models to understand the gut-brain axis in neurological diseases

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          Abstract

          Increasing evidence has accumulated that gut microbiome dysbiosis could be linked to neurological diseases, including both neurodegenerative and psychiatric diseases. With the high prevalence of neurological diseases, there is an urgent need to elucidate the underlying mechanisms between the microbiome, gut, and brain. However, the standardized aniikmal models for these studies have critical disadvantages for their translation into clinical application, such as limited physiological relevance due to interspecies differences and difficulty interpreting causality from complex systemic interactions. Therefore, alternative in vitro gut–brain axis models are highly required to understand their related pathophysiology and set novel therapeutic strategies. In this review, we outline state-of-the-art biofabrication technologies for modeling in vitro human intestines. Existing 3D gut models are categorized according to their topographical and anatomical similarities to the native gut. In addition, we deliberate future research directions to develop more functional in vitro intestinal models to study the gut–brain axis in neurological diseases rather than simply recreating the morphology.

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          Most cited references163

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          Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche.

          The intestinal epithelium is the most rapidly self-renewing tissue in adult mammals. We have recently demonstrated the presence of about six cycling Lgr5(+) stem cells at the bottoms of small-intestinal crypts. Here we describe the establishment of long-term culture conditions under which single crypts undergo multiple crypt fission events, while simultanously generating villus-like epithelial domains in which all differentiated cell types are present. Single sorted Lgr5(+) stem cells can also initiate these cryptvillus organoids. Tracing experiments indicate that the Lgr5(+) stem-cell hierarchy is maintained in organoids. We conclude that intestinal cryptvillus units are self-organizing structures, which can be built from a single stem cell in the absence of a non-epithelial cellular niche.
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            Gut Microbiota Regulate Motor Deficits and Neuroinflammation in a Model of Parkinson's Disease.

            The intestinal microbiota influence neurodevelopment, modulate behavior, and contribute to neurological disorders. However, a functional link between gut bacteria and neurodegenerative diseases remains unexplored. Synucleinopathies are characterized by aggregation of the protein α-synuclein (αSyn), often resulting in motor dysfunction as exemplified by Parkinson's disease (PD). Using mice that overexpress αSyn, we report herein that gut microbiota are required for motor deficits, microglia activation, and αSyn pathology. Antibiotic treatment ameliorates, while microbial re-colonization promotes, pathophysiology in adult animals, suggesting that postnatal signaling between the gut and the brain modulates disease. Indeed, oral administration of specific microbial metabolites to germ-free mice promotes neuroinflammation and motor symptoms. Remarkably, colonization of αSyn-overexpressing mice with microbiota from PD-affected patients enhances physical impairments compared to microbiota transplants from healthy human donors. These findings reveal that gut bacteria regulate movement disorders in mice and suggest that alterations in the human microbiome represent a risk factor for PD.
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              Microfluidic organs-on-chips.

              An organ-on-a-chip is a microfluidic cell culture device created with microchip manufacturing methods that contains continuously perfused chambers inhabited by living cells arranged to simulate tissue- and organ-level physiology. By recapitulating the multicellular architectures, tissue-tissue interfaces, physicochemical microenvironments and vascular perfusion of the body, these devices produce levels of tissue and organ functionality not possible with conventional 2D or 3D culture systems. They also enable high-resolution, real-time imaging and in vitro analysis of biochemical, genetic and metabolic activities of living cells in a functional tissue and organ context. This technology has great potential to advance the study of tissue development, organ physiology and disease etiology. In the context of drug discovery and development, it should be especially valuable for the study of molecular mechanisms of action, prioritization of lead candidates, toxicity testing and biomarker identification.
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                Author and article information

                Contributors
                Journal
                Front Med Technol
                Front Med Technol
                Front. Med. Technol.
                Frontiers in Medical Technology
                Frontiers Media S.A.
                2673-3129
                14 September 2022
                2022
                : 4
                : 931411
                Affiliations
                [ 1 ]School of Interdisciplinary Bioscience and Bioengineering, Pohang University of Science and Technology (POSTECH) , Pohang, South Korea
                [ 2 ]Department of Mechanical Engineering, Pohang University of Science and Technology (POSTECH), Pohang, South Korea
                [ 3 ]Department of Convergence IT Engineering, Pohang University of Science and Technology (POSTECH), Pohang, South Korea
                [ 4 ]Institute of Convergence Science, Yonsei University , Seoul, South Korea
                Author notes

                Edited by: Pedro Morouço, Polytechnic Institute of Leiria, Portugal

                Reviewed by: Anna-Maria Pappa, Khalifa University, United Arab Emirates Wei Long Ng, Nanyang Technological University, Singapore

                [* ] Correspondence: Jinah Jang jinahjang@ 123456postech.ac.kr

                Specialty Section: This article was submitted to Regenerative Technologies, a section of the journal Frontiers in Medical Technology

                Article
                10.3389/fmedt.2022.931411
                9515506
                5631cfdd-625f-449b-ba37-bad69b1eb2fc
                © 2022 Han and Jang.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 29 April 2022
                : 22 August 2022
                Page count
                Figures: 5, Tables: 0, Equations: 0, References: 164, Pages: 0, Words: 0
                Funding
                Funded by: Basic Science Research Program through the National Research Foundation of South Korea (NRF), doi 10.13039/501100014188;
                Award ID: 2020R1A6A1A03047902
                Funded by: National Research Foundation of South Korea (NRF) grant funded by the Ministry of Science and ICT, doi 10.13039/100007431;
                Award ID: 2021R1A2C2004981
                Categories
                Medical Technology
                Review

                gut-brain axis,neurological disease,enteroendocrine function,biofabrication,in vitro gut models

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