{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T19:09:39Z","timestamp":1782328179236,"version":"3.54.5"},"reference-count":47,"publisher":"AIP Publishing","issue":"2","funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["NINDS\/NIA R03-NS118156"],"award-info":[{"award-number":["NINDS\/NIA R03-NS118156"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["NCCIH R21-AT010933"],"award-info":[{"award-number":["NCCIH R21-AT010933"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["NIEHS P30-ES023513"],"award-info":[{"award-number":["NIEHS P30-ES023513"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["NIBIB R01-EB034279"],"award-info":[{"award-number":["NIBIB R01-EB034279"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000001","name":"National Science Foundation","doi-asserted-by":"publisher","award":["DMR-2003849"],"award-info":[{"award-number":["DMR-2003849"]}],"id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000001","name":"National Science Foundation","doi-asserted-by":"publisher","award":["DGE-2152260"],"award-info":[{"award-number":["DGE-2152260"]}],"id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007707","name":"University of California, Davis","doi-asserted-by":"publisher","award":["College of Engineering Next Level Research Seed Funding"],"award-info":[{"award-number":["College of Engineering Next Level Research Seed Funding"]}],"id":[{"id":"10.13039\/100007707","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["pubs.aip.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2025,3,1]]},"abstract":"<jats:p>The gut\u2013brain axis (GBA) connects the gastrointestinal tract and the central nervous system (CNS) via the peripheral nervous system and humoral (e.g., circulatory and lymphatic system) routes. The GBA comprises a sophisticated interaction between various mammalian cells, gut microbiota, and systemic factors. This interaction shapes homeostatic and pathophysiological processes and plays an important role in the etiology of many disorders including neuropsychiatric conditions. However, studying the underlying processes of GBA in vivo, where numerous confounding factors exist, is challenging. Furthermore, conventional in vitro models fall short of capturing the GBA anatomy and physiology. Microfluidic platforms with integrated sensors and actuators are uniquely positioned to enhance in vitro models by representing the anatomical layout of cells and allowing to monitor and modulate the biological processes with high spatiotemporal resolution. Here, we first briefly describe microfluidic technologies and their utility in modeling the CNS, vagus nerve, gut epithelial barrier, blood\u2013brain barrier, and their interactions. We then discuss the challenges and opportunities for each model, including the use of induced pluripotent stem cells and incorporation of sensors and actuator modalities to enhance the capabilities of these models. We conclude by envisioning research directions that can help in making the microfluidics-based GBA models better-suited to provide mechanistic insight into pathophysiological processes and screening therapeutics.<\/jats:p>","DOI":"10.1063\/5.0253041","type":"journal-article","created":{"date-parts":[[2025,3,7]],"date-time":"2025-03-07T15:05:09Z","timestamp":1741359909000},"update-policy":"https:\/\/doi.org\/10.1063\/aip-crossmark-policy-page","source":"Crossref","is-referenced-by-count":3,"title":["Microfluidic tools to model, monitor, and modulate the gut\u2013brain axis"],"prefix":"10.1063","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-3949-7277","authenticated-orcid":false,"given":"Hyehyun","family":"Kim","sequence":"first","affiliation":[{"name":"Department of Biomedical Engineering, University of California\u2014Davis 1 , Davis, California 95616,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-8437-4313","authenticated-orcid":false,"given":"Gregory","family":"Girardi","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, University of California\u2014Davis 1 , Davis, California 95616,","place":["USA"]},{"name":"U.S. Naval Research Laboratory 2 , Washington, D.C. 20375,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-4455-1509","authenticated-orcid":false,"given":"Allison","family":"Pickle","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, University of California\u2014Davis 1 , Davis, California 95616,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6513-8922","authenticated-orcid":false,"given":"Testaverde S.","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, University of California\u2014Davis 1 , Davis, California 95616,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2401-3562","authenticated-orcid":false,"given":"Erkin","family":"Seker","sequence":"additional","affiliation":[{"name":"Department of Electrical and Computer Engineering, University of California\u2014Davis 3 , Davis, California 95616,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"317","published-online":{"date-parts":[[2025,3,7]]},"reference":[{"issue":"10","key":"2025032117565657900_c1","doi-asserted-by":"publisher","first-page":"625","DOI":"10.1038\/s41575-018-0062-1","article-title":"The metabolic role of vagal afferent innervation","volume":"15","year":"2018","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"issue":"3","key":"2025032117565657900_c2","doi-asserted-by":"publisher","first-page":"1162","DOI":"10.1021\/ac802579z","article-title":"Microfluidic perfusion system for automated delivery of temporal gradients to islets of Langerhans","volume":"81","year":"2009","journal-title":"Anal. Chem."},{"issue":"20","key":"2025032117565657900_c3","doi-asserted-by":"publisher","first-page":"3961","DOI":"10.1039\/D2LC00683A","article-title":"Influence of microchannel geometry on device performance and electrophysiological recording fidelity during long-term studies of connected neural populations","volume":"22","year":"2022","journal-title":"Lab Chip"},{"issue":"6726","key":"2025032117565657900_c4","doi-asserted-by":"publisher","first-page":"1146","DOI":"10.1126\/science.adn2600","article-title":"Active-reset protein sensors enable continuous in vivo monitoring of inflammation","volume":"386","year":"2024","journal-title":"Science"},{"issue":"12","key":"2025032117565657900_c5","doi-asserted-by":"publisher","first-page":"2165","DOI":"10.1039\/c2lc40074j","article-title":"Human gut-on-a-chip inhabited by microbial flora that experiences intestinal peristalsis-like motions and flow","volume":"12","year":"2012","journal-title":"Lab Chip"},{"issue":"7","key":"2025032117565657900_c6","doi-asserted-by":"publisher","first-page":"7142","DOI":"10.1021\/acs.chemrev.1c00480","article-title":"Emerging roles of microfluidics in brain research: From cerebral fluids manipulation to brain-on-a-chip and neuroelectronic devices engineering","volume":"122","year":"2022","journal-title":"Chem. Rev."},{"issue":"9","key":"2025032117565657900_c7","doi-asserted-by":"publisher","first-page":"e13724","DOI":"10.1111\/cpr.13724","article-title":"Advances in gut\u2013brain organ chips","volume":"57","year":"2024","journal-title":"Cell Proliferation"},{"key":"2025032117565657900_c8","doi-asserted-by":"publisher","DOI":"10.3389\/fmedt.2022.931411","article-title":"Recent advances in biofabricated gut models to understand the gut-brain axis in neurological diseases","volume":"4","year":"2022","journal-title":"Front. Med. Technol."},{"issue":"4","key":"2025032117565657900_c9","doi-asserted-by":"publisher","first-page":"915","DOI":"10.1016\/j.cell.2016.10.027","article-title":"The central nervous system and the gut microbiome","volume":"167","year":"2016","journal-title":"Cell"},{"issue":"7","key":"2025032117565657900_c10","doi-asserted-by":"publisher","first-page":"965","DOI":"10.1038\/nn.4030","article-title":"Host microbiota constantly control maturation and function of microglia in the CNS","volume":"18","year":"2015","journal-title":"Nat. Neurosci."},{"issue":"4","key":"2025032117565657900_c11","doi-asserted-by":"publisher","first-page":"627","DOI":"10.1016\/j.neuron.2019.05.035","article-title":"Transneuronal propagation of pathologic \u03b1-synuclein from the gut to the brain models Parkinson\u2019s disease","volume":"103","year":"2019","journal-title":"Neuron"},{"issue":"3","key":"2025032117565657900_c12","doi-asserted-by":"publisher","first-page":"327","DOI":"10.1038\/s41593-020-0589-7","article-title":"Gut-seeded \u03b1-synuclein fibrils promote gut dysfunction and brain pathology specifically in aged mice","volume":"23","year":"2020","journal-title":"Nat. Neurosci."},{"issue":"8","key":"2025032117565657900_c13","doi-asserted-by":"publisher","first-page":"599","DOI":"10.1038\/nmeth777","article-title":"A microfluidic culture platform for CNS axonal injury, regeneration and transport","volume":"2","year":"2005","journal-title":"Nat. Methods"},{"issue":"4","key":"2025032117565657900_c14","doi-asserted-by":"publisher","first-page":"517","DOI":"10.1002\/ana.23747","article-title":"Neuron-to-neuron transmission of \u03b1-synuclein fibrils through axonal transport","volume":"72","year":"2012","journal-title":"Ann. Neurol."},{"issue":"1","key":"2025032117565657900_c15","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1186\/s42234-023-00140-3","article-title":"Microfluidic compartmentalization of rat vagal afferent neurons to model gut-brain axis","volume":"10","year":"2024","journal-title":"Bioelectron. Med."},{"issue":"7","key":"2025032117565657900_c16","doi-asserted-by":"publisher","first-page":"941","DOI":"10.1038\/s41593-018-0175-4","article-title":"A 3D human triculture system modeling neurodegeneration and neuroinflammation in Alzheimer\u2019s disease","volume":"21","year":"2018","journal-title":"Nat. Neurosci."},{"issue":"1","key":"2025032117565657900_c17","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1016\/j.jaci.2009.05.038","article-title":"Intestinal barrier function: Molecular regulation and disease pathogenesis","volume":"124","year":"2009","journal-title":"J. Allergy Clin. Immunol."},{"issue":"3","key":"2025032117565657900_c18","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1038\/nri3608","article-title":"Intestinal epithelial cells: Regulators of barrier function and immune homeostasis","volume":"14","year":"2014","journal-title":"Nat. Rev. Immunol."},{"issue":"1","key":"2025032117565657900_c19","doi-asserted-by":"publisher","first-page":"11535","DOI":"10.1038\/ncomms11535","article-title":"A microfluidics-based in vitro model of the gastrointestinal human\u2013microbe interface","volume":"7","year":"2016","journal-title":"Nat. Commun."},{"issue":"1","key":"2025032117565657900_c20","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41378-022-00443-6","article-title":"Modeling gut neuro-epithelial connections in a novel microfluidic device","volume":"9","year":"2023","journal-title":"Microsyst. Nanoeng."},{"issue":"5986","key":"2025032117565657900_c21","doi-asserted-by":"publisher","first-page":"1662","DOI":"10.1126\/science.1188302","article-title":"Reconstituting organ-level lung functions on a chip","volume":"328","year":"2010","journal-title":"Science"},{"issue":"8","key":"2025032117565657900_c22","doi-asserted-by":"publisher","first-page":"104813","DOI":"10.1016\/j.isci.2022.104813","article-title":"A microengineered brain-chip to model neuroinflammation in humans","volume":"25","year":"2022","journal-title":"iScience"},{"issue":"45","key":"2025032117565657900_c23","doi-asserted-by":"publisher","first-page":"E10539","DOI":"10.1073\/pnas.1810819115","article-title":"Intestinal barrier dysfunction orchestrates the onset of inflammatory host\u2013microbiome cross-talk in a human gut inflammation-on-a-chip","volume":"115","year":"2018","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2025032117565657900_c24","doi-asserted-by":"publisher","first-page":"2409718","DOI":"10.1002\/adfm.202409718","article-title":"A pumpless, high-throughput microphysiological system to mimic enteric innervation of duodenal epithelium and the impact on barrier function","journal-title":"Adv. Funct. Mater."},{"issue":"1","key":"2025032117565657900_c25","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41392-022-01259-6","article-title":"The blood\u2013brain barrier: Structure, regulation and drug delivery","volume":"8","year":"2023","journal-title":"Signal Transduction Targeted Ther."},{"key":"2025032117565657900_c26","doi-asserted-by":"publisher","first-page":"119980","DOI":"10.1016\/j.biomaterials.2020.119980","article-title":"Vascularized neural constructs for ex-vivo reconstitution of blood-brain barrier function","volume":"245","year":"2020","journal-title":"Biomaterials"},{"issue":"8","key":"2025032117565657900_c27","doi-asserted-by":"publisher","first-page":"847","DOI":"10.1038\/s41551-021-00744-7","article-title":"A neurovascular-unit-on-a-chip for the evaluation of the restorative potential of stem cell therapies for ischaemic stroke","volume":"5","year":"2021","journal-title":"Nat. Biomed. Eng."},{"issue":"6921","key":"2025032117565657900_c28","doi-asserted-by":"publisher","first-page":"384","DOI":"10.1038\/nature01339","article-title":"Nicotinic acetylcholine receptor \u03b17 subunit is an essential regulator of inflammation","volume":"421","year":"2003","journal-title":"Nature"},{"issue":"2","key":"2025032117565657900_c29","doi-asserted-by":"publisher","first-page":"C427","DOI":"10.1152\/ajpcell.00439.2005","article-title":"Leptin and CCK modulate complementary background conductances to depolarize cultured nodose neurons","volume":"290","year":"2006","journal-title":"Am. J. Physiol. Cell Physiol."},{"issue":"6","key":"2025032117565657900_c30","doi-asserted-by":"publisher","first-page":"601","DOI":"10.3390\/bios13060601","article-title":"Cultured vagal afferent neurons as sensors for intestinal effector molecules","volume":"13","year":"2023","journal-title":"Biosensors"},{"issue":"17","key":"2025032117565657900_c31","doi-asserted-by":"publisher","first-page":"2107876","DOI":"10.1002\/adma.202107876","article-title":"Advanced materials and sensors for microphysiological systems: Focus on electronic and electrooptical interfaces","volume":"34","year":"2022","journal-title":"Adv. Mater."},{"issue":"7","key":"2025032117565657900_c32","doi-asserted-by":"publisher","first-page":"2926","DOI":"10.1021\/acsbiomaterials.0c01110","article-title":"In-line analysis of organ-on-chip systems with sensors: Integration, fabrication, challenges, and potential","volume":"7","year":"2021","journal-title":"ACS Biomater. Sci. Eng."},{"issue":"6","key":"2025032117565657900_c33","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1109\/MPUL.2011.942928","article-title":"Solving medical problems with BioMEMS","volume":"2","year":"2011","journal-title":"IEEE Pulse"},{"issue":"5","key":"2025032117565657900_c34","doi-asserted-by":"publisher","first-page":"821","DOI":"10.3390\/cells12050821","article-title":"Electrophysiological activity of primary cortical neuron-glia mixed cultures","volume":"12","year":"2023","journal-title":"Cells"},{"issue":"13","key":"2025032117565657900_c35","doi-asserted-by":"publisher","first-page":"2264","DOI":"10.1039\/C7LC00155J","article-title":"Organs-on-chips with integrated electrodes for trans-epithelial electrical resistance (TEER) measurements of human epithelial barrier function","volume":"17","year":"2017","journal-title":"Lab Chip"},{"issue":"20","key":"2025032117565657900_c36","doi-asserted-by":"publisher","first-page":"10019","DOI":"10.1021\/acs.analchem.6b02028","article-title":"Aptamer-based microfluidic electrochemical biosensor for monitoring cell-secreted trace cardiac biomarkers","volume":"88","year":"2016","journal-title":"Anal. Chem."},{"issue":"50","key":"2025032117565657900_c37","doi-asserted-by":"publisher","first-page":"20560","DOI":"10.1073\/pnas.1210269109","article-title":"Microfluidic chambers for monitoring leukocyte trafficking and humanized nano-proresolving medicines interactions","volume":"109","year":"2012","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"issue":"7","key":"2025032117565657900_c38","doi-asserted-by":"publisher","first-page":"520","DOI":"10.1038\/s41551-019-0397-0","article-title":"A complex human gut microbiome cultured in an anaerobic intestine-on-a-chip","volume":"3","year":"2019","journal-title":"Nat. Biomed. Eng."},{"issue":"1","key":"2025032117565657900_c39","doi-asserted-by":"publisher","first-page":"262","DOI":"10.1038\/s41467-017-00259-3","article-title":"Membrane-free culture and real-time barrier integrity assessment of perfused intestinal epithelium tubes","volume":"8","year":"2017","journal-title":"Nat. Commun."},{"issue":"9","key":"2025032117565657900_c40","doi-asserted-by":"publisher","first-page":"865","DOI":"10.1038\/nbt.4226","article-title":"A linked organ-on-chip model of the human neurovascular unit reveals the metabolic coupling of endothelial and neuronal cells","volume":"36","year":"2018","journal-title":"Nat. Biotechnol."},{"issue":"8","key":"2025032117565657900_c41","doi-asserted-by":"publisher","first-page":"1176","DOI":"10.1016\/j.celrep.2015.04.043","article-title":"Synaptic contacts enhance cell-to-cell tau pathology propagation","volume":"11","year":"2015","journal-title":"Cell Rep."},{"issue":"6","key":"2025032117565657900_c42","doi-asserted-by":"publisher","first-page":"831","DOI":"10.1007\/s00401-020-02227-6","article-title":"Neuronal activity modulates alpha-synuclein aggregation and spreading in organotypic brain slice cultures and in vivo","volume":"140","year":"2020","journal-title":"Acta Neuropathol."},{"issue":"13","key":"2025032117565657900_c43","doi-asserted-by":"publisher","first-page":"10568","DOI":"10.3390\/ijms241310568","article-title":"Proof-of-concept human organ-on-chip study: First step of platform to assess neuro-immunological communication involved in inflammatory bowel diseases","volume":"24","year":"2023","journal-title":"Int. J. Mol. Sci."},{"key":"2025032117565657900_c44","volume-title":"Animal Use in Research: Federal Agencies Should Assess and Report on Their Efforts to Develop and Promote Alternatives","author":"U.S.G.A. Office","year":"2019"},{"issue":"2","key":"2025032117565657900_c45","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1038\/s41591-019-0739-1","article-title":"iPSC modeling of young-onset Parkinson\u2019s disease reveals a molecular signature of disease and novel therapeutic candidates","volume":"26","year":"2020","journal-title":"Nat. Med."},{"issue":"9","key":"2025032117565657900_c46","doi-asserted-by":"publisher","first-page":"1149","DOI":"10.1038\/s41593-022-01131-4","article-title":"A CRISPRi\/a platform in human iPSC-derived microglia uncovers regulators of disease states","volume":"25","year":"2022","journal-title":"Nat. Neurosci."},{"key":"2025032117565657900_c47","doi-asserted-by":"publisher","first-page":"757","DOI":"10.1038\/s41422-024-01004-4","article-title":"Body\u2013brain axis: Orchestrating immune responses","year":"2024","journal-title":"Cell Res."}],"container-title":["Biomicrofluidics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.aip.org\/aip\/bmf\/article-pdf\/doi\/10.1063\/5.0253041\/20430326\/021301_1_5.0253041.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.aip.org\/aip\/bmf\/article-pdf\/doi\/10.1063\/5.0253041\/20430326\/021301_1_5.0253041.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,21]],"date-time":"2025-03-21T18:21:52Z","timestamp":1742581312000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.aip.org\/bmf\/article\/19\/2\/021301\/3338892\/Microfluidic-tools-to-model-monitor-and-modulate"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,1]]},"references-count":47,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2025,3,1]]}},"URL":"https:\/\/doi.org\/10.1063\/5.0253041","relation":{},"ISSN":["1932-1058"],"issn-type":[{"value":"1932-1058","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2025,3]]},"published":{"date-parts":[[2025,3,1]]},"article-number":"021301"}}