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An Intestinal Organ Culture System Uncovers a Role for the Nervous System in Microbe-Immune Crosstalk
Open accessAbstract
Investigation of host-environment interactions in the gut would benefit from a culture system that maintained tissue architecture yet allowed tight experimental control. We devised a microfabricated organ culture system that viably preserves the normal multicellular composition of the mouse intestine, with luminal flow to control perturbations (e.g., microbes, drugs). It enables studying short-term responses of diverse gut components (immune, neuronal, etc.). We focused on the early response to bacteria that induce either Th17 or RORg+ T-regulatory (Treg) cells in vivo. Transcriptional responses partially reproduced in vivo signatures, but these microbes elicited diametrically opposite changes in expression of a neuronal-specific gene set, notably nociceptive neuropeptides. We demonstrated activation of sensory neurons by microbes, correlating with RORg+ Treg induction. Colonic RORg+ Treg frequencies increased in mice lacking TAC1 neuropeptide precursor and decreased in capsaicin-diet fed mice. Thus, differential engagement of the enteric nervous system may partake in bifurcating pro- or anti-inflammatory responses to microbes.
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“In vitro intestine models have been created using human fetal intestinal tissue explants, but they deteriorate within 24 hours of culture.45, 46”
From Microfluidic Organ-on-a-Chip Models of Human Intestine (2018) · cites this paper as [46]
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“They found that previous observations made in vivo could be robustly reproduced, while being able to extract compelling new insights due to the tightly controlled nature of their system (Yissachar et al., 2017).”
From Understanding the Holobiont: How Microbial Metabolites Affect Human Health and Shape the Immune System (2017) · cites this paper as Yissachar et al., 2017
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“Yissachar et al. recently reported the development of a highly functional, microfluidics-based intestinal organ culture system.”
From Understanding the Holobiont: How Microbial Metabolites Affect Human Health and Shape the Immune System (2017) · cites this paper as Yissachar et al., 2017
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The NQR Complex Regulates the Immunomodulatory Function of Bacteroides thetaiotaomicron
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BackgroundTryptophan metabolites at the service of neuroimmune sensing of microbes
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BackgroundNeuro-immune cell interactions in the regulation of intestinal immune homeostasis
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Teratani, T., Mikami, Y., & Kanai∥, T. (2022) · International Immunology · doi:10.1093/intimm/dxac033 · Cited by 9
Ex vivo intestinal permeability assay (X-IPA) for tracking barrier function dynamics
Bootz-Maoz, H., Simon, A., Mare-Roumani, S. D., Bennet, Y., Toister, E., Romano, H., Zheng, D., Amidror, S., Elinav, E., & Yissachar, N. (2023) · npj Biofilms and Microbiomes · doi:10.1038/s41522-023-00409-0 · Cited by 8
Martinez, B., Schwerdtfeger, L., Richardson, A., Tobet, S. A., & Henry, C. S. (2022) · Analytical Chemistry · doi:10.1021/acs.analchem.1c05146 · Cited by 9
Ménage à trois: regulation of host immunity by enteric neuro-immune-microbiota cross talks
Yissachar, N. (2019) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2019.10.006 · Cited by 8
Advancing Lung Immunology Research: An Official American Thoracic Society Workshop Report
Rahimi, R. A., Cho, J. L., Jakubzick, C., Khader, S. A., Lambrecht, B. N., Lloyd, C. M., Molofsky, A. B., Talbot, S., Bonham, C. A., Drake, W. P., et al. (2022) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/rcmb.2022-0167st · Cited by 8
Microbiome and infectious disease: diagnostics to therapeutics
Zaatry, R., Herren, R., Gefen, T., & Geva‐Zatorsky, N. (2024) · Microbes and Infection · doi:10.1016/j.micinf.2024.105345 · Cited by 7
Monzani, R., Gagliardi, M., Saverio, V., Clemente, N., Monzani, A., Rabbone, I., Nigrelli, F., Pellizzaro, S., Ferrario, E., Saettone, S., et al. (2025) · Biology Direct · doi:10.1186/s13062-025-00644-9 · Cited by 8
“Small intestine (s.i.) from 13 days old Balb/c mice, feed with a gluten-free diet for at least three-generation [6, 31, 32], were freshly resected and cultivated in a sili-cone-based Gut-Ex-Vivo System (GEVS), as previously described [7, 12, 13, 33].”
Naim, G., Romano-Zadaka, H., Amidror, S., Levy, D. J., Cohen, A., Sochen, C., Gilberg, H., Farah, N., Rudenko, V., Yarden‐Rabinowitz, Y., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-64995-7 · Cited by 8
“For example, enteric neurons sense microbial signals and subsequently modulate innate lymphoid cells (ILC) 3–6 , macrophages and monocytes 7–9 , effector and regulatory T cells 10,11 , and the epithelial barrier 12,13 , collectively orchestrating barrier defense and mucosal immunity.”
InfluentialMonzani, R., Gagliardi, M., Clemente, N., Saverio, V., Pańczyszyn, E., Santoro, C., Yissachar, N., Visciglia, A., Pane, M., Amoruso, A., et al. (2022) · Biology · doi:10.3390/biology11111574 · Cited by 7
“We recently described an evolution of an organ on chip model originally developed by Yissachar and colleagues [12], a Gut-Ex-Vivo System (GEVS) to study both celiac disease [13] and IBD [3], providing evidence showing the consistency and reliability of the system, together with reduced numbers and suffering of animals.”
MethodKim, S., Kim, T., Kim, H., Kim, J., Rogers, J. A., & Hahn, S. K. (2024) · Advanced Materials · doi:10.1002/adma.202413189 · Cited by 6
Applying 3D cultures and high-throughput technologies to study host-pathogen interactions
Martinis, E. C. P. D., Alves, V. F., Pereira, M. G., Andrade, L. N., Abichabki, N. D. L. M., Abramova, A., Dannborg, M., & Bengtsson‐Palme, J. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1488699 · Cited by 6
“This kind of approach, taking into consideration diverse genetic backgrounds, may help the study of diseases linked to dysbiosis, such as In fl ammatory Bowel Disease (43, 44).”
The role of gut microbiota in neuropathic pain: insights into immune mechanisms
Gong, Z., Zou, J., Fang, Y., Li, J., Luo, Y., Xue, Q., Yu, B., Hua, B., & Liu, Z. (2025) · The Journal of Headache and Pain · doi:10.1186/s10194-025-02260-4 · Cited by 10
“Moreover, Clostridium ramosum , a potent inducer of RORγ+ Tregs [245], augments Treg populations within the intestinal milieu by decreasing neuronal cell body density and reducing nerve fiber caliber in the myenteric plexus, thereby attenuating the inhibitory influence of enteric neurons on Tregs…”
Chen, H., Li, J., Pan, X., Hu, Z., Cai, J., Xia, Z., Qi, N., Liao, S., Spritzer, Z., Bai, Y., et al. (2024) · Parasites & Vectors · doi:10.1186/s13071-023-06090-8 · Cited by 6
“Epithelial cells possess the fastest proliferation and renewal abilities [34].”
BackgroundRegulation of Host Immunity by the Gut Microbiota
Partney, H., & Yissachar, N. (2022) · Progress in inflammation research · doi:10.1007/978-3-030-91051-8_4 · Cited by 6
Immunocompetent Human Intestinal Models in Preclinical Drug Development
Weindl, G. (2020) · Handbook of experimental pharmacology · doi:10.1007/164_2020_429 · Cited by 6
Intestine Explants in Organ Culture: A Tool to Broaden the Regenerative Studies in Echinoderms
Bello, S. A., & García‐Arrarás, J. E. (2022) · Journal of Marine Science and Engineering · doi:10.3390/jmse10020244 · Cited by 6
Sensory neurons regulate stimulus-dependent humoral immunityPreprint
Aguilar, D., Zhu, F., Millet, A., Millet, N., Germano, P. M., Pisegna, J. R., Akbari, O., Doherty, T. A., Swidergall, M., & Jendzjowsky, N. G. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.01.04.574231 · Cited by 6
Gut flora reflects potential risk factors for cognitive dysfunction in patients with epilepsy
Hong, B. (2024) · Journal of Health Population and Nutrition · doi:10.1186/s41043-024-00639-8 · Cited by 5
“SCFAs have been shown to reduce neuroinflammation and improve blood-brain barrier integrity, suggesting their potential in preventing neurodegenerative diseases [23].”
BackgroundChen, Y., Wang, D., Liao, Y., Zuo, G., & Lu, X. (2024) · Discover Medicine · doi:10.1007/s44337-024-00135-2 · Cited by 5
Dóra, D., Kovács, T., & Nagy, N. (2020) · Orvosi Hetilap · doi:10.1556/650.2020.31685 · Cited by 5
“Egy intestinalis ex vivo kísérleti rendszer Clostridium ramosum baktériummal történő fertőzése alapján azt feltételezik, hogy bizonyos mikrobák képesek közvetlen módon aktiválni a bél nociceptiv szenzoros rostjait és ezzel beindítani a korai gyulladásos és fájdalmi választ emésztőrendszeri infekciók esetében [35].”
BackgroundInfluentialThe translational roadmap of the gut models, focusing on gut-on-chip
Malaguarnera, G., Graute, M., & Homs-Corbera, A. (2021) · Open Research Europe · doi:10.12688/openreseurope.13709.1 · Cited by 9
“Yissachar and colleagues implemented a gut organ culture, accommodating a mice gut tissue fragment in a bath of nutrients 43 .”
An Intestinal Gut Organ Culture System for Analyzing Host-Microbiota Interactions
Azriel, S., Bootz-Maoz, H., Shemesh, A., Amidror, S., & Yissachar, N. (2021) · Journal of Visualized Experiments · doi:10.3791/62779 · Cited by 5
Immunology: The Neuronal Pathway to Mucosal Immunity
Löser, S., & Maizels, R. M. (2018) · Current Biology · doi:10.1016/j.cub.2017.11.025 · Cited by 5
Cortez, B. R. D. S., & Guedes, R. M. C. (2023) · Veterinary World · doi:10.14202/vetworld.2023.347-356 · Cited by 4
“This model has the characteristic of maintaining the stimulus polarized and preserving the intestinal architecture, allowing the researcher to assess interactions between the microbiome, nervous system, and intestinal immune response (Figure-10) [49].”
BackgroundSantillán-Cortez, D., Castell-Rodríguez, A. E., González‐Arenas, A., Suárez‐Cuenca, J. A., Hautefeuille, M., Pérez‐Koldenkova, V., Añorve-Bailón, D., Garcı́a, S., Toledo-Lozano, C. G., Escamilla-Tilch, M., et al. (2024) · Bioengineering · doi:10.3390/bioengineering11101008 · Cited by 4
Magrone, T., & Jirillo, E. (2018) · Endocrine Metabolic & Immune Disorders - Drug Targets · doi:10.2174/1871530319666181128160411 · Cited by 4
Bijarchian, F., Taghiyar, L., Azhradi, Z., & Eslaminejad, M. B. (2021) · PubMed Central · doi:10.22038/ijbms.2021.57887.12870 · Cited by 4
“Novel culture methods which include 3D cultures, organoids, or organ chips (organs-on-chips) have better reproducibility and control of the tissue or organ microenvironment (40-43).”
BackgroundDifferentiation, regulation and function of regulatory T cells in non-lymphoid tissues and tumors
Ni, H., & Chen, Y. (2023) · International Immunopharmacology · doi:10.1016/j.intimp.2023.110429 · Cited by 5
Ke, T., Fan, X., Zheng, S., Liu, X., Sun, H., Fan, H., Yang, M., Lu, Q., Xie, H., Zhou, H., et al. (2025) · Advanced Materials · doi:10.1002/adma.202515996 · Cited by 3
Yeganeh, M., Zito, A., Sadat, M., Pierro, A., & Rogers, I. M. (2025) · Journal of Tissue Engineering and Regenerative Medicine · doi:10.1155/term/2583925 · Cited by 3
“In summary, intestinal EVOP systems are a useful platform that have been used to investigate molecular pathways41 and cellular interactions [42], as well as vasculature [44, 45] and motility dynamics [43] that are difcult to observe in vivo.”
InfluentialShu, M., Huang, L., Chen, Y., Wang, Y.-X., Xie, Z., Li, S.-H., Zhou, J.-W., Wei, L.-H., Fu, T.-Z., Liu, B., et al. (2024) · Cancer Letters · doi:10.1016/j.canlet.2024.216835 · Cited by 4
Imaging the enteric nervous system
Hazart, D., Moulzir, M., Delhomme, B., Oheim, M., & Ricard, C. (2025) · Frontiers in Neuroanatomy · doi:10.3389/fnana.2025.1532900 · Cited by 4
Designing multicellular intestinal systems
Schwerdtfeger, L., & Tobet, S. A. (2019) · Elsevier eBooks · doi:10.1016/b978-0-12-819178-1.00010-1 · Cited by 3
Metadata
- Authors
- Yissachar, N., Zhou, Y., Ung, L., Lai, N. Y., Mohan, J. F., Ehrlicher, A., Weitz, D. A., Kasper, D. L., Chiu, I. M., Mathis, D., & Benoist, C.
- Affiliations
- Harvard University (US)
- Corresponding author
- Chiu, Isaac M.
- Mathis, Diane
- Benoist, Christophe
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2017-03
- Volume
- 168
- Issue
- 6
- Pages
- 1135-1148.e12
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC5396461
- OpenAlex
- W2592427302
- Cited by
- 242
- References
- 49
- Citations by year
- 2026: 10 · 2025: 21 · 2024: 27 · 2023: 22 · 2022: 29 · 2021: 26 · 2020: 33 · 2019: 27 · 2018: 31 · 2017: 16
- FWCI
- 11.95
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Sponsored Research Agreement
- UCB
- JPB Foundation
- Howalt family
- NIH (R37-AI051530, DP2AT009499)
- Harvard Digestive Disease Center
- Schuyler Pierce Memorial Fellowship
- JDRF (3-2014-216)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- enteric nervous system, gut microbiota, host-microbe interactions, Th17 cells, sensory neurons, TAC1, capsaicin, inflammation
- MeSH terms
- Animals, Clostridium, Intestines, Organ Culture Techniques, Symbiosis, Mice
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