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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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Castan, L., Bøgh, K. L., Maryniak, N. Z., Epstein, M. M., Kazemi, S., O’Mahony, L., Bodinier, M., Smit, J. J., van Bilsen, J. H. M., Blanchard, C., et al. (2019) · Allergy · doi:10.1111/all.13943 · Cited by 60
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“Yissachar et al. (2017) reported to develop a novel system that are able to reproduce previous observations made in vivo.”
BackgroundShort-chain fatty acids are potential goalkeepers of atherosclerosis
Feng, Y., & Xu, D. (2023) · Frontiers in Pharmacology · doi:10.3389/fphar.2023.1271001 · Cited by 66
Modelling host–microbiome interactions in organ-on-a-chip platforms
Shin, Y. C., Than, N., Min, S., Shin, W., & Kim, H. J. (2023) · Nature Reviews Bioengineering · doi:10.1038/s44222-023-00130-9 · Cited by 58
“…can be introduced in an excised mouse intestine, cultured in a three-dimensional (3D)-printed mould, through a continuous luminal flow, while a surrounding layer of the excised intestine tissue can be independently manipulated with replenished culture medium to control oxygen and pH levels 40 .”
Liu, Z., Sun, X., Sun, X., Wang, S., & Xu, Y. M. (2019) · Journal of Ocean University of China · doi:10.1007/s11802-019-4019-y · Cited by 57
Gut-on-chip for ecological and causal human gut microbiome research
Moossavi, S., Arrieta, M., Sanati‐Nezhad, A., & Bishehsari, F. (2022) · Trends in Microbiology · doi:10.1016/j.tim.2022.01.014 · Cited by 54
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Neuronal, stromal, and T-regulatory cell crosstalk in murine skeletal muscle
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Immunological regulation of skeletal muscle adaptation to exercise
Langston, P. K., & Mathis, D. J. (2024) · Cell Metabolism · doi:10.1016/j.cmet.2024.04.001 · Cited by 55
Optical Imaging Approaches to Monitor Static and Dynamic Cell‐on‐Chip Platforms: A Tutorial Review
Arandian, A., Bagheri, Z., Ehtesabi, H., Nobar, S. N., Aminoroaya, N., Samimi, A., & Latifi, H. (2019) · Small · doi:10.1002/smll.201900737 · Cited by 48
Li, Y., Ye, Z., Zhu, J., Fang, S., Meng, L., & Zhou, C. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.844335 · Cited by 45
In Vitro Models of the Small Intestine: Engineering Challenges and Engineering Solutions
Hewes, S. A., Wilson, R. L., Estes, M. K., Shroyer, N. F., Blutt, S. E., & Grande-Allen, K. J. (2020) · Tissue Engineering Part B Reviews · doi:10.1089/ten.teb.2019.0334 · Cited by 51
“Other useful systems have been developed to allow coculture of intestinal explants with other cell types, such as hepatocytes, or to introduce luminal flow.(96,97) Although the complexity of intestinal explants makes them the most physiological of in vitro models, the inclusion of all of the cell types can make interp…”
BackgroundGut microbiota and therapy for obesity and type 2 diabetes
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“The authors found that observations made previously in vivo could be reliably replicated in vitro with the organoid system, while being able to extract compelling new insights due to the tightly controlled nature of the organoid system (159).”
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BackgroundPhenotypic and Functional Diversity in Regulatory T Cells
Sjaastad, L. E., Owen, D. L., Tracy, S. I., & Farrar, M. A. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.715901 · Cited by 50
Nociceptor neurons promote IgE class switch in B cells
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Environmental perception and control of gastrointestinal immunity by the enteric nervous system
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Human colon function ex vivo: Dependence on oxygen and sensitivity to antibiotic
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Potential Application of Living Microorganisms in the Detoxification of Heavy Metals
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The intrinsic and extrinsic elements regulating inflammation
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Bashir, B., Alam, S., Khandale, N. B., Birla, D., Vishwas, S., Pandey, N. K., Gupta, G., Paudel, K. R., Dureja, H., Kumar, P., et al. (2024) · Ageing Research Reviews · doi:10.1016/j.arr.2024.102236 · Cited by 40
Enteric Microbiota–Gut–Brain Axis from the Perspective of Nuclear Receptors
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2D- and 3D-Based Intestinal Stem Cell Cultures for Personalized Medicine
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Profiling of how nociceptor neurons detect danger – new and old foes
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In Vitro Models of Intestine Innate Immunity
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Organoids, organs-on-chips and other systems, and microbiota
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TREGking From Gut to Brain: The Control of Regulatory T Cells Along the Gut-Brain Axis
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Microbial monotherapy with Prevotella histicola for patients with multiple sclerosis
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“In a similar study using a mouse model, the authors devised an organ culture system that involved a luminal flow to preserve the viability of the tissues and to control perturbations [38].”
MethodPeripheral neurotransmitters in the immune system
Chen, C.-S., Barnoud, C., & Scheiermann, C. (2020) · Current Opinion in Physiology · doi:10.1016/j.cophys.2020.09.009 · Cited by 34
Zhou, F., Zhou, Q., Zhu, Z., Hua, K., Chen, L., & Ding, J. (2020) · Annals of Translational Medicine · doi:10.21037/atm-20-622 · Cited by 31
“ramosun is considered as an inducer of Tregs in vivo (32-34).”
BackgroundGut Microbiome in Critical Illness (Review)
Chernevskaya, E., & Nv, B. (2018) · General Reanimatology · doi:10.15360/1813-9779-2018-5-96-119 · Cited by 33
Homeostatic, repertoire and transcriptional relationships between colon T regulatory cell subsets
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“P and neuron - produced IL6 (32, 34), in a triangular cross talk between gut microbiota, enteric or extrinsic neurons, and Tregs.”
BackgroundAn Interphase Microfluidic Culture System for the Study of Ex Vivo Intestinal Tissue
Baydoun, M., Treizeibré, A., Follet, J., Benamrouz-Vanneste, S., Creusy, C., Dercourt, L., Delaire, B., Mouray, A., Viscogliosi, É., Certad, G., et al. (2020) · Micromachines · doi:10.3390/mi11020150 · Cited by 33
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Method
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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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