The DOI matches its Crossref record; 49 of the 49 references it cites were found in a registry or an index.
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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Cites
The capsaicin receptor: a heat-activated ion channel in the pain pathway
Caterina, M. J., Schumacher, M. A., Tominaga, M., Rosen, T. A., Levine, J. D., & Julius, D. J. (1997) · Nature · doi:10.1038/39807 · Cited by 9,132 · cited 1×
“Conversely, because SP and related neuropeptides are released from dense-core vesicles upon activation of sensory neurons, we fed weanling mice with a diet rich in capsaicin, the active ingredient in chili peppers that activates nociceptor neurons (Caterina et al., 1997).”
BackgroundEnrichr: interactive and collaborative HTML5 gene list enrichment analysis tool
Chen, E. Y., Tan, C. M., Kou, Y., Duan, Q., Wang, Z., Meirelles, G. V., Clark, N. R., & Ma’ayan, A. (2013) · BMC Bioinformatics · doi:10.1186/1471-2105-14-128 · Cited by 7,814 · cited 1×
“1:genepatternmodules:4:1.5.20 Gene-E The Broad Institute https://software.broadinstitute.org/ GENE-E/ Enrichr Chen et al. (2013).”
InfluentialSingle Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche
Sato, T., Vries, R. G., Snippert, H. J., van de Wetering, M., Barker, N., Stange, D. E., van Es, J. H., Abo, A., Kujala, P., Peters, P. J., et al. (2009) · Nature · doi:10.1038/nature07935 · Cited by 7,204 · cited 5×
“These stipulations differed from the motivations behind the existing organoid (Sato et al., 2009), monolayer (Haller et al.”
BackgroundInfluentialInduction of Intestinal Th17 Cells by Segmented Filamentous Bacteria
Ivanov, I. I., Atarashi, K., Manel, N., Brodie, E. L., Shima, T., Karaoz, U., Wei, D., Goldfarb, K. C., Santee, C. A., Lynch, S. V., et al. (2009) · Cell · doi:10.1016/j.cell.2009.09.033 · Cited by 4,554 · cited 5×
“Indeed, Tac1 had been previously observed in lists of SFB-induced transcripts (Tan et al., 2016; Ivanov et al., 2009).”
BackgroundInfluentialInteractions Between the Microbiota and the Immune System
Hooper, L. V., Littman, D. R., & Macpherson, A. J. (2012) · Science · doi:10.1126/science.1223490 · Cited by 4,173 · cited 1×
“With the growing realization that symbiotic microbes help educate and tune the immune system (Hooper et al., 2012; Mowat and Agace, 2014), there is a need for experimental systems to finely analyze host-microbiota interactions.”
BackgroundModeling Development and Disease with Organoids
Clevers, H. (2016) · Cell · doi:10.1016/j.cell.2016.05.082 · Cited by 3,196 · cited 3×
“, 2000), organoid (Sato et al., 2009; Clevers, 2016) or ‘‘gut-on-a-chip’’ devices (Kim et al.”
BackgroundJung, S., Aliberti, J., Graemmel, P., Sunshine, M. J., Kreutzberg, G. W., Sher, A., & Littman, D. R. (2000) · Molecular and Cellular Biology · doi:10.1128/mcb.20.11.4106-4114.2000 · Cited by 2,632
Molecular Analysis of Commensal Host-Microbial Relationships in the Intestine
Hooper, L. V., Wong, M. H., Thelin, A., Hansson, L., Falk, P. G., & Gordon, J. I. (2001) · Science · doi:10.1126/science.291.5505.881 · Cited by 2,202 · cited 5×
“Indeed, Tac1 had been previously observed in lists of SFB-induced transcripts (Tan et al., 2016; Ivanov et al., 2009).”
InfluentialThe microbiome and innate immunity
Thaiss, C. A., Zmora, N., Levy, M., & Elinav, E. (2016) · Nature · doi:10.1038/nature18847 · Cited by 2,012 · cited 2×
“We know, just for the immune system, that the host/microbiome duet engages a bewildering array of cell-types: myeloid cells like macrophages and dendritic cells, innate lymphoid cells (ILC), T regulatory and effector cells (Treg, Teff), and B lymphocytes (Thaiss et al., 2016; Honda and Littman, 2016).”
BackgroundRegional specialization within the intestinal immune system
Mowat, A. M., & Agace, W. W. (2014) · Nature reviews. Immunology · doi:10.1038/nri3738 · Cited by 1,882 · cited 1×
“With the growing realization that symbiotic microbes help educate and tune the immune system (Hooper et al., 2012; Mowat and Agace, 2014), there is a need for experimental systems to finely analyze host-microbiota interactions.”
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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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