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 created using human fetal intestinal tissue explants deteriorate within 24 hours of culture.
“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]
The Results section describes intestinal cultures from prenatal and young mice, not human fetal tissue, and reports that they remained viable during the culture period; some epithelial degradation appeared in cultures continued longer than 24 hours. The Discussion says the system cannot be used with human organs and places clear structural problems at 30–40 hours. These findings contradict the attributed species and timing. (LLM, conf=0.88)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredYissachar et al. found that their microfluidics-based system could reliably reproduce observations previously made in vivo.
“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
Yissachar et al. developed a highly functional, microfluidics-based intestinal organ culture system.
“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× · see citing works
“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× · see citing works
“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× · see citing works
“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× · see citing works
“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× · see citing works
“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× · see citing works
“, 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 · see citing works
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× · see citing works
“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× · see citing works
“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).”
BackgroundThe microbiota in adaptive immune homeostasis and disease
Honda, K., & Littman, D. R. (2016) · Nature · doi:10.1038/nature18848 · Cited by 1,846 · cited 2× · see citing works
“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 1,769 · cited 1× · see citing works
“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.”
BackgroundKim, H. J., Huh, D., Hamilton, G., & Ingber, D. E. (2012) · Lab on a Chip · doi:10.1039/c2lc40074j · Cited by 1,734 · cited 2× · see citing works
“An exciting advance is the ‘‘gut-on-a-chip’’ device with separated compartments that can be seeded with different components, including microbes, to study cross-talk between cell types during the response to microbes (Kim et al., 2012, 2016).”
Gut immune maturation depends on colonization with a host-specific microbiota
Chung, H., Pamp, S. J., Hill, J. A., Surana, N. K., Edelman, S. M., Troy, E. B., Reading, N. C., Villablanca, E. J., Wang, S., Mora, J. R., et al. (2012) · Cell · doi:10.1016/j.cell.2012.04.037 · Cited by 1,241 · cited 3× · see citing works
“Recent advances in intestinal in vitro culture systems include the intestinal organoid culture (Sato et al., 2009; Clevers, 2016), which was developed and is ideally suited to study epithelial development, but lacks the other components, notably immunocytes.”
Th17 cell induction by adhesion of microbes to intestinal epithelial cells
Atarashi, K., Tanoue, T., Ando, M., Kamada, N., Nagano, Y., Narushima, S., Suda, W., Imaoka, A., Setoyama, H., Nagamori, T., et al. (2015) · Cell · doi:10.1016/j.cell.2015.08.058 · Cited by 1,071 · cited 7× · see citing works
“(D) Bar plot comparing the induction by SFB or B. fragilis (log2 fold change) of adhesion-mediated IEC activation signature genes (from Atarashi et al., 2015). illustrated for the strict anaerobe C. ramosum in Figure 2E).”
BackgroundResultInfluentialBacteria activate sensory neurons that modulate pain and inflammation
Chiu, I. M., Heesters, B. A., Ghasemlou, N., Von Hehn, C. A., Zhao, F., Tran, J., Wainger, B., Strominger, A., Muralidharan, S., Horswill, A. R., et al. (2013) · Nature · doi:10.1038/nature12479 · Cited by 949 · cited 3× · see citing works
“…the intestinal nervous system and can respond to microbial stimulation and regulate inflammation (Meseguer et al., 2014; Ochoa-Cortes et al., 2010; Chiu et al., 2013; Riol-Blanco et al., 2014), we interrogated a shorter list of neuropeptides more specifically expressed in nociceptive neurons by…”
BackgroundKim, H. J., Li, H., Collins, J. J., & Ingber, D. E. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1522193112 · Cited by 926 · see citing works
Sustained in vitro intestinal epithelial culture within a Wnt-dependent stem cell niche
Ootani, A., Li, X., Sangiorgi, E., Ho, Q. T., Ueno, H., Toda, S., Sugihara, H., Fujimoto, K., Weissman, I. L., Capecchi, M. R., et al. (2009) · Nature Medicine · doi:10.1038/nm.1951 · Cited by 906 · cited 1× · see citing works
“Gut culture device We tested a protocol for culture of intestinal sphere-like organoids in a collagen gel with an air-liquid interface, previously reported by Ootani et al. (2009).”
MethodIL-1 pathways in inflammation and human diseases
Gabay, C., Lamacchia, C., & Palmer, G. (2010) · Nature Reviews Rheumatology · doi:10.1038/nrrheum.2010.4 · Cited by 897 · cited 2× · see citing works
“, 2015) that likely denotes a fast response of the ILC compartment, the Il1rn receptor antagonist of the IL1 family (often the initial indicator of an IL1 response) (Gabay et al., 2010), the EGF-family member Epiregulin (Ereg), and Il1rl1 that encodes the Il-33-receptor (aka ST2).”
BackgroundIndividual intestinal symbionts induce a distinct population of RORγ <sup>+</sup> regulatory T cells
Sefik, E., Geva-Zatorsky, N., Oh, S., Konnikova, L., Zemmour, D., McGuire, A. M., Burzyn, D., Ortiz-Lopez, A., Lobera, M., Yang, J., et al. (2015) · Science · doi:10.1126/science.aaa9420 · Cited by 879 · cited 12× · see citing works
“Gene expression in colon cultures was again profiled after 2 hr, and we correlated the expression of each transcript across the microbe panel versus the frequency of RORg+ Tregs in mice monocolonized with the same symbionts (Figure 4C) (data from Sefik et al., 2015).”
InfluentialSelf-citationThe microbiota regulates type 2 immunity through RORγt <sup>+</sup> T cells
Ohnmacht, C., Park, J.-H., Cording, S., Wing, J. B., Atarashi, K., Obata, Y., Gaboriau-Routhiau, V., Marques, R., Dulauroy, S., Fedoseeva, M., et al. (2015) · Science · doi:10.1126/science.aac4263 · Cited by 863 · cited 20× · see citing works
“They support a functional scenario in which SP inhibits RORg+ Treg differentiation: the microbes’ differential ability to trigger nociceptor neurons and release SP would be an important component in their ability to induce RORg+ Tregs.”
BackgroundInfluentialMining the Human Gut Microbiota for Immunomodulatory Organisms
Geva-Zatorsky, N., Sefik, E., Kua, L., Pasman, L., Tan, T. G., Ortiz-Lopez, A., Yanortsang, T. B., Yang, L., Jupp, R., Mathis, D., et al. (2017) · Cell · doi:10.1016/j.cell.2017.01.022 · Cited by 762 · cited 1× · see citing works
“Several of them also responded to longterm C. ramosum colonization in vivo (Geva-Zatorsky et al., 2017) (e.g., Taf1d, Pla2g12b, and Naaladl1) or overlapped with the in vivo response to SFB (i.e., those encoding the reactive oxygen species (ROS)-producers Duoxa2 and Duox2 and the antimicrobial…”
BackgroundIn vitro production of functional sperm in cultured neonatal mouse testes
Sato, T., Katagiri, K., Gohbara, A., Inoue, K., Ogonuki, N., Ogura, A., Kubota, Y., & Ogawa, T. (2011) · Nature · doi:10.1038/nature09850 · Cited by 752 · see citing works
Complex Optical Surfaces Formed by Replica Molding Against Elastomeric Masters
Younan Xia, A., Kim, E., Zhao, X., Rogers, J. A., Prentiss, M. G., & Whitesides, G. M. (1996) · Science · doi:10.1126/science.273.5273.347 · Cited by 643 · cited 1× · see citing works
“Both the chip and the lid are made from poly(dimethylsiloxane) (PDMS; Sylgard 184, DowCorning, Midland, MI) by replica molding of a 3D printedmaster (Xia et al., 1996).”
MethodSteinhoff, M. S., von Mentzer, B., Geppetti, P., Pothoulakis, C., & Bunnett, N. W. (2014) · Physiological Reviews · doi:10.1152/physrev.00031.2013 · Cited by 628 · cited 1× · see citing works
“…gut intrinsic primary afferent neurons from adult mice are technically challenging to isolate and culture, we utilized primary adult DRG sensory neurons as a surrogate, which include nociceptor neurons that innervate the colon and SI (T7-L6 DRG neurons) (Robinson et al., 2004; Tan et al., 2008).”
Nociceptive sensory neurons drive interleukin-23-mediated psoriasiform skin inflammation
Riol‐Blanco, L., Ordovás-Montañés, J., Perro, M., Naval, E., Thiriot, A., Álvarez, D., Paust, S., Wood, J. N., & von Andrian, U. H. (2014) · Nature · doi:10.1038/nature13199 · Cited by 596 · cited 2× · see citing works
“…system and can respond to microbial stimulation and regulate inflammation (Meseguer et al., 2014; Ochoa-Cortes et al., 2010; Chiu et al., 2013; Riol-Blanco et al., 2014), we interrogated a shorter list of neuropeptides more specifically expressed in nociceptive neurons by mining…”
BackgroundPrimary afferent tachykinins are required to experience moderate to intense pain
Cao, Y. Q., Mantyh, P. W., Carlson, E. J., Gillespie, A.-M., Epstein, C. J., & Basbaum, A. I. (1998) · Nature · doi:10.1038/32897 · Cited by 595 · cited 2× · see citing works
“…(SP) encoded by Tac1 might negatively regulate colonic Treg differentiation in two ways: first, we compared the frequency of RORg+ Treg in the colonic LP of Tac1 / mice (Cao et al., 1998) and their Tac1-proficient littermates (all housed in SPF conditions that promote high RORg+ Treg frequencies).”
BackgroundSano, T., Huang, W., Hall, J. A., Yang, Y., Chen, A., Gavzy, S. J., Lee, J.-Y., Ziel, J. W., Miraldi, E. R., Domingos, A. I., et al. (2015) · Cell · doi:10.1016/j.cell.2015.08.061 · Cited by 547 · cited 5× · see citing works
“These stipulations differed from the motivations behind the existing organoid (Sato et al., 2009), monolayer (Haller et al.”
InfluentialTRPA1 channels mediate acute neurogenic inflammation and pain produced by bacterial endotoxins
Meseguer, V., Alpizar, Y. A., Luis, E., Tajada, S., Denlinger, B., Fajardo, O., Manenschijn, J.-A., Fernández-Peña, C., Talavera, A., Kichko, T., et al. (2014) · Nature Communications · doi:10.1038/ncomms4125 · Cited by 479 · see citing works
Haller, D., Bode, C., Hammes, W. P., Pfeifer, A. M. A., Schiffrin, E. J., & Blum, S. (2000) · Gut · doi:10.1136/gut.47.1.79 · Cited by 466 · see citing works
Tan, T. G., Sefik, E., Geva-Zatorsky, N., Kua, L., Naskar, D., Teng, F., Pasman, L., Ortiz-Lopez, A., Jupp, R., Wu, H.-J. J., et al. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1617460113 · Cited by 427 · see citing works
Lécuyer, E., Rakotobé, S., Garnier‐Lengliné, H., Lebreton, C., Picard, M., Juste, C., Fritzen, R., Eberl, G., McCoy, K. D., Macpherson, A. J., et al. (2014) · Immunity · doi:10.1016/j.immuni.2014.03.009 · Cited by 364 · see citing works
Tsilingiri, K., Barbosa, T., Penna, G., Caprioli, F., Sonzogni, A., Viale, G., & Rescigno, M. (2012) · Gut · doi:10.1136/gutjnl-2011-300971 · Cited by 364 · cited 1× · see citing works
“…other end of the spectrum are in vitro culture systems, in which cell lines or explanted mucosa are grown in monolayers that can be supplemented with microbes (Haller et al., 2000; Tsilingiri et al., 2012), offering tight experimental control but lacking the cellular complexity and architecture.”
BackgroundInhibition of mechanical allodynia in neuropathic pain by TLR5-mediated A-fiber blockade
Xu, Z., Kim, Y. H., Bang, S., Zhang, Y., Berta, T., Wang, F., Oh, S. B., & Ji, R. (2015) · Nature Medicine · doi:10.1038/nm.3978 · Cited by 343 · see citing works
Chiu, I. M., Barrett, L. B., Williams, E. K., Strochlic, D. E., Lee, S., Weyer, A. D., Lou, S., Bryman, G. S., Roberson, D. P., Ghasemlou, N., et al. (2014) · eLife · doi:10.7554/elife.04660 · Cited by 237 · cited 2× · see citing works
“…(Meseguer et al., 2014; Ochoa-Cortes et al., 2010; Chiu et al., 2013; Riol-Blanco et al., 2014), we interrogated a shorter list of neuropeptides more specifically expressed in nociceptive neurons by mining transcriptional profiling datasets of purified DRG nociceptors (Chiu et al., 2014).”
Regulation of immune tolerance by anti-inflammatory neuropeptides
González‐Rey, E., Chorny, A., & Delgado, M. (2006) · Nature reviews. Immunology · doi:10.1038/nri1984 · Cited by 233 · cited 2× · see citing works
“Although several of these neuropeptide genes may be active in non-neuronal cell types such as enteroendocrine cells (Gonzalez-Rey et al., 2007), the breadth of the effects and the panel of neuronal signatures that are regulated (Figures 4 and 5) suggested the involvement of sensory neurons in the…”
BackgroundTRPA1 and Substance P Mediate Colitis in Mice
Engel, M. A., Leffler, A., Niedermirtl, F., Babeș, A., Zimmermann, K., Filipović, M. R., Izydorczyk, I., Eberhardt, M. J., Kichko, T. I., Mueller–Tribbensee, S. M., et al. (2011) · Gastroenterology · doi:10.1053/j.gastro.2011.07.002 · Cited by 218 · cited 1× · see citing works
“Accordingly, SP is thought to play a pro-inflammatory role in the GI tract, as inhibition of SP signaling ameliorates experimental colitis (Weinstock et al., 2003; Engel et al., 2011).”
Robinson, D. R., McNaughton, P. A., Evans, M. L., & Hicks, G. A. (2004) · Neurogastroenterology & Motility · doi:10.1046/j.1365-2982.2003.00456.x · Cited by 204 · cited 1× · see citing works
“…gut intrinsic primary afferent neurons from adult mice are technically challenging to isolate and culture, we utilized primary adult DRG sensory neurons as a surrogate, which include nociceptor neurons that innervate the colon and SI (T7-L6 DRG neurons) (Robinson et al., 2004; Tan et al., 2008).”
Mao, Y.-K., Kasper, D. L., Wang, B., Forsythe, P., Bienenstock, J., & Kunze, W. A. (2013) · Nature Communications · doi:10.1038/ncomms2478 · Cited by 178 · cited 10× · see citing works
“Similarly, whole-mount tissue staining for the neural markers Tuj1 and nNOS demonstrated that the enteric nervous system (ENS) structure andspatial organizationweremaintained in thecultured tissue (Figures 1E and S3B; Movie S2).”
BackgroundInfluentialSelf-citationGrowth and host interaction of mouse segmented filamentous bacteria in vitro
Schnupf, P., Gaboriau‐Routhiau, V., Gros, M., Friedman, R. C., Moya‐Nilges, M., Nigro, G., Cerf–Bensussan, N., & Sansonetti, P. J. (2015) · Nature · doi:10.1038/nature14027 · Cited by 175 · cited 1× · see citing works
“SFB is very difficult to grow in vitro (Schnupf et al., 2015).”
BackgroundPainful Pathways Induced by TLR Stimulation of Dorsal Root Ganglion Neurons
Jia, Q., Buzás, K., Fan, H., Cohen, J. I., Wang, K., Mont, E. K., Klinman, D. M., Oppenheim, J. J., & Howard, O. M. Z. (2011) · The Journal of Immunology · doi:10.4049/jimmunol.1001241 · Cited by 168 · see citing works
Bacterial cell products signal to mouse colonic nociceptive dorsal root ganglia neurons
Ochoa‐Cortés, F., Lomas-Ramos, T. L., Miranda‐Morales, M., Spreadbury, I., Ibeakanma, C. O., Barajas‐López, C., & Vanner, S. J. (2010) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00494.2009 · Cited by 112 · see citing works
Cunin, P., Caillon, A., Corvaisier, M., Garo, E., Scotet, M., Blanchard, S., Delneste, Y., & Jeannin, P. (2011) · The Journal of Immunology · doi:10.4049/jimmunol.1002535 · Cited by 104 · cited 1× · see citing works
“SP modulates immune cell proliferation, can diminish interleukin-10 (IL-10) production (Janelsins et al., 2013) and supports Th17 differentiation by inducing pro-inflammatory IL-1b and IL12/IL-23 cytokine production by monocytes (Cunin et al., 2011).”
BackgroundTan, L. L., Bornstein, J. C., & Anderson, C. R. (2008) · Neuroscience · doi:10.1016/j.neuroscience.2008.06.071 · Cited by 100 · cited 2× · see citing works
“Because gut intrinsic primary afferent neurons from adult mice are technically challenging to isolate and culture, we utilized primary adult DRG sensory neurons as a surrogate, which include nociceptor neurons that innervate the colon and SI (T7-L6 DRG neurons) (Robinson et al., 2004; Tan et al., 2008).”
MethodCellular Organization of Neuroimmune Interactions in the Gastrointestinal Tract
Margolis, K. G., Gershon, M. D., & Bogunovic, M. (2016) · Trends in Immunology · doi:10.1016/j.it.2016.05.003 · Cited by 86 · cited 1× · see citing works
“The interest in intestinal neuro-immune interactions and their relations with the microbiota is rapidly increasing (Margolis et al., 2016).”
BackgroundJenkinson, E. J., & Anderson, G. (1994) · Current Opinion in Immunology · doi:10.1016/0952-7915(94)90104-x · Cited by 82 · cited 2× · see citing works
“Our initial attempts were inspired by fetal thymic organ cultures (FTOC) (Jenkinson and Anderson, 1994), which have proven invaluable in elucidating T cell differentiation in the thymus.”
ResultJanelsins, B., Sumpter, T. L., Tkacheva, O. A., Rojas‐Canales, D. M., Erdös, G., Mathers, A. R., Shufesky, W. J., Storkus, W. J., Falo, L. D., Morelli, A. E., et al. (2013) · Blood · doi:10.1182/blood-2012-07-446054 · Cited by 77 · see citing works
Substance P Regulates Th1-Type Colitis in IL-10 Knockout Mice
Weinstock, J. V., Blum, A. M., Metwali, A., Elliott, D. E., Bunnett, N. W., & Arsenescu, R. I. (2003) · The Journal of Immunology · doi:10.4049/jimmunol.171.7.3762 · Cited by 66 · cited 1× · see citing works
“Accordingly, SP is thought to play a pro-inflammatory role in the GI tract, as inhibition of SP signaling ameliorates experimental colitis (Weinstock et al., 2003; Engel et al., 2011).”
BackgroundPain and Itch: Beneficial or Harmful to Antimicrobial Defense?
Baral, P., Mills, K., Pinho-Ribeiro, F. A., & Chiu, I. M. (2016) · Cell Host & Microbe · doi:10.1016/j.chom.2016.05.010 · Cited by 32 · cited 1× · see citing works
“Yet, little is known about how nociceptor neurons sense signals from the gut microbiota (Baral et al., 2016).”
BackgroundKovalenko, P. L., Yuan, L., Sun, K., Kunovska, L., Seregin, S. S., Amalfitano, A., & Basson, M. D. (2013) · PLoS ONE · doi:10.1371/journal.pone.0079745 · Cited by 15 · cited 2× · see citing works
“A very early and transient responsewas observed forSlfn3, which encodes a factor that influences epithelial enterocyte differentiation (Kovalenko et al., 2013) or the epithelial tight junction gene Cldn4.”
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Blander, J. M., Longman, R., Iliev, I. D., Sonnenberg, G. F., & Artis, D. (2017) · Nature Immunology · doi:10.1038/ni.3780 · Cited by 649 · see citing works
Propionic Acid Shapes the Multiple Sclerosis Disease Course by an Immunomodulatory Mechanism
Duscha, A., Gisevius, B., Hirschberg, S., Yissachar, N., Stangl, G. I., Dawin, E., Bader, V., Haase, S., Kaisler, J., David, C., et al. (2020) · Cell · doi:10.1016/j.cell.2020.02.035 · Cited by 639 · see citing works
Microfluidic Organ-on-a-Chip Models of Human Intestine
Bein, A., Shin, W., Jalili-Firoozinezhad, S., Park, M. H., Sontheimer-Phelps, A., Tovaglieri, A., Chalkiadaki, A., Kim, H. J., & Ingber, D. E. (2018) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2017.12.010 · Cited by 601 · see citing works
Moor, A. E., Harnik, Y., Ben-Moshe, S., Massasa, E. E., Rozenberg, M., Eilam, R., Bahar Halpern, K., & Itzkovitz, S. (2018) · Cell · doi:10.1016/j.cell.2018.08.063 · Cited by 480 · see citing works
Pain and immunity: implications for host defence
Baral, P., Udit, S., & Chiu, I. M. (2019) · Nature reviews. Immunology · doi:10.1038/s41577-019-0147-2 · Cited by 487 · see citing works
The Enteric Network: Interactions between the Immune and Nervous Systems of the Gut
Yoo, B. B., & Mazmanian, S. K. (2017) · Immunity · doi:10.1016/j.immuni.2017.05.011 · Cited by 479 · see citing works
“A recent study by Yissachar et al. utilized an intestinal organ-culture system to show that gut bacteria can modulate the neuro-immune environment of the intestines (Yissachar et al., 2017); however, it remains unknown whether neural components are sufficient or necessary for this regulation.”
BackgroundEngineering bacteria for diagnostic and therapeutic applications
Riglar, D. T., & Silver, P. A. (2018) · Nature Reviews Microbiology · doi:10.1038/nrmicro.2017.172 · Cited by 460 · see citing works
Role of the Gut Microbiome in the Pathogenesis of Obesity and Obesity-Related Metabolic Dysfunction
Bouter, K. E. C., van Raalte, D. H., Groen, A. K., & Nieuwdorp, M. (2017) · Gastroenterology · doi:10.1053/j.gastro.2016.12.048 · Cited by 433 · see citing works
Gut Microbiota and Complications of Type-2 Diabetes
Iatcu, O. C., Steen, A., & Covașă, M. (2021) · Nutrients · doi:10.3390/nu14010166 · Cited by 433 · see citing works
Fecal Microbiota Transplantation in Neurological Disorders
Vendrik, K. E. W., Ooijevaar, R. E., de Jong, P. R. C., Laman, J. D., van Oosten, B. W., van Hilten, J. J., Ducarmon, Q. R., Keller, J. J., Kuijper, E. J., & Contarino, M. F. (2020) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2020.00098 · Cited by 413 · see citing works
Nociceptor neurons affect cancer immunosurveillance
Balood, M., Ahmadi, M., Eichwald, T., Ahmadi, A., Majdoubi, A., Roversi, K., Roversi, K., Lucido, C. T., Restaino, A. C., Huang, S., et al. (2022) · Nature · doi:10.1038/s41586-022-05374-w · Cited by 389 · see citing works
Chen, R., Xu, Y., Wu, P., Zhou, H., Lasanajak, Y., Fang, Y., Tang, L. Y., Ye, L., Li, X., Cai, Z., et al. (2019) · Pharmacological Research · doi:10.1016/j.phrs.2019.104403 · Cited by 374 · see citing works
The intestinal neuro-immune axis: crosstalk between neurons, immune cells, and microbes
Jacobson, A. R., Yang, D., Vella, M., & Chiu, I. M. (2021) · Mucosal Immunology · doi:10.1038/s41385-020-00368-1 · Cited by 313 · see citing works
“When Th17-inducing or Treg-inducing bacteria are infused into a microfabricated intestine culture system, these bacteria elicit differential effects on enteric neuron gene expression.(90) The frequency of RORgt Treg cells negatively correlate with expression of Tac1, which encodes the neuropeptides neurokinin A and su…”
BackgroundTissue regulatory T cells: regulatory chameleons
Muñoz-Rojas, A. R., & Mathis, D. (2021) · Nature Reviews Immunology · doi:10.1038/s41577-021-00519-w · Cited by 281 · see citing works
Self-citationBeyond Host Defense: Emerging Functions of the Immune System in Regulating Complex Tissue Physiology
Rankin, L. C., & Artis, D. (2018) · Cell · doi:10.1016/j.cell.2018.03.013 · Cited by 271 · see citing works
Gut-on-a-chip: Current progress and future opportunities
Ashammakhi, N. A., Nasiri, R., de Barros, N. R., Tebon, P. J., Thakor, J., Goudie, M. J., Shamloo, A., Martín, M. G., & Khademhosseini, A. (2020) · Biomaterials · doi:10.1016/j.biomaterials.2020.120196 · Cited by 238 · see citing works
Organ‐on‐chip models: Implications in drug discovery and clinical applications
Mittal, R., Woo, F. W., Castro, C. S., Cohen, M. A., Karanxha, J., Mittal, J., Chhibber, T., & Jhaveri, V. M. (2018) · Journal of Cellular Physiology · doi:10.1002/jcp.27729 · Cited by 235 · see citing works
Trapecar, M., Communal, C., Velazquez, J., Maass, C. A., Huang, Y.-J., Schneider, K., Wright, C. W., Butty, V., Eng, G., Yilmaz, O., et al. (2020) · Cell Systems · doi:10.1016/j.cels.2020.02.008 · Cited by 204 · see citing works
Chudzik, A., Orzyłowska, A., Rola, R., & Stanisz, G. J. (2021) · Biomolecules · doi:10.3390/biom11071000 · Cited by 212 · see citing works
“Investigations of the BGM axis involve animal studies in germ-free (GF) animals [92], prebiotic and probiotic studies in rodent models [93–95], probing the effects of antibiotics [96], fecal transplantation [97] and cultured gut organ systems [98].”
BackgroundCohen, L. J., Cho, J. H., Gevers, D., & Chu, H. (2019) · Gastroenterology · doi:10.1053/j.gastro.2019.03.017 · Cited by 201 · see citing works
High-Throughput Screen Identifies Host and Microbiota Regulators of Intestinal Barrier Function
Grosheva, I., Zheng, D., Levy, M., Polansky, O., Lichtenstein, A., Golani, O., Dori-Bachash, M., Moresi, C., Shapiro, H., Mare-Roumani, S. D., et al. (2020) · Gastroenterology · doi:10.1053/j.gastro.2020.07.003 · Cited by 200 · see citing works
“tissue architecture and mimic in vivo conditions.(33) Media containing different concentrations of putrescine were perfused continuously through the gut lumen for 2 hours (Supplementary Figure 8A).”
MethodLiu, S., Rezende, R. M., Moreira, T. G., Tankou, S. K., Cox, L. M., Wu, M., Song, A., Dhang, F. H., Wei, Z., Costamagna, G., et al. (2019) · Cell Host & Microbe · doi:10.1016/j.chom.2019.10.008 · Cited by 196 · see citing works
“The human symbiont Clostridium ramosum was also demonstrated to induce Treg (Sefik et al. 2015; Yissachar et al. 2017).”
Gut-innervating nociceptors regulate the intestinal microbiota to promote tissue protection
Zhang, W., Lyu, M., Bessman, N. J., Xie, Z., Arifuzzaman, M., Yano, H., Parkhurst, C. N., Chu, C., Zhou, L., Putzel, G., et al. (2022) · Cell · doi:10.1016/j.cell.2022.09.008 · Cited by 183 · see citing works
Intestinal Microbiota Influences Non-intestinal Related Autoimmune Diseases
Opazo, M. C., Ortega-Rocha, E. M., Coronado-Arrázola, I., Bonifaz, L. C., Boudin, H., Neunlist, M., Bueno, S. M., Kalergis, A. M., & Riedel, C. A. (2018) · Frontiers in Microbiology · doi:10.3389/fmicb.2018.00432 · Cited by 179 · see citing works
“The MS patient develops several symptoms that lead to chronic disability including cognition impairment, loss of motor control, and sensitivity (Yong et al., 2017).”
BackgroundExperimental models to study intestinal microbes–mucus interactions in health and disease
Etienne‐Mesmin, L., Chassaing, B., Desvaux, M., Paepe, K. D., Gresse, R., Sauvaitre, T., Forano, É., de Wiele, T. V., Schüller, S., Juge, N., et al. (2019) · FEMS Microbiology Reviews · doi:10.1093/femsre/fuz013 · Cited by 178 · see citing works
An Immunologic Mode of Multigenerational Transmission Governs a Gut Treg Setpoint
Ramanan, D., Sefik, E., Galván-Peña, S., Wu, M., Yang, L., Yang, Z., Kostic, A. D., Golovkina, T. V., Kasper, D. L., Mathis, D. J., et al. (2020) · Cell · doi:10.1016/j.cell.2020.04.030 · Cited by 173 · see citing works
“, 2015), through several potential mechanisms (Verma et al., 2018; Yissachar et al., 2017; Hang et al., 2019; Song et al., 2020).”
Chen, L., Li, J., Zhu, W., Kuang, Y., Liu, T., Zhang, W., Chen, X., & Peng, C. (2020) · Frontiers in Microbiology · doi:10.3389/fmicb.2020.589726 · Cited by 175 · see citing works
Yan, Y., Ramanan, D., Rozenberg, M., McGovern, K., Rastelli, D., Vijaykumar, B., Yaghi, O., Voisin, T., Mosaheb, M., Chiu, I., et al. (2021) · Immunity · doi:10.1016/j.immuni.2021.02.002 · Cited by 165 · see citing works
Self-citationHuman organoids-on-chips for biomedical research and applications
Wang, H., Ning, X., Zhao, F. H., Zhao, H., & Li, D. (2024) · Theranostics · doi:10.7150/thno.90492 · Cited by 138 · see citing works
“Moreover, accumulating evidence indicates that intestinal epithelium and other cell types participate in the complex crosstalk between gut microbiome and host immunity [57, 75, 217-223].”
BackgroundTiming the Microbes: The Circadian Rhythm of the Gut Microbiome
Liang, X., & FitzGerald, G. A. (2017) · Journal of Biological Rhythms · doi:10.1177/0748730417729066 · Cited by 132 · see citing works
“A recently described mouse intestine culture system (Yissachar et al., 2017) may facilitate investigations of the microbial influence on intestinal circadian rhythms.”
BackgroundDelvalle, N. M., Dharshika, C., Morales‐Soto, W., Fried, D. E., Gaudette, L., & Gulbransen, B. D. (2018) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2018.05.009 · Cited by 127 · see citing works
Regulatory T cells in the face of the intestinal microbiota
Ramanan, D., Pratama, A., Zhu, Y., Venezia, O., Sassone-Corsi, M., Chowdhary, K., Galván-Peña, S., Sefik, E., Brown, C., Gélineau, A., et al. (2023) · Nature Reviews Immunology · doi:10.1038/s41577-023-00890-w · Cited by 126 · see citing works
“Accordingly, Tac1 -deficient mice showed increased proportions of colonic RORγ + pT reg cells, whereas capsaicin, which activates sensory neurons, reduced colonic T reg cells 126 .”
BackgroundSelf-citationT Cell Responses to the Microbiota
Ivanov, I. I., Tuganbaev, T., Skelly, A. N., & Honda, K. (2022) · Annual Review of Immunology · doi:10.1146/annurev-immunol-101320-011829 · Cited by 128 · see citing works
The Gut-Brain Axis in Inflammatory Bowel Disease—Current and Future Perspectives
Günther, C., Rothhammer, V., Karow, M., Neurath, M., & Winner, B. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22168870 · Cited by 123 · see citing works
Clavel, T., Neto, J. C. G., Lagkouvardos, I., & Ramer‐Tait, A. E. (2017) · Immunological Reviews · doi:10.1111/imr.12578 · Cited by 125 · see citing works
Beyond the tumour microenvironment
Laplane, L., Duluc, D., Bikfalvi, A., Larmonier, N., & Pradeu, T. (2019) · International Journal of Cancer · doi:10.1002/ijc.32343 · Cited by 123 · see citing works
Epithelial Gasdermin D shapes the host-microbial interface by driving mucus layer formation
Zhang, J., Yu, Q., Jiang, D., Kang, Y., Yu, W., Chi, Z., Chen, S., Li, M., Yang, D., Wang, Z., et al. (2022) · Science Immunology · doi:10.1126/sciimmunol.abk2092 · Cited by 123 · see citing works
Precision Medicine Goes Microscopic: Engineering the Microbiome to Improve Drug Outcomes
Lam, K. N., Alexander, M., & Turnbaugh, P. J. (2019) · Cell Host & Microbe · doi:10.1016/j.chom.2019.06.011 · Cited by 115 · see citing works
A chemogenetic screen reveals that Trpv1-expressing neurons control regulatory T cells in the gut
Zhu, Y., Meerschaert, K. A., Galván-Peña, S., Bin, N., Yang, D., Basu, H., Kawamoto, R., Shalaby, A., Liberles, S. D., Mathis, D. J., et al. (2024) · Science · doi:10.1126/science.adk1679 · Cited by 120 · see citing works
“Most germane here, we showed previously that the control of ROR g + T reg cells by gut microbes is associated with perturbations of the ENS, proposing a triangular interaction between gut microbes, ROR g + T reg cells, and the intestinal nervous system ( 45 , 46 ).”
BackgroundFucoxanthin: A Promising Phytochemical on Diverse Pharmacological Targets
Mumu, M., Das, A., Emran, T. B., Mitra, S., Islam, F., Roy, A., Karim, M. M., Das, R. C., Park, M. N., Chandran, D., et al. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.929442 · Cited by 108 · see citing works
The Use of Defined Microbial Communities To Model Host-Microbe Interactions in the Human Gut
Elzinga, J., John van der, O. O. S. T., de Vos, W. M., & Smidt, H. (2019) · Microbiology and Molecular Biology Reviews · doi:10.1128/mmbr.00054-18 · Cited by 101 · see citing works
The emergence of 3D bioprinting in organ-on-chip systems
Fetah, K., Tebon, P. J., Goudie, M. J., Eichenbaum, J., Ren, L. M., de Barros, N. R., Nasiri, R., Ahadian, S., Ashammakhi, N. A., Dokmeci, M. R., et al. (2019) · Progress in Biomedical Engineering · doi:10.1088/2516-1091/ab23df · Cited by 99 · see citing works
“Finally, a unique approach to maintaining physiological properties ex vivo was developed by Yissachar et al [195].”
BackgroundThe mammalian mycobiome: A complex system in a dynamic relationship with the host
Lai, G. C., Tan, T. G., & Pavelka, N. (2018) · WIREs Systems Biology and Medicine · doi:10.1002/wsbm.1438 · Cited by 91 · see citing works
Sense and Immunity: Context-Dependent Neuro-Immune Interplay
Foster, S. L., Seehus, C. R., Woolf, C. J., & Talbot, S. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.01463 · Cited by 92 · see citing works
“In intestinal organ cultures, capsaicin-sensitive enteric nervous system neurons seem to distinguish among different bacterial infections (62).”
BackgroundUpdate on regulation and effector functions of Th17 cells
Sandquist, I., & Kolls, J. K. (2018) · F1000Research · doi:10.12688/f1000research.13020.1 · Cited by 91 · see citing works
Neuroimmune Interactions in the Intestine
Wallrapp, A., & Chiu, I. M. (2024) · Annual Review of Immunology · doi:10.1146/annurev-immunol-101921-042929 · Cited by 91 · see citing works
Crosstalk between gut microbiota and host immune system and its response to traumatic injury
Ullah, H., Arbab, S., Tian, Y., Chen, Y., Liu, C., Li, Q., & Li, K. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1413485 · Cited by 93 · see citing works
Osman, A., Yan, B., Li, Y., Pavelko, K. D., Quandt, J., Saadalla, A. M., Singh, M. P., Kazemian, M., Gounari, F., & Khazaie, K. (2021) · Nature Immunology · doi:10.1038/s41590-021-00987-1 · Cited by 81 · see citing works
Sanchez, J. B., & Kadrofske, M. M. (2019) · Neurogastroenterology & Motility · doi:10.1111/nmo.13569 · Cited by 81 · see citing works
Microfluidic lumen-based systems for advancing tubular organ modeling
Virumbrales-Muñoz, M., Ayuso, J. M., Gong, M. M., Humayun, M., Livingston, M. K., Lugo-Cintrón, K. M., McMinn, P. H., Álvarez-García, Y. R., & Beebe, D. J. (2020) · Chemical Society Reviews · doi:10.1039/d0cs00705f · Cited by 77 · see citing works
Engineering microphysiological immune system responses on chips
Miller, C. P., Shin, W., Ahn, E. H., Kim, H. J., & Kim, D.-H. (2020) · Trends in biotechnology · doi:10.1016/j.tibtech.2020.01.003 · Cited by 74 · see citing works
The gut microbiota promotes the pathogenesis of schizophrenia via multiple pathways
Yuan, X., Kang, Y., Zhuo, C., Huang, X., & Song, X. (2019) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2019.02.152 · Cited by 73 · see citing works
The Role of the Gut Microbiota in Coronary Heart Disease
Liu, H., Zhuang, J., Tang, P., Li, J., Xiong, X., & Deng, H. (2020) · Current Atherosclerosis Reports · doi:10.1007/s11883-020-00892-2 · Cited by 74 · see citing works
Age-Related Changes in Thymic Central Tolerance
Srinivasan, J., Lancaster, J. N., Singarapu, N., Hale, L. P., Ehrlich, L. I. R., & Richie, E. R. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.676236 · Cited by 67 · see citing works
Pratama, A., Schnell, A., Mathis, D. J., & Benoist, C. O. (2019) · The Journal of Experimental Medicine · doi:10.1084/jem.20190428 · Cited by 70 · see citing works
Mechanisms of microbial–neuronal interactions in pain and nociception
Lagomarsino, V. N., Kostic, A. D., & Chiu, I. M. (2020) · Neurobiology of Pain · doi:10.1016/j.ynpai.2020.100056 · Cited by 70 · see citing works
Proteomic and Metaproteomic Approaches to Understand Host–Microbe Interactions
Starr, A. E., Deeke, S. A., Li, L., Zhang, X., Daoud, R., Ryan, J., Ning, Z., Cheng, K., Nguyen, L. V. H., Abou-Samra, E., et al. (2017) · Analytical Chemistry · doi:10.1021/acs.analchem.7b04340 · Cited by 67 · see citing works
Powering ex vivo tissue models in microfluidic systems
McLean, I. C., Schwerdtfeger, L., Tobet, S. A., & Henry, C. S. (2018) · Lab on a Chip · doi:10.1039/c8lc00241j · Cited by 68 · see citing works
Ertürk-Hasdemir, D., & Kasper, D. L. (2018) · Annals of the New York Academy of Sciences · doi:10.1111/nyas.13660 · Cited by 65 · see citing works
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 · see citing works
Prebiotics metabolism by gut-isolated probiotics
Rawi, M. H., Zaman, S. A., Pa’ee, K. F., Leong, S. S., & Sarbini, S. R. (2020) · Journal of Food Science and Technology · doi:10.1007/s13197-020-04244-5 · Cited by 61 · see citing works
“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 58 · see citing works
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 57 · see citing works
“…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 56 · see citing works
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 52 · see citing works
Kennedy, R., Kuvshinov, D., Sdrolia, A., Kuvshinova, E., Hilton, K., Crank, S., Beavis, A. W., Green, V., & Greenman, J. (2019) · Scientific Reports · doi:10.1038/s41598-019-42745-2 · Cited by 53 · see citing works
Neuronal, stromal, and T-regulatory cell crosstalk in murine skeletal muscle
Wang, K., Yaghi, O., Spallanzani, R. G., Chen, X., Zemmour, D., Lai, N. Y., Chiu, I. M., Benoist, C. O., & Mathis, D. J. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1922559117 · Cited by 52 · see citing works
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 52 · see citing works
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 · see citing works
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 · see citing works
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 47 · see citing works
“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
Zhang, L., Wang, P., Huang, J., Xing, Y., Wong, F. S., Suo, J., & Li, W. (2024) · Frontiers in Endocrinology · doi:10.3389/fendo.2024.1333778 · Cited by 51 · see citing works
“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).”
BackgroundNoben, M., Vanhove, W., Arnauts, K., Ramalho, A. S., Assche, G. V., Vermeire, S., Verfaillie, C. M., & Ferrante, M. (2017) · United European Gastroenterology Journal · doi:10.1177/2050640617722903 · Cited by 46 · see citing works
“More recently, an elegant study showed a more advanced model of a murine colon explant system in which the colon was excised and placed into a chamber where flow of medium was controlled, as well as the luminal flow.(53) The enteric nervous system was involved in proor anti-inflammatory responses by modulating inducti…”
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 44 · see citing works
Nociceptor neurons promote IgE class switch in B cells
Mathur, S., Wang, J.-C., Seehus, C. R., Poirier, F., Crosson, T., Hsieh, Y.-C., Doyle, B., Lee, S., Woolf, C. J., Foster, S. L., et al. (2021) · JCI Insight · doi:10.1172/jci.insight.148510 · Cited by 45 · see citing works
“Nociceptor neurons dampen innate immunity against pathogens and fungi (4, 5, 23, 35–39), but whether these neurons control humoral immunity remains unknown.”
Environmental perception and control of gastrointestinal immunity by the enteric nervous system
Schneider, K. M., Kim, J., Bahnsen, K., Heuckeroth, R. O., & Thaiss, C. A. (2022) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2022.09.005 · Cited by 42 · see citing works
Human colon function ex vivo: Dependence on oxygen and sensitivity to antibiotic
Schwerdtfeger, L., Nealon, N. J., Ryan, E. P., & Tobet, S. A. (2019) · PLoS ONE · doi:10.1371/journal.pone.0217170 · Cited by 44 · see citing works
Singh, A. K., Brito, I., & Lammerding, J. (2018) · Trends in cancer · doi:10.1016/j.trecan.2018.01.008 · Cited by 41 · see citing works
Potential Application of Living Microorganisms in the Detoxification of Heavy Metals
Chen, R., Tu, H., & Chen, T. (2022) · Foods · doi:10.3390/foods11131905 · Cited by 41 · see citing works
The intrinsic and extrinsic elements regulating inflammation
Mollaei, M., Abbasi, A., Hassan, Z. M., & Pakravan, N. (2020) · Life Sciences · doi:10.1016/j.lfs.2020.118258 · Cited by 41 · see citing works
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 39 · see citing works
Enteric Microbiota–Gut–Brain Axis from the Perspective of Nuclear Receptors
Duszka, K., & Wahli, W. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19082210 · Cited by 37 · see citing works
2D- and 3D-Based Intestinal Stem Cell Cultures for Personalized Medicine
Liu, Y., & Chen, Y.-G. (2018) · Cells · doi:10.3390/cells7120225 · Cited by 37 · see citing works
Profiling of how nociceptor neurons detect danger – new and old foes
Crosson, T., Roversi, K., Balood, M., Othman, R., Ahmadi, M., Wang, J.-C., Pereira, P. J. S., Tabatabaei, M., Couture, R., Eichwald, T., et al. (2019) · Journal of Internal Medicine · doi:10.1111/joim.12957 · Cited by 37 · see citing works
In Vitro Models of Intestine Innate Immunity
Roh, T. T., Chen, Y., Rudolph, S., Gee, M. M., & Kaplan, D. L. (2020) · Trends in biotechnology · doi:10.1016/j.tibtech.2020.07.009 · Cited by 38 · see citing works
Organoids, organs-on-chips and other systems, and microbiota
May, S., Evans, S., & Parry, L. (2017) · Emerging Topics in Life Sciences · doi:10.1042/etls20170047 · Cited by 36 · see citing works
TREGking From Gut to Brain: The Control of Regulatory T Cells Along the Gut-Brain Axis
Choi, J., Kim, B., Akuzum, B., Chang, L., Lee, J., & Kwon, H. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.916066 · Cited by 36 · see citing works
Microbial monotherapy with Prevotella histicola for patients with multiple sclerosis
Mangalam, A. K., & Murray, J. A. (2018) · Expert Review of Neurotherapeutics · doi:10.1080/14737175.2019.1555473 · Cited by 34 · see citing works
Sarrabayrouse, G., Landolfi, S., Pozuelo, M., Willamil, J., Varela, E., Clark, A. P., Campos, D., Guise, C. H.-D., Santiago, A., Machiels, K., et al. (2020) · EBioMedicine · doi:10.1016/j.ebiom.2019.102611 · Cited by 34 · see citing works
“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 · see citing works
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 · see citing works
“ramosun is considered as an inducer of Tregs in vivo (32-34).”
BackgroundGut Microbiome in Critical Illness (Review)
Александровна, Ч. Е., & Nv, B. (2018) · General Reanimatology · doi:10.15360/1813-9779-2018-5-96-119 · Cited by 33 · see citing works
Homeostatic, repertoire and transcriptional relationships between colon T regulatory cell subsets
Ramanan, D., Chowdhary, K., Candéias, S. M., Sassone‐Corsi, M., Gélineau, A., Mathis, D. J., & Benoist, C. O. (2023) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2311566120 · Cited by 32 · see citing works
“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 31 · see citing works
“adapted the air–liquid interface culture model to a microfluidic format preventing loss of architecture of the mucosa up to 40 h [30].”
Method
- 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.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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