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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 capsaicin receptor: a heat-activated ion channel in the pain pathway
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“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
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InfluentialSingle Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche
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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×
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BackgroundModeling Development and Disease with Organoids
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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×
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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×
“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).”
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×
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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×
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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×
“(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×
“…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 922
Sustained in vitro intestinal epithelial culture within a Wnt-dependent stem cell niche
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“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×
“, 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 + 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×
“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 + 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×
“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×
“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
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×
“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×
“…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 607 · cited 2×
“…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×
“…(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×
“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
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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 386
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“…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 345
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 242 · cited 2×
“…(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×
“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×
“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×
“…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×
“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×
“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
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
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 106 · cited 1×
“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×
“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 89 · cited 1×
“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×
“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
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×
“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×
“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×
“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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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.
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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