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Neuroepithelial circuit formed by innervation of sensory enteroendocrine cells
Open accessAbstract
Satiety and other core physiological functions are modulated by sensory signals arising from the surface of the gut. Luminal nutrients and bacteria stimulate epithelial biosensors called enteroendocrine cells. Despite being electrically excitable, enteroendocrine cells are generally thought to communicate indirectly with nerves through hormone secretion and not through direct cell-nerve contact. However, we recently uncovered in intestinal enteroendocrine cells a cytoplasmic process that we named neuropod. Here, we determined that neuropods provide a direct connection between enteroendocrine cells and neurons innervating the small intestine and colon. Using cell-specific transgenic mice to study neural circuits, we found that enteroendocrine cells have the necessary elements for neurotransmission, including expression of genes that encode pre-, post-, and transsynaptic proteins. This neuroepithelial circuit was reconstituted in vitro by coculturing single enteroendocrine cells with sensory neurons. We used a monosynaptic rabies virus to define the circuit's functional connectivity in vivo and determined that delivery of this neurotropic virus into the colon lumen resulted in the infection of mucosal nerves through enteroendocrine cells. This neuroepithelial circuit can serve as both a sensory conduit for food and gut microbes to interact with the nervous system and a portal for viruses to enter the enteric and central nervous systems.
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“Enteroendocrine and enterochromaffin cells (ECCs) form close synaptic connections with certain vagal afferent fibers through cell extensions called neuropods [25, 26].”
From Role of diet and its effects on the gut microbiome in the pathophysiology of mental disorders (2022) · cites this paper as [26]
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“A basolateral cytoplasmic process of the L cells -the neuropod -was shown to establish a functional synaptic contact with the enteric glia and vagal afferents.”
From The Microbiota-Gut-Brain Axis (2019) · cites this paper as Bohorquez et al., 2015
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The metabolic role of vagal afferent innervation
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Eicher, A. K., Kechele, D. O., Sundaram, N., Berns, H. M., Poling, H. M., Haines, L. E., Sanchez, J. G., Kishimoto, K., Krishnamurthy, M., Han, L., et al. (2021) · Cell stem cell · doi:10.1016/j.stem.2021.10.010 · Cited by 140
Gut feelings: mechanosensing in the gastrointestinal tract
Mercado‐Perez, A., & Beyder, A. (2022) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-021-00561-y · Cited by 138
Gut microbiota regulates neuropathic pain: potential mechanisms and therapeutic strategy
Lin, B., Wang, Y., Zhang, P., Yuan, Y., Zhang, Y., & Chen, G. (2020) · The Journal of Headache and Pain · doi:10.1186/s10194-020-01170-x · Cited by 137
Self-citationEnteric neuroimmune interactions coordinate intestinal responses in health and disease
Wang, H., Foong, J. P. P., Harris, N. L., & Bornstein, J. C. (2021) · Mucosal Immunology · doi:10.1038/s41385-021-00443-1 · Cited by 130
“1).(50) This is most prominent for a subclass of EE cell, enterochromaffin (EC) cells, which synthesize and release 5-hydroxytryptamine (5-HT, serotonin).”
BackgroundVagal sensory neurons and gut-brain signaling
Yu, C. D., Xu, Q. J., & Chang, R. B. (2020) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2020.03.006 · Cited by 135
Microbial involvement in Alzheimer disease development and progression
Bulgart, H. R., Neczypor, E. W., Wold, L. E., & Mackos, A. R. (2020) · Molecular Neurodegeneration · doi:10.1186/s13024-020-00378-4 · Cited by 116
High fat diet induces microbiota-dependent silencing of enteroendocrine cells
Ye, L., Mueller, O., Bagwell, J., Bagnat, M., Liddle, R. A., & Rawls, J. F. (2019) · eLife · doi:10.7554/elife.48479 · Cited by 120
Self-citationNeuroimmunophysiology of the gut: advances and emerging concepts focusing on the epithelium
Sharkey, K. A., Beck, P. L., & McKay, D. M. (2018) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-018-0051-4 · Cited by 117
Schlieve, C. R., Fowler, K. L., Thornton, M. E., Huang, S., Hajjali, I., Hou, X., Grubbs, B. H., Spence, J. R., & Grikscheit, T. C. (2017) · Stem Cell Reports · doi:10.1016/j.stemcr.2017.07.017 · Cited by 115
“EECs express cellular elements necessary for neurotransmission and, in themature intestine, serve as part of a neuroepithelial circuit important in enteric sensory activity (Bohorquez et al., 2015).”
BackgroundKUWAHARA, A., MATSUDA, K., KUWAHARA, Y., ASANO, S., INUI, T., & MARUNAKA, Y. (2020) · Biomedical Research · doi:10.2220/biomedres.41.199 · Cited by 112
“In addition to paracrine or hormonal signaling mechanisms, a synapse may form between the EECs and enteric nerves projecting to the epithelium (Bohórquez et al. 2015).”
BackgroundNeuroimmune Communication in Health and Disease
Reardon, C., Murray, K. M., & Lomax, A. E. (2018) · Physiological Reviews · doi:10.1152/physrev.00035.2017 · Cited by 119
“Elegant studies have demonstrated synapses between EEC and the underlying afferent innervation and that these interactions occur throughout the gastrointestinal tract including in the colon (26, 27).”
BackgroundYonekura, S., Terrisse, S., Alves Costa Silva, C., Lafarge, A., Iebba, V., Ferrere, G., Goubet, A.-G., Fahrner, J.-E., Lahmar, I., Ueda, K., et al. (2022) · Cancer Discovery · doi:10.1158/2159-8290.cd-21-0999 · Cited by 112
Organ and brain crosstalk: The liver-brain axis in gastrointestinal, liver, and pancreatic diseases
Matsubara, Y., Kiyohara, H., Teratani, T., Mikami, Y., & Kanai∥, T. (2021) · Neuropharmacology · doi:10.1016/j.neuropharm.2021.108915 · Cited by 116
Gutsy Moves: The Amygdala as a Critical Node in Microbiota to Brain Signaling
Cowan, C. S. M., Hoban, A. E., Ventura‐Silva, A. P., Dinan, T. G., Clarke, G. A., & Cryan, J. F. (2017) · BioEssays · doi:10.1002/bies.201700172 · Cited by 110
Gut Microbiota Interaction with the Central Nervous System throughout Life
Ojeda, J., Ávila, A., & Vidal, P. M. (2021) · Journal of Clinical Medicine · doi:10.3390/jcm10061299 · Cited by 112
“These cells elongate in the presence of trophic factors, such as neurotrophins, and are supported by enteric glia to contact a nerve terminal [14].”
BackgroundGut peptides and the microbiome: focus on ghrelin
Leeuwendaal, N. K., Cryan, J. F., & Schellekens, H. (2021) · Current Opinion in Endocrinology Diabetes and Obesity · doi:10.1097/med.0000000000000616 · Cited by 106
Puzan, M. L., Hosic, S., Ghio, C., & Koppes, A. N. (2018) · Scientific Reports · doi:10.1038/s41598-018-24768-3 · Cited by 100
Enteric nervous system and intestinal epithelial regulation of the gut-brain axis
Dowling, L. R. C., Strazzari, M. R., Keely, S., & Kaiko, G. E. (2022) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2022.07.015 · Cited by 112
The critical role of CCK in the regulation of food intake and diet-induced obesity
Cawthon, C. R., & Serre, C. B. D. L. (2021) · Peptides · doi:10.1016/j.peptides.2020.170492 · Cited by 99
Qiao, C.-M., Sun, M., Jia, X.-B., Shi, Y. W., Zhang, B.-P., Zhou, Z.-L., Zhao, L., Cui, C., & Shen, Y. (2019) · Experimental Cell Research · doi:10.1016/j.yexcr.2019.111772 · Cited by 101
Biologically inspired approaches to enhance human organoid complexity
Holloway, E. M., Capeling, M. M., & Spence, J. R. (2019) · Development · doi:10.1242/dev.166173 · Cited by 99
“One caveat to this model was that the neurons failed to associate with the HIO epithelium, whereas in the native intestine the ENS forms connections with the enteroendocrine cells of the epithelium to convey nutrient sensing information (Bohórquez et al., 2015).”
BackgroundRole of enteric glia and microbiota-gut-brain axis in parkinson disease pathogenesis
dos Santos, J. C. C., Lima, M. P. P., Brito, G. A. D. C., & Viana, G. S. D. B. (2022) · Ageing Research Reviews · doi:10.1016/j.arr.2022.101812 · Cited by 100
Organ-on-Chip Approaches for Intestinal 3D In Vitro Modeling
Pimenta, J. M., Ribeiro, R. D. C., Almeida, R., Costa, P. F., da Silva, M. A., & Pereira, B. (2021) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2021.08.015 · Cited by 94
“0 DTD JCMGH877 proof 11 ENS is thought to be linked with the intestinal epithelium by neuronal and glial projections that connect to enteroendocrine cells.(79) Studies have focused on the interplay of the intestinal mucosa with the ENS.”
BackgroundNeuro-immune regulation of mucosal physiology
Chesné, J., Cardoso, V., & Veiga‐Fernandes, H. (2018) · Mucosal Immunology · doi:10.1038/s41385-018-0063-y · Cited by 94
Reappraising the role of the vagus nerve in GLP-1-mediated regulation of eating
Brierley, D. I., & de Lartigue, G. (2022) · British Journal of Pharmacology · doi:10.1111/bph.15603 · Cited by 92
“In support of this idea, vagal sensory fibres abundantly terminate in the intestinal mucosa in close apposition to enteroendocrine cells of the villi (Boh orquez et al., 2015; Richards et al., 2014).”
BackgroundPharmacology and physiology of gastrointestinal enteroendocrine cells
Mace, O. J., Tehan, B. G., & Marshall, F. H. (2015) · Pharmacology Research & Perspectives · doi:10.1002/prp2.155 · Cited by 93
“1G) (Chen et al. 2006; Bohorquez and Liddle 2011, 2015; Bohorquez et al. 2011, 2014, 2015).”
Dissecting the Physiology and Pathophysiology of Glucagon-Like Peptide-1
Paternoster, S., & Falasca, M. (2018) · Frontiers in Endocrinology · doi:10.3389/fendo.2018.00584 · Cited by 92
“Surprisingly, the EECs in the colon have been demonstrated to physically connect through a basal process named Neuropod, with afferent nerve cells residing in the lamina propria, defining a neuroepithelial circuit that expands the physiology of these cells (59).”
BackgroundDissecting the Role of Subtypes of Gastrointestinal Vagal Afferents
Wang, Y. B., de Lartigue, G., & Page, A. J. (2020) · Frontiers in Physiology · doi:10.3389/fphys.2020.00643 · Cited by 98
Self-citationMechanosensitive Piezo Channels in the Gastrointestinal Tract
Alcaino, C., Farrugia, G., & Beyder, A. (2017) · Current topics in membranes · doi:10.1016/bs.ctm.2016.11.003 · Cited by 89
Cellular 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
“Microbial signals may activate enteric neurons indirectly; enteroendocrine cells are able to transmit luminal chemosensory signals to neurons through the release of hormones as well as through synaptic transmission to sensory neurons [107].”
BackgroundNeto, D. P. A., Bosque, B. P., de Godoy, J. V. P., Rodrigues, P. V., Meneses, D. D., Tostes, K., Tonoli, C. C. C., Carvalho, H. F., González-Billault, C. E., & Fonseca, M. D. C. (2022) · iScience · doi:10.1016/j.isci.2022.103908 · Cited by 90
Enteroendocrine cell regulation of the gut-brain axis
Barton, J. R., Londregan, A., Alexander, T. D., Entezari, A. A., Covarrubias, M., & Waldman, S. A. (2023) · Frontiers in Neuroscience · doi:10.3389/fnins.2023.1272955 · Cited by 95
“Rabies tracing from CCK+ and PYY+ EECs revealed that these pseudopods formed direct synaptic connections with peripheral neurons, and that these connections could be recapitulated in vitro (Bohórquez et al., 2015).”
BackgroundAdvances in Enteric Neurobiology: The “Brain” in the Gut in Health and Disease
Kulkarni, S., Ganz, J., Bayrer, J. R., Becker, L. S., Bogunovic, M., & Rao, M. (2018) · Journal of Neuroscience · doi:10.1523/jneurosci.1663-18.2018 · Cited by 85
“The average life span of most intestinal epithelial cells is only 5–7 d, but some EECs can persist for 60 d (Bohórquez et al., 2015).”
BackgroundInfluential
Metadata
- Authors
- Bohórquez, D. V., Shahid, R. A., Erdmann, A., Kreger, A. M., Wang, Y., Calakos, N., Wang, F., & Liddle, R. A.
- Affiliations
- Duke Medical Center (US)
- Durham VA Medical Center (US)
- Venue
- Journal of Clinical Investigation
- Published
- 2015-01-02
- Volume
- 125
- Issue
- 2
- Pages
- 782-786
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC4319442
- OpenAlex
- W2119429325
- Cited by
- 484
- References
- 28
- Citations by year
- 2026: 42 · 2025: 51 · 2024: 45 · 2023: 45 · 2022: 47 · 2021: 60 · 2020: 47 · 2019: 38 · 2018: 41 · 2017: 22 · 2016: 29 · 2015: 17
- FWCI
- 38.12
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- DukeSpace (Duke University) (submittedVersion)
- DukeSpace (Duke University) (submittedVersion, cc-by-nc-nd)
- Funders
- U.S. Department of Veterans Affairs (I01 BX002230)
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (F32DK094704, R01DK098796, R01DK091946, K01DK103832)
- Topics
- Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Keywords
- enteroendocrine cells, sensory neurons, enteric nervous system, neurotransmission, gut-brain signaling, satiety, rabies virus, small intestine
- MeSH terms
- Animals, Cell Communication, Cells, Cultured, Colon, Intestine, Small, Coculture Techniques, Enteroendocrine Cells, Neuroepithelial Cells, Mice
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