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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A basolateral cytoplasmic process of L cells, the neuropod, establishes a functional synaptic contact with enteric glia and vagal afferents.
“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
The Introduction identifies the neuropod as an enteroendocrine-cell process escorted by enteric glia, and the Results and Discussion report direct contact with nerve fibers and evidence of synaptic connectivity. But the paper does not show a functional synapse with glia, and it says whether the connected neurons are intrinsic or extrinsic remains to be characterized; it therefore does not establish that they are vagal afferents. Page numbers are unavailable in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredEnteroendocrine and enterochromaffin cells form close synaptic connections with certain vagal afferent fibers through neuropods.
“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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BackgroundGut Microbiota, Nitric Oxide, and Microglia as Prerequisites for Neurodegenerative Disorders
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Aging Microbiota-Gut-Brain Axis in Stroke Risk and Outcome
Honarpisheh, P., Bryan, R. M., & McCullough, L. D. (2022) · Circulation Research · doi:10.1161/circresaha.122.319983 · Cited by 172 · see citing works
The Role of the Gut Microbiota in the Pathogenesis of Parkinson's Disease
Yang, D., Zhao, D., Ali Shah, S. Z., Wu, W., Lai, M., Zhang, X., Li, J., Guan, Z., Zhao, H., Li, W., et al. (2019) · Frontiers in Neurology · doi:10.3389/fneur.2019.01155 · Cited by 162 · see citing works
The Form and Function of PIEZO2
Szczot, M., Nickolls, A. R., Lam, R. M., & Chesler, A. T. (2021) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-081720-023244 · Cited by 165 · see citing works
Gut enterochromaffin cells drive visceral pain and anxiety
Bayrer, J. R., Castro, J., Venkataraman, A., Touhara, K. K., Rossen, N. D., Morrie, R. D., Maddern, J., Hendry, A., Braverman, K. N., Garcia‐Caraballo, S., et al. (2023) · Nature · doi:10.1038/s41586-023-05829-8 · Cited by 163 · see citing works
Peterson, C. T. (2020) · Journal of Evidence-Based Integrative Medicine · doi:10.1177/2515690x20957225 · Cited by 160 · see citing works
“While paracrine transmission of hormonal sensory signals from EECs has been long understood, recently the direct enteroendocrine cell to nerve contact has recently been observed in vivo via the axon-like processes of EECs.(59,69,70) Such observations lead to interesting speculation regarding the nature of a neural pat…”
BackgroundNociceptive neurons promote gastric tumour progression via a CGRP–RAMP1 axis
Zhi, X., Wu, F., Qian, J., Ochiai, Y., Lian, G., Malagola, E., Zheng, B., Tu, R., Zeng, Y., Kobayashi, H., et al. (2025) · Nature · doi:10.1038/s41586-025-08591-1 · Cited by 169 · see citing works
“Sensory nerves can interact directly with epithelial cells in the normal gut 24,27,43,44 , with regulation, for example, of enteroendocrine cells 43 and of goblet cells 24 to drive mucous production.”
Enteroendocrine Cells: Sensing Gut Microbiota and Regulating Inflammatory Bowel Diseases
Yu, Y., Yang, W., Li, Y., & Cong, Y. (2019) · Inflammatory Bowel Diseases · doi:10.1093/ibd/izz217 · Cited by 151 · see citing works
“21, 22 These studies suggest that the EECs may affect neighboring cells or neurons by exocytosis of biological mediators through a paracrine effect, or by directly activating the afferent synaptic transmission.”
BackgroundToward Understanding Microbiome-Neuronal Signaling
Jameson, K. G., Olson, C. A., Kazmi, S. A., & Hsiao, E. Y. (2020) · Molecular Cell · doi:10.1016/j.molcel.2020.03.006 · Cited by 150 · see citing works
“Separate studies suggest that subsets of ECs may synapse with 5-HT-receptive afferent fibers of chemosensory vagal or dorsal root neurons (Bellono et al., 2017; Bohórquez et al., 2015), suggesting a direct path for microbial regulation of local 5-HT to impact the central nervous system.”
BackgroundParkinson's disease: Alterations in iron and redox biology as a key to unlock therapeutic strategies
Ma, L., Azad, M. G., Dharmasivam, M., Richardson, V., Quinn, R. J., Feng, Y., Pountney, D. L., Tonissen, K. F., Mellick, G. D., Yanatori, I., et al. (2021) · Redox Biology · doi:10.1016/j.redox.2021.101896 · Cited by 148 · see citing works
“enteroendocrine cells contain α-synuclein [18] and synapse with enteric nerves, forming a neuroepithelial circuit [19].”
BackgroundMultifunctional microelectronic fibers enable wireless modulation of gut and brain neural circuits
Sahasrabudhe, A., Rupprecht, L. E., Orguc, S., Khudiyev, T., Tanaka, T., Sands, J., Zhu, W., Tabet, A., Manthey, M., Allen, H., et al. (2023) · Nature Biotechnology · doi:10.1038/s41587-023-01833-5 · Cited by 150 · see citing works
Self-citationMicrobiota–neuroepithelial signalling across the gut–brain axis
Ohara, T. E., & Hsiao, E. Y. (2025) · Nature Reviews Microbiology · doi:10.1038/s41579-024-01136-9 · Cited by 147 · see citing works
“…insights into the role of immune cells in coordinating brain–body circuits and enteric glia in shaping intestinal neural activity 13,116 , microbiota–neuroepithelial interactions probably involve the influence of multiple cellular inputs as part of a larger interconnected web of biological systems.”
Microbiota‐gut‐brain axis as a regulator of reward processes
García‐Cabrerizo, R., Carbia, C., O’Riordan, K. J., Schellekens, H., & Cryan, J. F. (2020) · Journal of Neurochemistry · doi:10.1111/jnc.15284 · Cited by 147 · see citing works
“Recently, a new route of communication between EECs and the enteric nervous system has been described (Bohórquez et al., 2014, 2015; Kaelberer et al., 2018).”
BackgroundThe Gut and Parkinson's Disease—A Bidirectional Pathway
Santos, S. F., de Oliveira, H. L., Yamada, E. S., Neves, B. C., & Pereira, A. (2019) · Frontiers in Neurology · doi:10.3389/fneur.2019.00574 · Cited by 144 · see citing works
Enteric nervous system: the bridge between the gut microbiota and neurological disorders
Geng, Z.-H., Zhu, Y., Li, Q.-L., Zhao, C., & Zhou, P.-H. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2022.810483 · Cited by 144 · see citing works
“…are molecular signatures that are highly conserved across whole classes of microbes but are absent in the host, such as LPS or polysaccharide A (PSA) on the surface of gram-negative bacteria or peptidoglycan (PGN) on the surface of gram-positive bacteria (Medzhitov, 2007; Boller and Felix, 2009).”
BackgroundThe metabolic role of vagal afferent innervation
Waise, T. M. Z., Dranse, H. J., & Lam, T. K. T. (2018) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-018-0062-1 · Cited by 140 · see citing works
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 137 · see citing works
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 130 · see citing works
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 131 · see citing works
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 128 · see citing works
“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 125 · see citing works
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 · see citing works
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 118 · see citing works
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 116 · see citing works
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 · see citing works
“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 · see citing works
“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 116 · see citing works
“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 · see citing works
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 110 · see citing works
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 107 · see citing works
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 107 · see citing works
“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 103 · see citing works
Puzan, M. L., Hosic, S., Ghio, C., & Koppes, A. N. (2018) · Scientific Reports · doi:10.1038/s41598-018-24768-3 · Cited by 100 · see citing works
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 110 · see citing works
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 · see citing works
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 99 · see citing works
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 96 · see citing works
“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 96 · see citing works
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 92 · see citing works
“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 92 · see citing works
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 · see citing works
“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 91 · see citing works
“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 91 · see citing works
“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 92 · see citing works
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 · see citing works
Cellular Organization of Neuroimmune Interactions in the Gastrointestinal Tract
Margolis, K., Gershon, M., & Bogunovic, M. (2016) · Trends in immunology · doi:10.1016/j.it.2016.05.003 · Cited by 79 · see citing works
“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 88 · see citing works
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 90 · see citing works
“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 83 · see citing works
“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
- 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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