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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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“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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“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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Does gut brain axis has an impact on Parkinson’s disease (PD)?
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Revisiting the concept of incretin and enteroendocrine L-cells as type 2 diabetes mellitus treatment
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Vagus Nerve Mediated Liver-Brain-Axis Is a Major Regulator of the Metabolic Landscape in the Liver
Brito, C. F., Fonseca, R. C., Rodrigues‐Ribeiro, L., Guimarães, J. S. F., Vaz, B. F., Tofani, G. S. S., Batista, A. C. S., Diniz, A. B., Fernandes, P., Nunes, N. A. M., et al. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26052166 · Cited by 17
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“…release hormones and transmitters when appropriately stimulated (Cox 2016; Gribble and Reimann 2016; Kaji and Kaunitz 2017; Steensels and Depoortere 2018) and appear to have synaptic-like connections to sensory neurons and/or subepithelial glial cells (Bohorquez et al. 2015; Bellono et al. 2017).”
Glucose Sensing in the Hepatic Portal Vein and Its Role in Food Intake and Reward
Bacharach, S. Z., Tordoff, M. G., & Alhadeff, A. L. (2023) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2023.03.012 · Cited by 17
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BackgroundCrucial Role of Central Nervous System as a Viral Anatomical Compartment for HIV-1 Infection
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BackgroundThe olfactory receptor Olfr78 promotes differentiation of enterochromaffin cells in the mouse colon
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Sodium oligomannate activates the enteroendocrine-vagal afferent pathways in APP/PS1 mice
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“An important progress in the fi eld is the discovery of direct synaptic connections between EECs and vagal afferent terminals, which may represent a rapid pathway for the transduction and transmission of gastrointestinal signals to the brain [10, 13, 15].”
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“Studies (Bohorquez et al. 2015; Janssen et al. 2011) reported that the enteroendocrine cells in the small intestine were able to sense the simple nutrient signals (e.g. amino acids and fatty acids) and to release satiety related peptides (e.g. cholecystokinin CCK and peptide YY).”
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“They call this EEC innervation neuropod cells [50].”
BackgroundThiriet, M. (2018) · Biomathematical and biomechanical modeling of the circulatory and ventilatory systems · doi:10.1007/978-3-319-89315-0_5 · Cited by 14
Dual real-time in vivo monitoring system of the brain-gut axis
Nishimura, Y., Fukuda, Y., Okonogi, T., Yoshikawa, S., Karasuyama, H., Osakabe, N., Ikegaya, Y., Sasaki, T., & Adachi, T. (2020) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2020.01.090 · Cited by 13
“Gut-sensing information is transmitted to the central nervous system (CNS) through sensory neurons [2,6,7].”
BackgroundZhang, J., Zhou, Y., Mei, X., Yan, S., Mao, J. Y., Li, Y., Bian, Z., Li, L., Ji, D., Lu, T., et al. (2026) · Journal of Neuroinflammation · doi:10.1186/s12974-026-03763-w · Cited by 16
“Direct synaptic connections between enteroendocrine cells and sensory neurons form a neuroepithelial circuit for immediate gut-to-brain signal transmission [97–100]. the secretion of 5-HT from enteroendocrine cells, which subsequently stimulates enteric neurons and vagal sensory ganglia [99].”
Zhang, Q., Liu, Y., Tang, R., Kong, S., Lv, D., Li, H., Yang, H., & Lin, L. (2024) · Carbohydrate Polymer Technologies and Applications · doi:10.1016/j.carpta.2024.100567 · Cited by 12
Lewy body diseases and the gut
Sampson, T. R., Tansey, M. G., West, A. B., & Liddle, R. A. (2025) · Molecular Neurodegeneration · doi:10.1186/s13024-025-00804-5 · Cited by 13
Self-citationChristensen, L. F. B., Alijanvand, S. H., Burdukiewicz, M., Herbst, F., Kjeldal, H., Dueholm, M. S., & Otzen, D. E. (2021) · Protein Science · doi:10.1002/pro.4137 · Cited by 11
“Enteric nerve fibers extend through the different layers of the GI tract and have been shown to connect directly with enteroendocrine cells (EECs).(15) Both EECs and intestinal epithelial cells express Toll-like receptors (TLRs) 1, 2 and 4(16) and are therefore able to recognize different structures, often referred to…”
BackgroundRole of Wnt signaling in the maintenance and regeneration of the intestinal epithelium
Gasnier, M., Lim, H. Y. G., & Barker, N. (2023) · Current topics in developmental biology/Current Topics in Developmental Biology · doi:10.1016/bs.ctdb.2023.01.001 · Cited by 14
From organotypic culture to body‐on‐a‐chip: A neuroendocrine perspective
Schwerdtfeger, L., & Tobet, S. A. (2018) · Journal of Neuroendocrinology · doi:10.1111/jne.12650 · Cited by 13
Mulak, A. (2019) · Expert Review of Neurotherapeutics · doi:10.1080/14737175.2020.1701437 · Cited by 13
The Microbiome–Neurodegeneration Interface: Mechanisms, Evidence, and Future Directions
Böckels, L., Alexa, D., Antal, D. C., Gațcan, C., Alecu, C., Kacani, K., Cretu, R. A., Piseru, E.-A., Bîlcu, R. V., & Cuciureanu, D. I. (2026) · Cells · doi:10.3390/cells15020135 · Cited by 13
Nutrient sensing in the gut and the regulation of appetite
Gribble, F. M., & Reimann, F. M. (2022) · Current Opinion in Endocrine and Metabolic Research · doi:10.1016/j.coemr.2022.100318 · Cited by 12
Zhu, Z., Wu, Y., Liu, Z., Li, Y., & Jiang, M. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23169358 · Cited by 11
“A further study [36,37] has shown that Neuropod cells use glutamate as a neurotransmitter that can rapidly process glucose stimuli.”
BackgroundTau expression and phosphorylation in enteroendocrine cells
Chapelet, G., Béguin, N., Castellano, B., Grit, I., de Coppet, P., Oullier, T., Neunlist, M., Blottière, H. M., Rolli‐Derkinderen, M., Dréan, G. L., et al. (2023) · Frontiers in Neuroscience · doi:10.3389/fnins.2023.1166848 · Cited by 13
“Morphologically, EEC were shown to exhibit neuronlike features including the expression of pre- and post-synaptic proteins together with the presence of neurite-like processes, called neuropods (Bohórquez et al., 2015).”
BackgroundNeutrophils in the Focus: Impact on Neuroimmune Dynamics and the Gut–Brain Axis
Kršek, A., & Batičić, L. (2024) · Gastrointestinal Disorders · doi:10.3390/gidisord6030039 · Cited by 13
“These cells sense luminal contents, including metabolites and endotoxins, and produce over twenty hormones that regulate food consumption, GI motility, and secretion via the enteric ENS [165,173,174].”
BackgroundYoshioka, Y., Tachibana, Y., Uesaka, T., Hioki, H., Sato, Y., Fukumoto, T., & Enomoto, H. (2022) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2022.03.117 · Cited by 10
Anatomical basis of gastrin- and CCK-secreting cells and their functions. A review
Iwanaga, T. (2023) · Biomedical Research · doi:10.2220/biomedres.44.81 · Cited by 11
Effects of AP-1 and NF-κB inhibitors on colonic endocrine cells in rats with TNBS-induced colitis
El‐Salhy, M., & Umezawa, K. (2016) · Molecular Medicine Reports · doi:10.3892/mmr.2016.5444 · Cited by 11
“These cells were flask‐shaped and occasionally contained a long basal cytoplasmic process, often known as a ‘neuropod’ (43-46) (Figs.”
BackgroundMechanisms of the effect of gut microbes on depression through the microbiota-gut-brain axis
Zhou, X., Wang, S., Wang, X., Chen, X., Zhou, P., Ma, K., & Zhang, P. (2025) · Frontiers in Nutrition · doi:10.3389/fnut.2025.1634548 · Cited by 14
“The ECC releases neuropeptides, including cholecystokinin, transmitting signs from epithelium to submucosal plexus and central nervous system, therefore modulating metabolism (e.g., 5-HT and kynurenine) within the MGB axis (149, 150).”
Michalak, M., Katzenmaier, E., Roeckel, N., Woerner, S. M., Fuchs, V., Warnken, U. H., Yuan, Y. P., Peer Bork, B., Neu‐Yilik, G., Kulozik, A. E., et al. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21155234 · Cited by 10
“However, in this context, it is interesting to note that a recent transgenic mouse study uncovered direct physical contact between enteroendocrine cells and neurons innervating the small intestine and colon [35].”
BackgroundAbdellah, N., Remoortel, S. V., Mohey‐Elsaeed, O., Mustafa, M., Ahmed, Y. A., Timmermans, J., & Buckinx, R. (2018) · The Anatomical Record · doi:10.1002/ar.23780 · Cited by 10
Fundamental Neurochemistry Review: The role of enteroendocrine cells in visceral pain
Londregan, A., Alexander, T. D., Covarrubias, M., & Waldman, S. A. (2023) · Journal of Neurochemistry · doi:10.1111/jnc.16022 · Cited by 12
“However, these fibers may form synapses with hybrid visceral structures with neuron-like properties at their peripheral terminals (Bohórquez et al., 2015).”
BackgroundXie, Z.-F., Wang, S., Gao, Y., Zhang, Y.-D., Han, Y., Huang, J., Gao, M.-N., & Wang, C.-G. (2024) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-024-05091-0 · Cited by 9
“This information may exert anti-inflammatory and neuroprotective effects through the intestinal activation of VN afferent fiber neurons [105, 107, 109].”
Gut neuropeptide involvement in Parkinson’s disease
Templeton, H., Tobet, S. A., & Schwerdtfeger, L. (2025) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00383.2024 · Cited by 11
NMDA Receptor Antagonists Increase the Release of GLP-1 From Gut Endocrine Cells
Cyranka, M., Monfeuga, T., Vedovato, N., Larabee, C. M., Chandran, A., Toledo, E. M., & de Wet, H. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.861311 · Cited by 9
“However, it is well established that enteroendocrine cells form direct, physical contacts with extrinsic enteric-associated neurons (both the sensory afferents and autonomic efferents) which innervate the gut and directly link the gut to the brain via the vagus nerve (Bohórquez et al., 2015; Kaelberer et al., 2018).”
BackgroundNeuroimmunophysiology of the gastrointestinal tract
McKay, D. M., Defaye, M., Rajeev, S., MacNaughton, W. K., Nasser, Y., & Sharkey, K. A. (2024) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00075.2024 · Cited by 9
Duodenal chemosensory system: enterocytes, enteroendocrine cells, and tuft cells
Akiba, Y., Hashimoto, S., & Kaunitz, J. D. (2020) · Current Opinion in Gastroenterology · doi:10.1097/mog.0000000000000685 · Cited by 10
“Monosynaptic rabies virus tracing from lumen to subepithelial nerves [30] indicates that the epithelium monitors the luminal environment by subepithelial sensory neural pathways.”
BackgroundBody-first Parkinson’s disease and variant Creutzfeldt–Jakob disease – similar or different?
Woerman, A. L., & Tamgüney, G. (2022) · Neurobiology of Disease · doi:10.1016/j.nbd.2022.105625 · Cited by 8
“EECs, which face the lumen of the gut, have axon-like processes on the basal surface of the cell that connect with enteric neurons expressing α-synuclein (Bohorquez et al., 2015).”
BackgroundHerath, M., Cho, H., Marklund, U., Franks, A. E., Bornstein, J. C., & Hill‐Yardin, E. L. (2023) · Biomolecules · doi:10.3390/biom13071063 · Cited by 9
“Although initial studies of NLGN3 expression in the GI tract have been reported in rodents [7,14,15] and humans [14], the distribution of NLGN3 expression in different cell populations of the mouse enteric nervous system has not been profiled.”
BackgroundA direct effect of the autonomic nervous system on somatic stem cell proliferation?
Davis, E. A., & Dailey, M. J. (2018) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00266.2018 · Cited by 8
“In particular, SNS nerve terminals are densely concentrated at the base of the crypt where the IESCs are located (23, 41), whereas PNS nerves make direct synaptic contact with intestinal epithelial cells (10).”
BackgroundShaaban, A., Maaß, F., Schwarze, V., Lund, M. L., Beuermann, S., Chan, M., Harenberg, C., Bewick, G. A., Keating, D. J., Benseler, F., et al. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.05.28.446100 · Cited by 8
Gut microbiota: the indispensable player in neurodegenerative diseases
Li, S., Cai, Y., Wang, S., Luo, L., Zhang, Y., Huang, K., & Guan, X. (2024) · Journal of the Science of Food and Agriculture · doi:10.1002/jsfa.13509 · Cited by 11
Spinal sensory innervation of the intestine
Wolfson, R. L. (2025) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2025.102973 · Cited by 9
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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