A neuropod cell is a specialized enteroendocrine cell (i.e., sensory epithelial cell) within the gut that is capable of synapsing with afferent nerves.[2][3] Previously, transmission of sensory signals from enteroendocrine cells were thought to only occur in a paracrine fashion, in which secreted peptide hormones diffused through the lamina propria and contacted either intrinsic or extrinsic neurons, entered the circulation, and/or acted on specific target tissues.[4][5] However, neuropod cells, discovered by Dr. Diego V. Bohórquez in 2015 and later coined in 2018, were observed forming synaptic connections with nerves in the mucosa of the small and large intestine of rodents.[3][6] These synapses were revealed to involve neurons originating from the dorsal root ganglia and the vagal nodose ganglia of the spinal cord, which suggested that sensory information from the gut lumen could be conveyed to the brain within milliseconds of activation.[6] Also, it was found that these neuropod cells contained both pre- and postsynaptic proteins, suggesting that information could not only be conveyed to, but also received by neurons.[3][6][7] This newly found transmission mechanism of luminal senses from the gut to the brain may spark a new area of exploration within the gut-brain axis and sensory neurobiology.

This is a 3D reconstruction of a neuropod cell utilizing a serial block face scanning electron microscopy (SBEM) data set in Imaris software.[1] On the left side of the cell has microvilli extending into the gut lumen and the right side has a neuropod extending into the basal lamina propria.[1]

Nutrient sensing and behavior

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Although it has been understood for some time that there is a relationship between consumed food, cravings, and bodily health, it is only of recent that the mechanisms underlying gut sensation of food have been discovered. Integral to this sensation of nutrients and the regulation of postprandial physiology are enteroendocrine cells.[8] These cells are not only able to assess nutrient content of ingested food by sensing glucose, fatty acids, amino acids, monoacylglycerols, and oligopeptides, but they may also drive appetitive decisions.[8][9] Although sugar and artificial sweeteners generate a sweet taste, natural sugar is preferred and can even be distinguished from artificial sweeteners by mice lacking taste receptors.[10][11][12] This suggests that the gut is important for not only discerning between the two sugars, but also guiding the animal's preference for the natural sugar over the artificial sweetener. Upon infusion of natural sugar or artificial sweetener into the small intestine, duodenal neuropod cells transduced luminal information onto distinct vagal nodose neuron populations either through glutamatergic neurotransmission (sucrose) or purinergic neurotransmission (sucralose).[9] Moreover, the animal's preference for sucrose over sucralose was abolished (90.8% to 58.9% sucrose preference) after utilizing a flexible fiberoptic cable (optogenetics) to selectively silence duodenal neuropod cells.[9] These data suggest that duodenal neuropod cells are not only capable of distinguishing natural sugar from artificial sweetener by utilizing different neurotransmitters and through activation of different neuronal populations, but they also capable of driving appetitive preferences for the natural sugar.

Microbial interactions

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Gut microbiota have been known to prime the immune system and to aid in the preservation of a healthy central nervous system, which has been extensively documented in germ-free and gnotobiotic mice that present with overzealous immune systems and an abundance of neurological deficits.[13][14] Interestingly, within these germ-free mice the general abundance of chromogranin A-positive enteroendocrine cells decreased in the ileum and increased in the colon, suggesting a potential connection between the microbiota and the normal distribution of gut sensory cells.[15] Furthermore, human and murine enteroendocrine cells possess receptors for microbe-associated molecular patterns (MAMPS) like bacterial lipopolysaccharide (LPS) and receptors for a range of bacterial metabolites like short chain fatty acids (SCFAs).[16][17] The presence of these receptors suggest that the synaptically connected neuropod cells may be responsible for detecting microbial signals and metabolites within the gut lumen and then conveying said information to the brain. Finally, specific pathogenic bacteria (e.g., Chlamydia trachomatis) have been implicated in the pathogenesis of irritable bowel syndrome by directly infecting enteroendocrine cells and upregulating distinct neurotransmitter transporters like glutamate.[18][19] Also, helminth infections with Trichinella spiralis can lead to a significant reduction in food consumption, which is dependent on enteroendocrine cell presence and abundance.[20] These findings suggest that not only can pathogenic bacteria gain access to neuropod cells and possibly the associated central nervous system, but they may also be able to direct behavior of the host.

References

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  1. ^ a b Bohórquez, Diego V.; Samsa, Leigh A.; Roholt, Andrew; Medicetty, Satish; Chandra, Rashmi; Liddle, Rodger A. (2014). "An enteroendocrine cell-enteric glia connection revealed by 3D electron microscopy". PLOS ONE. 9 (2): e89881. Bibcode:2014PLoSO...989881B. doi:10.1371/journal.pone.0089881. ISSN 1932-6203. PMC 3935946. PMID 24587096.
  2. ^ Liu, WW; Bohórquez, DV (October 2022). "The neural basis of sugar preference". Nature Reviews. Neuroscience. 23 (10): 584–595. doi:10.1038/s41583-022-00613-5. PMC 9886228. PMID 35879409.
  3. ^ a b c Bohórquez, Diego V.; Shahid, Rafiq A.; Erdmann, Alan; Kreger, Alex M.; Wang, Yu; Calakos, Nicole; Wang, Fan; Liddle, Rodger A. (2015-01-02). "Neuroepithelial circuit formed by innervation of sensory enteroendocrine cells". Journal of Clinical Investigation. 125 (2): 782–786. doi:10.1172/jci78361. ISSN 0021-9738. PMC 4319442. PMID 25555217. S2CID 3532608.
  4. ^ Bertrand, Paul (2009). "The cornucopia of intestinal chemosensory transduction". Frontiers in Neuroscience. 3: 48. doi:10.3389/neuro.21.003.2009. ISSN 1662-453X. PMC 3112321. PMID 20582275.
  5. ^ Cummings, David E.; Overduin, Joost (2007-01-02). "Gastrointestinal regulation of food intake". Journal of Clinical Investigation. 117 (1): 13–23. doi:10.1172/jci30227. ISSN 0021-9738. PMC 1716217. PMID 17200702.
  6. ^ a b c Kaelberer, Melanie Maya; Rupprecht, Laura E.; Liu, Winston W.; Weng, Peter; Bohórquez, Diego V. (2020-07-08). "Neuropod Cells: The Emerging Biology of Gut-Brain Sensory Transduction". Annual Review of Neuroscience. 43 (1): 337–353. doi:10.1146/annurev-neuro-091619-022657. ISSN 0147-006X. PMC 7573801. PMID 32101483.
  7. ^ Bellono, Nicholas W.; Bayrer, James R.; Leitch, Duncan B.; Castro, Joel; Zhang, Chuchu; O’Donnell, Tracey A.; Brierley, Stuart M.; Ingraham, Holly A.; Julius, David (June 2017). "Enterochromaffin Cells Are Gut Chemosensors that Couple to Sensory Neural Pathways". Cell. 170 (1): 185–198.e16. doi:10.1016/j.cell.2017.05.034. ISSN 0092-8674. PMC 5839326. PMID 28648659.
  8. ^ a b Psichas, Arianna; Reimann, Frank; Gribble, Fiona M. (2015-02-09). "Gut chemosensing mechanisms". Journal of Clinical Investigation. 125 (3): 908–917. doi:10.1172/jci76309. ISSN 0021-9738. PMC 4362249. PMID 25664852.
  9. ^ a b c Buchanan, Kelly L.; Rupprecht, Laura E.; Kaelberer, M. Maya; Sahasrabudhe, Atharva; Klein, Marguerita E.; Villalobos, Jorge A.; Liu, Winston W.; Yang, Annabelle; Gelman, Justin; Park, Seongjun; Anikeeva, Polina; Bohórquez, Diego V. (February 2022). "The preference for sugar over sweetener depends on a gut sensor cell". Nature Neuroscience. 25 (2): 191–200. doi:10.1038/s41593-021-00982-7. ISSN 1546-1726. PMC 8825280. PMID 35027761.
  10. ^ Damak, Sami; Rong, Minqing; Yasumatsu, Keiko; Kokrashvili, Zaza; Varadarajan, Vijaya; Zou, Shiying; Jiang, Peihua; Ninomiya, Yuzo; Margolskee, Robert F. (2003-08-08). "Detection of sweet and umami taste in the absence of taste receptor T1r3". Science. 301 (5634): 850–853. Bibcode:2003Sci...301..850D. doi:10.1126/science.1087155. ISSN 1095-9203. PMID 12869700. S2CID 23351136.
  11. ^ de Araujo, Ivan E.; Oliveira-Maia, Albino J.; Sotnikova, Tatyana D.; Gainetdinov, Raul R.; Caron, Marc G.; Nicolelis, Miguel A. L.; Simon, Sidney A. (2008-03-27). "Food reward in the absence of taste receptor signaling". Neuron. 57 (6): 930–941. doi:10.1016/j.neuron.2008.01.032. ISSN 1097-4199. PMID 18367093. S2CID 47453450.
  12. ^ Ren, X.; Ferreira, J. G.; Zhou, L.; Shammah-Lagnado, S. J.; Yeckel, C. W.; de Araujo, I. E. (2010-06-09). "Nutrient Selection in the Absence of Taste Receptor Signaling". Journal of Neuroscience. 30 (23): 8012–8023. doi:10.1523/jneurosci.5749-09.2010. ISSN 0270-6474. PMC 6632684. PMID 20534849.
  13. ^ Dinan, Timothy G.; Cryan, John F. (2016-12-04). "Gut instincts: microbiota as a key regulator of brain development, ageing and neurodegeneration". The Journal of Physiology. 595 (2): 489–503. doi:10.1113/jp273106. ISSN 0022-3751. PMC 5233671. PMID 27641441.
  14. ^ Wiertsema, Selma P.; van Bergenhenegouwen, Jeroen; Garssen, Johan; Knippels, Leon M. J. (2021-03-09). "The Interplay between the Gut Microbiome and the Immune System in the Context of Infectious Diseases throughout Life and the Role of Nutrition in Optimizing Treatment Strategies". Nutrients. 13 (3): 886. doi:10.3390/nu13030886. ISSN 2072-6643. PMC 8001875. PMID 33803407.
  15. ^ Duca, Frank A.; Swartz, Timothy D.; Sakar, Yassine; Covasa, Mihai (2012). "Increased oral detection, but decreased intestinal signaling for fats in mice lacking gut microbiota". PLOS ONE. 7 (6): e39748. Bibcode:2012PLoSO...739748D. doi:10.1371/journal.pone.0039748. ISSN 1932-6203. PMC 3387243. PMID 22768116.
  16. ^ Bogunovic, Milena; Davé, Shaival H.; Tilstra, Jeremy S.; Chang, Diane T. W.; Harpaz, Noam; Xiong, Huabao; Mayer, Lloyd F.; Plevy, Scott E. (June 2007). "Enteroendocrine cells express functional Toll-like receptors". American Journal of Physiology. Gastrointestinal and Liver Physiology. 292 (6): G1770–G1783. doi:10.1152/ajpgi.00249.2006. ISSN 0193-1857. PMC 3203538. PMID 17395901.
  17. ^ Kaji, Izumi; Karaki, Shin-Ichiro; Tanaka, Ryo; Kuwahara, Atsukazu (February 2011). "Density distribution of free fatty acid receptor 2 (FFA2)-expressing and GLP-1-producing enteroendocrine L cells in human and rat lower intestine, and increased cell numbers after ingestion of fructo-oligosaccharide". Journal of Molecular Histology. 42 (1): 27–38. doi:10.1007/s10735-010-9304-4. ISSN 1567-2387. PMID 21113792. S2CID 12495871.
  18. ^ Dlugosz, A.; Zakikhany, K.; Muschiol, S.; Hultenby, K.; Lindberg, G. (2011-08-21). "Infection of human enteroendocrine cells with Chlamydia trachomatis: a possible model for pathogenesis in irritable bowel syndrome". Neurogastroenterology & Motility. 23 (10): 928–934. doi:10.1111/j.1365-2982.2011.01765.x. ISSN 1350-1925. PMID 21883697. S2CID 35175527.
  19. ^ Dlugosz, Aldona; Muschiol, Sandra; Zakikhany, Katherina; Assadi, Ghazaleh; D’Amato, Mauro; Lindberg, Greger (2014). "Human enteroendocrine cell responses to infection with Chlamydia trachomatis: a microarray study". Gut Pathogens. 6 (1): 24. doi:10.1186/1757-4749-6-24. ISSN 1757-4749. PMC 4067063. PMID 24959205.
  20. ^ Worthington, John J.; Klementowicz, Joanna E.; Rahman, Sayema; Czajkowska, Beata I.; Smedley, Catherine; Waldmann, Herman; Sparwasser, Tim; Grencis, Richard K.; Travis, Mark A. (2013-10-03). "Loss of the TGFβ-Activating Integrin αvβ8 on Dendritic Cells Protects Mice from Chronic Intestinal Parasitic Infection via Control of Type 2 Immunity". PLOS Pathogens. 9 (10): e1003675. doi:10.1371/journal.ppat.1003675. ISSN 1553-7374. PMC 3789784. PMID 24098124.