Enteroendocrine cells

A complex word that says it all

Enteroendocrine cells (or EECs) carry a complex name that can be broken down to words of Greek origin; ‘enteron’ for intestine, ‘endo’ for within, and ‘krine’ meaning secrete. It’s all Greek to me, you may think. When the name components are brought together, they refer to the localisation of these cells within the gut (small and large intestine) and their function of secreting hormones in response to signals from the intestinal lumen.

The road from the gut to the brain is complex. While senses like taste, smell, sight, hearing, and touch are transmitted to the brain through sensory cells connected to nerves, the stimuli received from the gut are communicated to the brain indirectly, through the slow diffusion of hormones (1, 2). Many cells need to send the stimulus to ensure that the signal reaches the brain on time which explains why, although they represent only 1% of the intestinal epithelial cell population, EECs are the largest endocrine system in mammals (3–6), acting within minutes to hours following a meal.

Message in a bottle

EECs are derived from intestinal pluripotent cells, the same type that produces their neighbours, enterocytes. Morphologically, EECs can be described either as ‘open type’, shaped like a bottle with its opening facing the intestinal lumen, or as ‘closed type’, found near the intestinal basolateral membrane (7–9). Open type EECs have microvilli (small protrusions of the cell membrane), that are used for sensing the intestinal lumen signals, such as glucose, fat and amino acid levels, through which the feelings of hunger or satiety are regulated. Closed-type EECs are activated by humoral or neural signals. By extending protrusions called ‘neuropods’, they connect with the nerves of the enteric nervous system, forming synapses, through which they transmit communication signals (10). Both open- and closed-type EECs pack their ‘communication’ material in cytoplasmic granules which they then release towards the basolateral membrane through exocytosis, as a response to mechanical, neural or chemical stimulation (7).

The main role of EECs is to respond to the intestinal nutrients and metabolic products of the gut microbiota by secreting hormones (3). These hormones can act locally, as signals to neighbouring cells, or enter the bloodstream to transmit signals further away in the body (11). EECs are classified into at least eight different subtypes (named by letters of the alphabet), according to their localisation and hormone-secreting profile (7, 12). Some examples of EEC subtypes include EC cells that control gut motility as well as nausea and vomiting, L cells which regulate appetite and insulin release, and K cells that stimulate insulin release and regulate gut mucosal growth (7). EEC localisation and subtype, together with nutrient-uptake patterns, control the concentration of hormones in the bloodstream over time (12). What‘s more, EECs are capable of switching between subtypes and can modify their hormone secretion profile, depending on nutrient-sensing signals from the intestinal lumen (7, 13).

All together, EECs have a central role in nutrient sensing, intestinal motility and glucose metabolism. If we could take a peek behind the scenes, we would see the orchestrated secretion of hormones by different EEC subtypes that regulate our behavior towards food; ghrelin, secreted by the X/A-like subtype, promotes appetite, whereas its secretion is suppressed by the intake of nutrients. Next GLP1 and CCK, produced by the L subtype, induce the feeling of satiety. Meanwhile, sugar uptake induces the secretion of GLP1 and GIP, by the L and K subtypes, respectively, which promote insulin release that, in turn, lowers blood sugar (9).

Signaling near and far

EECs function as the messenger between the intestinal lumen and the enteric nervous system, whose neurons cannot sense the gut contents. Further down the communication line comes the central nervous system that sends and receives signals to and from the brain (3), which is how the term gut-brain axis has arisen to describe the two-way communication between these systems (3). Finely tuned signaling between the gut and brain is essential for gut homeostasis as well as for higher cognitive functions (3, 14). As a consequence, EECs, as sensors of nutrients and microbiota metabolites, have a central role in the physiological tolerance versus the pathological reaction of our body to the contents of our gut (15). It is in this context that EECs are increasingly the subject of studies related to inflammatory bowel diseases (Crohn’s, celiac, ulcerative colitis) as well as metabolic diseases, such as obesity and diabetes (7).

The pathological impact of EEC signaling can be local, in which case it has been linked to inflammatory bowel diseases. Surface receptors expressed by EECs include G-protein coupled receptors, responsible for rapid response to ligand detection, and Toll-like receptors, both of which sense bacterial metabolites in the gut. The molecules secreted by the EECs include cytokines which can, in turn, mobilize immune cells and therefore implicate EECs in the inflammatory response. An example of a proinflammatory molecule secreted by EECs is interleukin (IL)-17C, which is thought to have a role in the progression of ulcerative colitis and Crohn’s disease (7, 16).

In the case of diabetes, one of the most common yet not necessarily hereditary metabolic diseases, the exact role of EECs is not fully understood but variations in EEC numbers as well as their secretion profile have been observed. K and L EEC subtypes are thought to be involved in diabetes, as they control glucose homeostasis (7) and appetite through feelings of reward and aversion towards food (8).

Taking a step even further, the signaling of gut microbiota can reach as far as the brain (17, 18), all thanks to EEC hormonal signaling. EECs have been found to produce alpha-synuclein, a marker protein in Parkinson’s disease. In fact, EECs can form connections with nerves that contain alpha-synuclein. This results in a network through which gut microbiota toxins may be able to influence alpha-synuclein misfolding and trafficking from the gut to the brain (7).

Another disease where EECs are suspected to have a contribution is schizophrenia, a neuropsychiatric disorder associated with serotonin dysregulation, among other parameters. EECs produce serotonin, through which they control intestinal motility. However, as EECs can signal far beyond the intestine, it has been suggested that serotonin-producing EECs may be linked to the pathophysiology of schizophrenia, although further investigation is required (7).

Overall, with their controversial impact as beneficial or detrimental controllers of various bodily functions through hormone secretion, EECs remain an interesting, yet not fully understood, target for therapeutics development aiming at the regulation of microbiota or neurological signaling pathways (7).

Recognising and appreciating the labs working in this space:

1. Rodger Liddle, Department of Medicine, Duke University School of Medicine, Durham, North Carolina, USA, https://medicine.duke.edu/divisions/gastroenterology/research/basic-and-translational-research-labs/liddle-lab
2. Bayrer Lab, UCSF, San Francisco, California, USA, https://bayrerlab.ucsf.edu/
3. Arthur Beyder, Mayo Clinic, https://www.mayo.edu/research/labs/gastrointestinal-mechanotransduction/projects
4. Liberles Lab, Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, https://liberles.hms.harvard.edu/
5. Daniel Drucker, Laboratory of Medicine and Pathobiology, University of Toronto, Canada, https://lmp.utoronto.ca/faculty/daniel-drucker, X: @DanielJDrucker
6. Diego Bohorquez, Department of Medicine, Duke University School of Medicine, Durham, North Carolina, USA, https://gutbrains.com/
7. Julie In, Health Sciences Department, The University of New Mexico, Albuquerque, New Mexico, USA, https://hsc.unm.edu/directory/in-julie.html
8. Yoshinori Marunaka, Research Unit for Epithelial Physiology and Research Center for Drug Discovery and Pharmaceutical Development Science, Research Organization of Science and Technology, Ritsumeikan University, Japan
9. Knight Lab- The Neurobiology of Homeostasis, School of Medicine, University of California San Francisco, San Francisco, California, USA, https://knightlab.ucsf.edu/, X: @zaknight
10. The Organoid Group, Hubrecht Institute, Utrecht, Netherlands, X: @TheCleversLab

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References

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7. Atanga, Roger et al. “Intestinal Enteroendocrine Cells: Present and Future Druggable Targets.” International journal of molecular sciences vol. 24,10 8836. 16 May. 2023, doi:10.3390/ijms24108836
8. Bai, Ling et al. “Enteroendocrine cell types that drive food reward and aversion.” eLife vol. 11 e74964. 1 Aug. 2022, doi:10.7554/eLife.74964
9. Hayashi, Marito et al. “Enteroendocrine cell lineages that differentially control feeding and gut motility.” eLife vol. 12 e78512. 22 Feb. 2023, doi:10.7554/eLife.78512
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12. Gribble, Fiona M, and Frank Reimann. “Enteroendocrine Cells: Chemosensors in the Intestinal Epithelium.” Annual review of physiology vol. 78 (2016): 277–99. doi:10.1146/annurev-physiol-021115–105439
13. Beumer, Joep et al. “Enteroendocrine Dynamics — New Tools Reveal Hormonal Plasticity in the Gut.” Endocrine reviews vol. 41,5 (2020): bnaa018. doi:10.1210/endrev/bnaa018
14. Loh, Jian Sheng et al. “Microbiota-gut-brain axis and its therapeutic applications in neurodegenerative diseases.” Signal transduction and targeted therapy vol. 9,1 37. 16 Feb. 2024, doi:10.1038/s41392–024–01743–1
15. Kanova, Marcela, and Pavel Kohout. “Serotonin-Its Synthesis and Roles in the Healthy and the Critically Ill.” International journal of molecular sciences vol. 22,9 4837. 3 May. 2021, doi:10.3390/ijms22094837
16. Friedrich, M et al. “Intestinal neuroendocrine cells and goblet cells are mediators of IL-17A-amplified epithelial IL-17C production in human inflammatory bowel disease.” Mucosal immunology vol. 8,4 (2015): 943–58. doi:10.1038/mi.2014.124\
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