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Interactions of Gut Endocrine Cells with Epithelium and Neurons

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ABSTRACT

Even the simplest animals possess sophisticated systems for sensing and securing nutrients. After all, ensuring adequate nutrition is essential for sustaining life. Once multicellular animals grew too large to be nourished by simple diffusion of nutrients from their environment, they required a digestive system for the absorption and digestion of food. The majority of cells in the digestive tract are enterocytes that are designed to absorb nutrients. However, the digestive tracts of animals ranging from worms to humans contain specialized cells that discriminate between nutrients and nondigestible ingestants. These cells “sense” both the environment within the gut lumen and nutrients as they cross the gut epithelium. This dual sensing is then translated into local signals that regulate the gut epithelium or distant signals through hormones or nerves. This review will discuss how sensors of the gut interact with cells of the epithelium and neurons to regulate epithelial integrity and initiate neural transmission from the gut lumen. © 2017 American Physiological Society. Compr Physiol 8:1019‐1030, 2018.

Figure 1. Figure 1. Anatomy of an EEC. EECs are single cells dispersed among enterocytes and other cells of the intestinal mucosa. The apical surface of most EECs is covered with microvilli and is open to the gut lumen. The basal region contains secretory vesicles and rests on the lamina propria. Secreted hormones are taken up into the blood. Some EECs (not pictured here) like ghrelin cells of the stomach are not exposed to the gut lumen.
Figure 2. Figure 2. Morphology of EECs throughout the GI tract. Many EECs in the proximal intestine have short and often multiple neuropods while EECs in the ileum and colon characteristically possess single neuropods that extend along the base of adjacent enterocytes. Modified, with permission, from ().
Figure 3. Figure 3. 3D image of an EEC with a prominent neuropod and other neuron‐like features. (A) Serial block face scanning electron microscopy (SBEM) of an image with a tissue volume of 52327 µm3. (B) All nuclei from 145 epithelial cells, including 129 enterocytes, 11 goblet cells, 4 cells of various types, and 1 EEC. (C) The EEC was traced on each slice to reveal its entire ultrastructure. On the left, the cell has a tuft of microvilli exposed to the gut lumen, and on the right, there is a prominent neuropod that extends toward the basal lamina propria. (D) This neuropod is populated by mitochondria, in particular at the tip (blue), secretory vesicles (yellow), and filament‐like structures (orange). Top panels show the reconstructions of the cells, and bottom panels show a representative SBEM image of each feature. Structures of interest in the bottom panel have been pseudocolored to facilitate their visualization. Bars = 1 µm. From () with permission.
Figure 4. Figure 4. EEC‐neural connection. Schematic diagram illustrating the recently described connection between EECs and enteric nerves. It is believed that both enteric and vagal nerves innervate EECs.
Figure 5. Figure 5. EEC‐neural connection forms in vitro. (A) Coculture scheme of an enteroendocrine cell and a primary sensory neuron. EEC, enteroendocrine cell; TG, trigeminal neuron. (B) Time‐lapse sequence showing how a single Cck‐GFP EEC (green) connects to a sensory neuron (DiI‐labeled, red) in vitro. (C) The EEC–neuron connection is stable at 23 min, 14 s, and cells remained connected for 88 h until the end of the experiment. Time, hours:minutes. Scale bars: 10 μm. Modified, with permission, from ().
Figure 6. Figure 6. Nutrients stimulate EECs through apical and basolateral receptors and transporters. Transporters for glucose (SGLT1), amino acids, and di‐ and tri‐peptides are expressed on the apical surface of EECs. Other transporters (e.g., GLUT2) and receptors for long (FFAR1 and FFAR4) and short (FFAR2 and FFAR3) chain fatty acids, fatty acids and lipoproteins (ILDR1), and amino acids (CaSR) are located on the basolateral surface of EECs and respond to absorbed nutrients.
Figure 7. Figure 7. Paracrine signaling in the intestine. Paracrine regulation of gastrin and gastric acid secretion by somatostatin‐producing cells in the stomach unveiled a route by which EECs may regulate neighboring cells. In the intestine, local release of PYY controls enterocyte fluid secretion and growth.
Figure 8. Figure 8. Fine tuning of EECs. It is likely that EECs respond to signals from neighboring cells such as enterocytes, glia, and efferent nerves. Absorbed fatty acids and locally released chylomicrons and lipoproteins stimulate receptors such as ILDR1 (red). Glia produce neurotrophins, which induce neuropod growth and some EECs, are also innervated by efferent nerves. An example illustrates nerve growth factor binding to the receptor TrkA (gray).


Figure 1. Anatomy of an EEC. EECs are single cells dispersed among enterocytes and other cells of the intestinal mucosa. The apical surface of most EECs is covered with microvilli and is open to the gut lumen. The basal region contains secretory vesicles and rests on the lamina propria. Secreted hormones are taken up into the blood. Some EECs (not pictured here) like ghrelin cells of the stomach are not exposed to the gut lumen.


Figure 2. Morphology of EECs throughout the GI tract. Many EECs in the proximal intestine have short and often multiple neuropods while EECs in the ileum and colon characteristically possess single neuropods that extend along the base of adjacent enterocytes. Modified, with permission, from ().


Figure 3. 3D image of an EEC with a prominent neuropod and other neuron‐like features. (A) Serial block face scanning electron microscopy (SBEM) of an image with a tissue volume of 52327 µm3. (B) All nuclei from 145 epithelial cells, including 129 enterocytes, 11 goblet cells, 4 cells of various types, and 1 EEC. (C) The EEC was traced on each slice to reveal its entire ultrastructure. On the left, the cell has a tuft of microvilli exposed to the gut lumen, and on the right, there is a prominent neuropod that extends toward the basal lamina propria. (D) This neuropod is populated by mitochondria, in particular at the tip (blue), secretory vesicles (yellow), and filament‐like structures (orange). Top panels show the reconstructions of the cells, and bottom panels show a representative SBEM image of each feature. Structures of interest in the bottom panel have been pseudocolored to facilitate their visualization. Bars = 1 µm. From () with permission.


Figure 4. EEC‐neural connection. Schematic diagram illustrating the recently described connection between EECs and enteric nerves. It is believed that both enteric and vagal nerves innervate EECs.


Figure 5. EEC‐neural connection forms in vitro. (A) Coculture scheme of an enteroendocrine cell and a primary sensory neuron. EEC, enteroendocrine cell; TG, trigeminal neuron. (B) Time‐lapse sequence showing how a single Cck‐GFP EEC (green) connects to a sensory neuron (DiI‐labeled, red) in vitro. (C) The EEC–neuron connection is stable at 23 min, 14 s, and cells remained connected for 88 h until the end of the experiment. Time, hours:minutes. Scale bars: 10 μm. Modified, with permission, from ().


Figure 6. Nutrients stimulate EECs through apical and basolateral receptors and transporters. Transporters for glucose (SGLT1), amino acids, and di‐ and tri‐peptides are expressed on the apical surface of EECs. Other transporters (e.g., GLUT2) and receptors for long (FFAR1 and FFAR4) and short (FFAR2 and FFAR3) chain fatty acids, fatty acids and lipoproteins (ILDR1), and amino acids (CaSR) are located on the basolateral surface of EECs and respond to absorbed nutrients.


Figure 7. Paracrine signaling in the intestine. Paracrine regulation of gastrin and gastric acid secretion by somatostatin‐producing cells in the stomach unveiled a route by which EECs may regulate neighboring cells. In the intestine, local release of PYY controls enterocyte fluid secretion and growth.


Figure 8. Fine tuning of EECs. It is likely that EECs respond to signals from neighboring cells such as enterocytes, glia, and efferent nerves. Absorbed fatty acids and locally released chylomicrons and lipoproteins stimulate receptors such as ILDR1 (red). Glia produce neurotrophins, which induce neuropod growth and some EECs, are also innervated by efferent nerves. An example illustrates nerve growth factor binding to the receptor TrkA (gray).
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Teaching Material

R. A. Liddle. Interactions of Gut Endocrine Cells with Epithelium and Neurons. Compr Physiol 8: 2018, 1019-1030.

Didactic Synopsis

Major Teaching Points:

  • Enteroendocrine cells (EECs) are sensory cells of the gastrointestinal tract.
  • EECs synthesize and secrete gut hormones in response to ingested nutrients through nutrient transporters and receptors.
  • EECs connect to enteric neurons and sensory afferent nerves and have the tools to send and receive signals with the nervous system.
  • EECs act locally in a paracrine manner to influence intestinal secretion and mucosal integrity.

Didactic Legends

The figures—in a freely downloadable PowerPoint format—can be found on the Images tab along with the formal legends published in the article. The following legends to the same figures are written to be useful for teaching.

Figure 1 Anatomy of an enteroendocrine cell. This figure illustrates that EECs are single cells dispersed among enterocytes and other cells of the intestinal mucosa. The apical surface of most EECs is covered with microvilli and is open to the gut lumen. The basal region contains secretory vesicles and rests on the lamina propria. Secreted hormones are taken up into the blood.

Figure 2 Morphology of EECs throughout the GI tract. This figure illustrates that many EECs in the proximal intestine have short and often multiple neuropods while EECs in the colon characteristically possess single neuropods that extend along the base of adjacent enterocytes. Modified, with permission, from (8).

Figure 3 3D image of an EEC with a prominent neuropod and other neuron-like features. This figure illustrates a 3D image of an EEC. Note the tuft of microvilli on the left and the prominent neuropod of the right. The neuropod contains abundant mitochondria, in particular at the tip (blue), secretory vesicles (yellow), and filament-like structures (orange). Bars  =  1 µm. From (9) with permission.

Figure 4 EEC-neural connection. This figure illustrates the recently described connection between EECs and enteric nerves. It is believed that both enteric and vagal nerves innervate EECs.

Figure 5 EEC-neural connection forms in vitro. This figure captures images from a time-lapse sequence showing how a single EEC (green) connects to a sensory neuron (DiI-labeled, red) in vitro. Time, hours:minutes. Scale bars: 10 μm. Modified, with permission, from (10).

Figure 6 Nutrients stimulate EECs through apical and basolateral receptors and transporters. This figure illustrates the proposed locations of transporters for glucose (SGLT1), amino acids, and di- and tri-peptides on the apical surface of EECs. Other transporters (e.g., GLUT2) and receptors for long (FFAR1 and FFAR4) and short (FFAR2 and FFAR3) chain fatty acids, fatty acids and lipoproteins (ILDR1), and amino acids (CaSR) are located on the basolateral surface of EECs and respond to absorbed nutrients.

Figure 7 Paracrine signaling in the intestine. This figure illustrates the proposed local release of PYY that is believed to control enterocyte fluid secretion and growth.

Figure 8 Fine tuning of EECs. This figure illustrates the concept that EECs respond to signals from neighboring cells such as enterocytes, glia, and efferent nerves. Absorbed fatty acids and locally released chylomicrons and lipoproteins stimulate receptors such as ILDR1 (red). Glia produce neurotrophins (gray) which induce neuropod growth and some EECs are also innervated by efferent nerves.

 


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Rodger A. Liddle. Interactions of Gut Endocrine Cells with Epithelium and Neurons. Compr Physiol 2018, 8: 1019-1030. doi: 10.1002/cphy.c170044