A path for α-synuclein from the gut to the nervous system. Enteroendocrine cells (EECs) express α-synuclein and connect to α-synuclein-containing enteric nerves. This circuit provides a possible ...route for bacteria or toxins in the gut to induce abnormal α-synuclein formation that could transfer to the nervous system to initiate Parkinson’s disease.
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•Parkinson’s disease is characterized by Lewy bodies in the brain and peripheral nerves.•Misfolding and aggregation of α-synuclein leads to Lewy body formation.•Misfolded α-synuclein can spread in a prion-like fashion.•Epidemiological and experimental evidence suggest PD arises in the gut.•Like neurons, enteroendocrine cells express α-synuclein and could be a source of PD.
Parkinson’s disease (PD) is a debilitating neurodegenerative condition associated with tremor, rigidity, dementia, and gastrointestinal symptoms such as constipation, nausea and vomiting. The pathological hallmarks of PD are Lewy bodies and neurites in the brain and peripheral nerves. The major constituent of Lewy bodies is the neuronal protein α-synuclein. Misfolding of α-synuclein confers prion-like properties enabling its spread from cell to cell. Misfolded α-synuclein also serves as a template and induces misfolding of endogenous α-synuclein in recipient cells leading to the formation of oligomers that progress to fibrils and eventually Lewy bodies. Accumulating evidence suggests that PD may arise in the gut. Clinically, gastrointestinal symptoms often appear in patients before other neurological signs and aggregates of α-synuclein have been found in enteric nerves of PD patients. Importantly, patients undergoing vagotomy have a reduced risk of developing PD. Experimentally, abnormal forms of α-synuclein appear in enteric nerves before they appear in the brain and injection of abnormal α-synuclein into the wall of the intestine spreads to the vagus nerve. Ingested toxins and alterations in gut microbiota can induce α-synuclein aggregation and PD, however, it is not known how PD starts. Recently, it has been shown that sensory cells of the gut known as enteroendocrine cells (EECs) contain α-synuclein and synapse with enteric nerves, thus providing a connection from the gut to the brain. It is possible that abnormal α-synuclein first develops in EECs and spreads to the nervous system.
The ion channels Piezo1 and TRPV4 have both, independently, been implicated in high venous pressure– and fluid shear stress–induced vascular hyperpermeability in endothelial cells. However, the ...mechanism by which Piezo1 and TRPV4 channels execute the same function is poorly understood. Here we demonstrate that Piezo1 regulates TRPV4 channel activation in endothelial cells and that Piezo1-mediated TRPV4 channel opening is a function of the strength and duration of fluid shear stress. We first confirmed that either fluid shear stress or the Piezo1 agonist, Yoda1, led to an elevation in intracellular calcium (Ca2+i) and that application of the Piezo1 antagonist, GsMTx4, completely blocked this change. We discovered that high and prolonged shear stress caused sustained Ca2+i elevation that was blocked by inhibition of TRPV4 channel opening. Moreover, Piezo1 stimulated TRPV4 opening through activation of phospholipase A2. TRPV4-dependent sustained Ca2+i elevation was responsible for fluid shear stress–mediated and Piezo1-mediated disruption of adherens junctions and actin remodeling. Blockade of TRPV4 channels with the selective TRPV4 blocker, HC067047, prevented the loss of endothelial cell integrity and actin disruption induced by Yoda1 or shear stress and prevented Piezo1-induced monocyte adhesion to endothelial cell monolayers. These findings demonstrate that Piezo1 activation by fluid shear stress initiates a calcium signal that causes TRPV4 opening, which in turn is responsible for the sustained phase calcium elevation that triggers pathological events in endothelial cells. Thus, deleterious effects of shear stress are initiated by Piezo1 but require TRPV4.
Visceral pain associated with irritable bowel syndrome afflicts 15% of the US population. Although treatments are limited, guanylyl cyclase C (GUCY2C) agonists alleviate pain and constipation. Until ...now, it was assumed that the activation of GUCY2C and production of cGMP in enterocytes stimulated fluid secretion and reduced visceral sensation. The recent discovery that a subtype of enteroendocrine cells (EECs) known as neuropod cells synapse with submucosal neurons unveiled a pathway for communicating gut signals to the nervous system. In this issue of the JCI, Barton et al. report that GUCY2C is enriched in neuropod cells and is involved with sensory nerve firing. Selective deletion of GUCY2C in mouse models suggests that defective GUCY2C neuropod-cell signaling underlies visceral pain. These studies introduce possibilities for dissociating the secretory and analgesic effects of GUCY2C agonism. Although further work remains, unveiling the role of neuropod cells is a major step in understanding visceral pain.
The John Williams autobiography: “The Pancreas and Me Liddle, Rodger A.
Pancreatology : official journal of the International Association of Pancreatology (IAP) ... et al.,
03/2024, Volume:
24, Issue:
2
Journal Article
Due to progressive inflammation, chronic pancreatitis destroys both the exocrine and endocrine pancreas and sensitizes pancreatic nerves, leading to unremitting pain. Unfortunately, there are no ...treatments for pancreatic inflammation and approaches to ameliorate pain are suboptimal. Pancreatic inflammation is particularly problematic because damage to acinar cells causes local release of digestive enzymes, which initiate pancreatic autodigestion. The combination of autodigestion and inflammation is unique to pancreatitis and undoubtedly contributes to the difficulty in devising effective treatments. In this issue of the JCI, Saleh et al. describe a nonsurgical technique to ablate pancreatic acinar cells, thus eliminating the source of digestive enzymes and preventing autodigestion. In mice and a nonhuman primate model, this approach effectively reduced inflammation and pain while preserving islet cell function. These findings support the concept that ongoing acinar cell damage is at the root of chronic pancreatitis and provide a possible strategy for clinical treatment.
All cells in the body are exposed to physical force in the form of tension, compression, gravity, shear stress, or pressure. Cells convert these mechanical cues into intracellular biochemical ...signals; this process is an inherent property of all cells and is essential for numerous cellular functions. A cell's ability to respond to force largely depends on the array of mechanical ion channels expressed on the cell surface. Altered mechanosensing impairs conscious senses, such as touch and hearing, and unconscious senses, like blood pressure regulation and gastrointestinal (GI) activity. The GI tract's ability to sense pressure changes and mechanical force is essential for regulating motility, but it also underlies pain originating in the GI tract. Recent identification of the mechanically activated ion channels Piezo1 and Piezo2 in the gut and the effects of abnormal ion channel regulation on cellular function indicate that these channels may play a pathogenic role in disease. Here, we discuss our current understanding of mechanically activated Piezo channels in the pathogenesis of pancreatic and GI diseases, including pancreatitis, diabetes mellitus, irritable bowel syndrome, GI tumors, and inflammatory bowel disease. We also describe how Piezo channels could be important targets for treating GI diseases.
Merely touching the pancreas can lead to premature zymogen activation and pancreatitis but the mechanism is not completely understood. Here we demonstrate that pancreatic acinar cells express the ...mechanoreceptor Piezo1 and application of pressure within the gland produces pancreatitis. To determine if this effect is through Piezo1 activation, we induce pancreatitis by intrapancreatic duct instillation of the Piezo1 agonist Yoda1. Pancreatitis induced by pressure within the gland is prevented by a Piezo1 antagonist. In pancreatic acinar cells, Yoda1 stimulates calcium influx and induces calcium-dependent pancreatic injury. Finally, selective acinar cell-specific genetic deletion of Piezo1 protects mice against pressure-induced pancreatitis. Thus, activation of Piezo1 in pancreatic acinar cells is a mechanism for pancreatitis and may explain why pancreatitis develops following pressure on the gland as in abdominal trauma, pancreatic duct obstruction, pancreatography, or pancreatic surgery. Piezo1 blockade may prevent pancreatitis when manipulation of the gland is anticipated.
The enteroendocrine cell is the cornerstone of gastrointestinal chemosensation. In the intestine and colon, this cell is stimulated by nutrients, tastants that elicit the perception of flavor, and ...bacterial by-products; and in response, the cell secretes hormones like cholecystokinin and peptide YY--both potent regulators of appetite. The development of transgenic mice with enteroendocrine cells expressing green fluorescent protein has allowed for the elucidation of the apical nutrient sensing mechanisms of the cell. However, the basal secretory aspects of the enteroendocrine cell remain largely unexplored, particularly because a complete account of the enteroendocrine cell ultrastructure does not exist. Today, the fine ultrastructure of a specific cell can be revealed in the third dimension thanks to the invention of serial block face scanning electron microscopy (SBEM). Here, we bridged confocal microscopy with SBEM to identify the enteroendocrine cell of the mouse and study its ultrastructure in the third dimension. The results demonstrated that 73.5% of the peptide-secreting vesicles in the enteroendocrine cell are contained within an axon-like basal process. We called this process a neuropod. This neuropod contains neurofilaments, which are typical structural proteins of axons. Surprisingly, the SBEM data also demonstrated that the enteroendocrine cell neuropod is escorted by enteric glia--the cells that nurture enteric neurons. We extended these structural findings into an in vitro intestinal organoid system, in which the addition of glial derived neurotrophic factors enhanced the development of neuropods in enteroendocrine cells. These findings open a new avenue of exploration in gastrointestinal chemosensation by unveiling an unforeseen physical relationship between enteric glia and enteroendocrine cells.
Enteroendocrine cells (EECs) are specialized sensory cells in the intestinal epithelium that sense and transduce nutrient information. Consumption of dietary fat contributes to metabolic disorders, ...but EEC adaptations to high fat feeding were unknown. Here, we established a new experimental system to directly investigate EEC activity in vivo using a zebrafish reporter of EEC calcium signaling. Our results reveal that high fat feeding alters EEC morphology and converts them into a nutrient insensitive state that is coupled to endoplasmic reticulum (ER) stress. We called this novel adaptation 'EEC silencing'. Gnotobiotic studies revealed that germ-free zebrafish are resistant to high fat diet induced EEC silencing. High fat feeding altered gut microbiota composition including enrichment of
bacteria, and we identified an
strain sufficient to induce EEC silencing. These results establish a new mechanism by which dietary fat and gut microbiota modulate EEC nutrient sensing and signaling.
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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