Mechanical stimulation releases 5-HT from enterochromaffin cells (EC) to trigger a secretomotor reflex. Our animal studies indicate that purines (ATP/ADP/ADO) operate at all levels of the reflex. Purinergic mechanisms are potential therapeutic targets in IBD, IBS or diarrheal disorders;but chronic inflammation or GI disease can alter purine gene expression to disrupt gut function. Despite implications for translational neurogastroenterology, little is known about purines in human gut reflexes or alterations in IBD or IBS. Development of effective treatments is hampered by our poor understanding of human gut neurobiology and neuroplasticity and difficulties in studying it. Our data support a novel Purinergic hypothesis that 'Purines are critical determinants of mechanosensory reflexes in human gut': EC cells express P2X3 and P2Y1R and their activation by ATP co-released with 5-HT cause amplification of 5-HT release evoked by mechanical stimulation. ATP-gated P2X3 or metabotropic P2Y1R are positive autocrine signals of 5-HT release. P2X3 activation contributes to speed and sensitivity and P2Y1 exerts slow-sustained amplification of 5-HT release. Negative autocrine signals are transduced through P2Y12 and A3R. 'Plurichemical'purinergic transmission occurs in the human ENS. 5-HT (and ATP) release triggers an ENS reflex where multiple purines act at these receptors to modulate neurogenic secretion of fluid and electrolytes. ADO inhibits immune activation of the ENS by biopsy supernatants (SUP). In IBD (or IBS) heightened immune-neural / EC activation and purinoceptor plasticity or altered purine handling mechanisms is associated with disturbed gut function. We developed novel, cutting-edge in vitro techniques for critical evaluation of purinergic mechanisms in human gut reflexes - molecular, Ca2+ imaging or electrochemical detection is used to study purinergic autocrine mechanisms of 5-HT release in BON (EC) cells, naive EC cells in intact mucosa or EC cells isolated by FACS sorting. LSM Ca2+ neuroimaging provides adequate temporal and spatial resolution to study neural circuit behavior in human ENS in normal or inflamed surgical tissue (or biopsy);this is complemented by IHC, radioligand, and molecular approaches. Secretomotor function is evaluated by studies on neurogenic secretion / ISC responses to drugs. A large volume of clinical cases and pilot data in >265 patients support Aim 1. To identify purinergic components of mechanosensory transduction in human EC cells and IBD Aim 2. To investigate plurichemical and purinergic transmission in the human ENS Aim 3. To determine in ENS whether functional and molecular interactions occur between inflammatory/immune mediators and purinergic signaling mechanisms in IBD (and IBS) Aim 4. To identify purinergic pathways in neurogenic secretomotor function and disturbances in function in IBD Studies will fill a critical gap in our knowledge of human ENS/purinergic signaling, and establish purines as critical regulators of 5-HT release, neural activity, neurosecretion and mechanosensory reflexes;immune- neural activation and plasticity in IBD/IBS - providing a sound basis for further translational studies.

Public Health Relevance

Inflammatory Bowel Diseases (IBD) and functional disorders like Irritable bowel syndrome (IBS) are associated with significant morbidity and economic burden. Development of effective treatments is hampered by our poor understanding of human gut neurobiology, neuroplasticity, species differences in extrapolating animal data to humans and difficulties in studying it. Purines (ATP/ADP/ADO) are potential therapeutic targets in IBD, IBS or diarrheal disorders. Studies in human gut tissues or biopsy/supernatants will reveal purinergic mechanisms of function and dysfunction in IBD and IBS - Studies may reveal novel therapeutic targets.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Special Emphasis Panel (ZRG1-DKUS-C (03))
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Hamilton, Frank A
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Ohio State University
Schools of Medicine
United States
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Gulbransen, Brian D; Christofi, Fievos L (2018) Are We Close to Targeting Enteric Glia in Gastrointestinal Diseases and Motility Disorders? Gastroenterology 155:245-251
Burnstock, Geoffrey; Jacobson, Kenneth A; Christofi, Fievos L (2017) Purinergic drug targets for gastrointestinal disorders. Curr Opin Pharmacol 37:131-141
Liñán-Rico, Andromeda; Ochoa-Cortes, Fernando; Zuleta-Alarcon, Alix et al. (2017) UTP - Gated Signaling Pathways of 5-HT Release from BON Cells as a Model of Human Enterochromaffin Cells. Front Pharmacol 8:429
Soghomonyan, Suren; Abdel-Rasoul, Mahmoud; Zuleta-Alarcon, Alix et al. (2017) Clopidogrel IBS Patients Have Higher Incidence of Gastrointestinal Symptoms Influenced by Age and Gender. Dig Dis Sci 62:2728-2743
Ochoa-Cortes, Fernando; Turco, Fabio; Linan-Rico, Andromeda et al. (2016) Enteric Glial Cells: A New Frontier in Neurogastroenterology and Clinical Target for Inflammatory Bowel Diseases. Inflamm Bowel Dis 22:433-49
Linan-Rico, Andromeda; Ochoa-Cortes, Fernando; Beyder, Arthur et al. (2016) Mechanosensory Signaling in Enterochromaffin Cells and 5-HT Release: Potential Implications for Gut Inflammation. Front Neurosci 10:564
Liñán-Rico, Andromeda; Turco, Fabio; Ochoa-Cortes, Fernando et al. (2016) Molecular Signaling and Dysfunction of the Human Reactive Enteric Glial Cell Phenotype: Implications for GI Infection, IBD, POI, Neurological, Motility, and GI Disorders. Inflamm Bowel Dis 22:1812-34
Gombash, Sara E; Cowley, Christopher J; Fitzgerald, Julie A et al. (2015) SMN deficiency disrupts gastrointestinal and enteric nervous system function in mice. Hum Mol Genet 24:5665
Gombash, Sara E; Cowley, Christopher J; Fitzgerald, Julie A et al. (2015) SMN deficiency disrupts gastrointestinal and enteric nervous system function in mice. Hum Mol Genet 24:3847-60
Liñán-Rico, A; Wunderlich, J E; Enneking, J T et al. (2015) Neuropharmacology of purinergic receptors in human submucous plexus: Involvement of P2X?, P2X?, P2X? channels, P2Y and A? metabotropic receptors in neurotransmission. Neuropharmacology 95:83-99

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