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Robert Cowles, MD

Associate Professor of Surgery (Pediatrics)

Contact Information

Robert Cowles, MD

Mailing Address

  • Pediatric Surgery

    PO Box 208062

    New Haven, CT 06520-8062

    United States

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Yale Medicine

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Research Summary

My laboratory is interested in the relationship between the enteric nervous system (ENS) and intestinal mucosal homeostasis. The ENS controls nearly every function of the bowel via a variety of neurotransmitters and peptide hormones. Understanding these actions has the potential to lead to new treatments for intestinal disorders.

Extensive Research Description

Our laboratory has found that serotonin (5-HT) and acetylcholine (ACh) are regulators of enterocyte turnover in the small intestine. Mouse models of 5-HT excess result in taller villi, deeper crypts, increased crypt cell division and increased enterocyte apoptosis in the ileum. Pharmacologic enhancement of 5-HT signaling has similar effects. The neural and cellular mechanisms that are involved in this process are under active investigation.

Other studies within our laboratory seek to understand how the enteric nervous system (ENS) responds to injury and how the microbiome may affect mucosal proliferation. The ENS is equivalent to the central nervous system (CNS) but its layers of protection from injury are significantly less. This suggests that it must have an ability to replace injured and dead components. In preliminary studies, we have found that intestinal ischemic injury results in neurogenesis in the ENS, a novel finding.

Coauthors

Research Interests

Biliary Tract; Digestive System Diseases; Epithelial Cells; Epithelium; Liver; Neuroglia; Neurons; Pancreas; Gastrointestinal Tract

Research Image

Enteric Neurogenesis

Whole mount section of the enteric nervous system (ENS) stained with anti-GFAP (red-glia) and an anti-GFP (green-new neuron) immunofluorescent antibodies revealing newly generated neurons after bowel resection in a mouse.

Selected Publications

  • Butyrate and the Intestinal Epithelium: Modulation of Proliferation and Inflammation in Homeostasis and Disease.Salvi PS, Cowles RA. Butyrate and the Intestinal Epithelium: Modulation of Proliferation and Inflammation in Homeostasis and Disease. Cells 2021, 10 PMID: 34359944, PMCID: PMC8304699, DOI: 10.3390/cells10071775.
  • Serotonin as a Mitogen in the Gastrointestinal Tract: Revisiting a Familiar Molecule in a New Role.Shah PA, Park CJ, Shaughnessy MP, Cowles RA. Serotonin as a Mitogen in the Gastrointestinal Tract: Revisiting a Familiar Molecule in a New Role. Cellular And Molecular Gastroenterology And Hepatology 2021, 12: 1093-1104. PMID: 34022423, PMCID: PMC8350061, DOI: 10.1016/j.jcmgh.2021.05.008.
  • National Survey of Pediatric Intestinal Rehabilitation Programs in the United States.Park CJ, Shaughnessy MP, Zhang L, Armenia SJ, Caty MG, Cowles RA. National Survey of Pediatric Intestinal Rehabilitation Programs in the United States. JPEN. Journal Of Parenteral And Enteral Nutrition 2021, 45: 1249-1258. PMID: 32797633, DOI: 10.1002/jpen.1997.
  • Outcomes following adoption of a standardized protocol for abscess drain management in pediatric appendicitis.Eysenbach LM, Caty MG, Christison-Lagay ER, Cowles RA, Dillon B, Goodman TR, Ozgediz DE, Stitelman DH, Solomon DG. Outcomes following adoption of a standardized protocol for abscess drain management in pediatric appendicitis. Journal Of Pediatric Surgery 2021, 56: 43-46. PMID: 33143877, DOI: 10.1016/j.jpedsurg.2020.09.050.
  • Duodenal Duplication Cyst.Shah PA, Saluja S, Cowles RA. Duodenal Duplication Cyst. Journal Of Gastrointestinal Surgery : Official Journal Of The Society For Surgery Of The Alimentary Tract 2021, 25: 1635-1637. PMID: 33443687, DOI: 10.1007/s11605-020-04890-2.
  • Reducing Underdiagnosis of Hirschsprung-Associated Enterocolitis: A Novel Scoring System.Lewit RA, Veras LV, Cowles RA, Fowler K, King S, Lapidus-Krol E, Langer JC, Park CJ, Youssef F, Vavilov S, Gosain A. Reducing Underdiagnosis of Hirschsprung-Associated Enterocolitis: A Novel Scoring System. The Journal Of Surgical Research 2021, 261: 253-260. PMID: 33460971, PMCID: PMC8166452, DOI: 10.1016/j.jss.2020.12.030.
  • Laparoscopy is increasingly used for pediatric inguinal hernia repair.Shaughnessy MP, Maassel NL, Yung N, Solomon DG, Cowles RA. Laparoscopy is increasingly used for pediatric inguinal hernia repair. Journal Of Pediatric Surgery 2021, 56: 2016-2021. PMID: 33549307, DOI: 10.1016/j.jpedsurg.2021.01.032.
  • Trends in fundoplication volume for pediatric gastroesophageal reflux disease.Maassel NL, Shaughnessy MP, Solomon DG, Cowles RA. Trends in fundoplication volume for pediatric gastroesophageal reflux disease. Journal Of Pediatric Surgery 2021, 56: 1495-1499. PMID: 33745746, DOI: 10.1016/j.jpedsurg.2021.02.045.
  • Point-of-Care Ultrasound to Evaluate the Acute Abdomen: A Case of Bowel Perforation After Unknown Single Magnet Ingestion.Malik R, Leviter J, Gross I, Saluja S, Cowles RA, Riera A. Point-of-Care Ultrasound to Evaluate the Acute Abdomen: A Case of Bowel Perforation After Unknown Single Magnet Ingestion. Pediatric Emergency Care 2022, 38: e1022-e1024. PMID: 34116554, DOI: 10.1097/PEC.0000000000002460.
  • Cholecystectomy Is Superior to Medical Management for Biliary Pain in Pediatric Patients.Shah PA, Saluja S, Cowles RA. Cholecystectomy Is Superior to Medical Management for Biliary Pain in Pediatric Patients. Journal Of Gastrointestinal Surgery : Official Journal Of The Society For Surgery Of The Alimentary Tract 2021, 25: 2435-2436. PMID: 34255291, DOI: 10.1007/s11605-021-05083-1.
  • The M1 muscarinic acetylcholine receptor in the crypt stem cell compartment mediates intestinal mucosal growth.Greig CJ, Armenia SJ, Cowles RA. The M1 muscarinic acetylcholine receptor in the crypt stem cell compartment mediates intestinal mucosal growth. Experimental Biology And Medicine (Maywood, N.J.) 2020, 245: 1194-1199. PMID: 32611198, PMCID: PMC7437377, DOI: 10.1177/1535370220938375.
  • Mucosal characteristics vary across developmental stages in the small intestine of C57BL/6J mice.Park CJ, Shaughnessy MP, Cowles RA. Mucosal characteristics vary across developmental stages in the small intestine of C57BL/6J mice. Life Sciences 2020, 260: 118428. PMID: 32931798, DOI: 10.1016/j.lfs.2020.118428.
  • Surgical modifications of the Kasai hepatoportoenterostomy minimize invasiveness without compromising short- and medium-term outcomes.Park CJ, Armenia SJ, Keung CH, Compton JT, Cowles RA. Surgical modifications of the Kasai hepatoportoenterostomy minimize invasiveness without compromising short- and medium-term outcomes. Journal Of Pediatric Surgery 2019, 54: 537-542. PMID: 30041859, DOI: 10.1016/j.jpedsurg.2018.06.028.
  • Potentiation of serotonin signaling protects against intestinal ischemia and reperfusion injury in mice.Tackett JJ, Gandotra N, Bamdad MC, Muise ED, Cowles RA. Potentiation of serotonin signaling protects against intestinal ischemia and reperfusion injury in mice. Neurogastroenterology And Motility : The Official Journal Of The European Gastrointestinal Motility Society 2019, 31: e13498. PMID: 30394002, DOI: 10.1111/nmo.13498.
  • The 5-HT4 Receptor Agonist Prucalopride Stimulates Mucosal Growth and Enhances Carbohydrate Absorption in the Ileum of the Mouse.Park CJ, Armenia SJ, Zhang L, Cowles RA. The 5-HT4 Receptor Agonist Prucalopride Stimulates Mucosal Growth and Enhances Carbohydrate Absorption in the Ileum of the Mouse. Journal Of Gastrointestinal Surgery : Official Journal Of The Society For Surgery Of The Alimentary Tract 2019, 23: 1198-1205. PMID: 30109470, DOI: 10.1007/s11605-018-3907-6.
  • Retracing our STEPs: Four decades of progress in intestinal lengthening procedures for short bowel syndrome.Greig CJ, Oh PS, Gross ER, Cowles RA. Retracing our STEPs: Four decades of progress in intestinal lengthening procedures for short bowel syndrome. American Journal Of Surgery 2019, 217: 772-782. PMID: 30514435, DOI: 10.1016/j.amjsurg.2018.11.025.
  • Potentiation of serotonin signaling leads to increased carbohydrate and lipid absorption in the murine small intestine.Park CJ, Armenia SJ, Shaughnessy MP, Greig CJ, Cowles RA. Potentiation of serotonin signaling leads to increased carbohydrate and lipid absorption in the murine small intestine. Journal Of Pediatric Surgery 2019, 54: 1245-1249. PMID: 30879746, DOI: 10.1016/j.jpedsurg.2019.02.027.
  • Orally Dosed Citalopram Stimulates Small Intestinal Mucosal Growth.Zhang L, Greig CJ, Cowles RA. Orally Dosed Citalopram Stimulates Small Intestinal Mucosal Growth. The Journal Of Surgical Research 2019, 236: 326-331. PMID: 30694773, DOI: 10.1016/j.jss.2018.11.033.
  • Serum Citrulline Levels Exhibit Circadian Variation and Fluctuations in Relation to Food Intake in Mice.Park CJ, Shaughnessy MP, Armenia SJ, Cowles RA. Serum Citrulline Levels Exhibit Circadian Variation and Fluctuations in Relation to Food Intake in Mice. Gastroenterology Research 2019, 12: 88-92. PMID: 31019618, PMCID: PMC6469904, DOI: 10.14740/gr1146.
  • Potentiated serotonin signaling in serotonin re-uptake transporter knockout mice increases enterocyte mass and small intestinal absorptive function.Greig CJ, Zhang L, Cowles RA. Potentiated serotonin signaling in serotonin re-uptake transporter knockout mice increases enterocyte mass and small intestinal absorptive function. Physiological Reports 2019, 7: e14278. PMID: 31724827, PMCID: PMC6854605, DOI: 10.14814/phy2.14278.
  • Guidelines for the management of postoperative soiling in children with Hirschsprung disease.Saadai P, Trappey AF, Goldstein AM, Cowles RA, De La Torre L, Durham MM, Huang EY, Levitt MA, Rialon K, Rollins M, Rothstein DH, Langer JC. Guidelines for the management of postoperative soiling in children with Hirschsprung disease. Pediatric Surgery International 2019, 35: 829-834. PMID: 31201486, DOI: 10.1007/s00383-019-04497-y.
  • Mucosal homeostasis is altered in the ileum of gnotobiotic mice.Greig CJ, Alper A, Goodman AL, Cowles RA. Mucosal homeostasis is altered in the ileum of gnotobiotic mice. The Journal Of Surgical Research 2018, 231: 331-337. PMID: 30278949, DOI: 10.1016/j.jss.2018.05.055.
  • Distribution of muscarinic acetylcholine receptor subtypes in the murine small intestine.Muise ED, Gandotra N, Tackett JJ, Bamdad MC, Cowles RA. Distribution of muscarinic acetylcholine receptor subtypes in the murine small intestine. Life Sciences 2017, 169: 6-10. PMID: 27866962, DOI: 10.1016/j.lfs.2016.10.030.
  • Muscarinic acetylcholine receptors participate in small intestinal mucosal homeostasis.Greig CJ, Cowles RA. Muscarinic acetylcholine receptors participate in small intestinal mucosal homeostasis. Journal Of Pediatric Surgery 2017, 52: 1031-1034. PMID: 28359586, DOI: 10.1016/j.jpedsurg.2017.03.037.
  • Enhanced serotonin signaling stimulates ordered intestinal mucosal growth.Tackett JJ, Gandotra N, Bamdad MC, Muise ED, Cowles RA. Enhanced serotonin signaling stimulates ordered intestinal mucosal growth. The Journal Of Surgical Research 2017, 208: 198-203. PMID: 27993209, DOI: 10.1016/j.jss.2016.09.036.
  • Improved capacity to evaluate changes in intestinal mucosal surface area using mathematical modeling.Greig CJ, Cowles RA. Improved capacity to evaluate changes in intestinal mucosal surface area using mathematical modeling. Microscopy Research And Technique 2017, 80: 793-798. PMID: 28295852, DOI: 10.1002/jemt.22866.
  • Enhanced serotonin signaling increases intestinal neuroplasticity.Greig CJ, Gandotra N, Tackett JJ, Bamdad MC, Cowles RA. Enhanced serotonin signaling increases intestinal neuroplasticity. The Journal Of Surgical Research 2016, 206: 151-158. PMID: 27916355, DOI: 10.1016/j.jss.2016.07.021.
  • Neuronal serotonin regulates growth of the intestinal mucosa in mice.Gross ER, Gershon MD, Margolis KG, Gertsberg ZV, Li Z, Cowles RA. Neuronal serotonin regulates growth of the intestinal mucosa in mice. Gastroenterology 2012, 143: 408-17.e2. PMID: 22609381, PMCID: PMC3687781, DOI: 10.1053/j.gastro.2012.05.007.
  • Sphingosine-1-phosphate mediates calcium signaling in guinea pig enteroglial cells.Segura BJ, Zhang W, Xiao L, Turner D, Cowles RA, Logsdon C, Mulholland MW. Sphingosine-1-phosphate mediates calcium signaling in guinea pig enteroglial cells. The Journal Of Surgical Research 2004, 116: 42-54. PMID: 14732348, DOI: 10.1016/s0022-4804(03)00281-6.
  • Stimulation of rat pancreatic exocrine secretion by cocaine- and amphetamine-regulated transcript peptide.Cowles RA, Segura BJ, Mulholland MW. Stimulation of rat pancreatic exocrine secretion by cocaine- and amphetamine-regulated transcript peptide. Regulatory Peptides 2001, 99: 61-8. PMID: 11257316, DOI: 10.1016/s0167-0115(01)00226-9.
  • Functional overlap of IP(3)- and cADP-ribose-sensitive calcium stores in guinea pig myenteric neurons.Turner DJ, Segura BJ, Cowles RA, Zhang W, Mulholland MW. Functional overlap of IP(3)- and cADP-ribose-sensitive calcium stores in guinea pig myenteric neurons. American Journal Of Physiology. Gastrointestinal And Liver Physiology 2001, 281: G208-15. PMID: 11408274, DOI: 10.1152/ajpgi.2001.281.1.G208.
  • Doctor-patient communication in surgery: attitudes and expectations of general surgery patients about the involvement and education of surgical residents.Cowles RA, Moyer CA, Sonnad SS, Simeone DM, Knol JA, Eckhauser FE, Mulholland MW, Colletti LM. Doctor-patient communication in surgery: attitudes and expectations of general surgery patients about the involvement and education of surgical residents. Journal Of The American College Of Surgeons 2001, 193: 73-80. PMID: 11442257, DOI: 10.1016/s1072-7515(01)00936-x.
  • Cholinergic stimulation of rat acinar cells increases c-fos and c-jun expression via a mitogen-activated protein kinase-dependent pathway.Turner DJ, Cowles RA, Segura BJ, Mulholland MW. Cholinergic stimulation of rat acinar cells increases c-fos and c-jun expression via a mitogen-activated protein kinase-dependent pathway. Journal Of Gastrointestinal Surgery : Official Journal Of The Society For Surgery Of The Alimentary Tract 2001, 5: 661-72. PMID: 12086906, DOI: 10.1016/s1091-255x(01)80110-4.
  • Laparoscopic biopsy of abdominal retroperitoneal lymphadenopathy for the diagnosis of lymphoma.Cowles RA, Yahanda AM. Laparoscopic biopsy of abdominal retroperitoneal lymphadenopathy for the diagnosis of lymphoma. Journal Of The American College Of Surgeons 2000, 191: 108-13. PMID: 10898191, DOI: 10.1016/s1072-7515(00)00279-9.
  • Solitary hepatic cysts.Cowles RA, Mulholland MW. Solitary hepatic cysts. Journal Of The American College Of Surgeons 2000, 191: 311-21. PMID: 10989905, DOI: 10.1016/s1072-7515(00)00345-8.
  • Cholinergic intrapancreatic neurons induce Ca²+ signaling and early-response gene expression in pancreatic acinar cells.Turner DJ, cowles RA, Segura BJ, Romanchuk G, Barnhart DC, Mulholland MW. Cholinergic intrapancreatic neurons induce Ca²+ signaling and early-response gene expression in pancreatic acinar cells. Journal Of Gastrointestinal Surgery : Official Journal Of The Society For Surgery Of The Alimentary Tract 2000, 4: 475-80. PMID: 11077322, DOI: 10.1016/s1091-255x(00)80089-x.
  • Epidermoid cyst of the spleen.Cowles RA, Yahanda AM. Epidermoid cyst of the spleen. American Journal Of Surgery 2000, 180: 227. PMID: 11084135, DOI: 10.1016/s0002-9610(00)00446-3.
  • Useful techniques for the resection of foot melanomas.Cowles RA, Johnson TM, Chang AE. Useful techniques for the resection of foot melanomas. Journal Of Surgical Oncology 1999, 70: 255-9; discussion 259-60. PMID: 10219023, DOI: 10.1002/(sici)1096-9098(199904)70:4<255::aid-jso11>3.0.co;2-b.
  • Index Admission Cholecystectomy and Recurrence of Pediatric Gallstone Pancreatitis: Multicenter Cohort Analysis.Muñoz Abraham AS, Osei H, Bajinting A, Cowles RA, Greenspon J, Hosfield BD, Keller MS, Landman MP, Owens H, Shaughnessy MP, St Peter SD, Sujka J, Vogel AM, Villalona GA. Index Admission Cholecystectomy and Recurrence of Pediatric Gallstone Pancreatitis: Multicenter Cohort Analysis. Journal Of The American College Of Surgeons 2022, 234: 352-358. PMID: 35213498, DOI: 10.1097/XCS.0000000000000062.
  • Jejunoileal mucosal growth in mice with a limited microbiome.Shaughnessy MP, Park CJ, Salvi PS, Cowles RA. Jejunoileal mucosal growth in mice with a limited microbiome. PloS One 2022, 17: e0266251. PMID: 35349599, PMCID: PMC8963542, DOI: 10.1371/journal.pone.0266251.
  • Variability in pediatric appendectomy: The association between disposable supply cost and procedure duration.Salvi PS, Cowles RA, Oh PS, Solomon DG. Variability in pediatric appendectomy: The association between disposable supply cost and procedure duration. Surgery 2022 PMID: 35581029, DOI: 10.1016/j.surg.2022.04.006.
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