General Surgery

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Division of General Surgery

TOKU TAKAHASHI, MD, PHD

Education
1977 Kobe University School of Medicine, Kobe, Japan
1985 Graduate School of Hyogo College of Medicine, Nishinomiya, Japan
1990 Postdoctoral Fellow, Division of Gastroenterology, University of Michigan

Professional Training and Employment
1985 Assistant Professor, Second Department of Surgery, Hyogo College of Medicine,
        Nishinomiya, Japan
1990 Vice President, Sadamitsu Hospital, Kakogawa, Japan
1992 Research Investigator, Division of Gastroenterology, University of Michigan, 
        Ann Arbor, MI
1996 Assistant Research Scientist, Division of Gastroenterology, University of Michigan, 
        Ann Arbor, MI
2000 Associate Professor, Department of Surgery, Duke University, Durham, NC
2007 Professor, Department of Surgery, Duke University, Durham, NC
2008 Professor, Department of Surgery, Medical College of Wisconsin, Milwaukee, WI

Research Interest
Dr. Takahashi's research interest is brain-gut axis and nerve-gut interaction in gastrointestinal (GI) motility.
 

Table of Contents:

Projects
a. Pathophysiological role of nitric oxide of the myenteric plexus

Nitric oxide (NO) has been demonstrated as an important inhibitory neurotransmitter in GI tract. NO of the stomach plays an important role in mediating accommodation reflex 1, 2. NO of the pylorus regulates gastric emptying in rats 3, 4 and dogs 5. NO of the proximal colon contributes to fecal storage and absorption of excess fluid 6. NO enhances colonic transit by mediating descending relaxation and facilitating propulsion of the colonic contents 7. NO is produced by the activation of neuronal NO synthase (nNOS) in the myenteric plexus. Expression of nNOS is altered by extrinsic denervation 8, 9, diabetes 10, colitis 11 and aging 12. The pathophysiological significance of nNOS of the myenteric plexus was summarized in his review article 13.

b. Effects of hyperglycemia on gastric emptying (supported by VA-Merit Award)

Hyperglycemia associated with diabetes alters gastric motor function. Acute hyperglycemia inhibits gastric distension-induced pyloric relaxation via vagal dependent mechanisms 14. Acute hyperglycemia impairs postprandial coordination between the antrum and pylorus in conscious rats 15, 16. Acute hyperglycemia attenuates the neuronal activity of the dorsal motor nucleus of vagi 17. In contrast, accelerated gastric emptying and augmented antro-pyloric coordinations are observed 2 weeks after streptozotocin (STZ)-injection in rats 18. Ghrelin regulates postprandial contractions 19 as well as interdigestive contractions 20, 21 of the rat stomach. Accelerated gastric emptying observed in the early stage of diabetes is mediated via an increased ghrelin release 18.

c. Contractile effects of orphanin FQ in rat colon (supported by NIH RO1)

Orphanin FQ (OFQ) structurally resembles dynorphin A. OFQ-immunopositive neuronal fibers were found in the colonic myenteric plexus 22. In situ hybridization revealed that OFQ receptor-mRNA was expressed in the colonic myenteric plexus but not in the muscle layers. OFQ causes significant contractions in the rat colon but not in the stomach or small intestine in vitro. The mechanisms and sites of action of OFQ seem to be region specific; OFQ inhibits cholinergic transmission in the stomach and small intestine, whereas OFQ stimulates colonic contraction via inhibiting purinergic inhibitory motor neurons within the myenteric plexus 23. OFQ accelerates colonic transit by promoting migrating colonic contractions, while dynorphin A delays colonic transit by causing non-migrating colonic contractions 24.

d. Mechanism of acupuncture on GI motility (supported by NIH R21)

Although acupuncture has been used to treat gastrointestinal symptoms in China for more than 3,000 years, mechanism of the beneficial effects of acupuncture remains unclear. Acupuncture on the abdomen causes a relaxation of the stomach 25, while acupuncture on the lower leg (ST-36) causes a contraction in rats 26, 27. Acupuncture-induced gastric relaxation is mediated via somato-sympathetic reflex. Its afferent limb is composed of abdominal cutaneous and muscle afferent nerves and its efferent limb is the gastric sympathetic nerve. The reflex center is within the medulla, 25, 28. In contrast, the contractile effects of acupuncture at ST-36 are mediated via vagal efferent pathway 26, 27. Acupuncture at ST-36 accelerates colonic motility and transit in normal conditions in conscious rats. The stimulatory effect acupuncture is mediated via a sacral parasympathetic efferent pathway (pelvic nerve) 29. In contrast, acupuncture at ST-36 attenuates accelerated colonic transit induced by restraint stress in rats 30. In conscious dogs, acupuncture at the wrist prevents emesis induced by vasopressin. The anti-emetic effect of acupuncture is mediated via a central opioid pathway 31, 32. Acupuncture at ST-36 reduces rectal distension-induced blood pressure changes in conscious dogs. The anti-nociceptive effect of acupuncture is also mediated via a central opioid pathway 33. Our studies suggest that acupuncture may be useful to treat the patients with functional GI disorders, like functional dyspepsia (FD) and irritable bowel syndromes (IBS) 34.

e. Stress-induced GI motility disorders (supported by NIH RO1)

Stress is one of the most important contributing factors in the pathogenesis of functional GI disorders. Restrain stress delays solid gastric emptying in rats. The inhibitory effect of restraint stress on gastric emptying is mediated via central corticotropin releasing factor (CRF) and peripheral sympathetic neurons 35, 36. Restraint stress augments postprandial gastric motility and impairs the coordination between the antrum and pylorus in rats 37. In contrast to gastric emptying, restrain stress accelerates colonic transit in rats 38, 39. The stimulatory effect of restraint stress on colonic transit is mediated via central CRF 40, 41, peripheral parasympathetic neurons and 5-HT3 receptors 42-44.

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References 

  1. Takahashi T, Owyang C. Vagal control of nitric oxide and vasoactive intestinal polypeptide release in the regulation of gastric relaxation in rat. J Physiol (Lond) 1995;484:481-92.
  2. Takahashi T, Owyang C. Characterization of vagal pathways mediating gastric accommodation reflex in rats. J Physiol (Lond) 1997;504:479-88.
  3. Ishiguchi T, Nishioka S, Takahashi T. Inhibitory neural pathway regulating gastric emptying in rats. J Auton Nerv Syst 2000;79:45-51.
  4. Ishiguchi T, Takahashi T, Itoh H, Owyang C. Nitrergic and purinergic regulation of the rat pylorus. Am J Physiol 2000;279:G740-7.
  5. Ueno T, Uemura K, Harris MB, Pappas TN, Takahashi T. Role of vagus nerve in postprandial antropyloric coordination in conscious dogs. Am J Physiol Gastrointest Liver Physiol 2005;288:G487-95.
  6. Takahashi T, Owyang C. Regional differences in the nitrergic innervation between the proximal and the distal colon in rats. Gastroenterology 1998;115:1504-12.
  7. Mizuta Y, Takahashi T, Owyang C. Nitrergic regulation of colonic transit in rats. Am J Physiol 1999;277:G275-9.
  8. Nakamura K, Takahashi T, Taniuchi M, Hsu CX, Owyang C. Nicotinic receptor mediates nitric oxide synthase expression in the rat gastric myenteric plexus. J Clin Invest 1998;101:1479-89.
  9. Nakao K, Takahashi T, Utsunomiya J, Owyang C. Extrinsic neural control of nitric oxide synthase expression in the myenteric plexus of rat jejunum. J Physiol (Lond) 1998;507:549-60.
  10. Takahashi T, Nakamura K, Itoh H, Sima AA, Owyang C. Impaired expression of nitric oxide synthase in the gastric myenteric plexus of spontaneously diabetic rats. Gastroenterology 1997;113:1535-44.
  11. Mizuta Y, Isomoto H, Takahashi T. Impaired Nitrergic Innervation in Rat Colitis Induced by Dextran Sulfate Sodium. Gastroenterology 2000;118:714-723.
  12. Takahashi T, Qoubaitary A, Owyang C, Wiley JW. Decreased expression of nitric oxide synthase in the colonic myenteric plexus of aged rats. Brain Res 2000;883:15-21.
  13. Takahashi T. Pathophysiological significance of neuronal nitric oxide synthase in the gastrointestinal tract. J Gastroenterol 2003;38:421-30.
  14. Ishiguchi T, Nakajima M, Sone H, Tada H, Kumagai A, Takahashi T. Gastric distension-induced pyloric relaxation: central nervous system regulation and effects of acute hyperglycaemia in the rat. J Physiol 2001;533:801-13.
  15. Ishiguchi T, Amano T, Matsubayashi H, Tada H, Fujita M, Takahashi T. Centrally administered neuropeptide Y delays gastric emptying via Y2 receptors in rats. Am J Physiol Regul Integr Comp Physiol 2001;281:R1522-30.
  16. Ishiguchi T, Tada H, Nakagawa K, Yamamura T, Takahashi T. Hyperglycemia impairs antro-pyloric coordination in conscious rats. Auton Neurosci 2002;95:112-120.
  17. Takahashi T, Matsuda K, Kono T, Pappas TN. Inhibitory effects of hyperglycemia on neural activity of the vagus in rats. Intensive Care Med 2003;29:309-11.
  18. Ariga H, Imai K, Chen C, Mantyh C, Pappas T, Takahashi T. Does ghrelin explain accelerated gastric emptying in the early stage of diabetes mellitus? Am J Physiol (in press).
  19. Ariga H, Nakade Y, Tsukamoto K, Imai K, Chen C, Mantyh C, Pappas TN, Takahashi T. Ghrelin accelerates gastric emptying via early manifestation of antro-pyloric coordination in conscious rats. Regul Pept 2008;146:112-6.
  20. Ariga H, Imai K, Chen C, Mantyh C, Pappas TN, Takahashi T. Fixed feeding potentiates interdigestive gastric motor activity in rats: importance of eating habits for maintaining interdigestive MMC. Am J Physiol Gastrointest Liver Physiol 2008.
  21. Ariga H, Tsukamoto K, Chen C, Mantyh C, Pappas TN, Takahashi T. Endogenous acyl ghrelin is involved in mediating spontaneous phase III-like contractions of the rat stomach. Neurogastroenterol Motil 2007;19:675-80.
  22. Yazdani A, Takahashi T, Bagnol D, Watson SJ, Owyang C. Functional Significance of a Newly Discovered Neuropeptide, Orphanin FQ, in Rat Gastrointestinal Motility. Gastroenterology 1999;116:108-117.
  23. Takahashi T, Bagnol D, Schneider D, Mizuta Y, Ishiguchi T, Le PK, Galligan JJ, Watson SJ, Owyang C. Orphanin FQ causes contractions via inhibiting purinergic pathway in the rat colon. Gastroenterology 2000;119:1054-63.
  24. Takahashi T, Mizuta Y, Owyang C. Orphanin FQ, but not dynorphin A, accelerates colonic transit in rats. Gastroenterology 2000;119:71-9.
  25. Tada H, Fujita M, Harris M, Tatewaki M, Nakagawa K, Yamamura T, Pappas TN, Takahashi T. Neural mechanism of acupuncture-induced gastric relaxations in rats. Dig Dis Sci 2003;48:59-68.
  26. Tatewaki M, Harris M, Uemura K, Ueno T, Hoshino E, Shiotani A, Pappas TN, Takahashi T. Dual effects of acupuncture on gastric motility in conscious rats. Am J Physiol Regul Integr Comp Physiol 2003;285:R862-72.
  27. Imai K, Ariga H, Chen C, Mantyh C, Pappas TN, Takahashi T. Effects of electroacupuncture on gastric motility and heart rate variability in conscious rats. Auton Neurosci 2008;138:91-8.
  28. Iwa M, Tateiwa M, Sakita M, Fujimiya M, T. T. Anatomical evidence of regional specific effects of acupuncture on gastric motor function in rats. Auton Neurosci (in press).
  29. Iwa M, Matsushima M, Nakade Y, Pappas TN, Fujimiya M, Takahashi T. Electroacupuncture at ST-36 accelerates colonic motility and transit in freely moving conscious rats. Am J Physiol Gastrointest Liver Physiol 2006;290:G285-92.
  30. Iwa M, Nakade Y, Pappas TN, Takahashi T. Electroacupuncture elicits dual effects: stimulation of delayed gastric emptying and inhibition of accelerated colonic transit induced by restraint stress in rats. Dig Dis Sci 2006;51:1493-500.
  31. Tatewaki M, Strickland C, Fukuda H, Tsuchida D, Hoshino E, Pappas TN, Takahashi T. Effects of acupuncture on vasopressin-induced emesis in conscious dogs. Am J Physiol Regul Integr Comp Physiol 2005;288:R401-8.
  32. Takahashi T, Tsuchida D, Pappas TN. Central effects of morphine on GI motility in conscious dogs. Brain Res 2007;1166:29-34.
  33. Iwa M, Strickland C, Nakade Y, Pappas TN, Takahashi T. Electroacupuncture reduces rectal distension-induced blood pressure changes in conscious dogs. Dig Dis Sci 2005;50:1264-70.
  34. Takahashi T. Acupuncture for functional gastrointestinal disorders. J Gastroenterol 2006;41:408-17.
  35. Nakade Y, Tsukamoto K, Pappas TN, Takahashi T. Central glucagon like peptide-1 delays solid gastric emptying via central CRF and peripheral sympathetic pathway in rats. Brain Res 2006;1111:117-21.
  36. Nakade Y, Tsuchida D, Fukuda H, Iwa M, Pappas TN, Takahashi T. Restraint stress delays solid gastric emptying via a central CRF and peripheral sympathetic neuron in rats. Am J Physiol Regul Integr Comp Physiol 2005;288:R427-32.
  37. Nakade Y, Tsuchida D, Fukuda H, Iwa M, Pappas TN, Takahashi T. Restraint stress augments postprandial gastric contractions but impairs antropyloric coordination in conscious rats. Am J Physiol Regul Integr Comp Physiol 2006;290:R616-24.
  38. Nakade Y, Mantyh C, Pappas TN, Takahashi T. Fecal pellet output does not always correlate with colonic transit in response to restraint stress and corticotropin-releasing factor in rats. J Gastroenterol 2007;42:279-82.
  39. Nakade Y, Tsukamoto K, Iwa M, Pappas TN, Takahashi T. Glucagon like peptide-1 accelerates colonic transit via central CRF and peripheral vagal pathways in conscious rats. Auton Neurosci 2006.
  40. Nakade Y, Pappas T, Takahashi T. Peripheral plasma CRF concentration does not correlate with augmented colonic motility in response to restraint stress in rats. . Clin Exp Pharm Physiol (in press).
  41. Tsukamoto K, Nakade Y, Mantyh C, Ludwig K, Pappas TN, Takahashi T. Peripherally administered CRF stimulates colonic motility via central CRF receptors and vagal pathways in conscious rats. Am J Physiol Regul Integr Comp Physiol 2006;290:R1537-41.
  42. Nakade Y, Fukuda H, Iwa M, Tsukamoto K, Yanagi H, Yamamura T, Mantyh C, Pappas TN, Takahashi T. Restraint stress stimulates colonic motility via central corticotropin-releasing factor and peripheral 5-HT3 receptors in conscious rats. Am J Physiol Gastrointest Liver Physiol 2007;292:G1037-44.
  43. Tsukamoto K, Ariga H, Mantyh C, Pappas TN, Yanagi H, Yamamura T, Takahashi T. Luminally released serotonin stimulates colonic motility and accelerates colonic transit in rats. Am J Physiol Regul Integr Comp Physiol 2007;293:R64-9.
  44. Takahashi T, Nakade Y, Fukuda H, Tsukamoto K, Mantyh C, Pappas T. Daily intake of high dietary fiber slows accelerated colonic transit induced by restrain stress in rats. . Dig Dis Sci (in press).

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Fellowships
Fellowships and several educational opportunities are available at Dr. Takahashi’s laboratory. The positions are open to medical students and physicians who wish to gain additional experience in gastrointestinal physiology. Trainees typically become involved in numerous ongoing projects. Much of the research relates to gastrointestinal motility and physiology, but also several projects are focused on investigating inflammatory mechanisms of the colon, effects of acupuncture, and novel approaches to surgical conditions. Trainees are encouraged to apply to local and national funding opportunities. For further questions regarding educational opportunities, please contact to Toku Takahashi (ttakahashi@mcw.edu).

Present Fellows:

  • Hiroshi Taniguchi, PhD (2007-)
  • Hitoshi Nakajima, MD (2007-)
  • Jun Zheng, MD PhD (2007-)

Past Fellows:

  • Kazumi Nakamura, MD (1996-1997)
  • Kenji Hosoda, MD (1996-1998)
  • Koji Nakao, MD (1997-1999)
  • Yohei Mizuta, MD PhD (1997-1998)
  • Tadashi Ishiguchi, MD (1998-2000)
  • Hitoshi Tada, MD (2000-2001)
  • Mikio Fujita, MD, PhD (2000-2001)
  • Toru Kono, MD, PhD (2001)
  • Akiko Shiotani, MD PhD (2002)
  • Naoki Kihara, MD (2001-2002)
  • Sebastian G. de la Fuente, MD (2000-2003)
  • Kazunori Fujino, MD (2003-2004)
  • Kenichiro Uemura, MD (2002-2004)
  • Makoto Tatewaki, MD, PhD (2002-2004)
  • Tomio Ueno, MD, PhD (2002-2004)
  • Jose Balestrini, BS (2002-2004)
  • Woo Yong Lee, MD (2003-2004)
  • Masahiro Iwa, PhD (2004-2005)
  • Hiroyuki Fukuda, MD (2003-2005)
  • Daisuke Tsuchida, MD (2003-2005)
  • Yoji Takami, MD (2003-2005)
  • Yukiomi Nakade, MD, PhD (2004-2006)
  • Kiyoshi Tsukamoto, MD (2005-2006)
  • Constant Masere, MD (2005-2006)
  • Hajime Ariga, MD (2005-2007)
  • Kenji Imai, PhD (2006-2007)
  • Erito Mochiki, MD, PhD (2006-2007)

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