Yosuke Kodama

Denervation suppresses gastric tumorigenesis.

Surgical or pharmacologic interruption of muscarinic innervation to the stomach suppresses gastric tumor growth in mice and humans. Treating Cancer by Getting on Its Nerves The nervous system plays a role in the regulation of many different organs, including the gut. Now, Zhao et al. have shown that the vagal nerve, which signals to the stomach through muscarinic receptors, contributes to the growth of gastric tumors. The authors demonstrated that vagotomy (surgical interruption of the vagal nerve) can prevent gastric cancer in mice and reduce the recurrence of gastric tumors in human patients. Moreover, the same result can be achieved in mice treated with Botox or anticholinergic drugs to inhibit vagal nerve signaling, raising the hope of a safer treatment for gastric cancer without irreversible side effects. The nervous system plays an important role in the regulation of epithelial homeostasis and has also been postulated to play a role in tumorigenesis. We provide evidence that proper innervation is critical at all stages of gastric tumorigenesis. In three separate mouse models of gastric cancer, surgical or pharmacological denervation of the stomach (bilateral or unilateral truncal vagotomy, or local injection of botulinum toxin type A) markedly reduced tumor incidence and progression, but only in the denervated portion of the stomach. Vagotomy or botulinum toxin type A treatment also enhanced the therapeutic effects of systemic chemotherapy and prolonged survival. Denervation-induced suppression of tumorigenesis was associated with inhibition of Wnt signaling and suppression of stem cell expansion. In gastric organoid cultures, neurons stimulated growth in a Wnt-mediated fashion through cholinergic signaling. Furthermore, pharmacological inhibition or genetic knockout of the muscarinic acetylcholine M3 receptor suppressed gastric tumorigenesis. In gastric cancer patients, tumor stage correlated with neural density and activated Wnt signaling, whereas vagotomy reduced the risk of gastric cancer. Together, our findings suggest that vagal innervation contributes to gastric tumorigenesis via M3 receptor–mediated Wnt signaling in the stem cells, and that denervation might represent a feasible strategy for the control of gastric cancer.

Topical application of acetic acid in cytoreduction of gastric cancer. A technical report using mouse model

Background and Aim:  Application of acetic acid topically to the mucosal or serosal side of the stomach has been well used to create a chronic gastric ulcer model. The aim of the present study was to apply it as a new cytoreductive approach in a mouse model of gastric cancer.

Mechanistic Comparison between Gastric Bypass vs. Duodenal Switch with Sleeve Gastrectomy in Rat Models

Background Both gastric bypass (GB) and duodenal switch with sleeve gastrectomy (DS) have been widely used as bariatric surgeries, and DS appears to be superior to GB. The aim of this study was to better understand the mechanisms leading to body weight loss by comparing these two procedures in experimental models of rats. Methods Animals were subjected to GB, DS or laparotomy (controls), and monitored by an open-circuit indirect calorimeter composed of comprehensive laboratory animal monitoring system and adiabatic bomb calorimeter. Results Body weight loss was greater after DS than GB. Food intake was reduced after DS but not GB. Energy expenditure was increased after either GB or DS. Fecal energy content was increased after DS but not GB. Conclusion GB induced body weight loss by increasing energy expenditure, whereas DS induced greater body weight loss by reducing food intake, increasing energy expenditure and causing malabsorption in rat models.

Vagal Blocking for Obesity Control: a Possible Mechanism-Of-Action

BackgroundRecently, the US FDA has approved “vagal blocking therapy or vBLoc® therapy” as a new treatment for obesity. The aim of the present study was to study the mechanism-of-action of “VBLOC” in rat models.MethodsRats were implanted with VBLOC, an intra-abdominal electrical device with leads placed around gastric vagal trunks through an abdominal incision and controlled by wireless device. Body weight, food intake, hunger/satiety, and metabolic parameters were monitored by a comprehensive laboratory animal monitoring system. Brain-gut responses were analyzed physiologically.ResultsVBLOC reduced body weight and food intake, which was associated with increased satiety but not with decreased hunger. Brain activities in response to VBLOC included increased gene expression of leptin and CCKb receptors, interleukin-1β, tumor necrosis factor, and transforming growth factor β1 in the brainstem; increased CCK, somatostatin, and tyrosine hydroxylase in the hippocampus; increased NPY, AgRP, and Foxa2 in the hypothalamus; and reduced CCKb receptor, melanocortin 4 receptor, and insulin receptor in the hypothalamus. Plasma concentrations of CCK, gastrin, glucagon, GLP-1, and PYY and gastric acid secretion were unchanged in response to VBLOC.ConclusionsBased on the present study, we may suggest that VBLOC induces satiety through vagal signaling, leading to reduced food intake and loss of body weight.

Gene expression profiling of gastric mucosa in mice lacking CCK and gastrin receptors

The stomach produces acid, which may play an important role in the regulation of bone homeostasis. The aim of this study was to reveal signaling pathways in the gastric mucosa that involve the acid secretion and possibly the bone metabolism in CCK1 and/or CCK2 receptor knockout (KO) mice. Gastric acid secretion was impaired and the ECL cell signaling pathway was inhibited in CCK2 receptor KO mice but not in CCK1 receptor KO mice. However, in CCK1+2 receptor double KO mice the acid secretion in response to pylorus ligation-induced vagal stimulation and the ECL cell pathway were partially normalized, which was associated with an up-regulated pituitary adenylate cyclase-activating polypeptide (PACAP) type 1 receptor (PAC1). The basal part of the gastric mucosa expressed parathyroid hormone-like hormone (PTHLH) in a subpopulation of likely ECL cells (and possibly other cells) and vitamin D3 1α hydroxylase probably in trefoil peptide2-immunoreactive cells. In conclusion, mice lacking CCK receptors exhibited a functional shift from the gastrin-CCK pathways to the neuronal pathway in control of the ECL cells and eventually the acid secretion. Taking the present data together with previous findings, we suggest a possible link between gastric PTHLH and vitamin D and bone metabolism.

Effects of duodenal switch alone or in combination with sleeve gastrectomy on body weight and lipid metabolism in rats

Background:A combined procedure of sleeve gastrectomy and duodenal switch (SG+DS) has been applied to the treatment of super obesity. The aim of the present study was to test whether duodenal switch alone (DS) leads to similar weight loss and changes in lipid metabolism as SG+DS.Methods:Male Sprague–Dawley rats underwent sham surgery (Sham, N=7), duodenal switch alone (DS, N=5) or sleeve gastrectomy followed by duodenal switch (SG+DS, N=5). Body weight, feed and water intakes, and ambulatory activity were recorded 2 months post surgery. Tissue and faecal lipids, faecal bile acids, plasma cytokines and lipid metabolism-related gene expression in adipose tissue and liver were analysed.Results:Daily energy intake, relative feed uptake, ambulatory activity and body weight reduction were similar between DS and SG+DS rats. The hepatic triacylglycerol content was higher and faecal secretion of triacylglycerol was lower after SG+DS compared to DS (P<0.05). Faecal bile acid secretion was higher in SG+DS than in DS rats (P<0.05) despite similar hepatic CYP7A1mRNA level. Plasma levels of proinflammatory cytokines interleukin (IL)-1b, IL-2, IL-4, IL-5, IL-6, IL-12, granulocyte-macrophage colony stimulating factor and tumour necrosis factor alpha were higher in SG+DS than in DS rats (P<0.05).Conclusions:Although DS and SG+DS had similar efficacy in terms of body weight loss, SG+DS resulted in a poorer regulation of lipid metabolism than DS.

Erratum to: Vagal Blocking for Obesity Control: a Possible Mechanism-Of-Action

1 Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway 2 Department of Clinical Neuroscience and Rehabilitation, The Sahlgrenska Academy at Gothenburg University, Gothenburg, Sweden 3 Rowett Institute of Nutrition and Health, University of Aberdeen, Aberdeen, Scotland 4 Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden 5 Department of Biomedical Sciences, the Panum Institute, University of Copenhagen, Copenhagen, Denmark 6 Department of Clinical Biochemistry, Rigshospitalet, Copenhagen, Denmark 7 Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, Netherlands 8 Center for Obesity Research, Department of Surgery, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway OBES SURG (2017) 27:186 DOI 10.1007/s11695-016-2370-2

Su2070 Comparison of Different Surgical Procedures in Animal Models for a Better Consideration of Personalized Bariatric Surgery

S A T A b st ra ct s increase in serum amylase, AST, ALT was observed in the Aged group compared to the Young group (p<0.05). Two hours after AP a transient liver mitochondrial dysfunction occurred in young animals, mainly due to uncoupling of oxidative phosphorylation, and that was partially recovered. Liver mitochondrial dysfunction did not occur in the Sham group of young animals. However, in aged animals two hours after AP there was a liver mitochondrial dysfunction that was also noted in sham aged animals, suggesting a previous degenerative process similar to that found in cellular ischemia. Likewise, it was observed an increase of MDA content in young animals two hours after AP in comparison to the sham group. The aged animals showed an increase of MDA content both in the sham group and in the AP group. Conclusion: This study demonstrates that liver mitochondrial function is transiently compromised in young animals submitted to AP. However, in aged animals unexpectedly the pre-existing severe mitochondrial dysfunction remained unchanged after induction of AP associated with a sustained oxidative stress. These findings may have significant therapeutic implications in the clinical setting.

Su2097 Evidence for the Hindgut Hypothesis After Ileal Interposition Associated With Sleeve Gastrectomy: Increased Number of GLP-1-Producing Cells in Interposed Ileum and Pancreatic Islets in Rats

Results: After II alone, satiety ratio i.e., intermeal interval/meal size, was reduced while calorie intake was increased at two weeks postoperatively. Respiratory exchange ratio, i.e., VCO2/VO2, was increased to above 1.0 (i.e., carbohydrate metabolism) during both daytime and nighttime two and six weeks postoperatively. After SG alone, satiety ratio and respiratory exchange ratio were unchanged, and the number of GLP-1-producing cells was not increased in the ileum (in terms of volume density), but increased in the pancreatic islets (number of cells per islet). After II-SG, rate of eating was reduced, while meal duration (minutes/gram) was increased during both daytime and nighttime at two and six weeks postoperatively. The number of GLP-1-producing cells increased by about 2.5-fold in the interposed ileum, and also increased to the same extent in the pancreatic islets as seen after SG alone. The increased GLP-1-producing cells in the pancreas were distributed around the insulin-producing β cells.

Tu1980 Altered Eating Behavior by Subdiaphragmatic Truncal Vagus Nerve Stimulation in Rats

Background: Stress is a major contributing factor to the pathophysiology of IBS and accelerates colonic transit and increases in defecation. The parasympathetic vagal and pelvic nerves regulate colonic motility and defecation in physiological state. It was shown that physical stress altered colonic functions via vagal efferent in rats. However, it remains still unclear whether the pelvic efferent pathway is involved in accelerating colonic and rectal functions induced by stress. The aim of this study was to investigate whether distal colonic transit and defecation are accelerated via pelvic efferent nerve in psychological stress-loaded rats. We also evaluated the effect of HPA-axis activation on stress -induced defecation. Method: The rats were subjected to water avoidance stress (WAS) or sham stress for 1-hr or 2-hr. The number of fecal pellets was counted for 1-hr in WASor sham stress-rats. Adrenalectomy (Adx), subdiaphragmatic vagotomy (Vag), pelvic nerve rectal branches (Rectal nerves) transection (RNT), or each sham operation was performed at 1 week before WAS. Colonic transit was assessed by the distribution of phenol red injected from catheter located in proximal colon. The distal part of colonic and rectal transit was measured over a 2-hr WAS period from the evacuation rate of a bead inserted into distal colon. c-Fos immunoreactivity (IR), used as a marker of neuronal activation, was monitored in longitudinal muscle/myenteric plexus (LMMP) whole mount preparations of proximal and distal colon after WAS and sham stress. Results: WAS significantly accelerated colorectal transit and defecation with a marked elevation of plasma corticosterone (CORT) levels. Increased defecation induced by WAS was significantly reduced by Vag and RNT, even though CORT levels were elevated. WASinduced acceleration of transit in distal colon and rectum was significantly reduced by RNT, compared with sham-operation. The number of c-Fos-IR cells were significantly increased by WAS in LMMP of proximal and distal colon. In RNTrats, an increase in c-Fos IR cells after WAS was decreased in distal colon, but not in proximal colon, whereas Vag did not affect an increase of c-Fos IR cells in distal colon. In contrast, in Adx-rats WAS increased the number of defecation without an elevation of plasma CORT. Conclusion: It is concluded that psychological stress accelerated distal colonic transit and rectal transit via a parasympathetic efferent pelvic pathway. It seems that the stimulation of pelvic nerve in response to stress activates myenteric neurons in distal colon, followed by an increase of colonic motility. On the other hand, a vagal efferent pathway affects proximal colonic transit. However, an increase in defecation induced by acute psychological stress might not involve the activation of the HPA axis.