Brain-Gut Axis

A better understanding of the brain-gut axis is of primary importance in the context of the bidirectional cross talk occurring through the autonomic nervous system and circulating hormones. There is a growing recognition that such interactions regulate digestive function, gut inflammation, and feeding behavior and can lead to the development and modulation of some gut pathophysiology. Our focus has been to delineate the signaling molecules in the brain that influence parasympathetic activity regulating gastric and colonic secretory motor function. We also assess the signaling to the brain occurring through capsaicin sensitive afferents activated by gut hormones and visceral pain. In particular, we investigate the brain and peripheral chemical coding involved under physiological conditions related to the cephalic phase and stress, and taking place in disease models of gastric erosions, postoperative ileus, irritable bowel syndrome, Parkinson’s disease and obesity.

Brain vagal stimulation by thyrotropin-releasing hormone (TRH): Role in cephalic phase and modulation of the resistance of gastric mucosa

The gastric response to the cephalic phase is known to be vagal dependent. The vagal efferent fibers have their cell bodies in the dorsal vagal motor nucleus (DMN) and innervate the gastric enteric neurons. We established that the three amino acid peptide, thyrotropin releasing hormone (TRH) expressed in the brain stem, activates gastric vagal efferent activity and gastric myenteric neurons. This is achieved through TRH neurons originating from the raphe pallidus and obscurus nuclei sending efferent projections to DMN neurons. We showed that the activation of the TRH receptor 1 expressed on DMN neurons by TRH is involved in orchestrating the digestive components of the vagally mediated cephalic phase, thereby optimizing the process of gastric acid and pepsin secretion, propulsive motility, and duodenal bicarbonate and pancreatic secretion occurring under conditions of impending nutrient ingestion.

Using TRH as a physiologic tool to produce different intensities of centrally initiated vagal stimulation, we demonstrated that TRH in the brain stem induces a vagal-dependent stimulation of gastric serotonin, histamine, nitric oxide and prostaglandin release, as well as the recruitment of efferent function of capsaicin-sensitive afferents releasing calcitonin gene-related peptide. We showed that the release of these transmitters has implications in the stimulation/modulation of gastric acid secretion, mucosal blood flow and motility, and resistance of gastric mucosa to injury. In particular, we discovered that conditions of low central vagal activity lead to an increase in the resistance of the gastric mucosa to injury induced by stress or ethanol, while chronic high-intensity central vagal stimulation in fasted rodents results in the development of gastric erosions. We delineated the peripheral mechanisms involved in these dual responses through vagally mediated changes in gastric acid secretion, mucosal blood flow and motility.

Role in preventing postoperative gastric ileus

Tracey’s recent work brought new insight to the function of the vagus nerve, pointing to its role in modulating inflammation through α7-nicotinic receptors. In addition, intestinal inflammation triggered by the handling of the intestine was identified as a contributing mechanism that is clinically a relevant target for treatment of postoperative ileus. We demonstrated that abdominal surgery-induced postoperative gastric ileus is associated with the infiltration of neutrophils in the gastric muscularis externa and reduction of the prokinetic gastric hormone, ghrelin. Importantly, we showed that central vagal activation induced by TRH injected near the DMN neurons (intracisternal) prevents the neurogenic (early phase) of postoperative gastric ileus (POGI), as well as the gastric inflammatory response occurring at 6 h.

Dr. Pu-Qing Yuan is presently delineating the cellular mechanisms involved in the central vagal activation-induced anti-inflammatory response in the stomach that contributes to the abrogation of postoperative gastric ileus in rats. We are also investigating a new ghrelin agonist as a promising candidate to reverse POGI through dual potent enteric prokinetic action combined with central vagal activation of the anti-inflammatory reflex.

Approach

  • Rat model of abdominal surgery-induced postoperative gastric and colonic ileus.
  • State-of-the-art technologies in neuroanatomy (CLARITY technique combined with targeted double or triple labeling, including anterograde tracing and 3D imaging of vagal fibers, enteric neurons and macrophages).
  • Molecular assessment of inflammatory mediators.
  • Functional study (gut transit and chemical stimulation of vagal activity).

Grants

  • VA Merit Award IO1BX003951, Mechanisms and Therapeutic Interventions of Post-operative Gastric Ileus. Y. Taché, PI, P-Q Yuan, Co-Investigator; 07/01/17-06/30/21. Objective: to unravel the central vagal cholinergic regulation of gastric inflammation during postoperative ileus.
  • NIH DK-41301 Digestive Diseases Center Grant, Animal Core. Y. Taché, Director, M. Million, Associate Director, L. Wang, Co-Investigator; 11/01/2014-10/31/2019.

Representative publications

  1. Yuan PQ, Taché Y. Abdominal surgery induced gastric ileus and activation of M1 like macrophages in the gastric myenteric plexus: Prevention by central vagal activation in ratsAm J Physiol Gastrointest Liver Physiol 2017 Oct 1;313:G320-G329
  2. Taché Y, Adelson D, Yang H. TRH/TRH-R1 receptor signaling in the brain medulla as a pathway of vagally mediated gut responses during the cephalic phaseCurr Pharm Des. 2014;20(16):2725-30
  3. Taché Y. Brainstem neuropeptides and vagal protection of the gastric mucosal against injury: Role of prostaglandins, nitric oxide and calcitonin-gene related peptide in capsaicin afferentsCurr Med Chem. 2012;19(1):35-42
  4. Miampamba M, Million M, Taché Y. Brain-gut interactions between central vagal activation and abdominal surgery to influence gastric myenteric ganglia Fos expression in ratsPeptides. 2011 May;32(5):1078-82
  5. Stengel A, Goebel M, Luckey A, Yuan PQ, Wang L, Taché Y. Cold ambient temperature reverses abdominal surgery-induced delayed gastric emptying and decreased plasma ghrelin levels in ratsPeptides. 2010 Dec;31(12):2229-35
  6. Taché Y, Yang H, Miampamba M, Martinez V, Yuan PQ. Role of brainstem TRH/TRH-R1 receptors in the vagal gastric cholinergic response to various stimuli including sham-feedingAuton Neurosci. 2006 Apr 30;125(1-2):42-52
  7. Miampamba M, Yang H, Sharkey KA, Taché Y. Intracisternal TRH analog induces Fos expression in gastric myenteric neurons and glia in conscious ratsAm J Physiol Gastrointest Liver Physiol. 2001 May;280(5):G979-91