Introduction to GI Physiology

Categorize (as excitatory or inhibitory) the effects of acetylcholine, nitric oxide, substance P, and vasoactive intestine peptide (VIP) on smooth muscle cells:

Excitatory = contraction of smooth muscle Inhibitory = relaxation of smooth muscle Excitatory: -ACh -Substance P Inhibitory: -VIP -NO

Describe how extrinsic nerves (sympathetic and parasympathetic) affect gastrointestinal motility:

• Motility: term that refers to contraction and relaxation of the walls and sphincters of the gastrointestinal tract ○ Parasympathetic stimulation increases the frequency of action potentials and the force of gastric and intestinal smooth muscle contractions ○ Sympathetic stimulation decreases the frequency of action potentials and the force of gastric and intestinal smooth muscle contractions

Describe the physiologic effects of cholinergic and anticholinergic medications on salivary secretion:

(Remember from MSI that Muscarinic stimulation causes exocrine gland secretion) Anticholinergic Drugs (Atropine): -Inhibit saliva production by inhibiting the parasympathetic cholinergic (muscarinic receptors) --> Results in Dry Mouth Cholinergic Drugs: -Stimulate the Parasympathetic Muscarinic Receptors --> Results in Moist Mouth Sympathetic stimulation is not great enough to overcome anti-cholinergic effects on saliva production

Describe the volume and composition of salivary fluid coming from major salivary glands. State the physiological function of the components of saliva. Indicate the components of the saliva important in oral hygiene:

• Produced at a rate of 1L/day • Composed of water, electrolytes, α-amylase, lingual lipase, kallikrein, and mucus • Three major salivary glands: ○ (1) Parotid glands: § Glands composed of serous cells § Secrete water, ions, and enzymes ○ (2) Submandibular glands: § mixed glands composed of serous and mucous cells § serous cells secrete aqueous fluid § mucous cells secrete mucin glycoproteins for lubrication ○ (3) Sublingual glands: § Same as submandibular glands • Function: ○ Initial digestion of starches/lipids by salivary enzymes ○ Dilution and buffering of foods ○ Lubrication of ingested foods with mucus to aid its movement through esophagus ○ protects our teeth from decay by attacking microbial organisms via RNase and DNase

List the proteins secreted into the gastric lumen by chief cells, parietal cells, and mucous cells. Contrast the functions and regulation of these secretions. Indicate which are protective against which disease:

Chief cells (zymogenic cells) ○ Produce, store, and secrete pepsinogen (ACTIVATED BY ACIDIC pH to become pepsin, the major gastric protease) Parietal cells (oxyntic cell) ○ Secrete HCl (creates acidic environment) + intrinsic factor (binds vitamin B12 for absorption in ILEUM) ○ ***protective against pernicious anemia Mucous cells (mucous protects you by making you sticky vs acid - aka bicarb) ○ Secrete mucus + bicarbonate ○ ***protective against peptic ulcer disease

Describe how the gut is innervated: Explaining in general terms the roles of the parasympathetic and sympathetic nervous systems and how they interact with the enteric nervous system to regulate gastrointestinal functions

Enteric nervous system: contained within the submucosal plexuses (Meissner's plexus) and the myenteric plexuses Gastrointestinal tract is regulated by the autonomic nervous system via 2 components: the extrinsic (parasympathetic + sympathetic) and intrinsic (enteric nervous system) components Parasympathetic innervations:supplied by the vagus nerve (cranial nerve X) and the pelvic nerve Vagus nerve innervates upper GI tract: striated muscle of upper third of esophagus, wall of stomach, small intestine, ascending colon Pelvic nerve innervates lower GI tract: striated muscle of external anal canal and walls of transverse, descending, and sigmoid colons Parasympathetic NS has preganglionic fibers that synapse on ganglia in the myenteric and submucosal plexuses -> info is relayed to smooth muscle, endocrine, and secretory cells of the GI tract Postganglionic parasympathetic neurons are either cholinergic (releasing ACh) or peptidergic (releasing peptides such as Substance P or Vasoactive Inhibitory peptide) Sympathetic NS: Preganglionic Fibers synapse in ganglia OUTSIDE the GI tract (unlike Parasympathetic Preganglionic fibers). 4 Sympathetic ganglia serve the GI Tract: celiac, superior mesenteric, inferior mesenteric, hypogastric Postganglionic Fibers are adrenergic (releasing NE) and synapse on the ganglia in the myenteric and submucosal plexuses OR directly innervate smooth muscle, endocrine, secretory cells From Autonomic NS Problem Set (2/1/16): Parasympathetic Innervation will contract GI smooth muscle and relax the GI sphincters Sympathetic Innervation will relax GI smooth muscle and contract the GI sphincters Enteric nervous system: can direct functions of GI tract even without the extrinsic innervation. Controls contractile, secretory, endocrine functions, which are modulated by parasympathetic and sympathetic NS Also receives input from mechanoreceptors and chemoreceptors in the mucosa Interneurons can relay information between ganglia in the ENS

Summarize in a diagram of a cross-section of the gastrointestinal tract how the neurons of the enteric nervous system may synapse with each other and the components of the different tissue layers:

FIGURE: The integration of the extrinsic (parasympathetic and sympathetic) nervous system with the enteric (myenteric and submucosal plexuses) nervous system. The preganglionic fibers of the parasympathetic synapse with ganglion cells located in the enteric nervous system. Their cell bodies, in turn, send signals to smooth muscle, secretory, and endocrine cells. They also receive information from receptors located in the mucosa and in the smooth muscle that is relayed to higher centers via vagal afferents. This may result in vagovagal (long) reflexes. Postganglionic efferent fibers from the sympathetic ganglia innervate the elements of the enteric system, but they also innervate smooth muscle, blood vessels, and secretory cells directly. The enteric nervous system relays information up and down the length of the gastrointestinal tract, and this may result in short or intrinsic reflexes.

Describe how acinar secretions are modified by duct cells to produce the final salivary fluid that enters the buccal cavity: Contrast the plasma and saliva concentrations of Na+, Cl-, and HCO3- at low secretion rates and at high secretion rates:

Initial Saliva produced by the Acinar Cells is isotonic In the duct, Na/K ATPase Pumps and Cl channels result in... -Absorption of Na and Cl -Secretion of K and HCO3 ...Into the saliva, raising concentrations of K and HCO3 and lowering concentrations of Na and Cl relative to plasma There is a net absorption of solute because more NaCl is absorbed than KHCO3 is secreted. Ductal Cells are water-impermeable, so water is not absorbed along with solute, making the final saliva hypotonic At Lower Flow Rates. Saliva has: -Lower osmolality -Lower concentrations of Na, Cl, HCO3 -Higher concentrations of K At Higher Flow Rates: -Saliva composition approaches that of plasma *The only ionic species that does not follow the "contact-time" rule is HCO3 whose saliva secretion is selectively stimulated concomitantly with saliva production-> High flow rates result in higher bicarb saliva concentrations and the vice versa for slow flow rates.

Describe the stimuli and neural pathways involved in promoting salivary secretion:

Saliva production is increased by both parasympathetic and sympathetic nervous systems, with parasympathetic being more important. Parasympathetic stimulation (from cranial nerves VII and IX) increase production by increasing transport processes in acinar and ductal cells and by causing vasodilation (increasing blood flow). Parasympathetic receptors on these cells are muscarinic (M1) causing increased IP3 and increased Ca2+ within the cell. Sympathetic stimulation also increases the production of saliva and the growth of salivary glands but to a smaller effect. Sympathetic receptors on acinar and ductal cells are β-adrenergic, increasing cAMP within cell. Saliva production is increased via the parasympathetic pathway by food in the mouth, smells, conditioned reflexes and nausea. It is decreased by inhibition of the parasympathetic pathway during sleep, dehydration, fear, and anticholinergic drugs.

Describe the major anatomical and functional characteristics of the enteric nervous system and the major cellular divisions of enteric ganglia (sensory nerves, interneurons, and motor neurons):

The ENS is comprised of ganglia from the submucosal and myenteric plexuses. The Parasympathetic and Sympathetic NS provide extrinsic innervation to modulate these plexuses, but the ENS can function by itself The submucosal and myenteric plexuses also receive information from sensory receptors in the mucosa: mechanoreceptors (sensing tension in the gut wall) and chemoreceptors (sensing substances in the gut lumen) Interneurons allow the ganglia within the plexuses to talk to one another Motor neurons allow for a change in digestive gland activity or inducing smooth muscle contractions/relaxation

Describe the control of peristalsis by the enteric nervous system:

The interneurons and motorneurons are characterized by a single axon and fast depolarization, and project in an oral or anal direction. During peristalsis, ascending cholinergic motorneurons provide the muscle contraction that propels intraluminal contents distally, and descending nitrergic motorneurons relax the muscle to allow intraluminal contents to move forward. Ascending inhibitory and descending excitatory pathways also exist. In the upper gut these may have roles in mediating defensive patterns of motility, such as retropulsion during emesis. A second type of neuron, often described as an intrinsic primary afferent neuron (IPAN), has multiple axons that project circumferentially to different enteric neurons, as well as axons that project to the mucosa. These neurons are thought to act as enteric sensory neurons. Connections between IPANs and interneurons/motorneurons (or with other IPANs) mean that the luminal and mucosal environment can cause changes in motility. IPANs are involved in initiating peristalsis, and also ensure that the contractions and relaxations are dynamic and not stationary. For example, by subsequently detecting the increase in muscle tension created by an ascending contraction, the contraction can be terminated. As the intraluminal contents move along the intestine, this repetitive initiation and termination of the peristaltic reflex creates a dynamic peristaltic wave.

Contrast the muscular composition and function in the upper versus lower esophagus. Explicitly consider the upper and lower esophageal sphincters with regards to function:

Upper esophagus: Muscular composition: The pharynx, upper esophageal sphincter, and upper third of the esophagus are composed of striated muscle. Function: Swallowing Upper esophageal sphincter: The sphincter opens, mediated by the swallowing reflex, to allow the bolus to move from the pharynx to the esophagus. Once the bolus enters the esophagus, the sphincter closes, which prevents air reflux into the pharynx. Lower esophagus: ○ Muscular composition: The lower two thirds of the esophagus and lower esophageal sphincter are composed of smooth muscle. ○ Function: Motility (propelling the food bolus from the pharynx to the stomach) ○ Lower esophageal sphincter: As the bolus approaches the lower esophageal sphincter, it opens. This opening is mediated by peptidergic fibers in the vagus nerve that release VIP as their neurotransmitter. As soon as the bolus enters the orad stomach, the lower esophageal sphincter contracts. The lower esophageal sphincter functions to prevent the acidic gastric components from entering the lower esophagus.

Describe local and central reflex mechanisms involved in receptive relaxation of the proximal stomach. Outline how this reflex regulates gastric pressure:

• As mentioned in LO 16, receptive relaxation of the proximal (orad) region of the stomach increases the volume of the orad stomach and lowers the pressure in the stomach. ○ This facilitates movement of the bolus into the stomach from the esophagus. • The receptive relaxation is vagovagal reflex (both afferent and efferent limbs of the reflex are carried in the vagus nerve). ○ Mechanoreceptors detect distention of the stomach and duodenum and relay this information to the CNS via sensory neurons. ○ The CNS sends efferent information to the smooth muscle wall of the orad stomach, causing it to relax. ○ The neurotransmitter released from these postganglionic peptidergic vagal nerve fibers is VIP (NO was also mentioned in the lecture). In the lecture, Dr. Noramly mentioned the food in the duodenum (AA, peptides, FA) stimulates I cells which secretes CCK, which in turn stimulates the dorsal vagal complex (DVC), which leads to release of ACH and NO. Please see her sketch below.

Categorize and define modes of communication in the gastrointestinal tract (endocrine, neurocrine, paracrine, juxtocrine):

• Endocrine: ○ Peptides released by endocrine cells of GI tract. ○ Hormones released into portal circulation, pass through the liver, and enter systemic circulation. ○ Can target GI tract itself or cells elsewhere in the body. ○ Includes: gastrin, cholecystokinin (CCK), secretin, and glucose-dependant insulinotropic peptide (GIP) • Paracrine: ○ Peptides released by endocrine cells of GI tract. ○ Act locally (by diffusion through interstitial fluid or traveling through capillaries) ○ Site of secretion must be a short distance from site of action ○ Includes: somatostatin (peptide) and histamine (non-peptide) • Neurocrine: ○ Synthesized in neurons of GI tract and released following an action potential. ○ Acetylcholine, norepinephrine, vasoactive intestinal peptide (VIP), gastrin-releasing peptide (GRP), enkephalins, neuropeptide Y, and substance P. • Juxtocrine: ○ While paracrine signaling requires close proximity only juxtacrine requires that the signaling and receiving cell be in physical contact. ○ Example: ICCs and smooth muscle cells are connected via gap junctions (juxtacrine signaling)

Describe how dysfunction in the spatial or temporal characteristics of the swallowing reflex and/or esophageal pressure wave and/or sphincter relaxation can lead to the following swallowing defects/disorders: heartburn, achalasia and aspiration of food:

• Heartburn ○ Usually, lower esophagus sphincter (LES) keeps acidic contents in the stomach out of the esophagus ○ Heartburn can be caused by gastroesophageal reflux, where the contents of the stomach reflux into the esophagus. ○ Gastroesophageal can be caused by either 1) LES hypotension (reduced basal tone--so it cannot close completely) or 2) increased intra-abdominal pressure (that overwhelms LES). • Achalasia ○ Caused by impaired LES relaxation (= it's tense and does not open) ○ And loss of peristaltic sequencing of the esophageal contractions (= loss of pressure wave). § due to motor disorder involving the lower two thirds (smooth muscle segment) of the esophagus, which is caused by degeneration of intramural myenteric plexus neurons. ○ Symptoms include dysphagia (difficulty swallowing), chest pain, and regurgitation • Aspiration of food ○ Overall, the food gets in the larynx because the larynx is not closed for various reasons. There are three types mentioned in the handout: § Pre-deglutitive aspiration □ due to premature spilling of food into the oropharynx before the oral phase of swallowing is triggered. ® In the pharyngeal phase, the epiglottis would move to cover the opening to the larynx, and the larynx would move upward against the epiglottis to prevent food from entering the trachea § Inter-deglutitive aspiration □ due to weakness or incoordination of muscles in the laryngeal group and failure of protective laryngeal closure § Post-deglutitive aspiration □ due to abnormal bolus clearance from the hypopharynx and lingering bolus residue in the vicinity of the laryngeal entrance (so they get in the larynx once the deglutition apnea ceases and the airway opens).

List the mechanisms contributing to gastric mucosal defense and how these can be compromised by drugs or pathogens:

• Lymphocytes are activated by antigens presented to them from lumen • Immune cells and cells of tissue defense (mast cells + macrophages) release substances that act locally within gut wall • Bacterial products are detected by pattern-recognition receptors to activate local defense mechanisms ○ --> secretion of antimicrobials from Paneth cells (found in small intestine - NOT STOMACH) Pro-H+ (and therefore anti-mucosal defence): Histamine • Gastrin • Ach (inhibited by atropine) Anti-H+ (and therefore pro mucosal defence): • Prostaglandins (inhibited by COX inhibitors) • Somatostatin

Summarize briefly how the physical and chemical compositions of luminal contents are sensed and what cellular and systemic responses to luminal stimuli may occur:

• Nutrients and food components ○ Taste, Carbohydrates, Protein breakdown products, Free fatty acid, Phytochemicals (specific chemical entities of herbs and spices). • Mechanical distortion, stretch and tension ○ Sensed by mechanosensitive channels of nerve endings and enteroendocrine cells. • Other physicochemical attributes ○ Temperature, osmolarity, acidity • Internal secretions ○ Bile acid • Bacteria, viruses, fungi, protozoa and helminths: their antigens and products • Toxins Luminal contents activate four major effector systems: • the enteroendocrine system ○ Enteroendocrine cells (purple) in the mucosal epithelium sense luminal chemicals and release hormones that act locally on nerve endings, on enteric neurons, on the epithelium and on cells of the immune system. Hormones that enter the circulation act at remote sites. • the nervous system ○ Some afferent neurons have cell bodies in the gut wall (intrinsic primary afferent neuron and intestinofugal neurons) and the cell bodies of others are in extrinsic ganglia (extrinsic primary afferent neurons). • the gut immune system ○ Lymphocytes are activated by antigens presented to them from the lumen. Immune cells and cells of tissue defence, such as mast cells and macrophages, also release substances that act locally within the gut wall. • the nonimmune defence system of the gut ○ Bacterial products are detected by pattern-recognition receptors to activate local defence mechanisms, including secretion of antimicrobials from Paneth cells (red).

Describe the progression of peristaltic waves across the body and antrum of the stomach and correlate to their role in mixing and propulsion of gastric contents:

• The distal part of the body and antrum of the stomach (the caudad region) have a thick muscle wall and produce the contractions necessary for mixing and digesting food. • Waves of contraction begin in the middle of the body of the stomach and move distally along the caudad stomach. • These are vigorous contractions that increase in strength as they approach the pylorus. • The contractions mix the gastric contents and periodically propel a portion of the gastric contents through the pylorus into the duodenum. ○ Much of the chyme is not immediately injected into the duodenum, however, because the wave of contraction also closes the pylorus. Most of the gastric contents are propelled back into the stomach for further mixing and further reduction of particle size, a process known as retropulsion.

Describe the dynamic pressure changes that occur in the regions of the esophagus after initiation of the swallowing reflex and how these pressure changes would propel a bolus of food from the mouth to the stomach:

• The upper esophageal sphincter opens allowing the bolus of food to move from the pharynx to the esophagus. Once the bolus enters the esophagus, the upper esophageal sphincter closes. • A primary peristaltic contraction, mediated by the swallowing reflex, involves a series of coordinated sequential contractions in the esophagus. ○ As each segment of the esophagus contracts, it creates an AREA OF HIGH PRESSURE just behind the bolus, pushing it down the esophagus. ○ Each sequential contraction pushes the bolus further along. If the person is sitting or standing, this action is ACCELERATED BY GRAVITY. • As the peristaltic wave and food bolus approach the lower esophageal sphincter, it opens . At the same time that it opens, the orad region of the stomach also relaxes, a phenomenon called RECEPTIVE RELAXATION. ○ Receptive relaxation decreases the pressure in the orad stomach and facilitates movement of the bolus into the stomach. ○ As soon as the bolus enters the stomach, the lower esophageal sphincter contracts, returning to its resting tone. At this resting tone, the pressure at the sphincter is higher than the pressure in the esophagus or in the orad stomach. • If the primary peristaltic contraction does not clear the esophagus of food, a second peristaltic contraction mediated by the enteric nervous system, clears the esophagus of remaining food.

Describe major motor patterns in the GI tract and their functions during fasting (migrating motor complex or MMC) and during digestion:

○ During digestion § Peristalsis- contractions that function to move food through the GI tract by propelling food/chyme in one direction; primarily occurs in esophagus and stomach § Segmentation- contractions that function to mix the luminal contents by splitting a bolus and propelling chyme in both directions ;relaxation allows the bolus to merge back together; primarily occurs in the small and large intestine ○ During fasting § Migrating motor complex- intense propulsive contractions (lasting about 3-6 minutes each) that occur at 90-minute intervals and function to clear the stomach of any residue remaining from the previous meal; occurs in the stomach and small intestine □ Motilin- involved in initiation of the MMC □ Enteric nerves play vital role in coordination of MMC ○ Other: mass movements- function to move the contents of the large intestine over large distances; occur in the colon usually 1-3 times per day

Describe the function of gastric peristalsis, the pyloric sphincter, and duodenal feedback in controlling gastric emptying rate:

○ Peristalsis functions to propel food/chyme in a single direction by contracting smooth muscle behind the bolus/chyme and relaxing smooth muscle in front of it (muscles behind bolus narrow and lengthen and those in front of bolus widen and shorten) § The greater the peristalsis, the faster the gastric emptying rate ○ Pyloric sphincter- regulates entry of food from the stomach to the duodenum ○ Duodenal feedback- responses of the duodenum to certain chemical compositions of meals (see LO #21) can slow or speed up the rate of gastric emptying; through the ENTERIC NERVOUS SYSTEM, the receptors in the duodenum communicate with the gastric smooth muscle to change its contraction rate

Describe how the physical and chemical composition of a meal is sensed by the stomach and duodenum to affect the rate of gastric emptying:

○ Physical § Liquids empty more rapidly than solids and isotonic solutions empty more rapidly than hyper- or hypotonic solutions § Entry into the duodenum has a size restriction of 1mm^3 or else retropulsion in the stomach occurs until particles are the correct size ○ Chemical § Fat entry into the duodenum causes I cells to release CCK to slow the rate of gastric emptying to allow for adequate digestion and absorption § H+ ion entry (and thus low pH) into the duodenum is detected by H+ receptors in the duodenal mucosa □ These receptors stimulate a reflex in gastric smooth muscle via interneurons in the myenteric plexus to ensure that gastric contents are delivered slowly to the duodenum permitting time for neutralization of H+ by pancreatic HCO3-