Chapter 9: The Digestive System

Think of the GI tract as one long conveyor belt running through a factory - except instead of building something, it tears things apart. Food enters at one end (mouth) and waste exits at the other (anus), passing through specialized stations along the way.

The technical name for this tube is the alimentary canal. It runs about 9 meters (30 feet) from mouth to anus. Here is a crucial insight: the lumen (interior) of this tube is technically outside your body. Food sitting in your stomach has not actually entered your tissues yet. It must be digested and then absorbed across the intestinal wall to truly enter the body.

The Route: Station by Station

Food follows this path, in order:

1. Oral cavity (mouth) - mechanical and chemical digestion begin
2. Pharynx - shared passage with respiratory tract
3. Esophagus - transport tube to stomach
4. Stomach - acid bath and protein digestion
5. Small intestine (duodenum, jejunum, ileum) - most digestion and absorption
6. Large intestine (cecum, colon, rectum) - water absorption, feces formation
7. Anus - elimination

Four accessory organs contribute secretions but food never passes through them: salivary glands, liver, gallbladder, and pancreas.

Two Types of Digestion

Mechanical digestion physically breaks food into smaller pieces without changing its chemical structure. Chewing is the most obvious example, but the stomach’s churning and the small intestine’s segmentation contractions also count. The purpose is to increase surface area so enzymes can work faster.

Chemical digestion uses enzymes to break covalent bonds in macromolecules:

The Four Histological Layers

Every region of the alimentary canal shares the same four-layer wall structure, from innermost to outermost:

1. Mucosa - innermost layer; contains the epithelium that contacts food, plus the lamina propria (connective tissue with blood vessels and lymph) and muscularis mucosae (thin smooth muscle)
2. Submucosa - dense connective tissue with blood vessels, lymphatics, and the submucosal plexus (Meissner’s plexus) of the enteric nervous system
3. Muscularis externa - two layers of smooth muscle (inner circular, outer longitudinal) responsible for peristalsis; contains the myenteric plexus (Auerbach’s plexus) between the muscle layers
4. Serosa (or adventitia) - outermost connective tissue covering; serosa where the organ is surrounded by peritoneum, adventitia where it is not (esophagus)

Peristalsis and Segmentation

Peristalsis is the wave-like contraction that pushes food forward through the GI tract. Behind the food bolus, circular muscle contracts (squeezing); ahead of it, longitudinal muscle contracts (shortening, which widens the lumen). This coordinated wave moves food in one direction - mouth to anus.

Segmentation is a back-and-forth contraction pattern found mainly in the small intestine. Unlike peristalsis, segmentation does not push food forward. It chops and mixes the chyme with digestive juices, ensuring maximum contact between enzymes and food.

Sphincters: The Gatekeepers

Sphincters are rings of smooth muscle that act as one-way valves between GI regions:

Digestion begins the instant you take a bite. Your teeth grind the food into smaller pieces (mechanical digestion), and enzymes in saliva immediately start breaking chemical bonds (chemical digestion). By the time you swallow, starch digestion is already underway.

Mastication: The First Station

Chewing (mastication) is the only voluntary step of mechanical digestion. Your teeth cut, tear, and grind food into a soft mass called a bolus. This increases the surface area available for enzymes - a whole cracker has far less exposed surface than a chewed-up cracker.

Saliva: More Than Just Water

Saliva is produced by three pairs of salivary glands:

Saliva contains:

• Water and mucus - moisten food and lubricate the bolus for swallowing
• Salivary amylase - begins starch digestion
• Lingual lipase - begins fat digestion (secreted by glands at the back of the tongue)
• Lysozyme and IgA - antimicrobial defense
• Bicarbonate - buffers acids to protect tooth enamel

Saliva production is controlled by the autonomic nervous system. Parasympathetic stimulation (rest and digest) increases saliva flow. Sympathetic stimulation (fight or flight) decreases it - that is why your mouth goes dry when you are nervous.

Salivary Amylase: Starch Digestion Starts Here

Salivary amylase hydrolyzes the alpha-1,4-glycosidic bonds in starch, breaking it into maltose and maltotriose (shorter chains). This enzyme works best at a neutral pH (~6.8) and is inactivated once it reaches the acidic stomach.

Try this: hold a plain cracker in your mouth for 30 seconds without swallowing. It starts to taste sweet. That sweetness is maltose being released as salivary amylase breaks down the starch in real time.

Lingual Lipase: Fat Digestion Also Starts Here

Lingual lipase is secreted by glands at the back of the tongue. It begins triglyceride digestion in the mouth, although its activity continues in the stomach because lingual lipase is acid-stable (it works at low pH). It is most important for digesting milk fat in infants.

What Does NOT Get Digested in the Mouth?

Protein digestion does not begin until the stomach (pepsin requires acidic pH). If you mix saliva with protein in a test tube, nothing happens to the protein - there are no proteases in saliva.

The esophagus is a simple transport tube - no digestion or absorption happens here. Its only job is to move the food bolus from the pharynx to the stomach. But that job involves an elegant reflex that keeps food out of your lungs.

The Swallowing Reflex (Deglutition)

Swallowing has three phases:

1. Voluntary (oral) phase - Your tongue pushes the bolus to the back of the mouth toward the pharynx. This is the only voluntary part of swallowing.

2. Pharyngeal phase (involuntary) - Once the bolus touches the pharynx, a reflex takes over:

• The soft palate rises to close off the nasal passages (prevents food from going up your nose)
• The epiglottis folds down to cover the trachea (prevents food from entering the airway)
• The upper esophageal sphincter relaxes to let the bolus enter the esophagus
• Breathing is briefly inhibited

3. Esophageal phase (involuntary) - Peristaltic waves push the bolus down the esophagus toward the stomach. This takes about 8-10 seconds. Gravity helps but is not required - you can swallow while upside down because peristalsis does the work.

Esophageal Anatomy

The esophagus is about 25 cm long and runs behind the trachea. Key features:

• Upper third - contains skeletal muscle (voluntary-ish, used in the initial swallowing push)
• Middle third - mix of skeletal and smooth muscle
• Lower third - smooth muscle only (completely involuntary)
• No serosa - the esophagus has adventitia instead (unlike most of the GI tract, which has serosa)

The Lower Esophageal Sphincter (LES)

At the junction between the esophagus and stomach sits the lower esophageal sphincter (also called the cardiac sphincter). It stays contracted to prevent stomach acid from splashing back into the esophagus, and relaxes only when a peristaltic wave delivers a bolus.

When the LES fails to close properly, stomach acid enters the esophagus. This causes the burning sensation of acid reflux.

The stomach is a muscular sac that serves as a holding tank and processing plant. It stores food, mixes it with acid and enzymes, and slowly releases the resulting slurry (chyme) into the small intestine. The stomach’s acid is so strong it could dissolve a nail - yet the stomach lining survives because of a constantly renewed mucus shield.

Stomach Anatomy

The stomach has four main regions:

1. Cardia - where the esophagus connects; just below the lower esophageal sphincter
2. Fundus - the upper dome that often collects swallowed air
3. Body - the largest region; main site of mixing and digestion
4. Pylorus - the lower region that connects to the duodenum via the pyloric sphincter

The inner surface is thrown into folds called rugae, which flatten as the stomach expands (like an accordion). This allows the stomach to stretch from ~50 mL (empty) to ~1-1.5 L (after a large meal).

Gastric Glands: The Acid Factory

Scattered across the stomach lining are millions of gastric pits - small depressions that lead down to gastric glands. These glands contain four specialized cell types:

HCl: The Chemical Weapon

Parietal cells secrete HCl into the stomach lumen using the H+/K+ ATPase (proton pump). This pump exchanges H+ ions (into the lumen) for K+ ions (into the cell), using ATP. The result is a lumen pH of about 1.5-2 - acidic enough to kill most bacteria and denature proteins.

The HCl does three things:

1. Activates pepsinogen into pepsin (the active protease)
2. Denatures proteins - unfolds them, exposing peptide bonds to enzymatic attack
3. Kills pathogens - acts as a first line of defense against ingested bacteria

Pepsinogen to Pepsin: The Zymogen Cascade Begins

Chief cells secrete pepsinogen, the inactive form of the protease pepsin. This is a critical safety mechanism - if chief cells secreted active pepsin, the enzyme would digest the cells that made it.

Once pepsinogen contacts HCl in the lumen, the acid cleaves off a small peptide fragment, converting pepsinogen into active pepsin. Pepsin then:

• Digests proteins into shorter peptide fragments
• Works optimally at pH ~2 (and is inactive above pH ~6)
• Can activate more pepsinogen (positive feedback loop)

Intrinsic Factor: The B12 Key

Parietal cells also secrete intrinsic factor, a glycoprotein that binds vitamin B12 in the stomach. The intrinsic factor-B12 complex is absorbed later in the ileum (the last segment of the small intestine). Without intrinsic factor, B12 cannot be absorbed, which leads to a form of anemia caused by B12 deficiency.

Gastric Motility and Chyme Formation

The stomach’s three smooth muscle layers (an extra oblique layer compared to the rest of the GI tract) churn and mix food with gastric juice. After 2-6 hours of mechanical and chemical digestion, food is converted into a thick, acidic paste called chyme.

Chyme is released into the duodenum in small squirts through the pyloric sphincter. The rate of gastric emptying is regulated by:

• Duodenal feedback - fat and acid in the duodenum slow gastric emptying (via CCK and secretin)
• Gastrin - speeds up gastric emptying
• Volume and composition - liquids empty faster than solids; carbohydrates faster than proteins; fats are the slowest

The small intestine is the MVP of digestion. Despite its name (“small” refers to diameter, not length), it stretches about 6-7 meters and is where 90% of digestion and absorption occur. Its secret weapon is surface area - an internal architecture of folds, fingers, and micro-fingers that gives it the absorptive area of a tennis court packed into a tube you could coil inside your abdomen.

The Three Segments

The Duodenum: Where Chemistry Happens

The duodenum is the first and shortest segment (~25 cm). It receives:

• Acidic chyme from the stomach through the pyloric sphincter
• Bile from the liver/gallbladder via the common bile duct
• Pancreatic juice from the pancreas via the pancreatic duct

Both the common bile duct and pancreatic duct empty into the duodenum at the ampulla of Vater (hepatopancreatic ampulla), controlled by the sphincter of Oddi.

The duodenum is the principal site for chemical digestion. It neutralizes stomach acid with pancreatic bicarbonate, emulsifies fats with bile, and unleashes a battery of pancreatic and brush-border enzymes.

The duodenum also has an endocrine role: it secretes secretin (in response to acid) and cholecystokinin (CCK) (in response to fats and proteins).

The Jejunum: Absorption Powerhouse

The jejunum is the middle segment and the primary site of nutrient absorption. Its walls are densely packed with villi, giving it a velvety appearance. Most amino acids, monosaccharides, fatty acids, and water-soluble vitamins are absorbed here.

Water-soluble nutrients (amino acids, monosaccharides) are absorbed into capillaries within each villus and travel via the hepatic portal vein to the liver for processing.

Fats take a different route - they enter lacteals (lymphatic vessels within each villus) and travel through the lymphatic system before entering the bloodstream.

The Ileum: The Final Stretch

The ileum is the longest segment and connects to the large intestine at the ileocecal valve. It has two specialized absorption jobs:

1. Vitamin B12 - the intrinsic factor-B12 complex formed in the stomach is absorbed exclusively in the ileum by receptor-mediated endocytosis
2. Bile salts - recycled back to the liver via the hepatic portal vein in a process called enterohepatic circulation (bile salts are reused 6-8 times per day)

The ileum also contains Peyer’s patches - clusters of lymphoid tissue that monitor intestinal bacteria and mount immune responses against pathogens. They are part of the gut-associated lymphoid tissue (GALT).

The Surface Area Amplification System

The small intestine achieves its enormous surface area through three levels of folding:

Each villus contains:

• A capillary network for absorbing water-soluble nutrients
• A lacteal (lymphatic vessel) for absorbing fats
• Smooth muscle that contracts to “pump” absorbed nutrients into vessels

Intestinal Crypts: The Cell Factory

At the base of each villus are crypts of Lieberkuhn (intestinal crypts). These contain stem cells that constantly produce new enterocytes. The intestinal epithelium renews itself every 3-5 days - one of the fastest cell turnover rates in the body.

The small intestine is where the heavy enzymatic machinery lives. Two sources supply the enzymes: the pancreas (secreted into the lumen) and the brush border of the intestinal epithelium itself. Together, they finish the digestion of every macromolecule into its absorbable building blocks.

Pancreatic Enzymes: The Heavy Artillery

The exocrine pancreas produces a cocktail of digestive enzymes delivered to the duodenum through the pancreatic duct. These enzymes work at a slightly alkaline pH (~7-8), which is maintained by pancreatic bicarbonate that neutralizes the acidic chyme from the stomach.

The Trypsin Activation Cascade

This is one of the most important enzyme cascades for the MCAT. All pancreatic proteases are secreted as inactive zymogens to prevent the pancreas from digesting itself.

The cascade works like a row of dominoes:

1. Enteropeptidase (also called enterokinase) - an enzyme embedded in the duodenal brush border - cleaves trypsinogen into active trypsin
2. Trypsin then activates everything else:
   • Chymotrypsinogen → chymotrypsin
   • Procarboxypeptidase → carboxypeptidase
   • Proelastase → elastase
   • More trypsinogen → trypsin (autocatalysis)

Complete Pancreatic Enzyme Table

Note that amylase, lipase, and nucleases are secreted in their active forms - they are not zymogens. Only the proteases need to be secreted as zymogens because only proteases pose a self-digestion risk.

Brush-Border Enzymes: The Finishing Touches

Brush-border enzymes are embedded in the microvilli membrane of enterocytes throughout the small intestine. They perform the final digestion steps, breaking dimers and short chains into individual monomers ready for absorption.

Disaccharidases

Peptidases

Other Brush-Border Enzymes

• Enteropeptidase - converts trypsinogen to trypsin (the cascade starter)
• Nucleotidases and nucleosidases - break nucleotides into bases, sugars, and phosphate groups

The Complete Digestion Summary

The liver is the body’s largest internal organ and the central processing hub for everything you absorb from the GI tract. The gallbladder is its sidekick - a small storage pouch that concentrates bile and squirts it into the duodenum on demand. Together, they make fat digestion possible.

Bile: Dish Soap for Fat

Bile is produced by hepatocytes (liver cells) and modified by bile duct cells. It contains:

Critical distinction: Bile does NOT enzymatically digest fat. Emulsification is physical, not chemical - no covalent bonds are broken. Bile salts simply coat large fat globules with their amphipathic structure and split them into tiny droplets (and later micelles), increasing the surface area available for pancreatic lipase to act. Without bile, lipase can only attack the thin outer surface of a large fat glob, and fat digestion plummets. This is one of the clearest MCAT test points: bile is a detergent, not an enzyme.

The Bile Duct System

Bile flows through a branching duct system:

1. Hepatocytes produce bile and secrete it into tiny bile canaliculi
2. Canaliculi merge into the right and left hepatic ducts
3. These join to form the common hepatic duct
4. The cystic duct branches off to the gallbladder (for storage)
5. Below the cystic duct junction, the common bile duct carries bile to the duodenum
6. The common bile duct merges with the pancreatic duct at the ampulla of Vater
7. The sphincter of Oddi controls flow into the duodenum

The Gallbladder: Storage and Concentration

Between meals, the sphincter of Oddi is closed, so bile backs up into the gallbladder via the cystic duct. The gallbladder concentrates bile by absorbing water and ions - making it 5-10x more concentrated than freshly produced hepatic bile.

When fatty chyme enters the duodenum, CCK is released. CCK causes the gallbladder to contract and the sphincter of Oddi to relax, squirting concentrated bile into the duodenum right when it is needed.

Enterohepatic Circulation: Recycling Bile

About 95% of bile salts are reabsorbed in the terminal ileum and returned to the liver via the hepatic portal vein. The liver recycles them into new bile. This recycling loop is called enterohepatic circulation, and bile salts may be reused 6-8 times per day.

The Hepatic Portal System: First Pass Through the Liver

All water-soluble nutrients absorbed from the GI tract (amino acids, monosaccharides, water-soluble vitamins) enter intestinal capillaries and drain into the hepatic portal vein, which carries them directly to the liver before they enter general circulation.

This “first-pass” allows the liver to:

• Detoxify harmful substances (alcohol, drugs, ammonia)
• Store glucose as glycogen (glycogenesis) or release it when needed (glycogenolysis)
• Synthesize plasma proteins (albumin, clotting factors)
• Convert ammonia to urea (for renal excretion)
• Process absorbed nutrients before distributing them to the body

Bilirubin and Bile Pigments

Bilirubin is a yellow breakdown product of hemoglobin from old red blood cells. The liver conjugates (makes water-soluble) bilirubin and excretes it in bile. In the intestine, bacteria convert bilirubin into pigments that give stool its brown color. Some of these pigments are reabsorbed and excreted in urine, giving it a yellow color.

The pancreas is a dual-function organ - part digestive gland, part hormone factory. Its exocrine portion (about 99% of the organ) produces digestive enzymes and bicarbonate. Its endocrine portion (tiny clusters called the Islets of Langerhans) produces hormones that regulate blood glucose. The MCAT expects you to know both sides.

Exocrine Pancreas: Enzymes and Bicarbonate

The exocrine pancreas consists of acinar cells organized into grape-like clusters. These cells produce pancreatic juice containing:

1. Digestive enzymes - proteases (as zymogens), lipase, amylase, nucleases (covered in detail in the enzyme section)
2. Bicarbonate (HCO3-) - produced by duct cells, neutralizes acidic chyme entering the duodenum, raising the pH from ~2 to ~7-8 where pancreatic enzymes work optimally

Pancreatic juice is delivered to the duodenum through the pancreatic duct, which merges with the common bile duct at the ampulla of Vater.

What Triggers Pancreatic Secretion?

Two duodenal hormones control the exocrine pancreas:

Endocrine Pancreas: The Islets of Langerhans

Scattered among the acinar cells are about 1-2 million tiny cell clusters called the Islets of Langerhans. They make up only ~1-2% of the pancreas by mass but are critical for metabolic regulation.

Blood Glucose Regulation: Insulin vs. Glucagon

After a carbohydrate-rich meal (fed state):

• Blood glucose rises
• Beta cells release insulin
• Insulin promotes: glucose uptake by cells (via GLUT4 in muscle/fat), glycogenesis in liver and muscle, lipogenesis, protein synthesis
• Blood glucose falls back to normal (~70-100 mg/dL)

During fasting or exercise:

• Blood glucose drops
• Alpha cells release glucagon
• Glucagon promotes: glycogenolysis (glycogen to glucose) in the liver, gluconeogenesis (making glucose from non-carbohydrate precursors like lactate, glycerol, amino acids)
• Blood glucose rises back to normal

Digestion breaks food into tiny building blocks. Absorption is the process of moving those building blocks across the intestinal epithelium into the blood or lymph. Each type of nutrient uses a specific transport mechanism, and the MCAT expects you to know them.

Carbohydrate Absorption

After digestion, carbohydrates exist as monosaccharides: glucose, galactose, and fructose. They are absorbed primarily in the jejunum.

Note that glucose and galactose absorption is Na+-dependent (secondary active transport), while fructose absorption is Na+-independent (facilitated diffusion through GLUT5).

Protein Absorption

Proteins are digested into amino acids, dipeptides, and tripeptides. All three forms can be absorbed:

• Amino acids - absorbed by Na+-dependent secondary active transport (similar to glucose) through specific amino acid transporters
• Dipeptides and tripeptides - absorbed by H+-dependent cotransport, then hydrolyzed into amino acids inside the enterocyte
• Once inside the cell, amino acids exit via facilitated diffusion into capillaries

All absorbed amino acids enter the hepatic portal vein and travel to the liver.

Lipid Absorption: The Special Route

Fat absorption is the most complex and the most frequently tested on the MCAT.

The full pathway:

1. Bile salts emulsify large fat globules into tiny micelles in the duodenal lumen
2. Pancreatic lipase digests triglycerides into 2 fatty acids + 1 monoglyceride
3. These products are carried to the enterocyte surface by micelles
4. Fatty acids and monoglycerides diffuse across the enterocyte membrane (they are hydrophobic - no transporter needed for long-chain fatty acids)
5. Inside the enterocyte’s smooth ER, fatty acids and monoglycerides are re-esterified back into triglycerides
6. Triglycerides are packaged with cholesterol and phospholipids in the Golgi to form chylomicrons
7. Chylomicrons are exocytosed from the basolateral membrane into lacteals (lymphatic vessels)
8. Lacteals drain into the lymphatic system, which empties into the thoracic duct and then the left subclavian vein

Vitamin Absorption

Water and Ion Absorption

The GI tract processes about 9 liters of fluid per day (2 L ingested + 7 L secreted). About 98% is reabsorbed:

• Small intestine absorbs most water and ions (~7.5 L) by osmosis following solute absorption
• Large intestine absorbs the remaining ~1.4 L
• Only ~100-200 mL is lost in feces

Sodium absorption drives water absorption. Na+ enters enterocytes via:

• SGLT1 (co-transported with glucose)
• Na+/amino acid cotransporters
• Na+/H+ exchangers
• Na+ channels in the colon (regulated by aldosterone)

Water follows Na+ by osmosis through tight junctions and aquaporins.

By the time chyme reaches the large intestine, digestion is essentially complete. The large intestine’s job is not to digest, but to reclaim water and electrolytes, house trillions of bacteria, and compact the leftovers into feces. It is shorter than the small intestine (~1.5 meters) but wider in diameter - hence the name.

Anatomy: Three Main Regions

1. The Cecum

The cecum is a pouch-like structure at the junction of the small and large intestines. Material enters from the ileum through the ileocecal valve, which prevents backflow. Attached to the cecum is the appendix.

The appendix was long considered a vestigial organ, but current evidence suggests it serves as a reservoir for beneficial gut bacteria. After a bout of diarrhea that flushes the colon, the appendix may help repopulate it with normal flora. It also contains lymphoid tissue for immune surveillance.

Inflammation of the appendix (appendicitis) is a common clinical condition that may appear as passage context on the MCAT.

2. The Colon

The colon has four segments that form an inverted U-shape:

1. Ascending colon - runs up the right side
2. Transverse colon - crosses horizontally
3. Descending colon - runs down the left side
4. Sigmoid colon - S-shaped curve connecting to the rectum

3. The Rectum and Anus

The rectum stores feces until defecation. Two sphincters control the exit:

The defecation reflex is initiated when the rectum is stretched by feces. The internal sphincter relaxes automatically (parasympathetic), but the external sphincter remains under voluntary control - allowing you to choose when to defecate.

Water Absorption: Turning Liquid to Solid

Chyme entering the large intestine is mostly liquid. The colon absorbs about 1.4 liters of water per day along with sodium, chloride, and other ions. This converts the liquid chyme into semi-solid feces.

• Sodium is absorbed via Na+ channels (regulated by aldosterone) and Na+/H+ exchangers
• Water follows sodium by osmosis
• Too much absorption = constipation (hard, dry stools)
• Too little absorption (or excess secretion) = diarrhea

Goblet Cells: Mucus Protection

The large intestine is lined with goblet cells that secrete mucus. This mucus:

• Lubricates the fecal mass for easier passage
• Protects the epithelium from mechanical abrasion
• Shields the lining from bacterial products and toxins

The mucus does not aid in digestion - its role is purely protective and lubricating.

Gut Microbiota: Your 100 Trillion Roommates

The large intestine hosts a vast community of bacteria (the gut microbiota). These organisms:

• Ferment undigested carbohydrates (fiber), producing short-chain fatty acids (acetate, propionate, butyrate) that provide ~10% of daily caloric intake
• Synthesize vitamin K and certain B vitamins (biotin, folate) - a key source since dietary vitamin K alone is often insufficient
• Compete with pathogenic bacteria for nutrients and space (colonization resistance)
• Train the immune system - gut flora stimulate development of GALT (Peyer’s patches, isolated lymphoid follicles) and teach the immune system to distinguish harmless microbes from pathogens

Bacteria and their byproducts make up a significant fraction of fecal mass.

What’s in Feces?

Normal feces contain:

• Water (~75%)
• Bacteria (living and dead)
• Undigested fiber and food residue
• Bile pigments (stercobilin - gives brown color)
• Sloughed epithelial cells
• Small amounts of fat, protein, and inorganic matter

The GI tract is the largest endocrine organ in the body. Specialized cells scattered throughout the stomach and small intestine release hormones that coordinate digestion like a relay team - each hormone passes the baton to trigger the next step. These hormones use the same signaling mechanisms as other endocrine hormones. The MCAT expects you to know the four major GI hormones, their triggers, and their effects.

The Big Four GI Hormones

Gastrin

• Source: G cells in the stomach antrum (pyloric region)
• Trigger: Stomach distension, peptides/amino acids in the stomach, vagal stimulation (parasympathetic)
• Effects:
  • Stimulates parietal cells to secrete HCl
  • Stimulates chief cells to secrete pepsinogen
  • Stimulates gastric motility
  • Promotes growth of gastric mucosa (trophic effect)
• Inhibited by: Low stomach pH (<2), somatostatin, secretin

Gastrin operates in a negative feedback loop: it stimulates HCl production, and when the stomach becomes sufficiently acidic (pH <2), gastrin release is suppressed.

Secretin

• Source: S cells in the duodenal mucosa
• Trigger: Acidic chyme entering the duodenum (pH <4.5)
• Effects:
  • Stimulates pancreatic duct cells to release bicarbonate (neutralizes acid)
  • Stimulates bile secretion from the liver
  • Inhibits gastrin release and gastric acid secretion (slows stomach activity)
• Inhibited by: Rising duodenal pH (the acid has been neutralized - job done)

Cholecystokinin (CCK)

• Source: I cells in the duodenal and jejunal mucosa
• Trigger: Fatty acids and amino acids in the duodenum
• Effects:
  • Stimulates gallbladder contraction (releases bile)
  • Stimulates pancreatic acinar cells to release digestive enzymes
  • Slows gastric emptying (gives the duodenum time to process)
  • Stimulates satiety (reduces appetite via hypothalamus)
  • Relaxes the sphincter of Oddi
• Inhibited by: Completion of fat and protein digestion

CCK is the reason fatty meals make you feel full faster and stay in your stomach longer.

Gastric Inhibitory Peptide (GIP)

Also called glucose-dependent insulinotropic peptide (same abbreviation - GIP).

• Source: K cells in the duodenum and jejunum
• Trigger: Glucose, fatty acids, and amino acids in the duodenum
• Effects:
  • Stimulates insulin release from pancreatic beta cells (the “incretin” effect)
  • Inhibits gastric acid secretion and motility (slows stomach)
  • Slows gastric emptying
• Key concept: Oral glucose causes more insulin release than the same dose of IV glucose, because GIP from the gut amplifies the pancreatic response (the “incretin effect”)

Master GI Hormone Table

Hunger and Satiety Hormones

Two hormones regulate appetite at the level of the hypothalamus:

Ghrelin - “the hunger hormone”

• Source: specialized cells in the stomach fundus
• Rises sharply before meals (when stomach is empty)
• Falls after eating
• Stimulates appetite, food-seeking behavior, gastric motility, gastric acid secretion, and growth hormone release
• Short-term regulator (meal-to-meal)

Leptin - “the satiety hormone”

• Source: adipose tissue (fat cells)
• Higher body fat = higher leptin levels
• Signals the hypothalamus that energy stores are sufficient
• Reduces appetite, increases energy expenditure
• Long-term regulator (body weight over weeks/months)
• Does NOT act directly on the stomach or intestines

Your gut has its own brain. The enteric nervous system (ENS) contains about 100 million neurons - more than the spinal cord - embedded in the walls of the GI tract from esophagus to anus. It can operate completely independently of the brain and spinal cord, earning it the nickname “the second brain.”

The Two Plexuses

The ENS is organized into two interconnected nerve networks (plexuses):

Myenteric plexus (Auerbach’s plexus)

• Located between the inner circular and outer longitudinal muscle layers of the muscularis externa
• Controls motility: peristalsis velocity, contraction intensity, sphincter relaxation
• Stimulation increases gut motility; inhibition relaxes sphincters and slows movement

Submucosal plexus (Meissner’s plexus)

• Located in the submucosa
• Controls secretion and absorption: regulates enzyme release, mucus production, and local blood flow
• Also responds to luminal stretch and chemical stimuli

The ENS Contains All Three Neuron Types

The enteric nervous system is a complete neural circuit:

• Sensory (afferent) neurons - detect mechanical stretch, chemical composition (pH, osmolarity, nutrients), and temperature in the lumen
• Interneurons - process information and coordinate responses
• Motor (efferent) neurons - control smooth muscle contraction, gland secretion, and blood vessel dilation

This means the ENS can carry out complete reflex arcs without any input from the brain or spinal cord. A chemical stimulus in the lumen can trigger enzyme secretion or a peristaltic wave entirely through local ENS circuits.

Autonomic Modulation: Parasympathetic vs. Sympathetic

While the ENS operates autonomously, the central nervous system modulates its activity through the autonomic nervous system:

The vagus nerve provides parasympathetic innervation to most of the GI tract (esophagus through the transverse colon). The distal colon, rectum, and internal anal sphincter receive parasympathetic input from pelvic splanchnic nerves (S2-S4).

”Rest and Digest” vs. “Fight or Flight”

After a meal, parasympathetic activity dominates:

• Increased salivation
• Increased gastric acid and enzyme secretion
• Increased peristalsis and motility
• Increased blood flow to the GI tract
• This is why you feel drowsy after a big meal - blood is diverted to the gut (“food coma”)

During stress or exercise, sympathetic activity dominates:

• Decreased salivation (dry mouth)
• Decreased secretion and motility
• Blood diverted away from the GI tract to skeletal muscles and brain
• Sphincters contract (no time for digestion when running from danger)

The Defecation Reflex

Defecation involves both the ENS and the CNS:

1. Feces distend the rectum, activating stretch receptors
2. Sensory signals travel to the sacral spinal cord (S2-S4) via pelvic nerves
3. Parasympathetic motor signals return, causing:
   • Increased colonic and rectal motility
   • Relaxation of the internal anal sphincter (involuntary)
4. The external anal sphincter (skeletal muscle, under voluntary somatic control) can be consciously relaxed to allow defecation or kept contracted to delay it

The Three Phases of Gastric Regulation

GI secretion is controlled in three overlapping phases: