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Revision for second years

GIT motility

  • Optimal time of exposure to various segments of the GIT is essential for effective digestion and absorption
  • Motility provides both mixing and propulsion
  • GIT function is highly regulated by neural, hormonal, local, chemical and physical factors
  • The GIT is composed of mainly smooth muscle that contracts when Ca2+ enters
  • The smooth muscle has intrinsic pacemakers but is mainly controlled by the nervous system and by hormonal sources
  • There is a dual innervation of the GIT with extrinsic sympathetic (inhibitory) and parasympathetic (excitatory) fibres; as well as intrinsic neurons in the enteric nervous system
  • BGDB: The functions of the major motor patterns in the stomach and intestine including peristalsis, segmentation, the “pyloric pump” and the migrating motility complex
  • Stomach grinds up food mechanically and releases it into the duodenum
  • Stomach’s role is in gross digestion (breaking large lumps into smaller lumps). The role of the small intestine is molecular digestion

Digestion and absorption

  • Nutrients are consumed as complex molecules (carbohydrates, lipids, proteins) that are enzymatically broken down into smaller absorbable molecules
  • Additional substances (ions, minerals, vitamins) do not require such digestion
  • All substances are transported across the lining of the gastrointestinal wall and into the bloodstream or lymphatics
  • Enzymatic processes are required for effective digestion of carbohydrate, lipid and protein
  • The “design” of the small intestinal absorptive surface maximized transport capacity
  • There are barriers to molecules during transport, or absorption, of molecules across the gastrointestinal wall
    • The physical and chemical nature of the nutrients impacts on these barriers
    • The transport and carrier mechanisms available for nutrient movement across the gut wall

The Stomach

The regions of the stomach
  • The stomach can be divided into four regions:
    • Cardia
    • Fundus
    • Body
    • (Pyloric) antrum (contains the pyloric sphincter to control release to duodenum).
  • The major functions of the stomach:
    • Temporary food storage
    • Control the rate at which food enters the duodenum
    • Acid secretion and antibacterial action
    • Fluidisation of stomach contents
    • Preliminary digestion with pepsin, lipases etc.
    • [BGDB] Motor functions of the stomach
  • Most of the enzymes you swallow (produced in the mouth) do not work in the stomach (low pH)
  • The duodenum has low storage capacity and can fill up. Then the vagus nerve carries signals to the brain that produce the sensation of nausea. The stomach increases the volume for storage of food.

Gastric (juice) secretions

  • Acid (H+, proton) – can cause denaturation of protein
  • Pepsin (as pepsinogen)
  • Mucous (and HCO3-)
    • Lubricates
    • Traps HCO3-, to prevent acid from getting into the epithelial cells
  • Intrinsic factor (the only indispensable secretion product)
    • Lets you absorb vitamin B12 in the small intestine

The functions of gastric secretions

  • Acid
    • Required to convert pepsinogen to active pepsin
    • Bacteriostatic – keeps bacteria from multiplying
  • Pepsin together with acid initiates digestion of protein
  • Mucous lubricates and protects against physical damage
  • Mucous plus HCO3- maintains a near neutral pH at the surface of the stomach lining
  • Intrinsic factor is critical for the ileal absorption of vit B12 (beyond the stomach)

Functional anatomy of the stomach

The functional anatomy of the stomach
The structure and relations of oxyntic glands
  • Oxyntic gland area – acid-secreting portion of the stomach
    • Body and fundus, upper 80%
    • Acid-secreting parietal cells
  • Pyloric gland area - endocrine cells are in the pyloric gland area
    • Antral region, lower 20%.
    • Gastrin-secreting G cells
  • Notes on diagram:
    • Stem cells are in every gland (epithelium has 7-day turnover)
    • People without parietal cells develop pernicious anaemia due to vit B12 deficiency.

1HMBPhys4.png

Acid secretion from Parietal cells

Acid secretion from parietal cells
  • Dissociation of water: H2O --> OH- + H+
    • H+ pumped actively into the lumen
  • OH- + CO2 --> HCO3-
    • Enzyme = carbonic anhydrase
    • HCO3- is transported into the blood.

Relevant transporters

  • Luminal H+/K+ ATPase is an active transport mechanism. The proton pump takes K+ out of the lumen, and pumps H+ into the lumen. The H+ comes from dissociation of water
  • Blood (basal) surface Na+/K+ ATPase is also an active transport mechanism
  • Passive chloride channels let Cl- out passively, to combine with H+. This maintains electrical neutrality.

Stimulators of parietal cell acid secretion

  • Parietal cells have receptors for three stimuli that cause acid secretion
  • This reflects a combination of neural, endocrine, and paracrine control:
    • Vagus (via enteric nervous system) - Acetylcholine (Ach): muscarinic [GPCR] receptors increase intracellular Ca2+. [Note: the vagus nerve doesn’t influence GIT directly… instead it branches to enteric nervous system to cause 1) contraction and 2) secretion)
    • Endocrine (G cells) – Gastrin: gastrin/CCK-B receptors increase Ca2+. Although these endocrine signals are released into the blood, they return very quickly to the cell
    • ECL cells (via blood) – Histamine: H2 receptors (increase cAMP). Paracrine action—doesn’t go to blood, just to nearby cells.
  • H2 blockers are the most common drugs to reduce acid secretion. [Modern: proton pump blockers]

1HMBPhys6.png

Potentiation between different stimulants (secretagogues)

The combined effects of small amounts of stimulants with different mechanisms of action is much greater than the effect of a moderate amount of a single stimulant
  • Very low levels of both H2 and Ach together produce very high acid secretion
  • The effect of a combination of stimulants is greater than the sum of the individual responses
  • Ach and histamine have different pathways, so that activating both of Ach and H2 receptors activates both pathways and produces a huge combined response. However, activating both Ach and gastrin doesn’t do this because both these receptors use the same pathway (Ca2+).

Digestive phases and regulation of gastric secretion

The phases of digestion
  • Cephalic phase – see/smell/think about food, the brain tells the stomach to prepare for a meal. We don’t actually need food in our stomachs for this to occur. Efferent fibres relax the stomach smooth muscle, letting food in.
  • Gastric phase – food distends the stomach, causing it to start to churn food
  • Intestinal phase – slow gastric emptying.

Cephalic phase of acid secretion

  • 20-30% of maximal secretory response to a meal (the preparatory acid secretion due to psychological stimulation is vigorous)
  • Driven by taste and smell through mechano- and chemoreceptors and by sight.

Gastric phase of acid secretion

Inhibition of gastrin release by somatostatin from D cells
  • >50% of maximal secretory response
  • Food enters the stomach, buffering the pH to approx. 6, which dis-inhibits gastrin release (i.e. the brake is off). That is, taking in food triggers and increase in acid release --> big pulse of acid (antacids are ineffective long-term)
  • Distension of the stomach walls via mechano-receptors initiate short (ENS) and long (vago-vagal) reflexes
  • G cells are also directly stimulated by digested protein (amino acids), calcium and caffeine (not blocked by vagotomy)
  • Gastrin release is:
    • Increased by gastrin-releasing peptide (GRP) from the ENS
    • Inhibited by release of somatostatin (SS) from the D cells.

Inhibition of gastrin release by somatostatin from D cells

  • Antral D cells stimulated by low pH
  • Body D cells stimulated by neural and hormonal mechanisms [Note: he cell shown in the diagram is an antral/body hybrid – stimulated by both]
  • Somatostatin acts on:
    • G cells to inhibit gastrin release
    • ECL cells to inhibit histamine release
    • Parietal cells to inhibit acid release
  • [See diagram] Activating a G cell inhibits release of somatostatin release from the D cell (so not “driving with the brake on”)
    • Thus we both activate and disinhibit G cells.

Intestinal phase of acid secretion

  • Approx. 5% of maximal secretory response
  • Amino acids contribute to gastrin release (from the intestinal mucosa)
  • The intestinal phase is more important in inhibiting acid secretion and gastric emptying

Interdigestive phase of acid secretion

  • Acid secretion rate is approximately 10% of maximal secretory response
  • Stomach contains a low volume of gastric juice at pH <2.0
  • A low pH inhibits gastrin release from the G cells and thus limits excessive acid production

Control of pepsinogen secretion

Control of pepsinogen secretion
  • Pro-enzyme (inactive form of enzyme) released from peptic (chief) cells.
  • Pepsinogen is activated by enzymes or by low pH. Other enzymes are deactivated at low pH, but pepsin is not.
  • Strongest stimulus is vagally-mediated (via ENS and Ach release). Release will occur in cephalic and gastric phases
  • H+ stimulates a local enteric (ENS) cholinergic reflex to release pepsinogen
  • Recall that H+ (pH 3-5) is required to activate pepsin (and pepsin will activate pepsin) and pH >5 is inhibitory

Control of Intrinsic Factor (IF) secretion

  • IF is secreted from the parietal (oxyntic) cells
  • It is required for protection/transport of vitamin B12. Uptake takes place in the terminal ileum
  • A lack of B12 leads to pernicious anaemia [see BGDA – folate]
  • Failure to secrete IF is associated with achlorydia and a lack of parietal cells
  • Loss of parietal cells -->
    • No IF
    • No acid secretion

Mucus secretion

  • Soluble mucus
    • Produced from mucus neck cells
    • Stimulated by vagally mediated Ach release
    • Mixes with gastric contents to lubricate
  • Insoluble or surface mucous
    • Produced in response to chemical and mechanical stimuli
    • Forms a protective gel layer which traps HCO3- and cellular debris. [Helicobacter pylori burrows into this gel layer and produces a cloud of HCO3- to protect itself]

Summary

  • Principle components of gastric juice are acid, pepsinogen, mucous, intrinsic factor as well as electrolytes
  • Acid serves to activate pepsinogen, initiates some foodstuff digestion and is bacteriostatic
  • Key in secretion of acid is the H+/K+ ATPase with the support of Na+/K+ ATPase and carbonic anhydrase
  • Major factors stimulating acid secretion are the hormone gastrin, the neurotransmitter acetylcholine (Ach) and histamine. Potentiation occurs between these factors to maximize secretion
  • During the cephalic phase of digestion vagal stimulation causes release of acid from parietal cells and gastrin from antral G cells
  • In the gastric phase distension initiates short and long reflexes to stimulate acid secretion and gastrin release. Products of protein digestion stimulate G cells directly
  • Acid secretion is inhibited by somatostatin, which is released by low pH and gastrin
  • Secretion of intrinsic factor is required for subsequent absorption of vitamin B12 in the terminal ileum