Phys Flashcards
What are the functions of the gut (5)?
Digestion of food Absorption of nutrients Excretion of waste Prevention of invasion by pathogens Contains microbiome
What is the difference between fermentation and digestion?
Fermentation is bacterial and yeast based
Digestion is enzymatic
What needs to be regulated in the gut?
- Contraction of smooth muscle
- Secretion of digestive enzymes and solvents
- Water re-absorbtion
- Coordinate widely separated regions.
Why is it important for the gut to control smooth muscle contractions?
1) mixing/segmentation mixes water, enzymes, food 2) peristalsis propels contents
Why is it essential to control secretion of digestive enzymes and solvents
b. Regulate secretion of digestive enzymes and the solvents they require for proper function
i. Water into GI lumen → essential as digestive enzymes are water soluble [10L in, 9.9L reabsorbed]
1. If this process fails → diarrhoea or constipation (18 hours for death cf. 3 days for kidney)
ii. Bile from gall bladder
What is it important to control water re-absorbtion
prevent dehydration
9.9L secreted into the gut needs to be recycled
What is it important to coordinate coordinate the separate regions of the gut?
Need to properly regulate in order to regulate gastric emptying and ensure appropriate absorption of nutrients and re-absorption of water
What nervous system acts at a local level to regulate contractile activity and secretion of water and electrolytes?
The ENS and the Interstitial cells of Cajal
They also have the basic elements required to produce complex motor programs
What is the Enteric nervous system?
It is the intrinsic NS of the gut, component of the ANS, it has many neurons (more than the spinal cord)
What is the myenteric plexus?
- Myenteric plexus → between longitudinal and circular muscle layers
a. Provides motor innervation to both muscular layers
b. Has both parasympathetic and sympathetic input
c. It is the major nerve supply to the gastrointestinal tract and controls GI tract motility
What is the submucosal plexus?
- Submucosal plexus secretes NPY and ACh (immunoreactive) → It is found beneath circular muscle
a. Present from esophagus to anus; only neuron cell bodies from pylorus to anus
b. Neurons control movement of water and electrolyte across gut
c. Cells grouped together in smaller ganglia connected by nerve trunks
What is the role of the endocrine cells of the gut?
Signal from intestinal mucosa to ancillary organs like brain, pancreas and gall bladder
How does the intestinal mucosa act as an endocrine organ?
i. Intestinal mucosa is largest endocrine organ → hormone release → local regulation at a paracrine level to activate ENS, endocrine systems acting on peripheral organs and CNS (appetite / satiety)
ii. Essential for 1) secretion of enzymes and solvents into intestinal lumen 2) appetite regulation
What are MUCOSAL ENTEROENDOCRINE (EE) CELLS?
Endocrine cells in the mucosa
Many types defined by mediators they contain eg. 5HT containing EC cells (CCK, secretin, somatostatin, glucagon like peptides 1,2)
What are Enterochromaffin like-cell (ECL)?
contain and release histamine [stomach acid secretion]
What is the role of serotonin in the GIT?
SEROTONIN → 90% located in the gut with EC cell; controversial role
a. Serotonin acts as sensory intermediate in the gut lumen → activation of nerve signals to the brain through primary afferent neurons AND ENS activation
What do the vago-vagal reflex pathways do?
Coordinate movements in upper GI tract
What are the specific roles of the Vegus in the upper GIT?
1) control of swallowing ie. esophagus
2) acid secretion in stomach
3) coordinates contractions of stomach + duodenum
What type of neurons does the vegus nerve trunk contain?
10% of efferent to upper GIT. + 90% of sensory (primary afferent) axons to brain
- Pathways that control the upper intestine involve substantial feedback going up from the stomach to the brain and then back again down the efferents to regulate function
- Final behavior is produced because the vagus modulates the activity of the enteric NS locally within the regions that are involved (regulating complex circuitry going on in the periphery)
What mediates the intestino-intestinal reflexes?
- Some mediated by Vagus
a. Likely to be excitatory - Others via Dorsal root ganglia and spinal cord
a. Likely to be inhibitory (spinal cord – sympathetic) - Viscero fugal neurons: (enteric Neurons)
a. Cell bodies within the intestine
What are the intestino-intestinal reflexes?
3) project from GIT to pre-vertebral sympathetic ganglia and produce reflex inhibition of proximal regions when distal regions are distended (e.g. distention of colon inhibits motor activity in SI = reduced SM contraction and secretory activity
What is the CNS role in the GIT
- anticipation,
- mood,
- activity:
- e.g. nervous/anxious/fear/stress butterflies, increased bowel movements.
What is the role of vagal and sympathetic input?
Vagal and sympathetic input usually modulate enteric neural circuits
What is the role of GI hormones?
Many GI hormones excite enteric neurons and extrinsic sensory neuron terminals via a paracrine action before entering blood stream
What is the role of interstitial cells of cajal?
act as pacemakers in the muscle = act largely independently of neural activity
i. Neural activity superimposes a level of excitation or inhibition that controls whether muscle contracts
ii. In the stomach they play dominant role in propulsion of material HOWEVER (although still important) in the intestine the myenteric plexus plays a more major role than ICC cells
What is the cephalic phase of eating?
a. Cephalic phase = triggered by sight, smell + taste [PRIOR to it entering mouth]
i. Causes salivation, gastric acid (30%) and pepsin secretion and relaxation of gastric corpus and fundus
ii. Operates via vagus (initiated in the cerebral cortex) NB. Salivation controlled by via vagus + SNS
iii. Sets up stomach to store food and begins the barrier function of the GIT
How is acid/pepsin secretion controlled?
4 different mediators interact
i. Acetylcholine from enteric neurons excited by vagal efferent neurons [activates parietal + chief]
ii. Gastrin from G cells in antrum and duodenum (also controlled by the vagus)
iii. Histamine from ECL cells excited by ACh from ENTERIC neurons
1. Inhibited by somatostatin from local D cells and duodenal D cells
iv. Somatostatin inhibits 1) parietal cells 2) G cells → role in protecting duodenum preventing ulcer
1. D cells stimulated by acid in duodenum and by gastrin (also reduces gastric emptying)
What happens during swallowing?
= chewed food swallowed and propelled by peristalsis along esophagus to stomach [VAGUS ONLY]
i. Upper and lower esophageal sphincters open and close at relevant times = opens when food arises
ii. Lowe esophageal sphincter is normally held closed to prevent reflux → chronic failure of this process is called GERD/GORD → erosion of esophageal mucosa → achalasia
What happens after chewed food enters the stomach?
i. Fundus and corpus (body) of stomach relax to accommodate the volume of food swallowed
1. Leads to distension, which activates enteric and vago-vagal reflexes
2. More acid and pepsin are secreted as a result of distension (other 2/3)
ii. Pacemaker activity propagates from corpus to antrum causing ripples of constriction to propagate towards pylorus (becoming stronger towards antrum) MAINLY due to ICC (slightly due to ENS)
iii. Food enters antrum → reflex inhibition of acid secretion in corpus
1. Strong constrictions resulting from large pacemaker potentials propagating from corpus to pylorus drive food towards this closed sphincter → grind it to produce chyme
2. Acid, protease and mechanical activity cause components of food to separate, liberating fat
3. Fat floats to top of stomach – fundus – forming a separate layer (leaves slowest)
4. Continual grinding in presence of protease converts food into a dilute paste
a. Diluted heavily by water in the stomach (secreted as part of acid secretion process)
5. Pylorus opens briefly, relaxation due to activity of enteric neurons that control the contractility of the pylorus (sphincter at distal end of the stomach)
a. Coordination between antrum, pylorus and duodenum in both directions through enteric nervous system + probably hormones as well (notably gastrin)
6. Squirt of food mixed with acid and pepsin enters duodenum (very dilute)
a. Initially high in protein + carbohydrate + low in fat, later high in fat
Tell me something about BAT
Same embryological origin as muscle - lots of mitochondria and uncoupling protein 1 (Energy is dissipated as heat)
How efficient are humans?
About 20% efficient - the rest is dissipated as heat
How does one measure energy expenditure?
Doubly labelled water (gold standard) Oxygen consumption Heart rate-based estimation of VO2 Activity monitors Population based algorithms
What are some determinants of energy expenditure?
Adrenaline, thyroid hormones Muscle mass and oxidative capacity Exercise/physical activity levels Non-exercise activity thermogenesis Shivering thermogenesis Brown fat?
How was BAT first discovered?
PET - using radioactively labelled glucose
What are some determinants of energy expenditure
Biology
Environment
Government policy
Global
What is the hormone which stimulates the sensation of hunger?
Ghrelin
What hormones are secreted by the gut and signal satiety?
CCK
Oxyntomodulin
GLP-1
PYY
What hormone is secreted by adipose tissue and signals satiety (more long term)
Leptin
What hormones are secreted by the pancreas and signal satiety?
Amylin
Insulin
PP
What do obesity drugs largely target?
CNS (i.e. attempt to regulate appetite)
What is observed in terms of ghrelin levels two people, one of higher initial weight both lose weight?
Even if they reach the same weight, the person who was initially heaver will likely have a higher ghrelin concentration - this is pretty good evidence for the ‘set point’
What happens when chewed food is swallowed?
It is propelled by peristalsis along the oesophagus to the the stomach (entirely neural control via VAGUS)
Chewing upregulates the cephalic phase of digestion
What are the role of the upper and lower oesophageal sphincters?
1) open/close at relevant times.
2) lower oesophageal sphincter is normally closed to prevent reflux
What happens when chewed food enters the stomach?
Fundus and corpus (body) of stomach relax to accommodate food:
(i) Leads to distension (stretch) → activates enteric and vago-vagal reflexes → more acid and pepsin secreted as result of this distension
(ii) Pacemaker activity (mediated by ICC) propagates from corpus to antrum → causes ripples of constriction to propagate (stronger and stronger) towards pylorus → forcing contents against pylorus.
What happens to food in the antrum (1)?
Food and acid entering antrum → reflex inhibition of HCl secretion in proximal corpus.
• Strong constrictions resulting from large pacemaker (ICC) potentials propagating from corpus to pylorus → drives food towards pyloric sphincter.
• HCl, protease and mechanical activity cause components of food to separate → fat is liberated and floats to fundus, forming a separate layer.
• → So proteins/carbs at the bottom, fat at the top (empties from stomach last).
What happens to food in the antrum (2)?
- Continual grinding in presence of protease converts food into a dilute paste
- Diluted heavily by water in the stomach (secreted as part of acid secretion process)
- Pylorus opens briefly, relaxation due to activity of enteric neurons that control the contractility of the pylorus)
- Squirt of food mixed with acid and pepsin enters duodenum (very acidic)
- Initially high in protein + carbohydrate + low in fat, later high in fat
- Fat or Protein in Dudoenum Appetite far more than Carbs will.
- Acid, distension and nutrients activate various key mechanisms.
How do D cells release and into what?
They release somatostatin via the portal vein
What does the release of somatostatin do?
(i) HCL secretion from Parietal Cells
(ii) Gastrin Release
(iii) Histamine Release
What is the vago-vagal reflex do?
- It causes the Brunner’s gflands to release mucous and bicarbonate.
- Inhibits gastric emptying
What does the Duodenal/o-pyloro-antral reflex do?
1) closes pylorus 2) inhibits gastric emptying
What causes the release of CCK and where is it released from?
Release is caused by nutrients (amino acids and fatty acids)
CCK is released from I cells (which is an enteroendocrine cell)
What cells does CCK excite?
Excites terminal of vagal afferent neurons (→ Vago Vagal reflex)
Excites terminals of enteric sensory neurons (→ Controls mixing and Peristalsis of GIT wall)
What role does CCK play as a hormone?
- Gall bladder contraction → bile enters common bile duct
- Also causes release of digestive enzymes from pancreas (adds to secretin effect to ensure proper environment for digestion in duodenum and jejunum)
- Also a satiety factor acting on hypothalamus to partly suppress appetite
What produces secretin?
S cells
What does secretin do?
Induces secretion of a bicarbonate rich solution from the pancreas (via the pancreatic duct)
• Also removes break on gastric emptying by preventing acid stimulated duodenal-antral reflex and vago-vagal reflexes [↓ somatostatin = ↑ acid in the next release.)
Why is it necessary to neutralise gastric acid?
• Neutralizing the acid inactivates pepsin (works best at pH 1-2) and stops somatostatin secretion from duodenal D cells → prevents damage to lumen wall.
What does it mean when we say then the mucosa ‘tastes’ food?
• Mucosal cells “taste” the lumen = human EC cells express components of taste pathways for bitter and umami → tastants cause release of serotonin from EC cells
What is the role of tastants
→ tastants cause release of serotonin from EC cells
What type of ‘taste’ receptors do L cells express?
express the components of sweet taste receptor (glucose, or glucose substitutes).
What do L cells release?
Contain and release glucagon-like peptides 1 and 2, plus pancreatic polypeptide Y (PPY)
What do the hormones released by L cells do?
They regulate appetite
Aside from altering appetite what is another role of PYY?
PYY can also act on enteric neurons → alter motor circuits in small intestine
What are the ways in which the mucosa senses the food?
Mechanical
Chemical
What information does the body get from mechanical stimuli in the intestinal mucosa?
Get some sensory information from mechanical stimuli → distension/mucosal deformation is detected
What information does the body get from chemical stimuli in the intestinal mucosa?
via EC and EE Cells:
(i) Nutrients and other stimuli act on apical surface receptors → depolarisation of the EE cell and mediators are released from basolateral surface
(ii) Mechanism of release is similar to that involved in synaptic transmitter release
(iii) Some EC cells and possibly some EE cells are mechanosensitive
What does it mean to say that the gut smells food?
- EC may “smell” the lumen = express olfactory molecules therefore odorants → 5HT release → neural
- Eg. peppermint can activate menthol receptors can activate reflexes within the gut wall itself (food sensitivities related to odorants?)
- Also evidence that EC cell release of serotonin can result from contraction of the circular muscle (likely to also cause hormonal release from other EE cells; not yet identified
What is retropulsion?
Constrictions towards pylorus (peristaltic contraction; closure of lumen and pushing on in a propagating fashion it goes from anal to oral rather than oral to anal)
What is the function of retropulsion?
Mixes pancreatic juices and bile with food activating and facilitating digestion.
Crucial for neutralizing of gastric acid
Why is retropulsion crucial for neutralizing of gastric acid?
Secretions that come down the common bile duct and pancreatic duct enter the duodenum 1/3 of the way along, so food coming to DUOD will not get exposed unless it gets pushed up.
What is the function of segmentation in the gut?
- LOCAL constrictions alternating with relaxation mixes food with digestive enzymes and bile allowing digestion.
- Also leads to turbulent flow → nutrients close to absorptive surface
What are the two processes by which food can move through the gut?
Content moves slowly via segmentation and occasionally more rapidly via peristalsis
What determines the extent of nutrient absorption?
- Rapid transit → less digestion, less nutrient release + absorption
- Ileum is mainly for absorption of water NOT nutrients; rapid transit means not enough water will be absorbed → too much water entering colon exceeding its capacity → diarrhoea
Which nutrient empties last into the duodenum what effect does this have?
Fat empties last, giving surge of CCK release → satiety signals (also other reasons to eat)
What happens in the passage of the digestive products from the jejunum to the colon?
- Basic mechanism the same, but stimuli change as digestion is completed
- Absorption of water starts to make content more viscous, altering feedback from muscle and increasing resistance to flow
Where does fermentation occur and what is its product?
In proximal part of colon fermentation leads to production of short chain fatty acids (bacteria)
What are cellulose and other indigestible components of food broken down into?
acetate, butyrate, propionate
What provides about 25% of the energy requirements of the colon?
• 25% of energy requirements within the colonic mucosa due to metabolizing short chain fatty acids
What do the short chain fatty acid stimulate?
Enteric reflexes
What triggers the urge to defecate?
• Distal colon/descending colon → distension – stretch – of rectum
Sacral reflex pathway to brain, activates urge to defecate which leads to defecation process
What are mass movement contractions and what do they do?
• Mass movement contractions move faecal matter from colon to rectum
Does defecation require conscious control?
Requires conscious (ie. cortical) neural activity to relax anal sphincter and contract abdominal muscles
What are conditions in which defecation is poorly controlled?
- Children and autistic patients have GI problems → constipation → overflow incontinence
- In IBS, threshold for this is reduced and can sense content not normally detectable
What are migrating motor complex and what do they do?
Create a wave of constriction initiated in the antrum or upper duodenum which propagates slowly to ileo-colonic junction
What triggers a MMC?
Possibly triggerd by release of motilin, but many other hormones are released
What does the MMC do?
Housekeeping function to keep bacteria + debris out of the small intestine and in the large intestine
Failure causes bacterial overgrowth (can lead to serious problems
Where is gastrin releasing peptide found and what does it do?
Found in nerve terminals near G cells.
Acts in parallel to vagally released acetylcholine
Where are digestive enzymes found?
Saliva
Gastric secretions (notably pepsin)
Mucosal surface of epithelium (secretions)
What sugars can the intestine absorb?
The intestine can only absorb monosaccharides and thus poly/disaccharides must be broken down before being absorbed
Can cellulose be absorbed?
No - it is excreted as fibre
What is an effective way of preventing hunger pain?
Sugar
What types of polysaccharides do humans digest?
Humans mainly digest glucose polymers (starches + derivatives)
What are the disaccharides that humans digest?
Lactose and sucrose
What are the dietary monosaccharides?
Glucose and fructose
Why is fructose used in a number of products as a substitute for glucose?
It is sweet but less well absorbed → it is a low calorie substitute.
The major drawback is that consumption is a risk factor for type II diabetes
What is the enzyme that begins digestion in the mouth?
Amylase
What bonds does amylase hydrolyse?
1:4α linkages of starch
What happens to amylase in the stomach and beyond?
It is inactivated by the low pH in the stomach
It is reactivated in the duodenum when the pH is neutralised
How effective is amylase?
It is relatively effective in the saliva though food is generally in big lumps making it harder to act.
It is not a major player in the small intestine
What does the pancreas secrete in response to CCK released by the duodenal mucosa?
Pancreatic α -amylase
How does pancreatic α -amylase get to its site of action?
Enters duodenum via pancreatic duct + pushed back to pylorus by retropulsion
What bonds are both amylases ineffective at breaking?
Both α-amylases break 1:4α linkages BUT NOT 1:6α linkages
Given that both α-amylases break 1:4α linkages BUT NOT 1:6α linkages what sugars are left intact?
Oligosaccharides
Where does the final part of carbohydrate digestion take place?
Occurs at brush border of the mucosal enterocytes (tips of villi) by segmentation
What does Isomaltase do?
Isomaltase breaks 1:6α linkages
What does sucrase do?
Sucrase breaks sucrose into glucose and fructose
What does maltase do?
Breaks down maltose into 2 glucose molecules
How are maltase and sucrase synthesised and activated?
Maltase and sucrase are synthesized as a single large glycoprotein (via Golgi)
→ inserted into brush border membrane and then glyocoproteins are separated and activated by pancreatic proteases (ie these proteases act on sugars too)
What is the relationship between isomaltase, sucrase and maltase?
Isomaltase breaks 1:6α linkages, and acts with sucrase and maltase to break down maltotriose and maltose
How are glucose and fructose absorbed in the duodenum and jejunum?
Glucose & fructose are rapidly absorbed across mucosal epithelium in duodenum and jejunum (predominately at tops of villi)
What does glucose transport rely on?
Largely depends on Na+ at epithelial surface → high salt intake = effective glucose transport
How is glucose transport enhanced?
By the sweet taste receptor (i.e. if you have something sugary before consuming glucose then the glucose transporters will be up-regulated and result in greater uptake)
What co-transporter is responsible for absorption of glucose?
Glucose and Na+ co-transported (NA+ gradient across cell membrane → energy for glucose transport) by the sodium-dependent glucose transporter (SGLT1)
Is the SGLT1 part of the GLUT family?
No - no homology with the GLUT family of glucose transporters
How is fructose absorbed through the gut?
Fructose transported by GLUT5 (facilitated diffusion) into epithelial cells + GLUT2 to interstitium
What is the pathway that glucose follows after absorption?
Extracellular space → blood vessel → liver: glucose → glycogen OR used by brain/heart
Are proteins digested in the mouth?
Nope
What is the primary digestive enzyme of protein in the stomach?
Pepsin
What cells in the stomach secrete pepsinogen?
Chief cells
What activates pepsinogen?
Gastric acid
What are the two types of pepsinogen and where are they secreted?
→ Pepsinogen I secreted in acid secreting regions [corpus]
→ pepsinogen II secreted close to pylorus
What does pepsin do?
Hydrolyses bonds between aromatic amino acids (phenylalanine, tyrosine) and a second amino acid, thus it produces polypeptides of diverse sizes.
Pepsin is important for breaking down cell-cell adhesion
What inactivates pepsin?
Pepsin is inactivated at neutral pH (and thus not effective in the duodenum)
What do the presence of AA in the duodenum cause?
The release of CCK
CCK goes to pancreas and causes the secretion of pancreatic proteases in form of inactive proenzymes
What are some endopeptidases involved in digestion?
Trypsin, elastase and the chymotrypsins
What do endopeptidases do?
Act at interior bonds of peptides –to produce short polypeptides (polypeptides)
What are some exopeptidases involved in digestion?
Carboxypeptidase & aminopeptidases
What is the role of an exopeptidase?
Acts at terminal ends of peptides to produce free AAs
What happens to the inactive pro-enzymes released by the pancreas?
Inactive proteases arrive in duodenal lumen
→ Enterokinase in brush border membranes activates trypsin from trypsinogen
→ Trypsin is an endopeptidases resulting in a cascade to activate other proenzymes
What happens to amino acids at the brush boarder?
Mix of short peptides (di-, tri-, tetra-) and free amino acids end up at brush border membrane
→Mix of aminopeptidases, carboxypeptidases, endopeptidases and dipeptidases –
→ Break down polypeptides to free AAs
What are the two means by which amino acids are transported across the brush boarder?
Co-transported with H+
Diffusion
Which amino acids are co-transported with H+?
Some di- and tri-peptides transported directly into epithelial cells via co transport with H+.
The entrocyte small peptidases will subsequently break them into free amino acids
How do free amino acids move across the brush boarder?
→ Free amino acids transported by 7 or more different transport systems
→ 5 require Na+ (similar to glucose transport), 2 of these also require Cl-
Is fat digested in the mouth?
Digestion starts in the mouth with the lingual phase (kind of)
Very minor effect and probably more for taste (we have recently discovered fatty acid taste receptors)
Is fat digested in the stomach?
There is an enzyme in the stomach called gastric lipase, it plays a minor role but lipids take longer to empty from the stomach giving it more time to act.
Gastric lipase may produce enough fatty acid to trigger CCK secretion from the duodenum
What lipolytic enzyme is released into the duodenum in response to CCK?
CCK causes the secretion of pancreatic lipolytic enzymes
→ Colipase is secreted (inactive form)
→ Colipase activated to lipase by trypsin
What activates cholesterol esterase, what is its role?
It is activated by bile.
It hydrolyses cholesterol esters, esters of fat soluble vitamins and phsopholipids
What needs to occur before enzymes can act on fat?
Emulsification (think making mayonnaise)
What are the emulsifying agents in the duodenum, what extrinsic factor is required for effective emulsification?
Bile salts and Lecithin
Vigorous mixing is required
What are micelles?
Bile salts form micelles with lecithin and monoglycerides
Micelles capture fatty acids, monoglycerides and cholesterol
How are lipids transported across the brush boarder?
Micelles are brought to the apical surface of epithelial cells, at the tips of villi
When in contact with membrane, fat soluble lipids dissolve in membrane and enter cells (some transporters may be involved for long carbon chain fatty acids)
Once inside epithelial cells, fatty acids and monoglycerides reform triglycerides in smooth ER
How is fat transported to the liver?
Absorbed cholesterol, MGs, FAs reform to make TG.
→ TGs coated with apolipoproteins
→ Forms chylomicrons
→ Chylomicrons secreted by exocytosis to enter lacteals (lymph of the SI)
→ Venous system
→ Liver
**Shorter 10-12 carbon fatty acids diffuse to venules without this processing
Where are short chain fatty acids produced in digestion?
Cellulose goes to proximal colon
→ Bacteria act on cellulose to produce SCFA
What are the short SCFA produced in the colon?
Acetate (60%)
Proprionate (25%)
Butyrate (15%)
Concentration is quite high in the lumen = ~80mM
How and where are SCFA absorbed?
Absorbed in distal small bowel and proximal part of colon via H+ dependent mechanism
What contribution to SCFA make to total energy intake?
Contribute significantly to total energy intake - especially important in herbivores
