Neuronal, blood innervation of intestine and general movement Flashcards
Digestion definition and listed physiological processes
Digestion is defined in the OED as “the physiological process whereby the nutritive part of the food consumed is, in the stomach and intestines, rendered fit to be assimilated by the system”.
The key physiological processes that concern us in this series of lectures are the
motility of the gastrointestinal tract,
chemical digestion,
absorption of released nutrients and
their transport and storage and finally excretion of waste.
Structures of the digestive system
Mouth (Salivary glands)
Pharynx-> Oesophagus -> Stomach (fundus, body, antrum)
Small intestine:
Duodenum(12)->Jejunum(empty)->Ileum (abosprtion): looking at pancreatic and liver (stored in gall-bladder) secretion
Large intestine
Caecum-> Colon (Ascend-, transverse, Descend-,Signoid)->
The structure is interchangeable since they are studied in dogs and discussed in humans digestive tract
The mammalian digestive tract consists of a tube divided functionally and anatomically into different sections. A section of small intestine is shown below.
The basic histological structure of the gut tube consists of the following:
- Mucosa: the innermost layer, consisting of the epithelium, the lamina propria (loose connective tissue containing glands, lymph nodules and capillaries) and the muscularis mucosae (a thin layer of smooth muscle which throws the mucosa into folds). In the small intestine, finger-like projections called villi increase the internal surface area.
- Submucosa: containing blood vessels, nerves and glands. The submucosal plexus (= Meissner’s plexus) is found here.
- Muscularis externa: including inner (circular) and outer (longitudinal) smooth muscle layers. The myenteric plexus (= Auerbach’s plexus) is located between the two layers.
- Serosa: the outermost layer of connective tissue, covered by simple squamous epithelium.
The blood supply to the intestine
The blood supply to the stomach, intestines, liver, spleen and pancreas is known as the splanchnic circulation. The diagram below shows resting values: around 1200 ml min-1 passes through the splanchnic bed. Of this, around 75% passes via the intestines to the liver in the hepatic portal vein; the rest represents the oxygenated blood reaching the liver directly via the hepatic artery.
Splanchnic blood flow increases up to around 2500 ml min-1 after a meal: functional hyperaemia. Metabolites which increase during digestive activity, certain gut hormones and absorbed substances contribute to this. Parasympathetic stimulation increases blood flow only locally, e.g. in the salivary gland. Elsewhere, increased flow following parasympathetic stimulation may largely be a secondary effect, following the increased metabolic rate which occurs with increased activity.
24% goes to the digestive system, which merged together using hepatic portal vein to deliver all of the absorbed nutrient to the liver. These 1200 ml/ min can double or more after a big meal which is facilitated by nutrient and some digestive hormone. But vasoconstriction can be also applied within just 300 ml/min during fight or flight mode.
Maximal sympathetic vasoconstriction can reduce splanchnic blood flow to as little as 300 ml min-1. Splanchnic vessels are also very responsive to circulating vasoconstrictors such as angiotensin II and ADH (at high levels).
The great veins of the gut act as capacitance vessels, holding about 20% of blood volume at rest. Venoconstriction can add about 400 ml from the mesenteric veins, plus another 200 ml or so from the liver, to the general circulation.
The blood supply to the villi
The epithelium encounters nutrient every day may get damaged, then the tight junction is used to preserve the integrity by removing the 1 epithelium gradually while interconnected ones develop another tight junction below.
New cells are generated in the crypts containing stem cells, then the daughter cells migrate upwards.
The arterial blood supply to each small intestinal villus ascends from the base while the venous supply descends: a counter-current arrangement. Water-soluble substances including monosaccharides and amino acids enter the descending vessels, which ultimately drain into the hepatic portal vein and are transported within this to the liver.
Products of fat digestion enter lacteals within the intestinal villi. Irregular contractions of the smooth muscle within the lamina propria of the villus, stimulated by an increase in interstitial fluid pressure, helps to empty the central lacteals by squeezing, and the lymph is moved in this way into the lymphatic system proper. Valves in the submucosal lymph vessels prevent backflow.
What are the implications of the counter-current arrangement of blood flow in the villus?
oxygen with a transverse gradient maintains a higher PO2 level at the tip. If blood supply is reduced like haemorrhage, the tip of villi will be low in oxygen, the gut will constrict+ counter-current gradient =damaged to the villa with microbe getting into the villi.
Gut epithelial turnover
The epithelium of the gut, comprised of a single layer of columnar epithelial cells, is vital in preventing microbial invasion of the body, and yet it is very vulnerable to mechanical damage. For that reason, it is subject to continual renewal: these cells have an unusually high turnover rate, and the entire gut epithelium is estimated to be replaced every 2-6 days! This does not happen all at once, of course: it is a continual process.
In the small intestine, old epithelial cells are shed from the villus tips, to be replaced by new ones moving up the sides of the villus in a conveyor-belt like fashion. New cells arise from a stem cell population in the crypts of Lieberkühn (the blind-ending tubules projecting into the gut lining between the villi). Before older cells are shed from the villus tips, new tight junctions are formed beneath them, between their neighbours. This ensures that the barrier function of the gut is not compromised, so microbes cannot invade the mucosa.
The enteric nervous system
The enteric nervous system (ENS) includes the submucosal and myenteric plexuses, which extend from about the middle of the oesophagus to the colon (see Goyal & Hirano, 1996). The submucosal plexus largely co-ordinates secretion, whereas the myenteric plexus largely co-ordinates motility.
Sensory cells located within the gut wall pass messages to the two plexuses relating to e.g. stretch or chemical composition of the lumen, allowing the plexuses to co-ordinate entirely intrinsic reflex activities such as some types of peristalsis. It is because the ENS can perform many of its functions independently that small bowel transplants in particular are so successful.
Roughly how many neurons are present in the ENS?
400-600 millions
Why do we need extrinsic nervous control of the gut?
-For skeletal muscle control
-To tell the ENS about external circumstances (SNS/PNS)
-Long distance traffic control, for vagovagal and long-distance reflexes, used for ‘traffic control’
Gastro-colic and Ileal brake,
Ileal brake: food products are digested in the ileum, but when the motility is too fast, hormones are applied including PYY, GLP-1 to slow things down via negative feedback.
Gastro-colic: feedforward to push the feces down may involve neurons and gastrin and CCK after ingestion.
Three phases of digestion
Cephalic phase: feed-forward control, neural signals to upper GI tract, stereotyped reflexes relating to the availability of the food.- salivate, muscle relax in stomach
Gastric phase:
Intestinal phase:
Feedback control more important
Hormonal signals more important
Responses relate to the quality of what is being detected (e.g. specific nutrients )
Autonomic innervation
Extrinsic innervation from the central nervous system (CNS) is provided by the autonomic nervous system (ANS). ANS fibres usually form synapses with ENS fibres, passing them information about the conditions of the body. ANS input is particularly important in the proximal gut and rectum, with intrinsic ENS and hormonal control becoming more important in-between.
Sympathetic nerve fibres synapse once outside the CNS: the cholinergic synapse may be in one of the paravertebral ganglia of the sympathetic chain, or (in the case of most fibres to the gut) in a separate prevertebral ganglion within the abdominal cavity. The postganglionic fibres are typically noradrenergic. The effect of sympathetic stimulation on gut motility and secretion is usually inhibitory, but sphincter contraction is stimulated.
Parasympathetic supply to the gut is carried in the vagus.
The three guts are separated, the foregut on the mid of second part of the duodenum, midgut is like 2/3 to the transverse of the large intestine.
The cholinergic preganglionic fibres synapse within the ENS, often with thousands of predominantly cholinergic postganglionic fibres. The effect of parasympathetic stimulation on gut motility and secretion is usually excitatory, but sphincters may be relaxed via inhibitory postganglionic fibres (often releasing VIP).
The pelvic nerves supply the distal colon, rectum and anus. It was long believed that these nerve fibres, arising in the sacral spinal cord, were parasympathetic. However, recent developmental evidence shows that they are actually sympathetic fibres.
Sensory neurons in the gut
Sensory nerve fibres in the intestinal tract fall into several categories:
1) Sensory fibres located entirely within the enteric nervous system (intrinsic primary afferent neurons or IPANs). These fibres form the afferent limbs of local reflexes including those responsible for peristalsis, mixing and secretion.
2) General visceral afferent fibres, with cell bodies in the dorsal root ganglia or a homologous ganglion of the vagus. Their axons transmit signals from the gut to the spinal cord or brain stem and are involved in certain stomach reflexes (e.g. receptive relaxation), pain and defaecation reflexes.
Approximately 50% of fibres in ‘sympathetic nerves’ to the gut and 75% of vagal fibres are afferent. Reflexes in which both afferent and efferent arms are carried by the vagus nerve are termed vagovagal reflexes. Pain signals nearly always travel in sympathetic nerves.
3) Intestinofugal afferent neurons: Sensory fibres with cell bodies in the enteric nervous system, which send axons with the sympathetic nerves to synapse in the prevertebral sympathetic ganglia (intestinofugal afferent neurons or IFANs). These fibres often form the afferent limbs of long-range inhibitory reflexes used for coordinating the activity of different parts of the gut. The IFANs and prevertebral ganglionic connections ‘short-circuit’ an otherwise long and multisynaptic pathway through the ENS.
Long-range reflexes
Ileal brake and gastrocolic reflex
Coordination of the activities of the gastrointestinal tract as a whole is achieved in part by ‘long-range’ reflexes, which usually involve a synapse in the prevertebral ganglia. Gastrointestinal hormones may contribute, either directly or through stimulating vagal afferent fibres to elicit a neural response. Some of these reflexes represent feedback mechanisms, reducing motility in proximal sections of the gut if it looks like contents are moving through too quickly, and some feed-forward reflexes, enhancing motility of distal parts of the gut in order to make room for what is to come. There are many named reflexes which you can find described in the text-books: here are two examples.
- The ‘ileal brake’ mechanism refers to the effect of nutrients (particularly fat) which have reached the ileum without being absorbed reducing the motility and secretion of more proximal parts of the digestive tract. This may involve the gut peptide hormones PYY and GLP-1 as well as nerve fibres.
- The gastrocolic reflex is where food entering the stomach promotes the motility of the colon, which may result in the urge to defaecate.
Apart from reflex activity, voluntary control may be exerted over swallowing or defaecation since striated muscle is present at each end of the digestive tract. Emotions, especially anxiety, may also influence bowel movements.
Gut smooth muscle, and its control
From middle to lower oesophagus onwards, the gut is lined with smooth muscle. Smooth muscle in the sphincters is tonically contracted for durations of minutes to hours, but it relaxes when required. Much of the other smooth muscle in the walls of the stomach and intestines contracts slowly and rhythmically: phasic contraction. In this case, a wave of depolarization spreads through gap junctions and the cells are also mechanically coupled, allowing a coordinated contraction. Smooth muscle in which the cells are electrically coupled is referred to as single-unit smooth muscle.
Smooth muscle cells: a review
- Smooth muscle cells are much smaller than skeletal muscle fibres (40-600 μm long but only 2-10 μm wide) and have just one nucleus per cell.
- Contraction is usually based on calcium entry through plasma membrane channels, augmented by calcium-induced calcium release from the sarcoplasmic reticulum.
- Indentations of the plasma membrane called caveolae increase the surface area and may act as calcium stores.
- The ratio of thin (actin) to thick (myosin) fibres is around 10:1, rather than 2:1 as in skeletal muscle.
- Z-lines are functionally replaced by dense bodies, which serve as attachment points for thin filaments and are themselves connected to the cytoskeleton. Some of the dense bodies on the plasma membrane mechanically anchor cells together.
- Troponin is absent.
Excitation-contraction coupling in gut smooth muscle
Calcium inside the cell binds to a protein called calmodulin, and this complex activates myosin light-chain kinase, which phosphorylates a regulatory light chain on myosin, allowing it to bind with actin and undergo the cross-bridge cycle. When the calcium level falls, the myosin is dephosphorylated by myosin light chain phosphatase, which prevents further cycling.
Peristalsis
Peristalsis is a general term referring to gut motility patterns which propel food in the anal direction. One type of peristalsis is the peristaltic reflex, which occurs when stretching of the gut wall elicits contraction of the longitudinal and circular muscle behind a bolus (mediated by ACh), but relaxation of the muscle in front of the bolus (mediated mainly by nitric oxide), propelling the food onwards (the “law of the intestine”).
The peristaltic reflex is mediated entirely within the ENS, so can occur without extrinsic innervation.
Detection of the food may be via mechanical stretch receptors in the myenteric plexus, or by mechanical or chemical stimuli to the mucosa promoting serotonin (5-HT) release from enterochromaffin cells: the 5-HT stimulates local sensory neurons. Both stretch and chemo-sensitive neurons modulate the activity of the smooth muscle of the muscularis externa indirectly, via the myenteric plexus.
Others forms of peristalsis exist in different parts of the gut. Peristalsis in the striated muscle portion of the oesophagus is controlled by somatic motor neurons (which cause sequential contractions of the striated muscle), while slow-wave activity is involved in the antrum of stomach and in the MMC (see Huizinga & Lammers, 2009). Reverse peristalsis (retroperistalsis) is possible in e.g. the colon.
The basal electrical rhythm
It’s NOT action potential by looking at both the time and amplitude with a slow and relatively small depolarisation.
The resting membrane potentials of smooth muscle cells of the gut range from around -70 to -40 mV. Slow waves of electrical activity are slow, undulating depolarizations of amplitude between 10 to 50 mV. These slow waves represent a basal electrical rhythm intrinsic to the gut, and they are responsible for phasic contractions. Between slow waves, the smooth muscle retains a basal level of tension referred to as tone. The rate of slow wave occurrence ranges from 3-12 cycles per minute, depending on the part of the gut; the exact shapes of the slow waves also vary by location.
ICCs are spontaneously generating slow waves while can be modulated by the ENS (interstitial cells of Cajal)
ICCs: modified smooth muscle
SAN: composed of cardiac muscle cells ]
-Both non-contractile modified muscle cells
-Electrically coupled to each other and ultimately to contractile cells
-Spontaneous electrical activity
-activity is modulated by ANS (OR ENS)
-Slow waves/ Action potential in the pacemaker
The interstitial cells of Cajal (ICCs) act as pacemakers in the gut, initiating and propagating the slow waves. They are specialised smooth muscle cells containing few contractile elements, located mainly between the longitudinal and circular muscle layers. The enteric nervous system mainly innervates the ICCs rather than the smooth muscle directly, in many parts of the gut.
Although not fully understood, the pacemaker activity of ICCs appears to be based on calcium being taken up or released from intracellular stores, resulting in changes in the activity of nearby plasma-membrane ion channels. The fine processes of the ICCs form gap junctions with each other and with nearby smooth muscle cells in both the circular and longitudinal layers: the slow waves are propagated within the ICC network and spread from there to the smooth muscle cells.
Interstitial cells of Cajah
The interstitial cells of Cajal (ICCs) act as pacemakers in the gut, initiating and propagating the slow waves. They are specialised smooth muscle cells containing few contractile elements, located mainly between the longitudinal and circular muscle layers. The enteric nervous system mainly innervates the ICCs rather than the smooth muscle directly, in many parts of the gut.
Although not fully understood, the pacemaker activity of ICCs appears to be based on calcium being taken up or released from intracellular stores, resulting in changes in the activity of nearby plasma-membrane ion channels. The fine processes of the ICCs form gap junctions with each other and with nearby smooth muscle cells in both the circular and longitudinal layers: the slow waves are propagated within the ICC network and spread from there to the smooth muscle cells.
Slow waves and contraction
Ca2+ action potential through voltage-gated calcium channels
This entire activities including slow waves are inhibited. On the right hand side, the excitation is by acetylcholine. Where larger contraction occurs with higher magnitude of slow waves.
In some parts of the gut, a regular slow wave without spikes can cause muscle contraction with that actual burst. The slow waves are related to contraction while being autonomic.
The depolarization of smooth muscle cells by slow waves originating in the ICCs results in the opening of L-type voltage-gated calcium channels in their plasma membranes.
If the amount of calcium that enters exceeds the contraction threshold, the smooth muscle will contract.
If it exceeds a certain electrical threshold, action potentials (‘spike potentials’) may be generated, based on calcium entry through more voltage-gated channels.
Spike potentials are superimposed onto the slow waves in smooth muscle of many parts of the gut. Each is longer in duration than a sodium-based AP in a nerve: up to 20 ms. Since more calcium enters the cell, a higher frequency of spikes elicits a stronger contraction, but not all smooth muscle requires spikes for contraction to occur.
Excitatory substances (e.g. ACh) increase the amplitude of slow waves, for example by opening cation channels with contribute to the depolarization. More depolarization results in more spikes, more calcium entering the cell and a stronger contraction. Inhibitory substances (e.g. NA) decrease slow-wave amplitude, often due to the opening of hyperpolarizing potassium channels. This results in a weaker contraction, or no contraction at all if the amplitude is under the contraction threshold.
Tonic contraction of sphincter muscle does not depend on slow-wave activity. It may be caused by a continuous sequence of action potentials, partial depolarization of the smooth muscle cell membrane without action potentials, or other mechanisms resulting in sustained levels of intracellular calcium.
Segmentation
Different from peristalsis, these segmental contractions are generated by slow waves, not helping to move but help to mix the food. So these two activities are mediated in different waves, with IPANs and intrinsic reflex for peristalsis and slow waves for segmentation.
They are all mediated by the cell in the gut itself, the gut does not require extrinsic innervation to tell it what to do.
Extinsic can only modulate it, that’s why transplant is often successful for intestine.
Segmentation is where different regions of the circular muscle of the gut tube wall contract to aid mixing. Slow waves initiated by the ICCs drive segmental contractions but are modulated by nerves and hormones (e.g. gastrin). Parasympathetic stimulation is excitatory, whereas sympathetic stimulation is inhibitory; segmentation contractions become very weak in the absence of appropriate myenteric stimulation.
