gastrointestinal physiology

Basic science

sURGeRY 27:6 225 © 2009 Published by elsevier Ltd.

Gastrointestinal physiologyJohn McLaughlin

AbstractThis contribution focuses on the gastrointestinal tract and its ability

to absorb nutrients, water and electrolytes, and also how it forms an

effective barrier against potentially harmful contents, such as bacteria.

its structure and function are also discussed.

Keywords gastrointestinal; physiology

The gastrointestinal tract must not only absorb nutrients, water and electrolytes, but must also form an effective barrier against the ingress of potentially harmful contents, such as bacteria. Its structure and function are highly adapted to serve these conflict-ing roles.

Secretion of gastric acid

The primary reason for secreting gastric acid is to kill ingested microorganisms. This appears less important in the developed world and acid secretion is pharmacologically stopped with impunity in millions of individuals. Acid denatures proteins, but gastric enzymes and defence molecules are pH-adapted to allow digestion to begin. At a pH of about 1 after a meal, gastric acid is injurious to tissues except the highly adapted gastric mucosa. A gel of mucus coats the epithelium, and bicarbonate is secreted locally so that the pH adjacent to the cell surface is 6–7. A surface coating of mucus also provides defence against autoproteolysis, serving as a gel with a progressive pH gradient occurring from the cell surface to the lumen. The epithelium is further protected by a variety of factors including: • prostaglandins (PGE2 in particular; its synthesis is blocked by

non-steroidal anti-inflammatory drugs, majorly contributing to their ulcerogenicity)

• epidermal growth factors (e.g. heparin-binding epidermal growth factors, amphiregulin)

• ‘trefoil’ peptides which are secreted into the lumen and may monitor for damage and protect the mucosa.Hydrochloric acid is secreted by parietal cells in the gastric

body (oxyntic mucosa), which express the H+–K+ ATPase or proton pump. When stimulated, particularly by histamine, proton

John McLaughlin FRCP is a Senior Lecturer in Medicine at Manchester

University, Manchester and Honorary Consultant in Gastroenterology

at Hope Hospital, Salford, UK. He is Clinical Director of the

Gastrointestinal Physiology service. Conflicts of interest: none

declared.

pumps are rapidly recruited to the apical surface by fusion of a vast intracellular canalicular membrane network and actively extrude H+ into the lumen against a concentration gradient of 106 (the largest concentration gradient in human physiology). H+ derives from the action of the enzyme carbonic anhydrase, which is abundant in parietal cells (CO2+H2O→H2CO3→HCO3

−+H+). Chloride is secreted in parallel via cyclic AMP-dependent apical channels.

Control secretion of gastric acid is intrinsic and extrinsic, and occurs in three phases.

The cephalic phase accounts for about 40% of total acid secre-tion and is triggered by food in the mouth, although the sight, smell or thought of food can trigger this, as can any conditioned reflex (Pavlov’s dogs secreted acid in response to a mealtime bell when food was not given). It is a vagal mechanism and is virtu-ally abolished by vagotomy. This is the rationale for vagotomy in the historical management of acid peptic disease, particularly ulcers. It is mediated by post-ganglionic cholinergic fibres acting on muscarinic (M3) receptors on the parietal cell.

The gastric phase is triggered by food in the stomach, particu-larly l-aromatic amino acids (l-tryptophan, l-phenylalanine) and small peptides liberated from initial digestion of protein, which directly stimulate the release of the hormone gastrin from antral G-cells. The sensory mechanism is not confirmed, but recent evi-dence suggests that the extracellular calcium receptor (originally cloned from parathyroid cells) acts as a polymodal nutrient sen-sor expressed by G-cells. Mechanical stretch also has a role via intrinsic neural reflexes and the vagal efferent nerves produce a gastrin-releasing peptide. Alcohol and caffeine further stimulate acid secretion.

Intestinal phase – food entering the intestine stimulates about 10% of acid secretion, which will persist with purely post-pyloric tube feeding. G-cells are also present in the duodenum, predomi-nantly secreting gastrin-28 which has a longer circulating half-life than gastrin-14, the predominant antral G-cell product (see below). The intestinal phase is more complex because inhibi-tory hormones are also released, particularly in response to fat (cholecystokinin (CCK), peptide YY) and acid (secretin, gastric inhibitory polypeptide). These inhibitory effects constitute the so-called ‘enterogastrone’ mechanism, and also contribute to slowing gastric emptying, particularly after fatty meals. The acid hypersecretion and hypergastrinaemia in surgical short bowel probably reflects the functional loss of enterogastrones because their tissue source has been removed surgically.

Gastrin and the feedback control of secretion of gastric acid: gastrin is a regulatory peptide but is not a major direct regulator of acid secretion by parietal cells. Amidated gastrins, the active moiety at the CCK-2 (CCK, gastrin) receptor, are produced by cleavage and post-translational modification from the prepro-gastrin precursor, the initial translational product of the gastrin gene. There is increasing evidence the progastrin has biological activity, related to cell proliferation and differentiation. The main target is the gastrin/CCK-2 receptor on the histamine-secret-ing enterochromaffin-like cell, not the parietal cell as had been thought. Histamine is secreted to act in a paracrine manner on nearby parietal cells, operating at H2-receptors to stimulate acid secretion via the mechanisms discussed above. Gastrin is trophic

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to the oxyntic mucosa indirectly via epidermal growth factors, which leads to the thickened folds found in Zollinger–Ellison syndrome. The enterochromaffin-like cell also operates under vagus nerve control, probably via pituitary adenylate cyclase-activating peptide.

There is also an epithelial inhibitory mechanism in which a fall in pH leads to an increase in the secretion of somatostatin from D-cells, which inhibit both G-cells and enterochromaffin-like cells. Hence, proton-pump inhibitors induce hypergastrinaemia. It is usually recommended that inhibitors of acid secretion should be stopped to measure and evaluate an elevated concen-tration of gastrin in plasma. The utility of measuring intragastric pH is often overlooked; hypergastrinaemia cannot be due to the medication if gastric acid secretion is not suppressed.

The D-cell is also an intermediary in the enterogastrone mech-anisms, and expression of the somatostatin gene appears to be downregulated in Helicobacter pylori antritis.

Proton-pump inhibitors: given that only the proton pump is common to acid secretion, it is not surprising that its inhibi-tors have transformed the management of acid-related disease. Anticholinergics are readily bypassed and not of value clinically, whereas H2-receptor antagonists and even vagotomy leave a sub-stantial proportion of acid secretion intact. Gastrin receptor antag-onists are in development. Acid is secreted with an osmotically appropriate volume of water, and so proton-pump inhibitors also reduce the volume of gastric juices, not just their acidity. This contributes to their effectiveness in gastro-oesophageal reflux disease and also their adjunctive use in short bowel with gastric hypersecretion.

Enterochromaffin-like cell hyperplasia

In addition to its role in secretion of gastric acid, gastrin is also a direct growth factor for the enterochromaffin-like cell, which explains the presence of enterochromaffin-like hyperplasia seen in some chronically hypochlorhydric and consequently hyper-gastrinaemic patients (e.g. in pernicious anaemia, in which there is autoimmune destruction of parietal cells). This can progress to small carcinoid nodules in a minority, and invasion and metastasis can occur in a very small minority. This underlies the rationale for antrectomy rather than total gastrectomy for corpus carcinoids, removing the anatomical source of gastrin. The risk of surgery appears higher than the risk of invasiveness and sur-veillance is adequate initially. The risk of aggressive neoplasia is higher in non-hypochlorhydric hypergastrinaemia (Zollinger–Ellison syndrome and/or multiple endocrine neoplasia (MEN1). Measuring intragastric pH is very helpful.

Biology of the intestinal epithelium

Gastrointestinal epithelial cells originate from a stem cell popula-tion in the crypt zone. There are four cell types resulting from differentiation pathways controlled by a complex array of tran-scription and differentiation factors. The key lineage commitment decision is whether to adopt the dominant pathway to an absorp-tive phenotype (enterocyte/colonocyte) or a secretory phenotype. This includes mucus-secreting goblet cells, hormone-secreting enteroendocrine cells (EECs) (Figure 1), and defence peptide-secreting Paneth cells. Progenitor cells originating from the stem cell population differentiate along an absorptive (enterocyte) or

Conceptual model: transepithelial signalling by EECs

EEC, enteroendocrine cell

Nutrients

Paracrine/endocrinefactors

Lumen

Apical

Basolateral

Neurones

Epithelia

Muscle

Immune cells

Figure 1

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secretory (EEC, Paneth cell, goblet cell) cell pathway under the control of specific differentiation and transcription factors.

In the small intestine, the cell types, except Paneth cells, ascend the crypt–villus axis, moving over a period of 3–5 days to be shed by apoptosis. Paneth cells move to the base of the crypts, and appear to have a longer lifespan. Increas-ing evidence implicates Paneth cells in the pathogenesis of inflammatory bowel disease, given their key role in epithelial recognition and defence against microorganisms. The Crohn’s gene, CARD15, encodes a Paneth cell protein. Abnormal epi-thelial structure in disease reflects changes in the regulation of epithelial turnover. Some of this may be adaptive; for example, increased turnover and goblet cell hyperplasia in response to nematode infection may contribute to parasite expulsion (‘weep and sweep’ hypothesis).

The epithelium as a barrier

The gut prevents the passage of bacteria and other undesirable substances (dietary contaminants, bacterial products) from the lumen into the organism. The colon contains tenfold more bac-teria than cells in the host body. This is mainly achieved by tight junctions between cells (Figure 2). These are complex structures comprising multiple proteins that constitute a pore close to the apical surface of the cells that filters molecules according to size. Key members are ZO-1, occludin and the claudin family. This constitutes the paracellular pathway, and is a minor route for the absorption of some small ions (e.g. calcium). Water also passes this way, with some movement occurring transcellularly. Increas-ing interest has focused on the regulation of tight junctions, and whether they contribute to the increase in intestinal permeability seen in injury and inflammation in the gut. Current research aims to identify factors that protect or restore the barrier, for example antioxidants and nutrients (e.g. glutamine). The gut microflora has an active symbiotic role in maintaining the barrier. Using pro-biotic bacteria to alter bacterial flora and enhance the barrier has

generated interest. Another approach is to give these with bacte-rial nutrients (prebiotics); the combination is termed a ‘synbi-otic’. A class of dietary fibre substances, fructo-oligosaccharides, has also been shown to modulate permeability, an effect also observed in germ-free (gnotobiotic) states. Changes in inflamma-tory signalling by epithelial cells occur in response to probiotic bacteria, suggesting an active intrinsic effect of fibre (previously thought to be inert and solely the target of bacterial fermenta-tion). There is also evidence that psychological stress increases gut permeability via these or other structures. Increased perme-ability leads to inappropriate fluxes of fluids and electrolytes, and may underpin bacterial translocation, prequelling sepsis.

The mucosa is immunologically active. Defence against injury is provided by secretory immunoglobin and various cell- mediated mechanisms, and sampling antigenic content via spe-cialized dendritic cells scattered throughout the gut. These can open tight junctions, passing processes between epithelial cells to sample luminal contents.

Enteroendocrinology

The gut is the largest endocrine, with up to 20 types of EEC scattered throughout the gastrointestinal epithelium. As noted above, EECs are derived by selective terminal differentiation from a common stem cell niche. EECs serve a variety of physi-ological roles, but their key function is to operate as transepithe-lial signal transduction conduits. The apical surface of most EECs is ‘open’ to the lumen, projecting microvillus processes that are believed to operate as chemosensors. Variables sensed intralumi-nally include nutrients, pH and osmolarity. Each EEC produces one or more regulatory peptide (or biogenic amines, principally histamine and 5-hydroxtryptamine) which are secreted predomi-nantly basolaterally by exocytosis. The released mediators were thought to act as true hormones (via the circulation to act at a distance) but many of their actions occur locally (paracrine effects). The epithelium is a target, for example, in the regulation

Absorption of glucose, galactose, salt and water

SGLT-1, sodium-dependent glucose and galactose transporters; GLUT –2, glucose transporters; cAMP, cyclic AMP;

VIP, vasoactive intestinal peptide.

Glucose and galactose absorbed

from the lumen via SGLT-1

Glucose and galactose exported

through the basolateral

membrane via GLUT-2

Sodium is required for the

transportation of

monosaccharides into both the

cytosol of the enterocyte and into

the basolateral space before

entering the portal circulation

Cl- transported via a Cl- channel

activated by cAMP and VIP

Lumen

Basolateral membrane

SGLT-1

Na+

Na+ Na+

Na+

2Cl–

K+

Glucose

Galactose

K+ K+

Enterocyte

Tight

junction

H2O

H2O

Na-K ATPase

Cholera toxin

cAMP

VIP

GLUT-2

Figure 2

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of local secretomotor events, but afferent nerve fibre terminals, particularly fibres of vagal origin, appear to be the major site of action for many enteroendocrine factors.

The key difference between EECs and other endocrine organs (e.g. pituitary gland, islets of Langerhans) is that the former exist as individual cells scattered throughout the epithelium. This has posed a major hurdle in studying these cells because there is no method for isolating EECs and studying their function.

The key endocrine cells of the stomach have been discussed in relation to acid secretion, but two other hormones from the stomach have major roles. Leptin, the ‘fat controller’ originally isolated from adipocytes, is also secreted by the pepsinogen-secreting chief cells of the stomach (which were not previously thought to have an endocrine nature), and to activate vagal afferent nerves to contribute to satiety. Ghrelin is secreted by a population of endocrine cells. This was originally identified as a growth hormone-releasing (GH-Relin) factor, not an effect believed to be mediated from the stomach. Ghrelin is unusual in being the first gut hormone described that rises in the plasma during fasting and falls upon feeding: it is unclear whether the rising level pre-prandially is a signal to eat, or whether the falling value after a meal constitutes a satiety signal. Ghrelin accelerates gastric emptying, and is being studied in models of gastropare-sis (e.g. diabetes). Reports that altered concentrations of ghrelin after gastric bariatric and bypass surgery contribute to the value of the procedure have been very inconsistent. Ghrelin and leptin may also contribute to gastric mucosal protection.

The duodenum is a major enteroendocrine territory, with immediate sampling of just-emptied gastric contents serving to modulate the secretory and motility patterns controlling digestion and absorption with maximal efficiency. Secretion of lipid-induced CCK by the I-cell subtype of EECs triggers pancreatobiliary secre-tions. CCK also delays the emptying of lipid-rich chyme from the stomach, in addition to limiting further food intake by inducing satiety (Figure 3). These effects of CCK are mediated largely by vagal reflexes. The CCK-1 receptor is expressed by vagal afferent neurones. The cell bodies lie in the nodose ganglion in the neck, and the synthesized receptors are transported down the axono-plasm to peripheral terminals where they are activated by CCK. Recent work suggests that the vagal circuitry responds to sev-eral factors inducing satiety (CCK, leptin, possibly cytokines) and hunger (endocannabinoids, ghrelin), and integrates these positive and negative signals in the short-term control of food intake. CCK has also been implicated in the hypophagic state associated with intestinal inflammation; CCK cell hyperplasia and hypersecretion appear to contribute to the reduction in food intake observed. Free fatty acids rather than intact triglyceride induce secretion of CCK (hence lipase inhibitors such as orlistat may blunt the satiating effects of meals). Secretion of CCK is also impaired in pancreatic insufficiency. The molecular basis of fatty acid sensing by EECs is unclear, but the recent identification of four fatty acid receptors (G protein-coupled receptor (GPR) 40, 41, 43 and 120) has yielded candidate mechanisms and potential pharmacologi-cal targets. The best characterized is GPR40, responsible for fatty acid-induced secretion of insulin by pancreatic β-cells.

Secretin cells respond to acidic pH and fatty acids to induce pancreatic alkaline secretions. Another key cell type, the L- cell, secretes glucagon-like peptides-1 and -2 and peptide YY. Glucagon-like peptide-1 also mediates delayed gastric and intestinal transit,

whereas glucagon-like peptide-2 is implicated in epithelial tro-phism and repair (this underpins its evaluation in the therapy of intestinal failure and short bowel). Glucagon-like peptide also has an ‘incretin’ effect, signalling to the pancreas to induce insulin secretion in the absence (but anticipation) of a rise in blood glu-cose. Peptide YY responds to nutrients, particularly fat, arriving in the terminal ileum; this heralds imminent malabsorption and hence nutrient wastage, and triggers the ‘ileal brake’ mechanism, further delaying gastrointestinal transit.

The other key endocrine cell of the gut is the enterochromaffin cell, whose major product is the amine 5-hydroxytryptamine. About 97% of the 5-hydroxtryptamine in the body is in the gut, and its release regulates motility and secretion throughout the intestine. Increased numbers of enterochromaffin cells and secretion of 5-hydroxtryptamine have been reported in gut infec-tion, but this appears to persist after resolution of infection, and may be a component of the functional gut symptoms frequently observed following enteritic episodes. Increased numbers of enterochromaffin cells have been reported in post-infectious irri-table bowel syndrome. There is little other evidence of disorders of the enterochromaffin system, other than rare tumours.

Gastrointestinal motility

‘Motility’ is the term used to describe the orderly processes that move the luminal contents from the mouth to the anus. The dominant process in the oesophagus and small bowel is peri-stalsis, in which a bolus is propagated by a wave of contrac-tion. Peristalsis is an intrinsic property controlled by the neural plexus, and persists in extrinsically denervated gut (Figure 4).

Response to a fatty meal

In response to a fatty meal, cholecystokinin (CCK) release coordinates responses including regulation of pancreatic exocrine secretion and control of gastrointestinal (GI) motility, in particular gallbladder emptying and gastric emptying; it has now been recognized as an important satiety factor. EEC, enteroendocrine cell

Fatty acids

EEC

CCK

Mucosal

Basolateral

Pancreticexocrine secretion

GI motility Gallbladderemptying

Satiety

Figure 3

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The intrinsic rhythm appears to be generated by specialized neurones called the interstitial cells of Cajal, which govern the activity of local smooth muscle. These neurones express the protein c-kit, and are therefore the likely cell of origin of gastrointestinal stromal tumours which are characterized immunohistochemically by c-kit positivity. Recent support-ing data have suggested that gastrointestinal stromal tumour cells retain some of the electrophysiological properties and ion channels typical of the interstitial cells of Cajal. Data also are accumulating for loss of interstitial cells of Cajal in disorders of gastrointestinal motility, particularly slow transit constipation with acquired megacolon, but also in acute obstruction, Chagasic megacolon and diabetic gastroenteropathy. It is however possible that interstitial cells of Cajal are lost as a secondary consequence of the motility disorder.

Gastrointestinal motility is largely an intrinsic property of the gut, but is subject to external influences. In general, the parasym-pathetic (vagal and sacral) pathways increase motility via post-ganglionic fibres utilizing acetylcholine, substance P and ATP. Sympathetic noradrenergic spinal fibres tend to inhibit motility; inhibitory α2-receptors are expressed on post-ganglionic vagal fibres and reduce cholinergic transmission. Hormones also affect motility. CCK inhibits gastric and small bowel motility, but stim-ulates the colon, and may be responsible for the gastrocolic reflex (in which eating can trigger an urge to defaecate). Thyroid hor-mones are stimulatory. Glucagon and opioids have strong anti-motility effects in the gut. Electrolyte disturbances (particularly K+ and Ca2+) can also have profound effects on neuromuscular function. Congenital or acquired abnormalities of visceral muscle or the enteric nervous system are likely to underlie the pseudo-obstructive syndromes. A wide range of common drugs is also able to influence motility.

Gastric motility: the pattern of motility is quiescent initially (phase I) in the fasting state. After about 40 minutes, activity restarts (phase II), with a gradual increase in contractions that

begin in the stomach and reach a peak of intensity (phase III) lasting about 10 minutes, before returning to phase I quiescence. This phase III pattern starts in the stomach (‘hunger contrac-tions’) and travels along the small bowel over about 90 minutes; it is termed the migrating motor complex. This acts as an ‘intestinal housekeeper’, sweeping out the small bowel to prevent stagna-tion and bacterial contamination. Gastric, biliary and pancreatic secretions are also triggered by the migrating motor complex, which is coincident with a peak in circulating motilin. This hor-mone is mimicked by erythromycin, a prokinetic antibiotic.

Feeding interrupts this pattern. The proximal stomach under-goes tonic relaxation via a vagal reflex, with further phasic relaxations. This allows the intragastric volume to rise without a commensurate increase in pressure. The loss of such ‘adaptive relaxation’ may partly contribute to the early fullness and rapid gastric emptying seen after vagotomy. In the fed state, rhythmical contraction of the antrum at a rate of 3 contractions per minute acts as a mechanical pump to emulsify food and, in coordination with the pylorus, propel food into the duodenum. The pylorus also acts as a sieve and relatively little food of greater than 3 mm in diameter passes through.

Foods rich in lipids markedly slow gastric emptying. They exert an inhibitory effect on the antral pump, stimulate pyloric contractions and maximally relax the proximal stomach. These effects are mainly mediated by CCK acting on CCK-1 receptors on vagal afferent fibres.

The time taken for gastric emptying is highly variable and can be up to 5 hours, depending on the type of nutrient, osmolal-ity and temperature. Meals light in nutrients, and liquids, can be emptied within 1 hour. Attempts to define normality must be interpreted cautiously, but many patients with functional dyspepsia and early satiety lie outside the apparent norms.

Intestinal motility: the small intestine propagates waves at a higher frequency than the antrum (about 12 contractions/minute) although peristalsis is also regulated by intrinsic reflexes

Peristalsis in the small intestine

ACh, acetylcholine;

VIP, vasoactive intestinal peptide;

NO, nitric oxide.

The muscles behind the bolus of food

contract, while the ones in front relax,

which moves the bolus along in the

direction of the arrow. Peristalsis is

controlled by the intrinsic neural plexus

network. Excitatory motor fibres

releasing ACh and substance P cause

contractions, while inhibitory motor

fibres release VIP and NO. Mucosal wall

receptors detect the food bolus and

interact with the excitatory and

inhibitory fibres to either increase or

decrease contraction

+ +

Excitatory motor fibre Inhibitory motor fibre

Contraction Relaxation

ACh

Substance P

VIP

NOMucosal

and wall

receptors

Myenteric

plexus

Figure 4

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to distension (Figure 4). Small intestinal transit to the caecum takes about 90 minutes.

The main function of the colon is water absorption, and movement of the contents slows down. Bacteria are present and the migrating motor complex dissipates at the ileocaecal valve. Reflux of colonic contents into the terminal ileum triggers expul-sive contractions to maintain relative sterility. Colonic transit may take 24–48 hours, and occurs by haustration and mass move-ment. Haustration comprises slow, segmental contractions over several centimetres, and is responsible for the gross appearance of the colon. Haustration mixes the colonic contents to facilitate water absorption.

Mass movement involves episodic muscle contractions over a longer segment of colon and occurs only a few times daily. It resembles peristalsis in that the distal segment of colon relaxes in anticipation, producing a wave that propagates at a rate of

about 1 cm/second to move the colonic contents distally. Their arrival in the sigmoid colon leads to an urge to defaecate, and an increase in amplitude has been noted in some patients with irritable bowel syndrome. ◆

FurThEr rEAdinG

aziz Q, Thompson DG. Brain-gut axis in health and disease.

Gastroenterology 1998; 114: 559–78.

champion Mc, Orr Wc, eds. evolving concepts in gastrointestinal

motility. Oxford: Blackwell science, 1996.

Dockray GJ. Gastrin and gastric epithelial physiology. J Physiol 1999;

15: 315–24.

smout aJMP, akkermans LMa. normal and disturbed motility of the Gi

tract. stroud: Wrightson Biomedical, 1992.

gastrointestinal physiology

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