BASIC SCIENCE

Digestion and absorption water must also be absorbed, leaving insoluble carbohydrates
for excretion. Discrete mechanisms are in place for digestion
and absorption for each nutrient, highlighting the complexity of
Anthony D Jackson the digestive process. Protective measures are in place to guard
John McLaughlin against the absorption of toxins and antigenic material in ingested
food. Neural, hormonal and local inputs converge to provide an
elaborate network of control over the numerous processes that
accompany passage of food through the alimentary canal, signi-
fying how finely and intricately adapted the gastrointestinal tract
is for its function.

Digestive process
Abstract The digestive process begins during mastication (i.e. food is
The gastrointestinal tract exists to support nutrition, digesting and mechanically broken into smaller physical particles) which gen-
­assimilating nutrients including water and salts. Disorders of the gut erates a larger surface area for the digestive enzymes in sub-
readily impair nutritional status, although there is considerable ­functional sequent sections of the gastrointestinal tract. Enzymes are also
reserve. Many macronutrients are structural components of ­animals and present in the oral secretions and mixed with food to carry out
plants, and therefore ingested in complex molecular forms that cannot the preliminary steps in the breakdown of fats (lingual lipase)
be readily absorbed. They must be digested to simpler components in and carbohydrates (salivary amylase).
the gastrointestinal tract before absorption and assimilation can ­occur. Further physical processing and mixing (by triturative antral
For the major complex macronutrients, (fat, carbohydrate, protein), contractions) with the strongly acidic secretions of the stomach
the gut secretes specific enzymes that catalyse the hydrolysis of these lead to the formation of a semi-solid paste (‘chyme’) which is
­nutrients to their basic oligomeric subunits, which are then taken up gradually released, when sufficiently fluid, into the small intes-
by specific transport proteins expressed in the epithelial membrane for tine. Gastric emptying is delayed by duodenal and ileal sensory
optimal transport from the lumen into enterocytes. The digestive proc- ‘braking’ mechanisms in response to nutrient sensing and endo-
ess is progressive, beginning in the oral cavity and continuing during crine reflexes, which are most potently triggered by fat.
passage to the small intestine, the key site of most nutrient absorption. The duodenum serves as a ‘mixing pot’ where chyme meets
The colonic bacterial flora salvages nutrients from otherwise indigestible the pancreatic digestive enzymes, and gastric acidity is neutral-
fibre. Micronutrients (vitamins, minerals), electrolytes and water must be ized by bicarbonate (secreted by pancreatic ductal cells and
absorbed; specific transport mechanisms exist for each. The magnitude duodenal Brunner’s glands) before contact is made with the
of specialized processes that act in conjunction to enable effective diges- more defenceless absorptive surfaces of the jejunum. Profuse
tion and absorption (along with the regulatory inputs that converge to secretion of mucus is also paramount in providing a protective
coordinate these events) demonstrate how finely adapted the gastroin- surface coating. The alkaline pancreatic secretions containing
testinal tract is to its function. the key digestive enzymes are released into the duodenum in
anticipation of the acidic chyme, providing the optimum pH for
Keywords absorption; basic science; carbohydrate; digestion; entero- the enzymatic processes of digestion to operate. Digestion of the
cytes; fat; minerals; nutrient transport; protein; vitamins liquefied food continues during the two-metre journey through
the jejunum, which is also the major site of nutrient absorption.
Extensive folding in the jejunum vastly increases surface area
A typical meal comprises a complex mixture of nutritive sub- to maximize absorption: transverse foldings of the jejunal sub-
stances that the gastrointestinal system must separate and break mucosa (‘plicae circulares’) are carpeted by fields of finger-like
down into its basic molecular subunits to permit systemic absorp- villi, whose epithelial cells express microvilli, multiplying the
tion and assimilation. total absorptive surface available by a factor of >500. Epithelial
This contribution begins with an overview of the entire pro- cells of the villi (enterocytes) absorb the end products of diges-
cess, then focuses upon specific classes of nutrients. tion and express membrane-bound enzymes in their microvilli
(‘brush-border enzymes’) that contribute to the final digestive
process.
Overview of the progress of nutrients through the gut
Stem cells in the intestinal crypts divide to produce epithelial
Carbohydrate, protein and fat are the macronutrients that con- cells that move up and along the lining of the villi over 4–6 days,
stitute the bulk of a meal. Dietary vitamins, mineral ions and displacing older cells further along, eventually causing them to
be shed by apoptosis into the lumen. Once shed, brush-border
enzymes remain active and continue to have a role in ongoing
Anthony D Jackson BSc(Hons)PhD Faculty of Life Sciences, Manchester digestion.
University, Manchester, UK. Conflicts of interest: none declared. Final absorption of nutrients and solutes from the gut lumen
is not a simple diffusive process. More than 350 solute-specific
John McLaughlin FRCP is a Senior Lecturer in Medicine at Manchester channels and transporters have been identified, subdivided
University, Manchester and Honorary Consultant in Gastroenterology at into 46 families of solute carriers. They represent the ­ gateway
Hope Hospital, Salford, UK. He is Clinical Director of the Gastrointestinal to all cells and are crucial to the cellular absorption of all
Physiology service. Conflicts of interest: none declared. ­macronutrients, micronutrients, vitamins and minerals.

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 BASIC SCIENCE

large lipid droplets prevents lipases full access to their substrate

Digestion and absorption of lipids
until emulsification occurs with bile salts. Release of chyme
Dietary fat is an important source of energy and daily consump- into the duodenum is sensed by enteroendocrine cells in the
tion may be 90–100 g, contributing about 30% of energy intake. duodenal epithelium, triggering the release of important hor-
The hydrophobic nature of fat presents the gut with particu- mones that coordinate events leading to lipid breakdown. Two
lar difficulty in digestion and absorption: it can be argued that key examples of duodenal enteroendocrine cells follow. The
much of the anatomical and regulatory sophistication of the gut acidity of chyme stimulates the release of the peptide secre-
is adapted to maximize lipid absorption, a valuable energy store tin from enteroendocrine S-cells. Secretin exerts its effects on
and thermal insulator supporting survival in evolutionary condi- the pancreatic ducts, causing the release of bicarbonate-rich
tions, principally privation. Most fats are ingested as structured secretions that neutralize the duodenal pH. (This is why proton
triglycerides, although a small proportion (∼5%) are composed pump inhibitors are valuable adjuncts in pancreatic replace-
from phospholipids. In health, the gastrointestinal tract absorbs ment therapy because alkaline pancreatic secretions are also
ingested fat with 95% efficiency, the remainder being excreted lost in pancreatic insufficiency, and the endogenous or supple-
in the faeces. Absorbing <95% is categorized as ‘malabsorp- mentary enzymes are poorly active in an acidic microenviron-
tion’ and presents clinically as steatorrhoea in more severe ment.) Lipids in the lumen trigger release of cholecystokinin
­situations. from enteroendocrine I-cells into the bloodstream. Cholecysto-
Triglycerides must be split into free fatty acids and monoglyc- kinin is the major stimulus for pancreatic acinar cells to secrete
erides (Figure 1) to be absorbed. Lingual lipases begin breaking their digestive enzymes via the cholecystokinin-1 receptor. The
down triglycerides during chewing, although very little diges- gallbladder responds to cholecystokinin by contracting, liberat-
tion of bulk lipids occurs until fats are emulsified with bile salts ing bile salts into the lumen. Cholecystokinin contributes to the
in the duodenum. Gastric lipases are secreted in the stomach, potent effect of lipids in delaying gastric emptying to maximize
but their contribution to lipid digestion is ancillary to the enzy- efficient digestion and absorption. Cholecystokinin mediates its
matic events that occur in conjunction with bile salts in the effects via paracrine activation of cholecystokinin-1 receptors on
small intestine. The family of lipases are water-soluble enzymes vagal afferent neurons, rather than acting solely as a classical
and can act only at the surface of fat droplets. The ­formation of hormone.

Breakdown of triglycerides

a
Lipid emulsion
Mixed micelle
BS
TG Triglycerides (TG) in the
duodenum are emulsified with
BS Monoglyceride bile salts (BS) released from the
Lipase gallbladder. Lipase, in concert
+ with co-lipase, liberates free fatty
Co-lipase acids and monoglycerides from
BS Fatty acid
TG, which form mixed micelles
with BS.
BS

Enterocyte
FATP4/CD36
Mixed micelles fuse with the
jejunal epithelium and lipid digestion
Chylomicron products access the cytosol. FATP4
and CD36 are transporters for free fatty
APO acids. TG are resynthesized in the cytosol
and complexed with apolipoproteins
+ (APO) to form chylomicrons, which enter
the lymphatics.
+
Lymphatics

Figure 1

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Pancreatic lipase is the principal enzyme involved in triglyc- Carbohydrate digestion is initiated by salivary amylase secreted
eride digestion, responsible for up to 70% of hydrolysis, though from the parotid and submandibular glands, which begins to
gastric and lingual lipases retain their activity in the small intes- break down starches and glycogens into simpler disaccharides
tine, thereby acting synergistically. Bile salts act as detergents and trisaccharides. Salivary amylase is inactive in the acidic pH
due to their amphipathic structure, breaking up large, hydro- of the stomach. The remaining polysaccharides are hydrolysed
phobic lipid droplets, giving increased exposure to the digestive by pancreatic α-amylase upon entry into the duodenum, yielding
lipases. The cofactor co-lipase is required for pancreatic lipase disaccharides and trisaccharides. Unlike lipids, sugars are freely
to be effective in attacking the lipid–bile salt mixture. This binds soluble in water and emulsification is not required. Sugar absorp-
to the surface of emulsified droplets and stabilizes the interac- tion occurs principally in the jejunum (Figure 2). Disaccharides
tions between pancreatic lipase and lipids, facilitating cleavage. and trisaccharides diffuse freely to the epithelium of jejunal villi
As free fatty acids are released, they complex with available bile but require further digestion by enzymes in the brush-border
salts, forming micelles that are about 2 nm in diameter. Phos- membrane before absorption can proceed. Only monosaccha-
pholipids are broken down by phospholipase-A2, which is also rides in the form of glucose, galactose and fructose are taken up
secreted in the pancreatic fluids. by epithelial cells and they gain entry via two main transporter
The formation of micelles is as important to absorption as proteins. Glucose and galactose enter the cell by the same trans-
digestion. Bile salts have amphipathic qualities and therefore have porter: sodium-glucose transport protein-1. Transport is driven
increased solubility in the aqueous environment of the lumen by the energy of a high extracellular Na+ gradient; two Na+ are
compared to free fatty acids and monoglycerides. To access the transported per molecule of glucose or galactose. The gradient
epithelium of the jejunal mucosa, lipids must pass through the is maintained by Na+/K+-ATPase pumps in the membrane of
still (or unstirred) water layer between villi, which does not mix enterocytes, which pump Na+ back out from the cell. Fructose
with the bulk contents of the lumen. Passage relies on simple has its own, selective carrier protein, GLUT5, which transports
diffusion along concentration gradients. Lipid micelles diffuse fructose without the requirement of the sodium gradient. Mono-
across more readily than free fatty acids because they are more saccharides pass through intestinal enterocytes without further
soluble in the aqueous phase, and fuse with the enterocytes of
the villi upon contact with the cell membrane. Proteins known to
transport fatty acids are expressed apically by jejunal enterocytes
(FATP4, CD36), suggesting that facilitated transport of fatty acids
into the epithelium from the lumen may also occur. From here, Sugar absorption in the jejunum
fatty acids can diffuse (in association with fatty acid-­binding
proteins in the cytoplasm) into the cytoplasm to be resynthe-
sized into triglycerides. Triglycerides are resynthesized from fatty
acids and monoglycerides within the enterocytes. Triglycerides Na+
are ‘packaged’ with apolipoproteins to form chylomicrons and
leave the cell by exocytosis. As with bile, the amphipathic apo-
lipoprotein component solubilizes chylomicrons, but their size SGLT1 GLUT5
prevents them from entering capillaries, hence they enter the sys-
temic circulation via the lymphatics. Lipids with shorter chains
are soluble without apolipoprotein and are exported directly into
the capillaries.
Bile salts are predominantly reabsorbed in the terminal ileum
and returned to the liver (‘enterohepatic recirculation’).
Several disease processes impair absorption of fat; pancreatic Na+
insufficiency and loss of surface area of the gut (short bowel, Na+/K+
ATPase
villus atrophy) are the most common. Faecal fat collection is a K+
widely used method to assess the efficiency of fat absorption, but
has serious flaws. It is increasingly replaced with more specific
and patient-friendly tests (e.g. isotopically labelled triglyceride GLUT2
Glucose
(triolein) breath testing, faecal elastase).
Galactose
Fructose Blood
Digestion and absorption of carbohydrate
Dietary carbohydrates are ingested as simple sugars, such as
monosaccharides (e.g. glucose) and disaccharides (sucrose) and Glucose and galactose are cotransported with Na+ into jejunal
complex polysaccharides (starches, glycogen). The energy intake enterocytes by the Na+/glucose cotransporter-1 (SGLT1). Fructose
from these types of carbohydrates can constitute up to 70% of is transported separately by the fructose transporter (GLUT5).
All three monosaccharides are transported out of the enterocyte
daily intake of energy from all nutrients. Other polysaccharides by the glucose transporter gene-2 (GLUT2).
such as cellulose (the predominant structural component of
plants) cannot be broken down because humans do not possess
the requisite enzymes. Figure 2

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 BASIC SCIENCE

processing; they leave the cell basolaterally to enter the blood absorbed in the jejunum and ileum by passive diffusion across
stream via the GLUT2 transporter (which is a cotransporter for a concentration gradient. The Na+/K+-ATPase pump on the
all three monosaccharides). basolateral membrane of intestinal epithelial cells exports Na+
Complex carbohydrates making up dietary fibre are not into the interstitial fluid and pumps K+ back into the cell in
digested by intestinal enzymes, so pass into the colon intact. exchange. The concentration gradient generated causes K+ to
They are a source of nutrition for colonic bacteria and are broken diffuse back into the interstitial fluid before entering local capil-
down, yielding short-chain fatty acids that are relatively soluble laries with Na+. HCO3− and Cl− released in pancreatic fluids
in water, and are readily absorbed and locally metabolized by are actively reabsorbed, mainly in the jejunum, but secondarily
colonocytes. in the ileum and colon.
About two litres of water may be consumed per day, yet
only approximately 100 ml are lost to the faeces. Ingested
Digestion and absorption of protein
water is added to by about seven litres of water in saliva, gas-
Virtually all ingested protein is absorbed by healthy humans; tric, pancreatic, biliary and intestinal secretions that require
faecally excreted protein is derived from colonic bacteria and reabsorption. The gastrointestinal tract must therefore be
shed epithelial cells, chiefly colonic cells. Proteolytic enzymes highly efficient at taking up water from the intestinal lumen.
are not present in salivary secretions. Inactive proteases (‘pep- Transport of intestinal water is principally driven by osmotic
sinogens’) are secreted in abundance by the stomach chief cells. pressure gradients and is thought to occur mainly by a para-
They are converted to active pepsins by the low pH of the stom- cellular route. Several isoforms of specific water channels
ach, cleaving proteins and polypeptides into amino acids and (aquaporins) are expressed along the length of the gastroin-
smaller peptides. Gastric pepsins become inactive in the neutral testinal tract and could be crucial to the transport of epithelial
pH environment of the small intestine, where pancreatic acinar water, particularly in alleviating osmotic pressure generated
proteases are the key enzymes in proteolysis. These power- by solute absorption. The jejunum is more prominent than the
ful proteolytic enzymes are secreted in the pancreatic juices ileum in water absorption but, in combination, these sites are
as inactive precursor enzymes (e.g. trypsinogen), essentially to ­responsible for the reabsorption of 8.5 litres of water per day.
prevent autodigestion of the pancreas. Trypsin, chymotrypsin, The colon is involved in only a small fraction of total reuptake
elastase and carboxypeptidases represent the fundamental acti- of water. It receives about 1000–1500 ml per day, of which it
vated enzymes in proteolysis. Trypsinogen is activated by the manages to take up 80–90%.
brush-border enzyme enterokinase. Once active, trypsin can Loss of function of the small intestine or colon can lead to
act in an autocatalytic manner to convert trypsinogen to tryp- significant diarrhoea via failure of water absorption, but disease
sin, and is responsible for converting the other proenzymes to states can lead to increased secretion which can exceed absorp-
their active form. In the duodenal and jejunal lumen, protein is tion, most dramatically in cholera and vasoactive intestinal
rapidly converted to small polypeptide chains and single amino polypeptide-secreting tumours via activation of guanyl cyclases.
acids, which are suitable for absorption. For the small polypep- Increased cellular concentrations of cyclic guanosine monophos-
tide chains that remain, a number of brush-border enzymes phate trigger net secretion of water and electrolytes.
are expressed, completing hydrolysis upon their diffusion to
the villus epithelium. Dipeptides, tripeptides and single amino
Minerals and vitamins
acids are cleaved from the polypeptide chains and are readily
absorbed by a large family of transporters. For amino acids, Essential dietary mineral ions include calcium, iron, magnesium
transport into enterocytes is facilitated by electrochemical gra- and copper.
dients involving Na+ and, in some cases, Cl−. Dipeptide and Calcium is absorbed at all sections of the intestine, although
tripeptide transport is driven by a H+ concentration gradient uptake is greater proximally. Entry into epithelial cells is mainly
that is generated by Na+/H+ exchanger expressed on the lumi- via calcium channels driven by electrochemical gradients
nal enterocyte membrane. Only single amino acids can leave (although some transport occurs paracellularly across tight junc-
enterocytes basolaterally to enter the circulation so additional tions). Upon entry into epithelial cells, calcium is bound to a
enzymes are present in the enterocytic cytosol to cleave dipep- cytosolic protein, calbindin, which delivers calcium to the baso-
tides and tripeptides into amino acids. Basolateral exit into the lateral membrane. Calcium is also transported through the cyto-
mucosal capillaries is also via amino acid-specific transport sol in vesicles which are released by exocytosis at the basolateral
proteins. membrane. Vitamin D is crucial to normal absorption of calcium
in the intestine. It upregulates the expression of cellular proteins
that are essential for calcium absorption (e.g. calbindin) by act-
Absorption of electrolytes and water
ing on nuclear receptors in epithelial cells and promoting gene
Virtually all of the electrolytes that are ingested are absorbed expression.
at some point along the gastrointestinal tract, the major sites Iron: in general, iron absorption is <5% of daily intake. Iron
for which are the jejunum, ileum and colon. Regulation of is present in food as Fe2+ (ferrous), Fe3+ (ferric) and in haem (in
electrolyte uptake is complex and is controlled by circulat- protein complexes).
ing hormones, luminal factors and neural inputs. Predomi- Fe2+ is the favoured state for absorption into duodenal epi-
nant absorption of Na+ occurs in the jejunum in cotransport thelial cells (Figure 3). Fe3+ has a greater tendency than Fe2+ to
with sugars (although active absorption occurs additionally form insoluble complexes with other ions in the lumen, hinder-
in the ileum and colon without the prerequisite sugars). K+ is ing its absorption. Ascorbate aids iron absorption by reducing

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 BASIC SCIENCE

Absorption of iron into duodenal epithelial cells

++
Fe2+
+++
Fe3+ ++ ++
Ferroxidase
DMT1 Entry of Fe2+ into duodenal epithelial cells is driven by an
H+ gradient. Fe2+ is oxidized intracellularly to Fe 3+ by the
H+ enzyme ferroxidase and iron-binding protein complexes
+++ with available Fe3+ . IREG1 is responsible for exporting Fe 3+
from the cell and into local capillaries, where it binds to
+++ +++ transferrin to travel in the blood.

IREG1
Iron-binding
protein
Blood +++

DMT1: Divalent metal transporter-1;

Transferrin–Fe 3+ complex IREG1: Iron-regulated transporter-1.

Figure 3

it to the Fe2+ state. Iron reductases in the brush border of the factor, which is secreted by gastric parietal cells and is neces-
duodenum also carry out this role. Fe2+ is taken up into epithe- sary for absorption. Pernicious anaemia, an autoimmune gas-
lial cells by the divalent metal cation transporter DMT1, which tritis with loss of parietal cells, culminates in achlorhydria and
cotransports H+ along with Fe2+(Fe3+ is not transported). Intra- malabsorption of B12. Gastrectomy also disables absorption
cellularly, Fe2+ is converted to Fe3+ by ferroxidase, whereupon
it is bound to iron-binding proteins that aid passage through the
cytosol and, as a result, prevent the formation of insoluble com-
plexes with available anions. Basolateral transport occurs by the Absorption of vitamin-B12
transporter protein IREG1 and Fe3+ enters the circulation chap-
eroned by its plasma carrier protein, transferrin.
In iron deficiency, the expression of iron transport mecha- IF
nisms is appropriately increased in enterocytes, enhancing the TC–B12
efficiency of iron absorption; this also occurs in pregnancy. B12
The defect in hereditary haemochromatosis leads to the same
Blood
enterocyte status, with a now inappropriate overexpression of
iron transporters progressively leading to the overload state. IF–B12
Internal- ?
Conversely, the hepatic antimicrobial peptide hepcidin down- ization
regulates iron transport in the intestine, probably by inhibiting
the function of the exit protein IREG1. This may be appropri-
ate acutely in depriving bacteria of iron, but may contribute
to the iron-deficiency state common in chronic inflammatory
­conditions.
Copper and magnesium: about one-half of the daily intake
of copper and magnesium is absorbed at sites in the small intes-
tine. Comparatively less is known about the cellular mechanisms
underlying epithelial transport, although DMT1 may also play a
role.
Vitamins are readily absorbed at all sites in the small intes-
tine. Fat-soluble vitamins (A, D, E, K) are absorbed along with
the digestion products of lipids in the micellar process. Water- Vitamin-B12 combines with intrinsic factor (IF) in the lumen which
in turn dimerizes. IF–B12 dimers bind to membrane receptors on
soluble vitamins (e.g. B-complex, ascorbic acid, folic acid), are
terminal ileal enterocytes which internalizes, importing the IF–B12
easily absorbed by intestinal epithelia—uptake is via simple complex into the cytosol. It is thought that, after passage through
diffusion, following concentration gradients, although specific the cytosol, extracellular transport is mediated by transport proteins
transporter proteins enhance uptake of most water-soluble vita- and appears in the systemic blood flow bound to transcobalamin-II
(TC).
mins (e.g. thiamine, folic acid).
Absorption of vitamin-B12 is more complex (Figure 4). This
water-soluble vitamin requires the chaperone protein, intrinsic Figure 4

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 BASIC SCIENCE

of B12. Intrinsic factor dimerizes in the intestinal lumen, each resection or disease (e.g. Crohn’s disease). Basolateral exit from
dimer binding two molecules of vitamin-B12. Receptor proteins ileal epithelial cells is largely uncharacterized, though potentially
in the brush-border membrane recognize the intrinsic factor–B12 involves active or facilitated transport by a carrier protein. B12
complex which is then internalized by endocytosis exclusively appears in the blood bound to transcobalamin-II, another chap-
in the terminal ileum. B12 deficiency also follows terminal ileal erone protein. ◆

SURGERY 27:6 236 © 2009 Published by Elsevier Ltd.