442 SECTION V Gastrointestinal Physiology
plasma. This osmolality is maintained throughout the rest of
the small intestine; the osmotically active particles produced
by digestion are removed by absorption, and water moves
passively out of the gut along the osmotic gradient thus gener-
ated. In the colon, Na+ is pumped out and water moves pas-
sively with it, again along the osmotic gradient. Saline
cathartics such as magnesium sulfate are poorly absorbed
salts that retain their osmotic equivalent of water in the intes-
tine, thus increasing intestinal volume and consequently
exerting a laxative effect.
Some K+ is secreted into the intestinal lumen, especially as a
component of mucus. K+ channels are present in the luminal
as well as the basolateral membrane of the enterocytes of the
colon, so K+ is secreted into the colon. In addition, K+ moves
passively down its electrochemical gradient. The accumulation
of K+ in the colon is partially offset by H+–K+ ATPase in the
luminal membrane of cells in the distal colon, with resulting
active transport of K+ into the cells. Nevertheless, loss of ileal
or colonic fluids in chronic diarrhea can lead to severe hypo-
kalemia. When the dietary intake of K+ is high for a prolonged
period, aldosterone secretion is increased and more K+ enters
the colon. This is due in part to the appearance of more Na+–
K+ ATPase pumps in the basolateral membranes of the cells,
with a consequent increase in intracellular K+ and K+ diffu-
sion across the luminal membranes of the cells.
GASTROINTESTINAL REGULATION
The various functions of the gastrointestinal tract, including
secretion, digestion, and absorption (Chapter 27) and motility
(Chapter 28) must be regulated in an integrated way to ensure
efficient assimilation of nutrients after a meal. There are three
main modalities for gastrointestinal regulation that operate in
a complementary fashion to ensure that function is appropri-
ate. First, endocrine regulation is mediated by the release of
hormones by triggers associated with the meal. These hor-
mones travel through the bloodstream to change the activity
of a distant segment of the gastrointestinal tract, an organ
draining into it (eg, the pancreas), or both. Second, some sim-
ilar mediators are not sufficiently stable to persist in the blood-
stream, but instead alter the function of cells in the local area
where they are released, in a paracrine fashion. Finally, the in-
testinal system is endowed with extensive neural connections.
These include connections to the central nervous system (ex-
trinsic innervation), but also the activity of a largely autono-
mous enteric nervous system that comprises both sensory
and secreto-motor neurons. The enteric nervous system inte-
grates central input to the gut, but can also regulate gut
function independently in response to changes in the luminal
environment. In some cases, the same substance can mediate
regulation by endocrine, paracrine, and neurocrine pathways
(eg, cholecystokinin, see below).FIGURE 26–21 Chloride secretion in the small intestine and
colon. Chloride uptake occurs via the sodium/potassium/2 chloride
cotransporter, NKCC1. Chloride exit is via the cystic fibrosis transmem-
brane conductance regulator (CFTR) as well as perhaps via other chlo-
ride channels, not shown.
2K+2CINa+ _Na+K+
Cl−CFTRK+Na+, K+-
ATPase3Na+NKCC1CLINICAL BOX 26–2
Cholera
Cholera is a severe secretory diarrheal disease that often oc-
curs in epidemics associated with natural disasters where
normal sanitary practices break down. Along with other
secretory diarrheal illnesses produced by bacteria and vi-
ruses, cholera causes a significant amount of morbidity and
mortality, particularly among the young and in developing
countries. The cAMP concentration in intestinal epithelial
cells is increased in cholera. The cholera bacillus stays in the
intestinal lumen, but it produces a toxin that binds to GM-1
ganglioside receptors on the apical membrane of intestinal
epithelial cells, and this permits part of the A subunit (A^1
peptide) of the toxin to enter the cell. The A^1 peptide binds
adenosine diphosphate ribose to the α subunit of Gs, inhibit-
ing its GTPase activity (see Chapter 2). Therefore, the consti-
tutively activated G protein produces prolonged stimulation
of adenylyl cyclase and a marked increase in the intracellular
cAMP concentration. In addition to increased Cl– secretion,
the function of the mucosal NHE carrier for Na+ is reduced,
thus reducing NaCl absorption. The resultant increase in
electrolyte and water content of the intestinal contents
causes the diarrhea. However, Na+–K+ ATPase and the Na+/
glucose cotransporter are unaffected, so coupled reabsorp-
tion of glucose and Na+ bypasses the defect. This is the phys-
iologic basis for the treatment of Na+ and water loss in diar-
rhea by oral administration of solutions containing NaCl and
glucose. Cereals containing carbohydrates are also useful in
the treatment of diarrhea.