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0009 Electrogenic Na

transfer The Na

ion moves into

the colonocyte across its apical membrane through

channels (that can be blocked by amiloride) under the

influence of a favorable electrochemical gradient

as the inside of the colonocyte is negative to the

lumen and has a low Na

concentration. It is then

pumped out of the cell across the basolateral mem-

brane by the agency of Na

-ATPase (the sodium

pump or Na

-activated adenosine triphospha-

tase), creating an electric current (rheogenic transfer)

and a positive potential difference at the serosa. The

ATPase, and thus current and Na

transfer, can be

inhibited by the cardiac glycoside, ouabain. Minera-

locorticoids, especially aldosterone, enhance the

entry of Na

across the apical membrane by the

electrogenic route and thus also increase the absorp-

tion of water.

0010 Neutral NaCl transfer This may represent coupled

 K

2Cl



cotransport, coupled Na

Cl



cotransport, or the coupling of dual ion exchanges

such as Na

for H

and Cl



for HCO



or OH



0011 Chloride ion absorption mechanisms Chloride ions

can be absorbed passively or actively.

0012 Passive absorption This is via an electrical potential

difference (pd)-dependent process as the serosal side

of the intestine is positive with respect to the lumen.

0013 Active absorption This occurs either as neutral

NaCl absorption (Na

-dependent process) or as

neutral Cl



HCO



exchange (Na

-independent

process). It has been estimated that in the human

colon in vivo the Cl



HCO



exchange accounts for

about 25% of overall Cl



absorption, the other 75%

being via the favorable electrical pd mechanism via

the paracellular route.

0014 Potassium ion absorption mechanisms Active K

absorption occurs in the distal colon of rat and

rabbit and has been shown to be an electroneutral

process which operates independently of Na

and



. In rabbit, this K

absorptive process seems to

reflect a K

–H

exchange which can be unmasked

by the presence of ouabain or the removal of Na

Recent studies in rat distal colon have identified

-ATPase as the mediator of this apical K

–H

exchange, although it is unclear whether a similar

mechanism operates in human colonocytes. There is

emerging evidence that K

movement across the

basolateral membrane reflects K

recycling via K

channels, which are beginning to be characterized in

biophysical and molecular terms. (See Potassium:

Physiology.)

0015Calcium and magnesium absorption While consid-

erable amounts of these ions are present in the lumen

of the colon, most are unavailable for absorption as

they are bound to insoluble macromolecules. More-

over, the total removal of the human colon (colect-

omy) does not upset the balance for these ions. There

is evidence from rat experiments that the colon has a

2þ

active transport system sensitive to enhance-

ment by vitamin D and to low calcium intake. In the

case of magnesium, other experiments with rats have

indicated that the ion is absorbed passively, depend-

ent on the electrochemical gradient and the solvent

drag of fluid absorption. (See Cholecalciferol: Physi-

ology; Magnesium.)

Secretion

0016The colon secretes the anions Cl



and HCO



and the

cations K

and H

0017Bicarbonate secretion In the human, approximately

70 mmol HCO



leaves the ileum to enter the colon

every day and although the organ secretes bicarbon-

ate, only a few mmol appear in the feces. This is

because the secreted HCO



is titrated by the H

ions manufactured by the bacterial population of

the colon. In diarrheal states, when there is an en-

hanced secretion of bicarbonate, stools can contain

an increased amount of bicarbonate.

0018The mechanisms and control of bicarbonate move-

ments are complex. Other ions move in association

with, or in exchange for, bicarbonate. Bicarbonate

can come from the plasma, passing between and

through cells, and can also come from the intracellu-

lar hydration of CO

, Hydrogen ions, produced from

cellular metabolism, can be secreted into the lumen

to influence the production and neutralization of

bicarbonate ions. Net bicarbonate secretion is

accomplished by a combination of bicarbonate and

hydrogen ion transport as the blood, cell cytoplasm,

and luminal contents contain bicarbonate and CO

A primary source of HCO



and H

ions appears to be

from the catalyzed hydrolysis of CO

,asNa

and Cl



absorption is modulated by ambient CO

. The colo-

nocytes are rich in carbonic anhydrase which can

supply bicarbonate and H

ions at high catalyzed

rates. The enzyme may also be directly involved in

ion transfer. Inhibition of carbonic anhydrase reduces

colonic absorption.

0019Chloride ion secretion The colon actively secret-

es Cl



ions. The intracellular Na

and K

of the

colonocyte are regulated by the basolateral Na

–K

transport ATPase pumping out Na

in exchange for

. The K

can diffuse out across the membrane by a

channel. This mechanism keeps the intracellular

1526 COLON/Structure and Function

low and the K

high, and produces a negative

intracellular pd. The uptake of Cl



ions is by the

coupled Na

–K

2Cl



cotransport carrier in the

basolateral membrane, and is sensitive to loop diuret-

ics such as furosemide (frusemide) and bumetanide.

Chloride ions leave the cell via apical Cl



channels,

under the influence of their intracellular–extracellular

concentration gradient and the negative intracellular

pd. These Cl



channels are normally closed and are

activated to open by increases in the intracellular

calcium ion (Ca

2þ

) and/or cyclic adenosine mono-

phosphate (cAMP) levels brought about by a variety

of neurotransmitters, secretagogues, hormones, and

paracrine agents. Because the efflux of the Cl



ions

depolarizes the apical membrane, the movement of



would gradually cease. To maintain the driving

force for the Cl



exit, an increase in the K

-conduct-

ance of the basolateral membrane occurs shortly

(20 s) after the increase in apical membrane Cl



conductance. The exit of K

ions across the basolat-

eral membrane induces a hyperpolarization and,

because of electrical coupling between the basolat-

eral and apical membranes, the hyperpolarization

maintains the pd across the apical membrane. Thus

the stimulation of Cl



secretion in colonocytes (as

in many other Cl



-secreting cells) requires the

coordination of four independent systems, the

apical Cl



channels, the basolateral Na

–K

2Cl



cotransporter, K

channels, and Na

-ATPase.

Observations in animals have indicated that secreting

cells are located predominantly in the crypts, al-

though surface colonocytes are also capable of secret-

ing Cl



ions.

0020 Potassium ion secretion Although it is known that

the colon absorbs and secretes K

, the cellular sites

have not yet been defined. Surface cells of rabbit

colon absorb and secrete K

, but it is not known

whether such processes are also found in the cells of

the crypts. In rats and rabbits fed high-potassium

diets or given aldosterone, K

secretion is accom-

plished first by the active uptake of K

at the colono-

cyte’s basolateral membrane by ouabain-sensitive

-K

–ATPase and Na

-K

–2Cl



cotransport. Its

exit across the apical membrane is then by barium-

sensitive K

channels that appear to be under the

control of cAMP and Ca

2þ

, since raising their

cAMP and or Ca

2þ

levels in the colonocytes increases

the secretion of K

. Adrenergic agonists also in-

crease the secretion of K

, which in rabbit colon is

mediated by b

-receptors. The mechanism involves

both increases in the basolateral pump activity and

in the conductance of the apical membrane to K

.In

diarrhea associated with colonic secretion (e.g.,

colitis) K

loss in the stools can be appreciable.

0021Short-chain fatty acids (SCFAs) Surprisingly, the

major anion of the colonic contents comes from

SCFAs (acetate, butyrate, propionate, etc.). These

originate predominantly from the bacterial metabol-

ism of carbohydrate passing into the colon from the

ileum. In the human colon, the daily production of

SCFAs is estimated to be greater than 300 mmol,

while the fecal excretion is only 10 mmol. This indi-

cates that 97% of the SCFAs are removed by the

colon. Their absorption is rapid and they enhance

the absorption of Na

.(See Essential Fatty Acids.)

0022The SCFAs are weak acids that can exist in solution

as two species, the undissociated molecule (acid form

HA) and the dissociated anion (A



). The balance of the

species depends on the environmental pH and the pK

values of the acid under question. In the colon, the

luminal pH is normally approximately 7 and the

SCFA pK approximately 4.8, so that the predominant

species is the ionized or anionic form. The pathways of

absorption of SCFAs across the colon are complex

because several mechanisms can operate. These in-

clude the following: (1) the generation of luminal

, either from bacteria or from colonocytes, to

provide H

ions which combine with the anionic

form of SCFA (A



) in an acid microclimate, creating

the undissocated acid form (HA) which could diffuse

across the apical membrane; (2) luminal H

ions from

the colonocytes exchange with Na

, forming the HA;

(3) the ionic form, A



, could diffuse across the tight

junctions between the cells; (4) anion exchange mech-

anisms (e.g., HCO



–A



) allow the movement of the

anionic form across the apical membrane.

0023In the human colon it has been proposed that

approximately 40% of SCFA absorption can be ac-

counted for by the Na

–H

exchange. As SCFA ab-

sorption is also associated with a rise in luminal

HCO



, the SCFA–HCO



exchange mechanism is

suggested to occur. In theory, changes in luminal pH

should affect SCFA movements and alterations in

acid–base balance should affect their absorption.

However, the mucus and unstirred layers at the apical

pole of the colonocytes act as a buffer and maintain

the surface acid microclimate in the face of consider-

able changes in the luminal pH.

0024SCFAs increase the absorption of NaCl partly

through the fatty acids acting as metabolic substrates

for the colonocytes and partly as a result of the SCFAs

directly influencing the transport mechanisms of the

apical membranes. Paradoxical results have also been

found in animal colons used in vitro, such as SCFAs

inhibiting Cl



absorption and in other cases actual

secretion of SCFAs by colonocytes. Other studies

have shown that SCFAs also cause electrogenic secre-

tion of Cl



by colonocytes which can be recorded

both in vivo and in vitro. As the SCFAs have been

COLON/Structure and Function 1527

claimed to be a fundamentally important metabolic

fuel for the colonocytes, their reduction or near ab-

sence in human conditions such as famine (starvation)

and malnourishment (marasmus and kwashiorkor)

has been suggested as a major cause of colonic

dysfunction and – its consequence – diarrhea. Other

studies have shown that colonic and rectal secretory

function in starved or malnourished rats can be en-

hanced, which would again predispose to diarrhea.

There are many unanswered questions and unsolved

problems in relation to SCFA and colonic ion and

fluid transfer. (See Kwashiorkor; Marasmus.)

Bacterial Fermentation

0025 Composition of colonic microflora The bacteria of

the human gastrointestinal tract form a complex eco-

system; over 400 species have been identified in the

feces of a single subject. In healthy humans, the upper

gastrointestinal tract is sparsely populated by bacteria

as most are killed by gastric acidity (except acid-

loving forms such as Streptococcus, Staphylococcus,

and Lactobacillus) and the passage of intestinal con-

tents is rapid. The bacterial flora of the small intestine

is between 10

and 10

colony-forming units (CFU)

per ml of content (mainly Gram-positive anaerobes);

this increases to 10

–10

CFU ml

1

in the distal ileum

and Gram-negative bacteria now become dominant.

After the ileocecal sphincter, the bacterial concentra-

tions increase enormously, reaching between 10

and

CFU ml

1

of fecal material, which can amount

to approximately 1.5 kg wet weight of bacteria.

Viable bacteria are said to make up one-third of the

fecal dry weight. The major species are Bacteroides,

Clostridium, Eubacterium, Peptococcus, Bifidobac-

terium, Streptococcus and Fusobacterium.(See Clos-

tridium: Occurrence of Clostridium perfringens;

Occurrence of Clostridium botulinum; Microflora

of the Intestine: Role and Effects; Staphylococcus:

Properties and Occurrence.)

0026 Metabolic capacity of colonic bacteria The meta-

bolic capacity of the colonic bacteria is diverse.

Luminal contents are potential substrates for bacterial

enzymic transformation by hydrolysis (examples are

estradiol glucuronide, cyclamate), dehydroxylation

(bile acids, amino acids), or reduction (unsaturated

fatty acids, food dyes, benzaldehydes). The bacteria

can also synthesize vitamins such as vitamin K, biotin,

and vitamin B

. Antibiotic treatment of humans is

known to lower the plasma levels of the first two,

suggesting that the bacteria may play a role in supply-

ing some of the daily requirements for these vitamins.

(See Biotin: Physiology; Cobalamins: Physiology.)

0027 Carbohydrates are fermented by the bacterial

enzymes to SCFA. The major carbohydrate sources

are plant cell wall polysaccharides (cellulose, pectins,

hemicellulose), starch, intestinal mucus, and mono-

and disaccharides. Depending on the amount of fiber

in the diet, between 20 and 70 g of carbohydrate is

estimated to be fermented per day in the human

colon. The SCFAs produced by the fermentation pro-

cess are absorbed by the colonocytes, for which they

represent an important metabolic source and act as a

promoter of NaCl and thus fluid absorption. (See

Carbohydrates: Digestion, Absorption, and Metabol-

ism; Dietary Fiber: Physiological Effects.)

0028Another important feature of the metabolic cap-

acity of the colonic bacteria is the potential for

creating candidate carcinogens and mutagens (e.g.,

nitrosamines) that may play a role in carcinogenesis,

especially of the colon. In the USA this is the most

frequently diagnosed cancer of internal organs. There

is some evidence that the western diet (high in beef,

fat, and protein, and low in fiber) is a possible cause

of the much higher incidence of colon cancer than is

found among Africans, Asians, and South Americans.

(SeeCancer: Diet inCancerPrevention; Nitrosamines.)

0029Migrants show a cancer incidence that approxi-

mates the prevailing rate of their residence rather

than their birthplace. There is, however, another

side to the bacterial coin of the colon – the inactiva-

tion of carcinogenic compounds by bacteria such as

Escherichia coli, Lactobacillus spp., and Bacteroides

spp.

0030Urea, ammonia, and nitrogen Some 6–9 g of urea

(approximately 20% of the daily urea synthesis) is

broken down in the human intestine, mainly by the

urease of the colonic bacteria. As only 0.4 g of this

urea enters the colon from the ileum, and there is

no urea and hardly any of its breakdown metabolite

ammonia in the feces, most of the urea apparently has

to enter the colon by another pathway in order to be

metabolized. Unfortunately, the urea permeability of

the cleansed human colon appears to be very low and

excludes its transmucosal diffusion as a major route.

There is evidence that the low permeability is caused

by removal of the colon contents which normally

increase the permeability of the mucosa to urea;

thus the entry path of urea into the untouched colon

is probably transmucosal. The catabolism of the urea

load produces 200–300 mmol of ammonia and 100–

150 mmol of bicarbonate per day. Practically all the

ammonia (99%) is absorbed across the mucosa by

nonionic diffusion for at colonic pH (6–7) ammonia

is largely present as the ammonium ion (NH

). The

absorbed ammonium is transported by the portal

system to the liver, where it enters the nitrogen pool

and is synthesized to urea or amino acids. This me-

tabolism of urea is of little importance to human

1528 COLON/Structure and Function

nutrition but the enterohepatic circulation of ammo-

nia is important in the genesis of hepatic encephal-

opathy. In hepatic disease, the liver can fail to

detoxify the ammonia and it then enters the general

circulation to produce neuropsychiatric disturbances

and even coma due to its cerebrotoxic action on the

brain. (See Liver: Nutritional Management of Liver

and Biliary Disorders.)

0031 The origin of ammonia in the large intestine is

mainly from the breakdown of urea, as described

above, but it can also be produced by the bacteria

from nonurea sources such as amine and amide nitro-

gen of proteins, peptides, and amino acids and from

plasma glutamine. The colonic bacteria not only pro-

duce ammonia but can also utilize it as a nitrogen

source for their own synthesis of amino acids and

proteins. The oral administration of poorly digested

carbohydrates is known to increase the fecal loss of

nitrogen. The probable explanation for this is that the

nondigestible carbohydrates are metabolized by the

bacteria in the colon as a preferential energy source

and stimulate the production of new bacteria which

are then lost in the feces.

0032 Effect of diet on microflora While there have been

numerous studies both in animals and in humans on

the effects of diet on the balance of the colonic micro-

flora, the data are conflicting with regard to the

ability of the diet to alter specific components of the

adult bacterial population. For example, different

studies on individuals fed on omnivorous and then

herbivorous diets have reported no change, small

increases, or decreases in fecal counts of Bacteroides.

Subjects in the UK and the USA eating the western

diet had more Bacteroides and fewer enterococci and

other aerobics than subjects eating a vegetarian diet in

Uganda, India, and Japan. Overall, it appears that

eating a meat-poor, high-carbohydrate diet increases

the fecal counts of aerobic bacteria, and decreases a

number of anaerobic bacteria. (See Vegetarian Diets.)

0033 Effect of dietary intake on colon contents Since the

production of colonic gas (see below) and SCFA is

so dependent upon the bacterial fermentation of

unabsorbed carbohydrate, much attention has been

paid to the proportion of dietary carbohydrate that

remains undigested, enters the large intestine and is

then broken down and ‘salvaged.’ Starch, rather than

dietary fiber, is the major substrate. In healthy adults

it is estimated that usually less than 5% of ingested

starch is unabsorbed and enters the colon, although

this may be increased to 12% by food processing.

0034 Colon gas production The major components of

intestinal gas are nitrogen, oxygen, carbon dioxide,

hydrogen, and methane. Gases such as hydrogen sul-

fide, volatile amines, organic acids, mercaptans, and

indoles, collectively amount to less than 1% of the

total but as they account for the characteristic un-

pleasant smell of the flatus they are socially import-

ant. The colon is the only source for the production of

hydrogen, which is used by the bacteria, expelled in

the flatus or absorbed and excreted in the breath.

Dietary substrates are the major source for its pro-

duction as it is low in the fasting subject. Fermentable

carbohydrates such as raffinose and stachyose (oligo-

saccharides found in beans), lactulose, and lactose (in

subjects with hypolactasia) all increase the produc-

tion of hydrogen. Measures of breath hydrogen can

be used as an index of its colonic production and also

as an indication of when food reaches the colon.

Colonic Function and Diarrhea

0035It is clear from the various accounts of colonic func-

tion that if its absorptive function is impaired or its

secretory activity enhanced or both occur, then diar-

rhea results. A large number of factors can alter the

basic net absorptive ‘tone’ of the colon to a net secre-

tory one and thus induce diarrhea. Examples include

bacterial toxins (cholera, E. coli STa (heat-stable

enterotoxin) and LT (heat-labile enterotoxin)),

mediators of inflammatory processes (eicosanoids,

histamine, kinins, substance P), neurotransmitters

(acetylcholine, vasoactive intestinal peptide (VIP),

serotonin), hormones (neurotensin, glucagon, chole-

cystokinin) and specific endogenous luminal contents

such as bile acids. Recently, studies on rats and mice

to elucidate the enigma of the terminal diarrhea

suffered by human victims of famine and severe

malnutrition have shown that starvation induces

hypersecretory responses of the enterocytes and colo-

nocytes to neurotransmitters and agents that activate

secretion. The mechanism of the hypersecretion is not

yet understood but one locus is probably at the apical

membrane after the release of the second messengers

that activate the Cl



secretion.

See also: Biotin: Physiology; Cancer: Diet in Cancer

Prevention; Carbohydrates: Digestion, Absorption, and

Metabolism; Cholecalciferol: Physiology; Clostridium:

Occurrence of Clostridium perfringens; Occurrence of

Clostridium botulinum; Cobalamins: Physiology; Dietary

Fiber: Physiological Effects; Essential Fatty Acids;

Kwashiorkor; Marasmus; Microflora of the Intestine:

Role and Effects; Sodium: Physiology; Staphylococcus:

Properties and Occurrence; Vegetarian Diets

Further Reading

Binder HJ and Sandle GI (1994) Electrolyte absorption and

secretion in the mammalian colon. In: Johnson LR (ed.)

COLON/Structure and Function 1529

Physiology of the Gastrointestinal Tract, 3rd edn. pp.

2133–2171. New York: Raven Press.

Goldin BR, Lichtenstein AH and Gorbach SL (1988)

The roles of the intestinal flora. In: Shils ME and

Young VR (eds) Modern Nutrition in Health and

Disease, pp. 500–515. Philadelphia: Lea and Febiger.

Kasper H and Goebell H (eds) (1982) Colon and Nutrition.

Falk symposium no. 32. Lancaster: MTP Press.

Lebenthal E and Duffey ME (eds) (1990) Textbook of

Secretory Diarrhea. New York: Raven Press.

Lomax RB, Warhurst G and Sandle GI (1996) Characteris-

tics of two basolateral potassium channel populations in

human colonic crypts. Gut 38: 243–247.

McBurney MI (1991) Passage of starch into colons of

humans: quantitation and implications. Canadian Jour-

nal of Physiology and Pharmacology 69: 130–136.

Roediger WEW (1990) The starved colon – diminished

mucosal nutrition, diminished absorption, and colitis.

Diseases of the Colon and Rectum 33: 858–862.

Sandle GI, McNicholas CM and Lomax RB (1994) Potas-

sium channels in colonic crypts. Lancet 343: 23–25.

Wrong OM, Edmonds CJ and Chadwick VS (1981) The

Large Intestine – Its Role in Mammalian Nutrition and

Homeostasis. Lancaster: MTP Press.

Diseases and Disorders

D N Moskovitz and Y-I Kim, University of Toronto,

Toronto, Ontario, Canada

Diet and Nutrition in Inflammatory Bowel

Disease

0001 The term ‘inflammatory bowel disease’ (IBD) refers

to primarily two disorders, ulcerative colitis (UC),

and Crohn’s disease (CD). Both diseases are chronic,

relapsing disorders of unknown etiology. CD and

UC, while different disease entities, share certain de-

mographic, epidemiologic, and therapeutic features.

Crohn’s Disease

0002 CD is a chronic inflammatory disorder that can affect

the small intestine and/or large intestine. It occurs

throughout the world, with a prevalence of 10–100

cases per 100 000 people. The disorder occurs most

frequently among people of European origin, is three

to eight times more common among Jews than among

non-Jews, and is more common among whites than

nonwhites. Although the disorder can begin at

any age, its onset most often occurs between 15 and

30 years of age. There appears to be a familial

aggregation of patients with CD such that 20–30%

of patients with CD have a family history of IBD.

0003Clinical presentation Diarrhea, abdominal pain,

weight loss, and fever are the typical clinical mani-

festations for most patients with CD (Table 1).

Diarrhea may have multiple causes, including exces-

sive fluid secretion and impaired fluid absorption by

the inflamed small or large bowel, bile salt mal-

absorption due to an inflamed or resected terminal

ileum, and steatorrhea related to extensive ileal dis-

ease or ileal resection with loss of bile salts. Bacterial

overgrowth from small bowel strictures, enterocolo-

nic fistulae, and extensive jejunal disease may also

lead to steatorrhea. Crampy abdominal pain is a

common manifestation of CD. The transmural nature

of the inflammatory process leads to fibrotic stric-

tures that often lead to repeated episodes of the

small bowel or, less commonly, colonic obstruction.

Gross bleeding is much less frequent than in ulcera-

tive colitis (except for some patients with Crohn’s

colitis). Transmural inflammation is also associated

with the development of sinus tracts that can lead to

serosal penetration and bowel-wall perforation. This

complication may be associated with an acute presen-

tation of localized peritonitis with fever, abdominal

pain, and tenderness, and often a palpable mass on

physical examination. Penetration of the bowel wall

often presents not as an acute abdomen but as an

indolent process related to fistulization. The actual

clinical manifestation of the fistula depends on the

area of involvement adjacent to the diseased bowel

segment. Symptoms and signs related to perianal

disease occur in up to one-third of patients with CD.

These include perianal pain and drainage from large

skin tags, anal fissures, perirectal abscesses, and ano-

rectal fistulae. Weight loss and fever are the primary

systemic symptoms in CD. There are many extra-

intestinal manifestations of CD (Table 2).

0004Pathology Inflammation, which may or may not be

accompanied by noncaseating granulomas, extends

through all layers of the gut wall. The inflammatory

tbl0001Table 1 Clinical differences between CD and UC

Symptom CD UC

Diarrhea þþþ

Abdominal pain þþ þ

Weight loss þþ 

Fever þþ

Fistula þ

Stricture þ

Bleeding þþþ

1530 COLON/Diseases and Disorders

process is often discontinuous, with normal bowel

separating portions of diseased bowel. The key patho-

logical feature of CD is an inflammatory process that

extends through all layers of the bowel wall. Micro-

scopic examination reveals (1) hyperplasia of peri-

lymphatic histiocytes, (2) diffuse granulomatous

infiltration, (3) discrete noncaseating granulomas in

the submucosa and lamina propria, (4) edema and

lymphatic dilation of all layers of the gut, and (5)

monocytic infiltration within lymph nodules and

Peyer’s patches on the serosal surface of the bowel.

Patients with CD can be divided into those with small

bowel disease alone (30%), those with both small

and large bowel involvement (50%), and those with

disease involving only the colon (20%). When CD

involves the small bowel, 80% of the time, the ter-

minal ileum is involved. When the colon is involved in

CD (Crohn’s colitis), all segments of the colon can be

affected. Although absence of rectal disease is more

characteristic of CD than of ulcerative colitis, the

rectum is involved in half those cases of CD in

which colonic disease exists.

0005 Etiology The etiological agent responsible for IBD

has not yet been determined. One hypothesis explain-

ing the developing of CD begins when the gastro-

intestinal immune system becomes exposed to a

mucosal antigen, perhaps even an antigen normally

present within the lumen. On this occasion, the

antigen does not evoke the typical antigen-specific

suppressor T-cell activity, mucosal unresponsiveness.

Rather, because of an antigen-specific immunoregu-

latory defect, it evokes helper T-cell activity and sets

in play an ongoing immune response. This immune

response as an epiphenomenon leads eventually to the

development of self-antigens and the appearance of

autoantibodies. Subsequently, in an attempt to down-

regulate the antigen-specific response, antigen-non-

specific suppressor T-cells appear. Initially, these

antigen-nonspecific suppressor T-cells may prevent

disease progression; however, they are gradually de-

pleted, leaving the unregulated antigen-specific helper

T-cell activity to predominate. This unregulated anti-

gen-specific immune response leads to the production

of lymphokines, which stimulate migration of inflam-

matory and cytolytic cells to the region. Through this

process, the microscopic and gross morphological

changes of IBD are manifest.

0006Treatment The treatment of IBD has evolved over

time (Table 3). Historically, therapeutic approaches

were based on current beliefs of the disease etiology.

The treatment of inflammatory bowel disease during

the early 1900s included vaccination, dairy diets,

astringents, antiseptics, opium, silver nitrate, and

rectal instillations of boracic acid. Early treatment

often consisted of rectal insufflation of hydrogen per-

oxide, irradiation of the right lower quadrant of the

abdomen, liver extract, and injections of peptides. In

the early 1900s, food was implicated in the cause of

inflammatory bowel disease. As a result, dietary pro-

grams emerged as treatments. During the 1930–50s,

clinical observations led to the use of psychotherapy

and psychoanalysis. While such early treatment was a

reflection of a lack of understanding of disease eti-

ology, as theories of the pathogenesis of IBD evolved,

so did the therapeutic modalities.

0007Medications have remained the mainstay of treat-

ment. It was not until the 1940–50s that sulfon-

amides began to be utilized. Sulfasalazine, the first

sulfonamide, consists of a 5-aminosalicylic acid

(5-ASA) attached to sulfapyridine (an antibiotic). It

was soon discovered that the active therapeutic

moiety was the 5-ASA component. As a result, the

5-ASA group of drugs consisting of asacol, pentasa,

and mesalamine was created, each drug differing in

their type and place of delivery to the gastrointestinal

tbl0002 Table 2 Extraintestinal manifestations of IBD

CD UC

Conjunctivitis þþþ þ

Iritis, uveitis, episcleritis þþþ þ

Ankylosing spondylitis þ þþþ

Arthritis þþþ þ

Erythema nodosum þþþ þ

Pyoderma gangrenosum þ þþþ

Aphthous ulcers of the mouth þþþ þ

Cancer þ þþþ

Toxic megacolon þ þþþ

Fissure, fistula þþþ þ

Pericholangitis þþ

Primary sclerosing cholangitis þ þþþ

Gallstones þþþ 

Bile duct carcinoma þþ

Chronic active hepatitis þþ

Amyloidosis þ

Nephrolithiasis þþþ 

tbl0003Table 3 Medications used in the management of IBD

Medication CD UC

5-ASA R R

Asacol, pentasa, mesalamine, osalazine M M

Antibiotics

Metronidazole, ciprofloxacin R

Steroids

Prednisone, budesonide R R

Immunomodulators R R

Azathioprine, 6-mp, cyclosporine, infliximib M M

M, used for maintenance; R, induces remission.

COLON/Diseases and Disorders 1531

tract. The 1970–80s saw the emergence of antibiotics

in the treatment of IBD. Studies have shown that

metronidazole is effective in both inducing and main-

taining remission in patients with IBD. Moreover, the

use of ciprofloxacin has proven effective in inducing

and maintaining remission in patients with CD. The

discovery of adrenocorticotropic hormone and, sub-

sequently, the glucocorticoids cortisone and prednis-

one in the 1950s provided a great impact on the

treatment of IBD. As a scientific approach to the

study of inflammatory bowel disease emerges, so do

therapeutic interventions targeted at changes in the

intestinal tract. As the study of the immune system

evolved in the late 1800s, new techniques for the

suppression of the immune response began to be de-

veloped. In the mid-1960s, 6-mercaptopurine, an im-

munosuppressant, was first utilized in the treatment

of IBD. Decades later, the use of immunosuppressants

cyclosporine and methotrexate became more preva-

lent.

0008 Nutritional issues Malnutrition is common in pa-

tients with CD. It has been reported that up to 75%

of hospitalized patients with CD are malnourished or

may present with weight loss, low albumin, anemia,

negative nitrogen balance, or vitamin D deficiency.

Even in the absence of active disease, 20% of patients

with CD were observed to be more than 10% below

the desirable body weight. The mechanisms contrib-

uting to chronic malnutrition in IBD are multifactor-

ial and include decreased oral intake, increased

gastrointestinal (GI) losses, malabsorption, increased

nutritional requirements, and drug–nutrient inter-

actions. The nutritional problems of patients with

IBD can be divided into those that concern macro-

nutrients and those that concern micronutrients.

0009 Anemia is a common finding in IBD, and it may be

related to iron, folate, or vitamin B

deficiency. Iron

deficiency resulting from blood loss is seen in about

80% of patients with UC and in about 40% of pa-

tients with CD, resulting from poor intake, blood loss

from the GI tract, and malabsorption. Macrocytic

anemia caused by vitamin B

malabsorption results

from involvement of the distal ileum in patients with

CD or from folate malabsorption and altered metab-

olism caused by drug–nutrient interactions and de-

creased intake of fresh vegetables in both CD and UC.

Although rare, deficiency of water-soluble vitamins

other than vitamin B

and folate has been reported in

patients with IBD, resulting in scurvy (vitamin C),

Wernicke encephalopathy (thiamin), photophobia

with dermatological changes (riboflavin), and pel-

lagra (niacin). Fat-soluble vitamin deficiency results

from malabsorption that may occur because of exten-

sive mucosal inflammation or bacterial overgrowth.

Vitamin K may be deficient in patients with malab-

sorption of dietary vitamin K and due to a lack of

synthesis by gut bacteria in those who have received

antibiotics. Zinc deficiency has been reported in

about 40% of patients with CD and is particularly

prevalent in patients with severe diarrhea or enteric

fistulas. Magnesium malabsorption is relatively

common in patients with IBD, especially in patients

with extensive small-bowel disease, in those with

magnesuria induced by corticosteroids, and in others

who have binding of magnesium by malabsorbed fat.

Metabolic bone disease in patients with IBD is well

recognized, with prevalence estimates of bone disease

ranging from 5 to 78%. Comparisons between pa-

tients with CD and UC reveal that osteoporosis may

be more prevalent in CD. Thus, risk factors for devel-

opment of osteoporosis include IBD, especially CD,

and treatment with steroids (Table 4).

0010Nutritional management Nutritional support has

been a focus of considerable interest in the manage-

ment of patients with IBD. A dietitian should be

consulted to prescribe suitable protein and energy

intakes and to modify the diet to account for food

intolerances or allergies.

0011A proper diet must correct calorie and micro-

nutrient deficits caused by self-imposed or iatrogenic

dietary restrictions. One must meet dietary goals that

are adequate for the nutritional needs of the patient.

Lactase deficiency is reported to occur in 5–15% of

whites of North European descent. In one series of

CD patients, 34% failed to absorb physiological

doses of lactose. In most patients, elimination of diet-

ary lactose decreases abdominal cramps and diarrhea,

but objective proof of lactase deficiency should be

obtained. Prolonged adherence to a milk free diet

may contribute to negative calcium balance. Most

patients with lactose malabsorption will require

only diminution of milk or icecream intake.

0012While food intolerance has been shown in patients

with IBD, it is not a universal problem. There is a

significant correlation between incidence of CD and

dietary changes. However, there is no role for elimin-

ation diets in the global management of IBD. Theor-

ies suggest that different diets affect CD by allowing

the patients to absorb more food and thus not suffer

tbl0004Table 4 Nutritional deficiencies in IBD

Anemia – iron, folate, vitamin B

Water-soluble vitamins – vitamin C, thiamin, riboflavin, niacin

Fat-soluble vitamins – A, D, E, K

Zinc

Magnesium

Calcium

1532 COLON/Diseases and Disorders

from malnutrition. Constant feeding will allow

greater absorption of food, allowing for greater cap-

ability of fighting disease. The role of various diets,

however, remains controversial. It is possible that

certain fats or proteins exacerbate disease. There has

been extensive research investigating the effects of

different fat compositions and the course of disease.

The main focus has been on the type of fat. Research-

ers have shown that the consumption of a diet with a

high ratio of polyunsaturated to saturated fatty acid

improves the intestinal function in CD patients. Spe-

cifically, the o-3 fatty acids have been proven to be

effective in CD management. Disease activity falls as

the composition of long-chain triglycerides falls in the

diet. For patients with UC, butyrate (a fatty acid with

four carbon atoms) has been shown to induce remis-

sion. o-3 fatty acids have also been shown to have

antiinflammatory properties that induce remission in

patients with ulcerative colitis. Whether nutrition can

control inflammation in the same way as medication

remains a controversial issue. It has been claimed that

if a patient takes nothing by mouth, this will induce

remission through bowel rest. Resting the bowel in

this way may cause malnutrition and further harm.

0013 In patients with narrowing of the lumen, the ra-

tionale for restricting dietary fiber is apparent. Fiber

intake can be reduced by avoiding coarse wholegrain

breads and cereals, nuts, and most fruits and vege-

tables. Fruit and vegetables may not pass through

strictures and may cause a bolus obstruction behind

a stricture. Patients with symptoms suggestive of mild

or partial bowel obstruction should avoid the intake

of raw fruits and vegetables.

0014 Patients with CD involving the small bowel and

patients with extensive small-bowel resection often

have fat malabsorption. Fatty acids and their deriva-

tives often exert a cathartic effect upon the colonic

mucosa. There is also a direct correlation between

loss of fat in stools and loss of calcium, magnesium,

and possibly zinc. Patients with steatorrhea experi-

ence symptomatic benefit from decreasing their

intake of dietary fat. A reduction in fat to 70–80 g

often suffices to alleviate diarrhea. The calories lost

by removal of calorie-dense fat from the diet must be

replaced by more easily absorbed calorie sources such

as sugars and starches.

0015 The target protein–energy intake should be 126–

146 kJ kg

1

day

1

, with 1.5–1.7 g per kilogram of

protein per day (Table 5). Fluid and electrolyte defi-

ciencies are best treated with an oral rehydration

solution. Patients should receive a solution consisting

of glucose 90 mmol l

1

, sodium chloride 45 mmol l

1

sodium citrate 45 mmol l

1

, and potassium chloride

20 mmol l

1

. Iron deficiency is best treated with iron

supplements. An appropriate dose is 300 mg of

ferrous sulfate or gluconate one to three times per

day. It is sometimes necessary to administer iron by

intravenous infusion or intramuscular injection, as

there is evidence that iron in the colon increases oxi-

dative stress and may exacerbate inflammation. Mag-

nesium deficiency is treated with oral supplements

including magnesium heptogluconate (Magnesium-

Rougier) or magnesium pyroglutamate (Mag 2). The

total dose of elemental magnesium required to ensure

normal serum magnesium varies between 5 and

20 mmol day

1

. Zinc deficiency as a result of losses

through the stool is common in IBD. Zinc supple-

ments should be considered in patients passing sig-

nificant amounts of stool. Zinc deficiency can be

treated by the administration of zinc gluconate, 20–

40 mg day

1

. Patients with CD should take folic acid,

1 mg day

1

. Folic acid nutrition is important in light

of recent data that folate supplementation may pro-

vide protection against both sporadic and IBD-asso-

ciated colorectal cancer. Supplementation with

thiamin, riboflavin, pyridoxine, niacin, and ascorbate

should be recommended using a standard vitamin

preparation. Calcium supplements of 1000–1500 mg

of elemental calcium per day is appropriate, while

vitamin D, 2000–4000 IU day

1

is often required.

0016Eicosapentaenoic acid (EPA) and docosahexaenoic

acid (DHA) are polyunsaturated fatty acids derived

from fish oil and marine mammals. Fish oil has been

observed to have antiinflammatory effects. Fish oil

modulates inflammatory mediators that are con-

sidered to be operative in CD. Fish oils have been

shown to reduce the production of leukotriene B

and thromboxane A

, inhibit the synthesis of cyto-

kines, and scavenge free radicals. Clinical studies

have shown a modest antiinflammatory effect of fish

oils in psoriasis, atopic dermatitis, and rheumatoid

arthritis. One study included 78 patients with CD in

remission who were randomly assigned to 4.5 g of a

fish oil preparation or to placebo capsules containing

the same amount of medium-chain triglycerides.

After one year, the number of patients still in remis-

sion was significantly higher in the fish oil group (59

vs. 26%). Another study from Spain found that a diet

rich in cold fish meat significantly reduced the rate of

relapse by 38% at 2 years follow-up. The difficulty in

tbl0005Table 5 Target energy and nutrient intake in CD

Energy 126–146 kJ kg

1

day

1

Protein 1.5–1.7 g kg

1

day

1

Iron Iron supplement 300 mg day

1

Magnesium Magnesium supplement 5–20 mmol day

1

Zinc Zinc gluconate 20–40 mg day

1

Folic acid 1 mg day

1

Calcium Elemental calcium 1000–1500 mg day

1

Vitamin D 2000–4000 IU day

1

COLON/Diseases and Disorders 1533

evaluating the efficacy of trials is in the high drop-out

rate of patients due to poor compliance with the fish-

oil diet. The advantage in using fish oil is that there is

no significant morbidity associated with fish oils. The

side-effects, unpleasant taste and odor, are considered

insignificant. A summary of trials suggests that fish-

oil preparations can be effective for the maintenance

of CD in remission. Further studies are necessary to

evaluate the effects of fish oils in conjunction with

currently available maintenance therapy for CD.

0017 Patients with more severe symptoms unresponsive

to medical therapy often require intensive nutritional

support. For the patient requiring hospitalization,

complete bowel rest, defined as the complete absence

of oral intake, is often employed. However, such

management causes malnutrition unless alternative

forms of energy are given.

0018 Elemental diets contain predigested forms of

macronutrients, no lactose or fiber, and vitamins,

minerals, and electrolytes sufficient to meet the

recommended dietary allowances for healthy people.

The diets are administered through flexible tubes

placed into the stomach or duodenum. It is not cer-

tain how an elemental diet works. It may be that

giving a patient a balanced nutritious diet improves

overall well-being. Others have suggested that an

elemental diet has a direct effect on the mucosa of

the bowel. These feeds are effective because they

provide minimal digestion, the reduction of fecal

bulk, and a reduction in gastric and pancreatic secre-

tions. Therapeutic value may also be related to

induced changes in epithelial growth kinetics. Almost

20 randomized controlled trials have evaluated the

efficacy of enteral feeding. All trials evaluated

the short-term efficacy on the CD activity index.

The trials compared either diet therapy versus stand-

ard pharmacotherapy or diet therapy where one for-

mula was compared to another. The trials used small

number of subjects, had high withdrawal rates, and

contained a heterogeneous patient population. Initial

controlled trials showed that feeding patients elemen-

tal diets was as effective as prednisone in inducing

disease remission. Later studies suggested that remis-

sion was more likely to occur with the use of prednis-

one. In summary, nutritional support is likely more

effective than placebo in inducing remission. Diets

low in long-chain triglycerides may be as effective as

prednisone.

0019 The logic of minimizing trauma and irritation of

inflamed bowel appears sound. Peripheral intra-

venous therapy during total bowel rest can maintain

adequate fluid and electrolyte balance and ensure

maintenance of vitamin and trace elements. The

goals of total parenteral nutrition (TPN) therapy in-

clude weight gain, positive nitrogen balance, and re-

mission of symptoms. Complications of TPN include

pneumothorax during line insertion, catheter-related

infections, cholestasis, and steatosis. TPN has been

shown to be effective in patients with active disease,

patients with fistula, patients with growth retard-

ation, and patients with short bowel. Trials reported

regarding TPN are small, with different types and

severity of disease. The experience of the TPN team

is highly variable. Several studies show that TPN can

induce remission in acute CD. TPN with bowel rest

achieved remission in 59 and 79% of patients in two

randomized controlled trials. It has been shown that

TPN may delay the time to surgery in some patients.

There was early enthusiasm regarding the use of TPN

in treating fistulous disease. TPN can improve the

nutritional status and result in decreased fistula

output, but better trials with a longer follow-up are

required before TPN can be used as a first-line

therapy for fistulous disease. TPN can reverse growth

arrest and has therefore been increasingly used as the

principal determinant of restored growth. Finally,

parenteral therapy is important in the management

of patients with short bowel. In short periods, it

allows for gut adaptation to occur. Long-term use is

required in patients whose functioning small bowel

remains completely or partially inadequate for nutri-

tional maintenance. In summary, data suggesting that

TPN induces disease remission are indirect and incon-

clusive but should be used to give nutritional support

to patients when other means of support are not

possible.

Ulcerative Colitis

0020UC is an inflammatory disease of unknown etiology

affecting the colonic mucosa from the rectum to the

cecum. It is a chronic disease characterized by rectal

bleeding and diarrhea. Histological features of the

disease may be seen in other inflammatory states of

the colon, such as those caused by bacteria or para-

sites. The diagnosis of ulcerative colitis, therefore,

rests on the discovery of a combination of clinical

and pathological criteria, investigation of the extent

and distribution of lesions, and exclusion of other

forms of inflammatory colitis caused by infectious

agents (Entamoeba histolytica, Clostridium difficile,

Campylobacter, Escherichia coli, and Shigella). UC is

an inflammatory state confined to the mucosa. The

colonic tissue displays small microabscesses, called

crypt abscesses, which involve the crypts of Lieber-

hn. Polymorphonuclear cells accumulate in the

crypt abscesses, and frank necrosis of the surrounding

crypt epithelium occurs; thus, the polymorphonuclear

infiltrates extend into the colonic epithelium. These

microabscesses in the crypts are not visible to the

naked eye; however, several crypt abscesses may

1534 COLON/Diseases and Disorders

coalesce to produce a shallow ulceration visible on

the mucosal surface. Occasionally, lateral extension

of crypt abscesses may undermine the mucosa on

three sides, and the resulting hanging fragment of

mucosa will appear endoscopically and radiographic-

ally as a ‘pseudopolyp.’ Following this mucosal de-

struction, highly vascular granulation tissue develops

in denuded areas, resulting in friability and bleeding.

The two most prominent symptoms of UC – diarrhea

and rectal bleeding – are related both to the extensive

mucosal damage that renders the colon less capable of

absorbing electrolytes and water, and to the highly

friable vascular granulation tissue, which bleeds

readily.

0021 Etiology It was once thought that UC was caused by

food allergy. The food most likely to cause the reac-

tion was cows’ milk. Other foods implicated in the

etiology of ulcerative colitis include eggs, wheat, to-

matoes, oranges, and potatoes. Circulating antibodies

to milk proteins are present in some normal subjects

but are more common and in higher titers in patients

with UC. Sensitivity to disaccharides, including

lactose, is noted in patients with UC.

0022 Nutritional management Five studies to date have

investigated the effect of fish oil supplementation on

chronic active UC. The studies, however, are small

and of short duration, have varying doses of o-3 fatty

acids, have significant rates of drop out, and are

confounded by the use of other medications. It can

be concluded, however, that fish oil appears to have

only a modest treatment effect on active UC and

does not seem to be beneficial in maintaining UC in

remission.

0023 Short-chain fatty acids (SCFA) have been proposed

as a topical treatment for active distal UC. SCFA are

organic acids produced by anaerobic fermentation of

undigested carbohydrates within the colonic lumen.

Acetate, propionate, and butyrate, the two-, three-,

and four-carbon SCFA, respectively, account for 90–

95% of SCFA in the colon, with isobutyrate, valerate,

iosovalerate, and caproate comprising the rest. Once

inside the colonocyte, SCFA are an important energy

source for the cell. Butyrate is the preferred SCFA to

meet colonic energy requirements, acetate is second,

and propionate is the least metabolized of the three.

The SCFA could account for up to 80% of the energy

requirements of the colon and for 5–10% of total body

energy requirements. Colonic biopsy specimens from

patients with UC have impaired utilization of butyrate

as measured by carbon dioxide production. It has been

suggested that UC may be the result of an energy-

deficiency state of the colonic epithelium. The exist-

ence of a deficiency of SCFA production has not been

consistently shown to exist in UC. It has therefore been

postulated that the problem may lie in the uptake or

oxidation of the SCFA by the colonocytes. The ration-

ale behind using SCFA in UC is that supraphysiologic

luminal SCFA concentrations may be able to overcome

the partial metabolic defect of the colonic mucosa to

oxidize SCFA. SCFA stimulate colonic cell prolifer-

ation, provide a more effective barrier between mucosa

and the intraluminal contents, dilate the resistance

arteries of the colon, and increase blood flow and

mucosal oxygen uptake. Four uncontrolled studies in-

vestigating the effect of SCFA on distal active UC have

been published. In all four trials, 50–78% of the pa-

tients had clinical improvement, some with complete

remission, during the study period ranging from 4 to 6

weeks. Disease activity indices and endoscopic appear-

ance all improved. Five randomized trials published to

date also support the role of SCFA in the management

of UC. These trials to date are limited by the small

number of subjects, varying combinations and concen-

trations of SCFA, and differences in study design and

patient populations. However, these trials collectively

suggest that SCFA irrigation can effectively treat re-

fractory distal UC that has failed to respond to stand-

ard topical, systemic, or combination therapies with a

pooled clinical response rate of 70.6%. As a first-line

treatment of mild to moderate distal UC, SCFA is asso-

ciated with a modest clinical response. SCFA is as

effective as topical corticosteroid and 5-ASA in indu-

cing clinical, endoscopic, and histologic improvement

in mild to moderate distal ulcerative colitis. SCFA is

free of significant side-effects and toxicity, and is well

tolerated. SCFA is associated with significant cost-

savings compared with standard typical corticoster-

oids or 5-ASA. Unresolved issues regarding SCFA

include their role in maintaining remission of distal

UC once active disease is brought under control. Fur-

thermore, the role of SCFA in preventing colon cancer

has yet to be delineated. Finally, the most effective

concentrations and compositions of SCFA have not

yet been determined.

0024The impetus for using SCFA in the treatment of

distal ulcerative colitis was the finding that topical

SCFA could effectively treat colonic inflammation in

diversion colitis. Diversion colitis is an inflammatory

process that occurs in segments of the colon after

surgical diversion of the fecal stream. Several studies

have documented that endoscopic abnormalities and

histologic changes occur in the distal colonic segment

of most patients after intestinal diversion. Pathologic

examination shows lymphoglandular complexes

expanding the submucosa with increased lympho-

cytes and plasma cells. Cryptitis with abscesses,

patchy neutrophil infiltration in the lamina propria,

and superficial erosions overlying lymphoid follicles

COLON/Diseases and Disorders 1535