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Probiotics and Prebiotics asFunctional Ingredients inInflammatory Bowel DiseaseMirjam A.C. Looijer-van Langen MD
Vimal Prajapati
Levinus A. Dieleman MD, PhD
Nutrition Today
November/December 2008
Volume 43 Number 6
Pages 235 - 242
Abstract
Inflammatory bowel disease is the name of a group of disorders that cause the intestines to become
inflamed (red and swollen). The inflammation lasts a long time and usually comes back over and over
again. More than 600,000 Americans have some kind of inflammatory bowel disease every year.
If you have inflammatory bowel disease, you may have abdominal cramps and pain, diarrhea, weight
loss and bleeding from your intestines. Two kinds of inflammatory bowel disease are Crohn's disease
and ulcerative colitis. Crohn's disease usually causes ulcers (open sores) along the length of the small
and large intestines. Crohn's disease either spares the rectum, or causes inflammation or infection with
drainage around the rectum. Ulcerative colitis usually causes ulcers in the lower part of the large
intestine, often starting at the rectum.
Inflammatory bowel diseases (IBDs) are chronic inflammatory disorders that include Crohn disease (CD),
ulcerative colitis (UC), and chronic pouchitis. Crohn disease can affect the entire gastrointestinal tract
anywhere from mouth to anus. The chronic inflammation is not limited to the lining of the bowel but
affects the entire bowel wall, sometimes resulting in intra-abdominal abscesses and fistula (abnormal
connections between the lumen of the bowel, other organs, or the surface of the skin) and intestinal
obstruction. Patients typically experience symptoms of mild diarrhea, right lower quadrant pain, and
low-grade fever. Ulcerative colitis is limited to the colon, and patients experience rectal bleeding,
abdominal pain, and diarrhea. The inflammation in UC is confined to the upper layer of the colonic wall
and the mucosa. Patients with CD and those with UC both experience periods of remission and relapses.Chronic pouchitis is a chronic inflammation of the ileoanal pouch. An ileoanal pouch is an internal
reservoir, constructed for patients with UC who have had their large intestine surgically removed mostly
because of severe inflammation refractory to medical treatment. Patients with pouchitis typically
present with bloody diarrhea, urgency in passing stools, or discomfort while passing stools. Rarely, pain
occurs with pouchitis.
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Inflammatory bowel disease is caused by multiple factors that disturb intestinal homeostasis. An
abnormal immune response to commensal bacteria or dietary factors in genetically susceptible hosts
plays a major role in the pathogenesis. Environmental factors including psychological stress, use of
nonsteroidal anti-inflammatory drugs, and cigarette smoking can also contribute to IBD. The current
treatment of IBD mainly consists of drugs directed against the overactive adaptive immune response,
such as 5-aminosalicylic acid compounds, steroids, azathioprine/6-mercaptopurine, methotrexate,cyclosporine, and biologics such as infliximab. Most patients respond well to these medications, but for
some, it is inadequate or induces intolerable adverse effects. Therefore, interest has been raised in
nutraceutical therapies such as probiotics, prebiotics, or a combination of these, called synbiotics, as a
good therapeutic option for nonresponding patients with IBD.
The
concept that ingestion of certain bacteria may promote health is not new. Fermented milk products
have been consumed by human beings for thousands of years with the belief that they provide health
benefits. For example, according to Persian tradition, Abraham of the Old Testamentowed his longevity
to sour milk.
In the early 20th century, the Russian immunologist, Elie Metchnikoff, proposed that ingestion of lacticacid bacteria promoted health and longevity of life. He based his theory on the observation that
Bulgarians who consumed large quantities of fermented milk lived longer than those who did not.
Around the same time, the first attempt to treat disease with bacteria was made by Dr Henry Tissier, a
French pediatrician, who discovered Y-shaped or "bifid" bacteria (now known as Bifidobacterium) and
recommended administration of isolated bifid cultures to infants with diarrhea to help restore a healthy
gut flora. Metchnikoff and Tissier are largely credited for being the first individuals to make scientific
suggestions about probiotic bacteria, although the termprobiotic was not coined until 1965.
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The termprobiotic, which literally means "for life," was first introduced by Lilly and Stillwell in 1965 to
describe "substances produced by one microorganism which stimulate the growth of another." Since
that time, the definition has undergone many revisions. In an attempt to provide an agreed upon
definition, a joint Food and Agricultural Organization/World Health Organization Expert Consultation
redefined probiotics as "live microorganisms which when administered in adequate amounts confer a
health benefit on the host." Currently, this is the most widely accepted definition.
Probiotics can be bacteria or yeast, although the vast majority is bacteria. The most common bacteria
used as probiotics are lactic acid bacteria from the genera Lactobacillus and Bifidobacterium. Certain
species from other genera such as Streptococcus, Enterococcus, and Escherichia have also been used but
to a lesser extent. The only yeast that is considered a probiotic is Saccharomyces boulardii. Probiotics
are available in a variety of food products, especially dairy products such as yogurt, milk, cottage cheese,
and dietary supplement products. Dietary supplements containing freeze-dried probiotics in capsule,
powder, or tablet form are becoming a popular choice.
Multiple mechanisms of action have been postulated to account for the beneficial effects of probioticsin IBD. In broad terms, probiotics are thought to improve the epithelial barrier function of the intestine,
alter the composition of the intestinal microflora, and modulate the immune response of the intestinal
mucosa. However, the exact mechanism is likely to vary from one probiotic organism to another.
Normal epithelial barrier function of the intestine requires an intact layer of epithelial cells and an
adequate production of overlying mucus to prevent uptake of potentially harmful organisms and
substances into the body. A disrupted and leaky intestinal epithelial barrier may be one of the initiating
events in the pathogenesis of IBD. In addition, increased apoptosis (programmed cell death) of intestinal
epithelial cells and decreased mucus production have been documented in patients with IBD and are
thought to contribute to the pathogenesis. Several probiotics have demonstrated the ability to enhancethe epithelial barrier function of the intestine. For example, Lactobacillus rhamnosus GG improves
barrier function by inhibiting apoptosis of intestinal epithelial cells. Streptococcus salivarius subsp
thermophilus and Lactobacillus acidophilus have been shown to enhance the tight junctions between
epithelial cells, thereby preventing infection from the invasion of pathogenic bacteria such as
enteroinvasive Escherichia coli. Also, several Lactobacillus strains have been found to increase mucus
production. Madsen showed that a synthetic probiotic mixture, VSL#3 (containing 4 Lactobacillus spp, 3
Bifidobacterium spp, and S salivarius subsp thermophilus), also restored the epithelial barrier function in
a chronic colitis mouse model. The improvement of the barrier function is probably the result of a direct
effect of probiotic bacteria or their secreted bacterial products.
Normally, there is a balance between the beneficial bacterial species and the detrimental bacterialspecies that make up the intestinal microflora. In IBD, a number of genetic and environmental factors
are thought to upset this balance such that there is a relative predominance of detrimental disease-
inducing bacteria that contribute to the chronic inflammatory process in IBD. Probiotics can help restore
a healthy intestinal microflora by directly increasing the population of beneficial bacteria and by
suppressing the growth and function of detrimental bacteria. For example, Bifidobacterium infantis has
been shown to suppress the growth ofBacteroides vulgatus, a pathogenic microbe possibly responsible
for the induction and perpetuation of IBD.
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Probiotic organisms can inhibit pathogenic bacteria in several ways. First of all, they competitively
exclude pathogens by occupying the limited physical space available for colonization in the gut. In
addition, probiotic organisms can either directly secrete antimicrobial substances (eg, organic acids,
hydrogen peroxide, and bacteriocins) and/or stimulate host intestinal cells to secrete antimicrobial
substances (ie, defensin molecules), which destroy pathogens before they can colonize the gut. Several
probiotics have demonstrated the ability to prevent epithelial adhesion and invasion of pathogenicbacteria. For example, E coliNissle 1917 inhibits epithelial adhesion and invasion of a pathogenic E coli
strain isolated from patients with CD.
Inflammatory bowel disease is thought to be caused by an overly aggressive
immune response to the endogenous gut microflora in genetically susceptible
individuals. This results in an increased production of chemical signals that
promote inflammation. These proinflammatory cytokines include, for example,
tumor necrosis factor [alpha] and interferon [gamma]. Anti-inflammatory
cytokines are interleukin 10 and transforming growth factor [beta]. Probiotic
organisms are generally thought to modify the immune system of the intestinal
mucosa by reducing the production of proinflammatory cytokines andincreasing the production of anti-inflammatory mediators. Studies have shown
that Lactobacillus plantarum, L rhamnosus GG, and VSL#3 can increase the
production of interleukin 10 and that specific lactobacilli and bifidobacteria
species can reduce the production of tumor necrosis factor [alpha] and
interferon [gamma]. The mechanisms by which probiotics exert their immunomodulatory effects are
complex and beyond the scope of this review.
Probiotics are generally well tolerated and have an excellent overall safety record. This is not surprising
because many of the organisms used as probiotics are commensal, nonpathogenic inhabitants of the
human gut and have been used safely in the production of fermented foods for centuries. The most
common adverse effects of probiotics include bloating, flatulence, and constipation. There have been
some reports of probiotics inducing serious infections such as bacterial and fungal sepsis. However,
these cases occurred in immunocompromised patients. There are no reports of such cases in healthy
people.
Animal models have been used extensively to study the efficacy of probiotics in treating chronic
intestinal inflammation and to elucidate the mechanisms by which probiotics work. Successful reduction
of intestinal inflammation in many of these experimental models has provided the support for human
clinical trials. Escherichia coliNissle 1917, VSL#3, and bifidobacteria-fermented milk have been shown to
have some success at inducing and maintaining remission of UC and reducing disease activity.
VSL#3 proved to be effective in maintaining remission of chronic relapsing pouchitis, preventing the
development of pouchitis compared with placebo treatment; in addition, it also significantly improved
patient quality of life. One study with L rhamnosus GG, however, was ineffective in reducing pouchitis
disease activity.
The efficacy of probiotics in CD is still controversial. For example, Lactobacillus salivarius, VSL#3, and S
boulardiiin combination with conventional therapy (mesalamine) have had some success. On the other
hand, there are numerous studies reporting the ineffectiveness of various probiotics in CD.
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Because the viability of probiotics in some food products and during transit through the gastrointestinal
tract is variable, the prebiotic concept has been developed. Prebiotics are nondigestible short-chain
carbohydrates, originally defined as selectively fermented ingredients that allow specific changes, both
in the composition and/or activity in the gastrointestinal microflora that confer benefits upon host's
well-being and health.
Substances are considered prebiotics according to the following conditions:
(1) when they are not broken down nor absorbed by enzymes in the upper part of the mammalian
gastrointestinal tract,
(2) when they are selectively fermented by one or a limited number of potentially beneficial bacteria in
the intestine, and
(3) when they are able to alter the colonic microflora toward a healthier composition.
Prebiotics have become very popular food ingredients. The most commonly used prebiotics, inulin and
oligofructose, are natural food ingredients or dietary fibers present in plants as storage carbohydrates.
Wheat, chicory, bananas, onions, leeks, Jerusalem artichokes, asparagus, and garlic contain prebiotics.
Most commercially used prebiotics are synthesized from sucrose or extracted from chicory roots. They
are used in, for example, confectioneries, bakery products, fruit juices, desserts, spreads, taste
improver, sweetener, and fat replacers and sometimes used as viscosity-increasing agents.
Inulin and oligofructose, also called [beta]-fructans, are composed of fructose units joined by [beta]-
glycosidic links. Because of their different fructose chain lengths, inulin and oligofructose are used for
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different purposes. Inulin has a longer chain length and is therefore less soluble and suitable as a fat
replacer.
Oligofructose is composed of a shorter chain length of fructose molecules and is, for example, used to
replace sugar. Depending on the diet, the daily intake of prebiotics in Western societies varies from 3 to
13 g per day.
Many substances are claimed to have prebiotics effects but only fructo-oligosaccharides, galacto-
oligosaccharides, lactulose, and inulin have been shown to meet all 3 before mentioned criteria. Other
potential prebiotic candidates are mentioned in.
Different medical conditions have been speculated to ameliorate upon treatment with prebiotics,
including improvement of mineral absorption, reduced risk for colon cancer, improvement of food
allergies, alleviation of constipation, regulation of lipid metabolism, and reduction of antibiotic-induced
diarrhea.
The working mechanisms of prebiotics are not fully understood yet, but many theories have been
formed. In broad terms, the beneficial effects are believed to be due to the stimulation of protective
intestinal organisms and the production of short-chain fatty acids (SCFAs) as fermentation products of
prebiotics.
The intestinal barrier functions to protect the individual from potential bacterial threats. The mucus
layer in the gastrointestinal tract plays a major role by preventing the attachment and translocation of
bacteria across the epithelial wall. A decrease in mucus production is seen in IBD. Prebiotics have been
shown to increase the mucus layer in a rat model of colitis.
As mentioned before, intestinal bacteria play an important role in the pathogenesis and attenuation of
IBD. Prebiotics change the intestinal microflora in animal models and human studies by increasing the
numbers of intestinal protective bacteria, for example, lactobacilli and bifidobacteria, and decreasing
the proportion of pathogenic bacteria. Several studies performed in infants confirmed this, showing that
the intestinal microbiota of breast-fed infants (containing milk oligosaccharides) is generally dominated
by bifidobacteria and lactic acid bacteria. In contrast, formula-fed infants' intestinal microflora contains
lower numbers of bifidobacteria and lactic acid bacteria and contains more bacteroides, clostridia, and
enterobacteriaceae. However, after the prebiotic diet is stopped, these microflora changes gradually
return to baseline levels.
Short-chain fatty acids include butyrate, acetate, and propionate. Butyrate is the major energy sourcefor colonic epithelial cells and plays an essential role in the maturation of colonic epithelium,
regeneration of mucosa, induction of epithelial cell differentiation, and stimulation of their apoptosis. A
reduced level of luminal SCFAs may play a role in the onset of IBD. The amount of SCFAs produced in the
colon depends on the composition of intestinal microflora, their substrates, and the gut transit time.
Fermentation of prebiotics by colon bacteria results in higher luminal SCFA production, which results in
acidification of the colonic content. Intraluminal acidification may inhibit the growth of harmful or
disease-inducing bacteria.
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Several studies show that the prebiotic effects are different for each prebiotic substance and that these
depend on intestinal pH, prebiotic dosages, intraluminal concentrations of prebiotics, duration of intake,
locations in the gut where fermentation occurs, and composition of endogenous intestinal microflora.
Prebiotics have been part of human diets for centuries and are generally recognized as safe to consume.
However, they can cause symptoms of abdominal pain, eructation, flatulence, bloating, abdominalcramps, and diarrhea. There are some reports of increased bacterial translocation of pathogenic
bacteria during prebiotic treatment, such as Salmonella, and in sepsis models, but these results are
controversial and are not seen in patients. More research in this area is needed.
The effects of prebiotics are most extensively studied in different rodent models of IBD. Various efficacy
of prebiotics and synbiotics (combination of probiotics and prebiotics) in different IBD models was
found, but in most studies, prebiotics seem to ameliorate intestinal inflammation. Inulin, starch,
lactulose, combination of oligofructose and inulin, and goat milk oligosaccharides reduced colitis. Some
fructo-oligosaccharides showed mixed results, whereas galacto-oligosaccharides failed to reduce
intestinal inflammation.
Currently, only a few studies with prebiotics in patients with IBD have been published. Emerging small
short-term studies using prebiotics or synbiotics showed reduction of inflammation in patients with
pouchitis, UC, and CD. A small open-label study in patients with active ileocolonic CD treated with a
combination of oligofructose and inulin showed a significant reduction in disease activity. A recent pilot
study investigated the adjunct effect of oligofructose-enriched inulin in patients with mild to moderate
UC with concomitant 5-aminosalicylic acid treatment (n = 19). This placebo-controlled study reported a
significant reduction of fecal calprotectin (marker of intestinal inflammation) in the prebiotic-treated
patients compared with the placebo group, suggesting that these prebiotics reduced chronic intestinal
inflammation.
A randomized double-blind crossover study in pouchitis patients after colectomy for UC treated with
inulin resulted in the reduction of mucosal inflammation However, Chermesh et al could not show
prevention of relapse of CD after surgical resection with synbiotic treatment, although this study may be
underpowered.
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Volume 43 Number 6 2008
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