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Transcript of Probiotics and Prebiotics as Functional Ingredients in Inflammatory Bowel Disease
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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
Probiotics and prebiotics are promising nutraceuticals that may exert a beneficial effect in many medicalconditions including inflammatory bowel disease. With the increasing occurrence of antibiotic
resistance, the search for medication with little side effects, and the need for options for patients with
inflammatory bowel disease who are unresponsive to current therapies, research into alternative
therapeutic options is justified. Preclinical studies have provided insights into the effects of probiotics
and prebiotics on the immune system and gut microbiota. This new information, along with the older
evidence, shows that probiotics and prebiotics may ameliorate chronic intestinal inflammation. This
article gives a short overview on current knowledge of probiotics and prebiotics.
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.
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,
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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.
Theconcept 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
lactic acid 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 ahealthy gut flora. Metchnikoff and Tissier are largely credited for being the first individuals to make
scientific suggestions about probiotic bacteria, although the termprobioticwas not coined until 1965.
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
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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 usedbut to a lesser extent. The only yeast that is considered a probiotic is Saccharomyces boulardii(Table
1). 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.
Table 1. Common Probiotic Organisms
Multiple mechanisms of action have been postulated to account for the beneficial effects of probiotics
in 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 toanother (Table 2).
Table 2. Proposed Benefits of Probiotics to the Well-being and Health of the Animal
Host
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 theability to enhance the 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 bacterial
species 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
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has been shown to suppress the growth ofBacteroides vulgatus, a pathogenic microbe possibly
responsible for the induction and perpetuation of IBD.
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
pathogenic bacteria. For example, E coliNissle 1917 inhibits epithelial adhesion and invasion of a
pathogenic E colistrain 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 tomodify the immune system of the intestinal mucosa by reducing the production of proinflammatory
cytokines and increasing 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 (Table 3). 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.
Table 3. Clinical Studies Testing Probiotics in the Treatment of Human Inflammatory
Bowel Disease
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.
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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.
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 arenondigestible 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,
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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
different purposes. Inulin has a longer chain length and is therefore less soluble and suitable as a fatreplacer.
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 inTable 4.
Table 4. Potential Candidate Prebiotic Substrates
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 (Table 5). 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.
Table 5. Proposed Benefits of Prebiotics to the Well-being and Health of the Animal
Host
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, anddecreasing 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.
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Short-chain fatty acids include butyrate, acetate, and propionate. Butyrate is the major energy source
for 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, whichresults in acidification of the colonic content. Intraluminal acidification may inhibit the growth of
harmful or disease-inducing bacteria.
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,
abdominal cramps, and diarrhea. There are some reports of increased bacterial translocation ofpathogenic 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 (Table 6). 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.
Table 6. Clinical Studies Testing Prebiotics or Synbiotics in the Treatment of Human
Inflammatory Bowel Disease
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.
Conclusion and Future Perspectives
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Probiotics and prebiotics are emerging as promising therapeutic options for the treatment and
prevention of flare-ups of IBD. A significant number of studies in both animal models and human IBD
have documented the efficacy of these therapies in ameliorating chronic intestinal inflammation. In
addition, these studies have led to a greater understanding of the mechanisms by which probiotics
and prebiotics exert their beneficial effects. However, it is important to remember that the
mechanisms elucidated cannot be generalized, as not all probiotics and prebiotic have similartherapeutic effects. Probiotics and prebiotics are widely available, are easy to consume, and are
recognized as safe to consume. Side effects are rare, but some adverse effects such as bloating and
flatulence tend to limit subsequent intake. The results obtained thus far warrant further rigorous well-
designed and larger clinical trials to firmly establish the safety and efficacy of probiotics and prebiotics
in IBD.
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55. Hoentjen F, Welling GW, Harmsen HJM, et al. Reduction of colitis by prebiotics in HLA-B27
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