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ORLANDO,
FL-- Understanding of the complex interactions between probiotics
and the gut is growing, but the dearth of clinical data is making
it difficult to turn science into medicine, Richard Fedorak, MD,
told attendees at Digestive Disease Week.
He noted that as one ages, the endogenous supply of benign flora
such as lactobacillus fall in number, while the number of possible
pathogens such as bacterioides and enterobacter increase. "Breastfed
babies have more lactobacillus and other probiotics in the gut than
do bottle-fed babies, and fewer pathogens such as E. coli and Clostridium
difficile, " said Dr. Fedorak, Professor of Medicine and Director,
Division of Gastroenterology, University of Alberta, Edmonton. "Our
luminal ecology changes with time and with the environment-whether
we are breast- or bottle-fed-and in the presence of diseases such
as Crohn's."
He noted that probiotics work via several mechanisms, competitive
exclusion of pathogenic microbes being one. "Probiotics also
line up in a nice row in the gut and form a wall that may prevent
pathogens from getting through the mucosa." Such a barrier
can change the pattern of glycosylation in the microvillus and lead
to altered microbial attachment, not just of bacteria but of viruses
as well.
Dr. Fedorak summarized existing evidence from clinical trials on
the efficacy of supplemental flora in gastrointestinal infections.
Ten randomized controlled trials in diverse settings from the U.S.
to Pakistan looked at the effect of probiotics in hospitalized children,
many of whom had rotavirus. Eight RCTs with 731 patients studied
whether diarrhea lasted more than three days in supplemented infants.
Meta-analysis showed that probiotics can reduce the risk that infectious
diarrhea will last more than three days. Lactobacillus GG, one of
the more promising strains, seemed to have a consistent effect compared
with other forms such as acidophilus or reuteri.
In an additional four trials involving 300 children, researchers
found a 24.8-hour reduction in the duration of diarrhea. "So
probiotic treatment appears to reduce the number of kids having
diarrhea longer than three days and also to reduce the duration
by about a day," Dr. Fedorak said. A large RCT in Italian children
found probiotics shortened duration of diarrhea by 18 hours, but
only in rotavirus infections.
As for diarrhea arising from other etiologies, an RCT of 124 patients
conducted a decade ago looked at recurrent colitis stemming from
Clostridium difficile. All participants received an antibiotic and
either a placebo or a probiotic. "This trial found that probiotics
did not make a difference if it was the first bout of colitis-the
antibiotic took care of that-but there was a marked benefit in recurrence
if you had already had several bouts of C. difficile colitis."
Moving to the stomach, Dr. Fedorak outlined two RCTS of H. pylori
infection. In both, patients were assigned to take a PPI, amoxycillin
and erythromycin, plus either a lactobacillus supplement or placebo
for two weeks. While supplementation did not appear to increase
H. pylori eradication rates, it did reduce the side effects of the
antibiotics, with patients reporting less gas, less pain and less
nausea. "So this was more a case of improving antibiotic compliance,
not H.P. elimination," he said.
While there is good evidence that probiotics reduce the severity
and duration of rotavirus diarrhea in children-with lacotbacillus
GG emerging as the most consistent winner-Dr. Fedorak raised the
question whether results could be duplicated in the adult population.
"And what is the best treatment: single, double or multiple
probiotics?"
Moving on to the potential of supplementation for the prevention
of infection, Dr. Fedorak outlined mechanisms by which they might
play such a role. Pathogens such as E. coli, for example, can recruit
inflammatory neutrophils into the lamina propria, but the presence
of benign probiotics can inhibit this migration. "But this
happens only with probiotic pre-incubation. Once the E. coli and
the neutrophils are in, you cannot get rid of the neutrophils,"
he said. At a media briefing, Dr. Fedorak noted that foods such
as onions, asparagus and Jerusalem artichokes contain carbohydrates
that promote the colonization of probiotics in the gut.
Interestingly, there is crosstalk between the probiotics and the
goblet cells. "Probiotics can induce mucous secretion by upregulating
mucin-producing genes to create a physical barrier that catches
pathogens as they try to migrate across the epithelim," he
said. Through crosstalk with probiotics, the goblet cells can decide
to change the mucin epitopes. "So the mucin now looks different,
and this enables the binding of different bacteria. You actually
begin to get rid of the old mucous and change the probiotics to
a different species."
Probiotics secrete antibacterial peptides that have proven useful
in the poultry industry to combat salmonella in birds' digestive
tracts. Friendly probiotics may interact in the gut with the toll-like
receptors of the innate immune system and with dendritic cells to
inhibit production of inflammatory T cells and thus prevent diarrhea.
Several probiotic trials in Poland, Italy and the U.S. have looked
at diarrhea prevention. The Polish trial involved 55 hospitalized
children given a floral supplement or placebo at admission. Investigators
found a seven per cent incidence of diarrhea in the treatment group,
versus 31 per cent in controls. But a long-term trial in Peru found
probiotic treatment made virtually no difference over 15 months.
"So it looks as though we can use probiotics to prevent diarrhea
only in the nosocomial setting," he said.
As for antibiotic-related diarrhea, a meta-analysis of nine RCTs
found a 15 per cent reduction with probiotic therapy. "So there's
very good evidence here for prevention," he said. In the case
of traveller's diarrhea, however, three trials involving 103,000
subjects from Finland, Germany and the US found no preventive effect-except
for individuals travelling to Turkey. These studies, however, were
all noted for a high noncompliance rate of 30 to 60 per cent.
In radiation-induced enteritis, one open-label study noted a 31
per cent incidence of diarrhea in 20 patients given VSL-3 during
six weeks of pelvic radiation, compared with 50 per cent in placebo-treated
patients. In contrast, an RCT of 206 patients showed no difference
in the index-assessed quantity of diarrhea between placebo and probiotics
recipients. "But supplemented patients reported feeling better
and assessed themselves as having better stools, so something was
happening here," he said.
In inflammatory bowel disease, Dr. Fedorak noted that two trials
found VSL beneficial in preventing relapse in antibiotic-induced
remission of pouchitis. One Italian study reported a 15 per cent
relapse rate versus 100 per cent with placebo over nine months,
and an American trial in a similar population with the same probiotics
reported comparable results. In contrast, an Italian study using
a different probiotic to treat acute inflammation in newly formed
pouches showed no benefit over placebo.
Dr. Fedorak noted that individual strains of probiotics have markedly
different patterns of adhesion and different effects on the immune
system. "So in the future, choosing a probiotic may be like
choosing an individual antibiotic-penicillin over a fluoroquinolone,
for example-to treat a specific infection," he said. "You'll
choose a probiotic according to some sensitivity you're looking
for and link it to the correct disease."
At this juncture, Dr. Fedorak believes probiotics should be reserved
for clinical trials. "If you're going to use them outside of
trials, align them with the best evidence." He called for more
investigation to define the specific mechanisms by which individual
strains work.
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