Their Tiny Worlds Are Under Scrutiny
COVER STORY |
In the lab, in the yogurt cup, in animal feed-- these microbes are
making their huge numbers felt
by Bob Beale
GUT REACTION: Researchers
have found that Lactobacillus GR-1 and RC-14 can penetrate Escherichia
coli biofilms, multiply, and survive.
Image: Courtesy of Mark Neysmith, © Gregor Reid
The human body plays host to a complex and thriving microbial ecosystem
of vast numbers of tiny creatures. Some of these species, already
well studied, can cause disease. But a renewed appreciation is growing
for many lesser-known species called probiotics that help maintain
health and may have the potential to prevent disease. A steady stream
of research papers on this topic is making its way into scientific
and medical journals. The food industry is especially active in
studying probiotics because the gastrointestinal tract is one of
the richest zones of biodiversity within the body, with at least
400 known species of bacteria commonly found there.
Apart from their possible inclusion in foods or their development
as food additives, many medical, dental, and veterinary researchers
are looking at a wide range of therapeutic possibilities for probiotics.
They include the treatment of ear, intestinal, and urinary tract
infections; reduction of blood cholesterol levels; and prevention
of skin and surgical wound infections, tooth decay and even some
The modern concept of probiotics has been around for almost a century,
yet the science behind it is still sparse. The validity of much
of the research into the efficacy of probiotics has been questioned
(or goes unpublished because of commercial secrecy); their impact
on human nutrition is still only vaguely understood; the selection
of desirable microbial strains is an uncertain process and often
based on commercial or technical factors; and the necessary tools
to monitor their performance in vivo are still being developed.
"There does seem to be lots of potential there, but it's a
very complicated area," says independent nutritionist Rosemary
Stanton, in Sydney, Australia, "I think it sounds good
and I want to be a believer. But when you read the studies they
don't match the headlines. The food industry is pushing to be able
to make more health claims for these products, but, based on what
we know so far, I think it would be foolish to allow that."
An adult body has about 10 trillion cells comprising 200 different
types, but bacteria greatly outnumber them. Gerald Tannock,
University of Otago, New Zealand, says the typical adult body, inside
and out, has 100 trillion bacterial cells consisting of at least
500 species, not to mention billions of viruses and fungi. Most
microbiota, also known as microflora, live in relative peace and
harmony with the body. Some aid digestion, act as a first line of
defense against invading pathogens, or help to keep the immune system
primed, says Tannock. Humans may have ancient symbiotic relationships
with many of them, and they seem to operate as members of any ecosystem
do, competing with each other for nutrients, energy, and habitats
and actively repelling or deterring invaders, he says.
Gregor Reid and colleagues at the Lawson Health Research
Institute, University of Western Ontario, Canada, reported that
competition between microbes and their mammalian hosts has been
evolving for millions of years. "The fact that we have survived
is in no small part owing to the ability of commensal bacteria to
protect the host from microbial-induced disease processes,"
they argued in a recent paper.
Experiments with germ-free animals have shown, paradoxically, that
they are often sickly. Absence of intestinal microbiota leaves the
animals' immune systems underdeveloped and can disrupt their intestinal
morphology, problems that can be reversed to varying degrees by
experimentally introducing probiotic species. Mahnaz Banasaz
and colleagues at the Karolinska Institute in Sweden recently published
experiments showing that one of the most widely studied probiotics,
Lactobacillus rhamnosus GG, is easily established in germ-free
rats and can markedly alter their gut morphology. After three
days of exposure, the rate of mitosis increases in the cells of
the upper small intestine, significantly increasing the number of
cells in the villi lining the intestinal wall, thus aiding absorption
of soluble food. Probiotic strains are now used routinely in livestock
nutrition, and some certainly seem to have potential for human use
against a variety of pathogens.
Probiotics may have potential to boost disease resistance, says
Tannock. It is well known, for example, that normal mammalian commensal
microbes can increase circulating specific and natural antibodies,
and thus reduce antibiotic use. Future clinical applications for
probiotics might include treating food allergies, reducing hypertension,
or using them as vectors for oral vaccines. A recent paper hypothesizes
that probiotics might even help detoxification in cases of mercury
poisoning. Proponents also note that probiotics have aided in
restoring intestinal flora after antibiotic therapy, reducing the
duration of rotaviral diarrhea and gastroenteritis in infants, and
preventing traveler's diarrhea.
PROBIOTICS EXPOSED: Bifidobacteria
isolated from the intestine.
Image: Courtesy of Glenn Gibson200
PROBIOTICS IN THE LAB
Establishing new species within a body is normally difficult because
the resident species are thought to exclude invaders through a process
known as colonization resistance. But antibiotic drugs can kill
many bacteria other than pathogens, and may, for example, disrupt
the digestive ecology enough to let antibiotic-resistant strains
gain a foothold, leading to diarrhea. Because the prospects for
new drugs that overpower resistant strains are few and probably
distant, researchers are turning to probiotics to help. "The
worldwide emergence of bacterial resistance to antibacterial agents
has produced a need for new methods of combating bacterial infections,"
argued Pentti Huovinen, chief physician at the Antimicrobial
Research Laboratory, National Public Health Institute, in Finland.
"Bacteriotherapy using harmless bacteria to displace pathogenic
organisms is an alternative and promising way of combating infections."
Researchers in Sweden are using a streptococcus-laced nasal
spray to reduce the recurrence of otitis media, a middle-ear infection.
The bacteria apparently deter pathogens from spreading from the
nose into the middle ear.
Reid's group found encouraging evidence after they simultaneously
added the probiotic Lactobacillus fermentum and potentially
deadly Staphylococcus aureus (commonly known as a golden
staph) simultaneously to simulated surgical wounds in rats which
had a strong protective effect against the disease-causing S.
Rolien Free and colleagues, University Hospital of
Groningen, Netherlands, used two strains of probiotic streptococci
to reduce the incidence of unwanted bacteria and fungi on prosthetic
Likewise, Richard Hull of Baylor College of Medicine
in Houston recently reported using probiotics to achieve significant
reductions in recurrent bladder infections among catheterized patients
with spinal-cord injuries.
Jeffrey D. Hillman, University of Florida College
of Dentistry in Gainesville, is inoculating rats with a territorially
aggressive but harmless, modified strain of Streptococcus mutans.
That strain displaces the harmful variant of the bacterium that
metabolizes lactic acid in the mouth and causes enamel damage to
teeth. Hillman predicted that dentists might one day use probiotic
sprays during routine cleaning procedures in children.
Andrew S. Neish and colleagues from Emory University
School of Medicine in Atlanta, Ga., have suggested that orally administered
probiotics might also be used to treat inflammatory disorders of
the intestinal tract. They reported experimental evidence that
nonpathogenic salmonellae interfere with an inflammatory signaling
pathway in intestinal mucosa, suggesting a possible mechanism by
which bacteria diminish the host's immune responses to their presence.
In an editorial accompanying publication of that report, Ramnik
J. Xavier and Daniel K. Podolsky, of Massachusetts General
Hospital in Boston, noted that probiotic therapy is already showing
some success in the treatment of inflammatory bowel disease. "A
better understanding of how the normal gut microflora remains largely
invisible to the host intestinal epithelium may provide a clearer
picture of the molecular pathways of chronic inflammation,"
Gaon and colleagues at the University of Buenos Aires also recently
found evidence that some lactobacillus are effective for treating
chronic diarrhea linked to the bacterial overgrowth that often accompanies
some anatomic disorders and partial small-bowel obstructions.
Probiotics have a well established place in Japan, where hundreds
of companies make and sell such products in Europe and increasingly
in the United States. Food companies are developing chemical compounds,
known as prebiotics, to selectively foster the growth of specific
commensal bacteria in the gut. "These compounds are often part
of a normal diet and are mainly nondigestible sugars, such as inulin
and its derivatives, as found in vegetables such as leeks, onions,
and garlic," says Glenn Gibson, University of Reading,
This scanning electron micrograph of human feces shows the diversity
of bacterial types in the intestinal ecosystem, and how many bacterial
inhabitants live in the gut. About 50% of fecal mass consists of
Photo: Courtesy of Gerald Tannock
The concept of edible germs has been already tried and tested in
the marketplace and well accepted by many consumers in dairy products
such as yogurt, which owes its character to live Lactobacillus cultures
and now often incorporates additional probiotic species, such as
bifidobacteria. Ironically, the supposed healthful qualities associated
with the long and widespread use of lactobacilli in yogurt may be
based on a misperception, Tannock says, "because they are not
numerically dominant in the intestinal tract and are absent from
the microflora of about 25% of human subjects."
Bifidobacteria are common, but Tannock says that "it may be
difficult to achieve probiotic colonization of the adult digestive
tract even when strains of intestinal origin are utilized."
The already established microflora would defend against the introduced
strain, just as they would against a pathogen entering the ecosystem.
In studies reported so far, it appears that large numbers of microbial
cells need to be ingested on a daily basis to achieve persistence
of the probiotic strain in the digestive tract. That need for
repeated ingestion is, of course, a major attraction to food manufacturers.
Gibson says this industry undoubtedly has bigger plans for probiotics:
"We are likely to see [probiotics] ... included soon in everything
from cheese to ice cream and even some preserved meats, such as
salami," he says.
He predicts, for example, that prebiotic additives aimed at fostering
the growth of certain intestinal microbes in bottlefed babies will
find their way into infant milk formulas within the next two years.
The thinking behind that proposal is that a breast-fed baby seems
to get fast, dual protection from intestinal disease by being rapidly
colonized with bifidobacteria from its mother, the growth of which
is selectively favored by a bifidus factor in her breast milk. Such
babies seem to get a better head start in life: There is evidence
that their intestinal tracts are colonized faster than those of
Caesarian-born infants, and they have fewer gastrointestinal infections
than bottle-fed babies.
The beneficial microbiota overwhelmingly dominate the intestinal
ecosystems of healthy babies. At weaning, the bifidobacteria lay
first claim to the gut habitat and alter its acidity, making it
hostile to potentially harmful species. Intriguingly, Reid's team
has suggested the future possibility of inoculating newborn infants
with probiotics (because it is difficult to artificially introduce
new organisms into an established microbial ecosystem) the
child might then enjoy lifelong protection with no need for external
replenishment of the probiotic strain.
Probiotic research and development is poised to make great advances
during the next five years, says Tannock. "A detailed understanding
of the intestinal microflora will quickly emerge as molecular technologies
are applied increasingly to analysis of intestinal communities,
in conjunction with the use of biochemical and bacteriological methodologies.
It is an exciting time to be involved in intestinal microflora research."
Bob Beale (www.bob.beale.org)
is a freelance writer in Sydney, Australia
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