Nurturing Our Microbes - Stewardship of the life teeming within us

March 7, 2008

Article Link:

http://www.sciencenews.org/articles/20080301/bob10.asp

Science News Online

Week of March 1, 2008; Vol. 173, No. 9

Nurturing Our Microbes

Stewardship of the life teeming within us can pay health dividends

Janet Raloff

Each of us is a metropolis. Bustling about in everyone's body are

tens of trillions of microbes. Some are descended from starter

populations provided by mom during birth. Additional bacteria,

yeasts, and other life forms hitchhike in with foods. By age 3,

everyone's gut hosts a fairly stable, yet diverse, ecosystem.

The bacteria that ferment milk into yogurt also perform a host of

beneficial functions in the gastrointestinal tract. They are among

microbes that can alter immunity, modulate the body's ability to mine

nutrients, and more. How they achieve such varied feats can be far

more subtle—and varied—than previously thought, new data show.

iStockphoto/E. Roell

Most of the tiny stowaways hide out in the gastrointestinal tract—the

gut-stealing a share of everything we eat or drink. But that's only

fair, because most of these bugs give as good as they take, explains

microbiologist Jeffrey I. Gordon. They not only help us digest food,

he says, but they also harvest nutrients, manufacture certain

vitamins, kill germs, neutralize bacterial toxins, and modulate the

immune system. Sickness, antibiotic therapy, or stress, however, can

disrupt the ecological balance among gut dwellers—known as flora—

diminishing their benefits.

Because these benefits are vital to health—and to averting disease—

drug manufacturers are eyeing gut microbes as potential therapeutic

targets. In the future, " pharmaceutical companies might be drugging

your bugs, not drugging you, " suggests Jeremy Nicholson of Imperial

College, London.

In the meantime, over-the-counter therapies exist to bug, not drug,

the bugs. Known as probiotics, these yogurts and other foods or

dietary supplements introduce or replenish beneficial gut species in

the digestive system (SN: 2/2/02, p. 72).

Probiotic microbes' role in fighting generic diarrheal disease is old

hat, but in the past decade, other influences on human immunity and

metabolism have emerged. Certain microbial supplements show the

potential to reduce the severity of colds and other infections,

temper body weight, and even help the elderly fight osteoporosis.

The rub: Research is showing that a probiotic's benefits can be very

specific. In fact, it might be more appropriate to view these

microbes as a cornucopia of diet-based, over-the-counter micro-

pharmacists—each able to dispense only a few therapies or services.

But for all the promise that probiotics offer, they're no panacea,

many researchers caution, and may even exhibit disturbing effects

(see " Not without Risks, " below). Within a given species, some

strains may confer health benefits, others may not.

Yet when the right bug is ingested for a particular condition, even a

small dose can trigger dramatic health benefits.

Dining partners

" The total number of microbes associated with our adult bodies

exceeds the total number of our human cells by a factor of 10, " says

Gordon, of Washington University in St. Louis. So effectively, " we're

sort of a superorganism—one that's 90 percent microbial. "

Other animals have evolved a similar symbiosis with—or even

dependence on—gut microbes, the scientist notes. Rodents born by

cesarean section (so they get none of their moms' intestinal flora)

and raised under germfree conditions end up smaller than normal, his

group found—despite eating " about 30 percent more food than their

microbe-laden counterparts. "

Germfree animals not only appear less efficient at harvesting

calories, he explains, but also " are prone to certain vitamin

deficiencies " because gut microbes synthesize certain nutrients, such

as vitamins B12 and K.

Gut flora also help the body mine minerals from the diet. " We have

measured this for calcium, " says Jürgen Schrezenmeir of Germany's

Federal Research Center for Nutrition and Food, in Kiel.

His team showed that supplementing rats' diets with a probiotic

strain of bacteria, Lactobacillus acidophilus, kept the animals from

losing bone, a symptom of early osteoporosis.

This probiotic, renowned for its copious production of lactic acid,

occurs naturally in some yogurts and other fermented dairy products.

Bonus intestinal acid should increase the solubility of several

minerals, including calcium, Schrezenmeir explains. Extra lactic acid

should also spur the growth of cells lining the gut, he says,

creating a bigger cadre to sop up released minerals.

To test these hypotheses, his group removed the ovaries from 6-month-

old female rats. The ensuing drop in the rodents' production of

estrogen mimicked the hormonal environment of postmenopausal women.

Over the next 16 weeks, the rats began losing bone, modeling what

happens in many elderly women. However, calcium uptake from the diet

was somewhat higher—and bone loss somewhat reduced—in animals given

L. acidophilus.

Calcium uptake and bone mass improved even more when the researchers

simply supplemented the animals' diet with a material on which lactic

acid bacteria prefer to feed. That supplement—known as a prebiotic—

contained carbohydrates that only bacteria can digest.

Rodents receiving both prebiotics and probiotics retained the most

bone and dietary calcium, the German team reported in the March 2007

Journal of Nutrition. Indeed, the combination restored bone mineral

density and bone structure to about the level in rats with intact

ovaries, Schrezenmeir says.

Tuning immunity

Probiotics are usually promoted as supporting intestinal health—a

polite way of hinting that they may reduce the risk of diarrhea or

bloating. Far less appreciated is the broad range of immune

conditions for which they show promise.

MICRO PHARMACY. This scanning electron micrograph of yogurt shows

bacteria that can both make lactic acid and, in some cases, promote

health.

Mediscan/Corbis

The gut " is the body's largest immune organ, " notes Arthur C.

Ouwehand of the University of Turku, Finland, and of Danisco

Innovation, a company that makes probiotics-enhanced foods. That's

why investigators at his and other research centers are exploring

probiotics to improve immunity.

A study in 2005 by Schrezenmeir and his colleagues showed that daily

treatment with a trio of probiotics didn't reduce the incidence of

colds. But the supplementation did reduce the severity and duration

of cold symptoms—including fever—compared with a group of people that

didn't get probiotics.

" We don't know the mechanism " for the probiotic advantage,

Schrezenmeir says. However, in individuals given probiotics, the

number of activated helper T cells—white blood cells that fight

infection—increased, as did the number of germ-killing cells.

Probiotics may move the immune system in the opposite direction as

well. Over the past year, several research teams reported some

success with probiotics in treating inflammatory bowel disease. At

least one study found they could help control exaggerated

inflammation in intensive care patients at high risk for multiple

organ dysfunction syndrome—a hyperinflammatory condition. And in a

paper last August, Ouwehand recounted how probiotics administered to

pregnant women and babies reduced the likelihood that high-risk

infants developed food allergies.

In its newest work, Schrezenmeir's team incubated immune cells from

the blood of healthy or allergic individuals together with several

immune-stimulating substances. Cells from all of the people

responded, but only cells from allergic people showed an exaggerated

response to allergens.

Adding four probiotic microbes or the naked DNA from probiotic

bacteria to the mix substantially ratcheted down the response of

immune cells, especially for people with allergies. About half of the

immune-dampening effect in probiotic-treated cells was attributed to

the live bugs, and half to their DNA—released when the beneficial

bugs died. The work will appear in an upcoming Immunobiology.

Probiotic benefits are typically attributed to the fact that

supplemented microbes were alive. However, receptors on the surfaces

of both immune cells and cells lining the gut can bind DNA,

Schrezenmeir notes. Probiotic DNA won't be accessible to those cells

until the microbe dies. His team's new data suggest that probiotics—

dead or alive—can affect systems in the body, perhaps by contributing

to the communications among the gut's native microbes.

Weight modulators

A number of food companies are investigating new health applications

for probiotic supplements and fortified foods. Among novel functions

being explored at the Nestlé research center in Lausanne,

Switzerland, is probiotics' control over calorie use.

Company scientists teamed up with researchers in England and Sweden

for rodent experiments using strains of L. paracasei and L.

rhamnosus, probiotics that Nestlé discovered years ago.

To create gut ecosystems in rats that model those of humans, the

scientists seeded the guts of newborn mice—animals that were still

germfree—with microbes from the digestive tracts of human babies.

Beginning 6 weeks later, the researchers doctored the animals'

drinking water for 14 days with one or the other of the probiotics.

In the Jan. 15 Molecular Systems Biology, Nestlé biochemist Sunil

Kochhar and his colleagues report that both strains of tested

lactobacilli increased the hosts' breakdown and use of simple

carbohydrates. The data suggest that by helping people absorb more of

the calories present in carbs, these or related probiotics might one

day help fight malnutrition in parts of the world where carbohydrate-

based diets are common, Kochhar says.

But probiotics can push this metabolic pendulum the other way.

Bile acids, produced mainly in the liver, play an important role in

emulsifying dietary fats, a step that readies such lipids for

digestion. The Nestlé probiotics broke down taurocholic acid, an

especially efficient emulsifying bile acid. The resulting cholic

acid " is not a good fat emulsifier, " notes Nicholson, a coauthor of

the study—and after the probiotic treatment there was a 50-fold

higher ratio of cholic to taurocholic acid in the treated animals'

guts.

This change diminished the rodents' uptake of dietary fat and also

reduced their synthesis of potentially harmful fatty substances in

the blood, such as low-density lipoprotein cholesterol.

Where obesity is a problem, the same bugs might help people limit

weight gain by diminishing their absorption of fats. " You only need

to take in 20 to 30 more calories a day than you expend to make you

fat in 2 or 3 years, " observes Nicholson. " What we're interested in

is looking for [probiotic] microbes that might help you absorb 50

calories less a day. "

These metabolic findings complement observations by Gordon's team.

The ecology of guts in lean and obese rodents is dominated by

different bacteria, the Washington University researchers reported in

2006 in Nature (SN: 5/19/07, p. 314). The same holds for people.

After collectively identifying all of the microbial genes present in

the guts of the naturally lean and obese mice, " we found that genes

involved in breaking down otherwise indigestible complex

carbohydrates were much better represented in the obese animals' gut

communities, " Gordon says.

His group then transplanted gut flora from a lean or obese mouse into

a germfree animal and fed all treated rodents the same amounts.

Animals that had received the gut microbes from obese animals gained

more fat than did the animals given flora from a lean mouse.

Such experiments " show that differences in gut ecology influence the

efficiency with which the bugs extract energy from foods, " Gordon

says. However, his team's data also show that gut microbes can alter

what share of consumed energy will be stored as body fat.

Identifying the specific microbes responsible for these effects could

point to new classes of weight-controlling probiotics, Gordon

suspects.

Special effects

For all of their potential weight-modulating similarities, the two

Nestlé probiotics had additional—and very different—actions. While

the L. rhamnosus treatment dramatically decreased gut populations of

potentially lethal bacteria known as Clostridium difficile (SN:

2/18/06, p. 104), the L. paracasei probiotic offered no defense

against these germs.

There may be some direct effect of the probiotic microbes on these

germs, or even on food metabolism, Nicholson says. But his new data

suggest that many of the probiotics' effects might best be

characterized as microbial diplomacy—where small delegations of

ingested germs persuade an army of resident microbes to adopt

activities that better benefit their host.

" Bacteria talk to each other all of the time, " he says. Although

there may be billions of local organisms, most " tend to behave like

multicellular organisms, " he explains. These mega-beings coordinate

their activity via microbial chatter. They signal their intent

through the production and secretion of specific molecules.

" What we think is happening, " Nicholson says, " is that the probiotic

bugs enter the gut, producing their chemical signals. " Relative to

the hordes of microbes living in the gut, the incoming microbes make

up only a teensy minority. However, based on the chemical dispatches

issued during their transit through the intestines, the gut's

longtime residents " start to change what they're doing. "

In the new study, Nicholson's group showed that the messages relayed

by each of the Nestlé probiotics seem to hit different families of

resident flora, leading to different metabolic effects. One

implication, he says, is that depending on which microbes permanently

inhabit any particular individual's gut, the probiotic's message may

resonate loudly or fall on deaf ears.

So which probiotic is most likely to work for an individual may

depend on the precise nature of his or her flora, Nicholson

maintains. The challenge, he says, will be to find out which flora

are present and in what numbers. In a paper due out soon in the

Proceedings of the National Academy of Sciences, his group will

report the ability to get a rough inventory of those flora by

analyzing their metabolic detritus in human urine.

Because of " the significant involvement of the gut microbiota in

human health and disease, " gut flora might make good targets for

medicines, Nicholson and his colleagues argue in the February Nature

Reviews: Drug Discovery.

Consider that there are only about 3,000 human genes available to

target with drug therapy—but " probably 100,000 gene targets in your

gut microbiome, " Nicholson says.

To succeed, drug companies will need a better picture of the human

gut's microbial genome. It so happens that the National Institutes of

Health recently established the Human Microbiome Project to nail that

down.

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Not without Risks

Probiotics exhibit a dark side

By design, probiotics should be helpful at best, benign at worst,

notes Jeremy Nicholson of Imperial College, London. Side effects can

occur, however, so unless people are battling an illness, he warns

against consuming such microbes indiscriminately.

" If it ain't broke, " he argues, " don't fix it. "

The downside of probiotic therapy usually amounts to unexpected

diarrhea. However, infections in the liver, heart, and other organs

have also been linked to probiotics, according to a 2006 review by

Robert J. Boyle of Royal Children's Hospital in Victoria, Australia

and his colleagues. Although the infectious agent in some cases was

identical to the probiotic used, Boyle's group notes that an indicted

strain of microbe may sometimes also " be found in the internal

microbiota of healthy humans, so the source of infection in these

cases is not conclusively [due to probiotics]. "

Last year, researchers reported in the September Pediatric Intensive

Care Medicine that they had shut down a pediatric trial with

Lactobacillus rhamnosus GG (LGG), a widely used probiotic, owing to

growing concern that it might actually spawn infections.

Looking to cut the risk of hospital-acquired infections in severely

ill children, Travis C.B. Honeycutt of WakeMed Health and Hospitals

in Raleigh, N.C., and his team began randomly assigning kids to

receive a probiotic or a placebo capsule daily while they were

hospitalized in an intensive care unit. However, when three reports

of LGG blood-borne infections in children emerged in quick succession

from neighboring physicians outside the trial, the North Carolina

researchers decided to perform an interim analysis to check whether

LGG was as benign as they had told their patients' parents it was.

" That analysis showed no benefit in our patients, " Honeycutt

recalls, " and a trend—although it was not statistically significant—

towards increasing infections in our probiotics group. "

But the really big wake-up call came last month, when Dutch

researchers published findings of a trial using probiotics in people

with acute pancreatitis. Patients provided nutrition laced with six

probiotics experienced a death rate nearly triple that of people fed

just the nutrients (SN: 2/23/08, p. 115).

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