From Science News Online

June 9, 2007

More research on " friendly " bacteria - an exceedingly complex

population that we really can't live without, and where a disruption

in the microbial community can result in disease.

Arne

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Science News Online

Week of May 19, 2007; Vol. 171, No. 20

Our Microbes, Ourselves

How bacterial communities in the body influence human health

andra Goho

In the womb, a fetus enjoys the protection of a sterile environment.

Only when the mother's amniotic sac ruptures before delivery does her

baby face microbes for the first time. As he's squeezed through the

birth canal, he picks up millions of bacteria from his mother. Most

of the microbes are friendly and quickly take up residence on the

baby's skin and in his gastrointestinal tract.

[iMAGE]

The bacteria not only persist but also form complex communities

throughout the newborn's body that will aid in his general well-being

throughout life. The body's microbes play a critical role in

digesting food, metabolizing drugs, and maintaining overall health.

In fact, in every person's body, there are 10 times as many microbial

cells as there are human cells. " The microbial part of ourselves is

highly evolved, " says Gordon, a microbiologist at Washington

University in St. Louis. " These organisms have learned to adapt to

life with us. "

It's no wonder then that this vast microbiota has captured the

attention of researchers working to understand not just health, but

also diseases, particularly those lacking clear diagnoses or

effective treatments. With new laboratory techniques, these

researchers have begun to survey the microbial communities in the

body. Several groups already report that disruptions in these

communities are related to conditions including obesity, inflammatory

bowel disease, vaginal infections, and gum disease.

Scientists have long recognized that the body's microbiota matters.

In the 19th century, Louis Pasteur declared that normal microbes are

important in human health and that their disruption can lead to

disease. Until recently, however, scientists studying human-microbial

populations had been hampered because the majority of such microbes

can't be cultured in the lab. Now, researchers can extract DNA from a

sample and rapidly identify thousands of bacterial species at once

without having to grow each bug in a dish.

New studies are also showing that microbes within a community work

together to influence health, a finding that may have a large impact

on conventional views of disease. Instead of an illness being caused

by the presence or absence of a single pathogen, " the real pathogenic

agent is the collective, " says Relman, an infectious-disease

investigator at Stanford University.

Gutting it out

Washington University's Gordon regards the gut as a

bioreactor & #151;something like a living septic tank that breaks down

organic matter. The human gut is filled with microbes that interact

with one another and their host in mutually beneficial ways (SN:

5/31/03, p. 344:

http://www.sciencenews.org/articles/20030531/bob9.asp).

Several years ago, Gordon and his group conducted a series of

experiments in which they transplanted microbial communities from the

guts of normal mice into mice reared in a sterile environment. The

formerly germ-free mice began to accumulate fat in their tissues. The

transplanted microbes not only permitted the mice to metabolize

nutrients that would otherwise have been lost but also appeared to

manipulate mouse genes in a way that increased the animals' capacity

to store fat, the team reported in 2004.

The researchers homed in on the gene for a protein called

fasting-induced adipocyte factor, which is known to regulate energy

storage. Normally, the protein is secreted from the cells lining the

gut. The protein blocks lipoprotein lipase, an enzyme that controls

the transfer of fat molecules from the blood into fat cells.

In mice that had received the transplanted gut microbes,

fasting-induced adipocyte factor was suppressed. This increased the

lipase's activity, resulting in more fat being stored.

The results prompted Gordon and his colleagues to hypothesize that

differences in gut-microbial communities might explain differences in

how well people harvest energy from food and store it as fat. So, the

group decided to compare the gut microbiota of lean and obese mice.

" We saw this amazing, mind-boggling shift in the relative

representation of the two principal groups of bacteria that normally

inhabit mammalian guts, " says Gordon. Those bacterial types are

called Firmicutes and Bacteroidetes.

The researchers identified the members of the animals' gut microbial

communities by sequencing a specific gene whose sequence varies from

one species to the next. Researchers frequently use this gene, called

the 16S ribosomal gene, as a mini & #150;bar code for identifying

bacteria.

Mice bred to be obese had a larger proportion of Firmicutes and a

smaller proportion of Bacteroidetes than their lean counterparts did.

The change wasn't the result of one bacterial species taking over a

group or of another species being suppressed. " Everything moved up or

down, " Gordon says.

To determine how changes in the bacterial communities relate to the

animals' body weights, Gordon and his team transferred gut microbes

from the obese and lean mice to germfree mice. The mice receiving gut

bacteria from obese animals gained significantly more fat than did

mice receiving gut microbes from lean animals, the team reported in

the Dec. 21/28, 2006 Nature.

In a separate report published in the same issue, the researchers

addressed whether a similar pattern exists in the human gut. The team

studied 12 people who volunteered to be randomly assigned to either a

low-calorie, fat-restricted diet or a low-calorie,

carbohydrate-restricted diet. The researchers monitored changes in

the volunteers' gut-microbial communities over the course of a year.

Sure enough, as individuals of both groups lost weight, the

proportion of Firmicutes in their guts rose, while the proportion of

Bacteroidetes dropped.

Gordon is quick to point out that gut-microbial ecology isn't the

only factor affecting body weight. Genetics and easy access to

high-calorie foods play important roles. Still, the research suggests

that microbial communities in the gut form alliances with one another

as well as with their host, and that scientists will need to

understand the entire community to understand obesity and many other

complex conditions.

Inflammatory bowel disease, for instance, is a perplexing spectrum of

conditions that includes Crohn's disease and ulcerative colitis. In a

preliminary study, Relman and his colleagues identified signs of

altered microbial communities in people with Crohn's disease.

Using tissue samples obtained from the colons of about a dozen

individuals, the researchers found that people with Crohn's disease

had more Escherichia coli, Pseudomonas, and other microbes known as

proteobacteria than did people with ulcerative colitis or healthy

individuals. However, the researchers still don't know whether these

microbes cause the disease and whether other microbes contribute to

it.

Microbial signs

Microbial communities are not only critical to maintaining a healthy

gut; they also play vital roles in many other parts of the body.

Fredricks, a microbiologist at the Fred Hutchison Cancer

Research Center in Seattle, has been investigating a syndrome called

bacterial vaginosis, a vaginal infection that affects 10 to 20

percent of women in the United States.

[iMAGE] INTESTINAL INSIGHTS. The bacterium Bacteroides

thetaiotaomicron is a prominent member of the diverse community of

microorganisms that inhabit the human gut. In collaboration with

other microbes, these natural symbionts boost the gut's efficiency in

extracting calories from food and storing them as fat.

Z. He and L. T. Angenent / Washington Univ. (St. Louis)

" It's a curious disease because we still don't fully understand what

causes it, " he says. Although doctors can treat the infection with

antibiotics, the rate of relapse is high. About half of affected

women will develop another infection within a year after treatment.

In late 2005, Fredricks and his colleagues described experiments in

which they sampled vaginal fluid from women with and without

bacterial vaginosis. Using the 16S ribosomal gene, the researchers

identified 35 bacterial species associated with the syndrome. More

than half of these species had never before been identified. Three

strains in particular showed up in almost all patients with bacterial

vaginosis and were rare in women free of the syndrome.

Fredricks says that the findings support his hypothesis that

bacterial vaginosis is " a disease by microbial community. " He

believes that these bacteria are always found together because they

are metabolically interdependent. " These bacteria can't exist as

single species, " he says.

Fredricks' lab is currently monitoring a group of 30 women for

changes in their vaginal flora over a month. The goal is to determine

how women acquire bacterial vaginosis and how the microbial community

causing the syndrome responds to antibiotics.

Investigations of the human microbiota could also shed light on

complex skin conditions such as psoriasis and eczema. At present,

most researchers consider psoriasis to be caused by the immune system

gone awry. But because human skin is home to a complex ecosystem of

mostly unidentified bacteria, Blaser, a microbiologist at the

New York University School of Medicine, suggests that microbes are

involved. " The field of investigative dermatology has almost

completely ignored the role of microbes, " he says.

To demonstrate the complexity of the skin's microbiota, Blaser's

group analyzed skin swabs taken from the inner forearms of six

healthy people. Reporting in the Feb. 20 Proceedings of the National

Academy of Sciences, the researchers identified 182 species of

bacteria. Each person showed a unique microbial makeup & #151;only four

species of bacteria were found in all six participants, and each

participant carried an average of 48 species. The results offer a

first glimpse of the diverse array of microbial species inhabiting

healthy skin, Blaser says.

The researchers resampled four of the participants 8 to 10 months

later and found many of the microbes previously identified along with

65 new bacterial species. All the volunteers had retained some of

their previous microbial residents and had acquired new ones. The

result suggests that each individual's skin harbors both a core set

of microbes and a group of transient members.

Blaser's lab is now examining people with psoriasis to see whether

there's a microbial signature for the skin disease.

However, identifying individual species may be irrelevant in some

cases of disease caused by microbial communities. " It might not

matter who is there but rather what the collective is doing, " says

Relman.

For instance, he's found that some people with severe gum disease

harbor an abundance of hydrogen-consuming microbes called

methanogens. Related to bacteria but properly classified as archaea,

methanogens live in the deep gaps between gums and teeth.

But not everyone with severe gum disease hosts methanogens. Other

people's afflicted mouths instead support large populations of

hydrogen-consuming bacteria called treponemes.

Hydrogen is a by-product of fermentation in oxygen-deprived

environments, such as the tooth-gum gaps, and it also limits growth

among hydrogen-producing microbes. Relman says that through a

behavior called syntropy, the hydrogen-consuming

microbes & #151;whether methanogens or treponemes & #151;work together

with the other microbes to stabilize the microbial community and keep

it going.

Similarly, Gordon's group found that two common species of gut

microbes work together to boost fat storage in germ-free mice (SN:

6/17/06, p. 373: Available to subscribers at

http://www.sciencenews.org/articles/20060617/fob5.asp).

These observations reinforce the notion that to develop new medical

therapies, researchers will need to consider all the interacting

members of a microbial population.

Human genome II

As they delve deeper into this area, scientists expect to find great

variation in the composition of microbial communities that inhabit

different parts of the body. The skin microbes on a person's forearm

probably differ from those on his or her back, and the microbial

communities in the colon most likely differ from those that inhabit

the small intestine, the stomach, and the esophagus. Considering that

the gastrointestinal tract is 6.5 meters long and contains up to 100

trillion microbes representing 1,000 different species, " we have our

work cut out for us for a while, " says Gordon.

[iMAGE]

Improvements in DNA-sequencing technology and computational tools are

accelerating the pace of research. Last year, a group of scientists

led by University of Buffalo (N.Y.) microbiologist Gill and

including Gordon and Relman completed the first survey of the

microbial genes in the human colon. In samples from two healthy

adults, the team tallied more than 60,000 genes. The researchers

reported their findings in the June 2, 2006 Science.

Rather than isolating each microbe and sequencing its entire genome,

the researchers treated the microbial community as a collective with

a single genome. The team analyzed all the microbial genes present

without regard to any single gene's cell of origin.

Called metagenomics, this form of analysis doesn't produce a list of

bacteria but instead describes the metabolic activities going on

within a microbial community. These activities include energy

conversion and the transport and break down of carbohydrates and

amino acids.

Scientists have been using metagenomics for several years to describe

microbial communities in soil and in the ocean. Only recently have

they started applying the technique to the microbiota in people.

The National Institutes of Health is considering a Human Microbiome

Project & #151;an extension of the Human Genome Project & #151;that would

create a genetic inventory of the microbial communities inhabiting

the body's major niches, such as the mouth, vagina, skin, and

intestinal tract. This spring, NIH is expected to decide whether to

proceed with the project.

The Human Genome Project was an international effort that took 13

years to complete. A survey of the entire microbiota of a person

would be an even more formidable undertaking. " In any one human,

there are a hundred times as many microbial genes as there are human

genes, " says Relman.

Furthermore, microbial communities may vary significantly over small

distances within any given part of the body. For instance, Relman has

found that a community's membership changes from one part of a

person's mouth to another. There are differences between the front

and back sides of teeth, he says, between the gum pockets of two

adjacent teeth.

To further complicate matters, different people harbor different

collections of microbes. Researchers will have to focus on the

microbiota within an individual and within groups of individuals. " I

think this is a global project in many senses of the word, " says

Gordon. Ideally, researchers would survey microbes from people living

in different ecosystems and under different socioeconomic conditions,

he says.

The knowledge derived from such investigations could have an enormous

impact not only on understanding human health and disease but also on

the development of new therapies. Take, for instance, the chemical

signals that microbes in the gut might use to manipulate human genes.

" These chemicals then become potential components of a 21st-century

medicine cabinet, " says Gordon.

Alternatively, pharmaceutical companies could develop drugs that

target specific bacterial compounds to restore a microbial community

in the body to its normal state.

Ultimately, says Gordon, " we will have a broader view of ourselves as

a life form, as a composite of different species. "

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References:

B & #228;ckhed, F.... and J.I. Gordon. 2004. The gut microbiota as an

environmental factor that regulates fat storage. Proceedings of the

National Academy of Sciences 101(Nov. 2):15718-14723. Available at

http://www.pnas.org/cgi/content/full/101/44/15718.

Eckburg, P.B., and D.A. Relman. 2007. The role of microbes in Crohn's

disease. Clinical Infectious Diseases 44(Jan. 15):256-262. Abstract

available at http://dx.doi.org/10.1086/510385.

Fredricks, D.N., T. Diedler, and J.M. Marrazzo. 2005. Molecular

identification of bacteria associated with bacterial vaginosis. New

England Journal of Medicine 353(Nov. 3):1899-1911. Available at

http://content.nejm.org/cgi/content/full/353/18/1899.

Gao, Z.... and M.J. Blaser. 2007. Molecular analysis of human forearm

superficial skin bacterial biota. Proceedings of the National Academy

of Sciences 104(Feb. 20):2927-2932. Abstract available at

http://www.pnas.org/cgi/content/abstract/104/8/2927.

Gill, S.... J.I. Gordon, D.A. Relman, et al. 2006. Metagenomic

analysis of the human distal gut microbiome. Science 312(June

2):1355-1359. Abstract available at

http://www.sciencemag.org/cgi/content/abstract/312/5778/1355.

Ley R.E.... and J.I. Gordon. 2006. Microbial ecology: Human gut

microbes associated with obesity. Nature 444(Dec. 21):1022-1023.

Abstract available at http://dx.doi.org/10.1038/4441022a.

Ley, R.E.... and J.I. Gordon. 2005. Obesity alters gut microbial

ecology. Proceedings of the National Academy of Sciences 102(Aug.

2):11070-11075. Available at

http://www.pnas.org/cgi/content/full/102/31/11070.

Turnbaugh, P.J.... and J.I. Gordon. 2006. An obesity-associated gut

microbiome with increased capacity for energy harvest. Nature

444(Dec. 21):1027-1031. Abstract available at

http://dx.doi.org/10.1038/nature05414.

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