Antibiotics alter GI tract microbes

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Public release date: 26-May-2004

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Kara Gavin

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University of Michigan Health System

Antibiotics alter GI tract microbes and increase lung sensitivity to

allergens

Study could help explain increasing rates of asthma, allergies and

inflammatory diseases

NEW ORLEANS ? Allergies making your life miserable? Tired of popping

antihistamines like candy? Can't go anywhere without your inhaler?

The real problem may not be your stuffed-up head. It could be the

microbes in your gut.

At the American Society for Microbiology meeting held here this week,

scientists from the University of Michigan Medical School will

present results of experiments with laboratory mice indicating that

antibiotic-induced changes in microbes in the gastrointestinal tract

can affect how the immune system responds to common allergens in the

lungs.

" We all have a unique microbial fingerprint ? a specific mix of

bacteria and fungi living in our stomach and intestines, " says

B. Huffnagle, Ph.D., an associate professor of internal medicine and

of microbiology and immunology in the U-M Medical

School. " Antibiotics knock out bacteria in the gut, allowing fungi to

take over temporarily until the bacteria grow back after the

antibiotics are stopped. Our research indicates that altering

intestinal microflora this way can lead to changes in the entire

immune system, which may produce symptoms elsewhere in the body. "

If confirmed in human clinical studies, Huffnagle believes his

research findings could help explain why cases of chronic

inflammatory diseases, like asthma and allergies, have been

increasing rapidly over the last 40 years ? a time period that

corresponds with widespread use of antibiotics.

To understand the implications of the U-M research, it's important to

know something about the complex relationship between the

gastrointestinal, respiratory and immune system in the human body.

Every time you inhale, air flows past mucus-producing cells and tiny

hairs designed to trap bits of pollen, dust and spores before they

enter the lungs. These trapped particles are swept into the stomach

with saliva and mucus as you swallow.

" Anything you inhale, you also swallow, " Huffnagle says. " So the

immune cells in your GI tract are exposed directly to airborne

allergens and particulates. This triggers a response from immune

cells in the GI tract to generate regulatory T cells, which then

travel through the bloodstream searching the body for these antigens.

These regulatory T cells block the development of allergic T cell

responses in the lungs and sinuses. "

Most of the time, in ways scientists don't completely understand, the

GI tract immune system modulates or dampens down the allergic T

cells' response to incoming allergens in the lungs, according to

Huffnagle. But when antibiotics reduce the bacterial population in

the GI tract, the number of yeast and other fungal organisms

increases.

In previous studies, researchers in Huffnagle's lab discovered that

fungi secrete molecules called oxylipins, which can control the type

and intensity of immune responses. Huffnagle says this suggests the

intriguing possibility that fungal oxylipins in the GI tract prevent

the development of regulatory T cells for swallowed allergens. In the

absence of regulatory T cells from the GI tract, T cells in the lungs

become sensitized to the presence of ordinary mold spores, pollen or

other allergens. The result is a hyperactive immune response, which

can produce allergy symptoms or even asthma.

To test Huffnagle's hypothesis, Mairi C. Noverr, Ph.D., a U-M

research fellow in internal medicine, gave a five-day course of oral

antibiotics to normal lab mice followed by a single oral introduction

of the yeast, Candida albicans, to create a consistent, reproducible

colony of microbes in the stomach and intestines. C. albicans is

normally found in the GI tract, and increased growth of C. albicans

in the gut is a common side-effect of antibiotics.

Two days after stopping the antibiotics ? at a time when the gut

bacteria were growing back - Noverr exposed the mice to a common mold

allergen called Aspergillus fumigatus by inoculating spores into the

nasal cavities of all the mice in her study. She then examined the

mice for the presence of an allergic response in the airways and

compared results between the mice that received antibiotics and those

that did not.

" Mice treated with antibiotics and colonized with C. albicans showed

increased pulmonary hypersensitivity to A. fumigatus compared with

mice that didn't receive antibiotics, " Noverr says. " The inflammatory

response grew stronger with every exposure to the allergen. "

" After antibiotics changed the mix of microbes in the GI tract, the

mice developed an allergic response in the lungs when exposed to

common mold spores, " Huffnagle explains. " Mice that didn't receive

the antibiotics were able to fight off the mold spores. "

Huffnagle and Noverr will discuss details of the experiment in a

symposia lecture and poster presentation at the ASM meeting. Complete

data from the study has been submitted for publication in a future

issue of Infection and Immunity.

Huffnagle maintains that disruptions in the growth of bacteria and

fungi in the GI tract somehow interfere with the ability of

regulatory T cells to dampen the immune response to respiratory

allergens. In future research, he hopes to determine exactly how

gastrointestinal microbes are involved in the process of immune

system modulation.

" We know from laboratory experiments that dietary antioxidants called

polyphenols, which are found in fruits and vegetables, can limit

fungal growth and that a diet high in saturated fats and sugars slows

the recovery of normal gut microflora, " Huffnagle adds. " The

Mediterranean diet is rich in sources of polyphenols, so it's

intriguing that Mediterranean-diet countries have lower rates of

allergies, asthma and other inflammatory diseases than Western-diet

countries like the United States, Canada and England.

" If we can determine exactly how microflora in the GI tract affect

the immune system, it may be possible one day to prevent or treat

allergies and inflammatory diseases with diet changes or probiotics ?

dietary supplements of 'healthy' bacteria designed to restore the

normal balance of microbes in the gut, " Huffnagle adds. " In the

medical community, probiotic therapy is becoming an area of

increasing interest. "

Until then, Huffnagle emphasizes the importance of a healthy low-

sugar diet, with lots of raw fruits and vegetables, after being

treated with antibiotics to help restore the normal mix of microbes

in your GI tract as quickly as possible. " The old saying, 'an apple a

day keeps the doctor away' may be more true than we thought, " he

says.

Huffnagle's research has been funded by the National Institutes of

Health and a New Investigator Award from the Burroughs-Wellcome Fund.

Other collaborators in the research include Dennis M. Lindell, a U-M

graduate student in immunology, and Noggle, a research

assistant in internal medicine.