Antibiotics alter GI tract microbes and increase lung sensitivity to allergens

"We all have a unique microbial fingerprint – a specific mix of bacteria and fungi living in our stomach and intestines," says Gary 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 Rachel Noggle, a research assistant in internal medicine.

Note: This is a basic scientific research study conducted in laboratory mice. Much additional research will be required before scientists will know if these results can be applied directly to people. Your physician is the best source of advice for questions about antibiotics and treatment of asthma, allergies and other inflammatory diseases.

Contact: Sally Pobojewski
pobo@umich.edu
734-615-6912

Kara Gavin
kegavin@umich.edu
734-764-2220

University of Michigan Health System