New model may help treat digestive problems

Every animal — including humans — is home to “friendly” gut bacteria that help digest food and perform other important functions. Now, a tiny, transparent fish is offering biologists a new window into understanding and treating human digestive problems.

Jeffrey Gordon

Jeffrey Gordon

School of Medicine researchers have shown for the first time that zebrafish can be raised in a germ-free environment.

Because zebrafish are transparent until they reach adulthood, they provide researchers with unique opportunities to watch the gut develop with and without the beneficial effects of symbiotic bacteria.

“To untangle the complex interactions between humans and their friendly gut bacteria, we need simple animal models that can function as living test tubes,” said principal investigator Jeffrey I. Gordon, M.D., the Dr. Robert J. Glaser Distinguished University Professor and head of the Department of Molecular Biology and Pharmacology.

“These models are key to identifying the genes and chemicals that allow friendly bacteria to enhance our health.”

A study, recently published in the online version of the Proceedings of the National Academy of Sciences, also is the first to describe which bacteria normally reside in the zebrafish gut.

The first author is John F. Rawls, Ph.D., a postdoctoral fellow in Gordon’s laboratory.

The germ-free zebrafish arrived 50 years after scientists announced a similar biological feat: a viable strain of mice with no bacteria in their bodies.

Gordon’s team believes zebrafish provide a nice complement to ongoing mouse research for several reasons.

First, the zebrafish gut is organized in ways similar to the mammalian gut, and an international effort to sequence the zebrafish genome is almost complete.

Zebrafish also are less than one centimeter long during development, so it is easy to raise large numbers at once. And finally, unlike mice, it is possible to watch the gut develop and function in zebrafish.

After months of trial and error, the team finally succeeded in developing germ-free zebrafish that survived until late juvenile stages.

The researchers discovered that several biological processes were disturbed in germ-free zebrafish.

These impairments were similar to those the team had documented previously in germ-free mice. For example, the ability to process nutrients was compromised, as was the zebrafish’s immune system.

To begin to decipher the mechanisms underlying the observed abnormalities, the team determined the genetic profile of three groups of fish: a group raised under conventional conditions with bacteria; a group raised in a germ-free environment; and an initially germ-free group later colonized with normal gut bacteria.

The comparison revealed 212 genes with different levels of expression in germ-free fish compared with the other two groups that had been exposed to bacteria.

The researchers found 66 zebrafish genes analogous to genes regulated by friendly bacteria in the mouse intestine.

The team then began compiling a list of bacterial species that reside in the zebrafish gut.

“We wanted to determine which constituents of the microbial community might be responsible for specific biological processes,” Rawls said. “Using a molecular approach, we were able to identify a large number of types of bacteria that exist within the zebrafish digestive tract.”

The team then systematically recolonized germ-free animals with selected microorganisms.

Using representatives from each of two major classes of organisms found within the zebrafish gut, they determined that some host responses are quite specific for a given type of bacteria, while others are more general.

“The power of using germ-free animals is that you can define how a single species, or combinations of bacterial species, function to help complete animal development and to benefit adult physiology,” Gordon said.

The team plans to use its germ-free zebrafish to characterize the chemicals produced by gut bacteria.

According to Gordon, the chemical messengers developed by symbiotic gut bacteria over the course of millions of years of evolution could provide new approaches for supporting and healing the digestive system.

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