The discovery expands the known taxonomic breadth of metabolic disease and suggests that the study of microbes found in human intestines may provide a greater understanding of the root causes of human metabolic dysfunction.
James Marden, professor of biology and an insect physiologist at Penn State, and Ruud Schilder, who in August 2006 earned his doctorate in biology at Penn State and is now a postdoctoral fellow at the University of Nebraska, are the first to show a non-mammalian species suffering from metabolic dysfunction in ways similar to humans. "Metabolic disease isn't some strange thing having just to do with humans," said Marden. "Animals in general suffer from these symptoms."
The work is also novel because it links metabolic disease to a supposedly harmless parasite living in the dragonfly's gut. The parasites, known as gregarines, belong to the Apicomplexa, a group of microorganisms that includes protozoa, which cause diseases like malaria and cryptosporidiosis. The dragonfly species that Marden and Schilder studied is Libellula pulchella. The microbes disrupting the dragonfly metabolism may hold clues for scientists looking for the root causes of metabolic diseases in humans, according to Marden and Schilder's paper
"All of these symptoms, and the underlying processes behind these symptoms that we're seeing in these dragonflies, are pretty much identical to what you see in mammalian metabolic syndrome and obesity," said Marden. "We're seeing it all relate back to this non-invasive protozoan in the gut." The work raises a fascinating question about what role microbial communities found in human intestines may play in human metabolic disorders like insulin resistance, type-2 diabetes, and obesity. In mammals, these metabolic disorders are known to be associated with a chronic inflammatory response, thought to be triggered by an accumulation of fat.
In Marden and Schilder's dragonflies, the reverse happens. Parasitic infection triggers an inflammatory response and immediate changes in metabolism. Unable to metabolize fat, the dragonflies accumulate fat around their muscles. This finding begs the question of whether something similar might be happening in human metabolic diseases, the root causes of which remain poorly understood despite intense study.
"Might disturbances in the microbial balance of human intestines trigger an immune system response that leads to metabolic disease?" Marden and Schilder asked. "More attention should be paid to the microbial balance in the intestines of people who suffer from obesity," said Schilder. "It seems plausible that disturbance in the microbial community in humans might trigger these inflammatory responses."
There are some other clues indicating that this may be an important question. "What we're finding in insects is that they become obese when parasites cause inflammation that affects metabolism," said Marden. "That seems akin to what's happening in humans when they get type-2 diabetes. It's not because there's been a change in the genetic composition of the population. it's because something has changed in our environment." One change in the human environment is the dramatic increase in soft-drink consumption among Americans, estimated to be 500 percent over 50 years from the 1940s to the 1990s. "We looked in the literature and found that consumption of high-fructose corn syrup often is associated with gastrointestinal distress, which may be a sign that fructose affects the gut microbial flora," said Marden.
Another clue is that some AIDS patients, with compromised immune systems, have chronic problems with Cryptosporidium (a protozoan parasite closely related to the one found in dragonflies) that over time impairs their metabolism in a similar fashion to what Schilder and Marden found for infected dragonflies. "That information gave us the courage to connect the dots," said Marden. "Granted, it is a big extrapolation to think that our dragonfly results might have any relevance for human disease, but it would be irresponsible for us to not point out these possibilities. People who study metabolic disease should test the hypothesis that changes in gut microbial composition can cause these syndromes."
Marden's lab, which studies how insect muscles work and affect the animal's survival and reproductive capabilities, can mechanically isolate single flight muscles and measure their mechanical power output under conditions similar to those in nature. The researchers noted that the muscles of some dragonflies are able to perform at 80 watts per kg. while others of the same species could perform at up to 220 watts per kg. The life of a dragonfly and successful mating requires intense competition for pond territory, aerial contests, and high-performance flight. "These guys are the jet fighters of the insect world," said Marden. Flight muscle makes up 60 percent of their body mass. The large variation in muscle output was intriguing because natural selection, over time, would weed out the submissive, poor flyers if the trait were genetically based. When the researchers looked in the gut of the dragonflies with poor muscle output, they found parasites.
Healthy dragonflies can adjust their muscle performance according to how much fat they have available in their bodies, but the dragonflies infected with parasites weren't making that adjustment, Marden observed. He and Schilder began looking for an explanation and ultimately found many key differences between the tissues and performance of healthy dragonflies and parasite-infected dragonflies that match symptoms of metabolic syndrome in humans. One symptom involves the signaling molecule, p38 MAP kinase, a common indicator of stress response in humans and other animals. The signaling molecule was chronically activated in the flight muscles of parasite-infected dragonflies, but not in muscles from healthy dragonflies. Activation of p38 MAP kinase has been shown to be related to the development of insulin resistance and metabolic disease in humans. "What's more, we could induce this activation in muscles from healthy individuals by exposing them to excretory-secretory products obtained from the gregarine parasites," said Schilder.
The researchers also found that the muscles of parasite-infected dragonflies oxidized only carbohydrates instead of a carbohydrate-lipid mix. A common symptom of metabolic syndrome is that muscles metabolize fewer lipids. The researchers also found that unused lipids accumulated in the dragonflies' thorax. Humans with metabolic disease tend to accumulate fat around skeletal muscle tissue.
Marden and Schilder's experiments also found the hemolymph carbohydrate concentrations in parasite-infected dragonflies to be about double those of healthy dragonflies, and found insulin to have little effect on those concentrations. Insulin resistance is an abnormality associated with metabolic syndrome in humans. The researchers found the parasites rapidly caused effects in the dragonflies. Dragonflies that drank water containing trace amounts of excretory-secretory substances obtained from live parasites showed effects in two days. Abnormal blood glucose concentrations are a symptom of metabolic syndrome in humans. Marden and Schilder also concluded that insects may be useful models to understand more about metabolic disease in humans. Their work was supported by grants from the U.S. National Science Foundation.
Barbara K. Kennedy | EurekAlert!
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