The connection between gut bacteria and obesity has gained some weight, with new findings demonstrating links in mice among immune-system malfunction, bacterial imbalance and increased appetite.

Mice with altered immune systems developed metabolic disorders and were prone to overeating. When microbes from their stomachs were transplanted into other mice, they also become obese.

“This supports the notion that some of the increase in obesity may be because of changes to gut bacteria,” said Andrew Gewirtz, an Emory University immunologist and co-author of the study, published March 4 in Science.

The findings are the latest in a growing body of research about the long-unappreciated role of bacteria in our bodies. Bacterial cells actually outnumber human cells in the body: From an outside perspective, people are not so much individual organisms as symbiotic human-bacteria collectives.

Disturbances to internal bacteria have been linked to asthma, cancer and many autoimmune diseases. Gut flora have also been linked to obesity. In 2006, researchers led by Washington University microbiologist Jeffrey Gordon documented bacterial changes in the stomachs of mice who became obese on high-fat diets.

When transplanted, their gut bugs turned other mice obese, suggesting that altered bacteria were not only an effect of weight gain, but a cause. The Science findings complement those, but also emphasize the immune system’s role and the possibility of appetite change.

“The reason why people are eating too much may not simply be because unhealthy food is cheap and available, but that their appetites may be driven by changes in gut bacteria,” said Gewirtz,

In the Science study, Gewirtz and Emery microbiologist Matam Vijay-Kumar studied a strain of mice deficient in TLR-5, a gene that’s required for immune systems to recognize many types of bacteria.

They found that TLR-5–deficient mice are about 20 percent heavier than regular mice. They overeat, have high blood pressure and high cholesterol, and are insulin-resistant. In humans, that constellation of conditions is known as metabolic syndrome, and in both people and mice leads to obesity and diabetes.

Earlier research had found unusual patterns of bacteria in the guts of those mice. When the researchers transferred bacteria from the stomachs of TLR-5–deficient mice to mice without gut bacteria, the recipients started to eat more, and soon developed metabolic syndrome.

“It’s a really exciting paper. It confirms and supports a lot of the findings we’ve had, and adds in the interaction between gut bacteria and the immune system,” said Peter Turnbaugh, a systems biologist who moved from Jeffrey Gordon’s lab to Harvard University. “It’s been thought for a long time that maybe the immune system is an important regulator of what’s in the gut.”

How gut bacteria produce metabolic changes isn’t known. They may process nutrients directly, or alter the activity of metabolism-regulating genes.

Mice used in the research are not considered exact models of bacteria and obesity in humans. Instead they’re models of these sorts of relationships likely to exist in people. Gewirtz’s team is now investigating whether people with metabolic syndrome have unusual gut bacteria.

The findings don’t suggest obesity is literally contagious, said Turnbaugh. But they do raise the possibility of altering the composition of gut bacteria, either directly or — more realistically — by learning what sort of environmental and lifestyle factors produce obesity-causing bugs.

One possible culprit is the ubiquitous presence of antibiotics, both prescribed and in the environment, said Gewirtz.

“It may be that an unintended consequence of this has been the upset of bacterial populations that are promoting obesity and metabolic syndrome,” he said.

Image: Left, regular and TLR-5–knockout mice. Right, a comparison of their insulin-producing islet cells./Andrew Gewirtz

Intricate cellular components are often cited as evidence of intelligent design. They couldn’t have evolved, I.D. proponents say, because they can’t be broken down into smaller, simpler functional parts. They are irreducibly complex, so they must have been intentionally designed, as is, by an intelligent entity.

But new research comparing mitochondria, which provide energy to animal cells, with their bacterial relatives, shows that the necessary pieces for one particular cellular machine — exactly the sort of structure that’s supposed to prove intelligent design — were lying around long ago. It was simply a matter of time before they came together into a more complex entity.

The pieces “were involved in some other, different function. They were recruited and acquired a new function,” said Sebastian Poggio, a postdoctoral cell biologist at Yale University and co-author of the study published Monday in the Proceedings of the National Academy of Sciences.

Mitochondria are descended from free-living bacteria, which several billion years ago were swallowed by complex cells. The mitochondria soon became central to the cells’ function.

Mitochondria couldn’t have lasted in their new home without the help of a protein machine called TIM23, which delivers other proteins harvested from the cell’s body. Bacteria don’t possess TIM23, suggesting that it evolved in mitochondria. This seems to pose a cellular chicken-and-egg question: How could protein transport evolve when it was necessary to survive in the first place?

The essential paradox applies to other protein-transporting cell systems, providing disbelievers of evolution with a key part of their critique. As articulated by intelligent design proponent Michael Behe, “This constant, regulated traffic flow in the cell comprises another remarkably complex, irreducible system. All parts must function or the system breaks down.”

According to evolutionary theory, however, cellular complexity is reducible. It requires only that existing components be repurposed, with inevitable mutations providing extra ingredients as needed. Flagella, the hairlike propellers used by bacteria to move, are one example of this. Their component parts are found throughout cells, performing other tasks.

Intelligent design mavens once cited flagella as evidence of their theory. Scientific fact dispelled that illusion. The mitochondria study does the same for protein transport.

“This analysis of protein transport provides a blueprint for the evolution of cellular machinery in general,” write the researchers, led by molecular biologist Trevor Lithgow at Australia’s Monash University. “The complexity of these machines is not irreducible.”

When they analyzed the genomes of proteobacteria, the family that spawned the ancestors of mitochondria, Lithgow’s team found two of the protein parts used in mitochondria to make TIM23.

The parts are located on bacterial cell membranes, making them ideally positioned for TIM23’s eventual protein-delivering role. Only one other part, a molecule called LivH, would make a rudimentary protein-transporting machine — and LivH is commonly found in proteobacteria.

The process by which parts accumulate until they’re ready to snap together is called preadaptation. It’s a form of “neutral evolution,” in which the buildup of the parts provides no immediate advantage or disadvantage. Neutral evolution falls outside the descriptions of Charles Darwin. But once the pieces gather, mutation and natural selection can take care of the rest, ultimately resulting in the now-complex form of TIM23.

“It hasn’t been possible up until this point to trace any of those proteins back to a bacterial ancestor,” said Dalhousie University cell biologist Michael Gray, one of the researchers who originally described the origins of mitochondria, but was not involved in the new study. “These three proteins don’t perform precisely the same function in proteobacteria, but with a simple mutation could be transformed into a simple protein transport machine that could start the whole thing off.”

“You look at cellular machines and say, why on earth would biology do anything like this? It’s too bizarre,” he said. “But when you think about it in a neutral evolutionary fashion, in which these machineries emerge before there’s a need for them, then it makes sense.”

Citation: “The reducible complexity of a mitochondrial molecular machine.” By Abigail Clements,1, Dejan Bursac, Xenia Gatsos, Andrew J. Perry, Srgjan Civciristova, Nermin Celik, Vladimir A. Likic, Sebastian Poggio, Christine Jacobs-Wagner, Richard A. Strugnell, and Trevor Lithgow. Proceedings of the National Academy of Sciences, Vol. 106 No. 33, August 25, 2009.

Image: Journal of Cell Science
Source: Brandon Keim