Failed Diets Explained
Jeffrey Gordon is tall and lean and wears the academic’s uniform of khakis and a button-down shirt. He doesn’t seem the type to love the newspaper cartoon Cathy, whose main character has spent most of her comic life complaining about diets and bathing-suit shopping–but he has a framed print of a strip from last January on his office wall. The strip was inspired by a landmark paper Gordon published in 2006, arguably the first major functional finding in human metagenomics. Dismissing various excuses for the failure of her diets, Cathy finally settles on what has to be the most bizarre excuse yet: “overly efficient intestinal microbes.” Amazingly, it’s scientifically justified.
In 2004, Gordon’s team published a paper describing a genetic survey of the bacterial populations of fat and lean mice. Mice genetically engineered to be obese, Gordon found, harbored different populations of microbes than lean mice. Two major groups of bacteria, the Bacteroidetes and the Firmicutes, dominate both the human and the mouse gut; the obese mice had a lower percentage of Bacteroidetes and a higher percentage of Firmicutes. In 2006, the researchers published a follow-up study of 12 obese people showing that the same pattern held true in humans. The differences seemed to be related more to weight than to genetics; after losing weight for a year on either a low-carb or a low-fat diet, the obese subjects had gut-microbe profiles that more closely resembled their lean counterparts’.
In both studies, the researchers used a genetic surveying method known as DNA barcoding. First they created a genetic soup containing DNA fragments from all the microbial species found in a sample taken from one of their subjects–whether mouse or human. Then they sequenced a small segment of DNA that occurs in a slightly different version in every species. Analyzing these “bar codes” allows researchers to gauge the number of different types of bacteria in a sample, even if some of those bacteria have never been cultured or sequenced before.
The finding that the microbial populations of lean and obese people differ raised a tantalizing question: could gut bacteria affect a person’s weight? To answer that question, Gordon and his collaborators needed more than just information on the different types of bacteria in the gut; they also needed to figure out whether the populations of gut microbes in obese and lean mice actually functioned differently.
The researchers attempted to sequence as much of the bacterial DNA from each mouse as they could. (Because this type of study analyzes DNA from hundreds to thousands of species, it is much more labor intensive than a traditional sequencing study, which analyzes fragments of DNA purified from a single species and then combines them like pieces in a linear jigsaw puzzle.) An analysis of the sequenced DNA revealed that the microbes from the obese mice had a higher percentage of genes involved in breaking down otherwise indigestible complex plant sugars that are common in the human diet. That means that animals harboring these microbes can more effectively squeeze the calories out of food. Cathy the beleaguered cartoon heroine was right: even if obese people eat the same amount of food as skinny people, they may be destined to gain more weight.
What’s more, this trait appears to be transferable. When germ-free mice had microbes from obese mice transplanted into their guts, they gained more fat than those with microbes from lean animals. “We don’t know what chemical signals mandate this change [in the microbial population],” says Gordon. “But we do know there is a dynamic relationship between the amount of fat you have and these bugs.”