The way it works, said Jeffrey I. Gordon, M.D., of Washington University, and colleagues, is that when an overweight person goes on a diet, one group of efficient bacteria moves out of the gut and another less-efficient group moves in to fill the void.
This finding suggested that manipulation of intestinal microbes might some day be used to treat obesity, they reported in the Dec. 21 issue of Nature.
When the investigators conducted a census of intestinal flora in obese people as they lost weight, they found that the proportion of Bacteriodetes and Firmicutes bacteria changed in tandem with the drop in excess poundage.
Whether the change in bacteria drives the weight loss, or the weight loss puts pressure on the bacterial composition of the gut, is unclear, the authors acknowledged, but the findings raise intriguing questions about the nature of obesity.
In studies with mice, the authors also found that bacteria in obese animals helped the body be more efficient at extracting energy from food, and that the trait could be transmitted from fat mice to thin.
When germ-free mice were populated with the type of gut bacteria typical in obese animals, they put on significantly more fat than germ-free mice colonized with "lean" bacteria, the investigators wrote.
"This is a potentially revolutionary idea that could change our views of what causes obesity and how we depend on the bacteria that inhabit our gut," wrote Randy J. Seeley, Ph.D., and Matej Bajzer of the Obesity Center at the University of Cincinnati, in an accompanying editorial. "But a great deal remains poorly understood. Most notably, it is not clear whether such small changes in caloric extraction can actually contribute to meaningful differences in body weight."
Dr. Gordon agreed that energy intake and expenditure -- diet and exercise -- are the major contributors to body weight, but noted that gut bacteria may also play a part.
"The amount of calories you consume by eating, and the amount of calories you expend by exercising are key determinants of your tendency to be obese or lean," said Dr. Gordon, director of the Center for Genome Sciences at Washington University. "Our studies imply that differences in our gut microbial ecology may determine how many calories we are able to extract and absorb from our diet and deposit in our fat cells."
The bugs in question are bacteria in the phyla Bacteriotedes and Firmicutes, species of which comprise more than 90% of intestinal microbes in both humans and mice. In an earlier study, the investigators had shown that genetically obese mice had 50% fewer Bacteroidetes and proportionately more Firmicutes in their guts than lean littermates, and that the differences in proportion held true across different species within the respective phyla.
In one of two studies published in Nature, the authors, led by Ruth Ley, Ph.D., a microbial ecologist in Dr. Gordon's group, reported follow-up results on microbial studies of 12 obese patients followed at a weight-loss clinic over a year. Half of the patients were on a calorie-restricted low-fat diet, and the other half were on a calorie-restricted low carbohydrate diet. The authors monitored the gut flora in the patients by sequencing 16S ribosomal RNA genes from stool samples.
At baseline the patients had the same relative proportions of gut microflora as the obese mice: short on Bacteriodetes species and long on Firmicutes. But as they lost weight, the proportions began to shift, as Bacteriodetes species enjoyed a population boom, and Firmicutes species dwindled in number. The changes occurred equally in patients on both diets.
In addition, just as they had seen in mice, the authors observed that Bacteriodetes species as a group increased, not just one or two species.
In the second study, led by Peter Turnbaugh, a Ph.D., student in Dr. Gordon's lab, the investigators conducted metagenomic studies in obese and lean mice using massively parallel DNA sequencing, and found that the microbiome in the obese mice had a greater capacity for digesting polysaccharides, indicating an enhanced ability to process food.
And when they transferred the microflora from obese or lean mice into germ-free animals, they found that the newly colonized animals who had received bugs from the cecum of obese mice laid in significantly more fat without an increase in caloric intake. In contrast, the once germ-free mice who got bacteria from their lean brethren put on some fat, but not nearly as much.
"Are some adults predisposed to obesity because they 'start out' with fewer Bacteroidetes and more Firmicutes in their guts?" Dr. Gordon asked. "Can features of a reduced Bacteroidetes-Firmicutes enriched microbial community become part of our definition of an obese state or a diagnostic marker for an increased risk for obesity? And can we intentionally manipulate our gut microbial communities in safe and beneficial ways to regulate energy balance?"
In their editorial, Dr. Seeley and Bajzer noted that the mechanism whereby differences in body weight translate in changes in intestinal bacteria are unknown.
"Given that acquiring food from the environment can be both calorically expensive and potentially dangerous, it would seem to be most adaptive to extract as many calories from every bite of food as possible," they wrote.
"Moreover, if caloric extraction does become more efficient, the regulatory system would dictate that the organism responds by reducing its caloric intake," they continued. "If a host organism had the ability to change its microbiota so as to increase caloric extraction, it would seem most adaptive to do so when facing famine conditions and losing weight. However, the data indicate just the opposite -- the microbiota seems to be more efficient in obese humans who already have the most stored energy, and shifts to being less efficient as the subjects lose weight."
|Neither the authors nor the editorialists declared any financial conflicts.|
- Reviewed by Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco