Credit: S. Harris/Springer Nature Limited

Eat less, do more exercise — a simple formula for maintaining a healthy weight. Or is it? In the mid-2000s, pioneering work by Jeff Gordon’s laboratory showed that there is more to obesity than that; our bacterial ‘partners’ have a thing or two to say about our fat storage and weight gain.

Our gut contains a dynamic and complex population of microorganisms, which are collectively known as the gut microbiota. Together, these microorganisms have a vast number of genes encoding proteins and enzymes, and therefore have the potential to contribute to our physiology, including our metabolism. So, could they have a role in obesity?

The first clues came in 2004, when Bäckhed et al. observed that germ-free mice were leaner and had lower body fat than mice colonised with a conventional microbiota, despite the fact that the latter eat less1. Notably, when the germ-free mice were colonised with the conventional gut microbiota, they gained weight and showed increased levels (over 50%) of body fat. They also had higher levels of the hormone leptin (which directly correlates with the amount of fat in the body) as well as fasting glucose and insulin, all within 10–14 days of colonisation.

But the mice were not eating more — in fact, they were eating less — so the presence, or absence, of a gut microbiota must have at least contributed to weight gain. When probed further, the gut microbiota was found to have a crucial role in helping us extract nutrients and energy from food1. The processed nutrients are delivered to the liver, and are ultimately converted to fat and deposited in the body.

With the gut microbiota now firmly confirmed as a key player in energy extraction and fat deposition, researchers wanted to determine whether it contributes to obesity. As a first step, in 2005, Ley et al. sought to define differences in the gut microbiota of obese and lean mice2. Indeed, a large shift was identified in the relative abundance of microbial taxa present in the gut of obese mice (ob/ob, which carry a mutation in the leptin gene) and lean mice. Specifically, obese mice were found to have far fewer (50% less) Bacteriodetes bacteria in the distal part of the gut than lean mice, and instead showed an increase in the proportion of Firmicutes2.

At this point, researchers knew that the gut microbiota contributes to energy extraction and fat deposition, and that obesity drives changes in the gut microbiota. Could it then be that obesity is, at least in part, driven by more efficient extraction of energy from food by the gut microbiota?

To test this hypothesis, in 2006, Turnbaugh et al. analysed the microbiomes of obese and lean mice3. They found that the microbiomes from obese mice are enriched in enzymes that break down polysaccharides that are indigestible to humans, in this way ‘helping’ the mice get more out of their food. Not only that, but obese mice had far less energy remaining in their faeces than lean mice — they were just better at getting energy out of food.

Importantly, transplantation of the microbiota from obese mice to lean mice resulted in the lean mice gaining a significant amount of body fat over a 14-day period, even though the amount of food they were eating was the same.

While the traditional advice of eating less and exercising more is still sound, it is now clear that the story is more complex than previously thought. These seminal studies jump started research into the role of the gut microbiota in weight gain in humans, as revealed by follow-up studies in human cohorts4,5,6, offering fresh insights and an exciting new avenue of exploration in the fight against obesity.