Ley, excited by the possibility that this difference in the ratio of Firmicutes to Bacteroidetes might prove to be fundamental to obesity, then checked the microbiotas of lean and obese humans. She found the same ratio – the obese people had far more Firmicutes and the lean people had a greater proportion of Bacteroidetes. It seemed almost too simple – could obesity and the composition of the gut microbiota be connected in such a straightforward way? Most importantly, were the microbes in obese mice and humans causing the obesity, or were they just a consequence of it?
It fell to a third member of Gordon’s lab group to find out – PhD student Peter Turnbaugh. Turnbaugh used the same kind of genetically obese mice as Ley had, but he transferred their microbes into germ-free mice. At the same time, he transferred the microbes of normal, lean mice into a second set of germ-free mice. Both sets of mice were given exactly the same amount of food, but fourteen days later, the mice colonised with the ‘obese’ microbiota had got fat, and those with the ‘lean’ microbiota had not.
Turnbaugh’s experiment showed not only that gut microbes could make mice fat, but also that they could be passed between individuals. The implications go far beyond moving bacteria from obese mouse to lean mouse. We could be doing it the other way round – taking microbes from lean people and putting them into obese people – weight loss with no dieting required. The therapeutic – and money-making – potential was not lost on Turnbaugh or his collaborators, who have patented the concept of altering the microbiota as a treatment for obesity.
But before we get too excited about the potential for a cure for obesity, we need to know how it all works. What are these microbes doing that makes us fat? Just as before, the microbiotas in Turnbaugh’s obese mice contained more Firmicutes and fewer Bacteroidetes, and they somehow seemed to enable the mice to extract more energy from their food. This detail undermines one of the core tenets of the obesity equation. Counting ‘calories-in’ is not as simple as keeping track of what a person eats. More accurately, it is the energy content of what a person absorbs. Turnbaugh calculated that the mice with the obese microbiota were collecting 2 per cent more calories from their food. For every 100 calories the lean mice extracted, the obese mice squeezed out 102.
Not much, perhaps, but over the course of a year or more, it adds up. Let’s take a woman of average height, 5 foot 4 inches, who weighs 62 kg (9 st 11 lb) and has a healthy Body Mass Index (BMI: weight (kg) /(height (m)²) of 23.5. She consumes 2,000 calories per day, but with an ‘obese’ microbiota, her extra 2 per cent calorie extraction adds 40 more calories each day. Without expending extra energy, those further 40 calories per day should translate, in theory at least, to a 1.9 kg weight gain over a year. In ten years, that’s 19 kg, taking her weight to 81 kg (12 st 11 lb) and her BMI to an obese 30.7. All because of just 2 per cent extra calories extracted from her food by her gut bacteria.
Turnbaugh’s experiment has set in motion a revolution in our understanding of human nutrition. The calorie contents of foods are normally calculated using standard conversion tables, so every gram of carbohydrate is deemed to contribute 4 calories, every gram of fat, 9 calories, and so on. These labels present the calories of a food item as a fixed value. They are saying: ‘This yogurt contains 137 calories’, and ‘A slice of this bread contains 69 calories.’ However, Peter Turnbaugh’s work suggests it is not that straightforward. That yogurt may well contain 137 calories for a person of normal weight, but it could also contain 140 calories for someone who is overweight, and who has a different set of gut microbes. Again, it’s a small difference, but it adds up.
If your microbes are working on your behalf to extract energy from your food, it is your particular community of microbes that determines how many calories you get from what you eat, not a standard conversion table. For those people who have dieted without success, this may be part of the explanation. A carefully calculated calorie-controlled diet, resulting in an overall loss of calories every day for a sustained period, should lead to weight loss. But if the ‘calories-in’ are underestimated, that could mean no change in weight, or even weight gain. This idea is backed up by another experiment carried out by Reiner Jumpertz in 2011 at the National Institute of Health in Phoenix, Arizona. Jumpertz gave human volunteers a fixed-calorie diet, and simply measured the calories that remained in their stool after digestion. Lean volunteers put on a high-calorie diet had a boost in the abundance of Firmicutes relative to Bacteroidetes. This change in gut microbes went along with a drop in the number of calories that were coming out in their stool. With the balance of bacteria shifted, they were extracting an extra 150 calories each day from the same diet.
The particular set of microbes we harbour determines our ability to extract energy from our food. After the small intestine has digested and absorbed as much as it can from what we’ve eaten, the leftovers move into the large intestine, where most of our microbes live. Here, they function like factory workers, each breaking down its own preferred molecules and absorbing what it can. The rest is left in a simple enough form for us to absorb through the lining of the large intestine. One strain of bacteria might have the genes needed to break down the amino-acid molecules that come from meat. Another strain might be best suited to breaking down the long-chain carbohydrate molecules that come from green vegetables. And a third could be most efficient at collecting up the sugar molecules that were not absorbed in the small intestine. The diet each of us eats affects which strains we harbour. So, for example, a vegetarian might not have many individuals of the amino-acid strain, as they can’t proliferate without a steady supply of meat.
Bäckhed suggests that what we can extract from our food depends on what our microbial factory has been set up to expect. If our vegetarian were to abandon her stance and indulge in a hog roast, she would probably not have enough amino-acid-loving microbes to make the most of it. But a regular meat-eater would have a sizeable collection of suitable microbes, and would extract more calories from the hog roast than the vegetarian. And so it follows for other nutrients. A person who eats very little fat would have very few microbes that are specialised for fat, and the odd doughnut or chocolate bar might make it through the large intestine without being efficiently stripped of its remaining calorific content. Someone who eats a daily tea-time treat, however, would have a large population of fat-munching bacteria, just waiting to strip their next doughnut to its bare essentials, providing our snacker with the full dose of calories.
Although the number of calories we absorb from our food is undoubtedly important, it’s not just how much energy our microbes extract for us that matters, but what they make the body do with that energy. Do we use it immediately to power our muscles and our organs? Or do we store it for later, in case there’s nothing to eat? Which of these things happens depends on our genes. But it’s not which gene variants you got from your parents that matters, it’s which genes are switched on and which are switched off, which are dialled up and which are dialled down.
Our own bodies do the turning on and off of genes, and the dialling up and down, using all sorts of chemical messengers. This control means that cells in our eyes can do different jobs than cells in our livers, for example. Or that cells in the brain can function differently when we’re working during the day than when we’re sound asleep in the middle of the night. But our bodies are not the only masters of our genetic output. Our microbes also get a say, controlling some of our genes to suit their needs.
Members of the microbiota are able to turn up production from genes which encourage energy to be packed away in our fat cells. And why not? The microbiota benefits from living in a human who can make it through the winter just as much as the human does. An ‘obese microbiota’ turns up these genes even more, forcing the storage of extra energy from our food as fat. Annoying as this may be for those of us who struggle to maintain the weight they’d like, this gene-control trick should be beneficial, as it helps us to make the most of our food and store that energy away for leaner times. In our past, in periods of feast and famine, having help to get through the famines would have been a life-saver.
Calories-in, then, goes deeper than what you put in your mouth. It’s what your gut absorbs, including what your microbes provide for you. Calories-out, too, is more complicated than how much energy you use being active. It’s also about what your body chooses to do with that energy: whether it stores it away for a rainy day, or burns it off