Originally, scientists thought it worked by limiting food consumption. But it's increasingly obvious that's not how the procedure works. The surgery somehow changes expression of thousands of genes in organs throughout the body, resetting the entire metabolism. In March, Lee Kaplan, director of the Massachusetts General Hospital Weight Center in Boston, published a study in Science Translational Medicine showing a substantial microbial contribution to that resetting.
He began with three sets obese mice, all on a high-fat diet. The first set received a sham operation—an incision in the intestine that didn't really change much, but was meant to control for the possibility that trauma alone could cause weight loss. These mice then resumed their high fat diet. A second set also received a sham operation, but was put on a calorically restricted diet. The third group received gastric bypass surgery, but was then allowed to eat as it pleased.
As expected, both the bypass mice and dieted mice lost weight. But only the bypass mice showed normalization of insulin and glucose levels. Without that normalization, says Kaplan, mice and people alike inevitably regain lost weight.
"I won't argue that all the effects of the gastric bypass can be transferred by the microbiota. What we've found is the first evidence that any can."
To test the microbial contribution to these outcomes, Kaplan transplanted the microbiota from each set to germ-free mice. Only rodents colonized with microbes from the bypass mice lost weight, while actually eating more than mice colonized with microbes from the other groups.
In humans, some studies show a rebound of anti-inflammatory bacteria after gastric-bypass surgery. Dandona has also noted a decline in circulating endotoxin after the procedure. "I would never argue, and won't argue, that all the effects of the gastric bypass can be transferred by the microbiota," says Kaplan. "What we've found is the first evidence that any can. And these 'any' are pretty impressive." If we understand the mechanism by which the microbiota shifts, he says, perhaps we can induce the changes without surgery.
NOW, NOT EVERYONE ACCEPTS that inflammation drives metabolic syndrome and obesity. And even among the idea's proponents, no one claims that all inflammation emanates from the microbiota. Moreover, if you accept that inflammation contributes to obesity, then you're obligated to consider all the many ways to become inflamed. The odd thing is, many of them are already implicated in obesity.
Particulate pollution from tailpipes and factories, linked to asthma, heart disease, and obesity, is known to be a cause of inflammation. So is chronic stress. And risk factors may interact with each other: In macaque troops, the high-ranking females, which experience less stress, can eat more junk food without developing metabolic syndrome than the more stressed, lower-ranking females. Epidemiologists have made similar observations in humans. Poorer people suffer the consequences of lousy dietary habits more than do those who are wealthier. The scientists who study this phenomenon call it "status syndrome."
Exercise, meanwhile, is anti-inflammatory, which may explain why a brisk walk can immediately improve insulin sensitivity. Exercise may also fortify healthy brown fat, which burns off calories rather than storing them, like white fat does. This relationship may explain how physical activity really helps us lose weight. Yes, exercise burns calories, but the amount is often trivial. Just compensating for that bagel you ate for breakfast—roughly 290 calories—requires a 20-minute jog. And that's not counting any cream cheese. Sleep deprivation may have the opposite effect, favoring white fat over brown, and altering the metabolism.
Brain inflammation precedes weight gain, suggesting that the injury might cause, or at least contribute to, obesity.
Then there's the brain. Michael Schwartz, director of the Diabetes and Obesity Center of Excellence at the University of Washington in Seattle, has found that the appetite regulation center of the brain—the hypothalamus—is often inflamed and damaged in obese people. He can reproduce this damage by feeding mice a high-fat diet; chronic consumption of junk food, it seems, injures this region of the brain. Crucially, the brain inflammation precedes weight gain, suggesting that the injury might cause, or at least contribute to, obesity. In other words, by melting down our appetite control centers, junk food may accelerate its own consumption, sending us into a kind of vicious cycle where we consume more of the poison wreaking havoc on our physiology.
Of course there's a genetic contribution to obesity. But even here, inflammation rears its head. Some studies suggest that gene variants that increase aspects of immune firepower are over-represented among obese individuals. In past environments, these genes probably helped us fight off infections. In the context of today's diet, however, they may increase the risk of metabolic syndrome.
Whether inflammation drives obesity or just contributes, how much of it emanates from our microbiota, or even whether it causes weight gain, or results from it—these are still somewhat open questions. But it is clear that chronic, low-grade inflammation, wherever it comes from, is unhealthy. And as Dandona discovered all those years ago, food can be either pro- or anti-inflammatory. Which brings us back to the question: What should we eat?
FIFTY YEARS AGO, due to the perceived link with heart disease, nutritionists cautioned against consuming animal fats and recommended hydrogenated vegetable oils, such as margarine, instead. Alas, it turned out that these fats may encourage the formation of arterial plaques, while some fats that were discarded—in fish and olive oil, for example—seem to prevent cardiovascular disease and obesity.
As people unwittingly cut out healthy fats, they compensated by consuming more sugar and other refined carbohydrates. But a high-sugar diet can produce endotoxemia, fatty liver, and metabolic syndrome in animals. So that's yet another reason to avoid refined, sugary foods.
What about popular weight loss regimes, like the Atkins diet, that emphasize protein? In a 2011 study by scientists at the University of Aberdeen, in Scotland, 17 obese men were given a high-protein, low-carb diet. It prompted a decline of anti-inflammatory microbes, whose fermentation byproducts are critical to colonic health, and produced a microbial profile associated with colon cancer. So although it may prompt rapid weight loss, a high-protein, low-carb diet may predispose people to colon cancer. In the rodent version of this experiment, the addition of a prebiotic starch blunted the carcinogenic effect. Again, it's not only what's present in your diet that matters, but also what's absent.
So, should we sprinkle a packet of fiber on our cheeseburger? Dandona has looked at this possibility and says that though this study has not yet been published, he's found that packeted fiber does, when eaten with a fast-food meal, soften the food's inflammatory effects. Fast-food companies could, in theory, pack their buns full of prebiotics, shielding their customers somewhat from metabolic syndrome.
But that's not really what Dandona or anyone else is advocating. The pill approach—the idea that we can capture a cure in a gel cap—may be part of what got us in trouble to begin with. Natural variety and complexity have their own value, both for our own bodies and for our microbes. This may explain why orange juice, which contains plenty of sugur, doesn't have inflammatory effects while a calorically equivalent quantity of sugar water does. Flavonoids, other phytochemicals, vitamins, the small amount of fiber it carries, and other things we have yet to quantify may all be protective.
Fast-food companies could, in theory, pack their buns full of prebiotics, shielding their customers somewhat from metabolic syndrome.
To that end, consider a study by Jens Walter (PDF), a scientist at the University of Nebraska-Lincoln. He supplemented the diet of 28 volunteers with either brown rice, barley, or both. Otherwise, they continued eating their usual fare. After four weeks, those who consumed both grains saw increased counts of anti-inflammatory bacteria, improved insulin sensitivity, and reduced inflammation—more so than subjects who just had one grain. Walter doesn't think it's an accident that those who ate both barley and brown rice saw the greatest improvement. The combination likely presented microbes with the largest array of fermentable fibers.
Scientists are also intensely interested in concocting "synbiotics," a mixture of probiotic bacteria and the prebiotic fibers that feed them. This type of combination may already exist in staple dishes and garnishes, from sauerkraut to kefir, in traditional cuisines the world over. In theory, such unpasteurized, fermented foods that retain their microbial communities are a health-producing triple whammy, containing prebiotic fibers, probiotic bacteria, and healthful fermentation byproducts like vitimins B and K. A smattering of recent studies suggest that embracing such grub could protect against metabolic syndrome. In one monthlong trial on 22 overweight South Koreans, unpasteurized fermented kimchi, which is made from cabbage, improved markers of inflammation and caused very minor decreases in body fat. Fresh, unfermented kimchi also helped, but not as much. In another double-blind, placebo-controlled study on 30 South Koreans, a pill of fermented soybean paste eaten daily for 12 weeks decreased that deadly visceral fat by 5 percent. Triglycerides, a risk factor for heart attacks, also declined. An epidemiological study, meanwhile, found that consumption of rice and kimchi cut the odds of metabolic syndrome. It all hints at a future where sauerkraut, kimchi, sour pickles, and other fermented foods that contain live microbial cultures do double duty as anti-obesity medicine.
So what else to eat? Onions and garlic are especially rich in the prebiotic fiber inulin, which selectively feeds good bacteria within. Potatoes, bananas, and yams carry loads of digestion-resistant starches. Apples and oranges carry a healthy serving of polysaccharides (another form of prebiotic). Nuts and whole grains do as well. Don't forget your cruciferous vegetables (cabbage, broccoli, and cauliflower) and legumes. There's no magic vegetable. Yes, some plant products are extra rich in prebiotics—the Jerusalem artichoke, for example—but really, these fibers abound in plants generally, and for a simple reason: Plants store energy in them. That's why they're resistant to degradation. They're designed to last. (For more on what foods to eat, see "Should I Take A Probiotic?")
The very qualities that improve palatability and lengthen shelf life—high sugar content, fats that resist turning rancid, and a lack of organic complexity—make refined foods toxic to your key microbes. Biologically simple, processed foods may cultivate a toxic microbial community, not unlike the algal blooms that result in oceanic "dead zones."
In fact, scientists really do observe a dead zone of sorts when they peer into the obese microbiota. Microbes naturally form communities. In obese people, not only are anti-inflammatory microbes relatively scarce, diversity in general is depleted, and community structure degraded. Microbes that, in ecological parlance, we might call weedy species—the rats and cockroaches of your inner world—scurry around unimpeded. What's the lesson? Junk food may produce a kind of microbial anarchy. Opportunists flourish as the greater structure collapses. Cooperative members get pushed aside. And you, who both contain and depend on the entire ecosystem, pay the price.