Now, on the face of it, it seems odd that a little inflammation should have such a great impact on energy regulation. But consider: This is about apportioning a limited resource exactly where it's needed, when it's needed. When not under threat, the body uses energy for housekeeping and maintenance—and, if you're lucky, procreation, an optimistic, future-oriented activity. But when a threat arrives—a measles virus, say—you reprioritize. All that hormone-regulated activity declines to a bare minimum. Your body institutes a version of World War II rationing: troops (white blood cells) and resources (calories) are redirected toward the threat. Nonessential tasks, including the production of testosterone, shut down. Forget tomorrow. The priority is to preserve the self today.
This, some think, is the evolutionary reason for insulin resistance. Cells in the body stop absorbing sugar because the fuel is required—requisitioned, really—by armies of white blood cells. The problems arise when that emergency response, crucial to repelling pillagers in the short term, drags on indefinitely. Imagine it this way. Your dinner is cooking on the stove. You're paying bills. You smell smoke. You jump up, leaving those tasks half-done, and search for the fire before it burns down your house. Normally, once you put the fire out, you'd return to your tasks and then eat dinner.
Junk food may not kill us directly, but rather by prompting the collapse of an ancient and mutually beneficial symbiosis.
But now imagine that you never find the fire, and you never stop smelling the smoke. You remain in a perpetual state of alarm. Your bills never get paid. You never eat your dinner. Your house smolders. Your life falls into disarray.
That's metabolic syndrome. Normal function ceases. Aging accelerates. Diabetes develops. Heart attacks strike. The brain degenerates. Life ends early. And it's all driven, in this understanding, by chronic, low-grade inflammation.
Where does the perceived threat come from—all that inflammation? Some ingested fats are directly inflammatory. And dumping a huge amount of calories into the bloodstream from any source, be it fat or sugar, may overwhelm and inflame cells. But another source of inflammation is hidden in plain sight, the 100 trillion microbes inhabiting your gut. Junk food, it turns out, may not kill us entirely directly, but rather by prompting the collapse of an ancient and mutually beneficial symbiosis, and turning a once cooperative relationship adversarial.
We're already familiar with a version of this dynamic: cavities. Tooth decay is as old as teeth, but it intensified with increased consumption of refined carbohydrates, like sugar, just before and during the industrial revolution. Before cheap sugar became widely available, plaque microbes probably occupied the warm and inviting ecological niche of your mouth more peaceably. But dump a load of sugar on them, and certain species expand exponentially. Their by-product—acid—which, in normal amounts, protects you from foreign bacteria—now corrodes your teeth. A once cooperative relationship becomes antagonistic.
Something similar may occur with our gut microbes when they're exposed to the highly refined, sweet, and greasy junk-food diet. They may turn against us.
A DECADE AGO, microbiologists at Washington University in St. Louis noticed that mice raised without any microbes, in plastic bubbles with positive air pressure, could gorge on food without developing metabolic syndrome or growing obese. But when colonized with their native microbes, these mice quickly became insulin resistant and grew fat, all while eating less food than their germ-free counterparts.
The researchers surmised that the microbes helped the rodents harvest energy from food. The mice, which then had more calories than they needed, stored the surplus as fat. But across the Atlantic, Patrice Cani at the Catholic University of Louvain in Brussels, Belgium, suspected that inflammation contributed, and that the inflammation emanated from native microbes.
To prove the principle, he gave mice a low dose of endotoxin, that molecule that resides in the outer walls of certain bacteria. The mice's livers became insulin resistant; the mice became obese and developed diabetes. A high-fat diet alone produced the same result: Endotoxin leaked into circulation; inflammation took hold; the mice grew fat and diabetic. Then came the bombshell. The mere addition of soluble plant fibers called oligosaccharides, found in things like bananas, garlic, and asparagus, prevented the entire cascade—no endotoxin, no inflammation, and no diabetes.
"If we take care of our gut microbiota, it will take care of our health," says one researcher. "I like to finish my talks with one sentence: 'In gut we trust.'"
Oligosaccharides are one form of what's known as a "prebiotic": fibers that, because they make it all the way to the colon intact, feed, as it were, the bacteria that live there. One reason we've evolved to house microbes at all is because they "digest" these fibers by fermenting them, breaking them down and allowing us to utilize their healthful byproducts, like acetic acid, butyric acid, B vitamins, and vitamin K.
Cani had essentially arrived at the same place as Dandona with his freshly squeezed orange juice. Only his controlled animal experiments allowed a clearer understanding of the mechanisms. Junk food caused nasty microbes to bloom, and friendly bugs to decline. Permeability of the gut also increased, meaning that microbial byproducts—like that endotoxin—could more easily leak into circulation, and spur inflammation. Simply adding prebiotics enjoyed by a select group of microbes—in this case, Bifidobacteria—kept the gut tightly sealed, preventing the entire cascade. The fortified bacteria acted like crowd-control police, keeping the rest of the microbial mob from storming the barrier.
"If we take care of our gut microbiota, it will take care of our health," Cani says. "I like to finish my talks with one sentence: 'In gut we trust.'"
So our sweet and greasy diet—almost certainly without evolutionary precedent—doesn't just kill us directly: It also changes gut permeability and alters the makeup of our microbial organ. Our "friendly" community of microbes becomes unfriendly, even downright pathogenic, leaking noxious byproducts where they don't belong. H.G. Wells would be proud of this story—the mighty Homo sapiens felled by microscopic life turned toxic by junk food. It's nothing personal; the bugs that bloom with an energy-dense diet may act in their own self-interest. They want more of that food sweet, fatty food on which they thrive.
AROUND THE TIME when Paresh Dandona began puzzling over the immune response to a fast-food breakfast, a Chinese microbiologist named Liping Zhao was realizing that he needed to change how he ate, or he might drop dead. He was 44 pounds overweight, his blood pressure was elevated, and his "bad" cholesterol was high.
He caught wind of the studies at Washington University in St. Louis suggesting that microbes were central to obesity. The research jibed with ancient precepts in Chinese medicine that viewed the gut as central to health. So Zhao decided on a hybridized approach—some 21st-century microbiology topped with traditional Chinese medicine.
He changed his diet to whole grains, rich in those prebiotic fibers important for beneficial bacteria. And he began regularly consuming two traditional medicinal foods thought to have such properties: bitter melon and Chinese yam.
Zhao's blood pressure began normalizing and his "bad" cholesterol declined. Over the course of two years, he lost 44 pounds. He sampled his microbes throughout. As his metabolism normalized, quantities of a bacterium called Faecalibacterium prausnitzii increased in his gut. Was its appearance cause or consequence? Others have observed that this bacterium is absent in people suffering from inflammatory diseases, such as Crohn's disease, as well as Type 2 diabetes. Scientists at the University of Tokyo have shown that colonizing mice with this bacterium and its relatives—called "Clostridium clusters"—protects them against colitis. But still, evidence of causation was lacking.
Then one day in 2008, a morbidly obese man walked into Zhao's lab in China. The 26-year-old was diabetic, inflamed, had high bad cholesterol, and elevated blood sugar. No one in his immediate family was heavy, but he weighed 385 pounds.
Aided by a high fat diet, the microbe appeared able to hijack the metabolism of both mice and man.
Zhao noticed something odd about the man's microbes. Thirty-five percent belonged to a single, endotoxin-producing species called Enterobacter cloacae. So he put the man on a version of his own regimen—whole grains supplemented with other prebiotics. As treatment progressed, the Enterobacter cloacae declined, as did circulating endotoxin and markers of inflammation.
After 23 weeks, the man had lost 113 pounds. That bacterial bloom had receded to the point of being undetectable. Counts of anti-inflammatory bacteria—microbes that specialize in fermenting nondigestible fibers—had increased. But could Zhao prove that these microbial changes caused anything? After all, the regimen may have simply contained far fewer calories than the patient's previous diet.
So Zhao introduced the Enterobacter into mice. They developed endotoxemia, fattened up and became diabetic—but only when eating a high fat diet. Mice colonized with bifidobacteria and fed a high fat diet, meanwhile, remained lean, as did germ-free mice. The enterobacter was evidently unique, an opportunist. Aided by a high fat diet, the microbe appeared able to hijack the metabolism of both mice and man.
Zhao, who related his own story to Science last year, has repeated a version of this regimen in at least 90 subjects, achieved similar improvements, and has more than 1,000 patients in ongoing trials. He declined to be interviewed for this article, saying that the response to his research, both by press and individuals seeking advice, had been overwhelming. "I receive too many emails to ask for help but I can not provide much," he wrote in an email. "I feel very bad about this and would like to concentrate on my research."
There's a flood of what you might call "fecoprospectors" seeking to catalog and preserve microbial diversity before it is lost in the extinction wave sweeping the globe.
Other researchers have tried an even more radical approach to treating the microbiome: the fecal transplant. It was originally developed to treat the potentially life-threatening gut infection caused by the bacterium Clostridium difficile. Studies so far suggest that it's 95 percent effective in ousting C. diff. and has no major side effects. "Fecal engraftment" is now being considered a method for rebooting microbiota generally. Scientists at the Academic Medical Center in Amsterdam mixed stool from lean donors with saline solution and, via a tube that passed through the nose, down the throat and past the stomach, introduced the mixture to the small intestine of nine patients with metabolic syndrome. Control subjects received infusions of their own feces.
Those who received "lean" microbes saw improvements in insulin sensitivity, though they didn't lose weight and saw the improvements disappear within a year. But Max Nieuwdorp, senior author on the study, aims to conduct the procedure repeatedly to see if the "lean" microbes will stick. And when he's identified which are important, he hopes to create an anti-obesity "probiotic" to be taken orally.
Probiotics are just bacteria thought to be beneficial, like the lactobacilli and other bacteria in some yogurts. In the future probiotics might be bacteria derived from those found in Amazonian Indians, rural Africans, even the Amish—people, in other words, who retain a microbial diversity that the rest of us may have lost. Already, the literature suggests that a gold rush has begun—a flood of what you might call "fecoprospectors" seeking to catalog and preserve the diversity and richness of the ancestral microbiota before it is lost in the extinction wave sweeping the globe.
Ultimately, the strongest evidence to support microbial involvement in obesity may come from a procedure that, on the face of it, has nothing to do with microbes: gastric bypass surgery. The surgery, which involves creating a detour around the stomach, is the most effective intervention for morbid obesity—far more effective than dieting.