Usually, science starts in the lab and then moves to patients. Gastric bypass surgery has taken the opposite path. Originally offered as a radical treatment for severe obesity, the surgery's effects on the digestive system and metabolism have turned out to be far more mysterious and fascinating than anyone expected. Now, a new study probes another of the surgery's effects: its impact on microbes in the gut and how changing these microscopic communities might drive weight loss.
The most popular type of gastric bypass surgery is called Roux-en-Y. Surgeons make a small pouch from the top of the stomach and separate it from the rest of the organ, then connect that directly to the middle of the small intestine. Originally, doctors believed that patients who underwent gastric bypass lost weight for a simple reason: Their stomach couldn't hold as much food, and they couldn't absorb as many nutrients.
But quickly, the picture got more complicated. In many people with type 2 diabetes, the disease vanishes almost immediately after surgery, too quickly to be explained by the gradual weight loss that happens later. Patients also describe not being as hungry, or craving foods like salad that they hadn't liked much before. "Food doesn't call out to them anymore," says Lee Kaplan, a molecular biologist and gastroenterologist at Harvard Medical School and Massachusetts General Hospital, both in Boston.
There are likely many mechanisms at work. Some may stem directly from how the altered digestive system works—secreting different levels of hormones, for example—or changes in nerve cells that communicate with the gut. Kaplan and Harvard University microbiologist Peter Turnbaugh, who had been studying gut microbes in obese and lean animals, were intrigued by other work suggesting that in both humans and rats, the microbial balance in fecal samples changed after gastric bypass. Along with a postdoc in Kaplan's lab, Alice Liou, they decided to test whether the surgery itself caused the changes in the population of gut microbes—known as the microbiota.
The researchers' colleagues divvied mice into three groups: those getting gastric bypass surgery; those given sham surgery; and those given sham surgery whose diet was restricted, to match what the bypass group weighed after the operation. In this way, the scientists could separate out the effects of surgery itself on microbial communities from the effects of losing weight or consuming less food. For 23 animals overall, they analyzed fecal samples before surgery and then weekly for 3 months. The result: Although the balance of microbes changed in both the dieting animals and those given bypass surgery, the difference was more dramatic in the surgery group. Those mice displayed specific patterns in their gut, the team reports today in Science Translational Medicine, including a boost in three types of bacteria called Bacteroidetes, Verrucomicrobia, and Proteobacteria. All are common in the guts of healthy people.
In a sense, the postop bacterial changes are not surprising, says endocrinologist David Cummings at the University of Washington, Seattle, (although he notes it's a "herculean feat" to manage gastric bypass surgery in animals as tiny as mice). Because it bypasses part of the stomach and small intestine, the surgery alters the intestinal environment, changing elements such as pH and bile concentrations.
The big step forward, Cummings says, is what the researchers did next: They performed a series of gut microbe transplants. Animals in each of the three groups—gastric bypass, sham surgery, and restricted diets—were killed and samples of their gut microbe communities diluted. Those were infused into the stomachs of mice raised in a germ-free environment and, therefore, without a gut microbiome of their own. The animals that got microbes from the gastric bypass donors lost about 5% of their body weight in 2 weeks—even though they weren't eating any less than controls. Microbes transplanted from the dieting animals that had had sham surgery didn't lead to any notable weight loss in the recipients.
"Something about the surgery changes the way this whole process is regulated," Kaplan says. He suspects microbial modifications linked to the bypass surgery—if they apply to humans—could help explain shifts in metabolism that doctors have long observed. The experiments were partially funded by Ethicon, a subsidiary of Johnson & Johnson, and Liou, Turnbaugh, and Kaplan have filed a patent application related to the research.
"It's now worth figuring out" how and why certain bacteria could lead to weight loss, Cummings says. Another important question, Turnbaugh says, is whether the transplants will have the same effect in animals who weren't raised in a sterile environment and who already have their own gut microbiome. These animals would more closely mimic people undergoing gastric bypass surgery. It's something he, Kaplan, and their colleagues are keen to learn more about.