How does obesity surgery do all that? Gut signaling changes found

How does bariatric surgery have consequences seemingly far greater than merely restricting the amount of food a patient can eat? A new study digs down into the molecular changes that come in the wake of a stomach-stapling procedure.
(Joseph Daniel Fiedler/For The Times)

Scientists and physicians who study the treatment of obesity have been puzzled for some years over bariatric surgery and its benefits.”Stomach stapling” surgery was long seen as a “plumbing adjustment” that prompts weight loss by restricting the stomach’s capacity. But mounting evidence demonstrates that it does much more than that. Bariatric surgery appears to set in motion a host of physiological and psychological changes beyond weight loss, in many cases resolving type 2 diabetes, righting problematic cholesterol readings, and not just curbing, but changing, appetites.

How it does all that, however, has remained a mystery that researchers are just beginning to pry open. In a series of experiments conducted on mice and reported this week in the journal Nature, new research suggests that a newly popular bariatric procedure called vertical sleeve gastrectomy sets in motion a cascade of signaling changes in the gut and elsewhere. Those changes, in turn, reshape the mix of gut bacteria in ways that appear to turn up metabolic function, lipid metabolism and signals that tell the brain it’s time to stop eating.

In vertical sleeve gastrectomy, the surgeon staples off roughly four-fifths of the stomach to create a banana-shaped tube where once a large pouch existed. The procedure accomplishes much of what the more complicated Roux-en-Y gastric bypass operation does, but does so more simply. For that reason — and because gastric banding is increasingly seen as less effective in promoting weight loss — surgeons are performing more sleeve gastrectomies in bariatric practices around the United States.


Researchers have already observed that certain bile acids circulate more copiously in the guts and blood of patients in the wake of bariatric surgery, but could only guess at why. They also have observed that the community of bacteria colonizing the guts of obese patients changes in the wake of bariatric surgery. But they could only guess at how.

A team of researchers from Sweden, Denmark and the University of Cincinnati in Ohio found that one link between these two changes is a genetic “switch,” or transcription factor, called FXR. Increased bile acid unlocks FXR, which improves metabolic function directly. But improved FXR signaling also promotes the growth of gut bacteria that help regulate fat metabolism, and suppresses gut bacteria that is linked to weight gain and metabolic disturbance, the group showed.

In their experiments, mice specially bred to lack the FXR genetic switch (and fed enough to make them obese) initially ate less and lost weight after they got a vertical sleeve gastrectomy. But within a week, their appetites rebounded, they showed a preference for consuming fat, and they quickly regained the weight.

By comparison, when the obese mice with a functioning FXR signaling system got the sleeve gastrectomy, they consistently ate less, showed a marked preference for consuming protein and carbohydrates over fat, lost weight and kept it off.

Finally, researchers conducted a census of the bacteria living in the mice’s gastrointestinal tracts. They found that compared to obese mice who got no sleeve gastrectomy, or got it but had been bred to lack the FXR switch, those who got the surgery and had an intact FXR signaling pathway had smaller populations of Bacteroides in their guts (a change that other studies have linked to fat loss and improved glucose control). Those mice also had more gut bacteria in the Porphyromonidaceae, Roseburia, Lactobacillus and Lactococcus families (all of which have been linked to better metabolic function).

“I really like this study,” said Dr. Jonathan Q. Purnell, an endocrinologist at Oregon Health & Sciences University who was not involved in the study. The authors, he said, have found one key link — there are probably more, Purnell added — between the increased bile acids and the enhanced gut microbiomes seen in bariatric surgery patients. Other studies have found that bariatric surgery effects changes in the appetite hormone ghrelin and activates other transcription factors that turn genes on and off, Purnell said.

The discovery that FXR signaling is key to bariatric surgery’s positive effects does several things, said study co-author Randy K. Seeley, professor of endocrinology at University of Cincinnati’s College of Medicine: it lays to rest any lingering belief that bariatric procedures induce weight loss only by shrinking the stomach’s capacity, Seeley said; it undermines any argument that metabolic improvements seen in bariatric surgery patients are simply a consequence of weight loss; and it bolsters the growing belief that gut bacteria may hold the key to weight control and healthy metabolic function.

The discovery also gives researchers a handle on how the broad benefits of bariatric surgery might be attained without the cost or risk of surgery, said Seeley.

“We need to figure out other ways you can do this,” Seeley said. Only 1% of patients who might benefit from such surgery are currently getting it, and that number is unlikely to ever get above 4%, experts estimate. As a result, Seeley said, scientists need to find ways to mimic bariatric surgery’s molecular effects in the body with a pill, a genetic “switching” device or by manipulating the bacteriological community in patients’ guts.