Image by Mary Margret, via Flickr
Image by Mary Margret, via Flickr

The Humble Heroes of Weight-Loss Surgery: Stomach Acids and Gut Microbes

Update, 3/31: Today Schauer’s group released an updated study of the STAMPEDE bariatric surgery clinical trial results three years out. Participants who underwent surgery not only had near-normal levels of blood glucose after three years, but also reported higher quality-of-life scores compared with people who did not get surgery. 

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If you heard of a treatment that effectively cured 40 percent of people with a devastating common disease — cancer, say, or Alzheimer’s — that would be front-page news, right? People would be gathering around water coolers across the world to gush about the progress of medical science.

We actually do have one such success story, though most people don’t think of it in such glowing terms: weight-loss surgery. A clinical trial published in 2012 studied obese people with diabetes after receiving either intensive medical therapy (which included lifestyle coaching, home glucose monitoring, diabetes medications, and a push to join Weight Watchers) or intensive medical therapy and weight-loss surgery. About 40 percent of those who got the surgery no longer had diabetes a year later, compared with 12 percent who had medical therapy alone. The vast majority of people who had surgery stopped taking their diabetes medications altogether. And the surgery group lost around 25 percent of their weight, whereas the medical therapy group lost just 5 percent.

When the study came out, “it did shake up the conventional thinking about diabetes, because it showed you can’t achieve these outcomes with drugs,” says Philip Schauer, director of the Bariatric and Metabolic Institute at the Cleveland Clinic, who led that trial.

And yet, despite the dramatic, scientifically supported advantages of bariatric surgery, relatively few obese patients have an operation. Around 200,000 bariatric surgeries are performed each year in the U.S., which Schauer (who’s a surgeon) points out is only about 1 percent of the 20 million Americans with severe obesity. “Surgery is definitely underutilized,” he says.

There are many reasons for this. Like all surgeries, this one comes with medical risks (about 1 in 300 patients die, and others get blood clots, gastrointestinal leaks, or bowel blockages). It’s no more risky than gallbladder or appendix surgery, but many patients and doctors perceive it to be worse, according to Schauer. Another hurdle is financial: The surgery costs up to $25,000, and about half of all insurance policies don’t cover it. Of the policies that do, many require patients to jump through hoops — such as first going on a nine-month, medically supervised diet — in order to qualify.

Even if there were no risks and no insurance barriers, bariatric surgery is probably not a practical solution for the escalating public-health problem of diabetes. Take one city: Cincinnati, Ohio. “According to our projections, by 2025 one-quarter of the population of Cincinnati will have type-2 diabetes,” says Randy Seeley, a neuroscientist at the University of Cincinnati and the director of the Cincinnati Diabetes and Obesity Center. Even if every diabetic who qualified for weight-loss surgery wanted to get it, “we don’t have enough surgeons and surgery tables.”

In today’s issue of Nature, Seeley and his colleagues have published a mouse study suggesting that, one day, doctors might be able to mimic the beneficial effects of surgery without actually doing the surgery.

That premise will seem crazy to most surgeons, and that’s because the conventional explanation for bariatric surgery’s effectiveness is mechanical. In the two most common procedures (known as Roux-en-Y gastric bypass, and vertical sleeve gastrectomy, or VSG), surgeons make the stomach drastically smaller:

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“The common-wisdom explanation is that this is the intestinal equivalent of wiring your jaw shut,” Seeley says. That is: With a much smaller stomach, patients simply can’t absorb as many calories, so they lose weight and the weight-loss cures their diabetes. But Seeley doesn’t think this explanation makes sense. “It’s bologna,” he says.

He points out that, anecdotally, patients don’t feel as hungry after surgery as they used to. What’s more, within days of surgery — long before any substantial weight loss has occurred — many patients show such improvement in blood glucose levels that they can stop taking diabetes medications. All of this suggests that surgery changes not just the structure of the stomach, but its biochemistry.

Older studies have shown, in both humans and mouse models, that these surgeries increase the level of circulating bile acids — fluids made by the liver that help break down fats. Nobody knows why bile acids go up after surgery, but Seeley’s study suggests that they play a key role in its beneficial effects.

In addition to breaking down fats, bile acids are hormones, or signaling molecules that bind to receptors in cells all over the gut, including one called the farsenoid-X receptor, or FXR.

To see whether bariatric surgery influenced FXR activity, Seeley’s group overfed two types of mice: normal animals, and those genetically engineered to lack the FXR gene. After ballooning in size, both types of obese mice underwent VSG surgery.

One week after surgery, both types of mice dropped a ton of weight compared with controls that had had a sham surgery. The normal mice sustained most of that weight loss for the duration of the experiment, about 14 weeks. In contrast, the animals lacking the FXR gene gained the weight back by the fifth week.

In other words, the mice lacking FXR went through the same mechanical changes as the others — their stomachs shrunk in exactly the same way — and yet didn’t benefit from weight-loss surgery.

“It’s really superb science,” Schauer says, though it’s far too early to know whether the same thing is happening in people. Nevertheless, it’s an important study because it suggests that drug therapies might one day be designed to mimic these changes in FXR and possibly replace surgery altogether, he says. “Even as a surgeon, I would say, yeah, that would be a big advance.”

It probably won’t be as simple as turning up the FXR dial, though. FXR is a complicated gene whose activity changes depending on tissue type and environmental circumstances. For example, mice lacking FXR are actually resistant to getting obese in the first place. FXR codes for a transcription factor, a protein that itself regulates dozens of other genes. “It’s doing lots of different things in different tissues,” Seeley says. “One of the things we don’t know is, which population of FXR matters?”

To add yet another level of complexity, the gene also has a big influence on gut bacteria. Seeley’s study found several bacterial strains that change in response to surgery in the normal animals but not in those lacking FXR. A strain called Roseburia, for example, went up 12-fold in normal mice after surgery but did not change in the mutants. This is provocative because two studies have shown that people with type-2 diabetes carry abnormally low levels of this bug in their guts. And this is just one of many other recent reports linking gut microbes to obesity and diabetes. A study published a year ago showed that in mice, gastric bypass surgery changes the microbial make-up of the gut, and that this shift might explain the animals’ subsequent weight loss. “We’re starting to see a picture emerge,” Seeley says.

Seeley is a lab rat; he’s not a surgeon and not a doctor. So I was surprised to hear him passionately riff on the overwhelming benefits of weight-loss surgery, and bemoan our stubborn cultural stigma against obese people. “People tend to think of surgery as a tool to help people’s compliance, and that’s a problem,” he says. In his view, surgery is not about physically preventing obese people from eating more. It’s about fundamentally changing their metabolism so that they no longer need to eat more.

And why, I asked him, is the average Joe so resistant to this idea?

“Lean people want to take credit for being lean. They want to say it’s because I control my environment, I don’t go to McDonald’s, I work out,” he says. “But you can’t say that and not blame the obese individual for being obese.”

This is, in my opinion, a tragedy. As I’ve written about before, an overwhelming amount of evidence now suggests that obesity has little to do with willpower. More than a decade ago, researchers at 16 clinics in the United States enrolled thousands of overweight and obese people with diabetes on a strict weight-loss regimen that focused on diet and exercise. As published last year, this intensive, long-term intervention did very little in terms of weight loss, and had no effect on death rates from heart disease.

Sometimes, Seeley says, he wishes he were a cancer researcher. When cancer researchers tell their seat neighbor on an airplane what they study, “they don’t have to hear that person’s personal hypothesis of the cell cycle,” he says. But with obesity, everybody’s got a story. “We all have a highly embedded idea of this in our own heads,” he says. “So it’s tricky to have a discussion about it as a biomedical issue.”