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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. 


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:

“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.”

25 thoughts on “The Humble Heroes of Weight-Loss Surgery: Stomach Acids and Gut Microbes

  1. Fascinating read. I used to work in utilization management for a national HMO and have accepted for years that bariatric surgery is a high risk last resort for the morbidly obese. Blew my mind to realize that it’s actually quite effective, but also seems to work primarily through changes to biochemistry.

  2. Also, this hit closer to home as a type 2 diabetic. Fortunately, well managed and very active. But I have been told repeatedly that diabetes can only be managed, not cured. I’m certainly not going to pursue bariatric surgery since I am in pretty solid shape, but it’s also heartening to see that it’s not necessarily a lifelong condition.

  3. The article gives a good piece of info for those who are diabetic and making decision about a medical procedure. Thanks for sharing the knowledge.

  4. Thanks, Virginia. Research should be done to see if gut bacteria explain a phenomenon that gets little attention: Most obese people do better on protein-centered diets. They cannot maintain a low-fat diet, but naturally thin people can. Gut bacteria are the most logical explanation

  5. Great article! Too often drugs are relied upon to “cure”. It’s too bad so many insurance companies make surgery a unrealistic option.

  6. Sudden calorie restriction without the gastric surgery can also apparently reverse type 2 diabetes in some cases – what’s interesting is that here too the blood sugar levels go down before substantial weight loss has occurred (after the first week of an 8-week, 800-kcal per day diet) – just as this article describes happening after gastric surgery. See http://www.ncl.ac.uk/magres/research/diabetes/reversal.htm. I’m biased as my mother was one of those who took part in the researchers’ second trial (not yet published) – it did work for her, and I hear there’s quite a following in the diabetic community who are attempting to do it for themselves. Fascinating to start understanding more about the reasons behind these biochemical changes.

  7. I too understood diabetes could only be managed, not cured. Can diabetes truly be cured and if so, any insights as to why the medical community doesn’t talk more about curing?

  8. Fascinating read, Virginia! I thought one of the most thought-provoking parts of the article concerns the ’cause’ of obesity/leanness. We as humans like to imagine that we can control our weight by means of diet, exercise, and mental toughness. But what if our metabolic structure controls our weight, and our mental perception of weight truly doesnt have the final say? Its puzzling. Personally, Ive struggled with weight issues in the past – not over-eating, but under-eating – and to imagine that I consciously may not have as much control over my weight as I initially thought is somehow freeing.

  9. in yoga they observed in india,if you walk six km everyday,you do not get type-2 diabetes ,this is a man made deficiency.

  10. I’ve seen this first hand after gastric bypass. Here’s a shocker I had lap-band surgery in 2007 and experienced the same wonderful results. Normal glucose readings within month of surgery. Lost 115# and maintain that loss. I’m basically diabetic free..best thing I’ve ever done for my self.. It’s a tool not a cure to obesity. Forced life style changes and choices.

  11. Hard to believe that the mutilation of internal organs is the best best we can do when treating a lifestyle disease. Type 2 diabetes was uncommon 75 years ago in Western society and remains extremely rare in primitive societies eating ancestral diets. Yet butchering the gut is somehow touted as the latest scientific advance?

    It’s likely that an unintended side effect of the Roux-en-Y gastric bypass is that it somehow resets deranged metabolism and/or alters the intestinal microbiome back to how nature intended it. Emulating the diet of those societies that did not suffer from diabetes would seem to be a far easier, less expensive, and safer alternative to achieve this rather than surgically altering the digestive tract. However, there’s not much money to be made by the medical establishment when the prescription only entails eating real food.

    1. Jeff’s comment, while intelligent, is easy to disprove. No patient submits to dangerous surgery lightly. Patients who undergo some form of gastric procedure to lose weight have tried and failed to lose weight for years. If a simple change in their diet was possible, they would universally do it, then brag about it. If a diet pill that worked was available, they would mortgage their houses to buy it. These brave patients have a disease that medicine cannot yet cure, and their surgeons are prolonging their lives. Before you accuse these doctors of being more interested in money than in the health of their patients, speak to a few. You will be surprised at the dedication of the overwhelming majority.

  12. Jeff C, spoken just like a person who’s never had a weight problem his entire life. Emulate the diet of eastern societies blah blah, woof woof. If you’ve been over weight your whole life, you would know more about nutrition than most nutritionists. I could give you the list of all the dietary lifestyles (not weight loss programs, though that list is pretty long as well) I’ve lived through my 48 years. Macrobiotic, vegan, vegetarian, high fat low carb, paleo and so on. In the end, the result is always the same. Short term weight loss followed by weight gain to higher than where I started and then the set point goes higher. I recently read an article about research that showed you can increase your body’s weight set point but can never decrease it. Willpower is not a long term solution. This condition requires a radical physiological change, because nothing else works. I would rather take my chances on the table than live with the probability that the diabetes will eventually catch up with me, taking my eyesight, extremities and eventually my life. I’ll be talking to my endocrinologist about this option when I see her in two weeks. Thank you for the information Virginia.

  13. My father and aunt both had gastric bypass surgery a few years ago after relentless attempts at weightloss that crept up over the years. Both are diabetes free after needing insulin and oral diabetes meds for years. My father checks his blood sugar occasionally to make sure he is still on track. Another nice “side effect” of the surgery is that they are no longer in & out of the hospital because of complications or flare-ups related to diabetes, heart problems or COPD. Before the surgery, my dad had 2 heart attacks and was in/out of the hospital for complications from any of his old multiple medical problems. Not only does he feel better, but his health insurance companies (Medicare & GM retiree health benefit) — and ultimately all of us — are saving a lot of money by not paying for multiple visits to the E.R., hospitalizations, piles of meds, etc.

  14. Gastric bypass surgey is a horrible mutilation that society inflicts upon those it considers different, much like sex reassignment surgery inflicted on children born with ambiguous genitalia.

    The fact that so many ignorant people accept these bizarre claims, it stands as a garish illustration of the barbarism so rampant in our nation. In a few years civilized people will look back on gastric bypass the way we look back on lobotomies, and trepination of the skull to let the evil spirits escape the brain.

  15. Nice article discription of biomedical effect of bariatric surgery is really awesome this new knowledge should help in designing customized treatement options

  16. Another great read, Virginia! I too will be discussing this research with my physician. I have had Type II Diabetes for a good number of years, and I am being treated with Insulin and oral meds. I have been obese for many years, and have pretty much given up the possibility of being diabetes free or losing weight. This is all very interesting, and I intend on following up on this research and whether surgery would be helpful for me. Thanks again, Virginia, for this very interesting read!

  17. ..yes, it’s true. I run 10km every other day, I eat lots of fruit, don’t heave down the chocolate bars and potato chips, and eat reasonably fat meals just once a day.

    And I’m not fat as a dross. So I mean, clearly I was born like this. Extreme overweight has nothing to do with training and eating reasonably – at all. It’s a genetic disease that white privileged people contract in vast numbers. And it has nothing to do with willpower in any way.

    In fact, maybe I’m just genetically wired to love running long distances and eating healthy food! Why, I hate eating a cheese-puck once in a while! It tastes so bad – really, the crisp bacon and melted cheese on top of a piece of carefully cooked meat – DISGUSTING!

    And the only way to deal with people who aren’t genetically determined to become fat – is to cut out a piece of the stomach. So you have to eat three nuts and a raisin every three hours, or else feel like you’re starving to death.

    Obviously – there’s no other solution to this obesity problem.

  18. Well – are we willing to be as open-minded, and more to the point – tabloid – about minimal (and I’m not being sarcastic here – I mean absolutely minimal) exercise. And minimal (again, not being sarcastic) eating discipline. As at least partial “treatment” for a long range of “obesity disorder” related illnesses?

    Because my impression more and more is that the idea of exercise having a positive effect in the long term when considering arthritis, joint pains, any amount of symptoms associated with obesity, such as diabetes and heart-diseases – is turning into superstition in certain milieus. That it may very well not have any documented effect. While obesity related conditions may very well turn up in healthy individuals no matter how much they train, so therefore it’s a separate disease, etc.

    Or, that moving around a bit is not really science. Unlike surgery, that is intended to let you lose weight – while maintaining the same activity level as before. With the amount of associated ills that lifestyle is bound to bring along with it. That will be treatable with any amount of other cures, I suppose.

    It’s just that I’m having difficulties with seeing the “two sides” perspective here between: 1. Humans are not meant to move around to get food, never were, and our uncovered genetic makeup – and science – now finally makes that apparent. And 2. If you’re bigger than you think you should be, you probably have a diagnosable illness.

    And I honestly don’t think it’s an amazing idea to underhandedly make an assumption such as that people are meant to sit still. Do it openly, and it’d make for an interesting perspective. Otherwise – maybe not to that degree.

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