Mystery of obesity: Failed ‘rectal transplant’ raises questions about role of gut microbes

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She had suffered miserably for months with Clostridium difficile, that ghastly, persistent intestinal infection that is notoriously resistant to antibiotics. So she and her doc turned to a therapy that, despite its yuck factor, has proved to be something of a miracle for vanquishing C. diff: a fecal transplant.

In this increasingly popular procedure, a healthy donor parts with a bowel movement that gets injected into the patient. The theory behind it is that “good” microbes in the donor stool can outcompete C. diff, and that seems to be exactly what happens nearly always. That’s certainly what happened in this case: Complete cure.

However. The patient weighed 136 at the time of the transplant, Not model-thin but not really fat either. In the next 16 months, though, she gained 34 pounds. Three years after the transplant she weighed 177 despite serious dieting and exercise.

The stool donor was the patient’s 16 year-old daughter. At 140 pounds at the time of the donation, the daughter was not really a sylph, and subsequently her weight increased to 170. The result is that the docs in this case have instituted a new rule: no fecal transplant donors who are overweight.

A commentary accompanying the paper reporting this event agrees: low body mass index should be a firm criterion for fecal transplant donors. Lots of factors cause weight gain–overeating, of course, and probably genes. But one newly fashionable candidate for obesity-promotion is particular microbes in the human gut. No one knows for sure that the daughter’s feces contained these bugs as well as the good ones that defeated C. diff. But better safe than sorry.

Human microbiome and human obesity

I suppose “no fatties wanted for fecal transplant donors” is a reasonable rule, given the state of our knowledge about microbes and obesity. Or, rather, given the state of our ignorance. At this point the idea that particular gut bugs can make us fat is mostly a suspicion, based nearly exclusively on revelations from animals. But the rewards for research with an impact on this huge health problem are potentially enormous, and a large number of scientists have gone to work on it.

So, what is known about the role of our microbiomes in obesity? A recent review in Nature quoted Fredrik Bäckhed, a gut microbe researcher at the University of Gothenburg in Sweden, “There are a lot of studies in humans, but those are only associations. There are a lot of studies of causation, but those are only in animals.”

If you have access only to data about a person, you can make a guess about whether he’s fat. You can look at his genes, for instance. That’s one way to tell if he’s likely to be fat, but it’s not a very good way. A much better way–almost a perfect way, in fact–is to look at the genes of the microbes in his gut. One way in which lean people differ from fat people is that their gut microbes are far more diverse. They have many more kinds of microbial genomes. But it hasn’t been clear whether the different and less diverse microbe populations in fat people are a cause of being fat, or a consequence of it.

Animal studies suggest that microbes are a cause. Transferring gut microbes from a fat lab mouse to a naturally slim germ-free mouse (a mouse with no microbiome of its own) makes it gain weight (although it doesn’t become obese.) Germ-free  mice gain weight if they get microbes from an obese human, too.

Researchers think there’s something (or somethings) in the microbiome that helps the animal store body fat. Note, however, that diet is also a crucial factor. In one experiment, mice infected with one bacterium from an obese person didn’t get obese themselves unless they were fed high-fat mouse chow.

Scientists are also beginning to learn something about the relationship between our genes and our resident microbes. As I wrote here at GLP last November, a twin study has shown that genes influence just which microbes are numerous in the human gut—and that some of these microbes form a kind of network that seems to accompany being lean.

What evolutionary theory says

You know those food cravings you have occasionally? For something sweet? Or a juicy steak? Oh, chocccccolate?

Suppose those food fantasies didn’t originate in your memories of past eating pleasures. How crazy is it to wonder if instead those cravings are messages–demands, really–from microbes living in your gut?

That’s the evolutionary theory three researchers put forth last fall. They argued “Microbes in the gastrointestinal tract are under selective pressure to manipulate host eating behavior to increase their fitness, sometimes at the expense of host fitness.” That pink-frosted cupcake does your hips and your heart no good, but may be just what a few of your resident bugs hunger for.

Some bugs, the authors point out, thrive on carbs. Others need certain fats. The urine of chocoholics contains microbial metabolites that are different from microbe metabolites in the urine of people who do not lust for chocolate, indirect evidence that their gut bugs differ. People who consume a probiotic drink containing certain Lactobacilli find that their moods improve, which could motivate them to keep right on drinking it and so replenishing their Lactobacillus population.

Stronger evidence that microbes alter host behavior comes from animal studies. “Butyrate, a short chain fatty acid largely produced by the microbiota, has been shown to have profound central nervous system effects on mood and behavior in mice,” they say. Microbes that affect behavior are not always bacteria. The single-cell parasite Toxoplasma gondi is notorious for rendering the rats it infects fearless in the presence of cats, thus making it more likely that T. gondi will be able to complete its normal life cycle in cat intestines.

This idea becomes more plausible when you realize that gut microbes have impacts all over the body, not just the gut. They affect metabolism, the brain, cardiovascular system, liver, and elsewhere. Hundreds of microbial compounds are present in human blood, traveling all over the body. Not so crazy to consider that they may be having an influence, maybe even driving our food desires.

Human obesity: Which microbes?

At this point there are no clear candidate microbes known for sure to have an impact on human obesity, with one possible exception. A certain amount of excitement seems to be attending work with Akkermansia muciniphila. As its name hints, this bacterium loves the mucus that lines the intestinal walls, and it is much less numerous in fat mice and humans than in their lean counterparts.

Administering live A. muciniphila to mice reverses metabolic disorders due to a high-fat diet, including fat-mass gain and diabetes symptoms such as insulin resistance. The European researchers who did this work say the mouse results “provide a rationale for the development of a treatment that uses this human mucus colonizer for the prevention or treatment of obesity and its associated metabolic disorders.”

Which is presumably why a recent conference on the prospects for probiotics–microbes believed to provide health benefits when consumed–spent a significant amount of time talking about A. muciniphila. Those in attendance concluded that this bug had potential for being turned into a commercial probiotic. A clinical trial is underway.

Tabitha M. Powledge is a long-time science journalist and a contributing columnist for the Genetic Literacy Project. She also writes On Science Blogs for the PLOS Blogs Network. Follow her @tamfecit.

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  • Eco-Sustainable

    Wow, what a very surprising article. People usually think that some individuals become obese because they refuse to control their dietary and other lifestyle habits. But the biological factors that determine obesity in human beings are actually complex. I already heard of obesity genes (or at least the heritability of obesity across generations) but the intestinal microbiome hypothesis is also an idea worthy of academic and scientific analysis. Go researchers!!!

  • Ben L

    Unfortunately for the gastroenterologists working on the conclusion, these limited sample sizes aren’t enough to determine causation. In fact, even the surprisingly qualitative approach of using the Wilcoxon rank-sum test in Le Chatelier et al.’s Nature paper (referenced above in the section about microbiome diversity). Also, the original twin study in mice used only 4 sets – so we still have a lot to learn with greater sample sizes. There is mounting evidence, that much is clear, and the chemical signaling that is known to occur between intestinal microorganisms and the rest of the body is profound.

  • ChurnYourOwn

    Good topic, but I feel the title is misleading. The transplant wasn’t a failure. As you state yourself, it was a success because the patient was cured of c-diff when antibiotics had previously failed. The weight gain appeared to be a side effect, albeit a very unfortunate one. As far as what to do about this, I would be so curious to see what impact a gut-healing diet would have on the patient, such as the GAPS diet. The idea is to starve the undesirable species and heavily feed the desirable ones so that they can thrive and help keep the obesity-linked ones in check. I can’t wait to see what more we learn on this topic over the next decade or so.

  • chubbybunny

    Wow! So misleading! First, weight is merely a number. How tall are they ? What was each person’s starting BMI? Also, this is a mother and daughter who both gained weight. They may have gained it by a bad diet and getting less exercise unrelated to this transplant. Anecdotal “evidence” stories are just Neat stories, not real and tested science.