Antibiotics fuel obesity by creating microbe upheavals

By Ed Yong | August 23, 2012 9:00 am

We aren’t single individuals, but colonies of trillions. Our bodies, and our guts in particular, are home to vast swarms of bacteria and other microbes. This “microbiota” helps us to harvest energy from our food by breaking down the complex molecules that our own cells cannot cope with. They build vitamins that we cannot manufacture. They ‘talk to’ our immune system to ensure that it develops correctly, and they prevent invasions from other more harmful microbes. They’re our partners in life.

What happens when we kill them?

Farmers have been doing that experiment in animals for more than 50 years. By feeding low doses of antibiotics to healthy farm animals, they’ve found that they could fatten up their livestock by as much as 15 percent. You can put the antibiotics in their feed or in their water. You can give the drugs to cows, sheep, pigs or chickens. You can try penicillins, or tetracyclines, or many other classes of antibiotics. The effect is the same: more weight.

Consistent though this effect is, no one really understands why it works. The safe bet is that the drugs are exerting their influence by killing off some of the microbiota. Now, Ilseung Cho from the New York University School of Medicine has confirmed that hypothesis. By feeding antibiotics to young mice, he has shown that the drugs drastically change the microscopic communities within their guts, and increase the amount of calories they harvest from food. The result: they became fatter.

Cho exposed young mice to a range of different antibiotics including penicillin, vancomycin, the two together, or chlortetracycline, all at levels that the US Food and Drug Administration approves for use in agriculture. After 7 weeks, the treated mice were no heavier than those that didn’t drink any drugs, but they had more body fat – around 23 percent, compared to a typical 20 percent.

The microbiotas of the antibiotic-treated mice had also changed. They had the same numbers of microbes as the normal mice, but they were heavier in bacteria from the Firmicutes group, and poorer in those from Bacteroidetes. That’s a familiar pattern to anyone interested in gut bacteria: many studies have found that the balance between these two bacterial groups sways to the Firmicutes’ favour in obese individuals. It’s the same for both mice and humans.

But the antibiotics didn’t just change the members of the rodents’ microbial communities. They also change what they did. In the guts of the treated mice, Cho found that certain genes were more active, including those that break down complex carbohydrates into short-chain fatty acids (SCFAs). These substances provide energy to intestinal cells and trigger the production of body fat.

Cho also found 466 genes that were deployed differently in the livers of the antibiotic-treated mice. Those involved in storing unused calories, by creating substances like fats and triglycerides, tended to be more active. It was the same story no matter which antibiotic Cho used.

This smorgasbord of changes suggests that the young rodents’ encounters with antibiotics had changed the microbes in their guts, to a cadre that was better at harvesting calories from otherwise indigestible food. To cope with their flood of liberated calories, they pile on more fat.

Scientists have seen patterns like this before, but on a much bigger scale. When natural habitats are disturbed to a large extent in a short space of time – whether by fire, volcanoes, diseases or human hunting – the entire system can change in irreversible ways. For example, in the Arctic Aleutian islands, introduced foxes killed local seabirds, depriving the land of nutrient-rich droppings and changing the very landscape from lush grasses to sparse shrubbery.  The changes in Cho’s study are similar, except instead of fox-ridden islands, we have antibiotic-assaulted guts. Our microbiotas, after all, are ecosystems in their own right, finely balanced and vulnerable to severe changes.

So what of humans? Could our increasing use of antibiotics be fuelling the rise in obesity rates? “The implication is that routine exposure to low levels of antibiotics might also promote obesity in humans, although further studies would be needed to determine this,” says Rob Knight from the University of Colorado, who studies the microbiome but was not involved in this work.

Such caution is warranted. Mice are not humans, and mouse microbiotas are not human microbiotas. There are enough similarities to think that Cho’s results would apply to us too, but some preliminary evidence is coming in. A second study by Martin Blaser, who led Cho’s research, followed the fates of 11,532 British children born in 1991 and 1992. It showed that those who took antibiotics in their first six months put on more weight than their peers in their first years of life.

For now, two things are clear. First, antibiotics have done a huge amount of good in treating bacterial infections and if we’re even talking about reducing their use, it’s because we have the luxury of health that they have provided. Second, they are clearly overused: prescribed for illnesses that they have no power over, and used to fatten livestock that aren’t sick. Currently, on average, every American child gets a course of antibiotics ever year.

The overuse of antibiotics has fuelled the rise of antibiotic-resistant bacteria, but their impact on our beneficial bacteria could be equally detrimental. Blaser has been vociferously banging on this drum for years. As he wrote in a comment piece for Nature, “Antibiotics kill the bacteria we do want, as well as those we don’t… Overuse of antibiotics could be fuelling the dramatic increase in conditions such as obesity, type 1 diabetes, inflammatory bowel disease, allergies and asthma… We must make use of the available technology to protect and study our bacterial benefactors before it is too late.”

References: Cho, Yamanishi, Cox, Methe, Zavadil, Li, Gao, Mahana, Raju, Teitler, Li, Alekseyenko & Blaser. 2012. Antibiotics in early life alter the murine colonic microbiome and adiposity. Nature http://dx.doi.org/10.1038/nature11400

Trasande, Blustein, Liu, Corwin, Cox & Blaser. 2012. Infant antibiotic exposures and early-life body mass. Int J Obesity http://dx.doi.org/10.1038/ijo.2012.132

Photo from Sheep Purple; image by Cho et al.

Comments (20)

  1. Bonnie Nordby

    Makes me wonder if using fecal transplant could reverse this.

  2. Fredda Weinberg

    ” Currently, every American child gets a course of antibiotics ever year.”

    Excuse me, but where did this come from?

  3. @Fredda – Sorry, that really should’ve said “Currently, on average, every…”

    And it comes from the paper.

  4. Daniel J. Andrews

    So this effect is seen in young mice. Any word on what happens when antibiotics are given to fully adult mice? Can a course of antibiotics given to humans in their 30s to 50s make them more likely to gain body fat?

  5. Fenella

    Hi Ed, in the second study about the British children, so far all the information I’ve seen seems to imply a lot more causation than the correlation implies, possibly? I can see the value in studying the effect that the correct mix of gut flora has on obesity, but is there anything in this report that indicates why a single course of antibiotics would prevent a child from reacquiring that flora even several years later? I also wonder about the consequences of such a study, whether founded or not, for medical treatment of infants. It’s very common for newborns who aspirate meconium during birth to have high white blood cell counts and to receive a course of antibiotics to prevent any chance of developing potentially life-threatening meningitis. In such cases in the future, are hospitals going to require traumatized new parents to decide whether they want their new baby to risk brain injury, or risk juvenile obesity? Are they going to have to sign a waiver?

  6. Cathy

    What of probiotics? Perhaps, after we let a course of antibiotics ravage our internal flora, we could restock it with the good stuff again. I know they’re all the rage among the snake oil salesmen these days, but that’s because there’s a nugget of truth in there someplace, too.

  7. @Daniel – I suspect the early age is important. Certainly in the second study with the infants, there was no assoication between antibiotics later on in life and weight gain.

    @Fenella – It’s an observational study so by its nature, it’s correlative not causative. There are some of the elements needed for causation like a plausible mechanism, but you’d need many repeats of the same design in different populations before you could say anything even remotely conclusive. As to the effect of a single course, other studies have suggested that the disturbances caused by antibiotic treatments last for a long period of time http://www.ncbi.nlm.nih.gov/pubmed/20705661

    @Cathy – Many people in the microbiome field suspect that probiotics could help, and Blaser mentions this in either his paper or his comment piece. But that will probably need to be specially tailored, and require a lot more research. Chugging a yogurt from the supermarket probably won’t do much good now.

  8. greg zurbay

    This is a very important area of research, one that if done well may result in radically reduced chronic disease and a large reduction in health care costs. We should lobby for increased government funding in this area, with the argument it should pay off big down the road. Japanese and Chinese research into probiotic support is likely far ahead of US research, and this should be fair warning as to how important this field has become.

    On the age factor there is a theory that the appendix acts as a reservoir for the “good” ( beneficial ) bacteria in case of food poisoning, it reseeds the gut after the bad bacteria is flushed out. When good bacteria quora they form sheets of like types that prevent colonization of other bacteria. If a young child looses the intestinal coating of good bacteria and the appendix is not well enough formed or supplied with beneficial bacteria to facilitate replenishment would this explain how the child might never gain the beneficial bacterial population?

  9. Drew Freyman

    I hope that as a next step someone is considering if/how a post-antibiotic, unbalanced system can be brought back into balance. Will the flora come back into balance by simply eating a balanced, healthy diet? Are there substances (i.e. pro-biotics) that hasten the process? I hope there are experiments in the pipeline.

  10. ophu

    Worser living through chemistry. And BigPharm.

  11. @Fenella

    It’s possible that people on first world diets may never obtain “normal” ratios of gut bacteria. Back in May Ed did an article http://blogs.discovermagazine.com/notrocketscience/2012/05/09/three-nations-divided-by-common-gut-bacteria/ on differences between the intestinal biomes of people in the US, Venezuela and Malawi.

    “The Malawian and Venezuelan babies also had more genes for harvesting the readily available sugars in breast milk, although these dwindle away as they get older. As their diet shifts towards high-fibre foods like corn and cassava, their gut bacteria become loaded with genes for breaking down more complex sugars and starches. For American babies, the opposite is true. With a lifelong diet of refined sugars ahead of them, the genes for harvesting these nutrients become more abundant as they get older. And since they eat high-protein diets, their gut bacteria become rife with genes for breaking down amino acids.”

    It will be interesting to watch this play out. How much of the change is from antibiotics and how much is from diet and lifestyle is a story that doesn’t seem to be completely told yet.

  12. Mary

    It could be the thing that finally gets some parents to understand that every viral infection should not get antibiotics. And that would be good. But if it delays treatments for real bacterial situations that need intervention, kids could suffer.

    But let’s not go too far with an idea that non-first-world guts would be ideal. There are also studies that show infections in these kids can be setting back brain development.

  13. This is not an easy correlation. I agree more needs to be done to understand what is a healthy balance.

    I have a lot of kittens go through my hands, and upper respiratory infections are common. That means antibiotics – sometimes weeks of different medicines because these fellows can be rescued from anywhere with all sorts of crud. Some need way more than a week of amoxi.

    Over time, some of my foster kittens stay with me so long they grow up into cats so there is a list of factors that could make them fat – antibiotics, neutering, grain in their dry food …

    However, my cats are all active and mostly eat a meat diet, rather than dry. Diet and life style is different than mice, and different than people.

    I currently have no fat cats in the house, and I can’t remember having a plump cat for years. Not all the cats in my house are young adult age either. This is anecdotal, but also illustrates that mice and antibiotics studies only gives a hint, rather than the answer.

  14. This is really interesting. If you look at obesity rates by age group there is a big increase for people born after the introduction of penicillin.

  15. Yes, but a LOT of things have changed since then, including big trends in diet and physical activity.

    Let’s not go overboard here.

    This isn’t THE explanation for the obesity epidemic, because such an explanation does not exist. Obesity is a multi-factorial problem with lots and lots of different interacting causes. What this tells us is that antibiotic exposure and microbiome disruption may be part of that.

  16. Stephen Cherniske

    Certainly, antibiotics should be used sparingly. How many parents believe that as soon as a child’s snot turns green, an antibiotic is required. That is simply not true, but I have heard it from pediatricians! This article, and others describing the emergence of supergerms, brings us to a difficult realization; that we have interfered with natural selection in a profound way. Could it be that in trying to protect and preserve the weakest (certainly a noble goal) we have endangered even the strongest? Time will tell.

  17. vince

    possible follow up tests

    1. more animals aside from rats/mice
    2. instead of prolonged doses of antibiotics, try say 1 week doses 2-3x a year, mimicking actual human use
    3. after long term antibiotic treatment, try various probiotics and see if body fat goes down
    4. in totally germ free rats (raised generation after generation in aseptic conditions), inoculate them with known bad or good bacteria and see what happens

  18. Shawn

    An now, for extra points:

    Science has shown that feeding low levels of antibiotics to animals makes them put on weight faster. Feeding low-level antibiotics to humans will:

    a) make them put on weight.
    b) make them lose weight.
    c) not change their weight gain.
    d) none of the above.

  19. zach k

    @1 – I am a grad student in the Blaser lab – fecal transplants to young, germ free mice from antibiotic treated mice have a similar effects on fat gain as sub-theraputic antibiotic treatment even if no antibiotics are given. (upcoming data!)

  20. Lori

    @Shawn
    Actual children get low doses of antibiotics constantly throughout the day if they eat any non organic animal products. Not to mention if there is any in their tap water! That is why when kids get sick they really get sick now. Several of my friends have their kids at the Dr. getting antibiotics at least once a month and several are now immune to all that are available in the US. They have to wait weeks while stuff in flown in from over seas!

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