tl;dr: Excess body fat and obesity are an immune response to gram-negative gut bacteria, not a metabolic problem. Fix it by taking oral polymyxin, or a comparable antibiotic. Further research into good antibiotics for this purpose would be appreciated.
Earlier this year, an article found that bacteria from an obese human could cause obesity in mice. They isolated the bacteria, put it in some randomly chosen mice, and after a few months the mice with the bacteria were fat and had diabetes problems while the control group was healthy. With a second experiment they found that the mechanism is the molecule lipopolysacharride (LPS aka endotoxin), found in the membrane of all gram-negative bacteria. When gram negative bacteria become established in the gut, the LPS triggers a inflammation response from the immune system which causes both fat accumulation and diabetes in the long run. So they’ve established very firmly that gut bacteria are sufficient to cause excess body fat, but whether that’s the main source in the general human population is unknown. (source: http://www.nature.com/ismej/journal/v7/n4/pdf/ismej2012153a.pdf, apologies if it’s behind an academic firewall)
So how does one get rid of gram-negative bacteria? It turns out that there is a common antiobiotic, polymyxin, which specifically targets LPS itself and kills bacteria which produce LPS. Polymyxin is among the most common topical antibiotics (along with neosporin), and can also be taken intravenously or orally. Intravenously it is a mild neurotoxin, but this is not an issue if taken orally.
Finally, it turns out that a study published back in 2006 administered polymyxin intravenously to rats. They found a 46% drop in adipose fat mass in rats given polymyxin. They had no idea what the mechanism was, hypothesized some vague connection to insulin signalling, and it just went down as one of those weird results. But now, in light of the more recent results, we can be pretty sure that gram-negative gut bacteria were the issue. The importance of this study is that it suggests gram-negative bacteria are a major cause of excess body fat in the general rat population, not just a special case of the 2013 study. So, it’s reasonable to suspect that polymyxin would fix most human obesity too. (source: http://link.springer.com/article/10.1007/s10989-005-9009-9)
Excess body fat and obesity are an immune response to gram-negative gut bacteria, not a metabolic problem. Fix it by taking oral polymyxin, or a comparable antibiotic.
So they’ve established very firmly that gut bacteria are sufficient to cause excess body fat, but whether that’s the main source in the general human population is unknown.
Quack quack goes the duck. I wouldn’t use such an experimental treatment even on your pet rat.
(It does sound vaguely promising, like thousands of other candidate substances in translational medicine that didn’t pan out.)
Edit: The paper is not from the journal Nature, it is instead from a different journal which is also published by the same company. The paper was published in The ISME Journal, with an impact factor of 7.4, compared to Nature’s impact factor of 31! So next time, please do your research.
The paper is open access, but your link is blocked unless entered directly (they probably don’t accept any non-site values for the HTTP referer field). This link should work.
Also, before you start taking antibiotics, here’s the relevant part from that abstract:
The obesity-inducing capacity of this human-derived endotoxin producer in gnotobiotic mice suggests that it may causatively contribute to the development of obesity in its human host.
No mention of using antibiotics, polymyxin isn’t mentioned once. As for the second study, there are reasons you don’t administer polymyxin intravenously, and its intravenous efficacy is much different from when taken orally.
the effect sizes were huge in both experiments.
No, there were no antibiotics used in the ISMEJ article: ” The volunteer lost 30.1 kg after 9 weeks, and 51.4 kg after 23 weeks, on a diet composed of whole grains, traditional Chinese medicinal foods and prebiotics (WTP diet, Supplementary Information; Supplementary Figure 1)”
So, it’s reasonable to suspect that polymyxin would fix most human obesity too.
Thanks for pointing out the journal error, that has been corrected. Also big thanks for the working link.
The “experiment” with the human subject in the ISMEJ article was stupid, which was why I didn’t mention it. Everything I’m saying is based on the mouse experiments.
I do think your interpretation of these experiments is way too restricted. In a frequentist sense, everything you’re saying is reasonable, since we don’t know how well various results generalize (mouse to human, intravenous to oral, etc...). But in a Bayesian sense, this is pretty good evidence. I guessed that polymyxin would reduce body fat (regardless of how it’s administered) just based on reading the ISMEJ article, which never mentioned antibiotics. That means the first article alone was enough to promote the hypothesis out of entropy. I then found the second article by searching for papers discussing polymyxin and obesity, and the result was what I expected (large drop in fat after polymyxin administration), so that’s a big evidential boost in favor.
Neither of those gives evidence for the mouse result generalizing to humans. However, we do know that gram-negative bacteria are pretty ubiquitous and do trigger an immune response in humans similar to that in mice, so based on the physical systems we should expect a similar response to antibiotics.
There was a special issue of Nature focusing on human microbiota a few months back which seems to have a lot more relevant research with humans, but I haven’t had time to go through them in depth yet (which is why this was a poorly-researched comment rather than a full discussion post).
Ah, but the cool thing is that you don’t need an experimental treatment. We’re talking bog-standard antibiotics, nothing unusual. The only unusual thing is what you’d be trying to do with those antibiotics.
And unlike the usual vaguely promising substances, the effect sizes were huge in both experiments. You don’t get a 46% drop in adipose fat from random noise.
My basic sanity check for any sort of experiment purporting to show a new mechanism responsible for obesity, is “under this mechanism, does it make sense for lots of people to be obese now in America, but hardly anyone a hundred years ago in America, or today in countries like Japan where people have high access to resources but eat less?”
If a mechanism for obesity leaves you confused by the patterns of obesity that occur in the real world, then it’s probably better not to afford it much likelihood.
I’m not sure what your response is supposed to be saying to the grandparent. Wouldn’t this make total sense if gut flora changed in the united states over the past 100 years? especially if you consider that period includes the introduction and widespread use of antibiotics as well as diet changes, chemical effects that are known to change gut flora. Because gut flora is acquired from the mother, it makes sense that different ethnic groups in different parts of the world would have different compositions also. Gut flora in various societies doesn’t seem to have been studied very much (I’m a lazy googler and only found one study that was tangential) but I wouldn’t be surprised if different nations had different gut flora.
Different nations may have different gut flora, but my past googling indicates a degree of national weight average and national caloric intake which would be awfully conspicuous if gut flora were the real mechanism at work.
Perhaps HFCS in particular encourages LPS bacteria. Or perhaps LPS bacteria particularly stimulates thirst for sweet liquids. It’s impossible to know without (preferably both of) historical LPS and a controlled experiment. Also, your link does not establish a causal link between sugary drink consumption and obesity, merely that they’ve been correlated for a few decades.
In addition, the researchers reviewed a study in schoolchildren that showed an educational program advocating fewer sugary sodas reduced weight gain and obesity among the kids after 12 months.
Which you would expect if the sodas had a causal relationship with obesity, and probably not if they didn’t.
Can you think of any observations, in humans, which favor the LPS bacteria model of obesity, rather than simply being reconcilable with it given enough ad hoc additions?
tl;dr: Excess body fat and obesity are an immune response to gram-negative gut bacteria, not a metabolic problem. Fix it by taking oral polymyxin, or a comparable antibiotic. Further research into good antibiotics for this purpose would be appreciated.
Earlier this year, an article found that bacteria from an obese human could cause obesity in mice. They isolated the bacteria, put it in some randomly chosen mice, and after a few months the mice with the bacteria were fat and had diabetes problems while the control group was healthy. With a second experiment they found that the mechanism is the molecule lipopolysacharride (LPS aka endotoxin), found in the membrane of all gram-negative bacteria. When gram negative bacteria become established in the gut, the LPS triggers a inflammation response from the immune system which causes both fat accumulation and diabetes in the long run. So they’ve established very firmly that gut bacteria are sufficient to cause excess body fat, but whether that’s the main source in the general human population is unknown. (source: http://www.nature.com/ismej/journal/v7/n4/pdf/ismej2012153a.pdf, apologies if it’s behind an academic firewall)
So how does one get rid of gram-negative bacteria? It turns out that there is a common antiobiotic, polymyxin, which specifically targets LPS itself and kills bacteria which produce LPS. Polymyxin is among the most common topical antibiotics (along with neosporin), and can also be taken intravenously or orally. Intravenously it is a mild neurotoxin, but this is not an issue if taken orally.
Finally, it turns out that a study published back in 2006 administered polymyxin intravenously to rats. They found a 46% drop in adipose fat mass in rats given polymyxin. They had no idea what the mechanism was, hypothesized some vague connection to insulin signalling, and it just went down as one of those weird results. But now, in light of the more recent results, we can be pretty sure that gram-negative gut bacteria were the issue. The importance of this study is that it suggests gram-negative bacteria are a major cause of excess body fat in the general rat population, not just a special case of the 2013 study. So, it’s reasonable to suspect that polymyxin would fix most human obesity too. (source: http://link.springer.com/article/10.1007/s10989-005-9009-9)
Quack quack goes the duck. I wouldn’t use such an experimental treatment even on your pet rat.
(It does sound vaguely promising, like thousands of other candidate substances in translational medicine that didn’t pan out.)
Edit: The paper is not from the journal Nature, it is instead from a different journal which is also published by the same company. The paper was published in The ISME Journal, with an impact factor of 7.4, compared to Nature’s impact factor of 31! So next time, please do your research.
The paper is open access, but your link is blocked unless entered directly (they probably don’t accept any non-site values for the HTTP referer field). This link should work.
Also, before you start taking antibiotics, here’s the relevant part from that abstract:
No mention of using antibiotics, polymyxin isn’t mentioned once. As for the second study, there are reasons you don’t administer polymyxin intravenously, and its intravenous efficacy is much different from when taken orally.
No, there were no antibiotics used in the ISMEJ article: ” The volunteer lost 30.1 kg after 9 weeks, and 51.4 kg after 23 weeks, on a diet composed of whole grains, traditional Chinese medicinal foods and prebiotics (WTP diet, Supplementary Information; Supplementary Figure 1)”
No.
Thanks for pointing out the journal error, that has been corrected. Also big thanks for the working link.
The “experiment” with the human subject in the ISMEJ article was stupid, which was why I didn’t mention it. Everything I’m saying is based on the mouse experiments.
I do think your interpretation of these experiments is way too restricted. In a frequentist sense, everything you’re saying is reasonable, since we don’t know how well various results generalize (mouse to human, intravenous to oral, etc...). But in a Bayesian sense, this is pretty good evidence. I guessed that polymyxin would reduce body fat (regardless of how it’s administered) just based on reading the ISMEJ article, which never mentioned antibiotics. That means the first article alone was enough to promote the hypothesis out of entropy. I then found the second article by searching for papers discussing polymyxin and obesity, and the result was what I expected (large drop in fat after polymyxin administration), so that’s a big evidential boost in favor.
Neither of those gives evidence for the mouse result generalizing to humans. However, we do know that gram-negative bacteria are pretty ubiquitous and do trigger an immune response in humans similar to that in mice, so based on the physical systems we should expect a similar response to antibiotics.
There was a special issue of Nature focusing on human microbiota a few months back which seems to have a lot more relevant research with humans, but I haven’t had time to go through them in depth yet (which is why this was a poorly-researched comment rather than a full discussion post).
Ah, but the cool thing is that you don’t need an experimental treatment. We’re talking bog-standard antibiotics, nothing unusual. The only unusual thing is what you’d be trying to do with those antibiotics.
And unlike the usual vaguely promising substances, the effect sizes were huge in both experiments. You don’t get a 46% drop in adipose fat from random noise.
My basic sanity check for any sort of experiment purporting to show a new mechanism responsible for obesity, is “under this mechanism, does it make sense for lots of people to be obese now in America, but hardly anyone a hundred years ago in America, or today in countries like Japan where people have high access to resources but eat less?”
If a mechanism for obesity leaves you confused by the patterns of obesity that occur in the real world, then it’s probably better not to afford it much likelihood.
I’m not sure what your response is supposed to be saying to the grandparent. Wouldn’t this make total sense if gut flora changed in the united states over the past 100 years? especially if you consider that period includes the introduction and widespread use of antibiotics as well as diet changes, chemical effects that are known to change gut flora. Because gut flora is acquired from the mother, it makes sense that different ethnic groups in different parts of the world would have different compositions also. Gut flora in various societies doesn’t seem to have been studied very much (I’m a lazy googler and only found one study that was tangential) but I wouldn’t be surprised if different nations had different gut flora.
Different nations may have different gut flora, but my past googling indicates a degree of national weight average and national caloric intake which would be awfully conspicuous if gut flora were the real mechanism at work.
Perhaps the presence of LPS bacteria and the corresponding immune response provoke a larger appetite.
That’s a possibility, but it’s one under which I would antipredict findings like this.
Perhaps HFCS in particular encourages LPS bacteria. Or perhaps LPS bacteria particularly stimulates thirst for sweet liquids. It’s impossible to know without (preferably both of) historical LPS and a controlled experiment. Also, your link does not establish a causal link between sugary drink consumption and obesity, merely that they’ve been correlated for a few decades.
Well, from that link
Which you would expect if the sodas had a causal relationship with obesity, and probably not if they didn’t.
See also this article.
Can you think of any observations, in humans, which favor the LPS bacteria model of obesity, rather than simply being reconcilable with it given enough ad hoc additions?
Fascinating finding and worth exploring further, but it isn’t a dichotomy. “Not” is not implied when “and” would work just as well.