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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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January 15, 2013

Is Obesity An Infectious Disease?

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Posted by Derek

Like many people, I have a weakness for "We've had it all wrong!" explanations. Here's another one, or part of one: is obesity an infectious disease?

During our clinical studies, we found that Enterobacter, a genus of opportunistic, endotoxin-producing pathogens, made up 35% of the gut bacteria in a morbidly obese volunteer (weight 174.8 kg, body mass index 58.8 kg m−2) suffering from diabetes, hypertension and other serious metabolic deteriorations. . .

. . .After 9 weeks on (a special diet), this Enterobacter population in the volunteer's gut reduced to 1.8%, and became undetectable by the end of the 23-week trial, as shown in the clone library analysis. The serum–endotoxin load, measured as LPS-binding protein, dropped markedly during weight loss, along with substantial improvement of inflammation, decreased level of interleukin-6 and increased adiponectin. Metagenomic sequencing of the volunteer's fecal samples at 0, 9 and 23 weeks on the WTP diet confirmed that during weight loss, the Enterobacteriaceae family was the most significantly reduced population. . .

They went on to do the full Koch workup, by taking an isolated Enterobacter strain from the human patient and introducing it into gnotobiotic (germ-free) mice. These mice are usually somewhat resistant to becoming obese on a high-fat diet, but after being inoculated with the bacterial sample, they put on substantial weight, became insulin resistant, and showed numerous (consistent) alterations in their lipid and glucose handling pathways. Interestingly, the germ-free mice that were inoculated with bacteria and fed normal chow did not show these effects.

The hypothesis is that the endotoxin-producing bacteria are causing a low-grade chronic inflammation in the gut, which is exacerbated to a more systemic form by the handling of excess lipids and fatty acids. The endotoxin itself may be swept up in the chylomicrons and translocated through the gut wall. The summary:

. . .This work suggests that the overgrowth of an endotoxin-producing gut bacterium is a contributing factor to, rather than a consequence of, the metabolic deteriorations in its human host. In fact, this strain B29 is probably not the only contributor to human obesity in vivo, and its relative contribution needs to be assessed. Nevertheless, by following the protocol established in this study, we hope to identify more such obesity-inducing bacteria from various human populations, gain a better understanding of the molecular mechanisms of their interactions with other members of the gut microbiota, diet and host for obesity, and develop new strategies for reducing the devastating epidemic of metabolic diseases.

Considering the bacterial origin of ulcers, I think this is a theory that needs to be taken seriously, and I'm glad to see it getting checked out. We've been hearing a lot the last few years about the interaction between human physiology and our associated bacterial population, but the attention is deserved. The problem is, we're only beginning to understand what these ecosystems are like, how they can be disordered, and what the consequences are. Anyone telling you that they have it figured out at this point is probably trying to sell you something. It's worth the time to figure out, though. . .

Comments (32) + TrackBacks (0) | Category: Biological News | Diabetes and Obesity | Infectious Diseases


COMMENTS

1. Morten G on January 15, 2013 8:25 AM writes...

Not to diminish the importance of this work but:
"I shouldn't eat junk food, soda, and cake?"

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2. SP on January 15, 2013 8:28 AM writes...

I've liked this theory for a while. Look at time lapse animations of the "obesity epidemic" maps, where states are colored by % obese BMI. It looks just like the animation from a movie like Outbreak only slowed down to take 30 years.
I'd also note that the spread starts somewhere near Arkansas. What have you done, Derek?

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3. Anonymous on January 15, 2013 8:54 AM writes...

Maybe the enterobacter population in question just don't like a healthy (low fat) diet and died out. Would you like fries with that?

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4. marcello on January 15, 2013 9:31 AM writes...

cause vs. effect??

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5. B on January 15, 2013 9:36 AM writes...

@4: My thoughts too, and I tend to sway a little more towards effect. Though in the gnotobiotic mice it appears to be causative.

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6. CatCube on January 15, 2013 9:50 AM writes...

@1, @4,

The "just put down the donut, fatty" kind of assumes that fat people and thin people experience hunger the same way. I was well under my screening table weight when I joined the Army, but never once thought about what I put into my mouth. If I was hungry for something, I ate it. When I wan't hungry, I didn't eat. This left me as an average weight for my height, and took no willpower on my part. I don't find it difficult to believe that some people might have it a lot harder, without them being vile dirtbags who don't care about their weight.

If (and that's a big if) this bacterium has something to do with an increase in obesity, isn't it possible that it increases cravings for sugar? Of course, it's also possible that the average diet of an obese person creates a stomach environment that is conducive to the growth of this bacterium. But it might be worth investigating, as the OP said.

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7. TheOtherGuy on January 15, 2013 10:07 AM writes...

WRT correlation vs. causation and fullfilling Koch's postulates, this is interesting work. However, I can't help but wonder if this is more supportive of all-cause gut inflammation as the etiology of obesity vs. bacterial-caused gut inflammation in particular.

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8. anchor on January 15, 2013 10:20 AM writes...

Derck: Maybe there is some link to enterobacter and obesity. Not the same, but am reminded of other pathogen mediated (is it behavioral?) changes that can inflict damage to the host. The pathogen Toxoplasma Gondi comes to my mind that is known to modify the behavioral pattern of its host (worms, mouse etc.)

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9. johnnyboy on January 15, 2013 10:33 AM writes...

A few thoughts: endotoxin is a constituent part of the cell wall of all gram-negative bacteria; it is not 'produced' by the bacteria per se, but rather is released when the bacteria dies and cell walls breaks down. Normal gut flora is a variable mix of many species, and having 35% of your flora being just one gram-negative species is definitely a severe imbalance. Although the intestinal mucosal lining is normally impermeable to the various bacterial toxins produced in the gut, it seems that concentrations of endotoxin following such a severe flora imbalance might get high enough to overcome normal mucosal resistance and start causing enterocyte degeneration and necrosis, which indeed could lead to all sorts of abnormalities in intestinal absorption. The fact that the patient had detectable circulating endotoxin is certainly indicative that there were abnormalities in absortion. It certainly seems possible that such intestinal lining abnormalities coupled with a high fat diet could lead to higher fat absorption, as is suggested by the mouse results (which I would want to see repeated elsewhere). WHat remains to be explained is why the patient had such a severe flora imbalance - did this have to do with a bad diet, or something else ?
Along those lines there have been intriguing results published recently linking birth by c-section with later obesity, which postulated that absence of exposure to the first source of bacterial flora (the birth canal) leads to a propensity to get unbalanced intestinal flora throughout life, and a predisposition to obesity. Seems a bit far-fetched, but weirder things have been shown true...

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10. johnnyboy on January 15, 2013 10:49 AM writes...

@6: hear hear. I would add that it is just not the experience of hunger that varies from person to person, but also metabolism. I am not obese or overweight but I have been struggling with weight gain pretty much all my life, and it is not because of overeating, or from eating donuts or junk food, because I don't - unfortunately some bodies seem more efficient at absorbing nutriments than others; couple that with sit-down jobs and the maddening availability of calorie-rich food everywhere, and it's not surprising that obesity is so prevalent. Some obese people may be so mainly because of behavioral issues, but vilifying millions of overweight westerners by saying 'put down the donut' is just glib and unhelpful.

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11. Rock on January 15, 2013 11:18 AM writes...

I wonder if this is somehow related to the unexpected benefits of bariatric surgery on diabetes (independent of weight loss). It has been a mystery for years now. Perhaps the surgery, or prep thereof, changes the gut flora.

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12. a. nonymaus on January 15, 2013 12:41 PM writes...

What effect on resting metabolic rate does circulating endotoxin have? If this bacterial endotoxin is ending up in the bloodstream, it could affect more than just the gut.

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13. Anonymous on January 15, 2013 12:58 PM writes...

Calories in - calories out = weight gain.

Obviously some people have more cravings, which will influence calories in. Other people have slow metabolisms which will influence calories out, but the equation is irrefutable.

Even with the gnotobiotic mice this bacteria was not causative of the weight gain, they were on a HIGH FAT DIET. The diet is causative.

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14. Michael O on January 15, 2013 1:10 PM writes...

This would not surprise me all that much. Your chances of getting cavities works in much the same way. Depending on their oral flora, two people can have nearly identical brushing habits, but one can have perfect teeth while the other is riddled with cavities.

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15. BioBritSD on January 15, 2013 1:54 PM writes...

@SP (#2)
I lie the infectious theory too. But I would caution that lots of (traditionally) non infectious things show infection-like spreading patterns. There is a reason ideas are infectious, and memes go viral. The pattern for obesity could equally well be infection, or given the slow time lapse, simply the spred of an idea - in this case the idea is that a larger size and/or more unhealthy habits are more normal (in other words, you are only as thin as the people around you are fat - so as your peers get larger, so do you).

I know little of the science. But I would expect that obesity, as like cancer, is not one disease but a myriad of many.

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16. dearieme on January 15, 2013 2:40 PM writes...

What happens to people who clear out their colons before endoscopy? Does that change their flora, or is it the wrong part of their system to be relevant to this issue?

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17. CatCube on January 15, 2013 3:01 PM writes...

@13

Yes, your equation is true. However, "Obviously some people have more cravings than others" is doing a lot of work.

Late last month, I lost 10 pounds. In a week. I got the bug going around real bad, and when I didn't have a complete lack of appetite, I didn't even feel like getting out of bed to actually eat. Losing that weight was really frickin' easy (indeed, it was totally unintentional as well as an absolutely unhealthy way to do so). If, less than a month later, you were to tell me to repeat the effort, I would be totally unable to do so since I'll have frequent hunger cravings and the energy to actually get food. So waving away how fat people just have somewhat stronger cravings that they need to suppress is probably giving them too little credit, and giving (most) thin people too much.

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18. SP on January 15, 2013 4:37 PM writes...

@15
Either way, I still blame Arkansas.

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19. Derek Lowe on January 15, 2013 5:21 PM writes...

Well, between the fried catfish and hushpuppies, the barbecue, and the fried chicken, there might be something to that Arkansas theory. But only if the infected masses take to consuming these Foods of the Gods - having consumed all of them at one meal one a few occasions, I feel qualified to advance that theory (!)

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20. Neuropharm on January 15, 2013 7:09 PM writes...

I thought this appropriate:

http://www.theonion.com/articles/scientists-discover-gene-responsible-for-eating-wh,691/

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21. zmil on January 15, 2013 8:36 PM writes...

"Calories in - calories out = weight gain.

Obviously some people have more cravings, which will influence calories in. Other people have slow metabolisms which will influence calories out, but the equation is irrefutable.

Even with the gnotobiotic mice this bacteria was not causative of the weight gain, they were on a HIGH FAT DIET. The diet is causative."

This equation is true, but ignores the complexity of measuring calories. Gut flora can in fact affect the caloric content of food, as can be seen by the fact that cows won't starve to death eating grass, while we will.

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22. iVoid on January 15, 2013 10:11 PM writes...

Cut carbs in your diet and reap the rewards is all I can say, its quite amazing

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23. David L. on January 16, 2013 10:56 AM writes...

This is great if obesity is caused by infectious disease and not overeating. For famine stricken populations it would be easier to infect everyone than to try and supply them with food. Trouble would be to have enough infection to sustain a normal weight but not so much they hit obesity /sarc

Obesity is a matter of caloric balance. Eat less, weigh less. Period.

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24. MoMo on January 16, 2013 2:21 PM writes...

There are also theories with data that suggest bacterial flora can produce low MW compounds that can suppress neurological development-autism, development disorders, irrationality-and that our HFCS influenced diets cause such bacteria to fluorish.

So why not obesity?

You are what you Eat!

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25. Brooks Moses on January 16, 2013 11:29 PM writes...

The interpretation of the "calories in - calories out" equation is also missing the effect of food content and timing on metabolism. I know someone who ate too little and skipped meals and gained weight on about 800 calories a day, because her metabolism was reacting to severe shortage; increasing her intake by a significant amount resulted in no more weight gain, and spreading her diet out to more meals per day resulted in some weight loss.

More to the point, Anonymous @13 is missing the point that the same strain of mice, on the same high fat diet but without these gut bacteria, do not gain weight. This isn't handwaving, it's properly controlled science.

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26. me on January 17, 2013 7:36 AM writes...

There have been numerous articles in the last 2 years linking the gut with type 2 diabetes - the lap band surgery that cures type 2 diabetes -before- weight loss, the link with the ulcer causing germ, etc. etc. This leads me (I have diabetes type 2) to believe that a cure is in the works. I hope it won't be long and won't involve surgery.

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27. Guppy on January 17, 2013 12:04 PM writes...

@16 The effect is probably very similar to what happens during a bout of secretory-type or osmotic-type diarrhea. Despite the volume of material dumped, there are still astronomical numbers of bacteria remaining; what appears to be clean and smooth mucosal surfaces to the eye is actually a well-populated, microscopically rugged terrain.

On the other hand, antibiotics can definitely produce major changes in GI flora.

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28. Anonymous on January 17, 2013 6:25 PM writes...

In regards to the comments about the link to bariatric surgery and diabetes, I currently work in that field, and the hypothesis that we are following is that the altered hormone secretion of the GI has profound effects on glucose homeostasis. There are many known as well as unknown peptides, some which are already fairly popular, such as GLP-1.

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29. Ruth on January 18, 2013 11:39 PM writes...

Exactly what was that "special diet" that resulted in the normalization of gut flora?

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30. Me on January 21, 2013 8:36 AM writes...

Yet another article on the relationship between gut bacteria and diabetes:
http://www.sciencedaily.com/releases/2013/01/130118064731.htm

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31. me on January 21, 2013 9:23 AM writes...

Sudden thought: The prep for a colonoscopy involves cleaning out the gut. This would (possibly)provide an opportunity for gut bacteria to change. Is it possible that this might provide a driving factor for the onset of type II diabetes? It wouldn't happen every time, of course, and there would be a time delay, but there ought to be enough statistics somewhere to do a quick look.

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32. Holly on March 30, 2013 1:59 AM writes...

There is new research just coming out on this very topic, which led me to this site. I am very interested in it because I have long known that something was wrong with the current model of calories in=calories out, namely that it isn't true.

I have known thin people who eat ALL DAY and eat whatever they want, and they are thin as bean poles. I've also known people who eat a normal diet and still struggle with their weight. It's hard to go on a "diet" when you don't overeat to begin with, which is what makes it so difficult for those people. Calories in=calories out is a ridiculous myth. I'm glad science is finally finding real answers to obesity.

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