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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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March 5, 2010

Your Own Personal Bacteria

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Posted by Derek

There's a report in Nature on the bacteria found in the human gut that's getting a lot of press today (especially for a paper about, well, bacteria in the human gut). A team at the Beijing Genomics Institute, with many collaborators, has done a large shotgun sequencing effort on gut flora and identified perhaps one thousand different species.

I can well believe it. The book I recommended the other day on bacteria field marks has something to say about that, pointing out that if you're just counting cells, that the cells of our body are far outnumbered by the bacteria we're carrying with us. Of course, the bacteria have an advantage, being a thousand times smaller (or more) than our eukaryotic cells, but there's no doubt that we're never alone. In case you're wondering, the average European subject of the study probably carries between 150 and 200 different types of bacteria, so there's quite a bit of person-to-person variability. Still, a few species (mostly Bacteroides varieties) were common to all 124 patients in the study, while the poster child for gut bacteria (E. coli) is only about halfway down the list of the 75 most common organisms. We have some Archaea, too, but they're outnumbered about 100 to 1.

What's getting all the press is that idea that particular mixtures of intestinal bacteria might be contributing to obesity, cancer, Crohn's disease and other conditions. This isn't a new idea, although the new study does provide more data to shore it up (which was its whole purpose, I should add). It's very plausible, too: we already know of an association between Helicobacter and stomach cancer, and it would be surprising indeed if gut bacteria weren't involved with conditions like irritable bowel syndrome or Crohn's. This paper confirms earlier work that such patients do indeed have distinctive microbiota, although it certainly doesn't solve the cause-or-effect tangle that such results always generate.

The connection with obesity is perhaps more of a stretch. You can't argue with thermodynamics. Clearly, people are obese because they're taking in a lot more calories than they're using up, and doing that over a long period. So what do bacteria have to do with that? The only thing I can think of is perhaps setting off inappropriate food cravings. We're going to have to be careful with that cause and effect question here, too.

One problem I have with this work, though, is the attitude of the lead author on the paper, Wang Jun. In an interview with Reuters, he makes a very common mistake for an academic: assuming that drug discovery and treatment is the easy part. After all, the tough work of discovery has been done, right?

"If you just tackle these bacteria, it is easier than treating the human body itself. If you find that a certain bug is responsible for a certain disease and you kill it, then you kill the disease," Wang said

For someone who's just helped sequence a thousand of them, Wang doesn't have much respect for bacteria. But those of us who've tried to discover drugs against them know better. Where are these antibiotics that kill single species of bacteria? No such thing exists, to my knowledge. To be sure, we mostly haven't looked, since the need is for various broader-spectrum agents, but it's hard to imagine finding a compound that would kill off one Clostridium species out of a bunch. And anyway, bacteria are tough. Even killing them off wholesale in a human patient can be very difficult.

Even if we magically could do such things, there's the other problem that we have no idea of which bacterial strains we'd want to adjust up or down. The Nature paper itself is pretty good on this topic, emphasizing that we really don't know what a lot of these bacteria are doing inside us and how they fit into what is clearly a very complex and variable ecosystem. A look at the genes present in the samples shows the usual common pathways, then a list that seem to be useful for survival in the gut (adhesion proteins, specific nutrient uptake), and then a massive long tail of genes that do we know not what nor why. Not only do we not know what's happening on other planets, or at the bottom of our own oceans, we don't even know what's going on in our own large intestines. It's humbling.

Dr. Wang surely realizes this; I just wish he'd sound as if he does.

Comments (25) + TrackBacks (0) | Category: Biological News | Diabetes and Obesity | Infectious Diseases


COMMENTS

1. Seminymous Coward on March 5, 2010 10:06 AM writes...

Why not just run everything in your database that's ever passed a tox screening on cultures of the relevant bacteria? It seems "toxic to some bacteria" would be a relatively common property in the space of all reasonable molecules, and, if it happens to exist in your list, you get the tricky part for free.

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2. anchor on March 5, 2010 10:07 AM writes...

What is holding him up? I am sure that people at WuXi can help him there faster than others.

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3. Lei Piran on March 5, 2010 10:11 AM writes...

The connection with obesity is perhaps more of a stretch. You can't argue with thermodynamics. Clearly, people are obese because they're taking in a lot more calories than they're using up, and doing that over a long period. So what do bacteria have to do with that? The only thing I can think of is perhaps setting off inappropriate food cravings. We're going to have to be careful with that cause and effect question here, too.

It may also have to do with how well the gut bacteria ferment complex carbohydrates that we have a hard time digesting. A person who is getting a bacterial assist on extracting calories from fermentable soluble fiber is going to be a tad more prone to be overweight than a person whose bacteria either don't ferment soluble fiber so well or which are very stingy with using the resulting short-chain fatty acids themselves.

I'd be surprised if it was a huge effect for the average American diet, though. Not that much soluble fiber.

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4. MedChem on March 5, 2010 10:24 AM writes...

I don't completely buy their logic, yet. Certain bacteria are thought to cause acic reflux. But in general, these different strains of bacteria could be the cause or RESULT of diseases, or simply have nothing to do with them. What's the rational to believe one way or the other?

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5. anon the II on March 5, 2010 10:51 AM writes...

Since I don't have a job and I need to feel useful, I'll make a few comments.

Dr. Wang's statements of the "We just did some nice science and the drugs will follow" sort are pretty standard fare. The people who write up Nobel Prizes are particularly egregious in this department.

to Lei Piran

I thought most of the gut's bacterial processing occurred past the point of absorption and that the impact was more on the packaging (solid vs gas) of the final product. I'd appreciate clarification from anyone on that.

to MedChem

Are you confusing acid reflux with ulcers?

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6. John FitzGibbon on March 5, 2010 11:21 AM writes...

So I think first of that gut bacteria are a play a huge role in disease. They can effect the uptake of compounds, drugs included, they can also cause chronic inflammation. Chronic inflammation plays a role in insulin resistance and can add to obesity in that manner.
My problem is with the concept of this being a representative sample. Two countries, no note about their diet, lifestyle etc. In smaller less in depth studies diet, lifestyle, upbringing and geographical location all play a role in the composition of the gut bacteria. It seems like a really limited study, and while it's a pile of data I wonder why it's in nature. It's got some serious problems to it. Science by press release is a great way to create funding, and unreasonable expectations.

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7. road on March 5, 2010 11:36 AM writes...

The idea that gut microbes contribute to obesity revolves around the fact that they can affect the number of calories we're able to extract from our diet. This is thought to be primarily due to their ability to catabolize otherwise-indigestible plant polysacharides, which they ferment into short-chain fatty acids which are absorbed by the host in the large intestine. In extreme cases this effect can be dramatic: germ-free mice consume 30% more food to achieve the same body-mass.

I think most-people in the field would agree, however, that the effect is likely to be subtle. Although, if your microflora predispose you to extract 5% more calories from the food you eat, over a life-time that can add up and may, in fact, have an observable impact on your metabolism. What is not entirely clear is how stable your particular microfloral population is over the course of days/weeks/years and how much it is shaped by genetics versus the environment (diet).

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8. In Vivo Veritas on March 5, 2010 11:37 AM writes...

There's some evidence out there that innoculating a lean mouse with the gut bacteria of an obese mouse will induce obesity in the formerly lean mouse. Another paper demonstrates that this obesity induction is partially blocked in mice lacking GPR41 - a FFA receptor. So the evidence builds that 1) nutrient extraction can be effected by gut bacteria and 2)bacteria-host communication via receptor stimulation can also occur. Could be that bacteria do influence body weight. But good luck targeting them with any specificity.

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9. Bored on March 5, 2010 11:48 AM writes...

There are evolutionary forces at work as well. Those bacteria got there because it was either advantageous for them, or us, or both of us. Trying to untangle that cause-and-effect, like Derek points out, is a Gordian Knot.

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10. lewis Robinson on March 5, 2010 11:50 AM writes...

#8 Correct -- here's some of the evidence. Sorry to be so long-winded, but this stuff is pretty interesting.

[ Nature vol. 444 pp. 1009 - 1010, 1022 - 1023, 1027 - 1031 '06 ] The two predominant populations of microbiota in mouse and human gut are the Firmicutes (Gram positive anaerobes) and Bacteroidetes (Gram negative anaerobes) -- together 93% of all species found. Add in Proteobacteria and Actinobacteria and you get 'up to' 99% of all organisms in thse 4 phyla. Fat people have a higher proportion of Formicutes than skinny ones. When the obese lost weight over a year, the Firmicute proportion dropped. However, they didn't acquire new organisms to do this, it was expansion and contraction of existing populations. Bacterial diversity remained constant over time. What they did was look at some 18,348 bacterial 16S rRNAs to tell the species apart. Most (70%) of the 4,074 species level phylogenetic types were unique to each person.

Colonization of adult germ-free mice with a distal gut microbial community harvested from conventionally raised mice produces a dramatic increase in body fat in 10 - 14 days even though food consumption decreases. This is because the bugs break down polysaccharides that the host can't digest. In addition the bugs regulate host genes which promote deposition of fat.

Differences in the microbiota of lean and obese mice confirm the result. Obese mice have more fermentation end products and fewer calories remaining in their feces than lean ones. Thus the bacteria in fat mice seem to help the host extract calories.

The microbiota of obese leptin deficient mice was transferred to lean abiotic (germfree) mice. Mice given the microbiota from fat mice extracted more calories from their food than abiotic mice given the microbiota from lean mice. Does this cause day after day obesity? Which comes first -- efficient food digestion or obesity?

The Firmicutes is the largest bacterial phylum containing over 250 genera -- lactobacillus, mycoplasma, Bacillus and Clostridium. Firmicutes account for 64% of mucosally associated colonic species, primarily clostridium XIVa and Clostridium IV.

The Bacteroidetes include 20 genera (Bacteroides the most abundant).

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11. SteveSC on March 5, 2010 12:05 PM writes...

I think everyone would agree that an organism floating in a 'soup' of bacteria would be affected by the types of bacteria in the soup, through competition for resources, microbial attack, etc.

When animals developed a gut it essentially compartmentalized that primitive external environment into a tube. We have some control over what we put in one end of the tube, but to the gut wall, the environment is not that much different from competing with the bacterial soup as nutrients float by.

To complicate matters, different portions of the gut absorb different nutrients at different rates (except simple sugars, which seem to be sucked up everywhere). So if bacteria slow down absorption (e.g., by coating the gut wall or the nutrients) and/or speed up transit, they could reduce absorption of specific nutrients. One can easily come up with scenarios that would increase the percentage of sugar absorption of a given nutrient mixture, which could have an effect on diabetes and/or body weight.

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12. daveh on March 5, 2010 2:46 PM writes...

Goodbye Bacteria. Hello Candidiasis. Or, if you're really lucky Aspergillosis.

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13. hibob on March 5, 2010 4:19 PM writes...

While knocking out indvidual species of bacteria without touching their beneficial relations doesn't seem likely - wouldn't it be nice as a chemist to be working on a project where you could chuck most of the ADME considerations? If your ideal compound stays in the gut and NEVER crosses the intestinal wall ...

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14. Shane on March 5, 2010 4:40 PM writes...

I know this is a chemistry blog but do we have to get stuck in a chemical mind set to start tweaking the bacterial populations?

Isn't the most selective and effective way to knock down bacteria the use of bacteriophage?

I believe the Russians are already using phage therapy for intractable/biofilm based bacterial infections (e.g. middle ear infections....nasty).

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15. Epicanis on March 5, 2010 4:47 PM writes...

Dang - I came here to answer the:

" Where are these antibiotics that kill single species of bacteria?"

question with "bacteriophages", but I see someone has already beaten me to it.

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16. Skeptic on March 5, 2010 6:30 PM writes...

Look at the other article in Nature about BGI itself. No PHD's. A huge narrow focus committment to crucial technology development.

Its analogous to the huge USA committment towards numerous calutrons (while other countries had none) that established their currency as the world reserve currency.

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17. Think on March 6, 2010 8:44 AM writes...

"If you just tackle these bacteria, it is easier than treating the human body itself. If you find that a certain bug is responsible for a certain disease and you kill it, then you kill the disease" -- attributed to Jun Wang

Ah, but what else do you mess up in the process? It unnerves me to read comments that promote the concept of making anything better by finding the bad guys and killing them. That may be effective short term, but it is not the whole story.

We persist in thinking of the gut as an *external* environment, with us being *host* to populations of some combination of beneficial, neutral and harmful bacteria. But all (naturally occurring) multi-cellular organisms are actually made up of constantly varying conglomerations of numerous cellular species.

Consider that we are multi-specied as well as multi-cellular organisms. Our health is a stateless balancing act within an extremely complex and dynamic system. Sure, individual thoughts arise out of the system, but physically, we are still a system - not an individual entity.

Think of cells as being the quantum elements of a largely analogue living system. There is no "us" and "them" in the gut biome -- only us. And "Us" have an amazingly complex balancing act that endeavors to push the entire system toward a state that promotes propagation of our genes -- all of our genes.

So, OK, I admit that I am a long winded philosopher. I am just cautioning against over-simplification. If we go down a road zapping a bug to lose weight and zapping another bug to prevent Crohn's disease, lets also give some thought as to why we evolved those bugs to begin with. A healthy gut is achieved through the interactions of thousands of different species -- that is large dynamic network of chemical communication pathways. Many of the populations' current immune diseases are likely side effects of previous simple solutions to earlier health problems.

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18. Chemoptoplex on March 6, 2010 11:35 PM writes...

Looking at the reader's digest version of the mouse studies above, would it be possible to periodically sterilize the gut and reinoculate with the beneficial strains?

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19. Tomas on March 8, 2010 1:54 AM writes...

Your out of touch to say that it will be a MIRACLE before we can target selective bacteria; Binnie Bassler shows us we can interrupt SPECIFIC species communication so that they don't launch an attack. We can also soon communicate directly with beneficial ones so they will be encouraged to perform helpful things at will.

http://www.ted.com/talks/bonnie_bassler_on_how_bacteria_communicate.html

I've had a great success treating a myriad of symptoms (gas, fatigue, bowels, candida, lactose intolerance) by eating foods and herbs good at destroying bad gut flora and replacing them with a brad spectrum of pro-biotics. (Not knowing which companies claims are false I try different one each month which should give me enough variety to colonize a good gut). I also believe eating foods raw and/or supplementing with enzymes are better for the gut bacteria as the bad types of flora love undigested fermenting guts.

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20. Jose on March 8, 2010 3:31 AM writes...

Skeptic- since you continue to bash "PHDs" please do everyone a favor and get it correct- it's "PhD."

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21. MattF on March 8, 2010 8:34 AM writes...

You don't think the bacteria themselves make any contribution to the metabolic energy balance? I'm not sure, particularly since the energy balance is a -marginal- issue-- it's the response to small changes that makes big differences over the long term.

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22. RKN on March 9, 2010 10:38 AM writes...

I'm presently at the HUPO (Human Proteome) conference in Denver and heard Jeffery Gordon deliver the opening talk on this subject. Cool stuff. He showed the ability to transfer the obesity phenotype to otherwise normal mice raised in a germ free environment using only the gut microbiota of obese mice. Mice were otherwise isogenic. Pretty cool, reasonably convincing.

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23. doctorpat on March 10, 2010 9:50 PM writes...

He showed the ability to transfer the obesity phenotype to otherwise normal mice

Interesting. Now do the reverse and watch the money roll in.

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24. note on March 13, 2010 11:48 AM writes...

I won't bore you with my opinions, but one fact:

" Where are these antibiotics that kill single species of bacteria?"

Isoniazid is specific to tuberculosis.

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25. Benta on March 30, 2010 10:08 AM writes...

"The connection with obesity is perhaps more of a stretch. You can't argue with thermodynamics. Clearly, people are obese because they're taking in a lot more calories than they're using up, and doing that over a long period. So what do bacteria have to do with that? The only thing I can think of is perhaps setting off inappropriate food cravings. We're going to have to be careful with that cause and effect question here, too."

Derek, you are falling into a common trap here, which is very relevant to the "cause-and-effect" discussion.

The argument goes:
Stored energy (tissue) = energy in (food) - energy out (consumption and excretion)

While this is correct thermodynamically, you are unwittingly relying on two assumptions which are not given.
1: there is no causality in the equation. It might be that it is actually the storage of tissue that is causing the caloric imbalance, not the other way round.
2: you are assuming the "energy in" and "energy "out" are independent variables. They are not. If you eat too much, your basic metabolism will increase. If you eat too little it will decrease (cold hands, feet etc.)

If you think the my first point is implausible, consider the sentence:
"My child is growing because he eats a lot." That would be ridiculous. Children eat a lot because they are growing, and this is under control of hormones. Growing in the lateral direction might also be under control of hormones, and a lot points in that direction.
This would imply that it is the type of food we eat and not the amount that is the controlling factor. Hence, perhaps, the success of Atkins-type diets.

Regards,

Benta.

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