There is no 'healthy' microbiome(nytimes.com)
nytimes.com
There is no 'healthy' microbiome
http://www.nytimes.com/2014/11/02/opinion/sunday/there-is-no-healthy-microbiome.html?_r=0
16 comments
>microbiome hackers
I really wish this wasn't a thing. I'm getting tired of all the "startups" in my field (microbio) who are pushing microbiome-based treatments. They're not currently regulated by the FDA and they are downright dangerous. The healthy gut is primarily made up of (~90%) Firmicutes, Bacteroidetes, and Clostridium of which the majority are uncultured, unsequenced and completely unstudied. Shifting the balance a little too much one way or another can potentially cause symptoms of Autism Spectrum Disorder. There are at least two startups in stealthmode that I know of that are pushing microbiome matching between "healthy" donors and "unhealthy" recipients -- very much like snake oil salesmen. One person's healthy is another's unhealthy but these groups and their VCs apparently don't give a shit (VC funding in science is a while other can of worms).
If you want to be a microbiome hacker, go contribute YOUR microbiome to publicly funded by you research. I suggest the American Gut Project[1][2] for people in the US and British Gut[3] for those in the UK and EU. For $99 you can learn about your microbiome and contribute to largest, most successful crowdfunded research in the world. This project is entirely supported by people like you and me, directly.
[1] http://humanfoodproject.com/americangut/
[2] https://fundrazr.com/campaigns/4Tqx5
[3] https://fundrazr.com/campaigns/4sSf3/ab/5qJ7f
I really wish this wasn't a thing. I'm getting tired of all the "startups" in my field (microbio) who are pushing microbiome-based treatments. They're not currently regulated by the FDA and they are downright dangerous. The healthy gut is primarily made up of (~90%) Firmicutes, Bacteroidetes, and Clostridium of which the majority are uncultured, unsequenced and completely unstudied. Shifting the balance a little too much one way or another can potentially cause symptoms of Autism Spectrum Disorder. There are at least two startups in stealthmode that I know of that are pushing microbiome matching between "healthy" donors and "unhealthy" recipients -- very much like snake oil salesmen. One person's healthy is another's unhealthy but these groups and their VCs apparently don't give a shit (VC funding in science is a while other can of worms).
If you want to be a microbiome hacker, go contribute YOUR microbiome to publicly funded by you research. I suggest the American Gut Project[1][2] for people in the US and British Gut[3] for those in the UK and EU. For $99 you can learn about your microbiome and contribute to largest, most successful crowdfunded research in the world. This project is entirely supported by people like you and me, directly.
[1] http://humanfoodproject.com/americangut/
[2] https://fundrazr.com/campaigns/4Tqx5
[3] https://fundrazr.com/campaigns/4sSf3/ab/5qJ7f
So I can't speak to the specifics of the startups you're referring to (I don't know who they are), but I will say I'm very surprised to have read this.
The responsible development of new therapies is almost always a good thing. I'm confused to hear you say they're not FDA regulated, since the FDA is very clear: if it's intended to treat a disease, it's regulated. Perhaps you could explain what I'm missing?
Also technical note: these microbes are not unknown/uncultured/unsequenced. See MetaHIT, the Human Microbiome Project and the American Gut Project you mentioned.
The responsible development of new therapies is almost always a good thing. I'm confused to hear you say they're not FDA regulated, since the FDA is very clear: if it's intended to treat a disease, it's regulated. Perhaps you could explain what I'm missing?
Also technical note: these microbes are not unknown/uncultured/unsequenced. See MetaHIT, the Human Microbiome Project and the American Gut Project you mentioned.
They're not marketed to cure a disease, they are "probiotics". They are using the yogurt rule
>Also technical note: these microbes are not unknown/uncultured/unsequenced. See MetaHIT, the Human Microbiome Project and the American Gut Project you mentioned.
Yes the are, we have metagenomics on them (v4 rDNA sequence reads) not full seq data. We can't ID which bug and then grow it. We just know some of its rDNA is in the mix. Being able to phylotype =/= known microbe.
>Also technical note: these microbes are not unknown/uncultured/unsequenced. See MetaHIT, the Human Microbiome Project and the American Gut Project you mentioned.
Yes the are, we have metagenomics on them (v4 rDNA sequence reads) not full seq data. We can't ID which bug and then grow it. We just know some of its rDNA is in the mix. Being able to phylotype =/= known microbe.
> They are using the yogurt rule
Ahh, you mentioned Autism spectrum, so I assumed that couldn't be the case.
> we have metagenomics on them (v4 rDNA sequence reads) not full seq data
There is plenty of genomic data beyond 16S. For the HMP, full sequencing of selected strains as well as hundreds of WGS metagenomes were done. And that's almost old news now, I'm sure there is even more being done currently. The result is basically either a full genome, or a set of giant chunks of the genome of the abundant microbes there. We don’t have all the genomes closed (although some are in the process!) but closing a genome is a very high bar and probably not worth it when you can get a lot of data from a fairly good set of large contigs.
Can the assemblies be chimeric/wrong/whatever? sure, some of them will be, but at this point most assemblies are fairly good :)
Ahh, you mentioned Autism spectrum, so I assumed that couldn't be the case.
> we have metagenomics on them (v4 rDNA sequence reads) not full seq data
There is plenty of genomic data beyond 16S. For the HMP, full sequencing of selected strains as well as hundreds of WGS metagenomes were done. And that's almost old news now, I'm sure there is even more being done currently. The result is basically either a full genome, or a set of giant chunks of the genome of the abundant microbes there. We don’t have all the genomes closed (although some are in the process!) but closing a genome is a very high bar and probably not worth it when you can get a lot of data from a fairly good set of large contigs.
Can the assemblies be chimeric/wrong/whatever? sure, some of them will be, but at this point most assemblies are fairly good :)
How do you think ubiome.com compares with these efforts? I did an analysis with them and feel like I got some insights, but I also felt that the way the data Is currently presented could lead to a lot of false conclusions, especially for people without a microbiology or statistical background.
I'm also curious about your statement about how many strains are unsewurnced and unstudied. I've read this elsewhere, and it makes me wonder if the species % data presented by ubiome is presented with false precision.
I'm also curious about your statement about how many strains are unsewurnced and unstudied. I've read this elsewhere, and it makes me wonder if the species % data presented by ubiome is presented with false precision.
µBiome is vapid consumerism in my opinion. They don't contribute data to the research community (as far as I know).
The vast, vast majority of all bacteria are not culturable in a lab. That being said, we use rRNA/rDNA sequencing[1] to build phylogenies based off of BLAST E-values[2], or how likely it is two sequences evolved separately from each other. We have cultured and sequenced enough of the big three (and many of the top 100 gut microbes) that we can be statistically sure that they're related. We can't say for sure two different but closely related sequences are two different, closely related species but we can say they're related OTUs[3]
[1] http://greengenes.lbl.gov/cgi-bin/nph-index.cgi
[2] http://www.ncbi.nlm.nih.gov/blast/Blast.cgi?CMD=Web&PAGE_TYP...
[3] http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1609233/
The vast, vast majority of all bacteria are not culturable in a lab. That being said, we use rRNA/rDNA sequencing[1] to build phylogenies based off of BLAST E-values[2], or how likely it is two sequences evolved separately from each other. We have cultured and sequenced enough of the big three (and many of the top 100 gut microbes) that we can be statistically sure that they're related. We can't say for sure two different but closely related sequences are two different, closely related species but we can say they're related OTUs[3]
[1] http://greengenes.lbl.gov/cgi-bin/nph-index.cgi
[2] http://www.ncbi.nlm.nih.gov/blast/Blast.cgi?CMD=Web&PAGE_TYP...
[3] http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1609233/
I quite liked that it was possible to download my raw data file from ubiome. I got my first results back a couple months ago. Then I got sick and in a while I'll know precisely how a course of antibiotics devastated my microbiome (but killed what it needed to, so I'll probably live.)
I take this article to be an argument against snake-oil panaceas, just broadly overstated in its phrasing. Not a generally useful piece, but a healthy rebuttal to the woo reductionists.
The linked author doesn't seem to have a clear thesis statement, but from the examples given (the Hadza and the Conquistadors) it appears the thesis statement could be something like this: "Each isolated ancient human community already has basically optimized microbiomes. In each such human niche, their traditional microbes can probably survive in that niche. Also, those same microbes will have been surviving for so long that second order optimizations (like ethnic genetic adaptation to the potentially harmful parts of their traditional microbiome package) have likely occurred. In the face of such 'bio-traditions', and their presumptively functional state, we should tread carefully, and study everything before we muck about too much."
This seems to me like an excellent argument for why people who grew up on family farms, or in jungles, or other vaguely historical places should not muck about too much with their microbiomes. Heck, even third generation New Yorkers are probably solid.
However, it seems to miss the point that urbanization, immigration, antibiotic use, and radically weird diets (to name a few factors) are happening all over the modern world.
Given the modern situation, having already been disrupted by biologically unprecedented events for centuries, it seems plausible that at least some of us are like sailors at sea, with the metaphorical equivalent of scurvy-before-its-etiology-was-determined.
Just as, if you have scurvy, it doesn't cost much to try eating citrus and see if it helps, it seems that for people who are already unhappy with their gut health, it probably doesn't cost much to experiment here.
If you can already see that your digestion/mood/hunger is funky by comparing it do to friends and family, and you can read the research on that suggests these processes can be affected by microbiomes, it seems plausible to me that checking out uBiome or General Biotics or one of the "dating websites for poop" (or whatever, I'm sure there are more of these things floating around) it doesn't seem that crazy to me. A bit crazy, yes. But way less crazy than the same experimentation would be for someone who is eating and living in the same manner as their mother's mother, and has no more tummy troubles than any of their grandparents.
I've published a little in this area, and I didn't know about the conquistador story, so the article was appreciated, but I'm also personally a fan of experimentation that is early, fast, and cheap and I didn't see any of the experimental cost benefit analysis that could have been there, and could have made the article better.
This seems to me like an excellent argument for why people who grew up on family farms, or in jungles, or other vaguely historical places should not muck about too much with their microbiomes. Heck, even third generation New Yorkers are probably solid.
However, it seems to miss the point that urbanization, immigration, antibiotic use, and radically weird diets (to name a few factors) are happening all over the modern world.
Given the modern situation, having already been disrupted by biologically unprecedented events for centuries, it seems plausible that at least some of us are like sailors at sea, with the metaphorical equivalent of scurvy-before-its-etiology-was-determined.
Just as, if you have scurvy, it doesn't cost much to try eating citrus and see if it helps, it seems that for people who are already unhappy with their gut health, it probably doesn't cost much to experiment here.
If you can already see that your digestion/mood/hunger is funky by comparing it do to friends and family, and you can read the research on that suggests these processes can be affected by microbiomes, it seems plausible to me that checking out uBiome or General Biotics or one of the "dating websites for poop" (or whatever, I'm sure there are more of these things floating around) it doesn't seem that crazy to me. A bit crazy, yes. But way less crazy than the same experimentation would be for someone who is eating and living in the same manner as their mother's mother, and has no more tummy troubles than any of their grandparents.
I've published a little in this area, and I didn't know about the conquistador story, so the article was appreciated, but I'm also personally a fan of experimentation that is early, fast, and cheap and I didn't see any of the experimental cost benefit analysis that could have been there, and could have made the article better.
The article gives a lot of neat background, but primarily
deconstructs a straw man argument.
He does a pretty good job of presenting the actual argument for microbiome experimentation at the end:
>our genomes have had little time to adapt to modern life, but our microbiomes have had plenty.
>It may be that a Hadza microbiome would work equally well in an American gut, but incompatibilities are also possible. The conquistadors proved as much. As they colonized South America, they brought with them European strains of Helicobacter pylori, a stomach bacterium that infrequently causes ulcers and stomach cancer, and these European strains also displaced native American ones. This legacy persists in Colombia, where some communities face a 25-fold higher risk of stomach cancer, most likely due to mismatches between their ancestral genomes and their H. pylori strains.
He does a pretty good job of presenting the actual argument for microbiome experimentation at the end:
>our genomes have had little time to adapt to modern life, but our microbiomes have had plenty.
>It may be that a Hadza microbiome would work equally well in an American gut, but incompatibilities are also possible. The conquistadors proved as much. As they colonized South America, they brought with them European strains of Helicobacter pylori, a stomach bacterium that infrequently causes ulcers and stomach cancer, and these European strains also displaced native American ones. This legacy persists in Colombia, where some communities face a 25-fold higher risk of stomach cancer, most likely due to mismatches between their ancestral genomes and their H. pylori strains.
If you brush before sleep (with triclosan, a very common antibacterial agent), you breathe >25% of your breaths through a mouth populated with antibacterial agents.
The prevalence of antibacterial agents in soaps, & toothpastes in the last 15 years coincides with the increases in asthma & digestive disorders.
The article says, essentially, "It's complex, and adaptive, so be careful how you force it away from a neutral state." Yet, adding antibacterial agents to toothpastes is quite a forceful change.
The prevalence of antibacterial agents in soaps, & toothpastes in the last 15 years coincides with the increases in asthma & digestive disorders.
The article says, essentially, "It's complex, and adaptive, so be careful how you force it away from a neutral state." Yet, adding antibacterial agents to toothpastes is quite a forceful change.
Bonus points for the quote This befuddling complexity is not confined to the vagina.
This article doesn't seem to consider the alternative hypothesis very seriously, so as one of the biohackers Ed is no doubt referring to, I'll do my best to summarize why it's not unreasonable to act before all the data is in.
Our knowledge about the microbiome is similar to our knowledge of nutrition: we don't know enough to claim optimality, but we do know enough to say that the modern default is bad.
My product is the microbiome equivalent of the paleo diet -- it simply restores non-pathogenic microbes which were the unintended victims of widespread food sterilization. In our (admittedly small) pilot study, over 90% of people felt this helped their digestion.
I believe this approach is more cautious than continuing to eat a modern diet. We didn't evolve eating sterile food.
http://www.generalbiotics.com/probiotics
Our knowledge about the microbiome is similar to our knowledge of nutrition: we don't know enough to claim optimality, but we do know enough to say that the modern default is bad.
My product is the microbiome equivalent of the paleo diet -- it simply restores non-pathogenic microbes which were the unintended victims of widespread food sterilization. In our (admittedly small) pilot study, over 90% of people felt this helped their digestion.
I believe this approach is more cautious than continuing to eat a modern diet. We didn't evolve eating sterile food.
http://www.generalbiotics.com/probiotics
"we do know enough to say that the modern default is bad."
Could you articulate why this statement is even plausible?
Could you articulate why this statement is even plausible?
Interesting. To be clear, the current state of affairs is eating sterilized food (often required by law to control pathogens), and taking antibiotics every 2 years[1].
This is bad a priori, since it's two deviations from the only known good condition -- the one we evolved in.
But I take it that argument was non-persuasive.
So here are some other people discussing the idea: The hygiene hypothesis[2] is broadly the theory that diseases of affluence[3] are related to living in overly sterilized conditions. Most if not all of the items discussed in [3] are correlated with your microbiome[4], with large studies underway to determine the role in more detail [5].
Okay, hope this helps. To answer your question a third way: most biologists working on the microbiome think it's plausible.
[1] http://www.nejm.org/doi/full/10.1056/NEJMc1212055
[2] http://en.wikipedia.org/wiki/Hygiene_hypothesis
[3] http://en.wikipedia.org/wiki/Diseases_of_affluence
[4] http://academy.asm.org/images/stories/documents/FAQ_Human_Mi... -- see pages 11+
[5] We have a bibliography at http://www.generalbiotics.com/science
edit: my co-founder wishes me to point out that I wrote this was to illustrate why eating ancestrally normal microbes is a plausible idea. Please don't take these links as me saying my product can prevent any diseases -- I don't have sufficient evidence to support that claim.
This is bad a priori, since it's two deviations from the only known good condition -- the one we evolved in.
But I take it that argument was non-persuasive.
So here are some other people discussing the idea: The hygiene hypothesis[2] is broadly the theory that diseases of affluence[3] are related to living in overly sterilized conditions. Most if not all of the items discussed in [3] are correlated with your microbiome[4], with large studies underway to determine the role in more detail [5].
Okay, hope this helps. To answer your question a third way: most biologists working on the microbiome think it's plausible.
[1] http://www.nejm.org/doi/full/10.1056/NEJMc1212055
[2] http://en.wikipedia.org/wiki/Hygiene_hypothesis
[3] http://en.wikipedia.org/wiki/Diseases_of_affluence
[4] http://academy.asm.org/images/stories/documents/FAQ_Human_Mi... -- see pages 11+
[5] We have a bibliography at http://www.generalbiotics.com/science
edit: my co-founder wishes me to point out that I wrote this was to illustrate why eating ancestrally normal microbes is a plausible idea. Please don't take these links as me saying my product can prevent any diseases -- I don't have sufficient evidence to support that claim.
In one section, the author criticizes microbiome hacking based on the fact that the experimenter does't have c. difficile. Does the author really believe that c. difficile, or other acute health problems, are the only possible results of an unhealthy microbiome?
It seems most plausible that dietary health is going to be a function health(microbiome, diet/environment, genetics). I doubt anyone thinks it will be a simple function, but along with acutely unhealthy microbiomes, there will be some obvious (given enough long-term data) problematic microbiomes across wide genetic and dietary variations, that don't quickly cause acute disease. And I don't think there will be as much variation as the author believes in healthy microbiomes once you start controlling for genetics and diets.