Whenever a new discipline, especially one using a ‘sexy’ technology, is brought to bear on human disease, it seems to be oversold in what it will actually accomplish. In addition, every problem is suddenly viewed through that lens, that if we understand how phenomenon X influences something, then WE CAN HAZ CUREZ. I’m worried that this is happening to the human microbiome, the study of the microbes that live in and on us (Note: I’m going to call this area of study ‘the human microbiome’ since a term like metagenomics doesn’t include classical microbiological techniques; calling it the Human Microbiome Project also seems inaccurate, since that’s a funded NIH initiative, not a field*).
For the record, I’ve been involved heavily in NIH’s Human Microbiome Project (HMP) for most of its existence. So I’m not approaching this as an outsider or as someone who pissed that studying the human microbiome is STEALING ALL TEH FUNDZ. I think the HMP is worthwhile. Also, it’s obvious that some diseases are associated with changes in the microbial fauna (I just heard a very good talk last week describing how cystic fibrosis exacerbations and colorectal cancer are associated with microbial community changes). There’s a lot of data indicating that Crohn’s Disease and other similar illness are also correlated with changes in the microbiome. Note that I said associated. A lot more work needs to be done to determine if there causal links. The community changes could simply be a result of the disease.
So there’s a role. But what I’ve noticed looking at various datasets is that, as we move away from severe disease towards ‘normal’ human variation (e.g., overweight or mildly obese people), there don’t seem to be strong associations.
In fact, my take on it (and I have to be vague intentionally) is that the microbiome is pretty variable among different ‘healthy’** people, and isn’t well correlated with many traits. Keep in mind that many of the early studies had really small sample sizes and haven’t been replicated and where they have the results are conflicting (Got Decline Effect?). Yet I still see a lot of claims (more in the popular press, but also by researchers) that we’ll be able to keep your weight under control by changing your microbiome, or that your hormones could be affected by your microbiome without much (or any) experimental data to back it up (and, no, if you’ve shown A, while B, C, D and so on could follow–and is fun to speculate about–it doesn’t mean they will). Then we speculate further by pondering whether we can understand what it means to be human without understanding our microbes (in a trivial sense, no).
This, I think, stems from a piss poor metaphor about the human microbiome. It’s de rigueur to begin a microbiome talk by stating that ninety percent of the cells in the human body are bacterial. Then there’s a statement about how we should regard these microbes as another organ, like your heart or liver. And that’s where things go off the rails.
The microbiome is not an organ. Those critters are not your ‘friends.’ They’re not necessarily your ‘enemies’ either, but many of them function like a protection racket–get rid of them, and really bad news moves in. There’s a reason why farmers want to give subtherapeutic levels of antibiotics to their animals to make them grow larger–those drugs are killing or inhibiting something that is decreasing the host’s growth***.
I would argue instead that we have co-evolved to be in homeostasis with our microbiome. If we didn’t, our phenotype (e.g., weight, hormone levels, etc.) would fluctuate wildly, since a person’s microbiome fluctuates wildly from day to day. In other words, we have evolved to dampen the effects of the microbiome’s inherent variability on our bodies. When most reasonably healthy people have different microbiomes from each other and differ widely in the same person at different times, that might be telling you something important.
I don’t want to set up a strawman here: there probably are some correlations between ‘normal’ human variability and microbial variation, although my current take on the data is that they’re pretty weak. And, as I noted at the outset, diseases that can only be described as a massive breakdown of health are associated with microbiological changes–and we need to understand those changes, even if they’re only diagnostic, not causal. But we shouldn’t overstate the case either. That’s not helping.
*We should be calling it human microbial ecology or something like that.
**Defining a healthy person is really difficult. I’m using the pornographic definition of health: I know it when I see it. Cuz this is a blog, not a paper.
***I’m not arguing for antibiotics in animal feeds by the way. Antibiotic resistance ain’t cool. But it does cast doubt on the ‘helpful’ microbiome perspective.
The effects of antibiotics in animal feed look a lot like hormesis, stimulatory effects of low doses of something toxic.
You are talking like antibiotics in animal feed are doing something “beneficial”. If animals have the capacity to grow bigger, mature faster, become fatter, and more efficiently convert feed into biomass, evolution could have configured them to do so without relying on antibiotics. Why didn’t animals evolve those same traits on their own, without antibiotics?
I suggest that in the wild, there are costs associated with growing bigger, maturing faster, becoming fatter and more efficiently converting feed into biomass, and those “costs” outweigh the reproductive benefits in the wild and so evolution didn’t configure animals to have those traits.
I appreciate that these traits are useful for farmers, but lets not kid ourselves that these traits are “benefits” to survival in the wild until we have collected and analyzed the data that says so.
My complaints of the Human Microbiome Project is that they (so far) have focused on a very narrow and restricted population of humans (but lots of them). Healthy individuals living in a city that bathe every day. To me, that is trying to find biodiversity by looking at what is growing on sidewalks and in the cracks in a city. To find real biodiversity you have to go into the wild. Looking at 500 different sidewalks will tell you one thing. Looking at 10 different rain forests will tell you something different.
My focus is on a particular type of bacteria living on the skin. I think this is a major factor in the health gradient between developed and undeveloped world. A gradient which involves the immune system, systemic inflammation, obesity, diabetes and heart disease.
Until the Human Microbiome Project starts looking at the microbiome gradient between developed and undeveloped world, they are not going to find if that microbiome gradient is important.
Actually, I’ve heard of an early study (about a decade ago now) where someone tracked the evolution of E. coli in his intestine over a week/month period by culturing samples off his used toilet paper.
Got a reference? Or is that apocryphal?
The basic (and I think valid) point is that evolution does matter here, more perhaps than in macro-scale community ecology (the old dumb kind). I’m not sure how reasonable homeostasis is when you have both community shifts and gut microbial evolution happening on a monthly timescale. Maybe things evolve towards “harmony,” maybe not. There’s probably some real interesting research one could do on that question.
Homeostasis really is a myth and the term should be abandoned.
Physiology controls things to the levels that physiology evolved to control them to, levels that facilitate survival and reproduction, not to levels that are “static” the way that the term homeostasis posits.
“Homeostasis is the property of a system, either open or closed, that regulates its internal environment and tends to maintain a stable, constant condition.”
Nothing in physiology is *static*. There is no data that suggests that anything is *static*.
Physiology evolved for organisms to survive and reproduce, there is no evolutionary pressure for things to remain *static*.
Researchers have not waited that long. Dynamics of culturable E. coli have been monitored in gut contents since T. Escherich in 1885. Usually what is observed is that there are surprisingly a very few clones in the gut of an individual at a given time. Turnover occurs in half-year/yearly time scales. That being said, E. coli is probably not the most important bug in the gut, at least during adult life, but a few clones can establish themselves and persist very well compared to others (introduction of new “clones” in healthy individuals is hard, and that’s the whole problem of “probiotics” makers).
The “toilet paper” study you mention sounds unreal, swabs will do the job the same and they are a proper and accepted way of collecting samples, although results may very be similar.
I can’t help but believe that the “answer” to many disease states lies in our microbiome. The gut is not only a massive reservoir of diverse, biologically active bacterial species, it is also an important organ of the immune system. How many diseases with unclear etiology do we attribute to some vague kind of immune dysfunction? I bet some of them are caused by distorted relationships between host and microbe, or even outright “infection”.
To reinforce my bias, I need only glance at my medical school microbiology textbook, which does not even mention Helicobacter pylori and gastric ulcers. It wasn’t that long ago…