YOU probably think that your body has things pretty much under control, being the finely evolved machine that it is, it knows where its at, and does a generally good job of looking after itself. You’d be right of course, but it doesn’t do this without a little help.
Some of this help comes in the form of your microbiome.
I have written previously about the exciting concept of the human microbiome in which I described how the number of bacterial cells on your body out number your own cells 10 to one, and asked to what degree you consider yourself to be human? The vast majority of these co-residents of you are organised into defined communities, the structure and diversity of which vary depending on where on the body they’re found: your mouth, your nose, various areas of your skin, your gut and urogenital tract. By understanding the interactions between each of these communities and our body, we can better understand their role in health and disease.*
In this the first of two posts on your microbiome, we’ll take a look at your gut.
The gut
Most people are undoubtedly familiar with the idea of ‘good bacteria’, in particular those of your gut, which we are encouraged to top-up on a daily basis with sickly sweet probiotic supplements containing various species of Lactococcus and/or Bifidobacterium. One can only imagine how on Earth we’ve coped throughout the course of evolutionary history without our daily supplement of Yakult.
The general scientific consensus on probiotics is that they don’t do any particular harm to most people, except perhaps your wallet, but occasionally the claims made by the manufacturers are often circumstantial, based on studies with poor methodologies, or are based solely upon observations from a petri dish or mouse model. Furthermore, when reliable evidence is documented, it is invariably for a very specific strain, thus there can be little confidence that is is a general property of the bacterial species as a whole.
Where the use of probiotics moves away from a general supplementation to being part of an active treatment for a condition, there is some evidence to suggest they may be of benefit, but on the whole, evidence is lacking and more research is certainly warranted. A Cochrane review (an international not-for-profit organization, providing up-to-date information about the effects of health care) in 2004, concluded:
“Probiotics appear to be a useful adjunct to rehydration therapy in treating acute, infectious diarrhoea in adults and children. More research is needed to inform the use of particular probiotic regimens in specific patient groups.”
However, in general there are insufficient data for the use of probiotics, over current standard therapies, in conditions such as eczema, Crohn’s disease, bacterial vaginosis and a slew of others. This is probably not helped by the fact that there is a good chance that the little pot of living bacterial joy you are consuming doesn’t actually contain any live bacteria of the type you think you’re getting.
A study published last month in the International Journal of Food Microbiology by an Italian team based the Istituto Superiore di Sanità in Rome, described a survey of such probiotics in Italy between 2005-6, seeking to identify and enumerate bacteria in commercially available supplements 1. A whopping 87% of samples showed evidence of not conforming to the Italian guidelines.
“Even though most labelled supplements (25 samples) indicated the presence of Bifidobacterium bifidum, this organism was only detected sporadically and always as dead cells.”
They also noted contaminants such as the food-poisoning pathogen Bacillus cereus, yikes.
It is worth pointing out that when you drink a probiotic supplement you are taking in a monoculture, a single strain of bacteria, and expecting it to work wonders in a zoo of arguably thousands of bacterial species, most of which we are unable to cultivate in a laboratory. We know this level of diversity exists in the gut because we can test for the DNA markers of such diversity, such as genes encoding 16S rRNA, which are highly conserved throughout all bacteria, varying little over time. This makes the relatively few differences there are between such genes a good means of grouping bacteria into their respective families.
Efforts to understand the human microbiome focus on understanding parts of the body such as gut, with the aim to understand the ecology from the gene level all the way up to structure, diversity and organisation of bacterial families present. We can think of the gut as a rainforest, which is made up of a variety of different niches, each with a particular group of organisms. By understanding how these communities vary in health and disease we can begin to understand the knock on effect of this on the ecosystem as a whole.
An interesting question regarding the gut microbiome is to what degree do our individual gut microbiomes allow us to digest otherwise indigestible components of our diet? A few years ago Jeffrey Gordon’s research team at the Genome Sequencing Centre, Washington University in St. Louis, identified that in mice there appeared to be a difference in the ratio of two phyla of bacteria, the Bacteriodetes and the Firmicutes (n.b. when talking about phyla, we are talking at the level of animals with backbones vs animals without backbones) 2. They found that in obese mice, the ratio was stacked in favour of Firmicutes, with lean mice having the inverse relationship. The microbiome associated with obese mice was found to be better at harvesting energy, perhaps a little too well given that they were able to metabolise sugars that lean mice would otherwise be unable to process. The aim is to understand the link between the different metabolism associated with a different microbiome, and how this impact the body’s storage of fat.
One fascinating finding, in the words of the lead author, Peter Turnbaugh, was:
“What we were able to do is harvest the microbial community from an obese mouse, or a lean mouse, and then directly colonize germ-free mice with either the obese flora, or the lean flora, and what we saw was the mice that were exposed to the microbes from an obese mouse actually gained more fat over the course of the experiment than the mice that were given lean microbial community.” [transcript of Nature podcast]
If you get the obese mice to lose weight, their microbiome correspondingly returns to similar ratios of Bacteriodetes and Firmicutes seen in the lean mice. The obvious question is, ‘what happens in humans?’ Well, in an accompanying back-to-back Nature publication they showed that the same changes in gut microbiome distribution occur in humans3. In a further study published last year 4, the same team found that families tend to share a core gut microbiome at the gene level, even though a different combination of species may provide these genes between different individuals. The gene-level core microbiome was enriched in genes involved in fat, sugar and protein metabolism 5. However, obese people had significantly reduced microbial diversity, with the enrichment of potentially relevant genes associated with change in balance of bacterial groups.
“The authors liken this reduced diversity to a fertilizer runoff, in which a subset of the microbial community blooms in response to abnormally high energy input, as opposed to the rainforest- or reef-like community of the lean gut, which displays high species diversity in the face of high energy flux.” 5
Not terribly flattering perhaps, but seemingly an apt description. These studies give us a fascinating insight into interactions between humans and their bacterial co-residents. The authors raise further questions regarding the extent to which a gene-level core microbiome can be transmitted from mother to child; what is the influence of genetics, behaviour, how spicy you like your curries? [n.b. the authors didn’t actually raise this last point]. It would be interesting to know whether this is something unique to the gut microbiome, or is it a phenomenon found in the other major microbiomes of the body?
Indeed, large studies are also looking at metabolomics, which is essentially characterising the small molecules produced as the end product of your genes being expressed. It is a chemical fingerprint that will be unique to each organism, and to individual tissues in people. It is possible that in the fullness of time we will understand how our genetic make-up, lifestyle, health and disease, influence the metabolic composition of your gut, and how this in turn influences, and is influenced by, your gut microbiome. Perhaps the next time you feel yourself getting hungry, or are feeling lethargic, you might ask yourself whether it’s really you, or is it the residents of your gut?
This of course returns us to where we started, our probiotic drinks. Perhaps we now have a broader understanding that it may be the particular suite of bacterial genes, the gene-level core microbiome, together with the genetic and chemical signature unique to each individual’s gut that are important, rather than any single bacterial strain offered, for a price, in a little pot.
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UPDATE:
It would be remiss of me not to also highlight a paper describing the Genomic Encyclopedia of Bacteria and Archaea (GEBA), published in Nature last year by Jonathan Eisen and his collaborators. Our means of identifying organisms in the type of metagenomic studies (the like of which I describe above) are limited by the database of the ~1000 genomic sequences of microbes currently sequenced. Each of those genomes were essentially cherry-picked for sequencing, generally because they represent microbes with economic or health importance to us, but they don’t give a great coverage of the whole range of microbes out there. Projects such as GEBA are therefore filling in the gaps, making microbiomal sequencing projects more fruitful.
The above paper has a good research blog write up over at Byte Size Biology.
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* A well written account of this endeavour, by science writer Courtney Humphries, can be found in a recent edition of Seed magazine.
1 Aureli, P., Fiore, A., Scalfaro, C., Casale, M., & Franciosa, G. (2009). National survey outcomes on commercial probiotic food supplements in Italy International Journal of Food Microbiology DOI: 10.1016/j.ijfoodmicro.2009.12.016 [Epub ahead of print] [PubMed]
2 Turnbaugh, P., Ley, R., Mahowald, M., Magrini, V., Mardis, E., & Gordon, J. (2006). An obesity-associated gut microbiome with increased capacity for energy harvest Nature, 444 (7122), 1027-131 DOI: 10.1038/nature05414 [PubMed]
3 Ley, R., Turnbaugh, P., Klein, S., & Gordon, J. (2006). Microbial ecology: Human gut microbes associated with obesity Nature, 444 (7122), 1022-1023 DOI: 10.1038/4441022a. [PubMed]
4 Turnbaugh, P., Hamady, M., Yatsunenko, T., Cantarel, B., Duncan, A., Ley, R., Sogin, M., Jones, W., Roe, B., Affourtit, J., Egholm, M., Henrissat, B., Heath, A., Knight, R., & Gordon, J. (2008). A core gut microbiome in obese and lean twins Nature, 457 (7228), 480-484 DOI: 10.1038/nature07540 [PubMed]
5 Tschöp, M., Hugenholtz, P., & Karp, C. (2009). Getting to the core of the gut microbiome Nature Biotechnology, 27 (4), 344-346 DOI: 10.1038/nbt0409-344 [PubMed]
Mental Indigestion 
Oh wow, not only did you get a great post past your personal-editor, but you wrote it about bacteria!
I’ve never been convinced about the probiotics myself (which doesn’t stop me taking them by the gallon whenever I’m on antibiotics on the basis that it can’t hurt). The thing I find most baffling about the ‘probiotic’-yoghurt is that often the first step in making it is to kill all the bacteria that would be present usually (for example in natural yoghurt) and then carefully add their own culture of bacteria.
“gene-level core microbiome can be transmitted from mother to child”
I was having a big discussion about this with a guy at a conference a few months ago. His viewpoint (which I never did find the time to do a paper-chase up on) was that apart from the occasional bacteria that might be passed through breast milk, or from the baby accidently swallowing a few times as it’s being born, most bacteria have to get inside the gut by the usual kids trick of putting random things in their mouth.
Ha, well, I took my editor out, got him a little bit drunk, fed him well, then tortured him into letting my writing through by sleep depriving him all week. I think it’s a winning, if not sustainable, tactic 😉
I would write about bacteria all the time if I could, being a classically trained bacteriologist, but I try to challenge myself to broader areas, as do you 😉
That being said, the scope for studies into the structure and function of our microbiomes is just too good to miss writing about. I could turn my blog over to this research entirely if I didn’t think people would grow weary of it.
I need to find an angle to write an actual feature on the subject, rather than a article-report.
I mostly blog about things other than bacteria because that’s what features in exams; the unfortunate byproduct of doing a ‘biochemistry’ rather than a ‘microbiology’ degree (not sure if those even exist). If I actually end up doing a PhD with bacteria, the non-bacteria posts are likely to dry up altogether!
Microbiomes are amazing, but I must admit I’ve never done any work on them, I’ve only ever worked with soil bacteria and (of course) E. coli.
This is very useful, the Forsythe Dental Research Group also reported that the bacteria inside periodontal pocket (between the gum and teeth) also cahnged in obese people compare to normal people. Whehter these changes occured first in the gut then in the gum or vice versa. Periodntist always very creative in linking the bacteria in the gum to any systemic diseases like heart attack, cancer,kidney disease, low birthweight, irritable bowel syndrome etc. This creativity help them get NIH funding.
Just to add a bit more detail; I have been reanalyzing the Wash U gut microbiome data and find that there are a few microbes often present at high numbers, which are highly variable between samplings, and a large number of microbes present at lower levels, which are nevertheless much more stable than you would expect. I’m guessing that those latter are more closely associated with the cells of the colon, whilst the former are opportunists, taking advantage of whatever nutrients were in excess in the last meal. The interesting thing is that people have very different complements of what I call ‘opportunists’: many microbes are present at high abundance in a few individuals, but completely absent from other people’s guts.
That’s a very interesting observation.
I’ve not had time to data mine their raw data, but it doesn’t surprise me that transient colonisers are present. My experience however is mainly with skin bacteria, and certainly in this environment the external environment will have a strong part to play in species diversity and gene dosage. S. aureus for example colonises roughly 20% of the population, yet this rises to 99% is hospital environments. We already know that the younger siblings of adolescents treated with antibiotics for acne have a high resistance phenotype of their own skin flora, even though they never have been directly exposed to such an antibiotic.
Whilst this is going to make analysis of the microbiome a bit of a headache, the metagenomic analysis of these microbiomes will continue to highlight the scope for potential horizontal gene transfer between resident and visiting populations.