Lessons from the Human Microbiome Project
It would be fair to say that as humans we have fought long and hard to make it to the top of the food chain and we would consider ourselves to be the most sophisticated and complex creations on the planet. Because of this, one of the greatest disappointments emerging from the Human Genome Project which was completed in 2003 was to find out how few genes humans actually have. Compared to many other organisms we are genetic paupers, with only around 23,000 genes encoding for proteins in our bodies. To put that in perspective, worms have 90,000 genes and Paris japonica, a striking rare native of Japan, has a genome 50x larger than ours. Clearly we would like to think we are more evolved and sophisticated than worms and plants.
However, as always, the story is not so simple. It turns out that even though we have a very compact genome, it is also very efficient. This is partly because of the presence of a large amount of non-encoding DNA, which contains amongst other things the promoter regions of our DNA that regulate which genes are expressed and therefore which proteins are produced. Crucially, it also regulates which patterns of various proteins are produced at the same time, and these patterns lead to large degrees of complexity. In one of the least prescient naming conventions of all time, this non-encoding DNA was originally termed ‘junk DNA’ as it was thought to have no purpose. It turns out to be critically important to the ability of our genome to develop the complexity we require to develop and function correctly.
Another large project which is in many ways parallel to the Human Genome Project has just been completed, the Human Microbiome Project. Funded by the US National Institute of Health and carried out by various organisations, this project was designed to characterise the amount and diversity of microorganisms that are present on and within our bodies. Unlike traditional culturing methods which can only show organisms that will grow on a plate, this project used 16s ribosomal RNA analysis to identify the genetic patterns of organisms. The researchers generated a massive data set of over 35 billion reads taken from 690 samples from 300 US subjects, across 15 body sites.[i] One of the most remarkable parts of this research was the large number of previously uncharacterised organisms that were identified, described by some as ‘biological dark matter.’ Depending on the site of sampling, up to 80% of the genetic material that was identified had never been detected previously and therefore likely represents many new species of organisms living within our bodies that we were previously unaware of.[ii]
We are 98% non-human
When you examine the sheer amount of genes that are encoding for proteins in our bodies, and the fact that compared to our genome of 23,000 genes there is an enormous microbial genome that is comprised of at least 1 million genes, it is apparent that human genes are seriously in the minority (see figure 1).
Figure 1. The human genome compared to the genome of our resident microbes or the microbiome.[i]
In fact it is probably more accurate to describe humans as a highly evolved multi-species superorganism which benefit from our combined metagenome. Microflora provide for many functions within our bodies that are essential to life, and reduce the need for our own genome to produce proteins to carry out these activities, helping to streamline the required human genome. Remarkably, of the 52 known phyla of bacteria, there are only 6 which typically colonise humans (see figure 2).[ii] This limitation to 6 main phyla is very stable across people and races, and argues strongly for co-evolution between our species and our colonists. It is likely that the human body has evolved mechanisms to selectively allow certain groups of organisms to colonise, and to exclude others. Perhaps this is because these groups fulfil various ecological niches and functions, such as assisting with the digestion and extraction of calories from food, synthesis of essential nutrients, production of anti-microbial peptides which inhibit other phyla, and the absorption and excretion of toxic metals from our food supply.
Figure 2 – Distribution of the 6 main phyla which colonise humans varies by body site and health status.
As can also be seen from figure 2, the distribution of these phyla varies dramatically between different body sites, and in various disease states. Conditions such as inflammatory bowel disease (IBD) are associated with a loss of bacterial diversity and a narrowing of the range of organisms present. It is know that there is a profound interplay between the gut microflora and the immune system and that IBD is also associated with a loss of tolerance to the resident microflora. Perhaps there is some factor in the normal diversity and patterns of microbial distribution that is supportive of immune tolerance, and its loss impairs healthy immune function. Tom Borody and others have pioneered the use of Faecal Microbial Transplants from healthy donor stool and have shown that regular application leads to a significant reduction or resolution of Ulcerative Colitis in a large percentage of patients. This provides strong support to the theory that IBD may be caused by the overgrowth of a yet to be characterised pathogen, or the loss of normal gut flora diversity. In healthy people the microbiome is surprisingly resilient and following perturbation via antibiotics or other interventions should normally return to its resting state relatively quickly. Failure to do so may well be a future diagnostic marker of disease risk.
New therapies are just around the corner…
When the Human Genome Project was completed there was a large amount of optimism around the development of an understanding of the genetic basis of disease, and potential solutions to a range of conditions that had proven intractable up until that point. Whilst the technology of sequencing genes has improved exponentially over the last 10-15 years, to the point that a genome can now be sequenced in a single day where the first took 15 years, there has been stubbornly little progress in treating disease. This is largely due to the fact that most disease which has a genetic basis is due to the complex interplay of a range of genes, each of which only contribute a small percentage of risk, with relatively few diseases being associated with single gene aberrations. Teasing apart this risk attributable to the complexity of 10 or 20 genes interacting together has proven very challenging.
Similarly, there are a number of groups who are speculating that the completion of the Human Microbiome Project will lead to new diagnostic platforms, new therapies and new understandings of the interaction between diet and microbiome on human nutritional requirements. Whilst this is all likely and ultimately beneficial, the added complexity of dealing with a genome 2 orders of magnitude larger than our own means it will be some time before meaningful therapies can be designed via the standard reductionist pharmaceutical model. However, there is already progress being made in other ways, such as in the application of live bacterial supplements (probiotics) for various conditions. Whilst we are very familiar with the application of probiotics for gastrointestinal disorders and a couple of other conditions such as allergy and poor immune resistance, there is an enticing array of new therapeutic targets that probiotic strains are being developed to address. Preliminary research has shown that there is a strong relationship between the ratio of Firmicutes to Bacteroidetes in the gut and obesity. People with a high BMI are much more likely to have high levels of Firmicutes and these bacteria have been shown to be highly efficient at harvesting calories from food that humans are otherwise unable to digest, passing extra calories along to their hosts in the process. Studies in mice have shown that colonisation of lean mice with the gut flora from obese mice leads to significant weight gain. A number of researchers are working on probiotic strains to help change the gut flora to a lean pattern and therefore help to reduce obesity.
Other research which is on the horizon and shows some promise include probiotics that help to normalise lipids, probiotics for blood sugar and even a probiotic that synthesises GABA and may be beneficial for patients suffering with anxiety.
A new definition of health
Despite the many TV commercials advertising antibacterial soaps which recommend that we sterilise our environments and our bodies of as many bugs as possible, it is becoming clear that we evolved alongside bugs, they serve many valuable purposes in our body and that we should no more try to be rid of them than we should try to get rid of our liver if it is misbehaving. In fact our gut microflora is described as a virtual organ and it performs many metabolic and other functions for us, allowing a happy and functional life despite our meagre genome. Health is then really about learning to live successfully with our microbiome and to make the most of the opportunities they provide, and to minimise the downside of exposure to pathogens. In fact even the term pathogen is now not so clear, with some organisms serving a positive role in some situations, and functioning as a pathogen at other times. An example of this is the emerging evidence that children with H. pylori colonising their stomachs are significantly less likely to develop allergy. To cultivate a healthy microbiome we need to attend to the terrain, much like a gardener encourages the growth of beneficial plants through clever planting, use of fertilisers and selective weeding as required. We maximise our internal terrain by managing stress, consuming pre and probiotics, eating a diet low in refined and processed foods, avoiding unnecessary use of antimicrobial medications and even teaching our patients to chew properly and eat slowly. In the future, health will be defined at least in part by the presence of a balanced microbiome, and healthiest amongst us will have an endogenous flora which is rich, diverse and supportive to optimal function.
 Cho I, Blaser M (2012) The human microbiome: at the interface of health and disease. Nature reviews Genetics 13:260–70. doi: 10.1038/nrg3182