Monday, August 31, 2009

Gutting it out

Only a small fraction of bacteria can be grown in laboratories; apparently nobody understands what they need in their environment well enough. This can be a problem for microbiologists trying to identify the bacterium causing a new infectious disease, but it also means that it has not been possible to know all of the little bugs to which we our bodies are willing or unwilling hosts. The same would be true for other animals, wild ones as well as our pets and farm species. We say 'willing or unwilling' because, of these pathogens, some are presumed to be harmless commensals, and others are necessary to our survival (such as the E. coli in our intestine, that we depend on for digestion, and similarly for other mammals such as grazers like cows and goats who need bacteria in their rumens to digest cellulose).

One of the characteristics of bacteria is that they can exchange structures (e.g., plasmids) that contain some actively used genes. This is where many if not all of the genes are that lead the bacteria to resist nasty things in their environments such as antibiotics that bacterial targets have evolved to protect themselves. A vulnerable strain of bacteria can acquire a gene that makes them antibiotic resistant. This is of course a very important current problem in farm animals and humans, driven by the amount of antibiotics we ingest. And farm animals are reservoirs of pathogens that can affect humans, so humans and the animals they live with are part of large bacterial-host ecosystems.

Since we can't culture most bacteria, our knowledge of who's where, and the characteristics of many bacterial species, has been quite limited. But DNA sequencing technology has opened the way to identifying our visitors. By extracting all the DNA from a sample of some tissue, fragmenting the DNA and sequencing the fragments, their owners can be identified, and their genetic makeup and function characterized. This is done by comparing the sequence fragments against all sequences currently known (in Genbank). Even if we don't identify an exact match, we can find a known species that is close enough to our tissue-sampled sequence to identify its place in the bacterial tree of life. Antibiotic resistance genes can be identified in the same way, too, since many are already known.

A new paper in Science (Functional Characterization of the Antibiotic Resistance Reservoir in the Human Microflora, Sommer et al., Aug 28, 2009, 1128-1131) reports on a detailed analysis of the antibiotic resistance genes found in the microbiome, the resident bacteria, of healthy individuals. The study was done in an effort to learn more about how antibiotic resistance genes are acquired by pathogens that infect humans.

This study found that, indeed, many of the resistance genes in multidrug resistant bacteria were acquired by lateral gene transfer--that is, the gene hopped into the pathogen on a plasmid from a different bacterium. Bacteria in the wild usually live in large communities of many different species, where they can promiscuously exchange plasmids, thus antibiotic resistance can spread rapidly.

The authors wondered if the extensive history of antibiotic use in humans might mean that microflora in the human gut might be a reservoir of resistance genes readily transferable to pathogens. They isolated DNA from saliva and fecal samples from two healthy individuals who had not taken antibiotics for at least a year, and sequenced fragments of bacterial DNA that were resistant to all the antibiotics they tested.

They found that there was some, but by no means complete overlap between the two people who were sampled, and that nearly half the resistance genes they identified in this way were identical to resistance genes in human pathogens. This doesn't tell them whether gene transfer went from the commensal microflora to the pathogen or vice versa, but Sommer et al. suggest that it's quite plausible that our gut microflora are a reservoir of resistance genes just waiting to jump into pathogens which are now controllable with drugs. The remaining genes, although not yet found in pathogens, were functional when transferred to E. coli, suggesting that if they do eventually find their way into pathogens, they will be active, although there seems to currently be a barrier to lateral gene transfer which isn't yet understood.

The authors conclude:
Many commensal bacterial species, which were once considered relatively harmless residents of the human microbiome, have recently emerged as multidrug-resistant disease-causing organisms. In the absence of in-depth characterization of the resistance reservoir of the human microbiome, the process by which antibiotic resistance emerges in human pathogens will remain unclear.
This study provides interesting ecological information about bacterial dynamics, and of course warns us that antibiotic resistance may be more complex, challenging, and difficult to predict than we have thought. It's evolution in action.

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