Gut feeling: germ warfare opens a new front
The widespread eradication of Helicobacter pylori may be implicated in the rise of conditions such as obesity, type 2 diabetes and asthma. Photo: Science photo library
As research projects go, it probably didn't sound too earth-shattering for the volunteers. Apart from demonstrating their good health, they simply had to give blood, stool and saliva samples and have swabs taken from various locations on their bodies.
We will probably never know their names, but the contribution of these 242 American men and women is having a profound impact on our understanding of health and illness, and even raising questions about what it means to be human. This research into the ''microbiome'' - the viruses, bacteria and other microbes living with us - also puts a whole new slant on long-standing public health problems, such as the overuse of antibiotics.
In June last year, after five years of work by about 200 scientists from 80 universities, the US-based Human Microbiome Project released its initial analyses of those volunteers' donations. The results paint an extraordinary, though preliminary, portrait of the richness of our microbial life. The researchers found more than 10,000 species of microbes living in and on their subjects, with each person carrying about 8 million different bacterial genes (compared with 22,000 or so human genes).
''The more closely we look, the more bacterial diversity we find,'' said one of the scientists, Susan Huse, from the Marine Biological Laboratory, when the microbiome ''map'' was released. ''We can't even name all these kinds of bacteria we are discovering in human and environmental habitats. It's like trying to name all the stars.''
Just as we unconsciously help the microbes in their quest for survival, so do many of them return the favour, whether by producing beneficial compounds, helping us to digest our foods, or boosting our immune system. By colonising our skin, gut and other surfaces, they help reduce the opportunities for more dangerous bugs to take hold. The research found that most healthy people carry pathogens, or microbes capable of causing disease, prompting speculation that there may be hitherto unrecognised benefits from such relationships.
Phillip Tarr, director of paediatric gastroenterology and nutrition at Washington University School of Medicine in St Louis, said that research into the human microbiome offers ''a whole new way of looking at human biology and human disease. These organisms, these bacteria, are not passengers. They're metabolically active. As a community, we have to reckon with them much like we have to reckon with the ecosystem in a forest or a body of water.''
As Amy McGuire, an associate professor of medicine and medical ethics at Baylor College of Medicine, told a media briefing about the study, the implications of this emerging field of science are profound. ''There are also very interesting questions about whether the fact that we have more microbial DNA in and on our bodies than human DNA changes how we think about what it means to be human,'' she said.
While these are early days, this burgeoning field of research seems to signal a profound shift in our relationship with the microbial world. ''This is only the beginning,'' writes Joy Yang, a researcher at the National Human Genome Research Institute. ''We have learned that the bacteria living in and on us are not invaders but are beneficial colonisers. The hope is that, as research progresses, we will learn how to care for our microscopic colonisers so that they, in turn, can care for our health.''
Yet we've been doing the opposite for many years by waging a long-running war with our microbiome. This has often been unintentional, through shifts in our food supply and way of life, or even in the way we give birth. (It's been suggested, for example, that the global growth in caesarean deliveries may have reduced the transmission of health-giving microbes from mother to baby.) But much of the warfare has been deliberate, conducted via an arsenal of antibiotics, antibacterial wipes and other efforts to avoid germs.
From the earliest days of antibiotics, the bugs fought back. According to Lyn Gilbert, an infectious diseases physician and clinical microbiologist at Westmead Hospital in Sydney, it was only a short time after penicillin became available for treatment of civilians in Sydney in 1946 that a resistant strain of Staphylococcus aureus was found in about half of the surgical wound infections at the Royal Prince Alfred Hospital.
While much concern about antibiotics overuse has focused on how it promotes the emergence of treatment-resistant organisms, perhaps the collateral damage has been much more profound.
''The Menace of Antibiotics'' was the title of a presentation at a major conference in San Francisco last October by Martin Blaser, a physician, epidemiologist and professor of microbiology at NYU School of Medicine. Blaser's talk covered many of the concerns he has raised in journal articles in recent years, suggesting that antibiotics have affected the microbiome in ways that have had adverse long-term health consequences.
Blaser suggests, for example, that the widespread eradication of Helicobacter pylori (a bacterium associated with stomach inflammation and duodenal ulcers) may be implicated in the rise of conditions such as obesity, type 2 diabetes and asthma. He also argues that the eradication of relatively benign bacteria leaves us exposed to the risk of being colonised by more harmful bugs.
Blaser's concerns are based largely on experimental and epidemiological evidence and are not proven, but he is sufficiently alarmed to have gone on the record calling for caution in the use of antibiotics during pregnancy and childhood, noting that the average child in developed countries has received between 10 and 20 courses of antibiotics by the age of 18.
At the Institute for Molecular Bioscience at the University of Queensland, Matthew Cooper also advocates a more judicious use of antibiotics, particularly the broad-spectrum types, and thinks it is sensible to avoid using antibiotics in children unless absolutely necessary.
He agrees that the drugs may affect our microbial colonisers in ways we don't yet understand, but stresses that the implications of the microbiome for health are complex and will not quickly or easily be understood.
Much of the research to date, Cooper points out, is showing associations between characteristics of the microbiome and disease, rather than cause and effect. One exception is a small European clinical trial that found faecal transplants to be more effective than conventional antibiotics in treating recurrent Clostridium difficile infection (a potentially serious form of antibiotic-associated diarrhoea).
An accompanying editorial in the New England Journal of Medicine predicted that the findings would encourage wider trials of ''intestinal microbiota therapy'' for inflammatory bowel disease, irritable bowel syndrome, bowel cancer prevention and metabolic disorders.
Cooper has been sufficiently impressed by the emerging evidence in another area to turn himself into a guinea pig. After reading studies suggesting that a high-fibre diet produces a type of bacteria in the gut that is associated with reversal of lung disease in mice, he put himself on a high-fibre supplement for two years to see if it would help his asthma. ''I thought, what the hell, have a go,'' he says. ''I was taking a steroid every day for asthma for 20 years.'' Now, he adds, ''I am no longer taking asthma medication.''
Cooper stresses that a study like this, with only one subject and no controls or placebos, is meaningless. But his research group is now studying the role of byproducts of good bacteria, short-chain fatty acids, and how they interact with key receptors in the human gut. These receptors bind to the fatty acids produced by good bacteria in response to a high-fibre diet, and then modulate inflammation in the body - one of the causes of diseases such as asthma.
While any wider significance to Cooper's self-experiment is not yet clear, he does hold to the adage that ''you are what you eat''.
Alongside the new field of microbiome research, scientists are continuing to expand our knowledge of how antibiotic resistance develops and spreads. We now know that not only do microbes evolve to survive antibiotic treatment, and not only do those treatments give a selective advantage to resistant germs, but also that resistant genes can move both within and between microbial species.
This makes humans more susceptible to infections, of course, and it also threatens many medical procedures that rely on antibiotic cover, from cancer surgery to joint replacements and organ transplantation. As the World Health Organisation's director-general, Margaret Chan, said last year: ''A post-antibiotic era means, in effect, an end to modern medicine as we know it.''
The costs are also overwhelming. In the late 1990s, for example, a single outbreak of a treatment-resistant infection in an intensive care unit at Westmead Hospital was estimated by one doctor to have cost $1 million. Not only did the infection double the time patients spent in the unit, but a study also found the death rate was twice as high among those who were infected.
While there is no shortage of alarming news, there are also signs of a growing momentum for action. Newcastle-based physician and microbiologist John Ferguson cites a heap of work being done by various committees and by the Australian Commission on Safety and Quality in Healthcare. New national standards for health services require an explicit focus on wiser use of antibiotics and better infection-control practices.
Public reporting of health service performance has been helpful in focusing the attention of service executives, Ferguson says. A number of health services have managed to improve hand-washing rates and other infection-control measures, reducing antibiotic resistance. As a result, he says, ''Australia is vastly ahead of where it was five years ago''.
One glaring gap, though, is the absence of national surveillance and reporting for antibiotic-resistant infections. Planning for such a system is under way, but must negotiate the differences and rivalries between states and between levels of government that so often impede healthcare improvement. Like many, Ferguson laments the lack of a national communicable diseases agency to help drive action across these divides and bring the veterinary and agricultural sectors into the discussion.
No doubt we will be hearing more calls for such an agency, with a Senate inquiry investigating progress on the implementation of a 1999 report from the Joint Expert Technical Advisory Committee on Antibiotic Resistance, which found that two-thirds of the antibiotics imported into Australia were used in animals.
Since then, many countries have tightened their regulation of antibiotic use in farming. After Denmark banned the use of antimicrobials as growth promoters in 2000, for example, levels of resistant bacteria in animals there have dropped and productivity has not suffered. According to the WHO, though, the quantities and classes of antimicrobials used in food animals are still insufficiently documented and controlled worldwide.
Peter Collignon, an infectious diseases physician and microbiologist from Canberra, will encourage the Senate inquiry to look more broadly at issues such as international trade and the quality of governance in countries such as India and China, which also have a bearing on our exposure to antibiotic resistance.
''Medical people look at it too simplistically, at what antibiotics doctors are prescribing,'' he says. ''You need to look at the total picture - environment, agriculture, water, poverty, health and housing. One of the best examples is that TB had a marked decrease before any drugs were available, and it was all to do with nutrition and housing.''
Meanwhile, Chris Del Mar, professor of public health at Bond University, would like the inquiry to consider tightening controls on doctors' use of antibiotics. Del Mar and his colleague Paul Glasziou suggest that public education campaigns should strongly discourage people from seeing GPs for colds and other viral infections, and instead promote self-care.
They argue that the ''good news'' about resistance - that it will diminish if fewer antibiotics are used - is not widely enough appreciated, and that there should also be more focus on ''delayed prescribing'', where patients are asked to wait before filling scripts. The new centre will also investigate the potential for alternatives to antibiotics, including the use of corticosteroids, caffeine (yes, coffee!), and non-steroidal drugs to relieve cold and flu symptoms.
■ Melissa Sweet is a health journalist and editor of the health policy blog Croakey. This is an edited version of an article that first appeared in Inside Story (inside.org.au), published by the Swinburne Institute for Social Research.