Treating disease with microbes: Bugs in the system ONE of the crucial transitions of modern health care was from herbal to chemical medicine. Doctors had known for millennia that willow bark and poppy sap relieve pain. But it was not until the late 19th century, when Felix Hoffman synthesised versions of their active ingredients, namely acetylsalicylic acid and diamorphine (or aspirin and heroin, as they are more commonly known), that proper pharmaceutical science got going. Just possibly, something similar is happening now. The past few years have shown that having good relations with the 100 trillion bacteria which inhabit the gut is essential to human health. If relations break down, hostile bacteria may invade and previously friendly ones may turn hostile. When things do go wrong, though, doses of corrective bacteria can make a difference. These may be administered orally, in foodstuffs such as yogurt, or (and those of a nervous disposition should look away now) anally, via transplants of faeces from healthy people. Some doctors, however, see these approaches as the equivalent of decoctions of willow bark and tinctures of opium. They would like to put the whole idea on a more scientific footing, and two groups of them have just published papers that are steps on the road to doing so. Trevor Lawley and his colleagues at the Wellcome Trust Sanger Institute, near Cambridge, hope to replace faecal transplants as a way of dealing with a bug called Clostridium difficile. This is a particular scourge of those being treated in hospital with oral antibiotics that, as a side-effect, kill many gut microbes and thus let C. difficile run wild. Faecal transplants are effective, but Dr Lawley wanted both to understand why they work and to see if a more tailored version of the treatment might be possible. He found that, in mice, at least, it is. He cultured the faecal bacteria of healthy mice and tried various combinations of them on animals infected with C. difficile. As he reports in the Public Library of Science, one combination of six species (three previously unknown to science) worked almost perfectly - and just as well as transplanting homogenised faeces. Moreover, it was not simply a case of these species being the main missing bacteria in the guts of the infected animals. The cocktail also stimulated the growth of other species that C. difficile was suppressing. If something similar works in people, then the scourge of hospital-transmitted C. difficile infection, which kills 14,000 people a year in America alone, might be eliminated. Elastic response Dr Lawley's treatment does, however, still use natural bacteria. Nathalie Vergnolle of France's National Institute of Health and Medical Research wants to go a stage further. Her putative therapy for inflammatory bowel disease, which she and her team describe in Science Translational Medicine, employs bugs that have been genetically engineered. There is evidence that treating bowel inflammation (which can result in things like Crohn's disease and ulcerative colitis) with bacteria such as Lactococcus lactis and Lactobacillus casei helps ease symptoms. These bacteria are found in dairy products like yogurt, which is the basis of claims that eating yogurt is good for your gut. But Dr Vergnolle reckons they could be tweaked to work better. One cause of inflammation is the activity of an enzyme called elastase. This, as its name suggests, degrades proteins that make the gut wall elastic. Inflammation reduces the abundance of another protein, elafin, which inhibits elastase's action. Dr Vergnolle therefore equipped both Lactococcus lactis and Lactobacillus casei with the gene that encodes elafin and let the bugs loose on mice with inflamed bowels. The result was a great success. The guts of her mice returned more or less to normal appearance, and chemical analysis showed that their levels of proteins called cytokines, which are associated with inflammation, also returned to normal. Whether either technique would work on people remains to be seen (though Dr Vergnolle did mix her bacteria with cells from the guts of colitis patients, and that calmed these cells down in the way the mouse guts were calmed). If they do work, they may open avenues for the bacterial treatment of other conditions linked to gut bacteria. These conditions include obesity, diabetes and even, possibly, autism. A new era of bacterial medicine could thus be about to dawn.