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SOMEHOW, the monkey poo had gone astray. Baffled, Glenn Gibson scratched his head. The biologist at the University of Reading, UK, had been expecting a parcel of monkey faeces from some colleagues in California. Instead, the courier had delivered an enormous box labelled 鈥渇rozen pork chops鈥�. 鈥淲e thought that was a bit odd,鈥� Gibson recalls. 鈥淏ut we thought maybe the California people had tried to disguise the samples to get them through Customs. So we opened the box.鈥� Sadly, the label was right.

The missing faeces were from infant monkeys that had been fed a dietary supplement. Gibson was anxious to find them because he planned to analyse them as part of a study into gut bacteria and health. It is hardly a glamorous job, but Gibson and other researchers are convinced that studying faeces, or rather the microbes they contain, will offer a radical approach to improving our health.

Their belief stems from accumulating evidence that gut bacteria play a pivotal role in a number of chronic and sometimes fatal diseases. These include inflammatory bowel diseases such as ulcerative colitis, irritable bowel syndrome, a painful condition afflicting more than a fifth of people in developed countries, and cancers such as colon cancer. Gut bacteria may even help shape our immune system and susceptibility to allergic conditions such as eczema.

The plan is to manipulate the behaviour of these bacteria in our favour. Beneficial bacteria could be encouraged to grow and crowd out or kill the harmful ones 鈥� a form of biological pest control for the gut. Researchers hope such treatments could tackle diseases that are currently hard to treat. What鈥檚 more, encouraging the growth of harmless bacteria we all have in our guts anyway is unlikely to cause any nasty side-effects. But first, we need to understand more about gut bacteria, and this is an enormous challenge.

Your gut is teeming with microbes. It is home to several hundred species of bacteria, along with viruses and other organisms such as yeasts. There are about a trillion bacteria per gram of stool passing through your large intestine, and they make up some 60 per cent of the solid mass of faeces. In fact, there are so many bacterial cells in your gut that they outnumber the cells of your own body by at least a factor of 10.

The interactions between all these bacteria are so complex that researchers view the community as an ecosystem. Bacteria compete with each other for space and food, and some even try to bump off their rivals. Two of the key genera, Lactobacillus (also known as lactobacilli or lactic acid bacteria) and Bifidobacterium (bifidobacteria), make acidic chemicals such as lactic acid that lower the pH of the gut and kill some other species. Other groups include the methane-producing methanogens and the sulphate-reducing bacteria, which make hydrogen sulphide, and each prefers to live in different parts of the gut (see Diagram). Some species make proteins called bacteriocins that kill other bacteria.

It is only in the past decade that biologists have been able to appreciate just how big and complex this ecosystem is. Before then, they had to grow bacteria in the lab before they could study them. Many species of bacteria, however, do not grow in the lab, meaning they were overlooked. In the 1990s, molecular biologists developed a way of extracting and copying bacterial genes from samples without first having to grow the bacteria in the lab. This meant they could directly test, say, seawater or soil for DNA that would reveal the existence of unknown species.

When Gibson and his team applied these techniques to the human gut in 1999, they discovered that only a quarter of the DNA they found corresponded to organisms whose sequences were recorded in gene databases (Applied Environmental Microbiology, vol 65, p 4799). This meant that a staggering three-quarters of the bacterial species in our guts were (and largely still are) unknown. So researchers hoping to understand the relationship between our guts and their bacteria really have their work cut out.

Such is the scale of the problem that 64 research groups in Europe have teamed up to form the EU Human Gut Flora Project, which aims to determine the links between food, intestinal bacteria and human health and disease. 鈥淚t鈥檚 an unexplained area,鈥� says Gibson, 鈥渂ut with a huge capacity for causing discomfort. More people go to the doctor with gut complaints than anything else.鈥�

There is already strong evidence that gut bacteria can produce harmful chemicals. Bacteria in the gut live on components of the food we eat, as well as on substances that our guts produce naturally, such as digestive juices. It is perhaps not surprising, then, that researchers have long suspected that gut bacteria can make us ill by producing harmful metabolic by-products, perhaps chemicals that cause inflammation by damaging or irritating gut cells, or others that damage DNA or encourage tumours to grow, resulting in colon cancer.

As early as the 1960s, researchers knew that the bacterial enzyme beta-glucuronidase converts cycasin, a chemical found in plants, into a carcinogen. Twenty years later, Ian MacDonald at Dalhousie University in Halifax, Canada, found that gut bacteria can produce carcinogens from the bile acids produced by the liver to digest fats. Another significant kind of carcinogen can be formed from nitrites, which are often found in preserved meat such as bacon and ham. The nitrites get turned into N-nitroso compounds when they react with amines and amides, which are digestive by-products of proteins. In 1988, human nutrition expert Ian Rowland of the University of Ulster in Coleraine, UK, compared the formation of N-nitroso compounds in mice with and without gut bacteria. They found that the concentration of these compounds was higher in mice with gut bacteria, suggesting they were produced by microbial action.

Dripping diet for high IQs

Rowland also discovered that different diets can affect the production of harmful chemicals. One example is IQ, a non-toxic chemical found in fried meat which gut bacteria convert into a carcinogen called 7-hydroxy-IQ. In 1993, Rowland discovered that the gut bacteria in mice fed a diet rich in beef dripping generated 7-hydroxy-IQ faster than bacteria in mice on a low-fat diet (Nutrition and Cancer, vol 10, p 67).

More recently, attention has turned to investigating the precise links between gut bacteria and disease, particularly ulcerative colitis. This severe chronic inflammatory disease affects the large intestine, and is found almost exclusively in western populations, affecting up to 1 in 1000 people. Symptoms include bloody faeces, intestinal pain and inflammation of the digestive tract. There is no cure, so it has to be managed using anti-inflammatory drugs.

No one knows the underlying cause of the inflammation, but researchers suspect that sufferers are genetically predisposed to develop an abnormal immune reaction to the bacteria living in their guts. This in turn disrupts the normal gut ecology. 鈥淏efore getting the disease, colitis patients probably don鈥檛 have a different microflora to other people, but this changes as a result of the disease,鈥� says George MacFarlane, who heads a group researching intestinal bacteria at the University of Dundee, UK.

People with colitis appear to harbour unusually high numbers of a group of bacteria called sulphate-reducing bacteria. These microbes are the principal gut bacteria that form sulphides, normally in the form of poisonous hydrogen sulphide gas.

All of these findings support the appealing idea of preventing or treating these illnesses by manipulating the balance of bacteria living in our guts. Of course, the idea of consuming 鈥渇riendly鈥� bacteria to promote health isn鈥檛 new 鈥� fermented yogurt drinks and pills containing bacteria have been widely available for years. The difference now is that various formulations and bacteria are being tested much more rigorously in clinical trials.

What鈥檚 more, researchers are sequencing the genomes of many of these bacteria, revealing ever more about their biology. The result is a better understanding of these 鈥減robiotic鈥� therapies, giving researchers the power to design effective formulations tailored to specific conditions.

鈥淧robiotics are a safe and inexpensive intervention and they show effectiveness against disease,鈥� says Mary Ellen Sanders, president of the International Scientific Association for Probiotics and Prebiotics, and a consultant on probiotics. 鈥淏ut the science needs to advance more. We need to get a better sense of which probiotics can do what for which people.鈥�

Researchers are now developing three main strategies for boosting the growth of specific kinds of bacteria in the gut. The first is the probiotic approach 鈥� simply swallowing specific beneficial bacteria such as lactic acid bacteria. A potential problem with this, however, is that the bacteria have to survive a trip through the stomach and small intestine to get to the large intestine. This exposes them to gastric acid, bile salts and pancreatic secretions, all of which can kill them.

So an alternative approach is to encourage the desirable bacteria already in the gut to flourish, by providing the foods on which they thrive. These 鈥減rebiotics鈥� are typically carbohydrates such as fructo-oligosaccharides and galacto-oligosaccharides that resist digestion in the stomach and small intestine and reach the colon intact. There they are selectively metabolised by bifidobacteria or lactobacilli already in the gut.

The third approach is to combine probiotics and prebiotics in one treatment, called a synbiotic. Introducing the beneficial bacteria along with their ideal food vastly improves their chances of surviving the hostile conditions of the stomach and small intestine.

Many studies have already looked into the effects of probiotics on gut health. For example, Erika Isolauri at the University of Turku in Finland showed that a strain of Lactobacillus casei reduced diarrhoea in children with rotavirus. Other work suggests that probiotics can help alleviate traveller鈥檚 diarrhoea and diarrhoea that results from misbalanced gut flora during antibiotic treatment.

Shailee Saran and Sareth Gopalan of the Centre for Research on Nutrition Support Systems in New Dehli, India, have even suggested that taking probiotics could boost children鈥檚 development. They hypothesised that repeated bouts of gastrointestinal infection damage the gut lining and result in undernourishment, so they gave a group of young children a curd containing Lactobacillus acidophilus, hoping it would help the gut lining heal. In 2002 they reported that these children had gained significantly more weight after six months than a control group who were given a supplement containing no probiotic bacteria (Nutrition, vol 18 p 393).

Studies on colon cancer have also produced striking results. In the 1980s Barry Goldin at Tufts University School of Medicine in Boston, Massachusetts, gave human volunteers fermented milk supplemented with lactic acid bacteria, which produce fewer carcinogens than other gut bacteria. He showed that this decreased the activity of harmful bacterial enzymes like beta-glucuronidase. And Rowland later showed that feeding rats lactic acid bacteria limits the conversion of IQ to carcinogenic 7-hydroxy-IQ. He also found that encouraging growth of lactic acid bacteria with a prebiotic decreases the formation of potential carcinogens in the gut.

The evidence is certainly exciting, but it remains tentative, as not all studies have demonstrated the same beneficial effects. A recent human trial of the effects of galacto-oligosaccharides found no significant changes in the level of bifidobacteria, or a reduction in carcinogens or the bacterial enzymes that make them. Although Gibson鈥檚 team did not conduct that particular trial, he thinks the result may be because the volunteers had plenty of bifidobacteria to start with 鈥� there seems to be a maximum possible population of bifidobacteria of about 10 grams.

Gibson and others are now investigating whether probiotics can help manage ulcerative colitis. He is hoping to treat patients by encouraging the growth of bifidobacteria at the expense of the harmful sulphate-reducing bacteria. Their trial, which is still under way, uses a 50-50 mixture of the prebiotics fructo-oligosaccharides and galacto-oligosaccharides.

MacFarlane is trying a similar approach and has just finished a trial of synbiotics. Although he is coy about revealing too much detail before his findings are published, they are consistent with the idea that synbiotics could help treat ulcerative colitis. 鈥淭he synbiotic had a very powerful anti-inflammatory effect,鈥� he says. His next study will examine the effects of sulphur in the diet of patients.

Gibson is also conducting a human trial on irritable bowel syndrome. This painful condition can cause bloating and alternating episodes of constipation and diarrhoea, and is thought to affect up to 22 per cent of people in developed countries. Previous work has shown that people who have IBS carry the yeast Candida albicans in their guts, so research is focusing on whether Candida is involved in IBS. Like MacFarlane鈥檚 study, the IBS trial uses a synbiotic treatment of Lactobacillus plantarum fortified with a prebiotic.

Researchers in France have decided to go one step further, and are trying to genetically engineer the perfect probiotic bacterium. A team lead by Bruno Pot at the Laboratory of Bacteriology of Ecosystems at the Pasteur Institute in Lille is tinkering with the genes of lactic acid bacteria to understand more about how the bacteria produce their protective effect. They also screen the new strains of bacteria they create to test their anti-inflammatory potential. Strains that show promise are given to mice that have colitis, and the best of those are selected for testing in a human clinical trial. The team is waiting for the results of the human trials.

Whether we could all benefit from taking probiotics is still an open question, but there鈥檚 everything to play for. Which is why someone perhaps ought to have a word with staff at London鈥檚 Heathrow Airport, where Gibson鈥檚 missing monkey poop eventually materialised. Incredulous customs officials had delayed the parcel, and the courier had mistakenly picked up another package destined for Reading. 鈥淣o one could believe that someone would want monkey poo,鈥� explains Gibson. 鈥淚 shudder to think that there might have been some poor restaurant owner in Reading expecting pork chops but got faeces instead.鈥�