Parkinson's in New Technology

Faecal transplant eases symptoms of Parkinson's



Parkinson's



A FEW years ago, John Gillies had trouble picking up his grandchild. He would stand frozen, waiting for his Parkinson's disease to relinquish its hold and allow him to move. Then in May 2008, Gillies was given antibiotics to treat constipation, and astonishingly his Parkinson's symptoms abated. What on earth was going on?

Thomas Borody, a gastroenterologist at the Centre for Digestive Diseases in New South Wales, Australia, put Gillies on antibiotics because he had found that constipation can be caused by an infection of the colon. "He has now been seen by two neurologists, who cannot detect classic Parkinson's disease symptoms any more," says Borody.

Borody's observations, together with others, suggest that many conditions, from Parkinson's to metabolic disorders such as obesity, might be caused by undesirable changes in the microbes of the gut. If that is true, it might be possible to alleviate symptoms with antibiotics, or even faecal transplants using donor faeces to restore the bowel flora to a healthy state.

Borody uses faecal transplants to cure people infected by the superbug Clostridium difficile, and to alleviate chronic constipation. Over the past decade, Borody has noticed that some of his patients also see improvements in symptoms of their other diseases, including Parkinson's, multiple sclerosis (MS), chronic fatigue syndrome (CFS) and rheumatoid arthritis. "Some CFS patients, given a faecal transplant, will regain their energy quite dramatically, and their foggy brains will get better," says Borody.

To test a possible link between the gut and Parkinson's disease, Borody and neurologist David Rosen of the Prince of Wales Private Hospital in Sydney are embarking on a pilot study, hoping to recruit people with both constipation and Parkinson's. The plan is first to treat them with antibiotics and eventually with faecal transplants. They hope both faecal transplants and antibiotics will treat gut infection and hence Parkinson's.

Rosen is cautious: "I wouldn't for one minute be suggesting that this is the next cure," he says. But the idea that Parkinson's could be caused by bacteria dovetails with work by neuroanatomists Heiko Braak and Kelly Del Tredici at the University of Ulm in Germany.

In 2003, Braak and Tredici showed that damage to the nervous system in Parkinson's progresses from the vagus nerve in the lower brain stem to the higher regions of the brain and eventually to the cerebral cortex. They also found damage in the enteric nervous system, which controls the gastrointestinal (GI) tract and communicates with the brain via the vagus nerve. This discovery prompted them to suggest that Parkinson's might be caused by a bug that breaks through the mucosal barrier of the GI tract and enters the central nervous system via the vagus nerve (Journal of Neural Transmission, DOI: 10.1007/s00702-002-0808-2).

So what about the dramatic improvements seen in people with autoimmune diseases, such as rheumatoid arthritis, after faecal transplant? Borody's hypothesis is that an infection of the colon releases antigens into the bloodstream, which trigger an immune response. Unless something is done to completely clear the colon of the antigen, the immune response is relentless, eventually leading to systemic inflammation that manifests itself as an autoimmune disease.

Interpreting Borody's results requires extreme caution. However, there is evidence from animal models that intestinal microbes can influence autoimmunity. For instance, Alexander Chervonsky of the University of Chicago and colleagues have linked microbes in the gut to type 1 diabetes, an autoimmune disorder caused by the destruction of insulin-secreting pancreatic cells. Over 80 per cent of a particular breed of engineered mice that are kept germ-free develop type 1 diabetes. When the same mice were dosed with a cocktail of bacteria similar to those present in the human gut, only 34 per cent of the mice developed type 1 diabetes, suggesting a connection between gut flora and autoimmune diabetes (Nature, DOI: 10.1038/nature07336).

Researchers are becoming increasingly aware of the link between gut flora and autoimmunity, says Arthur Kaser, an expert on inflammation and intestinal flora at the University of Cambridge. For instance, mice designed to develop autoimmune diseases do so in some labs but not in others. The discrepancy is down to differences in the intestinal flora of the mice. "Intestinal microbiota has a dramatic effect on [what] we currently consider as autoimmune disease," says Kaser.

Evidence for such links in humans is also growing: Anne Vrieze of the Academic Medical Center in Amsterdam, the Netherlands, and colleagues studied 18 obese men with metabolic syndrome, a collection of symptoms that includes low insulin sensitivity. The group received faecal transplants - either of their own stool or stool from lean, healthy donors.

The results of this first double-blind trial were presented at the annual meeting of the European Association for the Study of Diabetes in Stockholm, Sweden, in September. The researchers found that, six weeks after the infusions, insulin sensitivity improved significantly in the nine men who received donor stool.

Gut flora has also been linked to obesity. Over the past five years, Jeffrey Gordon of Washington University in St Louis, Missouri, and colleagues have shown that there are marked differences in the gut flora of obese and lean individuals. Their analysis suggested that the microbes in obese individuals are releasing nutrients from food that would have remained undigested in lean individuals. Importantly, they showed that transferring the microbiota from obese mice into lean mice caused the lean mice to put on weight (Nature, DOI: 10.1038/nature05414).

So can you reverse obesity in humans by transferring gut microbes from lean people into obese people? It's a question that Alex Khoruts, at the University of Minnesota Medical School in Minneapolis, hopes to answer. He is planning a trial in which obese people will be given faecal transplants, either of their own faeces or samples taken from lean, healthy donors. "The idea is to alter the composition of colon flora, and see whether it has an impact on obesity," says Khoruts.

"This is absolutely exciting," says Kaser. But he insists that we are far from understanding the nature of the microbes that populate our body - after all, the colon alone contains nine times as many bacterial cells as there are human cells in the body. And we don't yet know what constitutes "healthy" colon flora. This will make it difficult to justify any large-scale adoption of faecal transplants, he adds. If intestinal bugs are indeed causing autoimmune diseases, "you don't want to treat one disease and introduce another", says Kaser.

Nonetheless, he is convinced that human microbiota will become increasingly important in our understanding of disease. "Textbooks will have to be rewritten when we consider the contribution of intestinal microbiota," he says. "We have an elephant in the room that has not yet been appreciated."