Alterations of bacteria in the gut are directly associated with the severity of motor deficits in Parkinson's disease mouse models, according to novel findings that, if replicated in humans, could eventually have clinical implications in the long-speculated relationship between gut bacteria and Parkinson's disease.
"Our findings provide a completely new paradigm for how environmental factors may contribute to Parkinson's disease and possibly other neurodegenerative disorders," said senior author Sarkis Mazmanian, PhD, the Louis & Nelly Soux Professor of Microbiology in the Division of Biology and Biological Engineering at the California Institute of Technology, Pasadena, in a statement.
"The notion that these diseases may be impacted by pathology in the gut and not only in the brain is a radical departure from conventional research in neuroscience."
In addition to the prominent tremors and motor symptoms associated with Parkinson's disease, as many as 75% of patients also have gastrointestinal abnormalities, which can precede the appearance of motor symptoms by many years, prompting the authors to speculate on the role of gut bacteria and the disease.
To investigate the relationship, they engineered mice to overexpress the protein α-synuclein, which is believed to play a key role in Parkinson's disease, and to display symptoms of the disease.
The study was published online December 1 in the journal Cell.
In the first of the experiments, the mice were divided into three groups: two with complete microbiomes of intestinal bacteria, mimicking the complexity in humans, and a third group that was bred to be germ-free.
In several tasks designed to measure motor skills that become dysfunctional in Parkinson's disease, including running on treadmills, descending from a pole, and crossing a beam, the mice who were germ-free performed substantially better than those with a complex microbiome and those with gut microbiota showed greater motor deficits.
The researchers further sought to determine whether imbalances in short-chain fatty acids (SCFAs), which can be related to intestinal bacteria, would be associated with activated immune responses in the brain, as has been suggested in previous research.
They found that germ-free mice who were treated with microbially produced SCFAs did show activation of microglia, indicating neuroinflammation that is linked to the malfunction of neurons.
"Indeed, oral administration of specific microbial metabolites to germ-free mice promotes neuroinflammation and motor symptoms," the authors said.
In a third experiment, the mice were transplanted with fecal samples from human patients with and without Parkinson's disease.
The germ-free mice who received transplants with the human gut microbiota from patients with Parkinson's disease remarkably displayed a significant worsening of the hallmarks of Parkinson's disease, whereas those receiving fecal transplants from healthy human donors did not show the symptoms.
"We were very surprised to see this effect," first author Timothy Sampson, PhD, a postdoctoral scholar in biology and biological engineering at California Institute of Technology, told Medscape Medical News.
"We would have expected, based on initial data, that different populations of gut microbes might act in the same way in a fecal transplant, but instead what we found was that gut microbes from people with Parkinson's disease in fact altered the outcomes of motor function testing."
In terms of potential translation to humans and clinical implications of fecal transplants, Dr Sampson said the team is currently more focused on identifying specific organisms that are associated with the symptoms.
But he noted that mouse models involving fecal transplants have had some success in being replicated in humans, particularly with Clostridium difficile infection.
"The effects in mouse models with C difficile translated beautifully to humans, but with other models, such as ulcerative colitis and inflammatory bowel disease (IBD), the fecal transplants were effective in mice but that didn't translate to humans, so there are definitely caveats."
Another caveat is that the α-synuclein--expressing mouse model only recapitulates the earlier symptoms of Parkinson's disease, and models for later stages of the disease have not yet been developed, Dr Sampson said.
Research looking at a link between the gut and Parkinson's disease that involved human participants has included a study, reported by Medscape Medical News, showing that a truncal vagotomy, or removal of the vagus nerve, was associated with a reduced risk of developing Parkinson's disease. The finding suggested that the Parkinson's pathology may ascend from gut to brain via the vagus nerve, those researchers concluded.
James Beck, PhD, vice president of scientific affairs for the Parkinson's Disease Foundation, echoed the concern that mouse models in Parkinson's disease research have in the past failed to deliver in human trials but said the new findings are nevertheless promising.
"It's important to first note that this is a mouse study because too often we have seen success in treating Parkinson's disease in mice, and the effects haven't translated to humans," he told Medscape Medical News.
"But with that in mind, I think this is really exciting because it opens up a new area of research."
The role of bacteria in Parkinson's disease has been the focus of some research for many years, with particular interest in lipopolysaccharides and brain inflammation, but the new findings uncover important new insights, Dr Beck said.
"What this study does is different — they have teased out some of the specific differences in microbiota in Parkinson's disease, including the striking finding that adding bacteria was enough to trigger the disease in mice."
The research is likely to spark heightened research focus on the role of the intestinal microbiome in Parkinson's, Dr Beck added.
"I haven't heard about research involving fecal transplants and Parkinson's disease, for instance, but I imagine we will soon because this study is groundbreaking in that regard," he said.
The research could further prompt a new look at various unexplained aspects of Parkinson's disease potentially related to gut bacteria, such as the observation that smokers and coffee drinkers appear to have a decreased risk for the disease.
"We don't know why smoking and coffee consumption are associated with the decreased risk — it could have something to do with caffeine or nicotine, but this study raises the issue that people who drink coffee and/or smoke are likely to have different bacteria, and perhaps we should take a closer look at their gut biome to see if it somehow pertains to whether they develop Parkinson's or not," Dr Beck concluded.
The work was funded by the Larry L. Hillblom Foundation, the Knut and Alice Wallenberg Foundation, the Swedish Research Council, Mr. and Mrs. Larry Field, the Heritage Medical Research Institute, and the National Institutes of Health. Dr Mazmanian is the scientific founder of Axial Biotherapeutics, based in Boston, Massachusetts, which is working to translate the findings into potential microbial-targeted therapies for Parkinson's disease. Dr Beck has disclosed no relevant financial relationships.
Cell. Published online December 1, 2016. Abstract
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Cite this: Gut Microbiome Again Linked to Parkinson's Symptoms - Medscape - Dec 06, 2016.