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Gut microbiome contributes to Parkinson's disease

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By Anette Breindl
Senior Science Editor

Parkinson's disease (PD) has joined the list of disorders that are affected by the gut microbiome. In studies reported in the Dec. 1, 2016, issue of Cell, researchers showed that signals from the gut microbiome affected the level of neuroinflammation and the degree of motor dysfunction in an animal model of PD.

"We can't tell whether it's solely causal yet," senior author Sarkis Mazmanian told BioWorld Today. But "the microbiome at the very minimum contributes to [Parkinson's] disease."

Mazmanian and his team became interested in possible links between PD and the gut microbiome because they had been studying links between the microbiome and the immune system for a number of years, and there are "many parallels between the nervous system and the immune system – on the cellular and molecular levels they seem to function very similarly," he said.

Microbiome changes have now been linked to a number of neurodevelopmental and neuropsychiatric disorders, including depression, anxiety and autism spectrum disorders.

PD is another candidate for microbiome contributions for several reasons.

"A majority of people with Parkinson's have GI abnormalities, most often constipation," Mazmanian pointed out. And constipation predates the motor symptoms that are among the hallmarks of PD by many years

Additionally, although there are genetic risk factors, "most cases of Parkinson's don't seem to run in families," he said. "The fact that there's a large environmental contribution made us think that the microbiome might be involved."

In the work now published in Cell, Mazmanian and his team investigated how different microbiota affected in the development of neuroinflammation and motor symptoms in mouse models that overexpress alpha-synuclein, the protein that forms aggregates in PD.

They showed that germ-free mice, which lack a microbiome, had fewer motor symptoms than animals with a normal microbiome. Antibiotic treatment, too, which wipes out the gut microbiome, reduced motor symptoms in the animals.

Most strikingly, when the team performed human-to-PD-mouse fecal transplants, animals that received transplants from PD patients subsequently showed worse motor symptoms than those who got transplants from healthy individuals.

The team also pinpointed short-chain fatty acid signaling as mediating the gut's effects on the brain, in a path that led from SCFA secretion by the bugs, to activation of brain immune cells called microglia, to neuroinflammation, to motor deficits. Treating germ-free mice with short-chain fatty acids could mimic the effects of the microbiome on PD symptoms.

Mazmanian is a professor of microbiology at the California Institute of Technology. He is also the scientific founder of Axial Biotherapeutics Inc., a startup that has licensed IP from Caltech related to the link between the microbiome and neurological disease.

Axial CEO David Donabedian told BioWorld Today that the company, which just launched with a series A financing of $19.5 million by Longwood Fund, Domain Associates, Kairos Ventures, Heritage Medical Systems and a group of high net worth individuals, was initially focusing on autism spectrum disorders and PD.

Donabedian declined to specify exactly how the company plans to exploit the link between the microbiome and neurological disorders, other than to say that Axial is exploring several possibilities and will ultimately be guided by the biology in deciding which one to pursue. The company expects to initiate clinical trials within 18 to 24 months.

Research into the gut microbiome is young enough that it is sure to find itself with its own set of challenges. But targeting the microbiome may be a way to sidestep one big challenge of developing therapies for brain disorders – the blood-brain barrier, which is built to keep most things out of the brain and has stymied many an otherwise promising molecule.

There are specific transporters, though, for getting molecules that the brain needs across that barrier. In another paper in the Dec. 1, 2016, issue of Cell, researchers from the Austrian Institute of Science and Technology reported that defects in transport of the amino acids valine, leucine and isoleucine, collectively known as the branched-chain amino acids across the blood-brain barrier appear to underlie some autism spectrum disorder cases, highlighting both the existence and the importance of biological pathways into the brain.

Many microbe metabolites, too – including the short-chain fatty acids – have ways of getting across the blood-brain barrier. And other studies have shown that they appear to do so with some anatomical specificity. In postmortem studies, certain metabolites are found in higher concentrations in some brain regions than others.

"Microbes have potentially solved the problem of how to get things in and out of the brain, and they do so with ease," Donabedian said. "Essentially . . . you let the bugs just go to work."