Insights Into Gut-Brain Signaling Raise Hopes For Treating Neurological Disorders
New research offers mechanistic proof of signaling between gut and brain in Parkinson’s disease, showing that introducing an altered microbiome from PD patients into a mouse model can recreate the motor symptoms of the disease.
Disruptive innovations sometimes come directly from the development of a novel enabling technology. In other cases, however, they result from focusing on a known problem using a different lens. Such creativity underlies new research suggesting the potential for harnessing the microbiome to treat neurological disorders.
A Dec. 1 paper in Cell offers mechanistic proof of signaling between gut and brain in Parkinson’s Disease (PD). It shows that introducing an altered microbiome from PD patients into a mouse model can recreate the motor symptoms of PD. The work, from the laboratory of Sarkis Mazmanian at the California Institute of Technology, is the foundation for a newly funded start-up aimed at developing microbiome-based therapeutics for PD and, based on other work from the Caltech lab using a similar discovery approach, autism disorders.
The notion of a gut-brain signaling connection has been around for decades. But only recently, in part due to an explosion in animal research, have biologists identified pathways linking the gut to the brain, Mazmanian says. And only in the last couple of years has the microbiome been implicated in that crosstalk and some experimental validation emerged. “Only a handful of rigorous experimental lines of evidence link the microbiome to neurological activity in the brain,” he says.
Mazmanian notes his group’s work is the first to mechanistically link the microbiome to a neurodegenerative disease.
The bulk of this line of research has centered on anxiety-related behaviors and autism disorders, including studies that have identified changes that occur in the microbiome of children with autism and, more recently, in individuals with anxiety. Several publications have identified specific organisms and pathways linking the gut to the brain and shown that the microbiome may be mediating outcomes in both anxiety and autism disorders. However, Mazmanian notes his group’s work is the first to mechanistically link the microbiome to a neurodegenerative disease.
The researchers devised a preclinical model using mice that overexpress α-synuclein, a protein that in aggregate form causes motor dysfunction. α-synuclein overexpressing (ASO) mice display progressive deficits in motor function as well as defects in gut motility. They also bred ASO animals to be germ-free. A series of experiments comparing the motor and GI functions of germ-free ASO mice and germ-free wild-type mice, and also comparing specific-pathogen-free (SPF) ASO mice to SPF-wild-type animals, showed that the presence of gut microbiota promote the hallmark motor and intestinal dysfunction of PD.
With a germ-free mouse model, it may be hard to dismiss the possibility that an observed phenotype is due to abnormal development of the animal – because it did not get normal signals from its microbiome. But the researchers went further. They observed differing effects when comparing human microbiota transplanted into the animals from a healthy microbiome versus microbiota from a PD patient. They also gave adult animals antibiotics to deplete their microbiota, which alleviated or highly reduced the motor symptoms, and fed adult germ-free animals short-chain fatty acids (SCFA), which promote α-synuclein-mediated neuroinflammation, and observed the results. “All three lines of evidence suggest that for this model, active signaling is occurring,” Mazmanian says. “It is not a developmental issue.”
Both Parkinson’s disease and autism disorders have a very profound gastro-intestinal connection. Somewhere on the order of 70% and maybe up to 90% of children with autism have GI complications that can be severe: constipation, abdominal cramps, bloating, and alternating constipation and diarrhea. In PD, constipation can precede motor deficits by years if not decades. Indeed, Heiko Braak proposed in 2003 that PD could begin with an accumulation of α-synuclein in the GI tract, which propagates via the vagus nerve to the brain.
These conditions should be thought of as whole-body disorders, Mazmanian says
“When there is such a strong GI component, it leaves the door open for a role for the microbiome,” says Mazmanian. The same may be true of anxiety disorders. “It’s often believed that the physical symptoms of anxiety are a result of changes in neurochemistry,” he says. But whereas in PD and autism disorders the GI symptoms may drive the neurological symptoms, in anxiety it is believed to go the other way, he says, where something happens in the brain and subsequently results in a physical impact in the gut.
Generally, these conditions should not only be thought of as neurological conditions but as whole-body disorders, Mazmanian says. “Part of why our work appears to be moving the needle is because we are making connections that have been known but just not followed up on,” he says: neurologists know these peripheral or non-CNS co-morbidities are associated with these diseases, but those symptoms have never been thought to be part of the disease process, he says. His research and that of others is showing that GI symptoms are not just a consequence of something happening in the brain but may be contributing to, promoting or even causing those abnormalities in the nervous system. “It’s a conceptual shift,” he says.
The work could lead to development of single organisms or consortia as therapeutics for PD. Developing prebiotics, supplements or OTC probiotics are also viable approaches, Mazmanian says. “I am very enthusiastic about dietary approaches,” he adds. “There is no reason one is going to work better than the other.”
Start-up Axial Biotherapeutics Inc., launched in late November with a $19.5 million Series A round led by Longwood Fund and Domain Associates, has licensed worldwide rights to IP out of Mazmanian’s lab, including the PD assets and assets around treating autism disorders. In a related 2013 Cell publication, the Mazmanian group showed that a single microbe, Bacteroides fragilis, was able to ameliorate almost all symptoms in several mouse models of autism. Axial is developing that organism as a drug candidate, and also has other interventions for autism disorders not yet disclosed: it aims to be in the clinic in less than two years. The company’s drug development efforts in PD could lead to the isolation of organisms that modulate the disease: targeting bad actors could potentially alleviate symptoms and beneficial organisms could augment the microbiome of patients, CEO David Donabedian says.
Donabedian, formerly head of the venture and early stage transactions group at AbbVie Inc., met Mazmanian while the latter was establishing his first start-up, SymBiotix Biotherapies Inc., which is using a microbiome-oriented strategy to treat immune-mediated diseases including inflammatory bowel disease and multiple sclerosis. (In 2016, Abbvie inked a deal with Synlogic Inc., which is focused on developing synthetic biotic therapies for rare genetic metabolic disorders including urea cycle disorder and phenylketonuria. [See Deal])