Sarkis Mazmanian’s research has uncovered key links between the gut microbiome and Parkinson’s disease and has led to the development of a Phase 1 clinical trial for a new therapeutic candidate.
Image credit:JIM CORNFIELD, California Institute of Technology, Modified by Erin Lemieux
Back in 2013, when The Scientist first featured Sarkis Mazmanian, he had just been awarded a MacArthur Foundation Fellowship, commonly known as a “genius grant.” At that time, he was pioneering research into the gut-brain connection, autoimmunity, and inflammatory disorders. His earlier work in Dennis Kasper’s laboratory at Harvard Medical School had demonstrated the intricate links between the gut microbiome and immunity, revealing that a specific bacterial strain could reshape immune development in germ-free mice. “This one organism was able to drive the maturation of the immune system,” Mazmanian remarked during his initial interview.
Since joining the California Institute of Technology, Mazmanian has continued to make groundbreaking discoveries that have significantly expanded scientific understanding of the microbiome’s influence on health, behavior, and immunity. In celebration of The Scientist’s 40th Anniversary, Mazmanian shared some of his major findings, discussed how his research direction has evolved, and addressed some of the hype surrounding microbiome science. “We have now moved into Parkinson’s disease, anxiety, feeding behaviors, and Alzheimer’s disease, all through that same lens of using gut bacteria to understand ways of accessing the brain or modulating brain function so we can restore health, broadly speaking,” he explained.
Exploring the Gut-Brain Connection in Parkinson’s Disease
Mazmanian’s investigation into Parkinson’s disease began after he identified a significant gap in the existing literature. “Somewhere between 60 and 80 percent of Parkinson’s patients report some form of gastrointestinal issue,” he noted. This connection dates all the way back to James Parkinson’s 1817 essay, which first described the condition, then known as shaking palsy.
Mazmanian was puzzled by the lack of research into this clear association. When he discussed it with neurologists, they often dismissed it or wondered what actionable steps could be taken. “But the more Parkinson’s patients I talked to, many of them—certainly not all, but many—reported that their gastrointestinal symptoms really eroded their quality of life, particularly early in the course of disease,” Mazmanian shared. “Now we know that gastrointestinal symptoms, primarily in the form of constipation, can precede the diagnosis of Parkinson’s by many years.”
To investigate how the gut microbiome might contribute to Parkinson’s disease, Mazmanian utilized a mouse model of the condition. These animals overexpressed α-synuclein, a protein that forms amyloid plaques (or Lewy bodies), which accumulate in the brains of people with Parkinson’s disease and lead to the loss of dopamine-producing neurons. This research culminated in a 2016 publication in Cell, which Mazmanian describes as a straightforward yet profoundly impactful study. “If we remove the microbiome in a mouse model of Parkinson’s, all the symptoms go away,” he stated. “If we give the microbiome back, all the symptoms come back.”
To deepen the investigation, his team transplanted microbiomes from both Parkinson’s patients and healthy donors into the mice. “If the fecal sample—meaning the microbiome—came from a Parkinson’s patient, the symptoms were worse, suggesting that there’s something in the [Parkinson’s] microbiome that may actually be pathogenic,” he explained. These findings indicated that microbiome changes in Parkinson’s patients might not merely be a consequence of the disease but could actively contribute to its symptoms and progression.
Microbiome Composition, Bacterial Proteins, and an Amyloid Cascade
In more recent work, Mazmanian’s team employed a metagenomics approach to characterize the composition of gut microbiomes in Parkinson’s disease. “Broadly speaking, we found overgrowth of pro-inflammatory organisms and a depletion of anti-inflammatory organisms, along with a reduction in short-chain fatty acid-producing bacteria,” he reported. They also observed a notable increase in specific strains of E. coli that produce an amyloid protein called major curlin subunit (CsgA). “Amyloids are these self-aggregating proteins, and it’s been known for some time that different mammalian amyloids can cross-seed each other,” Mazmanian clarified.
This cross-seeding capability explains why post-mortem brains of Parkinson’s patients exhibit not only α-synuclein aggregation but also pathogenic proteins associated with other neurodegenerative diseases, such as Huntington’s disease and Alzheimer’s disease. Mazmanian sought to determine whether bacterial amyloid could trigger the aggregation of mammalian amyloid. While he acknowledged that other factors are known to initiate the α-synuclein cascade in Parkinson’s brains, his team’s mouse experiments demonstrated that CsgA can also induce this process.
Although gaps in knowledge remain, Mazmanian and his colleagues have formulated a working hypothesis regarding how gut bacteria might influence the brain in this manner. Specialized, hormone-producing epithelial cells lining the gut, known as enteroendocrine cells, could play a central role. “What we’ve shown in vitro, though not yet published, is that the bacterial amyloid CsgA, or E. coli carrying CsgA, can induce α-synuclein aggregation in enteroendocrine cells,” Mazmanian revealed. “We’re now examining this in mice.”
Drawing on the work of other researchers studying the gut-brain axis, Mazmanian understood that these enteroendocrine cells can communicate with the brain by forming synapses with enteric neurons. “So, we think the chain is that if there is bacterial amyloid in the lumen, some of it gets into the enteroendocrine cells and induces α-synuclein aggregation,” he proposed. “Then α-synuclein can pass trans-synaptically to neurons in the gut, and after that, I think the signal has now left the station. It can pass from neuron to neuron, up the vagus nerve, into the brainstem, and then up into the brain.”
Harnessing the Microbiome to Combat Disease
While Mazmanian also investigates the gut microbiome’s connection to other conditions, including autism and anxiety, his primary focus remains on Parkinson’s disease, which is the fastest-growing neurological disorder globally. His team is actively translating their discoveries into novel therapies aimed at preventing the onset and progression of the disease. Their CsgA research, for instance, has led to a therapeutic candidate currently undergoing Phase 1 clinical trials.
Another promising therapeutic avenue involves one of the potent anti-inflammatory bacterial strains consistently found to be depleted in the microbiomes of Parkinson’s patients: Faecalibacterium prausnitzii. In a recent study, Mazmanian and his team showed that treating their Parkinson’s disease mice with this strain alleviated motor symptoms, triggered anti-inflammatory immune responses, and promoted protective gene expression profiles in the animals’ colons.
However, Mazmanian cautioned that probiotics may not always be the most effective solution. “The microbiome is a source of drugs, but maybe the levels of the organisms we could ever reintroduce through probiotics are insufficient,” he explained. “If I knew which protein of F. prausnitzii was therapeutic in Parkinson’s, I wouldn’t need to give patients F. prausnitzii. I could simply provide high amounts of that protein. Alternatively, if I learned how F. prausnitzii mediates its anti-inflammatory effect—such as identifying which bacterial molecule interacts with which receptor on which cell type—I could develop a drug targeting that pathway.”
The unresolved question, Mazmanian noted, is whether the gastrointestinal symptoms observed in Parkinson’s disease actively drive the condition’s pathophysiology. “I know many people believe it does. I’m open-minded. Based on the research, I lean toward believing it, but I don’t think that’s conclusive yet. I think we need more research,” he concluded.