New study puts the gut microbiome at the center of the pathogenesis of Parkinson’s disease

Haydeh Payami, Ph.D.New research from the University of Alabama at Birmingham indicates that the gut microbiome is involved in multiple pathways in the pathogenesis of Parkinson’s disease. The results, published in Nature Communications, show a broad imbalance in the composition of the microbiome in people with Parkinson’s disease. The study is the largest microbiome study conducted at the highest resolution.

Investigators used metagenomics, the study of genetic material retrieved directly from the stool microbiome of people with PD and neurologically healthy control subjects.

“The primary goal of this study was to generate a comprehensive and unaltered view of the gut microbiome imbalance of PD,” said Haydeh Payami, Ph.D., professor in the Department of Neurology at the Marnix E. Heersink School of Medicine. and lead author on the study.

The study reports that the Parkinson’s disease metagenome is indicative of a disease-promoting microbiome.

“We found evidence for several mechanisms that we know are related to PD, but we didn’t know that they also occur in the gut and are orchestrated by the microbiome,” Payami said.

Investigators found an overabundance of opportunistic pathogens and immunogenic components, suggesting infection and inflammation at play, an overproduction of toxic molecules, and a curli overabundance of bacterial products. This induces PD pathology and dysregulation of neurotransmitters, including L-dopa. At the same time, there was a shortage of neuroprotective molecules and anti-inflammatory components, which makes recovery difficult.

Payami, John T. and Juanelle D. Strain Endowed Chair in Neurology, and his team recruited 490 people with Parkinson’s disease and 234 healthy controls. Just over half of the subjects were male and were mostly over 50 years old. All were from the Deep South region of the United States, which helped eliminate confusion by geographic and cultural influence on microbiome composition.

The researchers studied 257 species of organisms in the microbiome, and of these, the analysis indicated that 84, more than 30%, were associated with Parkinson’s disease.

“Of the 84 species associated with PD, 55 had abnormally high abundance in people with PD, and 29 were depleted,” Payami said. “We found that more than 30% of tested microorganisms and bacterial genes and pathways have altered abundances in Parkinson’s disease, indicating a generalized imbalance.”

The study, using the relatively new field of metagenomics, demonstrated an imbalance in the gut microbiome of patients with Parkinson’s disease.At one end of the spectrum, Bifidobacterium dentium increased seven-fold, Actinomyces oris 6.5-fold, and Streptococcus mutans six-fold. At the other end of the spectrum, Roseburia intestinalis was reduced 7.5 times and Blautia wexlerae five times. Overall, 36% of PD-associated species exhibited a more than doubled change in abundance, reflecting a 100% to 750% increase or decrease in PD compared to the healthy control group.

“This study created a large dataset at the highest resolution currently possible and made it publicly available without restriction to promote open science,” Payami said. “It includes extensive metadata on 490 people with PD, the largest PD cohort with microbiome data, and a unique cohort of 234 neurologically healthy older adults, which can be used in a wide range of studies. We have shown that there is a generalized imbalance in the Parkinson’s disease metagenome, creating an environment conducive to neurodegenerative events and preventing recovery.

Parkinson’s disease is a progressively debilitating disorder that affected 4 million people in 2005 and is expected to double to 8.7 million people by 2030. Although historically defined as a movement disorder, PD is a disease multisystemic. PD is thought to be caused by various combinations of genetic susceptibility and environmental triggers, although no causal combination has yet been identified. The link between PD and the gastrointestinal system has long been established.

“This is exciting research, as metagenomics is a new, albeit rapidly evolving, field and the resources, methods and tools, while state-of-the-art, are still under development,” Payami said. “Undoubtedly, more information will be revealed as we increase the sample size and as others also conduct metagenomics studies and share the data. We anticipate that in the near future we will have the tools and the analytical power to use metagenomics as a novel approach to study PD heterogeneity, search for biomarkers, delve into the origin and progression of PD subphenotypes, and investigate the potential to manipulate the microbiome to prevent, treat and halt the progression of PD.

Co-authors from the UAB Department of Neurology are Zachary A. Wallen, Ph.D., Guy Twa, Gwendolyn Cohen, Marissa N. Dean, MD, and David Standaert, MD, Ph.D. Other co-authors are Ayse Demirkan, Ph.D., University of Surrey, UK, and Timothy R. Sampson, Ph.D., Emory University.

The research was supported by the US Army Medical Research Material Command, the National Institutes of Health, the Parkinson’s Foundation, and Aligning Science Across Parkinson’s through the Michael J. Fox Foundation for Parkinson’s Research.