Summary: Researchers found significant differences in samples from the appendix of people with Parkinson’s disease, specifically in microbial composition correlating with higher levels of toxic bile acids.
Source: Van Andel Research Institute
What does bile acid production in the digestive tract have to do with Parkinson’s disease?
Quite a lot, according to a sweeping new analysis published in the journal Metabolites. The findings reveal that changes in the gut microbiome — the rich population of helpful microbes that call the digestive tract home — may in turn alter bile acid production by favoring synthesis of toxic forms of the acids.
These shifts were seen only in people with Parkinson’s and not in healthy controls, a critical difference that suggests bile acids may be a viable biomarker for diagnosing Parkinson’s early and tracking its progression. The insights also may provide new avenues for developing therapies that impede Parkinson’s-related changes in the gut, thereby potentially slowing or stopping disease onset and progression.
The research was led by the late Viviane Labrie, Ph.D., of Van Andel Institute, in collaboration with colleagues at VAI, Beaumont Health, Michigan State University College of Human Medicine and Oregon Health & Science University.
“It’s becoming increasingly clear that gut health is tightly linked to brain health,” said Peipei Li, Ph.D., the study’s first author and former postdoctoral fellow in the Labrie Lab. “Our findings provide exciting new opportunities for better understanding this relationship and possibly for developing new ways to diagnose — and even treat — Parkinson’s.”
To investigate differences in the microbiome, the team turned to the appendix, a frequently maligned bit of tissue that actually plays an important role in regulating gut microbes. Using a “multi-omics” approach, the team comprehensively analyzed and compared the microbiome composition of appendix samples from people with Parkinson’s and healthy controls. They found significant differences, with the changes in microbial composition of the Parkinson’s samples correlating with higher levels of toxic bile acids.
The findings track with a 2020 study led by scientists in Spain that suggest changes in bile acids in the plasma are associated with Parkinson’s disease.
“My lab has grown increasingly interested in bile acids and Parkinson’s disease following a study completed in collaboration with Dr. Patrik Brundin’s group a few years ago,” said Stewart Graham, Ph.D., director of Metabolomics Research at Beaumont Health. “We demonstrated that not only was there a significant shift in the bile acid metabolism due to changes we induced in the brain, but that these compounds have the potential to be used as early blood-based biomarkers of the disease. This is extremely important as this is when treatments are believed to be most effective.”
In recent years, research has revealed a growing number of links between the gut and Parkinson’s. For example, chronic constipation often is one of the earliest signs of Parkinson’s disease and can occur years or even decades before the onset of the disease’s hallmark motor symptoms. Other studies have shown that hepatitis C, which impacts the liver, increases the risk of developing Parkinson’s.
Importantly, a 2018 study by Labrie and colleagues demonstrated that removal of the appendix is associated with a 19-25% reduction in Parkinson’s risk when the surgery occurs early in life, before the start of the disease process. They also found that the appendix acts as a storehouse for Parkinson’s-related proteins called alpha-synuclein, clumps of which are a key pathological sign of Parkinson’s. However, alpha-synuclein was found in the appendixes of healthy controls as well as people with Parkinson’s, implying that the presence of the protein alone isn’t enough to trigger the disease.
Authors include Elizabeth Ensink, Ian Beddows, Ph.D., Noah Lubben, Meghan Schilthuis, J. Andrew Pospisilik, Ph.D., Patrik Brundin, M.D., Ph.D., and Lena Brundin, M.D., Ph.D., of VAI; Bryan Killinger, Ph.D., of Rush University Medical Center; Ali Yilmaz, Ph.D., of Beaumont Health; Jared Lamp, Ph.D., and Irving Vega, Ph.D., of Michigan State University College of Human Medicine; and Randy Woltjer, M.D., Ph.D., of Oregon Health & Science University. VAI’s Bioinformatics and Biostatistics Core and Michigan State University’s Genomics Core contributed to this work. Tissue was provided by the Oregon Brain Bank.
Funding: Research reported in this publication was supported by Van Andel Institute and the Farmer Family Foundation (P. Brundin, with L. Brundin, Pospisilik and Labrie as co-investigators).
Labrie also held awards from the Department of Defense, National Institute of Neurological Disorders and Stroke of the National Institutes of Health and Michigan State University through the Gibby & Friends vs. Parky Parkinson’s Disease Research Award. Graham holds awards from the National Institute of Neurological Disorders and Stroke of the National Institutes of Health, the National Institute on Aging of the National Institutes of Health, the Alzheimer’s Association and the Michael J. Fox Foundation.
Gut Microbiota Dysbiosis Is Associated with Elevated Bile Acids in Parkinson’s Disease
The gut microbiome can impact brain health and is altered in Parkinson’s disease (PD). The vermiform appendix is a lymphoid tissue in the cecum implicated in the storage and regulation of the gut microbiota. We sought to determine whether the appendix microbiome is altered in PD and to analyze the biological consequences of the microbial alterations. We investigated the changes in the functional microbiota in the appendix of PD patients relative to controls (n = 12 PD, 16 C) by metatranscriptomic analysis. We found microbial dysbiosis affecting lipid metabolism, including an upregulation of bacteria responsible for secondary bile acid synthesis. We then quantitatively measure changes in bile acid abundance in PD relative to the controls in the appendix (n = 15 PD, 12 C) and ileum (n = 20 PD, 20 C). Bile acid analysis in the PD appendix reveals an increase in hydrophobic and secondary bile acids, deoxycholic acid (DCA) and lithocholic acid (LCA). Further proteomic and transcriptomic analysis in the appendix and ileum corroborated these findings, highlighting changes in the PD gut that are consistent with a disruption in bile acid control, including alterations in mediators of cholesterol homeostasis and lipid metabolism. Microbially derived toxic bile acids are heightened in PD, which suggests biliary abnormalities may play a role in PD pathogenesis.