Rumblings of Parkinson’s: Gut Microbiome Shifts in Early Stage of Disease
By the time a person with Parkinson’s notices something is wrong, the microbes in his gut may have long known about it. Reporting April 28 in Genome Medicine, researchers led by Ullrich Wüllner of the University of Bonn in Germany describe striking changes in the microbial communities living in the intestines of people in the earliest stages of the disease. Based on specific shifts of microbial species in the PD gut, the researchers speculated that the microbiome could interfere with the production of short chain fatty acids, or the permeability of the mucosal gut barrier—two functions intimately linked with inflammation and potentially with neurodegeneration.
“[This study] adds to the considerable evidence that the microbiota are involved in the pathogenesis of Parkinson's disease (PD) and other neurodegenerations,” commented Robert Friedland of the University of Louisville in Kentucky, who was not involved in the work. “Their data clarify with greater detail than previously available the nature of bacterial populations in the colonic lumen in PD.”
The study is the latest in steady stream of papers describing an altered microbiome in people with PD (see Keshavarzian et al., 2015, Scheperjans et al., 2015, Unger et al., 2016). Whether these microbial changes are a cause or consequence of the disease process is unclear, although a study in mice colonized with human microbes suggested both may be true: PD somehow alters the composition of the intestinal flora, which in turn accelerates pathology (see Dec 2016 news).
Co-first authors Janis Bedarf in Bonn and Falk Hildebrand at the European Molecular Biology Laboratory in Heidelberg wanted to measure microbiome changes in the earliest stages of the disease, within one year of diagnosis and prior to starting dopaminergic therapy. L-dopa is known to cause constipation, Wüllner told Alzforum, hence might interfere with intestinal flora. The researchers also used next-generation sequencing to survey the entire microbiome, rather than sequencing only 16S rRNA as prior studies had done. This more comprehensive “metagenomics” approach allows quantification of microbial inhabitants down to the species level, and also accounts for bugs such as viruses and fungi.
The researchers compared the gut metagenomes taken from stool samples of 31 early PD patients to 28 healthy age-matched controls. To avoid effects of sex, they only included men in the study. The investigators observed significant differences between the two groups. In particular, they found increases in the Firmicutes family, in unclassified bacteria, and in the genus Akkermansia, and found decreases in Prevotella and Eubacterium genera in PD patients relative to controls. At the species level, men with PD had an overabundance of Akkermansia muciniphila and Alistipes shahii, and fewer Prevotella copri, Eubacterium biforme, and Clostridium saccharolyticum. The overall diversity of bacteria was the same between the groups. Notably, PD patients had fewer gut viruses, including bacterial and archaeal phages. Based on the abundance of six different bacterial taxa, the researchers could correctly identify 84 percent of the PD patients.
The researchers found no correlation between the microbiome and the severity of motor symptoms, or constipation. They expected this, given the early disease stage and few reported bowel problems among the participants. While not on L-dopa, some of the patients were taking other medications. The researchers found that people taking both MAO inhibitors and amantadine had greater diversity of microbial species, while those taking statins had alterations in five families of bacteria. However, these differences did not contribute to those observed between PD patients and controls.
To search for potential consequences of these microbial changes, the researchers took stock of microbial genes associated with metabolic pathways. Microbes in people with PD expressed lower levels of genes involved in the degradation of D-glucuronate, a chemical needed for excretion of drugs and toxins in the urine. The patients had higher levels of genes involved in tryptophan metabolism. Tryptophan is a precursor to serotonin; interestingly, people with PD tend to have lower levels of both. However, Wüllner pointed out that it is unclear how much gut bacteria contribute to overall serotonin levels, as human cells also metabolize tryptophan.
The researchers also inferred potential biological consequences based on the known functions of some microbial species. Akkermansia muciniphila—a species PD patients had more of—degrades mucin, an enzyme that breaks down the mucosal lining of the intestine. This bacterium is therefore thought to improve gut barrier function, which is commonly compromised in people with PD. However, the species has also been implicated in inflammation. On the other hand, people with PD had less Prevotella and Eubacteria, both of which produce short chain fatty acids (SCFAs). In particular, Prevotella is more prevalent in the gut of people in non-Western countries with diets rich in fiber, the substrate of SCFAs. While some studies have associated these SCFAs with reduced inflammation, recent studies in mice have implicated them in activating microglia in the brain, and exacerbating α-synuclein pathology (see Jun 2015 news and Dec 2016 news).
Despite the mouse data to the contrary, Wüllner hypothesizes that overall, SCFAs have an anti-inflammatory effect in the human gut, and perhaps a therapeutic effect in the brain. The researchers aim to test this by putting some PD patients on a high fiber diet, and thus boosting SCFA production by Prevotella and other species.
Friedland added that the role of these microbially-derived fatty acids neurodegenerative processes deserves further investigation. “This may be a mechanism by which neuroinflammation (which is a component of the Parkinson process in the brain) is influenced by the microbiota,” he wrote.
The researchers employed a statistical algorithm that predicted microbiome alterations were a consequence, not a cause, of PD pathogenesis. However, Wüllner was quick to note that accurately inferring causality will require a much larger sample size.—Jessica Shugart
- Do Microbes in the Gut Trigger Parkinson’s Disease?
- To Be Hale and Hearty, Brain Microglia Need a Healthy Gut
- Keshavarzian A, Green SJ, Engen PA, Voigt RM, Naqib A, Forsyth CB, Mutlu E, Shannon KM. Colonic bacterial composition in Parkinson's disease. Mov Disord. 2015 Sep;30(10):1351-60. Epub 2015 Jul 16 PubMed.
- Scheperjans F, Aho V, Pereira PA, Koskinen K, Paulin L, Pekkonen E, Haapaniemi E, Kaakkola S, Eerola-Rautio J, Pohja M, Kinnunen E, Murros K, Auvinen P. Gut microbiota are related to Parkinson's disease and clinical phenotype. Mov Disord. 2015 Mar;30(3):350-8. Epub 2014 Dec 5 PubMed.
- Unger MM, Spiegel J, Dillmann KU, Grundmann D, Philippeit H, Bürmann J, Faßbender K, Schwiertz A, Schäfer KH. Short chain fatty acids and gut microbiota differ between patients with Parkinson's disease and age-matched controls. Parkinsonism Relat Disord. 2016 Nov;32:66-72. Epub 2016 Aug 26 PubMed.
No Available Further Reading
- Bedarf JR, Hildebrand F, Coelho LP, Sunagawa S, Bahram M, Goeser F, Bork P, Wüllner U. Functional implications of microbial and viral gut metagenome changes in early stage L-DOPA-naïve Parkinson’s disease patients. Genome Science. April 28, 2017.
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Washington University School of Medicine
This paper has two major pluses over previous studies on the topic:
a) It compares PD patients naïve to L-DOPA with normal controls, avoiding L-DOPA as a confounding element;
b) It performs a metagenomic shotgun analyses, which allows high-resolution characterization of bacterial species as well as their metabolic functions.
The major conclusion is that the microbiota of PD and controls show significant differences in species and metabolic activities. The paper is open ended as it remains to be established whether these differences are primary or secondary in the pathogenesis of the disease.
I would like to emphasize one point that I think is rather provocative. PD patients in this study have reduced abundance of a Prevotella species. Prevotellaceae utilize fibers as substrate to produce short chain fatty acids (SCFA), suggesting that PD patients may have defective production of SCFA. This conclusion is in agreement with previous studies showing that feces from PD contain less SCFA-producing bacteria. However, this conclusion is seemingly contrast with the recent study by the Mazmanian group, who have shown that SCFA promote disease and neuroinflammation in a transgenic mouse model of PD based on overexpression of α-synuclein. Thus, the connection between intestinal microflora, metabolites and disease progression remains to be fully explored.
University of Louisville School of Medicine
The recent report by Bedarf et al. in Genome Medicine adds to the considerable evidence that the microbiota are involved in the pathogenesis of Parkinson's disease (PD) and other neurodegenerations. Their data clarify with greater detail than previously available the nature of bacterial populations in the colonic lumen in PD. The potential for the pathogenicity of intestinal microbial alterations noted by Bedard et al and others deserves consideration. Short chain fatty acids enhance the production to anti-inflammatory regulatory lymphocytes. This may be a mechanism by which neuroinflammation (which is a component of the Parkinson process in the brain) is influenced by the microbiota. Also, we have presented evidence that the production of amyloid proteins by the microbiota may be involved (see Oct 2016 news on Chen et al., 2016 and Friedland, 2015). We found that Fischer 344 rats exposed orally to the functional bacterial amyloid protein curli had enhanced cerebral inflammation and alpha synuclein aggregation, compared to animals exposed to bacteria without the ability to produce curli. The capacity for the production of amyloid proteins by bacterial populations observed by Bedardf et al. has not been explored.
Chen SG, Stribinskis V, Rane MJ, Demuth DR, Gozal E, Roberts AM, Jagadapillai R, Liu R, Choe K, Shivakumar B, Son F, Jin S, Kerber R, Adame A, Masliah E, Friedland RP. Exposure to the Functional Bacterial Amyloid Protein Curli Enhances Alpha-Synuclein Aggregation in Aged Fischer 344 Rats and Caenorhabditis elegans. Sci Rep. 2016 Oct 6;6:34477. PubMed.
Friedland RP. Mechanisms of molecular mimicry involving the microbiota in neurodegeneration. J Alzheimers Dis. 2015;45(2):349-62. PubMed.
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