While it is not intuitively obvious that intestinal pathogens might contribute to the cause or progression of Parkinson disease (PD), studies reflect the importance of the gut-brain axis on neuropsychiatric function as well as the discovery of a connection between gut-derived inflammation and disorders driven by systemic or organ-specific immunity.
Looking at the evidence
There are 5 published studies assessing differences in fecal microbiome in patients with PD compared with healthy controls. All are cross-sectional studies using genetic sequencing techniques to identify changes in the relative abundance of various bacterial populations.
All five studies reported significant differences between PD and controls. While the results vary somewhat among the studies, there is general consensus that the fecal bacterial population in PD reflects decreased representation of bacteria that produce short chain fatty acids (SCFA). SCFA such as butyrate have anti-inflammatory actions related to epigenetic changes and affect inflammation and intestinal permeability through actions mediated by SCFA receptors.1 There is also an increased representation of bacteria that promote local inflammation and negatively influence the integrity of the intestinal barrier.1-5
These observations are buttressed by reports that SCFA levels are lower in PD stool than in control stool.5 In addition, research shows that intestinal barrier function is impaired in PD and that increased permeability is associated with markers of bacterial penetration into the intestinal wall, immune activation, and local inflammation.6
While it is premature to conclude that changes in intestinal microbes influence the genesis or progression of PD, or even that these changes might be a biomarker of PD or its clinical subtypes, there is now convincing evidence that PD patients host an intestinal microbiota that is different from that of controls. Preliminary evidence indicates that these changes may be associated with inflammatory changes in the intestinal wall and speculation that gut-derived sterile inflammation might contribute to the etiopathogenesis of the disease.
Moreover, preclinical findings suggest that gut microbes might have an important effect on CNS determinants of Parkinsonism. One recent preclinical study found that in mice that overexpress alpha-synuclein, gut microbiota are required to produce motor deficits, activation of microglia, and alpha-synuclein pathology. In germ free alpha-synuclein overexpressing mice, reconstitution of the gut microbiome with stool from untreated early PD subjects potentiated behavioral measures of experimental parkinsonism.7
Looking to the future
Additional studies are needed to clarify the clinical importance of this research, which could impact diagnostic and treatment strategies. For instance, this research might lend itself to identification of microbial risk factors for the development of PD. One day we may be able to use enteric or stool biomarkers to diagnose early PD. Additional research may also lead to the development of disease-modifying therapies directed at restoring normal bacterial populations or targeting gut-derived inflammation.
In the recent studies, only a few of the patients were in early stages of PD. We need research focusing on early PD and on cohorts in the prodromal or premotor stage of the disease to better determine if changes are secondary to constipation or other intestinal changes that occur as a consequence of disease or whether they may be implicated in the disease etiopathogenesis. Such studies will help clarify whether bacterial changes are a valuable disease and progression biomarker. Longitudinal studies are necessary to define the stability of microbial changes and their association with disease progression or clinical disease subtypes. Finally, interventional clinical trials targeting abnormal microbiome or its consequences are required.
While the brain is precious and protected in its bony vault, it is essential that we recognize the prospect that other organ systems may be important in primary brain diseases. Novel research collaborations can only happen when basic and clinical scientists collaborate to explore the borders between their respective fields. In doing so, we have the opportunity to further explore PD and improve our patients’ lives.
Dr. Shannon is Detling Professor and Chair of the Department of Neurology at University of Wisconsin School of Medicine and Public Health in Madison, Wisconsin.
1. Keshavarzian, A, Green SJ, Engen PA, et al. Colonic bacterial composition in Parkinson disease. Mov Disord. 2015;30: 1351-1360.
2. Li W, Wu X, Hu X, et al. Structural changes of gut microbiota in Parkinson's disease and its correlation with clinical features. Sci China Life Sci. May 2017; Epub ahead of print.
3. Petrov VA, Saltykova IV, Zhukova IA, et al. Analysis of gut microbiota in patients with Parkinson disease. Bull Exp Biol Med. 2017;162: 734-737.
4. Scheperjans F, Aho V, Pereira PA, et al. Gut microbiota are related to Parkinson disease and clinical phenotype. Mov Disord. 2015;30:350-358.
5. Unger MM, Spiegel J, Dillmann D, et al. Short chain fatty acids and gut microbiota differ between patients with Parkinson's disease and age-matched controls. Parkinsonism Relat Disord. 2016;32:66-72.
6. Forsyth CB, Shannon KM, Kordower JH, et al. Increased intestinal permeability correlates with sigmoid mucosa alpha-synuclein staining and endotoxin exposure markers in early Parkinson disease. PLoS One. 2011;6: e28032.
7. Sampson TR, Debelius JW, Thron T, et al. Gut microbiota regulate motor deficits and neuroinflammation in a model of Parkinson disease. Cell. 2016;167:1469-1480.