Parkinson’s disease (PD) is a chronic, progressive, disabling neurodegenerative disorder that begins in mid to late life. Although at least 15 genes and genetic loci have been associated with PD, identified genetic causes are responsible for only about ten percent of cases. Epidemiologic studies have found that the majority of sporadic PD were associated with environmental factors. The role of gut microbiota is undisputable among all environmental factors. Accumulating evidences demonstrated that in the course of Parkinson’s disease (PD), the enteric nervous system (ENS) and parasympathetic nerves are among the structures earliest and most frequently affected by alpha-synuclein pathology. Accordingly, gastrointestinal dysfunction, in particular constipation often precedes the onset of motor symptoms by years. Recent research has shown that gut microbiota is critical in maintaining gastrointestinal homeostasis, and may interact with the autonomic and central nervous system via diverse pathways including the ENS and vagal nerve. Thus, we hypothesized that the gut microbiota was related with the gastrointestinal dysfunction in PD patients, as well as the development of PD pathology. The aim of this study is to analyze the structural change of gut microbiota in PD patients in comparison to healthy controls, and to explore the correlations between gut microbiota and Parkinson’s disease.
The study recruited 24 PD patients and 14 healthy volunteers, and collected their fecal samples for research. The isolated fecal DNA was used as a template for the amplification of the V3-V5 region of 16S rRNA gene on Miseq platform, and the multivariate statistical methods were employed to evaluate the diversity and structural changes of gut microbiota. The study found significant differentiation between the PD group and healthy controls. The gut microbiota of PD group is generally dysbiosis in comparison with the healthy controls. The characteristic of this structural change is the increase of cellulose degraders and the decrease of conditional pathogens. The genera Blautia（2.14v.s.0.52, p<0.05), Faecalibacterium(5.18 v.s.2.48, p<0.05) and Ruminococcus (3.68 v.s. 1.10,p<0.05), which were mainly responsible for cellulose degrading in the colon, were significantly decreased in PD group comparing to healthy controls. These genera facilitated the fermentation of resistant starch and cellulose in the colon, and produced short-chain-fatty-acids (SCFAs) as their metabolite. The SCFAs were trophic factors for enteric epithelial cells and were critical for regulating enteric immune response. Another important characteristic is the increase of conditional pathogens. The genera Escherichia-Shigella（0.55 v.s 2.2，p<0.05), Streptococcus(0.09v.s0.33，p<0.05), Proteus（0.001 v.s 0.2，p<0.05）, and Enterococcus（0.008v.s0.25，p<0.01）were significantly increased in PD group comparing to healthy controls. The proliferation of these conditional pathogens may cause chronic inflammation and produce endotoxins and neurotoxins, and may induce PD pathology thereby.
The study further correlated the structural change of gut microbiota with common clinical phenotypes of PD, such as UPDRS, duration, NMSS, constipation, HAMA and HAMD. The correlation analysis found that the structural change of cellulose degraders(Blautia, Faecalibacterium and Ruminococcus） were negatively correlated with UPDRS score and PD duration, but not with the age, gender and BMI index, indicating the decrease of cellulose degraders in the gut microbiota may related with PD pathology. We also found the structural changes of conditional pathogens (Enterococcus, Escherichia-Shigella and Proteus) were positively correlated with UPDRS score and PD duration, indicating the proliferation of these conditional pathogens may related with PD pathology.
Earlier studies on the gut microbiota of PD have reported that Blautia and Faecalibacterium were both negatively correlated with PD duration, but our study is the first to report that Blautia and Faecalibacterium were both negatively correlated with UPDRS score. Research has found that Enterococcus and EscherichiaShigella were significantly increased in colorectal cancer patients. Another research found that proteus mirabills were significantly increased in autism children. But it's the first time that the significant increase of these conditional pathogens were reported in PD patients and correlated with PD phenotypes.
The result of this study suggested that the gut microbiota may influence PD pathology from two aspects: first, the decrease of cellulose degraders may affect the metabolic function in the gut, reduce the production of SCFAs, thus, influence the regulation of inflammatory response and oxidative stress; second, the increase of conditional pathogens may stimulate the inflammation and oxidative stress in the host, produce more endotoxins and neurotoxins, which may facilitate the occurrence of PD pathology. After all, the structural change of gut microbiota may become sensitive biomarkers to predict and evaluate the risk for PD, and may provide a new solution for the early diagnosis and treatment for PD.