Parkinson’s disease-associated alterations of the gut microbiome can invoke disease-relevant metabolic changes

Abstract

25 26 Parkinson's disease (PD) is a systemic disease clinically defined by the degeneration of 27 dopaminergic neurons in the brain. While alterations in the gut microbiome composition have 28 been reported in PD, their functional consequences remain unclear. Herein, we first analysed 29 the gut microbiome of patients and healthy controls by 16S rRNA gene sequencing of stool 30 samples from the Luxembourg Parkinson's study (n=147 typical PD cases, n=162 controls). 31All individuals underwent detailed clinical assessment, including neurological examinations 32 and neuropsychological tests followed by self-reporting questionnaires. Second, we predicted 33 the potential secretion for 129 microbial metabolites through personalised metabolic modelling 34 using the microbiome data and genome-scale metabolic reconstructions of human gut 35 microbes. Our key results include: 1. eight genera and nine species changed significantly in 36 their relative abundances between PD patients and healthy controls. 2. PD-associated microbial 37 patterns statistically depended on sex, age, BMI, and constipation. The relative abundances of 38Bilophila and Paraprevotella were significantly associated with the Hoehn and Yahr staging 39 after controlling for the disease duration. In contrast, dopaminergic medication had no 40 detectable effect on the PD microbiome composition. 3. Personalised metabolic modelling of 41 the gut microbiomes revealed PD-associated metabolic patterns in secretion potential of nine 42 microbial metabolites in PD, including increased methionine and cysteinylglycine. The 43 microbial pantothenic acid production potential was linked to the presence of specific non-44 motor symptoms and attributed to individual bacteria, such as Akkermansia muciniphila and 45 Bilophila wardswarthia. Our results suggest that PD-associated alterations of gut microbiome 46 could translate into functional differences affecting host metabolism and disease phenotype. 47

Meta-analysis of the gut microbiome of Parkinson’s disease patients suggests alterations linked to intestinal inflammation

“…Among the most abundant taxa in PD there were bacteria belonging to the Christensenellaceae family (Fig 5, Supplementary Figure 10, 11), in line with previous reports 11,12,21,41 . This family is widespread in the gut of the human population and it is generally associated with healthy phenotypes, even though their abundances positively correlate to the intestinal transit time 59 .…”

“…The fact that the more abundant genera in PD belong to different families and even orders, support the idea of increased diversity in the gut-microbiota of PD patients (Fig 1, Supplementary Figure 1). The genus Lactobacillus , and the Lactobacillaceae family, were the most strongly enriched taxa in PD across the studies we re-analyzed, in line with previous findings 11,12,17,19,41 . Lactobacillus strains are low abundant members of the gut microbiota and their abundance varies greatly across human disease and chronic conditions 42 .…”

Understanding the host-microbe interactions using metabolic modeling

“…The study reported 9 metabolites to have the potential to be significantly altered in PD patients compared to healthy controls including methionine and cysteinylglycine, which are part of sulfur metabolism. Furthermore the authors showed that a higher presence of Akkermansia muciniphila, and Bilophila wadsworthia in PD patients, and identified a new research target in PD research with the use of metabolic networks [87]. Hertel et al confirmed these results by using the same approach as Baldini et al [87] to construct and simulate personalized community networks of 31 early stage, drug naïve PD patients and 28 age matched controls from data obtained from Bedarf et al [88].…”

“…The study reported 9 metabolites to have the potential to be significantly altered in PD patients compared to healthy controls including methionine and cysteinylglycine, which are part of sulfur metabolism. Furthermore the authors showed that a higher presence of Akkermansia muciniphila, and Bilophila wadsworthia in PD patients, and identified a new research target in PD research with the use of metabolic networks [ 87 ]. Hertel et al .…”

Concentrated Raw Fibers Enhance the Fiber-Degrading Capacity of a Synthetic Human Gut Microbiome

“…This finding further highlights the inverse correlation between relative AM abundance in the colon and dietary fiber intake. Of note, increased abundances of AM were found to be associated with various pathologies in human studies [12][13][14][15][16][17], supporting the idea that, besides promoting microbiota-mediated SCFA production, fiber supplementation considerably contributes to maintenance of mucosal barrier integrity by preventing from excess mucus degradation.…”