Integrated Analyses of Microbiome and Longitudinal Metabolome Data Reveal Microbial-Host Interactions on Sulfur Metabolism in Parkinson’s Disease

Abstract

SummaryParkinson’s disease (PD) exhibits systemic effects on the human metabolism, with emerging roles for the gut microbiome. Here, we integrate longitudinal metabolome data from 30 drug-naive, de novo PD patients and 30 matched controls with constraint-based modeling of gut microbial communities derived from an independent, drug-naive PD cohort, and prospective data from the general population. Our key results are (1) longitudinal trajectory of metabolites associated with the interconversion of methionine and cysteine via cystathionine differed between PD patients and controls; (2) dopaminergic medication showed strong lipidomic signatures; (3) taurine-conjugated bile acids correlated with the severity of motor symptoms, while low levels of sulfated taurolithocholate were associated with PD incidence in the general population; and (4) computational modeling predicted changes in sulfur metabolism, driven by A. muciniphila and B. wadsworthia, which is consistent with the changed metabolome. The multi-omics integration reveals PD-specific patterns in microbial-host sulfur co-metabolism that may contribute to PD severity.

Understanding the host-microbe interactions using metabolic modeling

“…Simulation with FBA concluded that four microbial reactions involved in homoserine metabolism are altered in PD patients, which is consistent with measured levels in plasma of PD patients and homoserine, the precursor of methionine, is part of sulfur metabolism. Furthermore, the authors showed an increase in two bacterial species both involved in sulfur metabolism, B. wadsworthia and A. muciniphila [ 89 ]. Both species have been reported in PD progression [ 90 ].…”

Integration of constraint-based modelling with faecal metabolomics reveals large deleterious effects ofFusobacteriaspecies on community butyrate production

“…Previously, we have demonstrated the use of personalised metabolic modelling for the stratification of paediatric inflammatory bowel disease patients and controls in a purely in silico approach (Heinken et al, 2019) and validated changes in the metabolome of Parkinson's Disease patients with personalised models built from an unrelated cohort (Hertel et al, 2019). Here, by integrating the AGORA based COBRA community modelling predictions with faecal metabolomics, we could validate our predictions regarding butyrate, glutarate, Fusobacteria and other butyrate producing species.…”

Diet, Microbiota and Brain Health: Unraveling the Network Intersecting Metabolism and Neurodegeneration

“…Higher levels of Akkermansia municiphila stimulate mucin degradation, increasing host susceptibility to IEB disruption. Furthermore, A. municiphila and Bilophila wadsworthia affect sulfur metabolism in PD leading to higher secretion of sulfite, a known neurotoxin causing mitochondrial dysfunction [ 251 ]. In addition, levels of taurine-conjugated bile acids, exploited in the gut lumen as a source of sulfite production, positively associated with scores of clinical severity.…”

“…Meng et al used systemic nutrigenomics to elucidate how ω-3 PUFAs counteract the harmful effects of fructose in brain rats [ 379 ], providing rational support for targeted dietary interventions in humans. Recent studies applying these approaches successfully identified key factors involved in PD pathogenesis [ 251 ]. This hold promises for future applications also in AD and ALS.…”