Changes in Gastrointestinal Microbiome Composition in PD: A Pivotal Role of Covariates

Abstract

Altered gut microbiota may trigger or accelerate alpha-synuclein aggregation in the enteric nervous system in Parkinson's disease (PD). While several previous studies observed gut microbiota alterations in PD, findings like diversity indices, and altered bacterial taxa itself show a considerable heterogeneity across studies. We recruited 179 participants, of whom 101 fulfilled stringent inclusion criteria. Subsequently, the composition of the gut microbiota in 71 PD patients and 30 healthy controls was analyzed, sequencing V3-V4 regions of the bacterial 16S ribosomal RNA gene in fecal samples. Our goal was (1) to evaluate whether gut microbiota are altered in a southern German PD cohort, (2) to delineate the influence of disease duration, stage, and motor impairment, and (3) to investigate the influence of PD associated covariates like constipation and coffee consumption. Aiming to control for a large variety of covariates, strict inclusion criteria were applied. Finally, propensity score matching was performed to correct for, and to delineate the effect of remaining covariates (non-motor symptom (NMS) burden, constipation, and coffee consumption) on microbiota composition. Prior to matching altered abundances of distinct bacterial classes, orders, families, and genera were observed. Both, disease duration, and stage influenced microbiome composition. Interestingly, levodopa equivalent dose influenced the correlation of taxa with disease duration, while motor impairment did not. Applying different statistical tests, and after propensity score matching to control for NMS burden, constipation and coffee consumption, Faecalibacterium and Ruminococcus were most consistently reduced in PD compared to controls. Taken together, similar to previous studies, alterations of several taxa were observed in PD. Yet, further controlling for PD associated covariates such as constipation and coffee consumption revealed a pivotal role of these covariates. Our data highlight the impact of these PD associated covariates on microbiota composition in PD. This suggests that altered microbiota may mediate the protective effect of i.e., coffee consumption and the negative effect of constipation in PD.

Association of Parkinson’s Disease With Microbes and Microbiological Therapy

“…Beta diversity emphasizes the similarity of intestinal microflora structure of different persons ( Table 2). According to the current research data, the beta diversity of PD patients is significantly different from that of healthy people, and in longitudinal follow-up, the difference of beta diversity of intestinal microflora of PD patients becomes more obvious (Barichella et al, 2019;Cosma-Grigorov et al, 2020). The diversity of intestinal microorganisms in human body reflects the regulation of metabolism and immune system.…”

“…In a study investigating the functional implications of microbial and viral gut metagenome changes in PD patients in the early stage without the use of L-dopa (Bedarf et al, 2017), it was found that various combinations of anti-PD drugs (mainly dopamine agonists, monoamine oxidase inhibitors, and amantadine) had no significant effect on the intestinal bacteria in PD patients. Heintz bushart et al analyzed PD patients taking levodopa and found that levodopa was an important covariate affecting the abundance of intestinal flora and duration of disease, but without affecting intestinal Enterobacteriaceae (Cosma-Grigorov et al, 2020). In order to evaluate the effect of antiparkinsonian drugs on microbial composition, Zhang et al analyzed the relationship between four antiparkinsonian drugs (levodopa, dopamine agonist, anticholinergic drug, and amantadine) and the intestinal microflora of PD patients.…”

“…At present, there are 17 studies on the comparison between PD patients and healthy people ( Keshavarzian et al., 2015 ; Scheperjans et al., 2015 ; Bedarf et al., 2017 ; Hill-Burns et al., 2017 ; Hopfner et al., 2017 ; Li et al., 2017 ; Petrov et al., 2017 ; Heintz-Buschart et al., 2018 ; Lin et al., 2018 ; Qian et al., 2018 ; Aho et al., 2019 ; Barichella et al., 2019 ; Pietrucci et al., 2019 ; Cirstea et al., 2020 ; Cosma-Grigorov et al., 2020 ; Qian et al., 2020 ; Zhang et al., 2020 ), including five studies from China ( Li et al., 2017 ; Lin et al., 2018 ; Qian et al., 2018 ; Qian et al., 2020 ; Zhang et al., 2020 ), three from Germany ( Bedarf et al., 2017 ; Hopfner et al., 2017 ; Cosma-Grigorov et al., 2020 ), two from Italy ( Barichella et al., 2019 ; Pietrucci et al., 2019 ), two from Finland ( Scheperjans et al., 2015 ; Aho et al., 2019 ), two from the United States ( Keshavarzian et al., 2015 ; Hill-Burns et al., 2017 ), one from Luxembourg ( Heintz-Buschart et al., 2018 ), one from Russia ( Petrov et al., 2017 ), and one from Canada ( Cirstea et al., 2020 ). A total of 13 studies reported the diversity of intestinal microflora, and the diversity index (α and β diversity) was primarily used to describe the overall characteristics of microbial community composition ( Table 2 ) ( Cosma-Grigorov et al., 2020 ). Among the 13 studies, α diversity was used as an index to measure the number of bacterial groups in a single fecal sample.…”

“…Fifteen families and 11 genera of microbes had been reported ( Keshavarzian et al., 2015 ; Scheperjans et al., 2015 ; Bedarf et al., 2017 ; Hill-Burns et al., 2017 ; Hopfner et al., 2017 ; Li et al., 2017 ; Petrov et al., 2017 ; Heintz-Buschart et al., 2018 ; Lin et al., 2018 ; Qian et al., 2018 ; Aho et al., 2019 ; Barichella et al., 2019 ; Pietrucci et al., 2019 ; Cirstea et al., 2020 ; Cosma-Grigorov et al., 2020 ; Qian et al., 2020 ; Zhang et al., 2020 ), of which 11 families and seven genera had been reported to increase in PD patients, while four families and four genera had been reported to decrease (see Tables 1 and 2 for details). It is worth noting that the abundance of Lactobacillusaceae and Verrucomicrobiaceae have been reported to increase in PD patients for many times (six times and eight times, respectively), whereas at the generic level, the main increase is akkermansia (six times reported).…”

Microbiome Markers of Pancreatic Cancer Based on Bacteria-Derived Extracellular Vesicles Acquired from Blood Samples: A Retrospective Propensity Score Matching Analysis

“…PSM reduced the influence of lifestyle variables which might attenuate the relevance between fecal bacteria and the risk of gastric cancer [ 48 ]. PSM was also used to control the effect of clinical variables on microbiota composition to find the relationship between fecal microbiota and Parkinson’s disease [ 49 ].…”