Gut dysbiosis evident in patients with prodromal PD and their first-degree relatives

A cross-sectional study from the Chinese University of Hong Kong suggests that Parkinson’s disease (PD)–like gut dysbiosis occurs at preclinical prodromal stages of PD, in patients with video-polysomnography (v-PSG)–confirmed REM sleep behavior disorder (RBD) and even in their younger first-degree relatives (RBD-FDR).

“Increasing evidence suggests that alpha-synuclein [α-syn] pathology characteristic of PD occurs in the enteric nervous system before it is evident in the CNS. It is hypothesized that PD-associated gut dysbiosis, especially the depletion of short-chain fatty acids [SCFA]–producing bacteria and enrichment of putative pathobionts, is related to intestinal hyperpermeability, immune activation, and pathological α-syn aggregation,” wrote the researchers. “We performed a large cross-sectional study across prodromal and early stages of PD to elucidate the association between gut microbiota and progression of α-synucleinopathy.” [Parkinsonism Relat Disord 2022;94:1-9; J Neuroinflammation 2019;16:129]

The study analyzed 441 stool samples from v-PSG–diagnosed RBD and PD patients and their FDRs. Of 127 RBD-FDR, 11 (8.7 percent) were diagnosed with probable RBD based on a structured clinical interview. [Nat Commun 2023;14:2501]

The prevalence of functional constipation showed an increasing trend from age- and sex-matched controls (n=108), to RBD-FDR, RBD (n=17), and early PD patients (n=36) (8.3 percent vs 9.4 percent vs 45.3 percent vs 69.4 percent; p<0.001). “Straining with defecation, a core feature of functional constipation, progressively increased across four groups even after adjusting for age and sex [8.8 percent vs 15.8 percent vs 45.4 percent vs 68.6 percent; p<0.001]. In addition, bowel movement frequency and stool consistency scores [where higher scores indicate more infrequent and harder stools, respectively] demonstrated increasing trends across the four groups [p<0.001],” reported the researchers.

The early PD group presented a distinct clustering pattern of microbiota vs the control group. At the same time, the microbiota composition in the RBD group was similar to that of early PD, but differed significantly from the control and RBD-FDR groups. The microbial compositional analysis revealed no significant differences between control and RBD-FDR groups.

The depletion of SCFA-producing Butyricicoccus and Faecalibacterium genera showed the strongest correlation with disease progression. Of note, the enrichment of pro-inflammatory mucin-degrading Collinsella genus was already evident at an earlier prodromal stage of α-synucleinopathy in RBD-FDR and is also widely reported in low-fiber diets and metabolic diseases. [Gut Microbes 2018;9:189-201] Study authors proposed that switching to a high-fiber diet may reverse the disruption effect of Collinsella and other mucin degraders, such as Akkermansia, and has the potential of modulating gut dysbiosis at prodromal and early α-synucleinopathy stages of PD. [Cell 2016;167:1339-1353]

“We found that in RBD patients, the overall microbiota composition shifted closely to early PD, with depletion of butyrate-producing bacteria and overabundance of mucin-degrading Collinsella and Oscillospiraceae_UCG-002 and -005 and hydrogen sulfide-producing Desulfovibrio. In RBD-FDR, who represent an even earlier prodromal stage of PD and a younger population, there were emerging RBD-/PD-like microbial changes, such as the increase in Collinsella and depletion of butyrate-producing [Eubacterium]_ventriosum_group. The predicted functional profile showed an overall increase in fatty acids fermentation to lactate and ethanol, and lower levels of deazapurine biosynthesis in RBD-FDR, RBD and early PD,” revealed the researchers.

“Mediation analysis suggested the potential causal pathway linking gut dysbiosis to constipation at prodromal α-synucleinopathy. Hence, interventions to ease constipation and cultivate specific microbes at prodromal stages of disease may be a promising strategy for future prevention and disease-modifying therapy of α-synucleinopathy,” they suggested.