Zooming into Gut Dysbiosis in Parkinson’s Disease: New Insights from Functional Mapping

Abstract

Gut dysbiosis has been involved in the pathogenesis and progression of Parkinson’s disease (PD), but the mechanisms through which gut microbiota (GM) exerts its influences deserve further study. Recently, we proposed a two-hit mouse model of PD in which ceftriaxone (CFX)-induced dysbiosis amplifies the neurodegenerative phenotype generated by striatal 6-hydroxydopamine (6-OHDA) injection in mice. Low GM diversity and the depletion of key gut colonizers and butyrate producers were the main signatures of GM alteration in this model. Here, we used the phylogenetic investigation of communities by reconstruction of unobserved states (PICRUSt2) to unravel candidate pathways of cell-to-cell communication associated with dual-hit mice and potentially involved in PD progression. We focused our analysis on short-chain fatty acids (SCFAs) metabolism and quorum sensing (QS) signaling. Based on linear discriminant analysis, combined with the effect size results, we found increased functions linked to pyruvate utilization and a depletion of acetate and butyrate production in 6-OHDA+CFX mice. The specific arrangement of QS signaling as a possible result of the disrupted GM structure was also observed. With this exploratory study, we suggested a scenario in which SCFAs metabolism and QS signaling might represent the effectors of gut dysbiosis potentially involved in the designation of the functional outcomes that contribute to the exacerbation of the neurodegenerative phenotype in the dual-hit animal model of PD.

Buty and the beast: the complex role of butyrate in Parkinson’s disease

“…However, this finding can be as a result of an as yet not understood therapeutic threshold for butyrate being exceeded which causes the normally beneficial SCFA to become, in fact, detrimental as demonstrated in vitro (Huang et al, 2014). One study that does replicate observations in humans is that of Turco et al (Turco et al, 2023). It was found that the combination of antibiotic induced dysbiosis in the 6-hydroxydopamine model of PD resulted in not only a more severe onset of PD like symptoms but also a reduction in butyrate in the stool of the animals (Turco et al, 2023).…”

“…One study that does replicate observations in humans is that of Turco et al (Turco et al, 2023). It was found that the combination of antibiotic induced dysbiosis in the 6-hydroxydopamine model of PD resulted in not only a more severe onset of PD like symptoms but also a reduction in butyrate in the stool of the animals (Turco et al, 2023). It is therefore unclear how these findings implicate butyrate in preclinical models of PD and more investigation is warranted.…”