Gene-environment-gut interactions in Huntington's disease mice are associated with environmental modulation of the gut microbiome

Abstract

Summary Gut dysbiosis in Huntington's disease (HD) has recently been reported using microbiome profiling in R6/1 HD mice and replicated in clinical HD. In HD mice, environmental enrichment (EE) and exercise (EX) were shown to have therapeutic impacts on the brain and associated symptoms. We hypothesize that these housing interventions modulate the gut microbiome, configuring one of the mechanisms that mediate their therapeutic effects observed in HD. We exposed R6/1 mice to a protocol of either EE or EX, relative to standard-housed control conditions, before the onset of gut dysbiosis and motor deficits. We characterized gut structure and function, as well as gut microbiome profiling using 16S rRNA sequencing. Multivariate analysis identified specific orders, namely Bacteroidales, Lachnospirales and Oscillospirales, as the main bacterial signatures that discriminate between housing conditions. Our findings suggest a promising role for the gut microbiome in mediating the effects of EE and EX exposures, and possibly other environmental interventions, in HD mice.

Faecal microbiota transplant ameliorates gut dysbiosis and cognitive deficits in Huntington’s disease mice

“…1C ), consistent with our recent findings. 12 However, an increase in gut permeability at the late disease stage (Week 20) was detected in both male and female Huntington’s disease mice compared with WT littermate controls ( P = 0.02 and P = 0.03, respectively) ( Fig. 4C ).…”

“… 5–8 R6/1 transgenic Huntington’s disease mice express the mutant human HTT transgene and provide an excellent preclinical model, exhibiting progressive cognitive, behavioural, cellular and molecular deficits closely modelling clinical Huntington’s disease, 9–11 including the onset of gut dysfunction at early stages of the disease with the potential to worsen with disease progression. 12 …”

Convergent pathways of the gut microbiota–brain axis and neurodegenerative disorders

“…In the context of HD, a preclinical model of HD exercise was able to delay the onset of the disease and cognitive impairment [ 202 ]. Recently, a study revealed the main bacterial signature (the orders of Bacteroidales, Lachnospirales, and Oscillospirales) that discriminates the effect of exercise and environmental enrichment in wild-type and HD mice, suggesting a promising role for the gut microbiome in mediating the positive effects of these interventions in HD [ 203 ].…”

Environmental enrichment and exercise housing protocols for mice

“…This protocol can help to improve reproducibility of results from studies involving environmental enrichment and exercise by offering consistent housing conditions between laboratories. For complete details on the use and execution of this protocol, please refer to Gubert et al. (2021) .…”

“…For complete details on the use and execution of this protocol, please refer to Gubert et al. (2021) .…”