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

ABSTRACT: 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.

SUBMITTER: Gubert C

PROVIDER: S-EPMC8760441 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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

Gubert Carolina C Love Chloe Jane CJ Kodikara Saritha S Mei Liew Jamie Jie JJ Renoir Thibault T Lê Cao Kim-Anh KA Hannan Anthony John AJ

iScience 20211224 1

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 ...[more]

PMID: 35059604

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Project description:Mutation of the adenomatous polyposis coli (APC gene), an early event in the adenoma-carcinoma sequence, is present in 70-80% of sporadic human colorectal adenomas and carcinomas. To test the hypothesis that mutation of the APC gene alters microbial interactions with host intestinal mucosa prior to the development of polyposis, culture-independent methods (targeted qPCR assays and Illumina sequencing of the 16S rRNA gene V1V2 hypervariable region) were used to compare the intestinal microbial composition of 30 six-week old C57BL/6 APCMin/+ and 30 congenic wild type (WT) mice. The results demonstrate that similar to 12-14 week old APCMin/+ mice with intestinal neoplasia, 6 week old APCMin/+ mice with no detectable neoplasia, exhibit an increased relative abundance of Bacteroidetes spp in the colon. Parallel mouse RNA sequence analysis, conducted on a subset of proximal colonic RNA samples (6 APCMin/+, 6 WT) revealed 130 differentially expressed genes (DEGs, fold change ? 2, FDR <0.05). Hierarchical clustering of the DEGs was carried out by using 1-r dissimilarity measurement, where r stands for the Pearson correlation, and Ward minimum variance linkage, in order to reduce the number of input variables. When the cluster centroids (medians) were included along with APC genotype as input variables, analysis of variance and covariance (ANCOVA) with stepwise variable selection, selected two of seven mouse gene clusters, in addition to APC genotype, as significantly associated (p = 0.011 and p = 0.004) with the increased relative abundance of Bacteroidetes spp. One of the two clusters includes several downregulated genes encoding immunoglobulin variable regions and non-protein coding RNAs. These results support the concept that mutation of the APC gene alters colonic-microbial interactions prior to polyposis. It remains to be determined whether interventions directed at ameliorating dysbiosis in APCMin/+mice, such as through probiotics, prebiotics or antibiotics, could reduce tumor formation. Comparing the differential gene expressions in proximal colonic mucosal samples from 6 six-week-old female Apc Min/+ and 6 six-week-old female WT mice

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

Publications

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

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