Tributyrin oral administration significantly attenuates the loss of intestinal butyrate‐producing bacteria and the ensuing cognitive dysfunction associated with Alzheimer’s Disease pathogenesis in 3xTg‐AD mice

Abstract

AbstractBackgroundAlzheimer’s Disease (AD) development is linked to the loss of overall gut microbial diversity. However, the specific alterations are only beginning to be examined. In this regard, decreases in intestinal butyrate‐producing bacteria have been indicated by pre‐clinical and clinical studies in AD. The current work, employing the 3xTg‐AD mouse model examined the causal association of loss of butyrate‐producing bacterial communities with cognitive dysfunction associated with AD pathogenesis.MethodCecal samples from tributyrin (TB) treated and untreated female 3xTg‐AD mice were used to perform metataxonomic analysis by sequencing the 16S rRNA gene (V4 region) on a large‐scale Illumina MiSeq platform. Inferred metagenomics analysis was performed using the PICRUSt2 pipeline. TB treatment (oral gavage, 2mg/kg, twice a week) was initiated at 6‐months of age until 17‐months. Spatial and short‐term memory functions were tested using the Y‐maze and Novel Object Recognition Test (NORT).ResultMetataxonomic analysis showed an age‐dependent, significant decline in alpha diversity represented by measures of OTUs, Chao‐1 and Shannon Index from 2‐ to 18‐months. Additionally, age‐dependent changes in gut microbial composition were demonstrated by a significant decrease in the Firmicutes‐to‐Bacteroidota (F/B) ratio. Further analysis of specific features of the gut microbiome demonstrated an age‐dependent decrease in total butyrate‐producing families within the Firmicutes phylum; particularly, a significant loss of critical butyrate producing family Ruminococcacea was identified. Predictive functional analysis using PICRUSt2 also showed a significant reduction in the abundance of specific bacterial genes involved in butyrate synthesis. Importantly, these age‐dependent markers of gut microbial dysbiosis coincided with diminished measures of spatial and short‐term memory. Notably, administration of TB, a butyrate pro‐drug, significantly attenuated the age‐dependent (i) decline in gut microbial diversity & butyrate‐producing bacteria and (ii) loss of spatial and short‐term memory.ConclusionThe findings from this study identify that decline in total butyrate‐producing families is a key pathogenic feature of AD‐associated microbial dysbiosis and cognitive dysfunction. Importantly, these findings have the potential to inform the development of treatment strategies targeting gut microbial dysbiosis using TB, to prevent onset and development of cognitive decline in AD.