Microbiome-metabolome signatures in mice genetically prone to develop dementia, fed a normal or fatty diet

Elena Sanguinetti,Mercedes M Pardo-Tendero,Patricia Iozzo,Marta Selma-Royo,Daniel Monleon,Silvia Burchielli,Maria Carmen Collado,Vannina G Marrachelli

doi:10.1038/s41598-018-23261-1

Abstract

Cognitive decline, obesity and gut dysfunction or microbial dysbiosis occur in association. Our aim was to identify gut microbiota-metabolomics signatures preceding dementia in genetically prone (3xtg) mice, with and without superimposed high-fat diet. We examined the composition and diversity of their gut microbiota, and serum and faecal metabolites. 3xtg mice showed brain hypometabolism typical of pre-demented stage, and lacked the physiological bacterial diversity between caecum and colon seen in controls. Cluster analyses revealed distinct profiles of microbiota, and serum and fecal metabolome across groups. Elevation in Firmicutes-to-Bacteroidetes abundance, and exclusive presence of Turicibacteraceae, Christensenellaceae, Anaeroplasmataceae and Ruminococcaceae, and lack of Bifidobacteriaceae, were also observed. Metabolome analysis revealed a deficiency in unsaturated fatty acids and choline, and an overabundance in ketone bodies, lactate, amino acids, TMA and TMAO in 3xtg mice, with additive effects of high-fat diet. These metabolic alterations were correlated with high prevalence of Enterococcaceae, Staphylococcus, Roseburia, Coprobacillus and Dorea, and low prevalence of S24.7, rc4.4 and Bifidobacterium, which in turn related to cognitive impairment and cerebral hypometabolism. Our results indicate an effect of transgenic background on gut microbiome-metabolome, enhanced by high-fat diet. The resulting profiles may precede overt cognitive impairment, suggesting their predictive or risk-stratifying potential.

Highlights

Abnormalities in the intestinal microbiota have been described in association with numerous diseases, most frequently obesity and bowel inflammation[1,2]
We aimed to target the pre-demented stage, the Y-maze test showed a non-significant ∼20–40% cognitive decline in 3xtg models
The emerging biology of gut-brain crosstalk has revealed the existence of a complex bidirectional system[25], in which neurodegenerative processes affecting the brain occur in the gut[5,6], and vice versa, factors primarily influencing the gut microbiota, e.g. high-fat diets, increase the risk of neurodegeneration

Summary

Introduction

Abnormalities in the intestinal microbiota have been described in association with numerous diseases, most frequently obesity and bowel inflammation[1,2]. The microbiota regulates the transport of nutrients across the gut barrier, and produces absorbable or non-absorbable metabolites, affecting circulating and faecal metabolic profiles[11,12]. These can modulate systemic inflammation, i.e. a hallmark of obesity and neurodegenerative diseases, or cross the blood-brain barrier to act directly on the brain[12,13,14]. We studied 3xtg transgenic mice at an early cerebral disease stage and control mice, both undergoing normal or high-fat feeding We examined their caecum and colon microbiota composition and diversity (within and between intestinal segments), and metabolites in faeces (caecum and colon) and serum. In vivo cerebral metabolism and cognitive function were assessed to confirm the subclinical disease stage

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Conclusion