Multiomics analysis of the metabolome and microbiota in a rat model of cerebral amyloidosis

CAMPANELLI, LORENZO; GALEANO, PABLO; GONZÁLEZ-JIMÉNEZ, ANDRÉS ; RODRÍGUEZ DE FONSECA, FERNANDO; CUELLO, AUGUSTO CLAUDIO; CASTAÑO, EDUARDO MIGUEL; MORELLI, LAURA

Oporto

Congreso; International Society of Neurochemistry (ISN-ESN) meeting; 2023

International Society of Neurochemistry (ISN)

Emerging literature indicates that gut microbiota could impact on the development of different pathologies including Alzheimers disease (AD), the leading cause of dementia in older adults. The intestinal microbiota is a complex ecosystem composed mainly from bacteria of the phyla Bacteroidetes and Firmicutes of which some are considered pathogenic while most of them are involved in homeostatic processes promoting beneficial health effects. Evidence using animal models indicates that the gut microbiota can communicate with the central nervous system (CNS), influencing brain function and behavior. However, the mechanisms by which microbiota may impact and generate an effect on AD have not been elucidated. Here we studied microbiota and metabolome of McGill R Thy1 APP rats, a transgenic (Tg) model of early stages of AD like amyloid pathology. Brains, stool and plasma samples were collected from 9 month old male control (Wistar) (n, 20) and Tg rats (n, 23). Fecal samples were split in two and one part (n, 43) was sent to StarSEQ GmbH (Germany) for 16S microbial rDNA genotyping using the 16S platform (Illumina) and the other one (n, 30) with plasma samples to Metabolon (USA) for untargeted UPLC/MS–MS metabolomics to characterize the fecal and plasma metabolome. We obtained information on 189 OTUs, 702 metabolites in feces and 686 in plasma. Together, these data were curated and analyzed using the R packages mixOmics, Metaboanalyst and Fella to define the type of microbe and the secreted compound that best discriminates Tg rats. On an exploratory basis, presence of Turicibacter and Lactobacillus (phylum Firmicutes) and lack of Gastranaerophilales (phylum Melainabacteria), Paraprevotella and Alloprevotella (phylum Bacteroidetes) in Tg rats were observed. We explored the correlations (r higher than 0.80) of this OTUs and rats metabolome and identified more than 10 metabolites which in turn are associated with the pathways of fatty acid metabolism and ketone bodies. This work represents a first step towards understanding the association of peripheral inputs, gut microbiota and the intestinal metabolome, on neurodegeneration, a topic of which very little is known to date.