Multi-omics analysis reveals gut-brain interactions mediating the anti-obesity effect of Akkermansia muciniphila

Previous studies have implicated a causal role for the gut bacterium Akkermansia muciniphila in counteracting diet-induced obesity and metabolic dysfunctions. However, a systems level understanding of the molecular mechanisms underlying the anti-obesogenic effect of A. muciniphila is lacking. Using fructose-induced obese mice as a model, we carried out multiomics studies to investigate the molecular cascades mediating the effect of A. muciniphila. We found that A. muciniphila colonization in fructose-induced obese mice triggered significant shifts in gut microbiota composition as well as alterations in numerous gut and plasma metabolites and gene expression in the hypothalamus. Among these, we found that the metabolite oleoyl-ethanolamide in the gut and circulation and hypothalamic oxytocin are the key regulators of gut-brain interactions that underlie the A. muciniphila anti-obesity effect. Our multiomics investigation elucidates the molecular regulators and pathways involved in the communication between A. muciniphila in the gut and hypothalamic neurons that counter fructose-induced obesity . Overall design: Freshly dissected hypothalami were dissociated with papain (Worthington, Lakewood, NJ, USA) for single cell isolation (Brewer and Torricelli, 2007). Single cells were barcoded using single-cell transcriptomes attached to microparticles (STAMPs) followed by generating cDNA library with the Drop-seq protocol by Macosko et al 2015 (Macosko et al., 2015). Cells were suspended in 0.01% BSA-PBS at a final concentration of 100 cells/µl for as previously described (Arneson et al., 2018). Paired-end sequencing data was generated using Illumina NovaSeq 6000 at a sequencing depth of ~40,000 read pairs per cell, with custom length of 26 for read 1 and 76 for read 2 and 8 bp index read for multiplexing.