Obesity-associated deficits in inhibitory control are phenocopied to mice through gut microbiota changes in one-carbon and aromatic amino acids metabolic pathways
María Arnoriaga‐Rodríguez, Jordi Mayneris‐Perxachs, Oren Contreras‐Rodríguez, Aurelijus Burokas, Juan-Antonio Ortega-Sanchez, Gerard Blasco, Clàudia Coll, Carles Biarnés, Anna Castells‐Nobau, Josep Puig, Josep Garre‐Olmo, Rafel Ramos, Salvador Pedraza, Ramón Brugada, Joan C. Vilanova, Joaquı́n Serena, Jordi Barretina, Jordi Gich, Vicente Pérez‐Brocal, Andrés Moyá, Xavier Fernández‐Real, Lluís Ramió‐Torrentà, Reinald Pamplona, Joaquím Sol, Mariona Jové, Wifredo Ricart, Manuel Portero‐Otín, Rafaël Maldonado, José Manuel Fernández‐Real
Abstract
Background Inhibitory control (IC) is critical to keep long-term goals in everyday life. Bidirectional relationships between IC deficits and obesity are behind unhealthy eating and physical exercise habits. Methods We studied gut microbiome composition and functionality, and plasma and faecal metabolomics in association with cognitive tests evaluating inhibitory control (Stroop test) and brain structure in a discovery (n=156), both cross-sectionally and longitudinally, and in an independent replication cohort (n=970). Faecal microbiota transplantation (FMT) in mice evaluated the impact on reversal learning and medial prefrontal cortex (mPFC) transcriptomics. Results An interplay among IC, brain structure (in humans) and mPFC transcriptomics (in mice), plasma/faecal metabolomics and the gut metagenome was found. Obesity-dependent alterations in one-carbon metabolism, tryptophan and histidine pathways were associated with IC in the two independent cohorts. Bacterial functions linked to one-carbon metabolism ( thyX,dut, exodeoxyribonuclease V), and the anterior cingulate cortex volume were associated with IC, cross-sectionally and longitudinally. FMT from individuals with obesity led to alterations in mice reversal learning. In an independent FMT experiment, human donor’s bacterial functions related to IC deficits were associated with mPFC expression of one-carbon metabolism-related genes of recipient’s mice. Conclusion These results highlight the importance of targeting obesity-related impulsive behaviour through the induction of gut microbiota shifts.