Metabolic and Neural Mechanisms Underlying the Associations Between Gut and Cognition: A Large-Scale Functional Network Connectivity Study.

There is a proof-of-concept that microbial metabolites provide a molecular connection between the gut and the brain. Extensive research has established a link between gut and human cognition, yet the metabolic and neural mechanisms underlying this association remain largely unknown. Here, we collected fecal samples, resting-state functional MRI, and cognitive data from a large and homogeneous sample of 157 healthy young adults. 16S rRNA gene sequencing was conducted with abundances of and metabolic pathways quantified by species annotation and functional prediction analyses, respectively. Large-scale intra- and internetwork functional connectivity was measured using independent component analysis. Results showed that gut were related to multiple metabolic pathways, which in turn were associated with widespread functional network connectivity. Furthermore, functional network connectivity mediated the associations between some related metabolic pathways and cognition. Remarkably, arginine and proline metabolism, phenylalanine metabolism, and biosynthesis of unsaturated fatty acids act as the key metabolic pathways that are most contributive, and the executive control and sensorimotor systems contribute most strongly at the neural level. Our findings suggest complex poly-pathway and poly-network processes linking to cognition, more generally yielding a novel conceptualization of targeting gut as an intervention strategy for individuals with cognitive impairment.