Multimodal MRI-based Study Of The Associations Between Gut Microbiota And Cognition In Healthy Young Adults

The concept of microbiome-gut-brain axis(MGB)has been extensively studied and confirmed in the past few years.There is bidirectional communication between the gut microbiota and the brain,this interaction may be via afferent vagal fibers,the immune system,or directly through the circulation.The scientific study of MGB has provided a wealth of robust generalizations about the influence of the gut microbes on the brain and behavior,particularly with respect to cognitive function.However,little is known about the underlying neural mechanisms how gut microbiota affect the cognition by the gut-brain axis.Here,we collected fecal samples,brain structural,perfusion,functional and diffusion MRIs from a large and homogeneous sample of 157 healthy young adults.In addition,3-back,digit span,and Go/No-Go tasks were employed to assess cognition.16 S r RNA gene amplicon sequencing technology was used to measure gut microbial diversity and complexity,and the abundances of microbes and metabolic pathways quantified by species annotation and functional prediction analyses,respectively.Based on this combined body of data,we seek to discover the potential associations between gut microbiome and cognition.1.Sex-dependent gut microbiota-brain-cognition associations Empirical evidence has demonstrated sex differences in both the gut microbiome and the brain.However,the effects of sex on the gut microbiota-brain associations have yet to be determined.Here,all participants and their gray matter volume(GMV),cerebral blood flow(CBF),functional connectivity strength(FCS)and white matter integrity were measured by brain structural,perfusion,functional and diffusion MRIs,respectively.Then,we performed integrated analysis of gut microbiota,MRIs,and cognitive performance.Correlation analyses were conducted to test for sex-dependent associations between microbial diversity and brain imaging parameters,and mediation analysis was performed to further characterize the gut microbiota-brain-cognition relationship.We found that higher gut microbial diversity was associated with higher GMV in the right cerebellum ?,higher CBF in the bilateral calcarine sulcus yet lower CBF in the left superior frontal gyrus,higher FCS in the bilateral paracentral lobule,and lower diffusivity in widespread white matter regions in males.However,these associations were absent in females.Of more importance,these neuroimaging biomarkers significantly mediated the association between gut microbial diversity and behavioral inhibition in males.These findings highlight sex as a potential influential factor underlying the gut microbiota-brain-cognition relationship,and expose the gut microbiota as a biomarker-driven and sex-sensitive intervention target for mental disorders with abnormal behavioral inhibition.2.Brain network topology and structural-functional connectivity couplingmediate the association between gut microbiota and cognition Increasing evidences indicated gut microbiota can influence cognition via the gut-brain axis,and brain networks play a critical role during the process.However,little is known about how brain network topology and structural-functional connectivity(SC-FC)coupling contribute to the gut microbiota-cognition.Here,the topological properties of brain structural and functional networks were acquired by diffusion tensor imaging and resting-state f MRI data and further calculated the SC-FC coupling for all participants.Then,we tested for potential associations between gut microbiota,complex brain networks and cognition.Results showed that gut microbiota could affect the global and regional topological properties of structural networks,as well as node properties of functional networks.Of note,causal mediation analysis further validated that gut microbial diversity and enterotypes indirectly influence the cognitive performance by mediation of the small-worldness(Gamma and Sigma)of structure networks and some nodal metrics of functional networks(mainly distributed in cingulate gyri and temporal lobe).Moreover,gut microbes could affect the degree of SC-FC coupling in inferior occipital gyrus,fusiform gyrus,and superior frontal gyrus,medial,which in turn influence the cognition.Our findings revealed novel insights,which are essential to provide the foundation for previously unexplored network mechanism in understanding cognitive impairment,particularly with respect to how the brain connectivity participates in the complex cross-talk between gut microbiota and cognition.3.Metabolic and neural mechanisms underlying the associations between gutBacteroides and cognition 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 Bacteroides and human cognition,yet the metabolic and neural mechanisms underlying this association remain largely unknown.Here,the abundances of Bacteroides 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(ICA).A combination with the data of cognitive performance,we explored the relationships between gut Bacteroides,metabolic pathways,brain,and cognition further.Results showed that gut Bacteroides 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 Bacteroides-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.The executive control and sensorimotor systems contribute most strongly at the neural level.Our findings suggest complex poly-pathway and poly-network processes linking Bacteroides to cognition,more generally yielding a novel conceptualization of targeting gut Bacteroides as an intervention strategy for individuals with cognitive impairment.