| Background The term microbiota–gut–brain axis refers to the bidirectional conduit that communicates the brain and the gut microbiota.There are multiple pathways of potential communication between the gut microbiome and the brain.Gut–brain interactions have received increasing attention in recent years,such that numerous findings suggest a fundamental influence of the gut microbiota on brain development and function.Alterations in gut microbiota have been associated with a wide range of brain disorders.It is generally assumed that the gut microbiota can affect and be reciprocally affected by many behavioral factors.Mounting preclinical evidence has implicated that there are many pathways of potential communication between the gut microbiota and the brain.However,the exact mechanism of such interaction in humans is still largely unclear.A full explanation of this important issue may provide scientific basis for the potential usefulness of the microbiota–gut–brain axis as biological markers for accurate diagnosis and effective treatment of brain disorders.Recent advances in non-invasive brain imaging techniques(multimodal MRI in particular)and microbiome sequencing have made it increasingly feasible to examine the associations between the gut microbiota and the brain in clinical and healthy populations.However,no studies have systematically explored the gut microbiota-brain imaging-behavior relationships and the mechanism in healthy young adults.Objectives By a combined analysis of multimodal MRI,16 S sequencing,and untargeted metabolomics,this study explored the gut microbiota-fecal/blood metabolites-brain imaging measures-behavior relationship,aiming at further elucidating the mechanism of the interaction in “microbiota-gut-brain axis”.1.To comprehensively investigate gut microbiota-brain-cognition association using multimodal MRI and 16 S sequencing.2.To clarify the relationship among the gut microbiota,large scale functional network connectivity and behavior on the basis of resting-state functional MRI and 16 S sequencing.3.To systematically investigate the relationship among gut microbiota,fecal and blood metabolites and brain imaging parameters on the basis of the previous two studies.Methods One hundred and fifty seven healthy young adults were involved in this study.We collected multimodal MRI data,fecal samples and blood samples.16 S sequencing was used to assess gut microbiota and untargeted metabolomics were used to assess the fecal and blood metabolites.1.Five brain imaging measures,including regional homogeneity(ReHo)and functional connectivity density(FCD)from resting-state functional MRI,cerebral blood flow(CBF)from arterial spin labeling,gray matter volume(GMV)from structural MRI,and fractional anisotropy(FA)from diffusion tensor imaging,were jointly analyzed with a data-driven multivariate fusion method.We comprehensively investigated the gut microbiota-brain relationships by performance of microbial diversity-brain correlation and between-enterotype comparison.Then,we explored the associations of gut microbiota related neuroimaging fusion measures with working memory and attention.Finally,we aimed to determine whether these identified neuroimaging biomarkers could mediate the relations between gut microbiota and cognition.2.Large-scale inter-and intranetwork functional connectivity was measured using a combination of resting-state functional MRI data and independent component analysis.We assessed the relationship between the gut microbiota and the brain by testing the associations of inter-and intranetwork functional connectivity with gut microbial diversity and enterotypes.Then,we investigated the potential associations of gut microbiota-linked functional connectivity with sleep quality and executive functions.Finally,we sought to establish the meditative role of these identified functional connectivity markers in accounting for the relations between gut microbiota and behaviors.3.Functional connectivity were calculated at voxel level,region level and network level.The relationship between functional connectivity and blood metabolites were explored by testing the correlation of functional connectivity of each level and blood metabolite content.Then,we investigate the association of functional connectivity-linked blood metabolites with fecal metabolite content.Then,the association of blood metabolite-linked fecal metabolites with the relative abundance of microbiota genera was assessed.Finally,we aimed at establishing the relationship of gut microbiota-fecal metabolites-blood metabolites-functional connectivity.Results1.Significant associations were found between gut microbial diversity and the value of ReHo,FCD,CBF,and GMV within the frontoparietal,default mode and visual networks,as well as with FA in a distributed set of juxtacortical white matter regions.In addition,there were FCD,CBF,GMV,and FA differences between Prevotella-versus Bacteroides-enterotypes in females and between Prevotella-versus Ruminococcaceae-enterotypes in males.Moreover,the identified neuroimaging fusion biomarkers could mediate the associations of microbial diversity with working memory and attention.2.Significant associations were found between gut microbial diversity and internetwork functional connectivity among the executive control,default mode and sensorimotor systems,and intranetwork connectivity within the executive control system.Moreover,some internetwork functional connectivity mediated the relations of microbial diversity with sleep quality,working memory,and attention.In addition,there was a significant effect of enterotypes on intranetwork connectivity of the executive control system,which could mediate the link between enterotypes and executive function.3.Gut microbiota-fecal metabolites-blood metabolites-functional connectivity relationship pathways were found at voxel-level,region-level and network-level functional connectivity,respectively.The related network of functional connectivity includes some high-level cognitive networks such as default mode,frontoparietal and limbic network and some primary networks such as sensorimotor,auditory and visual network.The related metabolites include glutamate,cholic acid,kynurenic acid and short chain fatty acid and so on.There were many related microbiota genera,especially Bacteroides,Prevotella and Bifidobacterium.Conclusions1.Our data revealed significant effects of the gut microbial diversity and community structure on regional neural activity,functional connectivity,blood perfusion,gray matter morphology,and white matter integrity in multiple brain systems.Moreover,the identified neuroimaging fusion biomarkers could mediate the associations between gut microbiota and cognition.Our findings not only expand existing knowledge of the microbiota-gut-brain axis,but also have potential clinical and translational implications by exposing the gut microbiota as a promising treatment and prevention target for cognitive impairment and related brain disorders.2.The results of this study provide first empirical evidence that the gut microbiota can modulate large-scale inter-and intranetwork functional connectivity(especially the executive control system)in young adulthood.Moreover,some functional network connectivity may act as mediators of the effects of gut microbiota on sleep and executive functions.Our findings not only may expand existing biological knowledge of the gut microbiota-brain-behavior relationships from the perspective of large-scale functional network organization,but also may ultimately inform a translational conceptualization of how to improve sleep quality and executive functions through the regulation of gut microbiota.3.Some microbiota-fecal metabolites-blood metabolites-multilevel functional connectivity relationship pathway were found.This study expanded the previous two results,demonstrating that gut microbiota might influence the brain through fecal and blood metabolites.These findings further revealed the potential molecular mechanism of the interaction in “microbiota-gut-brain axis”,which further lay the foundation for the prevention and treatment of neuropsychiatric disorders based on gut microbiota. |
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