Insular resting state functional connectivity is associated with gut microbiota diversity

Abstract

The gut microbiota has recently gained attention as a possible modulator of brain activity. A number of reports suggest that the microbiota may be associated with neuropsychiatric conditions such as major depressive disorder, autism and anxiety. The gut microbiota is thought to influence the brain via vagus nerve signalling, among other possible mechanisms. The insula processes and integrates these vagal signals. To determine if microbiota diversity and structure modulate brain activity, we collected faecal samples and examined insular function using resting state functional connectivity (RSFC). Thirty healthy participants (non-smokers, tobacco smokers and electronic cigarette users, n = 10 each) were studied. We found that the RSFC between the insula and several regions (frontal pole left, lateral occipital cortex right, lingual gyrus right and cerebellum 4, 5 and vermis 9) were associated with bacterial microbiota diversity and structure. In addition, two specific bacteria genera, Prevotella and Bacteroides, were specifically different in tobacco smokers and also associated with insular connectivity. In conclusion, we show that insular connectivity is associated with microbiome diversity, structure and at least two specific bateria genera. Furthemore, this association is potentially modulated by tobacco smoking, although the sample sizes for the different smoking groups were small and this result needs validation in a larger cohort. While replication is necessary, the microbiota is a readily accessible therapeutic target for modulating insular connectivity, which has previously been shown to be abnormal in anxiety and tobacco use disorders.

Keywords: fMRI; electronic cigarette; insula; microbiome; tobacco.

Figure 1.

Regions of interest (ROI). The left and right insular lobes were divided into right (r) and left (l) anterior, middle, and posterior parts. ROIs were drawn in AFNI, based on brain landmarks and coordinates published in previous literature. Insula ROIs were created in MNI space and entered into the CONN functional connectivity toolbox as seeds of interest for analyses, with middle insula as a priori hypothesis. We studied RSFC from the subdivided insula to the rest of the brain using seed-to-voxel analysis.

Figure 2.

Significant clusters resulting from seed-to-voxel resting state functional connectivity analyses using middle insula areas as seeds and measures of microbiota structure and diversity as regressors of interest. A) Cluster (−18 +48 +12) – significant regression of OTUs, using left (l) middle insula as seed; 131 voxels, frontal pole left. B) Cluster (+06 −56 −30) – significant regression of weighted UF component 2, using l middle insula as seed; 45 voxels, vermis 9.

Figure 3.

Significant clusters resulting from seed-to-voxel resting state functional connectivity analyses using additional insula ROIs as exploratory areas of interest and measures of microbiota structure and diversity as regressors of interest. A) Cluster (+12 −80 +50) – significant regression of OTUs, using right (r) inferior insula as seed. 223 voxels, lateral occipital cortex, superior division right. B) Cluster (+18 −68 −10) – significant regression of weighted UniFrac (wUF) component 2, using r anterior insula as seed. 232 voxels, lingual gyrus right. C) Cluster (+24 −70 −14) - significant regression of wUF component 2, using l anterior insula as seed. 125 voxels, cerebelum 4, 5 left. D) Cluster (−20 −52 −18) - significant regression of wUF component 2, using l anterior insula as seed. 125 voxels, cerebelum 4, 5 left.

Figure 4.

Significant clusters resulting from seed-to-voxel functional resting state connectivity analyses using insula ROIs, Bacteroides and Prevotella measures as regressors of interest, and tobacco status as covariate of no interest. A) Cluster (−56 −28 +12) – significant regression of Bacteroides, using l anterior insula as seed. 134 voxels, parietal operculum cortex left. B) Cluster (+32 −74 +56) – significant regression of Prevotella, using l anterior insula as seed. 184 voxels, lateral occipital cortex, superior division right. C) Cluster (+34 +30 +46) - significant regression of Prevotella, using r inferior insula as seed. 211 voxels, middle frontal gyrus right. Tobacco status was used as covariate of no interest.