Analysis of brain networks and fecal metabolites reveals brain\u2013gut alterations in premenopausal females with irritable bowel syndrome

Vadim Osadchiy,Bruce Naliboff,Emeran A Mayer,Arpana Gupta,Elaine Y Hsiao,Lin Chang,Kirsten Tillisch,Jonathan P Jacobs,Jennifer S Labus,Kan Gao

doi:10.1038/s41398-020-01071-2

Abstract

Alterations in brain–gut–microbiome (BGM) interactions have been implicated in the pathogenesis of irritable bowel syndrome (IBS). Here, we apply a systems biology approach, leveraging neuroimaging and fecal metabolite data, to characterize BGM interactions that are driving IBS pathophysiology. Fecal samples and resting state fMRI images were obtained from 138 female subjects (99 IBS, 39 healthy controls (HCs)). Partial least-squares discriminant analysis (PLS-DA) was conducted to explore group differences, and partial correlation analysis explored significantly changed metabolites and neuroimaging data. All correlational tests were performed controlling for age, body mass index, and diet; results are reported after FDR correction, with q < 0.05 as significant. Compared to HCs, IBS showed increased connectivity of the putamen with regions of the default mode and somatosensory networks. Metabolite pathways involved in nucleic acid and amino acid metabolism differentiated the two groups. Only a subset of metabolites, primarily amino acids, were associated with IBS-specific brain changes, including tryptophan, glutamate, and histidine. Histidine was the only metabolite positively associated with both IBS-specific alterations in brain connectivity. Our findings suggest a role for several amino acid metabolites in modulating brain function in IBS. These metabolites may alter brain connectivity directly, by crossing the blood–brain-barrier, or indirectly through peripheral mechanisms. This is the first study to integrate both neuroimaging and fecal metabolite data supporting the BGM model of IBS, building the foundation for future mechanistic studies on the influence of gut microbial metabolites on brain function in IBS.

Highlights

Alterations in brain–gut–microbiome (BGM) interactions have been implicated in the pathogenesis of irritable bowel syndrome (IBS)[1]
In detail, compared with healthy controls (HCs) females, 43 metabolites were significantly lower in IBS, lipids, such as Npalmitoyl-sphinganine (d18:0/16:0), palmitoyl-oleoyl-glycerol (16:0/18:1) (FC = 0.12, q = 1.1E−07), and oleoyl-oleoyl-glycerol (18:1/18:1) (FC = 0.19, q = 7.11167E−07), while 82 metabolites were significantly higher in IBS females, such as gamma-glutamylleucine (FC = 1.57, q = 8.44067E−11), 2-hydroxyglutarate (FC = 1.47, q = 1.2E−09), and Nacetylmethionine sulfoxide (FC = 1.73, q = 7.2E−08)
While not providing information about causality, our findings are an important foundation for future mechanistic studies

Summary

Introduction

Alterations in brain–gut–microbiome (BGM) interactions have been implicated in the pathogenesis of irritable bowel syndrome (IBS)[1]. Despite a growing body of preclinical and clinical studies, the precise mechanisms by which these interactions contribute to IBS symptom generation remains incompletely understood. Neuroimaging studies have previously demonstrated structural and functional differences between IBS patients (composed of the caudate, putamen, and globus pallidus)[2]. The basal ganglia, due in part to the structure’s many cortical and thalamic afferent and cortical efferent connections, is responsible for central processing and modulation of both visceral and somatic nociception[3,4]. As females tend to experience more severe and frequent. IBS symptoms than males, it is unsurprising that many of the described brain network alterations are sex-specific[2,5].

Methods

Results

Conclusion