Gut Microbiome and Plasma Metabolome Signatures in Middle-Aged Mice With Cognitive Dysfunction Induced by Chronic Neuropathic Pain.

Dongyu Hua,Shiyong Li,Jie Zhang,Zheng Xie,Yilin Zhao,Xuan Wang,Shan Li,Yue Wang,Ailin Luo

doi:10.3389/fnmol.2021.806700

Abstract

Patients with chronic neuropathic pain (CNP) often complain about their terrible memory, especially the speed of information processing. Accumulating evidence suggests a possible link between gut microbiota and pain processing as well as cognitive function via the microbiota-gut-brain axis. This study aimed at exploring the fecal microbiome and plasma metabolite profiles in middle-aged spared nerve injury (SNI) mice model with cognitive dysfunction (CD) induced by CNP. The hierarchical cluster analysis of performance in the Morris water maze test was used to classify SNI mice with CD or without CD [i.e., non-CD (NCD)] phenotype. 16S rRNA sequencing revealed a lower diversity of gut bacteria in SNI mice, and the increase of Actinobacteria, Proteus, and Bifidobacterium might contribute to the cognitive impairment in the CNP condition. The plasma metabolome analysis showed that the endocannabinoid (eCB) system, disturbances of lipids, and amino acid metabolism might be the dominant signatures of CD mice. The fecal microbiota transplantation of the Sham (not CD) group improved allodynia and cognitive performance in pseudo-germ-free mice via normalizing the mRNA expression of eCB receptors, such as cn1r, cn2r, and htr1a, reflecting the effects of gut bacteria on metabolic activity. Collectively, the findings of this study suggest that the modulation of gut microbiota and eCB signaling may serve as therapeutic targets for cognitive deficits in patients with CNP.

Highlights

Accumulating preclinical and clinical evidence suggests that cognitive impairment is a common comorbidity of chronic neuropathic pain (CNP) (Attal et al, 2014; Mazza et al, 2018; FonsecaRodrigues et al, 2021; Rouch et al, 2021)
We explored the alterations of gut microbiota and plasma metabolites by performing 16S rRNA sequencing and non-targeted metabolomics, which is the overarching goal of identifying potential biomarkers for predicting the comorbidity of CNP and cognitive impairment
After 1 month, spared nerve injury (SNI) mice were divided into cognitive dysfunction (CD) (54.8%) group or NCD (45.2%) group according to the hierarchical clustering analysis of the Morris water maze test (MWMT) performance (Figure 1B)

Summary

Introduction

Accumulating preclinical and clinical evidence suggests that cognitive impairment is a common comorbidity of chronic neuropathic pain (CNP) (Attal et al, 2014; Mazza et al, 2018; FonsecaRodrigues et al, 2021; Rouch et al, 2021). Studies have revealed that gut microbiota regulates the development of CNP or cognitive impairment through the vagus nerve, endocrine, and metabolic as well as immune communications (Sampson and Mazmanian, 2015; Sun et al, 2020; Chen et al, 2021). It is not known how the microbiota affects the comorbidity

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