Altered GABA and secondary bile acids in Guillain-Barré syndrome: association with gut dysbiosis.

OBJECTIVE: Guillain-Barré syndrome (GBS) is a rare, immune-mediated inflammatory disease of the complex peripheral nervous system that often follows acute infections, and may also be associated with long-term 'silent infections'. Long-term "silent infections" can alter the gut microbiota, which in turn may contribute to immune-mediated inflammatory diseases. Emerging evidence suggests that gut dysbiosis and altered serum metabolites are associated with GBS, but the causative link between GBS and gut microbiota remains unclear. Therefore, this study aimed to evaluate the association between gut microbiota structure and serum metabolic profile in GBS.

METHODS: Untargeted metabolomics profiling of serum and metagenomics sequencing of stool samples were performed to capture the global metabolic and microbial differences between GBS subjects and healthy controls. Multivariate statistical analyses, including PLS-DA, were applied to identify distinct clustering patterns and differential abundances of metabolites and gut microbiota. Pearson's correlation analysis was used to estimate the correlations between abundance of gut microbiota and serum metabolic profile. Seven different media were used to isolate the potential pathogens from GBS stool samples.

RESULTS: The metabolome data revealed that gamma-aminobutyric acid (GABA) metabolism and secondary cholic acid metabolism were perturbed in GBS. Specifically, GABA was increased significantly (approximately 14.3-fold), while multiple secondary cholic acids (methyl deoxycholate, glycodeoxycholic acid, glycolithocholic acid, taurolithocholic acid, and coprocholic acid) were decreased significantly in GBS subjects. Regarding the gut microbiota identified via metagenomic sequencing of stool samples, Ligilactobacillus salivarius, Enterocloster bolteae, and the opportunistic pathogenic Klebsiella pneumonia were notably more abundant in GBS subjects, while Bacteroides sp., Roseburia hominis and Paraprevotella xylaniphila were decreased significantly. In addition, pathogens such as K. pneumoniae were also isolated from GBS subjects. Further analysis of the metagenomic data revealed enrichment of prokaryotic genes involved in the GABA biosynthesis pathway, while genes associated with secondary cholic acid metabolism pathways were decreased in gut microbiome in GBS subjects. On this basis, correlation analysis revealed that changes in GABA were associated with altered levels of gut microbes including Enterococcus species, Ligilactobacillus salivarius and Enterocloster bolteae, whereas changes in secondary cholic acids were positively correlated with altered levels of Bacteroides species and Roseburia species.

CONCLUSION: GABA metabolism and secondary cholic acid metabolism were significantly disturbed in GBS subjects, potentially resulting from the dysbiosis of the gut microbiota. K. pneumonia and other no gut microbes were significantly enriched and isolated in GBS and may contribute to the inflammatory response in this immune-mediated inflammatory disease. These findings also suggest that GABA may be a promising biomarker for the diagnosis of GBS and that modulation of gut microbiota might impact the clinical course of GBS.