Gut microbiota in a mouse model of obesity and peripheral neuropathy associate with plasma and nerve lipidomics and nerve transcriptomics

Background: Peripheral neuropathy (PN) is a common complication in obesity, prediabetes, and type 2 diabetes. PN pathogenesis remains incompletely understood, although increasing attention has focused on the potential role of the gut microbiome as a link between dietary fat intake and nerve health. In a murine high-fat diet (HFD) obesity model of PN, dietary reversal to a low-fat standard diet (SD) restores the nerve lipidome and nerve function to normal. The current study assessed shifts in microbiome community structure by 16S rRNA profiling during the paradigm of dietary reversal (HFD-R) in various gut niches and correlations between dietary fat content (SD versus HFD) to gut flora and metabolic and PN phenotypes. PN-associated microbial taxa that correlated with the plasma and sciatic nerve lipidome and transcriptome were used to identify lipid species and genes intimately related to specific PN phenotypes and develop a specific microbiome signature. Results: HFD altered microbiome structure, which rapidly reversed in HFD-R. Specific taxa variants correlating positively with metabolic health associated inversely with PN, while specific taxa negatively linked to metabolic health positively associated with PN. Furthermore, certain PN-associated taxa variants of Lactobacillus, Lachnoclostridium, and Anaerotruncus, among others, positively correlated with several lipid species, especially elevated plasma sphingomyelins and sciatic nerve triglycerides in HFD. Negative correlations were also present with other taxa variants. Moreover, relationships emerged between specific PN-associated taxa variants and sciatic nerve transcriptome related to inflammation, lipid metabolism, and antioxidant defense pathways established in PN pathogenesis. Conclusions: The current results indicate that microbiome structure is altered with HFD and that certain taxa variants correlate with metabolic health and PN. Apparent links between PN-associated taxa and certain lipid species and nerve transcriptome-related pathways associated with PN pathogenesis further strengthen the feasibility of a potential gut-microbiome-peripheral nervous system signature in PN.