show Abstracthide AbstractPerturbance of gut microbiota (GM) composition has implications in onset and progression of an emerging number of diseases. Here we demonstrate a regulatory impact on proper development of the peripheral nervous system (PNS) and its functional connection to skeletal muscles (SM). We analysed peripheral nerves, dorsal root ganglia (DRG) and SM of neonatal and adult mice that were raised as a) germ free (GF) mice, b) gnotobiotic mice, i.e. selectively colonised with 12 known gut bacteria (OMM12), or c) colonised with complex GM (CGM). Stereological and morphometrical analysis mainly revealed that absence of GM impairs the development of median nerves, resulting in smaller diameter hypermyelinated axons. Accordingly, transcriptomic analysis on DRG and sciatic nerves highlighted a panel of differentially expressed developmental and myelination genes. Moreover, GF mice demonstrated histologically atrophic SM, impaired formation of neuromuscular junctions, and deregulated expression of related genes. Our results, for the first time, imply the existence of a “GM-PNS-axis”. Overall design: Comparative gene expression profiling analysis of RNA-seq data for neonatal and young adult CGM, GF and OMM12 mice on dorsal root ganglia (DRG) and sciatic nerves.