Interleukin 6 (IL-6), its receptor (IL-6R), with the IL-6 signal transducer gp130 (IL-6ST) are well known regulators of innate immunity but also affect neuron morphology and function. More recent evidence suggests that they also play a significant role in shaping microbiota composition and gut-barrier function (1). However, the exact pathways and mechanisms are still elusive. We therefore investigated the involvement of functional IL-6 signaling in the bilateral communication between primary afferent neurons and gut microbiota.Transgenic mice with a conditional depletion of gp130 in neurons expressing the nociceptor-specific ion channel Nav1.8 (SNS-gp130-/-) and littermate fl/fl controls of both sexes were used. Feces were collected, frequency and bolus weight were quantified, and fecal samples were subjected to 16S sequencing to identify microbiota strains. Efferent neuronal functions were assessed by measuring IL-6 and neuropeptide release, and colonic mucus thickness was observed by histological methods.IL6ST depletion in primary sensory neurons did not cause significant changes in gut motility. However, 16S analysis revealed genotype and sex-specific changes in fecal microbiota composition between the genotypes. Colonic mucus thickness was decreased in SNS-gp130-/- mice and this was associated with a reduction of neuropeptide but not IL-6 release.Our data suggest that Nav1.8 expressing neurons under the control of IL-6ST release neuropeptides into the gut wall, affecting the epithelial mucus as an important barrier and altering colonic microbiota composition. However, the precise cellular mechanisms of these regulatory functions still have to be elucidated.