Bukowski-Thall, G.; Fellendorf, F.; Gorkiewicz, S.; Ip, K. C. K.; Schmidt, L.; Durdevic, M.; Fabisch, H.; Mörkl, S.; Wagner-Skacel, J.; Bengesser, S.; Lenger, M.; Dalkner, N.; Gorkiewicz, G.; Högenauer, C.; Madl, T.; Moissl-Eichinger, C.; Farzi, A.; Reininghaus, E.

Bipolar disorder (BD) is a chronic mood disorder characterized by recurrent episodes of depression and (hypo-) mania. Fecal microbiota transplantation (FMT) is a powerful translational tool for investigating the connection between the gut microbiome and BD, and there is evidence FMT can transfer affective symptoms of BD from humans to mice. In this study, we compared the behavior, gut-brain metabolomic profiles, and inflammatory marker expression in two groups of adult female C57BL/6 mice, one receiving FMT from a human donor with BD in a mixed episode (YMRS = 14, HAM-D = 20) and another receiving FMT from a weight and age matched control donor without BD (HAM-D and YMRS = 0). Here we demonstrate that mice receiving FMT from individuals with BD had an increased abundance of the Bacteroidota phylum and decreased abundances of Parabacteroides merdae and Akkermansia muciniphila associated with altered levels of fecal metabolites, short-chain fatty acids, and related gut hormone expression relative to controls. BD mice also exhibited differential regulation of several metabolites and inflammatory markers in the amygdala, with glycine being the most prominently affected. Furthermore, BD mice exhibited increased anxiety-like behavior and decreased sociability, indicating that some aspects of the behavioral phenotype of BD are transferable from humans to mice via FMT. Taken together, these findings implicate the involvement of gut-brain signaling in the physiological and behavioral changes observed in our BD-FMT mouse model, and provide a promising translational framework for understanding the mechanisms of BD.