Microbiota Related Production of IL-6 as a Mechanism Underlying Symptoms in Patients with Major Depressive Disorder

Abstract

Major depressive disorder (MDD) is highly prevalent in our society, with many patients poorly responding to the available treatments. Accumulating evidence suggests that gut microbiota may be causally linked to depression, by interacting with the host immune or neural systems. Fecal microbiota transplantation (FMT) is a technique used to study disorders of the gut-brain axis by transplanting fecal microbiota of patients and healthy controls into germ-free mice to produce the phenotype of interest. With studies suggesting increased IL-6 among individuals with MDD, an FMT animal model of MDD was created using stool microbiota from MDD patients with the highest levels of serum IL-6 and age/sex-matched healthy controls with low serum IL-6. Our results provide evidence of elevated serum IL-6 correlating with increased presence of anxiety and depressive-like behavior. Six bacteria genera Acetanaerobacterium (p=0.0230), Bifidobacterium (p=0.0309), Blautia (p=0.0386), Candidatus soleaferrea (p=0.0446), Roseburia (p=0.0169), and Ruminococcus (p=0.0290) correlated with ileum tissue IL-6 concentration. There was a positive correlation between ileum and serum IL-6 concentrations (p=0.0108). Finally, using immunofluorescence we found an increased expression of IL-6 in the neural cells in the hippocampus and amygdala, among the MDD mice. Thus, this study demonstrates that alterations in gut microbiota correlate with intestinal tissue IL-6, which then correlate with serum IL-6 and elevated brains IL-6 in mice with MDD microbiota, as well as altered behaviors among mice with high serum IL-6. Overall, these results support the notion that IL-6 plays an important role in MDD, connecting gut microbiota to the brain.