Effects of Fzd6 on intestinal flora and neuroinflammation in lipopolysaccharide-induced depression-like mice.

Background: The gut microbiome is critical for the pathophysiology of depression, and inflammation is one of the factors contributing to depression. Fzd6 has been implicated in depression. This study aimed to elucidate the effects of the Fzd6 mutation on gut microbiota structure and the possible regulatory mechanisms involved in depression-associated neuroinflammation.

Methods: Wild-type (Fzd6^WT) and Fzd6 mutant (Fzd6^Q152E) male mice were treated with lipopolysaccharide (LPS) for 7 days. Behavioral experiments were used to detect the behavioral changes of mice in each group, and the composition of intestinal flora and systemic inflammation levels of mice were further detected.

Results: In LPS mice, the Fzd6 mutation enhanced depression-like behavior symptoms, increased the release of pro-inflammatory cytokines, decreased the release of anti-inflammatory cytokines, and caused intestinal flora disturbance. Subsequently, 16SrRNA sequencing revealed significant changes in the relative abundance of the inflammation-associated bacterial groups Ruminococcaceae and Lachnospiraceae in Fzd6^Q152E mice. In mice with depression, the levels of G protein-coupled receptors, GPR41 and GPR43, and glucagon-like peptide-1 (GLP-1) in the small intestine were down-regulated, and the expression of GLP-1 receptor (GLP-1R), peroxisome proliferators activated receptors gamma (PPAR-γ), and nuclear factor kappa-B inhibitor alpha (IκBα) in the hippocampus was also down-regulated, while the expression of nuclear factor kappa-B p65 (NF-κB p65) was up-regulated.

Limitations: The size of the spleen was not studied in this model, and the Fzd6 mutation itself does not cause systemic inflammation such as IL-6.

Conclusion: These results demonstrate that mutations in Fzd6 regulate the composition of the gut flora, which contributes to depression-associated inflammation.