Engineered Lactococcus lactis enabling on-site melanin synthesis alleviates IBD-related anxiety and depression by regulating tryptophan metabolism

Abstract Inflammatory bowel disease (IBD) is often accompanied by anxiety and depression. Gut microbiota and their metabolites may play important roles in IBD-related anxiety and depression. Here, in order to relieve IBD-related anxiety- and depression-like behaviors, an engineered Lactococcus lactis ( L. lactis) NZ9000 TyrL-pMG36e, which can produce tyrosinase in the intestine, was constructed, thereby facilitating the biosynthesis of melanin as the final product. The engineered probiotic NZ9000 TyrL-pMG36e could significantly increase the abundance of SCFA-producing gut microbiota and anxiety- and depression-alleviating probiotics. Interestingly, propionic acid was identified as the key SCFA relieving dextran sulphate sodium (DSS) induced colitis and anxiety- and depression-like behaviors by inhibiting microglia activation via regulating tryptophan metabolism. We found that propionic acid could upregulate the expression of tryptophan metabolism-related genes in microglia, thereby activating the aryl hydrocarbon receptor (AhR) to enhance the expression of IL-22, and this pathway exerts anti-inflammatory effects via IL-22-mediated signaling to inhibit microglial activation. AhR knockout (AhR KO) mice were also used to further elucidate the critical role of AhR, which may serve as a bridge between the gut microbiota and the central nervous system, particularly in modulating microglial activation. This study uncovers the underlying mechanisms of the microbiota-gut-brain axis behind IBD-related anxiety and depression, and is expected to provide a new strategy for the clinical treatment of IBD-related anxiety and depression. Graphical abstract Engineered probiotic Lactococcus lactis NZ9000 TyrL-pMG36e elevates gut microbiota-derived propionic acid to regulate microglial tryptophan metabolism via the AhR-IL-22 axis and alleviate IBD-related anxiety and depression. (Created with BioRender.com, with permission)