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

Year: 2026

Type: article

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)

Source: Journal of Nanobiotechnology

DOI: 10.1186/s12951-026-05222-3