Activation of aryl hydrocarbon receptor signaling by indole-3-lactic acid from Bacillus velezensis DS2 reinforces gut mucosal immunity and attenuates inflammaging in aged mice.

backgroundAging is characterized by progressive immunosenescence and inflammaging, in which impaired gut barrier and dysregulated mucosal immunity exacerbate systemic senescence. While probiotics modulate gut health, their role in mitigating age-related immune dysfunction via specific microbial metabolites remains unclear. This study aims to investigate the effects of Bacillus velezensis DS2, a novel probiotic, in alleviating inflammaging, with a focus on tryptophan-metabolic signaling and immune regulation.

resultsIn senescent endothelial cells, DS2-sourced indole-3-lactic acid (ILA) activated aryl hydrocarbon receptor (AhR) signaling. This activation reduced the expression of senescence markers (p16, γ-H2A.X) and decreased the levels of pro-inflammatory molecules (ICAM-1, VCAM-1). In aged mice, DS2 supplementation increased the abundance of beneficial bacteria, including Lactobacillus and Ligilactobacillus. DS2 administration also elevated plasma ILA and IL-22 levels, and reduced intestinal permeability. This was evidenced by the expansion of IL-22-producing type 3 innate lymphoid cells (ILC3s) and activation of the AhR-IL-22 axis. Consequently, DS2 enhanced intestinal barrier integrity and mitigated systemic inflammation (TNF-α, IL-6). Exogenous ILA was sufficient to recapitulate these benefits by potentiating gut mucosal immunity and attenuating inflammaging, as all these effects were abolished by the AhR antagonist CH223191.

conclusionsWe demonstrate that DS2 mitigates inflammaging by producing ILA, which acts as a key metabolite to activate the AhR-IL-22-ILC3 axis. Our findings highlight the potential of targeting the gut-immune axis with specific probiotics as a novel strategy against age-related immune decline.