Mycobacterium abscessus (MAB), a rapidly growing nontuberculous mycobacterium, is a leading cause of chronic pulmonary infections, particularly among immunocompromised individuals. Owing to its intrinsic antibiotic resistance and persistence, MAB remains a therapeutic challenge. Activation of the NLRP3 inflammasome plays a central role in host inflammation by promoting IL-1β maturation and pyroptosis. Here, we investigated the anti-inflammatory effects of heat-killed Lactobacillus kunkeei NCHBL-003 (HK-LK), derived from honeybees, in MAB-induced pulmonary inflammation. In bone marrow-derived macrophages (BMDMs), HK-LK pretreatment suppressed MAB-induced gene expression of NLRP3, IL-1β, and TNF-α, and reduced cleavage of caspase-1 and IL-1β, without impairing bacterial clearance. In vivo, oral administration of HK-LK alleviated MAB-induced pulmonary inflammation and suppressed NLRP3-associated protein expression in lung tissues, while lung bacterial loads remained unchanged. Notably, similar anti-inflammatory effects were observed in both wild-type and TLR2-deficient mice, suggesting that TLR2 contributes but is not solely responsible for HK-LK–mediated protection. Gut microbiota analysis revealed significant Bray–Curtis dissimilarity following HK-LK treatment, despite unchanged α-diversity and UniFrac metrics. HK-LK reduced the abundance of Firmicutes, implying a role for gut microbiota modulation in its protective effects. Collectively, these findings demonstrate that HK-LK mitigates MAB-induced inflammation by modulating the NLRP3 inflammasome pathway and gut microbiota, highlighting its potential as an adjunctive strategy for mycobacterial infections.
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