Microbiome-Modulating Effects of Heat-Treated Lactiplantibacillus plantarum LM1004 and Its Enhancement of NK Cell Activity: Evidence from a Clinical Trial and a Simulated Human Intestinal Microbiome Ecosystem.

Probiotics are increasingly recognized for their capacity to modulate gut microbiota, regulate microbial metabolic activity, and influence host immune responses, thereby contributing to the maintenance of immune homeostasis and overall health. In this study, we assessed the efficacy and safety of heat-treated Lactiplantibacillus plantarum LM1004 (HT-LM1004) in a randomized, placebo-controlled clinical trial and explored its mechanisms of action in a simulated human intestinal microbiome ecosystem. After 8 weeks of supplementation, we observed significantly enhanced natural killer (NK) cell activity with a concurrent improvement in white blood cell (WBC) counts relative to the placebo group, suggesting an overall enhancement of the host's primary immune defense baseline within the normal physiological range. Mechanistic investigations within the simulated human intestinal microbiome ecosystem demonstrated that HT-LM1004 increased microbial species diversity in the ascending colon (AC), followed by elevated richness in the transverse colon (TC) and descending colon (DC) at the End and Post time points, suggesting selective enrichment of low-abundance beneficial bacterial taxa. Metabolomics analyses indicated compartment-specific changes, especially within bile acid metabolism pathways, while non-bile acid metabolites were predominantly enriched in the DC. Short-chain fatty acid (SCFA) profiling also revealed distinct, time-dependent changes across the different gut compartments. Collectively, these results indicate that L. plantarum LM1004 boosts NK cell activity in humans by enriching low-abundance beneficial bacteria and modulating their metabolic products, underscoring its promise as a microbiome-based functional food and preventative option to support immune health.