Lactobacillus paracasei ZJUZ2-3 inhibits gastrointestinal tumors via the IAA-induced AHR/MTDH/NF-κB axis.

Lactobacillus paracasei abundance is markedly reduced in gastric cancer (GC) tissues, suggesting its potential protective role. From healthy gastric tissue of a GC patient, we isolated a novel strain, L. paracasei ZJUZ2-3, which exerted potent antitumor effects. Intratumoral injection of live ZJUZ2-3, but not heat-killed bacteria, attenuated gastrointestinal tumor growth in mice. Conditioned medium from ZJUZ2-3 similarly inhibited cancer cell proliferation, implicating a secreted metabolite. Metabolomic profiling identified indole-3-acetic acid (IAA) as the key bioactive compound. Consistent with this, genetic knockout of trpA (essential for IAA biosynthesis) in ZJUZ2-3 abolished its antitumor efficacy. IAA alone recapitulated the tumor-suppressive effects both in vitro and in vivo. Mechanistically, IAA activated the aryl hydrocarbon receptor (AHR), which then competitively bound to metadherin (MTDH). This interaction blocked MTDH phosphorylation and the subsequent activation of NF-κB signaling. Crucially, depletion of either AHR or MTDH abrogated IAA's efficacy, underscoring the essential role of this axis. Furthermore, ZJUZ2-3 synergized with conventional chemotherapy, potentiating tumor regression. While this study lacks humanized immune models and exploration of strain-specificity, our findings identify L. paracasei ZJUZ2-3 and its effector metabolite IAA as promising precision microbiome-based therapeutics targeting the AHR-MTDH-NF-κB pathway for adjuvant treatment of GC.