Lactobacillus paracasei ZJUZ2-3 suppresses gastric tumorigenesis by inhibiting NF-κB pathway via metabolite 3-IAA

BACKGROUND & AIMS: Lactobacillus paracasei is known to confer health benefits to human and has been found depleted in gastric tumor tissues. Here, we aimed to investigate the potential role of this bacterium as a prophylactic for gastric cancer (GC). METHODS: Isolation of L. paracasei from normal gastric tissues followed by whole genome sequencing was conducted. Antitumor effects of a L. paracasei isolate and its tumor-suppressive metabolite were assessed with gastric cancer cell lines and cell line-derived xenograft models. RESULTS: We validated that L. paracasei was depleted in GC tumor tissues in a cohort of 90 patients. A L. paracasei strain ZJUZ2-3 was then isolated. Intratumoral injection of ZJUZ2-3 suppressed GC tumourigenesis in nude mice. Coincubation with ZJUZ2-3 or its conditioned medium inhibited the proliferation of GC cells. But heat-killed ZJUZ2-3 lost the tumor-suppressive effect. Indole-3-acetic acid (IAA) was identified as a ZJUZ2-3-derieved metabolite mediating the antitumor effect. IAA inhibited proliferation and colony formation of GC cells as well as subcutaneous tumor growth in nude mice. Mechanically, as an aryl hydrocarbon receptor (AHR) ligand, IAA activated AHR, which could competitively bind MTDH to inhibit its phosphorylation, thus inhibiting nuclear factor kB (NF-kB) signaling pathway in GC cells. Consistently, inhibition or knockdown of AHR abolished the antitumor effect of IAA. CONCLUSION: L. paracasei ZJUZ2-3 inhibit GC proliferation and may be used as adjuvant therapy for gastric cancer. The tumor-suppressive effect is mediated by its metabolite IAA.