IDDF2024-ABS-0130 Faecalibacterium prausnitzii antagonizes helicobacter pylori colonization and inhibits gastric carcinogenesis

<h3>Background</h3> Probiotics could protect against cancers, however, the roles of probiotics in inhibiting GC and affecting <i>H. pylori</i> infection are largely unclear. We first identified <i>Faecalibacterium prausnitzii</i> is depleted in GC. We aimed to evaluate the antitumorigenic function and molecular mechanism of <i>F. prausnitzii</i> in GC and its interplay with <i>H. pylori</i>. <h3>Methods</h3> <i>F. prausnitzii</i> abundance was determined in 1343 human subjects consisting of 48 healthy controls (HC), 192 superficial gastritis (SG), 130 atrophy gastritis (AG), 123 intestinal metaplasia (IM), 80 gastric epithelial dysplasia (GED), 456 cancer adjacent normal (CAN) and 407 GC. The effect of <i>F. prausnitzii</i> on GC was evaluated in GC cells, patient-derived organoids (G9T, POA145), human GC xenograft, YTN16 allografts and N -methyl- N -nitrosourea (MNU) induced GC tumorigenesis mouse models. <i>F. prausnitzii</i> attachment to GC cells and its impact on <i>H. pylori</i> colonization was determined by scanning electron microscopy (SEM) and transmission electron microscopy (TEM) and was validated in mouse models. <h3>Results</h3> <i>F. prausnitzii</i> is significantly depleted in GC patients compared to non-GC (SG, AG, IM, GED or CAN) (P&lt;0.001). <i>F. prausnitzii</i> gavage reduced the colonization of <i>H. pylori SS1</i> (P=0.02) and <i>10996</i> (P&lt;0.0001) in stomach of mice through competing for their common receptor α-enolase on GC cells. Beyond inhibiting <i>H. pylori, F. prausnitzii</i> conditioned medium <i>(F. p CM)</i> inhibited GC cell growth (P&lt;0.0001) by inducing apoptosis (P&lt;0.05) and G1/S cell cycle arrest (P=0.003). Consistently, F. p CM suppressed GC patient-derived organoid growth (P&lt;0.0001). <i>F. prausnitzii</i> gavage inhibited growth of MKN74 xenografts (P&lt;0.0001) and YTN16 allografts (P&lt;0.0001) in mice. Moreover<i>, F. prausnitzii</i> gavage reduced tumor number (P=0.037) and tumor volume (P=0.012) in MNU-induced gastric carcinogenesis. Metabolic profiling of <i>F. p CM</i> revealed butyrate as the top enriched metabolite. Mechanistically, butyrate is directly bound to Toll-Like Receptor 4 (TLR4) on GC cells (Kd: 5.52µM), leading to Wnt/β-catenin signaling inhibition to suppress GC development. <h3>Conclusions</h3> <i>F. prausnitzii</i> is thus a promising prophylactic for GC prevention and anti<i>-H. pylori</i> therapy.