FAECALIBACTERIUM PRAUSNITZII INHIBITS GASTRIC CANCER AND ANTAGONIZES HELICOBACTER PYLORI COLONIZATION

Background: The roles of probiotics in inhibiting gastric cancer (GC) and effecting H. pylori infection are largely unclear. We identified Faecalibacterium prausnitzii is depleted in GC. We aimed to evaluate the antitumorigenic function and molecular mechanism of F. prausnitzii in GC and its interplay with H. pylori.

Methods: F. prausnitzii 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 intraepithelial neoplasia (IN), and 407 GC. Effect of F. prausnitzii on GC was evaluated in GC cells, patient-derived organoids, human GC xenografts, YTN16 allografts and MNU induced GC tumorigenesis mouse models. F. prausnitzii attachment to GC cells and its impact on H. pylori colonization was determined by electron microscopy and was validated in mouse models.

Results: F. prausnitzii is significantly depleted in GC patients compared to non-GC (SG, AG, IM, IN or CAN) (P<0.001). F. prausnitzii conditioned medium (F.p CM) inhibited GC cell growth (P<0.0001) by inducing apoptosis (P<0.05) and G₁/S cell cycle arrest (P=0.003). Consistently, F.p CM suppressed GC patient-derived organoids growth (P<0.0001). F. prausnitzii gavage inhibited growth of MKN74 xenografts (P<0.0001) and YTN16 allografts (P<0.0001) in mice. Moreover, F. prausnitzii gavage reduced tumor number (P=0.037) and tumor volume (P=0.012) in MNU-induced gastric carcinogenesis. Metabolic profiling of F.p CM revealed butyrate as the top enriched metabolite. We demonstrated that butyrate inhibited the growth of GC cells (P<0.0001), patient-derived organoids (P<0.0001) and YTN16 allografts (P<0.001). Mechanistically, butyrate directly bund to Toll-Like Receptor 4 (TLR4) on GC cells (K_d: 5.52µM), leading to TLR4 activation and suppression of GC cell growth. Beyond inhibiting GC growth, we observed a negative association of F. prausnitzii with H. pylori abundance in gastric mucosa in two cohorts of patients with HC, AG, IM, IN and GC (cohort I, 276 GC; cohort II, 30 HC, 21 AG, 27 IM, 25 IN and 29 GC), suggesting that F. prausnitzii might antagonize H. pylori. Indeed, F. prausnitzii co-culture suppressed the growth of H. pylori SS1 and two drug resistant strains 10996 and 10783 (P<0.0001 for all). F. prausnitzii also inhibited the attachment to GC cells (P<0.05 for all) and biofilm formation (P<0.05 for all) for all three H. pylori strains. F. prausnitzii gavage reduced the colonization of H. pylori SS1 (P=0.02) and 10996 (P<0.0001) in stomach of mice through competing for their common receptor α-enolase on GC cells.

Conclusion: F. prausnitzii inhibits GC by producing butyrate and antagonizes H. pylori colonization in gastric mucosa. F. prausnitzii is thus a promising prophylactic for GC prevention and anti-H. pylori therapy, including drug resistant H. pylori strains.