Gemella morbillorum Promotes Colorectal Carcinogenesis: LPBDCP‐Mediated Invasion Activates Ras Signaling and Destabilizes p53

Gut microbiota dysbiosis promotes colorectal cancer (CRC) tumorigenesis. A global fecal metagenomic analysis identified Gemella morbillorum as a key contributor to the CRC-associated microbiota. Fluorescence in situ hybridization revealed that Gemella morbillorum is enriched in CRC tumor tissues compared to adjacent normal tissues. In vitro and in vivo experiments elucidated the oncogenic effects of Gemella morbillorum on human CRC cell lines and mouse models. Multimodal imaging shows that Gemella morbillorum can internalize into host cells. RNA sequencing, co-immunoprecipitation, and mass spectrometry identified that Gemella morbillorum invades host cells via interaction between its LysM peptidoglycan-binding domain protein (LPBDCP) and host cell surface transmembrane protein TMEM140. This invasion triggers Ca^{2 +} influx, downregulates RASA4, and activates the PI3K-AKT-NF-κB and RAF-MEK-ERK signaling pathways. Following invasion, Gemella morbillorum secretes NAD-dependent protein deacetylase (NDPD), which induces p53 deacetylation and degradation. Collectively, these events accelerate cell proliferation, shorten the cell cycle, and inhibit apoptosis, thereby promoting malignant transformation. Genetic knockout of LPBDCP or TMEM140 effectively inhibits bacterial invasion and abrogates the oncogenic effects of Gemella morbillorum. In tumor-bearing mice, knockout of LPBDCP or NDPD eliminates the tumor-promoting effects of Gemella morbillorum. These results underscore Gemella morbillorum's role in CRC and pinpoint potential intervention targets.