<i>Acinetobacter baumannii</i> promotes gastric cancer metastasis via NA-mediated NAD metabolism reprogramming and glycolytic activation.

Abstract

Gastric cancer (GC) is one of the most common malignancies worldwide and it is the third leading cause of cancer-related death in China. While <i>Helicobacter pylori</i> is a known GC pathogen, its abundance declines in tumours and the role of other bacteria in GC metastasis remains unclear. We aim to investigate the mechanisms of other bacteria influencing GC progression and metastasis. Integrated intratumoural microbiome-metabolome analysis identified GC-associated microbes and metabolites. We then demonstrated the pro-metastatic role of <i>Acinetobacter baumannii</i> (<i>A. baumannii</i>, Ab) and its metabolite nicotinic acid (NA) using genetic, molecular and in vivo approaches. The abundance of <i>A. baumannii</i> was significantly increased in GC tissues, correlating with advanced tumour stage and intratumoural NA levels. Fluorescence in situ hybridisation confirmed its colonisation in GC tumours. In co-culture systems, <i>A. baumannii</i> increased NA levels, enhancing nicotinamide adenine dinucleotide (NAD) metabolism and increasing 1-Methylnicotinamide accumulation in tumour cells. Mutagenesis of the bacterial NA synthase gene <i>pncA</i> confirmed that <i>A. baumannii</i> excreted an NA-dependent pro-metastasis effect. Mechanically, <i>A. baumannii</i> promotes GC metastasis by reprogramming tumour cell glucose metabolism, reducing oxidative phosphorylation while enhancing glycolysis and activating the hypoxia-inducible factor-1 pathway in GC cells through metabolites both in vivo and in vitro. This study elucidates the role of <i>A. baumannii</i> in enhancing NAD metabolism in GC cells through NA synthesis, consequently promoting GC metastasis. These findings establish a microbiota-metabolism axis as a mechanistic foundation for developing targeted therapeutic strategies against GC metastasis.