The gatekeeper to gastric cancer; gastric microbiota invade the lamina propria inHelicobacter pylori-associated gastric carcinogenesis

Abstract

AbstractStomach cancer is the fourth leading cause of cancer-related deaths worldwide.Helicobacter pyloriis the main risk factor for gastric adenocarcinoma (GAC), yet the mechanism underpinning this association remains uncharacterised. Gastric intestinal metaplasia (GIM) represents the pre-cancerous stage and followsH. pylori-associated chronic gastritis (CG). Sequencing studies have revealed fewerH. pyloriand more non-H. pyloribacteria in GAC. However, the spatial organisation of the gastric microbiota in health and disease is unknown. Here, we have combined RNAin situhybridisation and immunohistochemistry to detectH. pylori, non-H. pyloribacteria and host cell markers (E-cadherin, Mucins 5AC and 2) from patients with CG (n=9), GIM (n=12), GAC and normal tissue adjacent to tumours (NATs) (n=3). Quantitative analysis of whole slide scans revealed significant correlations ofH. pyloriand other bacteria in CG and GIM samples. In contrast to sequencing studies, significantly fewer non-H. pyloribacteria were detected inH. pylori-negative patients. Importantly, whilstH. pyloriexclusively colonised the gastric glands, non-H. pyloribacteria invaded the lamina propria in 3/4 CG and 5/6 GIMH. pylori-positive patients. Bacterial invasion was observed in 3/3 GAC samples and at higher levels than matched NATs. We propose thatH. pylori‘holds the keys’ to disrupt the gastric epithelial barrier, facilitating the opportunistic invasion of non-H. pyloribacteria to the lamina propria. Bacterial invasion could be a significant driver of inflammation inH. pylori-associated carcinogenesis. This proposed mechanism would both explain the synergistic roles ofH. pyloriand other bacteria and redirect attempts to prevent, diagnose and treat GAC.