Giddings Harriet J, Teodósio Ana, Jones Jordanne, McMurray Jack L, Hunter Kelly, Alame Riad, Gardiner Isaac, Abdawn Zainab, Butterworth William, Henderson Ian R, Cole Jeffrey A, Shannon-Lowe Claire D, Rossiter-Pearson Amanda E
Institute of Microbiology and Infection, University of Birmingham, Birmingham, UK.
Department of Microbes, Infection and Microbiomes, School of Infection, Inflammation and Immunology, College of Medicine and Health, University of Birmingham, Birmingham, UK.
Helicobacter. 2025 Jan-Feb;30(1):e70016. doi: 10.1111/hel.70016.
Stomach cancer is the fourth leading cause of cancer-related deaths worldwide. Helicobacter pylori is the main risk factor for gastric adenocarcinoma (GAC), yet the precise mechanism underpinning this association remains controversial. Gastric intestinal metaplasia (GIM) represents the precancerous stage and follows H. pylori-associated chronic gastritis (CG). Sequencing studies have revealed fewer H. pylori and more non-H. pylori bacteria in GAC. However, the spatial organization of the gastric microbiota in health and disease is unknown.
Here, we have combined RNA in situ hybridization and immunohistochemistry to detect H. pylori, non-H. pylori bacteria, and host cell markers (E-cadherin, Mucins 5AC and 2) on tissue sections from patients with CG (n = 15) and GIM (n = 17).
Quantitative analysis of whole slide scans revealed significant correlations of H. pylori and other bacteria in CG and GIM. In contrast to sequencing studies, significantly fewer non-H. pylori bacteria were detected in H. pylori-negative patients. Importantly, whilst H. pylori exclusively colonized the gastric glands, non-H. pylori bacteria invaded the lamina propria in 6/9 CG and 8/10 GIM H. pylori-positive patients. A rapid and cost-effective modified Gram stain was used to confirm these findings and enabled detection of non-H. pylori bacteria in GIM samples.
The invasion of the gastric lamina propria by non-H. pylori bacteria during H. pylori-associated CG and GIM represents an overlooked phenomenon in cancer progression. Further work must determine the mechanisms underlying the synergistic roles of H. pylori and other bacteria in carcinogenesis. This observation should redirect attempts to prevent, diagnose, and treat GAC.
胃癌是全球癌症相关死亡的第四大主要原因。幽门螺杆菌是胃腺癌（GAC）的主要危险因素，然而这种关联背后的确切机制仍存在争议。胃肠化生（GIM）代表癌前阶段，发生在幽门螺杆菌相关的慢性胃炎（CG）之后。测序研究显示，GAC中幽门螺杆菌较少，而非幽门螺杆菌较多。然而，健康和疾病状态下胃微生物群的空间组织尚不清楚。
在这里，我们结合RNA原位杂交和免疫组化，在CG患者（n = 15）和GIM患者（n = 17）的组织切片上检测幽门螺杆菌、非幽门螺杆菌以及宿主细胞标志物（E-钙黏蛋白、黏蛋白5AC和2）。
全玻片扫描的定量分析显示，CG和GIM中幽门螺杆菌与其他细菌存在显著相关性。与测序研究不同，在幽门螺杆菌阴性患者中检测到的非幽门螺杆菌显著较少。重要的是，虽然幽门螺杆菌仅定植于胃腺，但在6/9例CG和8/10例GIM幽门螺杆菌阳性患者中，非幽门螺杆菌侵入了固有层。一种快速且经济高效的改良革兰氏染色法用于证实这些发现，并能够检测GIM样本中的非幽门螺杆菌。
在幽门螺杆菌相关的CG和GIM过程中，非幽门螺杆菌侵入胃固有层是癌症进展中一个被忽视的现象。进一步的研究必须确定幽门螺杆菌和其他细菌在致癌过程中协同作用的机制。这一观察结果应重新引导预防、诊断和治疗GAC的尝试。
