PO.TB10.14 · 肿瘤生物学
异位上消化道微生物组与多原发肺癌的关联：一项多中心横断面研究
Association of an ectopic upper gastrointestinal microbiome with multiple primary lung cancers: A multi-site cross-sectional study
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：多原发肺癌（MPLC）以其独立的多灶性起源为特征，其病因在很大程度上仍不明确，尤其是微生物组的作用。胃食管反流病（GERD）是肺癌的公认危险因素，但其与MPLC的特定关联，以及GERD介导的上消化道（UGI）微生物群向肺结节（PNs）易位的可能性尚未得到研究。我们假设GERD促进UGI向肺的微生物易位，从而促成MPLC中的促癌微环境。
材料与方法：在这项前瞻性病例对照研究（NCT06973499）中，使用经过验证的GERD-Q问卷评估了149例MPLC、41例孤立性原发肺癌（SPLC）和119例健康对照的GERD症状负荷。对21例MPLC患者的一个子集，我们采用PacBio全长16S rRNA基因测序对来自七个解剖区室的样本（包括UGI道和多个切除的PNs）进行了全面的多部位微生物组分析。采用了严格的污染对照。使用微生物来源追踪（SourceTracker2）量化UGI细菌易位，并通过系统发育分析确认菌株水平的一致性。
结果：与健康对照相比，MPLC患者高危GERD症状（GERD-Q评分>8）的患病率显著更高（26.2% vs. 16.0%；OR = 1.87，95% CI 1.01-3.44，P=0.048）；在SPLC患者中未观察到此关联（P=0.87）。关键的是，微生物来源追踪在MPLC患者22.9%的PNs（35个结节中的8个）中识别出显著的异位UGI来源细菌特征。将症状与微生物相联系，一项事后分析揭示出一个强趋势：高GERD负荷的MPLC患者其PNs中UGI微生物群的比例贡献大于低GERD负荷者（P = 0.0692）。最后，高分辨率系统发育分析证实同一个体内UGI和肺部位之间存在共有的、完全相同的Prevotella melaninogenica和Gemella haemolysans菌株，为活跃易位提供了确凿证据。
结论：本研究提供了首个直接的多部位证据，将GERD症状负荷与MPLC患者UGI微生物群向肺结节的活跃易位相联系。我们提出"GERD-微生物易位-多灶性癌变"轴作为一条新的致病途径，可能促成MPLC的病因和异质性。我们的发现将UGI-肺轴确定为新型诊断和治疗策略的潜在靶点，提示管理GERD或靶向易位的致病微生物组可能代表MPLC预防或阻断的新范式。
查看英文原文 English abstract
Background: The etiology of multiple primary lung cancers (MPLC), defined by their independent multifocal origins, remains largely unknown, particularly the contribution of the microbiome. Gastroesophageal reflux disease (GERD) is an established risk factor for lung cancer, but its specific association with MPLC and the potential for GERD-mediated translocation of upper gastrointestinal (UGI) microbiota into pulmonary nodules (PNs) has not been investigated. We hypothesized that GERD facilitates UGI-to-lung microbial translocation, contributing to a pro-carcinogenic microenvironment in MPLC.
Materials and Methods: In this prospective case-control study (NCT06973499), GERD symptom burden was assessed in 149 MPLC, 41 solitary primary lung cancer (SPLC), and 119 healthy controls using the validated GERD-Q questionnaire. For a subset of 21 MPLC patients, we performed comprehensive multi-site microbiome profiling using PacBio full-length 16S rRNA gene sequencing on samples from seven anatomical compartments, including the UGI tract and multiple resected PNs. Rigorous contamination controls were employed. Microbial source tracking (SourceTracker2) was used to quantify UGI bacterial translocation, with strain-level identity confirmed via phylogenetic analysis.
Results: MPLC patients exhibited a significantly higher prevalence of high-risk GERD symptoms (GERD-Q score >8) compared to healthy controls (26.2% vs. 16.0%; OR = 1.87, 95% CI 1.01-3.44, P=0.048); this association was not observed in SPLC patients (P=0.87). Crucially, microbial source tracking identified a significant, ectopic UGI-derived bacterial signature in 22.9% of PNs (8 of 35 nodules) from MPLC patients. Linking the symptom to the microbe, a post-hoc analysis revealed a strong trend where MPLC patients with a high GERD burden showed a greater proportional contribution of UGI microbiota to their PNs compared to those with a low GERD burden (P = 0.0692). Finally, high-resolution phylogenetic analysis confirmed shared, identical strains of Prevotella melaninogenica and Gemella haemolysans across UGI and pulmonary sites within the same individuals, providing definitive evidence of active translocation.
Conclusion: This study provides the first direct, multi-site evidence linking GERD symptom burden to the active translocation of UGI microbiota into pulmonary nodules in MPLC patients. We introduce the 'GERD-microbial translocation-multifocal carcinogenesis' axis as a novel pathogenic pathway that may contribute to the etiology and heterogeneity of MPLC. Our findings identify the UGI-lung axis as a potential target for novel diagnostic and therapeutic strategies, suggesting that managing GERD or targeting the translocated pathobiome could represent a new paradigm for MPLC prevention or interception.
利益披露 Disclosure
G. Pei, None..
Y. Guo, None..
N. Lyu, None..
Y. Huang, None.