基于孟德尔随机化与多维微生物组整合分析的肠道菌群与慢性胰腺炎因果关联研究

Causal associations between gut microbiota and chronic pancreatitis: an integrative analysis using Mendelian randomization and multi-omics data

摘要:

背景与目的 肠道微生物紊乱被认为参与慢性胰腺炎（CP）的发生发展，但其因果关系尚未明确。本研究基于孟德尔随机化（MR）联合多维度微生物组学分析，系统评估肠道菌群与CP的因果关联，并筛选关键菌属。方法 基于大规模全基因组关联研究（GWAS）汇总数据，采用双样本MR分析评估属水平肠道微生物对CP及血浆代谢物的因果效应。同步收集CP患者及小鼠模型粪便样本，进行16S rRNA测序分析菌群结构差异，并结合公共数据库数据进行交叉验证，以筛选与CP密切相关的关键菌属。结果 MR分析识别出8个与CP风险存在潜在因果关联的菌属，其中乳球菌属、考拉杆菌属、罗斯氏菌属等为潜在危险因素，而甲烷短杆菌属、毛螺菌科FCS020群等表现为保护因素。进一步发现22种血浆代谢物与CP显著相关。16S rRNA测序显示，CP患者及模型小鼠均存在明显肠道菌群失调，分别鉴定出59个和52个差异菌属。交叉验证结果表明，乳球菌属在MR分析、人群样本（P=0.008）及小鼠模型（P=0.003）中均具有一致性关联，为最关键候选菌属。结论 本研究整合遗传因果推断与多维微生物组证据，证实肠道菌群紊乱与CP之间存在潜在因果关系。乳球菌属可能在CP发生早期发挥促发作用，而在疾病进展阶段呈现耗竭，提示其在不同阶段具有动态调控作用。

Abstract:

Background and Aims Gut microbiota dysbiosis is implicated in the pathogenesis of chronic pancreatitis (CP), yet its causal relationship remains unclear. This study aimed to systematically evaluate the causal associations between gut microbiota and CP using Mendelian randomization (MR) integrated with multi-dimensional microbiome analyses.Methods Summary-level data from large-scale genome-wide association studies (GWAS) were used to perform two-sample MR analyses to assess the causal effects of gut microbial genera on CP and plasma metabolites. Fecal samples from CP patients and mouse models were subjected to 16S rRNA sequencing to characterize microbial alterations. Public datasets were incorporated for cross-validation to identify key CP-associated genera.Results MR analysis identified eight microbial genera with potential causal associations with CP. Lactococcus, Phascolarctobacterium, and Roseburia were identified as potential risk factors, whereas Methanobrevibacter and Lachnospiraceae FCS020 group showed protective effects. Additionally, 22 plasma metabolites were associated with CP. 16S rRNA sequencing revealed significant microbial dysbiosis, with 59 and 52 differentially abundant genera identified in humans and mice, respectively. Cross-validation consistently identified Lactococcus as the most critical genus across MR, human (P=0.008), and mouse (P=0.003) datasets.Conclusion By integrating genetic causal inference with microbiome profiling, this study provides evidence supporting a causal link between gut microbiota and CP. Lactococcus may exert stage-dependent effects, acting as a potential risk factor in disease susceptibility while being depleted during disease progression.