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OA

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.