遵义医科大学学报2025，Vol.48Issue(7)：700-712,13.
IgA肾病患者肠道菌群及代谢失衡与外周血中色氨酸代谢AhR和NLRP3炎性小体的相关性
Study on correlation between intestinal flora and metabolic disorder and AhR and NLRP3 in peripheral blood of patients with IgA nephropathy
摘要
Abstract
Objective To investigate the interplay among gut microbiota composition,serum tryptophan metabo-lism,and nlr family,pyrin domain containing protein B(NLRP3)inflammasome activation in patients with IgA nephropathy(IgAN)by integrating 16S rRNA sequencing and liquid chromatography-mass spectrometry(LC-MS).Furthermore,we seek to elucidate the mechanistic role of tryptophan metabolic pathways in regulating NL-RP3-driven inflammatory responses during IgAN progression.These findings are expected to provide novel insights into early intervention strategies and the identification of therapeutic targets for IgAN management.Methods A to-tal of 21 biopsy-confirmed primary IgA nephropathy(IgAN)patients(IgAN group)and 21 healthy controls(HCs)were enrolled from Affiliated Hospital of Zunyi Medical University during March 2022 and March 2023.All participants underwent fecal 16S rRNA sequencing and serum metabolomic profiling(via LC-MS).Compara-tive analysis of gut microbial composition and serum metabolic profiles was performed between the two groups.Se-rum levels of aryl hydrocarbon receptor(AhR),NLRP3 inflammasome,galactose-deficient IgA1(Gd-IgA1),in-terleukin-18(IL-18),and interleukin-6(IL-6)were quantified using ELISA.Differentially abundant gut micro-biota taxa and metabolites were identified.Integrative network analysis was subsequently applied to assess the cor-relations between these discriminative features and peripheral inflammatory biomarkers,as well as clinical param-eters.Results Compared with healthy controls,IgAN patients exhibited significant reductions in gut microbial di-versity,community richness,and structural stability,characterized by an overrepresentation of opportunistic patho-gensand depletion of commensal beneficial bacteria(P＜0.05).Concurrently,serum levels of inflammatory me-diators including AhR,Gd-IgA1,IL-18,and IL-6 were markedly elevated in IgAN patients(P＜0.05).Untarget-ed metabolomics identified 26 significantly downregulated metabolites(VIP＞2,P＜0.01)and 25 upregulated metabolites(VIP＞1.25,P＜0.01)in the IgAN group.Upregulated metabolites were predominantly enriched in tryptophan metabolism and arginine/proline metabolic pathways,while downregulated species clustered within primary bile acid biosynthesis,glycerophospholipid metabolism,and polyunsaturated fatty acid synthesis.Spearman correlation network analysis revealed significant positive correlations between the harmful Blautia genus and serum 5-HTP(r=0.427,P=0.004),as well as between Hungatella and serum 5-HTP(r=0.516,P=0.000 4).Among beneficial bacteria,the genus Lachnospira showed significant positive correlations with bile acid synthesis pathway intermediates,including 3β,7α-dihydroxy-5-cholanolic acid(r=0.411,P=0.006),5β-cho-lan-3α,7α,12α-triol(r=0.382,P=0.012),and 7α,12α-dihydroxycholest-4-en-3-one(r=0.308,P=0.046).Additionally,in peripheral blood of IgAN patients,the levels of clinical indicators such as serum creati-nine(r=0.684,P=0.000 1)and 24-hour urinary protein quantification(r=0.526,P=0.000 4),exhibited a significant positive correlation with the tryptophan metabolite 5-HTP.Furthermore,24-hour urinary protein quanti-fication,serum creatinine,and microscopic red blood cell count showed significant negative correlations with pri-mary bile acids(e.g.,3β,7α-dihydroxy-5-cholanolic acid r=-0.439,P=0.003;r=-0.561,P=0.000 1;r=-0.494,P=0.000 8 and 5β-cholan-3α,7α,12α-triol r=-0.512,P=0.005;r=-0.634,P=0.000 1;r=-0.361,P=0.018)and other unsaturated fatty acid synthesis pathways.Conclusion In patients with IgAN,significant dysbiosis of the gut microbiota leads to elevated AhR ligands derived from tryptophan metabolism,which in turn activates the NLRP3 inflammasome(via the IL-1 β pathway),exacerbating renal injury(manifested by elevated serum creatinine and urinary protein).Concurrently,the reduction of short-chain fatty acid(SCFA)-producing bacteria coexists with bile acid metabolism disorders,indicating bidirectional interactions between the gut microbiota and metabolic processes.Targeted regulation of the tryptophan AhR-NLRP3 axis mediated by gut microbiota is a potential therapeutic strategy.关键词
IgA 肾病/肠道菌群/16S rRNA/代谢组学/NLRP3Key words
IgA nephropathy/gut microbiota/16S rRNA/metabolomics/NLRP3分类
医药卫生引用本文复制引用
余政,王馨怡,胡倩,何元源,钟正霞..IgA肾病患者肠道菌群及代谢失衡与外周血中色氨酸代谢AhR和NLRP3炎性小体的相关性[J].遵义医科大学学报,2025,48(7):700-712,13.基金项目
贵州省卫健委科技基金资助项目(NO:gzwkj2021-133) （NO:gzwkj2021-133）
遵义市联合基金资助项目[NO:遵市科合HZ字(2021)18] （2021）
贵州省科学技术基金计划项目[NO:黔科合基础ZK(2024)一般292]. （2024）
