Du Zhiwei, Liu Xuxu, Xie Zhihong, Wang Qiang, Lv Zhenyi, Li Lianghao, Wang Heming, Xue Dongbo, Zhang Yingmei
Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
Department of General Surgery, Qilu Hospital of Shandong University, Shandong, China.
Am J Clin Nutr. 2025 Mar;121(3):643-653. doi: 10.1016/j.ajcnut.2024.12.026. Epub 2024 Dec 31.
The detrimental effects of a high-fat diet (HFD) extend beyond metabolic consequences and include systemic chronic inflammation (SCI), immune dysregulation, and gut health disruption.
In this study, we used Mendelian randomization (MR) to investigate the relationship between HFD, gut microbiota, and SCI.
Genetic variants associated with dietary fat were utilized to explore causal relationships. Genome-wide association study data for the analyses of the gut microbiota, inflammatory cytokines, immune cell characteristics, and serum metabolites were obtained from European individuals. Mediation analysis was used to reveal potential mediating factors. The GMrepo database was used to analyze the bacterial composition in different groups. Transcriptomic and single-cell sequencing analyses explored inflammation and barrier function in colonic tissue.
HFD consumption was linked to changes in the abundance of 3 bacterial families and 11 bacterial genera. Combined with the GMrepo database, the increased abundance of the genus Lachnospiraceae_FCS020group and the decreased abundance of genus Bacteroides and genus Barnesiella are consistent with the MR results. Transcriptomic and single-cell sequencing analyses revealed intestinal inflammation and mucosal barrier dysfunction in HFD-fed mice. MR revealed a link between HFD consumption and increased levels of interleukin (IL)-18 [odds ratio (OR): 3.64, 95%CI: 1.24, 10.69, P = 0.02], MIG (OR = 3.14, 95%CI: 1.17, 8.47, P = 0.02), IL-13 [OR = 3.21, 95% confidence interval (CI): 1.08, -9.52, P = 0.04], and IL-2RA (OR = 2.93, 95%CI: 1.01, 8.53, P = 0.049). Twenty-nine immune cell signatures, including altered monocyte and T-cell subsets, were affected by HFD consumption. Twenty-six serum metabolites that are linked to HFD consumption, particularly lipid and amino acid metabolites, were identified. The positive gut microbiota exhibit extensive associations with inflammatory cytokines. In particular, Lachnospiraceae_FCS020 group (OR: 1.93, 95% CI: 1.11, 3.37, P = 0.02) may play a mediating role in HFD-induced increases in IL-2RA concentrations.
Microbial dysbiosis appears to be an important mechanism for HFD-induced SCI. The Lachnospiraceae_FCS020 group may act as a key genus in HFD-mediated elevation of IL-2RA.
高脂饮食（HFD）的有害影响不仅限于代谢后果，还包括全身慢性炎症（SCI）、免疫失调和肠道健康破坏。
在本研究中，我们使用孟德尔随机化（MR）来研究HFD、肠道微生物群和SCI之间的关系。
利用与膳食脂肪相关的基因变异来探索因果关系。从欧洲个体中获取用于分析肠道微生物群、炎性细胞因子、免疫细胞特征和血清代谢物的全基因组关联研究数据。采用中介分析来揭示潜在的中介因素。使用GMrepo数据库分析不同组中的细菌组成。转录组学和单细胞测序分析探索结肠组织中的炎症和屏障功能。
食用HFD与3个细菌家族和11个细菌属的丰度变化有关。结合GMrepo数据库，毛螺菌科_FCS020组属丰度增加以及拟杆菌属和巴恩斯氏菌属丰度降低与MR结果一致。转录组学和单细胞测序分析揭示了喂食HFD的小鼠存在肠道炎症和粘膜屏障功能障碍。MR显示食用HFD与白细胞介素（IL）-18水平升高[比值比（OR）：3.64，95%置信区间（CI）：1.24，10.69，P = 0.02]、MIG（OR = 3.14，95%CI：1.17，8.47，P = 0.02）、IL-13[OR = 3.21，95%CI：1.08，-9.52，P = 0.04]和IL-2RA（OR = 2.93，95%CI：1.01，8.53，P = 0.049）之间存在关联。包括单核细胞和T细胞亚群改变在内的29种免疫细胞特征受食用HFD影响。鉴定出26种与食用HFD相关的血清代谢物，特别是脂质和氨基酸代谢物。阳性肠道微生物群与炎性细胞因子表现出广泛关联。特别是，毛螺菌科_FCS020组（OR：1.93，95%CI：1.11，3.37，P = 0.02）可能在HFD诱导的IL-2RA浓度升高中起中介作用。
微生物失调似乎是HFD诱导SCI的重要机制。毛螺菌科_FCS020组可能是HFD介导的IL-2RA升高的关键属。
