Gut Microbial Dysbiosis and Changes in Fecal Metabolic Phenotype in Precancerous Lesions of Gastric Cancer Induced With N-Methyl-N'-Nitro-N-Nitrosoguanidine, Sodium Salicylate, Ranitidine, and Irregular Diet.
Gut Microbial Dysbiosis and Changes in Fecal Metabolic Phenotype in Precancerous Lesions of Gastric Cancer Induced With N-Methyl-N'-Nitro-N-Nitrosoguanidine, Sodium Salicylate, Ranitidine, and Irregular Diet.
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N-甲基-N-硝基-N-亚硝基胍、水杨酸钠、雷尼替丁及不规律饮食诱发胃癌癌前病变的肠道菌群失调及粪便代谢表型变化
DOI：
10.3389/fphys.2021.733979
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发表时间：
2021
影响因子：
4
通讯作者：
Ding X
中科院分区：
文献类型：
--
作者：
Chu F;Li Y;Meng X;Li Y;Li T;Zhai M;Zheng H;Xin T;Su Z;Lin J;Zhang P;Ding X
背景与目的：胃癌前病变是胃癌发病风险增加的最重要的病理阶段，是预防胃癌发生的关键阶段。在本研究中，我们发现在N-甲基-N‘-硝基-N-亚硝基-N-亚硝基(MNNG)多因素诱发大鼠模型从慢性胃炎向GC恶变的过程中，肠道菌群发生了显著的变化。越来越多的证据表明，肠道微生物区系和代谢的改变可能与慢性炎症和胃肠道癌症有关。然而，肠道微生物区系与代谢产物、炎症因子的相关性以及PLGC形成的潜在机制尚未被揭示。方法：采用MNNG、饮用水杨酸钠、饲喂雷尼替丁、饮食不规律等多种因素建立PLGC大鼠模型。通过HE染色观察大鼠胃黏膜的病理状态，采用Luminex液体悬浮芯片检测大鼠血清中主要炎性细胞因子的水平。采用16S核糖体RNA(RRNA)基因测序和非靶向代谢组学方法检测粪便微生物组成和代谢产物。对肠道微生物区系、血清和肠道微生物区系中的炎性细胞因子以及粪便中的差异代谢物进行相关分析，以阐明其生物学功能。结果：与对照组相比，模型组大鼠胃黏膜形态和病理均有明显的恶性改变，血清中IL-1β、IL-4、IL-6、IL-10、干扰素-α、肿瘤坏死因子-α、巨噬细胞集落刺激因子等炎性细胞因子水平显著升高，而趋化因子(C-X-C Motif)配体1(CXCL1)水平显著降低。模型组和对照组大鼠肠道微生物区系组成和粪便代谢谱有显著差异。与对照组相比，模型组大鼠乳酸菌和双歧杆菌显著增加，而Turicibacter、Romboutsia、瘤胃球菌科_UCG-014、瘤胃球菌科_UCG-005和瘤胃球菌_1显著减少。与脂质代谢和过氧化物酶体增殖物激活受体(PPAR)信号通路相关的代谢产物也发生了显著变化。此外，模型大鼠血清炎性细胞因子差异性变化、粪便代谢表型变化与肠道微生物代谢紊乱有显著相关性。结论：炎症反应的激活、肠道微生物区系的紊乱和粪便代谢表型的改变可能与PLGC的发生密切相关。本研究为从炎症免疫动态平衡、肠道微生物区系、代谢功能平衡等角度揭示慢性胃炎和GC危险因素的发病机制提供了新的思路。
Background and Aims: Precancerous lesions of gastric cancer (PLGC) are the most important pathological phase with increased risk of gastric cancer (GC) and encompass the key stage in which the occurrence of GC can be prevented. In this study, we found that the gut microbiome changed significantly during the process of malignant transformation from chronic gastritis to GC in N-methyl-N′-nitro-N-nitrosoguanidine (MNNG) multiple factors-induced rat model. Accumulating evidence has shown that alterations in gut microbiota and metabolism are potentially linked to chronic inflammation and cancer of the gastrointestinal tract. However, the correlation of gut microbiota and metabolites, inflammatory factors, and the potential mechanism in the formation of PLGC have not yet been revealed. Methods: In this study, multiple factors including MNNG, sodium salicylate drinking, ranitidine feed, and irregular diet were used to establish a PLGC rat model. The pathological state of the gastric mucosa of rats was identified through HE staining and the main inflammatory cytokine levels in the serum were detected by the Luminex liquid suspension chip (Wayen Biotechnologies, Shanghai, China). The microbial composition and metabolites in the stool samples were tested by using 16S ribosomal RNA (rRNA) gene sequencing and non-targeted metabolomics. The correlation analysis of gut microbiota and inflammatory cytokines in the serum and gut microbiota and differential metabolites in feces was performed to clarify their biological function. Results: The results showed that compared to the control group, the gastric mucosa of the model rats had obvious morphological and pathological malignant changes and the serum levels of inflammatory cytokines including interleukin-1β (IL-1β), interleukin-4 (IL-4), interleukin-6 (IL-6), interleukin-10 (IL-10), interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), and macrophage colony-stimulating factor (M-CSF) increased significantly, while the level of chemokine (C-X-C motif) ligand 1 (CXCL1) in serum reduced significantly. There were significant differences in the composition of the gut microbiota and fecal metabolic profiles between the model and control rats. Among them, Lactobacillus and Bifidobacterium increased significantly, while Turicibacter, Romboutsia, Ruminococcaceae_UCG-014, Ruminococcaceae_UCG-005, and Ruminococcus_1 reduced significantly in the model rats compared to the control rats. The metabolites related to the lipid metabolism and peroxisome proliferator-activated receptor (PPAR) signaling pathway have also undergone significant changes. In addition, there was a significant correlation between the changes of the differential inflammatory cytokines in the serum, fecal metabolic phenotypes, and gut microbial dysbiosis in model rats. Conclusion: The activation of the inflammatory response, disturbance of the gut microbiota, and changes in the fecal metabolic phenotype could be closely related to the occurrence of PLGC. This study provides a new idea to reveal the mechanism of risk factors of chronic gastritis and GC from the perspective of inflammation-immune homeostasis, gut microbiota, and metabolic function balance.
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影响因子：
9.8
作者：
Correa, Pelayo;Piazuelo, M. Blanca;Wilson, Keith T.
通讯作者：
Wilson, Keith T.
影响因子：
4.6
作者：
Aviles-Jimenez F;Vazquez-Jimenez F;Medrano-Guzman R;Mantilla A;Torres J
通讯作者：
Torres J
影响因子：
6.4
作者：
Choueiri, Toni K.;Je, Youjin;Cho, Eunyoung
通讯作者：
Cho, Eunyoung
DOI：
10.3322/caac.21398
发表时间：
2017-07-08
期刊：
CA: a cancer journal for clinicians
影响因子：
--
作者：
Bhatt AP;Redinbo MR;Bultman SJ
通讯作者：
Bultman SJ
DOI：
10.1016/j.bpg.2017.09.010
发表时间：
2017-12-01
影响因子：
3.2
作者：
Lam, S. Y.;Yu, J.;Fuhler, G. M.
通讯作者：
Fuhler, G. M.