Parabacteroides distasonis attenuates toll-like receptor 4 signaling and Akt activation and blocks colon tumor formation in high-fat diet-fed azoxymethane-treated mice
Parabacteroides distasonis attenuates toll-like receptor 4 signaling and Akt activation and blocks colon tumor formation in high-fat diet-fed azoxymethane-treated mice
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DOI：
10.1002/ijc.31559
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发表时间：
2018-10-01
影响因子：
6.4
通讯作者：
Crott, Jimmy W.
中科院分区：
文献类型：
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作者：
Koh, Gar Yee;Kane, Anne;Crott, Jimmy W.
肠道菌群失调可能在结直肠肿瘤发生中发挥病因作用。我们之前观察到，小鼠粪便中 Parabacteroides distasonis (Pd) 的丰度与肠道肿瘤负荷和 IL-1 β 浓度呈负相关。在这里，我们评估了结肠癌细胞系中钯膜组分 (PdMb) 的抗炎能力。此外，我们还测试了 Pd 是否可以抑制小鼠结肠肿瘤的发生。六周大的雄性 A/J 小鼠被喂食低脂 (LF) 饮食、高脂 (HF) 饮食或 HF+ 全冻干 Pd（HF + Pd，0.04% wt/wt）24 周。节食 1 周后，小鼠每周接受 4 次氧化偶氮注射。 PdMb 强烈抑制促炎细胞因子的产生，并降低结肠癌细胞系中由大肠杆菌脂多糖诱导的 MyD88 和 pAkt (ser473) 的丰度。此外，PdMb 诱导结肠癌细胞系凋亡并阻断报告细胞系中 TLR4 的激活。在 0% 的 LF 小鼠（19 只中的 0 只）、25% 的 HF 小鼠（20 只中的 5 只）和 0% HF + Pd 小鼠（20 只中的 0 只）中观察到结肠肿瘤（p = 0.005）。与 HF 小鼠相比，后一组小鼠的结肠粘膜中 MyD88 和 pAkt (ser473) 的丰度也较低。总而言之，这些数据表明 Pd 具有抗炎和抗癌特性，这可能是通过抑制 TLR4 和 Akt 信号传导以及促进细胞凋亡来介导的。需要进一步的工作来在其他模型中证实这些发现并充分阐述作用机制。
Gut dysbiosis may play an etiological role in colorectal tumorigenesis. We previously observed that the abundance of Parabacteroides distasonis (Pd) in stool was inversely associated with intestinal tumor burden and IL-1 beta concentrations in mice. Here, we assessed the anti-inflammatory capacity of Pd membrane fraction (PdMb) in colon cancer cell lines. In addition, we tested whether Pd could suppress colon tumorigenesis in mice. Six-week-old male A/J mice were fed a low-fat (LF) diet, high-fat (HF) diet or HF+ whole freeze-dried Pd (HF + Pd, 0.04% wt/wt) for 24 weeks. After 1 week on diet, mice received 4 weekly injections of azoxymethane. PdMb robustly suppressed the production of pro-inflammatory cytokines and lowered the abundance of MyD88 and pAkt (ser473) induced by E. coli lipopolysaccharide in colon cancer cell lines. Moreover, PdMb induced apoptosis in colon cancer cell lines and blocked TLR4 activation in a reporter line. Colon tumors were observed in 0% of LF (0 of 19), 25% of HF (5 of 20) and 0% of HF + Pd mice (0 of 20) (p = 0.005). The latter group also displayed a lower abundance of MyD88 and pAkt (ser473) in colonic mucosa than HF mice. Taken together, these data suggest that Pd has anti-inflammatory and anti-cancer properties that are likely mediated by the suppression of TLR4 and Akt signaling, as well as promotion of apoptosis. Further work is needed to confirm these findings in additional models and fully elaborate the mechanism of action.