Institute for Biomedical Sciences, Georgia State University, Atlanta, Georgia.
Graduate Program in Immunology and Infectious Disease, The Pennsylvania State University, Philadelphia, Pennsylvania.
Cell Mol Gastroenterol Hepatol. 2020;9(2):313-333. doi: 10.1016/j.jcmgh.2019.09.009. Epub 2019 Oct 5.
BACKGROUND & AIMS: Consumption of a low-fiber, high-fat, Western-style diet (WSD) induces adiposity and adipose inflammation characterized by increases in the M1:M2 macrophage ratio and proinflammatory cytokine expression, both of which contribute to WSD-induced metabolic syndrome. WSD-induced adipose inflammation might result from endoplasmic reticulum stress in lipid-overloaded adipocytes and/or dissemination of gut bacterial products, resulting in activation of innate immune signaling. Hence, we aimed to investigate the role of the gut microbiota, and its detection by innate immune signaling pathways, in WSD-induced adipose inflammation.
Mice were fed grain-based chow or a WSD for 8 weeks, assessed metabolically, and intestinal and adipose tissue were analyzed by flow cytometry and quantitative reverse transcription polymerase chain reaction. Microbiota was ablated via antibiotics and use of gnotobiotic mice that completely lacked microbiota (germ-free mice) or had a low-complexity microbiota (altered Schaedler flora). Innate immune signaling was ablated by genetic deletion of Toll-like receptor signaling adaptor myeloid differentiation primary response 88.
Ablation of microbiota via antibiotic, germ-free, or altered Schaedler flora approaches did not significantly impact WSD-induced adiposity, yet dramatically reduced WSD-induced adipose inflammation as assessed by macrophage populations and cytokine expression. Microbiota ablation also prevented colonic neutrophil and CD103 dendritic cell infiltration. Such reduced indices of inflammation correlated with protection against WSD-induced dysglycemia, hypercholesterolemia, and liver dysfunction. Genetic deletion of myeloid differentiation primary response 88 also prevented WSD-induced adipose inflammation.
These results indicate that adipose inflammation, and some aspects of metabolic syndrome, are not purely a consequence of diet-induced adiposity per se but, rather, may require disturbance of intestine-microbiota interactions and subsequent activation of innate immunity.
低纤维、高脂肪的西式饮食（WSD）的摄入会导致肥胖和脂肪炎症，其特征是 M1:M2 巨噬细胞比例增加和促炎细胞因子表达增加，这两者都有助于 WSD 诱导的代谢综合征。WSD 诱导的脂肪炎症可能是由于脂质超负荷脂肪细胞中的内质网应激和/或肠道细菌产物的传播，导致先天免疫信号的激活。因此，我们旨在研究肠道微生物群及其通过先天免疫信号通路在 WSD 诱导的脂肪炎症中的作用。
用谷物基础饲料或 WSD 喂养小鼠 8 周，进行代谢评估，并通过流式细胞术和定量逆转录聚合酶链反应分析肠道和脂肪组织。通过抗生素和使用完全缺乏微生物群（无菌小鼠）或具有低复杂性微生物群（改变的 Schaedler 菌群）的无菌小鼠来消除微生物群。通过遗传缺失 Toll 样受体信号接头髓样分化初级反应 88（MyD88）来消除先天免疫信号。
通过抗生素、无菌或改变的 Schaedler 菌群方法消除微生物群并没有显著影响 WSD 诱导的肥胖，但显著降低了 WSD 诱导的脂肪炎症，如巨噬细胞群和细胞因子表达。微生物群消除也防止了结肠中性粒细胞和 CD103 树突状细胞的浸润。这些炎症指数的降低与预防 WSD 诱导的血糖异常、高胆固醇血症和肝功能障碍相关。MyD88 的遗传缺失也防止了 WSD 诱导的脂肪炎症。
这些结果表明，脂肪炎症和代谢综合征的某些方面不仅仅是饮食诱导的肥胖本身的结果，而是可能需要干扰肠道-微生物群相互作用和随后的先天免疫激活。
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