High-fat diet-derived free fatty acids impair the intestinal immune system and increase sensitivity to intestinal epithelial damage
High-fat diet-derived free fatty acids impair the intestinal immune system and increase sensitivity to intestinal epithelial damage
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DOI：
10.1016/j.bbrc.2019.11.158
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发表时间：
2020-02-19
影响因子：
3.1
通讯作者：
Watanabe, Mamoru
中科院分区：
文献类型：
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作者：
Tanaka, Shohei;Nemoto, Yasuhiro;Watanabe, Mamoru
在日本和其他亚洲国家，西方饮食引起的脂肪摄取增加被认为与炎症性肠病、结直肠癌和食物过敏的发病率增加有关;然而，其机制仍不清楚。高脂饮食（HFD）喂养的小鼠是用于检查体内脂肪摄入的影响的常见动物模型。据报道，HFD会加剧DSS诱导的结肠炎和肠道肿瘤发生，但HFD在疾病诱导前对肠道的影响往往被忽视。我们发现，肠道和肠道相关淋巴组织（GALT）形态HFD喂养的小鼠不同于标准饮食（SD）喂养的小鼠。为了阐明脂肪摄入增加肠道疾病的机制，我们分析了HFD喂养小鼠肠道的形态学和免疫学方面以及分子机制和生理学。喂食HFD 3周可诱导小肠、结肠和GALT萎缩，并减少小肠上皮内淋巴细胞（IEL）和固有层淋巴细胞（LPLs）的数量。喂食HFD仅1天可减少小肠（SI）-IEL和SI-LPLs的数量。喂食3周HFD的效果在返回SD后持续2周。HFD对肠道免疫系统的影响与肠道微生物无关。我们假设肠腔中丰富的HFD衍生的游离脂肪酸的细胞毒性损害肠道免疫系统。饱和和不饱和游离脂肪酸在体外对肠道T细胞具有毒性。口服游离脂肪酸可减少SI-IEL和LPL的数量。使用脂肪酶抑制剂减少管腔游离脂肪酸减弱了HFD诱导的肠道免疫系统变化，而使用他汀类药物减少血清游离脂肪酸则没有。因此，HFD诱导的游离脂肪酸损害肠道;这种作用被称为“肠道脂毒性”。由于HFD喂养后SI-LPL的持续减少加剧了吲哚美辛诱导的小肠损伤，因此在日本食用西式饮食引起的人体肠道脂毒性可能会增加肠道疾病，如IBD、结直肠癌或食物过敏。(C)2019爱思唯尔公司All rights reserved.
In Japan and other Asian countries, increased fat uptake induced by a westernized diet is thought to be associated with an increased incidence of inflammatory bowel disease, colorectal cancer and food allergies; however, the mechanism for this remains unclear. High-fat diet (HFD)-fed mice are common animal models used to examine the effect of fat intake in vivo. HFDs are reported to exacerbate DSS-induced colitis and intestinal tumorigenesis, but the effect of HFDs on the intestines before disease induction is often overlooked. We found that the intestinal and gut-associated lymphoid tissue (GALT) morphology of HFD-fed mice differed from that of standard diet (SD)-fed mice. To clarify the mechanism by which fat intake increases intestinal diseases, we analyzed the morphological and immunological aspects of the intestines of HFD-fed mice as well as the molecular mechanisms and physiology. Feeding an HFD for 3 weeks induced atrophy of the small intestine, colon and GALT and reduced the number of small intestinal intraepithelial lymphocytes (IELs) and lamina propria lymphocytes (LPLs).Feeding an HFD for only one day reduced the number of small intestinal (SI)-IELs and SI-LPLs. The effect of feeding a 3-week HFD continued for 2 weeks after returning to the SD. The effect of the HFD on the intestinal immune system was independent of the gut microbes. We hypothesized that the cytotoxicity of the abundant HFD-derived free fatty acids in the intestinal lumen impairs the intestinal immune system. Both saturated and unsaturated free fatty acids were toxic to intestinal T-cells in vitro. Orally administering free fatty acids reduced the number of SI-IELs and LPLs. Using a lipase inhibitor to reduce the luminal free fatty acids attenuated the HFD-induced changes in the intestinal immune system, while using a statin to reduce the serum free fatty acids did not. Thus, HFD-induced free fatty acids damaged the intestines; this effect was termed "intestinal lipotoxicity". Because sustained reduction of SI-LPLs after HFD feeding exacerbated indomethacin-induced small intestinal damage, lipotoxicity to the human intestines incurred by consuming a westernized diet in Japan may increase intestinal diseases such as IBD, colorectal cancer or food allergies. (C) 2019 Elsevier Inc. All rights reserved.