Intestinal autophagy links psychosocial stress with gut microbiota to promote inflammatory bowel disease
Intestinal autophagy links psychosocial stress with gut microbiota to promote inflammatory bowel disease
复制标题
肠道自噬将社会心理压力与肠道微生物群联系起来，促进炎症性肠病
DOI：
10.1038/s41419-019-1634-x
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发表时间：
2019-09-30
影响因子：
9
通讯作者：
Bai, Yu
中科院分区：
文献类型：
--
作者：
Wang, Shu-Ling;Shao, Bo-Zong;Bai, Yu
心理社会应激是炎症性肠病（IBD）的重要诱发因素，而自噬是IBD发生发展的一个新的中心问题。本研究探讨了自噬在应激相关IBD患者和动物模型中的潜在作用。在23例IBD患者中确定了心理社会应激与肠道自噬之间的相关性。促肾上腺皮质激素释放激素（CRH）是一种公认的心理社会应激诱导剂，在葡聚糖硫酸钠（DSS）诱导的IBD小鼠和脂多糖（LPS）刺激的骨髓源性巨噬细胞（BMDM）中给予。在IBD患者中，自噬标志物beclin-1、LC 3-II/I比率、Atg 16 L1和Atg 4 B显著增强。社会心理应激评分与beclin-1水平和LC 3 II/I比值呈正相关。在IBD小鼠模型中，CRH显著加重肠道炎症，增加潘氏细胞化生，并增强肠道自噬（beclin-1，Atg 16 L1，PIK 3R 4和Atg 4 B上调; GAA，CTSD和PPKAA 1下调）。此外，CRH诱导的肠道微生物生态失调由有害细菌数量的显著增加证明。在LPS刺激的BMDM中，CRH显著增加M1/M2极化，从而促进炎症。在IBD小鼠和LPS处理的BMDM中，氯喹阻断自噬消除了CRH的不利影响，而自噬诱导剂雷帕霉素对IBD病变产生了明显的保护作用。我们的数据表明，心理社会压力可能通过调节肠道微生物群和炎症来加重IBD，从而增强肠道自噬。这些数据表明，自噬作为一个有前途的治疗目标，心理社会压力相关的IBD。
Psychosocial stress is a critical inducing factor of inflammatory bowel diseases (IBD), while autophagy is a novel central issue of IBD development. The present study investigated the potential role of autophagy in stress-related IBD in patients and animal model. The correlation between psychosocial stress and intestinal autophagy was determined in 23 patients with IBD. Corticotropin-releasing hormone (CRH), a well-established inducer of psychosocial stress, was administrated in dextran sulfate sodium (DSS)-induced IBD mice and lipopolysaccharide (LPS)-stimulated bone marrow-derived macrophages (BMDM). In IBD patients, the autophagy markers beclin-1, LC3-II/I ratio, Atg16L1, and Atg4B were significantly enhanced. The psychosocial stress score was positively associated with the levels of beclin-1 and the LC3II/I ratio in intestinal biopsy specimens. In IBD mouse model, CRH significantly aggravated intestinal inflammation, increased Paneth cell metaplasia, and enhanced intestinal autophagy (beclin-1, Atg16L1, PIK3R4, and Atg4B upregulation; GAA, CTSD, and PPKAA1 downregulation). Additionally, the CRH-induced gut microbial dysbiosis was evidenced by a marked increase in the number of detrimental bacteria. In LPS-stimulated BMDM, CRH substantially increased M1/M2 polarization and thus promoted inflammation. In both IBD mice and LPS-treated BMDM, blockade of autophagy by chloroquine abrogated the unbeneficial effects of CRH, whereas autophagy inducer rapamycin resulted in a pronounced protective effect against IBD lesion. Our data demonstrate that psychosocial stress may link the enhanced intestinal autophagy by modulating gut microbiota and inflammation to aggravate IBD. These data indicate autophagy as a promising therapeutic target for psychosocial stress-related IBD.