Abstract：
OBJECTIVE: This study aims to disclose how loss of fucosyltransferase 2 (Fut2) impacts intestinal inflammation through cGAS-STING pathway that is closely associated with gut microbiota, and which microbial metabolite improves colitis in Fut2 deficiency.
METHODS: Chronic colitis was induced in intestinal epithelial Fut2 knock out mice (Fut2△IEC), whose intestinal inflammation and activity of cGAS-STING pathway were evaluated. 16S rRNA sequencing and metabolomics were performed using intestinal samples. 2-oxindole was used to treat RAW264.7 cells and Fut2△IEC mice with colitis (Fut2△IEC-DSS) to investigate the effect of 2-oxindole on cGAS-STING response and intestinal inflammation.
RESULTS: Fut2 loss exacerbated chronic colitis in mice, manifested by declined body weight, reduced colon length, increased disease activity index (DAI) and more colon injury in Fut2△IEC-DSS mice compared with WT-DSS (wild type mice with colitis). Lack of Fut2 promoted activation of cGAS-STING pathway. Fut2 deficiency had a primary impact on colonic microbiota, as shown by alteration of microbial diversity and structure, as well as decreased Lactobacillus. Metabolic structure and tryptophan metabolism in colonic luminal microbiota were also influenced by Fut2 loss. Fut2 deficiency also led to decreased levels of aryl hydrocarbon receptor (AHR) and its ligand 2-oxindole derived from tryptophan metabolism. 2-oxindole compromised cGAS-STING response through activating AHR in macrophages, and protected against intestinal inflammation and overactive cGAS-STING pathway in Fut2△IEC-DSS mice.
CONCLUSIONS: Fut2 deficiency promotes cGAS-STING pathway through suppressing 2-oxindole-AHR axis, ultimately facilitating the susceptibility to chronic colitis.
METHODS: Chronic colitis was induced in intestinal epithelial Fut2 knock out mice (Fut2△IEC), whose intestinal inflammation and activity of cGAS-STING pathway were evaluated. 16S rRNA sequencing and metabolomics were performed using intestinal samples. 2-oxindole was used to treat RAW264.7 cells and Fut2△IEC mice with colitis (Fut2△IEC-DSS) to investigate the effect of 2-oxindole on cGAS-STING response and intestinal inflammation.
RESULTS: Fut2 loss exacerbated chronic colitis in mice, manifested by declined body weight, reduced colon length, increased disease activity index (DAI) and more colon injury in Fut2△IEC-DSS mice compared with WT-DSS (wild type mice with colitis). Lack of Fut2 promoted activation of cGAS-STING pathway. Fut2 deficiency had a primary impact on colonic microbiota, as shown by alteration of microbial diversity and structure, as well as decreased Lactobacillus. Metabolic structure and tryptophan metabolism in colonic luminal microbiota were also influenced by Fut2 loss. Fut2 deficiency also led to decreased levels of aryl hydrocarbon receptor (AHR) and its ligand 2-oxindole derived from tryptophan metabolism. 2-oxindole compromised cGAS-STING response through activating AHR in macrophages, and protected against intestinal inflammation and overactive cGAS-STING pathway in Fut2△IEC-DSS mice.
CONCLUSIONS: Fut2 deficiency promotes cGAS-STING pathway through suppressing 2-oxindole-AHR axis, ultimately facilitating the susceptibility to chronic colitis.
摘要：
目的：本研究旨在揭示岩藻糖基转移酶2（Fut2）的缺失如何通过与肠道菌群密切相关的cGAS-STING途径影响肠道炎症，哪种微生物代谢产物能改善Fut2缺乏症的结肠炎。
方法：在肠上皮Fut2敲除小鼠（Fut2△IEC）中诱导慢性结肠炎，评估其肠道炎症和cGAS-STING途径的活性。使用肠样品进行16SrRNA测序和代谢组学。2-羟吲哚用于治疗RAW264.7细胞和Fut2△IEC结肠炎（Fut2△IEC-DSS）小鼠，以研究2-羟吲哚对cGAS-STING反应和肠道炎症的影响。
结果：Fut2丢失加剧了小鼠的慢性结肠炎，表现为体重下降，结肠长度减少，Fut2△IEC-DSS小鼠的疾病活动指数（DAI）和结肠损伤较WT-DSS（野生型结肠炎小鼠）增加。缺乏Fut2促进cGAS-STING途径的激活。Fut2缺乏对结肠微生物群产生主要影响，如微生物多样性和结构的改变所示，以及减少的乳酸菌。结肠腔微生物群中的代谢结构和色氨酸代谢也受Fut2损失的影响。Fut2缺乏还导致源自色氨酸代谢的芳烃受体（AHR）及其配体2-羟吲哚的水平降低。2-羟吲哚通过激活巨噬细胞中的AHR损害cGAS-STING反应，并保护Fut2△IEC-DSS小鼠肠道炎症和过度活跃的cGAS-STING通路。
结论：Fut2缺乏通过抑制2-羟吲哚-AHR轴促进cGAS-STING通路，最终促进对慢性结肠炎的易感性。
方法：在肠上皮Fut2敲除小鼠（Fut2△IEC）中诱导慢性结肠炎，评估其肠道炎症和cGAS-STING途径的活性。使用肠样品进行16SrRNA测序和代谢组学。2-羟吲哚用于治疗RAW264.7细胞和Fut2△IEC结肠炎（Fut2△IEC-DSS）小鼠，以研究2-羟吲哚对cGAS-STING反应和肠道炎症的影响。
结果：Fut2丢失加剧了小鼠的慢性结肠炎，表现为体重下降，结肠长度减少，Fut2△IEC-DSS小鼠的疾病活动指数（DAI）和结肠损伤较WT-DSS（野生型结肠炎小鼠）增加。缺乏Fut2促进cGAS-STING途径的激活。Fut2缺乏对结肠微生物群产生主要影响，如微生物多样性和结构的改变所示，以及减少的乳酸菌。结肠腔微生物群中的代谢结构和色氨酸代谢也受Fut2损失的影响。Fut2缺乏还导致源自色氨酸代谢的芳烃受体（AHR）及其配体2-羟吲哚的水平降低。2-羟吲哚通过激活巨噬细胞中的AHR损害cGAS-STING反应，并保护Fut2△IEC-DSS小鼠肠道炎症和过度活跃的cGAS-STING通路。
结论：Fut2缺乏通过抑制2-羟吲哚-AHR轴促进cGAS-STING通路，最终促进对慢性结肠炎的易感性。
