Park Ah-Mee, Khadka Sundar, Sato Fumitaka, Omura Seiichi, Fujita Mitsugu, Hsu Daniel K, Liu Fu-Tong, Tsunoda Ikuo
Department of Microbiology, Faculty of Medicine, Kindai University, Osaka, Japan.
Department of Dermatology, University of California Davis Health System, Sacramento, CA, United States.
Front Immunol. 2020 Sep 23;11:550366. doi: 10.3389/fimmu.2020.550366. eCollection 2020.
Non-steroidal anti-inflammatory drugs (NSAIDs) induce ulcers in the gastrointestinal tract, including the stomach and small intestine. NSAID-induced gastric ulcers can be prevented by taking acid-neutralizing/inhibitory drugs and cytoprotective agents. In contrast, there are no medicines to control NSAID-induced small intestinal ulcers, which are accompanied by a mucosal invasion of bacteria and subsequent activation of immune cells. Galectin-3 (Gal3), an endogenous lectin, has anti-microbial and pro-inflammatory functions. In the small intestine, since Gal3 is highly expressed in epithelial cells constitutively and macrophages inducibly, the Gal3 level can affect microbiota composition and macrophage activation. We hypothesized that the modulation of Gal3 expression could be beneficial in NSAID-induced intestinal ulcers. Using Gal3 knockout (Gal3KO) mice, we determined whether Gal3 could be a therapeutic target in NSAID-induced intestinal ulcers. Following the administration of indomethacin, an NSAID, we found that small intestinal ulcers were less severe in Gal3KO mice than in wild-type (WT) mice. We also found that the composition of intestinal microbiota was different between WT and Gal3KO mice and that bactericidal antibiotic polymyxin B treatment significantly suppressed NSAID-induced ulcers. Furthermore, clodronate, a macrophage modulator, attenuated NSAID-induced ulcers. Therefore, Gal3 could be an exacerbating factor in NSAID-induced intestinal ulcers by affecting the intestinal microbiota population and macrophage activity. Inhibition of Gal3 may be a therapeutic strategy in NSAID-induced intestinal ulcers.
www.ClinicalTrials.gov, identifier NCT03832946.
非甾体抗炎药（NSAIDs）会诱发胃肠道溃疡，包括胃和小肠。服用酸中和/抑制药物和细胞保护剂可预防NSAID诱发的胃溃疡。相比之下，尚无药物可控制NSAID诱发的小肠溃疡，此类溃疡伴有细菌的黏膜侵袭及随后免疫细胞的激活。半乳糖凝集素-3（Gal3）是一种内源性凝集素，具有抗微生物和促炎功能。在小肠中，由于Gal3在组成型上皮细胞和诱导型巨噬细胞中高表达，Gal3水平可影响微生物群组成和巨噬细胞激活。我们推测，调节Gal3表达可能对NSAID诱发的肠道溃疡有益。我们使用Gal3基因敲除（Gal3KO）小鼠来确定Gal3是否可能成为NSAID诱发肠道溃疡的治疗靶点。在给予非甾体抗炎药吲哚美辛后，我们发现Gal3KO小鼠的小肠溃疡比野生型（WT）小鼠的病情轻。我们还发现WT小鼠和Gal3KO小鼠的肠道微生物群组成不同，并且杀菌抗生素多粘菌素B治疗可显著抑制NSAID诱发的溃疡。此外，巨噬细胞调节剂氯膦酸盐可减轻NSAID诱发的溃疡。因此，Gal3可能通过影响肠道微生物群数量和巨噬细胞活性而成为NSAID诱发肠道溃疡的一个加重因素。抑制Gal3可能是治疗NSAID诱发肠道溃疡的一种策略。
