Fernando Maria R, Saxena Alpana, Reyes José-Luis, McKay Derek M
Gastrointestinal Research Group and Inflammation Research Network, Department of Physiology and Pharmacology, Calvin, Joan and Phoebe Snyder Institute for Chronic Disease, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
Gastrointestinal Research Group and Inflammation Research Network, Department of Physiology and Pharmacology, Calvin, Joan and Phoebe Snyder Institute for Chronic Disease, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
Am J Physiol Gastrointest Liver Physiol. 2016 May 15;310(10):G822-31. doi: 10.1152/ajpgi.00440.2015. Epub 2016 Mar 24.
The short-chain fatty acid butyrate is produced by fermentation of dietary fiber by the intestinal microbiota; butyrate is the primary energy source of colonocytes and has immunomodulatory effects. Having shown that macrophages differentiated with IL-4 [M(IL-4)s] can suppress colitis, we hypothesized that butyrate would reinforce an M(IL-4) phenotype. Here, we show that in the presence of butyrate M(IL-4)s display reduced expression of their hallmark markers Arg1 and Ym1 and significantly suppressed LPS-induced nitric oxide, IL-12p40, and IL-10 production. Butyrate treatment likely altered the M(IL-4) phenotype via inhibition of histone deacetylation. Functionally, M(IL-4)s treated with butyrate showed increased phagocytosis and killing of bacteria, compared with M(IL-4) and this was not accompanied by enhanced proinflammatory cytokine production. Culture of regulatory T cells with M(IL-4)s and M(IL-4 + butyrate)s revealed that both macrophage subsets suppressed expression of the regulatory T-cell marker Foxp3. However, Tregs cocultured with M(IL-4 + butyrate) produced less IL-17A than Tregs cocultured with M(IL-4). These data illustrate the importance of butyrate, a microbial-derived metabolite, in the regulation of gut immunity: the demonstration that butyrate promotes phagocytosis in M(IL-4)s that can limit T-cell production of IL-17A reveals novel aspects of bacterial-host interaction in the regulation of intestinal homeostasis.
短链脂肪酸丁酸是由肠道微生物群对膳食纤维进行发酵产生的；丁酸是结肠细胞的主要能量来源，并具有免疫调节作用。鉴于已表明用白细胞介素4分化的巨噬细胞[M(IL-4)s]可抑制结肠炎，我们推测丁酸会增强M(IL-4)表型。在此，我们表明在丁酸存在的情况下，M(IL-4)s显示其标志性标志物精氨酸酶1（Arg1）和抵抗素样分子α（Ym1）的表达降低，并显著抑制脂多糖诱导的一氧化氮、白细胞介素12p40和白细胞介素10的产生。丁酸处理可能通过抑制组蛋白去乙酰化改变了M(IL-4)表型。在功能上，与M(IL-4)相比，用丁酸处理的M(IL-4)s表现出细菌吞噬和杀伤能力增强，且这并未伴随着促炎细胞因子产生的增加。用M(IL-4)s和M(IL-4 + 丁酸)s培养调节性T细胞发现，这两个巨噬细胞亚群均抑制调节性T细胞标志物叉头框蛋白3（Foxp3）的表达。然而，与M(IL-4)共同培养的调节性T细胞相比，与M(IL-4 + 丁酸)共同培养的调节性T细胞产生的白细胞介素17A更少。这些数据说明了微生物衍生代谢产物丁酸在肠道免疫调节中的重要性：丁酸促进M(IL-4)s吞噬作用的证据表明其可限制T细胞产生白细胞介素17A，这揭示了细菌与宿主相互作用在调节肠道稳态中的新方面。
