Cytokine-induced beta cell dysfunction is a hallmark of type 2 diabetes (T2D). Chronic exposure of beta cells to inflammatory cytokines affects gene expression and impairs insulin secretion. Thus, identification of anti-inflammatory factors that preserve beta cell function represents an opportunity to prevent or treat T2D. Butyrate is a gut microbial metabolite with anti-inflammatory properties for which we recently showed a role in preventing interleukin-1β (IL-1β)-induced beta cell dysfunction, but how prevention is accomplished is unclear. Here, we investigated the mechanisms by which butyrate exerts anti-inflammatory activity in beta cells. We exposed mouse islets and INS-1E cells to a low dose of IL-1β and/or butyrate and measured expression of inflammatory genes and nitric oxide (NO) production. Additionally, we explored the molecular mechanisms underlying butyrate activity by dissecting the activation of the nuclear factor-κB (NF-κB) pathway. We found that butyrate suppressed IL-1β-induced expression of inflammatory genes, such as Nos2, Cxcl1, and Ptgs2, and reduced NO production. Butyrate did not inhibit IκBα degradation nor NF-κB p65 nuclear translocation. Furthermore, butyrate did not affect binding of NF-κB p65 to target sequences in synthetic DNA but inhibited NF-κB p65 binding and RNA polymerase II recruitment to inflammatory gene promoters in the context of native DNA. We found this was concurrent with increased acetylation of NF-κB p65 and histone H4, suggesting butyrate affects NF-κB activity via inhibition of histone deacetylases. Together, our results show butyrate inhibits IL-1β-induced inflammatory gene expression and NO production through suppression of NF-κB activation and thereby possibly preserves beta cell function.

细胞因子诱导的 β 细胞功能障碍是 2 型糖尿病 (T2D) 的标志。β细胞长期暴露于炎性细胞因子会影响基因表达并损害胰岛素分泌。因此，鉴定出保护 β 细胞功能的抗炎因子代表了预防或治疗 T2D 的机会。丁酸盐是一种具有抗炎特性的肠道微生物代谢物，我们最近展示了它在预防白细胞介素 1β (IL-1β) 诱导的 β 细胞功能障碍中的作用，但如何预防尚不清楚。在这里，我们研究了丁酸盐在 β 细胞中发挥抗炎活性的机制。我们将小鼠胰岛和 INS-1E 细胞暴露于低剂量的 IL-1β 和/或丁酸盐，并测量炎症基因的表达和一氧化氮 (NO) 的产生。此外，我们通过剖析核因子-κB (NF-κB) 通路的激活来探索丁酸盐活性的分子机制。我们发现丁酸盐抑制了 IL-1β 诱导的炎症基因的表达，例如Nos2、Cxcl1和Ptgs2，并减少 NO 的产生。丁酸盐不抑制 IκBα 降解或 NF-κB p65 核转位。此外，丁酸盐不影响 NF-κB p65 与合成 DNA 中靶序列的结合，但在天然 DNA 的情况下抑制 NF-κB p65 结合和 RNA 聚合酶 II 向炎症基因启动子的募集。我们发现这与 NF-κB p65 和组蛋白 H4 的乙酰化增加同时发生，表明丁酸盐通过抑制组蛋白去乙酰化酶影响 NF-κB 活性。总之，我们的结果表明丁酸盐通过抑制 NF-κB 活化来抑制 IL-1β 诱导的炎症基因表达和 NO 产生，从而可能保留 β 细胞功能。