Data_Sheet_1_Lactobacillus gasseri Suppresses the Production of Proinflammatory Cytokines in Helicobacter pylori-Infected Macrophages by Inhibiting the Expression of ADAM17.PDF

The ability of Helicobacter pylori to evade the host immune system allows the bacterium to colonize the host for a lifetime. Long-term infection with H. pylori causes chronic inflammation, which is the major risk factor for the development of gastric ulcers and gastric cancer. Lactobacilli are part of the human microbiota and have been studied as an adjunct treatment in H. pylori eradication therapy. However, the molecular mechanisms by which lactobacilli act against H. pylori infection have not been fully characterized. In this study, we investigated the anti-inflammatory effects of Lactobacillus strains upon coincubation of host macrophages with H. pylori. We found that Lactobacillus gasseri Kx110A1 (L. gas), a strain isolated from a human stomach, but not other tested Lactobacillus species, blocked the production of the proinflammatory cytokines TNF and IL-6 in H. pylori-infected macrophages. Interestingly, L. gas also inhibited the release of these cytokines in LPS or LTA stimulated macrophages, demonstrating a general anti-inflammatory property. The inhibition of these cytokines did not occur through the polarization of macrophages from the M1 (proinflammatory) to M2 (anti-inflammatory) phenotype or through the altered viability of H. pylori or host cells. Instead, we show that L. gas suppressed the release of TNF and IL-6 by reducing the expression of ADAM17 (also known as TNF-alpha-converting enzyme, TACE) on host cells. Our findings reveal a novel mechanism by which L. gas prevents the production of the proinflammatory cytokines TNF and IL-6 in host macrophages.

幽门螺杆菌（Helicobacter pylori）逃避免疫系统的能力使其能够在宿主体内终身定植。长期感染幽门螺杆菌可引发慢性炎症，而慢性炎症是发展成胃溃疡和胃癌的主要风险因素。乳杆菌（Lactobacilli）是人类微生物群的一部分，并被研究作为幽门螺杆菌根除治疗的辅助治疗方法。然而，乳杆菌对抗幽门螺杆菌感染的作用分子机制尚未得到充分阐明。在本研究中，我们调查了乳杆菌菌株对宿主巨噬细胞与幽门螺杆菌共培养时的抗炎作用。我们发现，源自人类胃部的乳杆菌菌株加瑟里氏菌Kx110A1（L. gas），而非其他测试的乳杆菌物种，能够阻断幽门螺杆菌感染巨噬细胞中促炎细胞因子TNF和IL-6的产生。有趣的是，L. gas 还抑制了在脂多糖（LPS）或脂肽A（LTA）刺激的巨噬细胞中这些细胞因子的释放，显示出其普遍的抗炎特性。这些细胞因子的抑制并非通过将巨噬细胞从M1（促炎）表型极化为M2（抗炎）表型，或通过改变幽门螺杆菌或宿主细胞的存活能力来实现。相反，我们展示出L. gas 通过降低宿主细胞上ADAM17（也称为TNF-α转化酶，TACE）的表达来抑制TNF和IL-6的释放。我们的发现揭示了L. gas 通过一种新颖的机制防止宿主巨噬细胞产生促炎细胞因子TNF和IL-6的新机制。