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肠道-肺轴通过膳食纤维、肠道微生物群和短链脂肪酸对肺部免疫状态的调节

Regulation of Lung Immune Tone by the Gut-Lung Axis via Dietary Fiber, Gut Microbiota, and Short-Chain Fatty Acids.

作者信息

Maruyama Daisuke, Liao Wen-I, Tian Xiaoli, Bredon Marius, Knapp Johannes, Tat Christine, Doan Thien N M, Chassaing Benoit, Bhargava Aditi, Sokol Harry, Prakash Arun

出版信息

bioRxiv. 2023 Aug 25:2023.08.24.552964. doi: 10.1101/2023.08.24.552964.

Abstract

Lung immune tone, i.e. the immune state of the lung, can vary between individuals and over a single individual's lifetime, and its basis and regulation in the context of inflammatory responses to injury is poorly understood. The gut microbiome, through the gut-lung axis, can influence lung injury outcomes but how the diet and microbiota affect lung immune tone is also unclear. We hypothesized that lung immune tone would be influenced by the presence of fiber-fermenting short-chain fatty acid (SCFA)-producing gut bacteria. To test this hypothesis, we conducted a fiber diet intervention study followed by lung injury in mice and profiled gut microbiota using 16S sequencing, metabolomics, and lung immune tone. We also studied germ-free mice to evaluate lung immune tone in the absence of microbiota and performed mechanistic studies on immune tone and metabolic programming of alveolar macrophages exposed to the SCFA propionate (C3). Mice on high-fiber diet were protected from sterile lung injury compared to mice on a fiber-free diet. This protection strongly correlated with lower lung immune tone, elevated propionate levels and enrichment of specific fecal microbiota taxa; conversely, lower levels of SCFAs and an increase in other fatty acid metabolites and bacterial taxa correlated with increased lung immune tone and increased lung injury in the fiber-free group. , C3 reduced lung alveolar macrophage immune tone (through suppression of IL-1β and IL-18) and metabolically reprogrammed them (switching from glycolysis to oxidative phosphorylation after LPS challenge). Overall, our findings reveal that the gut-lung axis, through dietary fiber intake and enrichment of SCFA-producing gut bacteria, can regulate innate lung immune tone via IL-1β and IL-18 pathways. These results provide a rationale for the therapeutic development of dietary interventions to preserve or enhance specific aspects of host lung immunity.

摘要

肺部免疫态势,即肺部的免疫状态,在个体之间以及个体一生中会有所不同,而且在对损伤的炎症反应背景下,其基础和调节机制尚不清楚。肠道微生物群通过肠-肺轴可影响肺损伤结果,但饮食和微生物群如何影响肺部免疫态势也不明确。我们推测肺部免疫态势会受到产生纤维发酵短链脂肪酸(SCFA)的肠道细菌的影响。为了验证这一假设,我们进行了一项纤维饮食干预研究,随后对小鼠进行肺损伤,并使用16S测序、代谢组学和肺部免疫态势分析肠道微生物群。我们还研究了无菌小鼠,以评估在没有微生物群的情况下的肺部免疫态势,并对暴露于SCFA丙酸盐(C3)的肺泡巨噬细胞的免疫态势和代谢编程进行了机制研究。与无纤维饮食的小鼠相比,高纤维饮食的小鼠对无菌性肺损伤具有保护作用。这种保护作用与较低的肺部免疫态势、丙酸盐水平升高以及特定粪便微生物分类群的富集密切相关;相反,无纤维组中较低水平的SCFAs以及其他脂肪酸代谢物和细菌分类群的增加与肺部免疫态势增加和肺损伤增加相关。C3降低了肺泡巨噬细胞的免疫态势(通过抑制IL-1β和IL-18)并对其进行代谢重编程(在LPS刺激后从糖酵解转变为氧化磷酸化)。总体而言,我们的研究结果表明,肠-肺轴通过膳食纤维摄入和产生SCFA的肠道细菌的富集,可通过IL-1β和IL-18途径调节肺部固有免疫态势。这些结果为饮食干预的治疗开发提供了理论依据,以维持或增强宿主肺部免疫的特定方面。

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