Department of Medicine, Division of Infectious Disease, University of Colorado Denver Anschutz Medical Campus, Aurora, CO, USA; Department of Immunology, University of Colorado Denver Anschutz Medical Campus, Aurora, CO, USA.
Department of Medicine, Division of Infectious Disease, University of Colorado Denver Anschutz Medical Campus, Aurora, CO, USA.
Immunobiology. 2021 Sep;226(5):152126. doi: 10.1016/j.imbio.2021.152126. Epub 2021 Jul 30.
An important function of the gut microbiome is the fermentation of non-digestible dietary fibers into short chain fatty acids (SCFAs). The three primary SCFAs: acetate, propionate, and butyrate, are key mediators of metabolism and immune cell function in the gut mucosa. We previously demonstrated that butyrate at high concentrations decreased human gut lamina propria (LP) CD4 T cell activation in response to enteric bacteria exposure in vitro. However, to date, the mechanism by which butyrate alters human gut LP CD4 T cell activation remains unknown. In this current study, we sought to better understand how exposure to SCFAs across a concentration range impacted human gut LP CD4 T cell function and activation. LP CD4 T cells were directly activated with T cell receptor (TCR) beads in vitro in the presence of a physiologic concentration range of each of the primary SCFAs. Exposure to butyrate potently inhibited CD4 T cell activation, proliferation, and cytokine (IFNγ, IL-17) production in a concentration dependent manner. Butyrate decreased the proliferation and cytokine production of T helper (Th) 1, Th17 and Th22 cells, with differences noted in the sensitivity of LP versus peripheral blood Th cells to butyrate's effects. Higher concentrations of propionate and acetate relative to butyrate were required to inhibit CD4 T cell activation and proliferation. Butyrate directly increased the acetylation of both unstimulated and TCR-stimulated CD4 T cells, and apicidin, a Class I histone deacetylase inhibitor, phenocopied butyrate's effects on CD4 T cell proliferation and activation. GPR43 agonism phenocopied butyrate's effect on CD4 T cell proliferation whereas a GPR109a agonist did not. Our findings indicate that butyrate decreases in vitro human gut LP CD4 T cell activation, proliferation, and inflammatory cytokine production more potently than other SCFAs, likely through butyrate's ability to increase histone acetylation, and potentially via signaling through GPR43. These findings have relevance in furthering our understanding of how perturbations of the gut microbiome alter local immune responses in the gut mucosa.
肠道微生物群的一个重要功能是将不可消化的膳食纤维发酵成短链脂肪酸（SCFAs）。三种主要的 SCFAs：乙酸盐、丙酸盐和丁酸盐，是肠道黏膜代谢和免疫细胞功能的关键介质。我们之前的研究表明，高浓度的丁酸盐可降低体外暴露于肠道细菌时人肠道固有层（LP）CD4 T 细胞的激活。然而，迄今为止，丁酸盐改变人肠道 LP CD4 T 细胞激活的机制尚不清楚。在本研究中，我们试图更好地了解 SCFAs 在浓度范围内如何影响人肠道 LP CD4 T 细胞的功能和激活。LP CD4 T 细胞在体外通过 T 细胞受体（TCR）珠直接激活，同时存在生理浓度范围内的每种主要 SCFAs。丁酸盐以浓度依赖的方式强烈抑制 CD4 T 细胞的激活、增殖和细胞因子（IFNγ、IL-17）的产生。丁酸盐降低了 Th1、Th17 和 Th22 细胞的增殖和细胞因子产生，LP 与外周血 Th 细胞对丁酸盐作用的敏感性存在差异。与丁酸盐相比，需要更高浓度的丙酸盐和乙酸盐才能抑制 CD4 T 细胞的激活和增殖。丁酸盐直接增加了未刺激和 TCR 刺激的 CD4 T 细胞的乙酰化，而 Class I 组蛋白去乙酰化酶抑制剂 apicidin 模拟了丁酸盐对 CD4 T 细胞增殖和激活的作用。GPR43 激动剂模拟了丁酸盐对 CD4 T 细胞增殖的作用，而 GPR109a 激动剂则没有。我们的研究结果表明，丁酸盐比其他 SCFAs 更有效地降低体外人肠道 LP CD4 T 细胞的激活、增殖和炎症细胞因子的产生，这可能是由于丁酸盐增加组蛋白乙酰化的能力，并且可能通过 GPR43 信号传递。这些发现对于进一步了解肠道微生物组的改变如何改变肠道黏膜中的局部免疫反应具有重要意义。
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