肺癌（LC）接受治疗的患者肠道微生物和短链脂肪酸（SCFA）之间的关联以及治疗反应尚不清楚。我们前瞻性收集了LC患者的粪便和血清样本，根据是否表现持久临床效益分为反应者和非反应者。通过使用16S核糖体DNA测序分析了肠道微生物的组成。使用气相色谱法检测了血清中SCFA的浓度。我们对异丁酸处理的A549细胞进行了细胞增殖、迁移、侵袭、细胞周期和凋亡实验。通过反转录定量PCR、蛋白质免疫印迹、免疫细胞化学和免疫荧光染色实验，研究了相关基因或蛋白质的表达。非反应者的肠道菌群α多样性较高，但β多样性较低，与反应者相比。与低α多样性的患者相比，高α多样性的患者的无进展生存期显着缩短。此外，这两组之间还观察到了β多样性。具体来说，反应者中寄生沙特雷拉菌、梭菌科和普雷沃特拉_7的丰度更高，而非反应者中的肠杆菌属和Christensenellaceae_R-7组的丰度更高。血清SCFA（尤其是乙酸和异丁酸）水平在反应者中趋高。异丁酸通过诱导细胞凋亡和G1/S细胞周期阻滞抑制了A549细胞的增殖、迁移和侵袭，同时上调了GPR41、GPR43和GPR5C的表达，下调了PAR1的表达，并增强了组蛋白乙酰转移酶的活性。我们揭示了肠道菌群和SCFA对LC患者治疗反应的影响，以及异丁酸的抗肿瘤作用，表明它们有潜在的作为治疗靶点的用途。版权所有 © 2023 Chen，Wu，Zhang和Zhao。

The association between gut microbes and short-chain fatty acids (SCFAs) and therapeutic responses of patients with lung cancer (LC) receiving therapy remains unknown.Fecal and serum samples were prospectively collected from patients with LC, classified as responders, if they presented durable clinical benefits, and non-responders, if not. The composition of gut microbes was analyzed using 16S ribosomal DNA sequencing. Serum SCFA concentrations were detected using gas chromatography. Cell proliferation, migration, invasion, cell cycle, and apoptosis assays were performed on isobutyric acid-treated A549 cells. Reverse transcription-quantitative PCR, Western blotting, immunocytochemistry, and immunofluorescence staining experiments have been performed to investigate the expression of associated genes or proteins.Non-responders harbored higher microbiome α-diversity but lower β-diversity compared with responders. Compared to the patients with low α-diversity, those with high α-diversity showed significantly shorter progression-free survival. Additionally, β-diversity has also been observed between these two groups. Specifically, Parasutterella, Clostridiaceae, and Prevotella_7 were more abundant among responders, whereas Bacteroides_stercoris and Christensenellaceae_R-7_group were more abundant in non-responders. The serum SCFA (especially acetate and isobutyrate) levels tended to be higher in responders. Isobutyric acid inhibited the proliferation, migration, and invasion of A549 cells by inducing apoptosis and G1/S arrest while upregulating the expression of GPR41, GPR43, and GPR5C and downregulating that of PAR1, and increasing the activity of histone acetyltransferases.We revealed the influence of gut microbiota and SCFAs on the therapeutic responses in patients with LC and the anti-tumor effect of isobutyric acid, indicating their potential use as therapeutic targets.Copyright © 2023 Chen, Wu, Zhang and Zhao.