Gut microbiome and serum short-chain fatty acids are associated with responses to chemo- or targeted therapies in Chinese patients with lung cancer

Huan-Huan Chen; Qi-Jun Wu; Tie-Ning Zhang; Yu-Hong Zhao

doi:10.3389/fmicb.2023.1165360

Gut microbiome and serum short-chain fatty acids are associated with responses to chemo- or targeted therapies in Chinese patients with lung cancer

Front Microbiol. 2023 Jul 19:14:1165360. doi: 10.3389/fmicb.2023.1165360. eCollection 2023.

Authors

Huan-Huan Chen^{1

2

3

4}, Qi-Jun Wu^{1

2

3}, Tie-Ning Zhang^{1

2

3

5}, Yu-Hong Zhao^{1

2

3}

Affiliations

¹ Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, Shenyang, China.
² Clinical Research Center, Shengjing Hospital of China Medical University, Shenyang, China.
³ Key Laboratory of Precision Medical Research on Major Chronic Disease, Shengjing Hospital of China Medical University, Shenyang, China.
⁴ Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China.
⁵ Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, China.

Abstract

Background: The association between gut microbes and short-chain fatty acids (SCFAs) and therapeutic responses of patients with lung cancer (LC) receiving therapy remains unknown.

Methods: 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.

Results: 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.

Conclusion: 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.

Keywords: chemotherapy; gut microbiome; lung cancer; short-chain fatty acid; targeted therapy.

Grants and funding

This study was supported by the National Key R&D Program of China (No. 2017YFC0907401 to Y-HZ), the Jie Bang Gua Shuai Project of Liaoning Province (No. 2021JH1/1040050 to Y-HZ), the Natural Science Foundation of China (No. 82073647 to Q-JW), and the LiaoNing Revitalization Talents Program (No. XLYC1907102 to Q-JW and No. XLYC1802095 to Y-HZ).