Antibiotic exposure impairs the efficacy of first-line chemoimmunotherapy in non-small cell lung cancer through the regulation of gut microbiome and bile acid metabolism

Abstract

Objective Previous antibiotic therapy is acknowledged to potentially reduce the efficacy of single-agent immune checkpoint inhibitors. Nevertheless, the impact of antibiotics on the results for patients undergoing chemoimmunotherapy remains unclear. This research investigated the influence of antibiotic treatment on the effectiveness of chemoimmunotherapy in advanced non-small cell lung cancer (NSCLC).

Methods We recorded the characteristics of patients with advanced NSCLC and assessed potential associations between the use of antibiotics and the efficacy of chemoimmunotherapy. A mouse model using Lewis lung carcinoma (LLC) cell lines was developed to assess the effects of antibiotics on the gut microbiome and metabolites. Fecal samples were analyzed using 16S rRNA gene sequencing and ultra-high-performance liquid chromatography-mass spectrometry (UHPLC-MS) methods. Mouse fecal and serum samples and 16 human stool samples were used to validate the identified differentially metabolites. Deoxycholic acid (DCA) was further applied to a LLC mouse model.

Results This study included 387 NSCLC patients, among whom 86 patients had used antibiotics within the 30 days before the first cycle of chemoimmunotherapy (ATB group), and 301 patients had not used antibiotics (non-ATB group). Notable discrepancies were observed in overall survival and progression-free survival between the two groups, with overall survival recorded at 18.4 months versus 32.0 months, and progression-free survival at 7.6 months versus 13.0 months, in the ATB and non-ATB groups respectively. At the phylum level, the relative abundances of Proteobacteria, Cyanobacteria, and Deinococcus were increased in the ATB mice, while Firmicutes, Bacteroidetes, and Verrucomicrobia were decreased. We detected significant differences in DCA levels in the fecal and serum samples from mice as well as in the fecal sample from humans between the ATB and non-ATB groups. The respective proportions of CD4⁺ and CD8⁺ cells were greater in the non-ATB group than in the ATB group, whereas the proportion of Ki67-positive cells was greater in the ATB group. DCA was applied to LLC mice, and DCA along with chemoimmunotherapy effectively inhibited tumor growth in a LLC mouse model. The expression of programmed cell death ligand 1 increased in the DCA group.

Conclusions Antibiotic exposure is associated with decreased efficacy of chemoimmunotherapy in patients with NSCLC via dysregulation of the gut microbiome and DCA metabolism.

Keywords

non-small cell lung cancer / antibiotic / chemoimmunotherapy / metabolism / deoxycholic acid / gut microbiome

Acknowledgements

This study was supported by the National Natural Science Foundation of China (grant No. 82370085 to C.C.), Wujieping Medical Foundation Clinical Research Special Fund (grant No. 320.6750.2025-6-88 to Y.L.), and Wenzhou Municipal Science and Technology Bureau (grant No. Y2020001 to H.X.). We are grateful for all the financial support of this study and to the participants in the study.

Author contributions

Hanyan Xu (Conceptualization, Formal Analysis, Methodology, Writing—original draft, Writing—review & editing), Jia Yu (Conceptualization, Formal Analysis, Methodology, Writing—original draft, Writing—review & editing), Lijing Xia (Formal Analysis, Validation), Xiong Lei (Formal Analysis, Investigation), Liwen Zhou (Methodology, Visualization), Pengcheng Lin (Formal Analysis, Methodology), Shanshan Su (Formal Analysis, Supervision), Yuping Li (Conceptualization, Writing—review & editing), and Chengshui Chen (Conceptualization, Writing—review & editing).

Supplementary material

Supplementary material is available at PCMEDI online.

Conflicts of interest

None declared.

Ethics statement

This study was approved by the ethics committee of the First Affil- iated Hospital of Wenzhou Medical University (ethics approval No. 2020084) and complies with the declaration of Helsinki. Informed consent was obtained from all participants.

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