Genetic associations in the gut–lung axis: a Mendelian randomization study and in vitro assessment of sodium butyrate in non-small cell lung cancer
- 1Department of Radiation Oncology, The First Affiliated Hospital of Guangxi Medical University , ,
- 2Department of Oncology, The Fourth Affiliated Hospital of Guangxi Medical University , ,
Abstract
Background
The gut microbiota may influence host immunity, but the relationship between specific microbial genera and non-small cell lung cancer (NSCLC) risk remains uncertain. We evaluated genetically proxied microbial abundance and conducted separate exploratory experiments with sodium butyrate (NaB).Methods
Two-sample Mendelian randomization (MR) used genus-level MiBioGen summary statistics and FinnGen/OpenGWAS NSCLC data (finn-b-C3_LUNG_NONSMALL; 1,627 cases and 217,165 controls). Instruments were selected at P < 1 × 10⁻⁵ with linkage disequilibrium clumping (r² < 0.001; 10,000 kb) and F > 10. Inverse variance weighting (IVW) was the primary estimator; Benjamini-Hochberg false discovery rate (BH-FDR) correction was applied across 119 genera. Sensitivity analyses included MR-Egger, weighted median, mode-based methods, heterogeneity, pleiotropy and leave-one-out analyses. NaB, used as a representative microbial metabolite rather than a taxon-specific product, was evaluated at 1 mM for 24 h in tumor-conditioned medium (TCM) experiments.Results
Six genera showed nominal inverse IVW associations with NSCLC risk (P = 0.0120-0.0498): Alistipes, Methanobrevibacter, Bacteroides, Ruminococcus gauvreauii group, Ruminococcus 1 and Peptococcus. None survived BH-FDR correction (q = 0.6072-0.9819). Sensitivity tests did not detect heterogeneity or directional pleiotropy for these genera, but alternative estimators and leave-one-out analyses did not consistently retain nominal significance. In THP-1-derived macrophages, NaB treatment altered polarization-associated transcripts, reduced the TCM-associated CCK-8 signal and increased acetylated histone H3 (Ac-H3) relative to TCM alone.Conclusion
The MR analysis identifies six suggestive microbial associations with NSCLC risk that require independent replication. Complementary NaB experiments show changes in macrophage-associated transcripts, metabolic viability and histone acetylation, providing a basis for further study of microbial metabolites in the tumor microenvironment.
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BibTeX
@article{yi2026genetic,
title = {{Genetic associations in the gut–lung axis: a Mendelian randomization study and in vitro assessment of sodium butyrate in non-small cell lung cancer}},
author = {Weili Yi and Li Qin and Dongning Huang and Fang Wu},
journal = {Frontiers in genetics},
year = {2026},
month = oct,
doi = {10.3389/fgene.2026.1900040},
url = {https://europepmc.org/article/PMC/PMC13719139},
note = {CC BY},
}
RIS
TY - JOUR
TI - Genetic associations in the gut–lung axis: a Mendelian randomization study and in vitro assessment of sodium butyrate in non-small cell lung cancer
AU - Weili Yi
AU - Li Qin
AU - Dongning Huang
AU - Fang Wu
PY - 2026
DA - 2026/10/16
JO - Frontiers in genetics
DO - 10.3389/fgene.2026.1900040
UR - https://europepmc.org/article/PMC/PMC13719139
AB - Background The gut microbiota may influence host immunity, but the relationship between specific microbial genera and non-small cell lung cancer (NSCLC) risk remains uncertain. We evaluated genetically proxied microbial abundance and conducted separate exploratory experiments with sodium butyrate (NaB).Methods Two-sample Mendelian randomization (MR) used genus-level MiBioGen summary statistics and FinnGen/OpenGWAS NSCLC data (finn-b-C3_LUNG_NONSMALL; 1,627 cases and 217,165 controls). Instruments were selected at P < 1 × 10⁻⁵ with linkage disequilibrium clumping (r² < 0.001; 10,000 kb) and F > 10. Inverse variance weighting (IVW) was the primary estimator; Benjamini-Hochberg false discovery rate (BH-FDR) correction was applied across 119 genera. Sensitivity analyses included MR-Egger, weighted median, mode-based methods, heterogeneity, pleiotropy and leave-one-out analyses. NaB, used as a representative microbial metabolite rather than a taxon-specific product, was evaluated at 1 mM for 24 h in tumor-conditioned medium (TCM) experiments.Results Six genera showed nominal inverse IVW associations with NSCLC risk (P = 0.0120-0.0498): Alistipes, Methanobrevibacter, Bacteroides, Ruminococcus gauvreauii group, Ruminococcus 1 and Peptococcus. None survived BH-FDR correction (q = 0.6072-0.9819). Sensitivity tests did not detect heterogeneity or directional pleiotropy for these genera, but alternative estimators and leave-one-out analyses did not consistently retain nominal significance. In THP-1-derived macrophages, NaB treatment altered polarization-associated transcripts, reduced the TCM-associated CCK-8 signal and increased acetylated histone H3 (Ac-H3) relative to TCM alone.Conclusion The MR analysis identifies six suggestive microbial associations with NSCLC risk that require independent replication. Complementary NaB experiments show changes in macrophage-associated transcripts, metabolic viability and histone acetylation, providing a basis for further study of microbial metabolites in the tumor microenvironment.
SN - 1664-8021
ER -