Prognostic value of gut microbiota-derived metabolites in non-small cell lung cancer: a retrospective cohort study of overall survival.

Background: Non-small cell lung cancer (NSCLC) is characterized by marked heterogeneity in survival, which remains incompletely accounted for by conventional clinicopathological factors. Gut microbiota-derived metabolites may shape tumor progression via regulation of inflammation, immunity, and host nutritional status, yet their prognostic relevance for overall survival (OS) of patients with NSCLC remains poorly defined. This study aimed to investigate the prognostic value of gut microbiota-derived metabolites in patients with NSCLC. Methods: This single-center retrospective cohort study enrolled consecutive adults with pathologically confirmed NSCLC who received diagnosis and treatment at our institution from January 2019 to April 2024. Patients were eligible for enrollment if they had complete baseline clinical data, adequate baseline fecal specimens for metabolite profiling, and complete follow-up information. Patients were excluded if they had recent antibiotic exposure, inflammatory bowel disease or severe gastrointestinal disorders, significant hepatobiliary disease, acute infections, severe inflammatory conditions, or missing key data. Baseline clinical variables and biological samples were obtained prior to antitumor treatment. The baseline concentrations of short-chain fatty acids (SCFAs) and bile acid-related metabolites and the baseline levels of neutrophil-to-lymphocyte ratio (NLR) and prognostic nutritional index (PNI) were systematically quantified. OS referred to the time from baseline sampling to all-cause death or last follow-up, and surviving patients were censored. Cox regression models and Kaplan-Meier analysis were used for survival assessment. Results: The 256 enrolled patients were classified into long-OS (n=112) and non-long-OS (n=144) groups, with 100 deaths recorded during follow-up. Shorter OS was associated with advanced stage, higher baseline levels of NLR and baseline concentrations of secondary bile acid (SBA)-related metabolites, and lower baseline levels of PNI and baseline concentrations of SCFAs. In the multivariate Cox regression model, advanced stage, higher NLR, and elevated SBA/primary bile acid (PBA) ratio were associated with inferior OS [hazard ratio (HR) =2.612, 95% confidence interval (CI): 1.284-5.314; HR =1.502, 95% CI: 1.327-1.700; HR =1.794, 95% CI: 1.453-2.215, respectively], whereas higher PNI and butyrate levels were associated with improved OS (HR =0.894, 95% CI: 0.858-0.932; HR =0.775, 95% CI: 0.716-0.838, respectively). Kaplan-Meier analysis further confirmed favorable survival in patients with high butyrate levels and worse survival in patients with an elevated SBA/PBA ratio. Conclusions: Butyrate depletion and SBA enrichment may represent clinically relevant microbiota-related metabolic dysregulation in NSCLC. These microbial metabolites have the potential to complement conventional inflammatory and nutritional markers for survival risk stratification and prognostic evaluation. Nevertheless, further prospective multicenter studies are warranted to validate our findings.