Analysis of Gut Microbiota Signature and Microbe-Disease Progression Associations in Locally Advanced Non-Small Cell Lung Cancer Patients Treated With Concurrent Chemoradiotherapy

Abstract

PurposeTo evaluate the association of gut microbiome signature and disease progression in locally advanced non-small cell lung cancer (LA-NSCLC) patients treated with concurrent chemoradiotherapy (CCRT) by fecal metagenome analysis.MethodsMetagenome-wide association studies on baseline fecal samples from 18 LA-NSCLC patients before CCRT and 13 controls from healthy first-degree relatives were performed. Among the 18 LA-NSCLC patients, six patients were defined as the long progression-free survival (long-PFS) group (PFS≥11 months) while another 12 were in the short-PFS group (PFS<11 months). Alpha diversity, taxonomic composition, and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional pathways were compared between groups.ResultsThe Firmicutes/Bacteroidetes value of long-PFS group was higher than those of short-PFS (p=0.073) and healthy individual groups (p=0.009). Meanwhile, long-PFS group had significantly higher diversities in Fungi, Archaea, and Viruses than short-PFS group. The KEGG pathways overrepresented in short-PFS group included fructose and mannose metabolism (p=0.028), streptomycin biosynthesis (p=0.028), acarbose and validamycin biosynthesis (p=0.013), ribosome biogenesis in eukaryotes (p=0.035), biosynthesis of vancomycin group antibiotics (p=0.004), apoptosis-fly (p=0.044), and tetracycline biosynthesis (p=0.044), while those overrepresented in long-PFS group included fatty acid biosynthesis (p=0.035), fatty acid metabolism (p=0.008), vancomycin resistance (p=0.008), longevity regulating pathway-worm (p=0.028), type II diabetes mellitus (p=0.004), and viral carcinogenesis (p=0.003). Further analysis of antibiotic resistome demonstrated that the short-PFS group had a trend with more antibiotic resistance genes than healthy control (p=0.070) and long-PFS groups (p=0.218). The vancomycin resistance sequences were significantly enriched in the long-PFS group compared to the short-PFS group (p=0.006).ConclusionsThe baseline gut microbiome composition and functionality might be associated with PFS in LA-NSCLC treated with CCRT. The outcome of CCRT might be modulated through bacterial metabolic pathways. The antibiotic resistance genes might play a role in disease progression and provide potential information on the relationship between the use of antibiotics and treatment efficacy of CCRT in LA-NSCLC.

Structure of gut microbiota and characteristics of fecal metabolites in patients with lung cancer

“…Our study showed a lower proportion of Firmicutes and a higher proportion of Proteobacteria and Actinobacteriota in LC patients, which is inconsistent with the results reported by Qian et al (2022) (Figure 1B). Overall, we found differences in the composition of the gut micro-biome between the LC patients and the HC group, characterized by loss of probiotics and overgrowth of potentially pathogenic bacteria.Interestingly, the ratio of Firmicutes to Bacteroidetes (FBR) has been used as an indicator of metabolism, nutrition and evaluation of gut micro-biome in cancer patients (Xi et al, 2022). Reduced FBR may be associated with the progression and recurrence of breast cancer (Okubo et al, 2020) and colorectal cancer (Gao et al, 2017).…”

Identification of microbial markers associated with lung cancer based on multi‐cohort 16 s rRNA analyses: A systematic review and meta‐analysis

“…For example, Acidovorax and Veillonella in the sputum can help diagnose squamous cell carcinoma with 80% sensitivity, while Capnocytophaga can be used to identify lung adenocarcinoma with 72% sensitivity 22 . Regarding prognosis, both LM and GM significantly differ between groups exhibiting long and short progression‐free survival durations 69,70 . Based on the oral microbiota, the predictive potential could reach 0.89 23 .…”

“… 22 Regarding prognosis, both LM and GM significantly differ between groups exhibiting long and short progression‐free survival durations. 69 , 70 Based on the oral microbiota, the predictive potential could reach 0.89. 23 In terms of the therapeutic effects of chemotherapy or immunotherapy, numerous studies have been carried out to screen response micro biomarkers and predict clinical side effects.…”

The difference of human gut microbiome in colorectal cancer with and without metastases

“…In the T group, the abundance of Proteobacteria_eggerthii was also higher than that in the M group, which was same with the result after CCRT that the abundance of Proteobacteria increased ( 66 ). After chemoradiotherapy, the Bacteroidetes abundance of individuals with short PFS was lower than that of individuals with long PFS, while the lower ratio may be associated with the progression and recurrence of colorectal cancer ( 67 ). Moreover, enrichment of Firmicutes could improve the sensitivity of ICI immunotherapy ( 68 ) and Bacteroides could enhance the anti‐CTLA‐4 therapy ( 69 ) and the anti-PD-1 immunotherapy ( 70 ).…”

“…Study had shown that Prevotella and 3-Oxo not only promoted the development of malignant tumors, but also reversed the anticancer effect of FOLFOX ( 73 ). Prevotella , as an important carrier of drug resistance genes, was one of the dominant bacteria in the transfer group ( 67 ).…”