Introduction

Lung cancer ( LC ) is one of the most common and the leading cause of cancer deaths worldwide [1]. Genetic susceptibility, gut microbiome and smoking are hypothesized to increase the risks of LC by sha** the tumor microenvironment and promoting the tumorigenesis [2]. Gut microbiota can influence the immune status of the host, which in turn increases susceptibility to malignancy. The gut microbiota and metabolites can enter the blood through the intestinal barrier, leading to a chronic inflammatory state in the organism [3]. Dysfunction of gut microbiota is believed to be associated with the occurrence and development of cancers, and studies have identified potential fecal biomarkers, satisfactory performances of these markers have been shown for diagnosing pancreatic cancer (AUC = 0.78–0.94) [4, 5], hepatocellular carcinoma (AUC = 0.8064) [6], lung adenocarcinoma (AUC = 0.76–0.976) [7, 8] and so on. Emerging studies have indicated that significant changes in the composition and function of the gut microbiota in patients with pulmonary diseases compared to healthy individuals [7, 9, 10]. The detection of differences in gut microbial communities between healthy individuals and LC patients could be used as a predictive tool for LC progression [11, 12]. Research on the role and mechanisms of intestinal flora and its metabolites in LC is beginning to receive widespread attention.

In recent years, many studies focus on the relationship between lung function and lung health. Kachuri et al. found that immune-mediated genetic pathways led to impaired lung function, with reduced FEV1 increasing the risk of squamous cell carcinoma and reduced FEV1/FVC increasing the risk of adenocarcinoma [13]. A large observational literature has found an increased risk of LC in patients with pulmonary insufficiency [14], but the possible relationship between LC and respiratory dysfunction has not been established. Li et al. revealed that the diversity of pulmonary microbiota in chronic obstructive pulmonary disease (COPD) patients with impaired lung function was similar [35, 36]. Mendelian randomization analysis revealed histological-specific effects of reduced FEV1 and FEV1/FVC on LC susceptibility, suggesting that these indicators of impaired lung function may be pathogenic risk factors [13]. In our study, pulmonary ventilation function is positively correlated with tumor stage. Reduced FEV1 has been shown to increase the risk of squamous cell carcinoma and reduced the ratios of FEV1 to FVC increase the risk of adenocarcinoma and lung cancer in never smokers [13]. Gut microbiota is believed to play an important role in altering lung function [37]. However, no studies have investigated whether alterations in gut microbiota and metabolites are associated with long-term lung dysfunction in LC patients. Our study showed that ZC group and QD group had a similar α-diversity, but the α-diversity of ZZD group was significantly reduced (P < 0.05). In addition, these groups could be significantly separated from each other based on PLS-DA. Of which, Hungatella was significantly decreased in the ZZD group, suggesting a negative correlation with the aggravation of tumor stage in LC patients. However, Subdoligranulum and Romboutsia were significantly elevated in ZZD group. Chriswell et al. suggested that subdoligranulum stimulated joint swelling and inflammation [38]. Ni et al. demonstrated that subdoligranulum is the dominant biomarker that distinguish vitiligo patients from healthy controls [39]. In contrast, Lloyd-Price at al. showed that subdoligranulum was markedly increased in inflammatory bowel diseases (IBD), considering as a butyrate producer [40]. Due to the variability of findings, therefore further research is needed to demonstrate the role of Subdoliganulum. It has been reported that invasive mechanical ventilation leads to lung microbiota changes in rat models, which mainly characterization by the Romboutsia and Tubriciactor genera [41]. We speculate that the alterations of genera may be related to the patient dietary habits and a history of nasal oxygen therapy. So the role of these genera in LC patients with pulmonary dysfunction needs to be further investigated in a larger sample cohort.

Then, in the metabolomics analysis of fecal samples, bile acids were significantly decreased in ZZD group. Bile acid biosynthesis changed is a collaborative effect between the host and gut microbiome [42]. The reduction of secondary bile acids may alter the composition of gut microbiota and promote an intestinal inflammation profile [43]. Nie et al. revealed that bile acid metabolism is related to poor prognosis, and may potentiate migration of lung adenocarcinoma (LUAD) [44]. TGR5, the bile acid receptor, as a negative regulator of the NF-κB and AKT pathway, may effectively inhibit the progression of non-small cell lung cancer (NSCLC) [45].

The ROC curve analysis identified four potential biomarkers of diagnostic significance, Stearoylethanolamide, Serylthreonine, Xestoaminol C and Farnesyl acetone with AUC of 0.8750, 0.8625, 0.8583 and 0.8583, respectively. Stearoylethanolamide, an endogenous cannabinoid-like compound with pro-apoptotic activity, is found in the human brain to support the blood-brain barrier in acute systemic inflammation [46, 47]. Terpenoids related compounds exhibit high antibacterial activity against gram-negative bacteria and the very high cytotoxic activity profile of farnesol gives it potential as an anticancer agent [48]. ROC curve analysis between the gut microbes and metabolites showed that the diagnostic power was significantly increased (AUC = 0.9). Previous studies revealed that combining of the bacteria and the clinical tumor markers showed a higher ROC value for predicting LC [49]. Besides, the diagnostic power for predicting colorectal cancer was significantly increased based on the combination of metabolites and bacterial markers [50]. These studies suggesting that joint multi-dimensional data could be used to better predict disease risks. In many cases, gut flora structure has been correlated with the severity of respiratory diseases, such as NSCLC, COVID-19 and COPD [51,52,53].

In conclusion, the intestinal microecology of patients with LC and benign pulmonary diseases patients were characterized in this study. It is revealed that impaired lung ventilation may influence disease severity in LC patients and a predictive model could be developed based on the combination of gut microbes and metabolites for assessing the severity of lung cancer. In the future, a larger sample of the validation queue is needed to validate that alterations in gut microbiota and metabolites are associated with long-term lung dysfunction in LC patients.

Conclusions

Our results showed that microbiome and metabolomics analyses provide important candidate to be used as clinically diagnostic biomarkers and therapeutic targets related to lung cancer with impaired pulmonary function.