According to our current comprehension, our two-sample MR study is the first to explore the causality connections between gut microbiota and pneumonia based on extensive and recently updated public GWAS databases. The results of our study uncovered several causal relationships at the genetic level between gut microbiota and pneumonia, as well as among the three phenotypes. These results significantly contribute to the comprehension of the involvement of gut microbiota in pneumonia pathological processes, thus providing novel perspectives on its diagnosis and treatment targets.
Our study results suggested that a greater abundance of family Defluviitaleaceae had a significant protective effect against pneumonia. Recently, increasing evidence has shown that Defluviitaleaceae is associated with several inflammation-related diseases, such as lung adenocarcinoma[32] and ulcerative colitis[33]. However, limited research has been undertaken concerning the correlation between Defluviitaleaceae and pneumonia. It was reported that family Defluviitaleaceae was negatively correlated with TLR4 expression[34]. As a cell surface receptor, TLR4 can recognize lipopolysaccharide (LPS) from gram-negative bacteria[35] and transmit signals via the MyD88- and TRIF-dependent pathways, which has the potential to enhance the synthesis of pro-inflammatory cytokines and induce type I IFN (IFN-β) responses, respectively[36]. TLR deficiency plays a protective role in microbe-induced chronic inflammatory and immune diseases[37]. Therefore, we hypothesized that family Defluviitaleaceae might impact the development of pneumonia by modifying the level of inflammation in the body. Further investigation is required in the future to explore the correlation and exact interaction mechanisms between the two.
Additionally, six nominal correlations between gut microbiota and the risk of developing pneumonia were identified in total. Among the two protective groups of bacteria, Lactobacillus and Bacillales both belong to the Firmicutes. A recent study suggested that intestinal processing could release and disseminate glycoconjugates derived from Firmicutes bacteria, leading to the release of the cytokine IL-34, which has the ability to stimulate macrophages and enhance immune responses against pneumonia, sepsis, and meningitis[38]. Similarly, a systematic review showed that the use of Lactobacillus probiotics could protect against viral infections in animal models by enhancing host immunity, inhibiting viral replication, and reducing the viral load[39]. In vitro, research also demonstrated that Lactobacillus possessed inhibitory properties against pathogenic bacteria, encompassing Pseudomonas aeruginosa, Escherichia coli, and Klebsiella pneumoniae[40]. These findings are congruent with the results we have obtained. In terms of the four gut microbiota hazardous to pneumonia, recent studies showed that the prevalence of Anaerotruncus exhibited a positive correlation with the generation of endotoxins and proinflammatory cytokines, such as LPS and interleukin-6 (IL-6)[41], while Barnesiella was negatively associated with LPS-induced gamma-interferon (IFN-γ) production[42]. Changes in the levels of these molecules in the bloodstream could reduce immune system function and induce multisystem inflammatory responses, including in the lungs. Oscillibacter was reported to increase in chronic obstructive pulmonary disease (COPD) patients[43]. Lyu et al. reported that Cyanobacteria might increase the probability of urinary tract infections[44]. In this study, we further recognized Oscillibacter and Cyanobacteria as plausible risk factors for the susceptibility of pneumonia, providing a new reference for future studies on the correlation between gut microbiota and pneumonia incidence.
The normal gut microbiota can protect against pneumonia through the inhibition of colonization by potentially pathogenic bacteria and the regulation of immune responses. Dysbiosis of gut microbiota may impair its function and predispose patients to lung infections[45]. The findings of the “gut-lung axis” may be helpful for clarifying the possible mechanisms underlying the influence of gut microbiota on pneumonia. First, gut microbiota plays a key role in driving postnatal immune system maturation and inducing homeostasis of the immune response[46]. For example, gut microbiome induces the production of type 2 and type 3 intrinsic lymphocytes, which can migrate to the respiratory tract through lymphatic and blood circulation and enhance the anti-infection immunity of the respiratory system[47]. Segmented filamentous bacteria (SFB), a symbiotic bacterium that colonizes the ileum of most animals, including humans, can enhance resistance to Staphylococcus aureus pneumonia in mice by promoting pulmonary type 17 immunity and IL-22 production[48]. In addition, various bioactive substances generated by gut microbiota have the potential to impact the occurrence of pneumonia directly or indirectly through the gut-lung axis. A previous study showed that gut microbiota protects against respiratory infection caused by Streptococcus pneumoniae or Klebsiella pneumoniae through granulocyte–macrophage colony-stimulating factor (GM-CSF) signaling[49]. Short-chain fatty acids (SCFAs) can also prompt differentiation of bone marrow hematopoietic stem cells towards the trajectories of monocytes and dendritic cells, which are capable of migrating from the bone marrow to the lungs, serving an anti-inflammatory function upon the activation of inflammation[50]. Deaminated tyrosine has the potential to safeguard mice against influenza virus infection by strengthening the type I interferon response[51].
There are several advantages to our MR study. First, for the first time, we performed a two-sample MR study to explore the causal relationships between gut microbiota and susceptibility to pneumonia, including its three phenotypes. The utilization of MR methods minimizes the impact of confounding variables and reverse causality on the obtained outcomes. Then, multiple sensitivity analyses discovered no supporting evidence of genetic heterogeneity or horizontal pleiotropy, confirming the robustness of our results. Third, the GWAS data used are the most recent or largest data as well as publicly available, providing genetic variation for thousands of human traits.
Despite this, our study has several limitations. The clinical relevance of our findings to other populations is restricted because of the primarily European demographic representation in the vast majority of GWAS data. Second, the results of MR analysis cannot be directly compared to effect values from clinical studies; rather, the results can be used only to determine the direction of the effect and enhance the validity of establishing causation. Finally, to obtain more valid IVs, we relaxed the threshold for filtering SNPs. In the future, further investigations should be carried out using larger sample sizes of GWAS data.