Elucidating the critical role of gut microbiota in the pathogenesis of bacterial pneumonia: insights from a Mendelian randomization analysis mediated by immune cell

Abstract

Background: The gut microbiota (GM) is recognized as a critical factor in sustaining overall health and regulating the immune system. However, the precise function of GM in the pathogenesis of bacterial pneumonia (BP), as well as the potential involvement of immune cells in these mechanisms, remains inadequately understood. Given that BP represents a substantial public health issue, elucidating the protective role of the gut microbiota against this condition is of considerable significance.

Methods: We employed a bidirectional two-sample univariate Mendelian randomization (UVMR) approach to investigate the potential causal relationship between GM and BP. Furthermore, we integrated UVMR with multivariate Mendelian randomization (MVMR) analysis to assess the mediating role of immune cells in the pathway linking GM to BP risk. We additionally performed a reverse analysis to exclude GM that could exhibit a reverse causal relationship with BP.

Results: Mendelian randomization (MR) analysis identified 18 GM significantly associated with BP, with 8 of these bacterial taxa linked to a reduced risk and 10 associated with an increased risk. Additionally, 50 immune cell traits exhibited suggestive associations with BP, with 27 immune cells potentially conferring protection and 23 immune cells potentially augmenting risk. Importantly, mediation MR analysis revealed that the protective effect of Clostridia on BP was predominantly mediated by the proportion of HLA DR + Natural Killer cells within CD3- lymphocytes (HLA DR + Natural Killer %CD3- lymphocytes) (Total effect IVW: OR = 0.724, 95% CI [0.552, 0.950], P = 0.020). The evaluation of the mediation effect revealed an effect size of -0.025 (95% CI [-0.061, -0.000]), with a mediation effect ratio of 7.143%.

Conclusion: The study identified specific components of the GM that confer a protective effect against BP. It revealed that the subsets of HLA DR + Natural Killer %CD3- lymphocytes are modulated by Clostridia, thereby enhancing the host's immune defense against BP.

Keywords: Bacterial pneumonia; Gut microbiota; Immune cells; Mendelian randomization.

Fig. 1

All results of gut microbiota. Our study is based on five analysis methods. Therefore, this figure displays the P-values and OR value of these methods. The five concentric heatmaps from outer to inner represent the IVW, the MR-Egger, the Simple Mode, the Weight Median and the Weight Mode analysis results of the gut microbiota, respectively. The darker the color, the more significant the results. OR, odds ratio; MR, Mendelian randomization; IVW, inverse-variance weighted

Fig. 2

Mendelian randomization analyses show causal effects between gut microbiota and bacterial pneumonia. The little squares colored in pink and blue indicate positive and negative ORs respectively from the IVW analysis (truncated at P-value < 0.05). OR, odds ratio; IVW, inverse-variance weighted; LCI, lower confidence intervals; UCI, upper confidence intervals

Fig. 3

Mendelian randomization analyses show causal effects between immune cells and bacterial pneumonia. The dots colored in red and green indicate positive and negative ORs respectively from the IVW analysis (truncated at P-value < 0.05). OR, odds ratio; IVW, inverse-variance weighted; LCI, lower confidence intervals; UCI, upper confidence intervals

Fig. 4

Mediation effect of Clostridia on bacterial pneumonia via the percentage of HLA DR + Natural Killer cells within CD3- lymphocytes

Fig. 5

The study design. A two-step MR study of GM on BP mediated by immune cells