Gao Xin, Wang Changle, Pan Bingxin, Liu Yawen, Yuan Shuo, Zheng Shaoru, Yu Dongmei, Han Lujuan, Meng Zhaohua
The Second Department of Infection, The Second Hospital of Hebei Medical University, Heping West Road 215, Shijiazhuang, 050061, China.
Department of Pathogenic Biology, Hebei Medical University, Zhongshan Road 361, Shijiazhuang, 050017, China.
BMC Infect Dis. 2025 Mar 18;25(1):378. doi: 10.1186/s12879-025-10758-0.
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.
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.
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%.
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.
肠道微生物群（GM）被认为是维持整体健康和调节免疫系统的关键因素。然而，GM在细菌性肺炎（BP）发病机制中的精确功能，以及免疫细胞在这些机制中的潜在参与情况，仍未得到充分了解。鉴于BP是一个重大的公共卫生问题，阐明肠道微生物群对这种疾病的保护作用具有相当重要的意义。
我们采用双向双样本单变量孟德尔随机化（UVMR）方法来研究GM与BP之间的潜在因果关系。此外，我们将UVMR与多变量孟德尔随机化（MVMR）分析相结合，以评估免疫细胞在连接GM与BP风险的通路中的中介作用。我们还进行了反向分析，以排除可能与BP存在反向因果关系的GM。
孟德尔随机化（MR）分析确定了18种与BP显著相关的GM，其中8种细菌分类群与风险降低有关，10种与风险增加有关。此外，50种免疫细胞特征与BP表现出提示性关联，其中27种免疫细胞可能具有保护作用，23种免疫细胞可能增加风险。重要的是，中介MR分析表明，梭菌对BP的保护作用主要由CD3 -淋巴细胞内HLA DR +自然杀伤细胞的比例（HLA DR +自然杀伤%CD3 -淋巴细胞）介导（总效应IVW：OR = 0.724，95% CI [0.552, 0.950]，P = 0.020）。中介效应评估显示效应大小为-0.025（95% CI [-0.061, -0.000]），中介效应比为7.143%。
该研究确定了GM中对BP具有保护作用的特定成分。研究表明，HLA DR +自然杀伤%CD3 -淋巴细胞亚群受梭菌调节，从而增强宿主对BP的免疫防御。
