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Background <p>The relationship between microbiota and the gut-lung axis has been extensively studied in both experimental and epidemiological contexts. However, it is still unclear whether the gut microbiome plays a causal role in the development of pneumonia.</p> Methods <p>Our study initially identified the genetic instruments in the gut microbiota GWAS across phylum, class, order, family, and genus levels. Pneumonia data were sourced from the open GWAS project of the Integrated Epidemiology Group (IEU). Mendelian randomization (MR) analysis employed several methods such as inverse variance weighting (IVW), weighted median, and MR-Egger, with Cochran's Q were calculated to assess heterogeneity via IVW and MR-Egger. Additionally, MR-PRESSO and MR-Egger intercepts were utilized to mitigate horizontal pleiotropy. A retrospective case–control study collected anal swab samples from severe pneumonia patients on the 1st and 3rd days after ICU admission. Samples were analyzed using 16S ribosomal ribonucleic acid (16S rRNA) and PERMANOVA analysis.</p> Results <p>Eleven potential causal relationships between the gut microbiome and pneumonia (critical care), as well as nine potential causal relationships between the gut microbiome and pneumonia (28-day death in critical care) were identified. By integrating the results of PERMANOVA analysis with Mendelian randomization analysis, we were able to determine a negative correlation between genus <i>Akkermansia</i> and lactate levels, as well as length of ICU days in patients with septic acute respiratory distress syndrome (ARDS). Moreover, we found a potential negative causal relationship between the <i>genus Akkermansia</i> and pneumonia (28-day death in critical care) (OR 0.42, 95% CI 0.22–0.79, <i>P</i> = 0.007).</p> Conclusions <p>Our Mendelian randomization analysis has provided evidence for a potential causal relationship between gut microbiota and pneumonia. Furthermore, we observed that the <i>genus Akkermansia</i> may decrease the risk of pneumonia (28-day death in critical care), as observed in septic ARDS patients which <i>Akkermansia</i> could reduce ICU days and lactate levels. These findings provide valuable insights into the gut-lung axis and have the latent to inform future research in this field.</p> Trial registration <p>The study was registered at the Chinese Clinical Trial Registry (<a href="https://www.chictr.org.cn/index.html">https://www.chictr.org.cn/index.html</a>, ChiCTR2300075450).</p>

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Causal relationship between gut microbiota and pneumonia: a Mendelian randomization and retrospective case–control study

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月3日

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  • Pengfei Huang,
  • Yanqi Liu,
  • Nana Li,
  • Qianqian Zhang,
  • Yinghao Luo,
  • Yuxin Zhang,
  • Yuxin Zhou,
  • Wenjing Mu,
  • Mengyao Yuan,
  • Yuhan Liu,
  • Yu Xin,
  • Hongxu Li,
  • Yahui Peng,
  • Xibo Wang,
  • Mingyan Zhao,
  • Kaijiang Yu,
  • Changsong Wang

摘要

Background

The relationship between microbiota and the gut-lung axis has been extensively studied in both experimental and epidemiological contexts. However, it is still unclear whether the gut microbiome plays a causal role in the development of pneumonia.

Methods

Our study initially identified the genetic instruments in the gut microbiota GWAS across phylum, class, order, family, and genus levels. Pneumonia data were sourced from the open GWAS project of the Integrated Epidemiology Group (IEU). Mendelian randomization (MR) analysis employed several methods such as inverse variance weighting (IVW), weighted median, and MR-Egger, with Cochran's Q were calculated to assess heterogeneity via IVW and MR-Egger. Additionally, MR-PRESSO and MR-Egger intercepts were utilized to mitigate horizontal pleiotropy. A retrospective case–control study collected anal swab samples from severe pneumonia patients on the 1st and 3rd days after ICU admission. Samples were analyzed using 16S ribosomal ribonucleic acid (16S rRNA) and PERMANOVA analysis.

Results

Eleven potential causal relationships between the gut microbiome and pneumonia (critical care), as well as nine potential causal relationships between the gut microbiome and pneumonia (28-day death in critical care) were identified. By integrating the results of PERMANOVA analysis with Mendelian randomization analysis, we were able to determine a negative correlation between genus Akkermansia and lactate levels, as well as length of ICU days in patients with septic acute respiratory distress syndrome (ARDS). Moreover, we found a potential negative causal relationship between the genus Akkermansia and pneumonia (28-day death in critical care) (OR 0.42, 95% CI 0.22–0.79, P = 0.007).

Conclusions

Our Mendelian randomization analysis has provided evidence for a potential causal relationship between gut microbiota and pneumonia. Furthermore, we observed that the genus Akkermansia may decrease the risk of pneumonia (28-day death in critical care), as observed in septic ARDS patients which Akkermansia could reduce ICU days and lactate levels. These findings provide valuable insights into the gut-lung axis and have the latent to inform future research in this field.

Trial registration

The study was registered at the Chinese Clinical Trial Registry (https://www.chictr.org.cn/index.html, ChiCTR2300075450).