Association Between Gut Microbiota and Pneumonia Risk: A Systematic Review and Mendelian Randomization.

Background: The gut-lung axis represents a critical pathway potentially modulating COVID-19 pathogenesis. We employed meta-analysis to investigate the Mendelian randomization (MR) studies for the putative causal relationships between gut microbiota composition/metabolites and COVID-19 severity. Methods: Adhering to PRISMA 2020 guidelines, we conducted a systematic review of MR studies (PubMed/Web of Science/Embase/Scopus/Cochrane; inception to June 2024). Data from 11 studies (aggregating 32,748,274 participants; 1,487 SNPs) underwent meta-analysis across four COVID-19 severity strata including susceptibility, infection, hospitalization, and critical disease. Study quality was evaluated using a validated MR framework assessing 32 core assumptions. Results: Elevated COVID-19 susceptibility risk was associated with Actinobacteria (OR 1.16, 95% CI 1.06-1.26) and Negativicutes (1.06, 1.03-1.09), whereas protective effects emerged for Oxalobacter (0.84, 0.71-0.99) and Ruminococcaceae UCG014 (0.88, 0.78-0.99). For COVID-19 infection, Negativicutes conferred increased risk (1.13, 1.02-1.26), while the Ruminococcus torques group (0.54, 0.39-0.74) and Parasutterella (0.90, 0.83-0.97) demonstrated protection. Hospitalization risk elevated with MollicutesRF9 (1.13, 1.04-1.22) and Alloprevotella (1.25, 1.07-1.45), contrasting with butyrate (0.97, 0.94-0.99) and Ruminiclostridium6 (0.81, 0.69-0.94) showing protective associations. Severe COVID-19 risk increased with Actinobacteria (1.20, 1.01-1.42), Bifidobacterium (2.09, 1.15-3.81), and Alloprevotella (1.66, 1.36-2.01), while Oxalobacter (0.84, 0.76-0.92) and Subdoligranulum (0.82, 0.76-0.89) exhibited protection. Notably, Actinobacteria, Negativicutes, and Alloprevotella constituted consistent risk factors across severity strata, whereas Oxalobacter and Parasutterella showed trans-stage protective effects. Butyrate production specifically attenuated hospitalization risk, and Bifidobacterium demonstrated strikingly elevated critical disease risk, contrasting with typical probiotic associations. Conclusions: This meta-analysis of MR studies provides robust evidence for severity-specific causal effects of the gut microbiota on COVID-19 outcomes. The identified microbial taxa and metabolites provide potential biomarkers for clinical risk stratification and targets for novel adjuvant therapeutic strategies.