Background: Previous animal studies have identified the protective capacity of the gut microbiota against respiratory infections. Nevertheless, the prospective association between human gut microbiota and pneumonia risk remains unknown.

Objectives: To evaluate the links between gut microbiota and incident pneumonia in a representative population sample.

Methods: We performed shotgun metagenome sequencing on stool samples from 6419 FINRISK 2002 participants. Participants were followed up for incident pneumonia using nationwide health register data. We employed multivariable-adjusted Cox regression models and permutational multivariate analysis of variance (PERMANOVA) to assess the association of gut microbiome alpha diversity, compositional variation (beta diversity), and taxonomic composition with pneumonia risk.

Results: Altogether, 685 patients (10.7%) developed pneumonia during a mean follow-up of 17.8 years. Alpha diversity was not associated with incident pneumonia (hazard ratio [HR] 1.00; 95% confidence interval [CI] 0.93 - 1.08), whereas community composition was (PERMANOVA R² = 0.03%; P = 0.02). We observed an inverse association between the relative abundance of butyrate-producing bacteria and incident pneumonia (HR per 1-SD increase 0.91; 95% CI 0.85-0.98). The relative abundance of Bacteroides_F pectinophilus, Eubacterium_G ventriosum, Agathobaculum butyriciproducens, Butyribacter intestini, Eubacterium_I ramulus, CAG-1427 sp000435675, and CAG-603 sp900066105 were inversely associated with pneumonia risk. The relative abundance of Clostridium_AQ innocuum was positively correlated with pneumonia risk.

Conclusions: The gut microbiota composition, and especially the relative abundance of butyrate-producing bacteria, was associated with lower pneumonia risk in the population. These findings warrant further studies to investigate whether microbiome modulation to increase short chain fatty acid production through diet, prebiotics, or probiotics could reduce pneumonia risk.

Keywords: Butyrate; Incidence; Microbiota-host interactions; Pneumonia; Prospective studies.