Background: A growing body of evidence suggests a relationship between gut microbiome and circulating cytokines, yet there is still a lack of large-scale population-based studies investigating gut microbiome-cytokine associations. In this cross-sectional study, we aimed at investigating the associations of gut microbiome (exposure variable) with 45 cytokines and C-reactive protein (CRP) (outcome variables) in the population-based FINRISK 2002 cohort (N = 2,398). Our analyses focused mainly on gut microbiome alpha diversity, beta diversity, differentially abundant taxa, and predicted functions. All statistical models were adjusted for age, sex, BMI, diabetes, and smoking.

Results: Using linear modeling, we identified an inverse association of the gut microbial alpha diversity (Shannon index) with CRP (β=-0.062 ± 0.019/standard deviation (SD), False Discovery Rate adjusted p-value (FDR-P) = 0.025), interleukin-8 (IL-8) (β=-0.066 ± 0.021/SD, FDR-P = 0.025), and interferon-γ-inducible protein 10 (IP-10) (β=-0.063 ± 0.02/SD, FDR-P = 0.025). For beta diversity, linear modeling revealed that the first axis of Principal Component Analysis (PCA) describing the most strongly varying parts of the microbial community composition across population was inversely associated with CRP (β=-0.071 ± 0.019/SD, FDR-P = 0.008) and the second axis was inversely associated with macrophage inflammatory protein-1β (MIP-1B) (β=-0.082 ± 0.021/SD, FDR-P = 0.008), and monokine induced by interferon-γ (MIG) (β=-0.071 ± 0.019/SD, FDR-P = 0.008). The majority of the top taxa contributing to the first and second PCA axes belonged to class Bacilli (7/10) and class Gammaproteobacteria (9/10), respectively. In addition to this, we detected 8 significant associations of specific gut microbiome taxa (species-level) with cytokines and CRP using linear models. The majority of significant taxa belonged to class Clostridia_258483 (5/8) and class Bacteroidia (2/8). We did not detect any significant associations between species-specific predicted MetaCyc pathways (using all prevalent pathways) and cytokines or CRP. When analysis was limited to pathways associated with significant species only, we observed a positive association between purine synthesis predicted pathways in B. thetaiotaomicron and CRP.

Conclusions: Taken together, these results show that CRP, MIP-1B, IL-8, and other cytokines are associated with gut microbial diversity and composition, as well as specific taxa. This could lay the groundwork for future experimental studies to assess the causality of these associations.

Keywords: C-reactive protein; Cytokines; Gut microbiome.