Gut microbiota-derived Proline-Leucine dipeptide aggravated sepsis-induced acute lung injury via activating Nod2/NF-κB signaling pathway

Abstract

Objective

Gut microbiota-derived metabolites can modulate lung tissue damage via the gut-lung axis. This study aimed to delineate the alterations in gut microbiota and metabolites associated with sepsis and elucidate their role in potentiating lung tissue damage.

Methods

We employed 16S rDNA sequencing and non-targeted metabolomics to assess the changes in gut microbiota and metabolites, utilizing a rat model of sepsis. Furthermore, we investigated the contributions of the gut microbiota-derived Proline-Leucine (Pro-Leu) dipeptide and lipopolysaccharide (LPS) in driving lung inflammation, utilizing both mouse models and MH-S cells.

Results

Our findings indicate that sepsis significantly diminished gut microbiota diversity and markedly increased the relative abundance of Bacteroidetes and Escherichia-Shigella, as well as the metabolite Pro-Leu. Notably, Pro-Leu levels correlated with changes in bacterial communities. Additionally, Pro-Leu effectively exacerbated sepsis-induced lung damage. Both Pro-Leu and LPS notably enhanced pro-inflammatory cytokine production (TNF-α, IL-6, and IL-1β) by up-regulating C/EBP-β, p-NF-κB, and NOD2 in lung tissues and MH-S cells.

Conclusions

Our findings suggest that Pro-Leu and LPS can synergistically intensify lung inflammation by activating the C/EBP-β/NOD2/NF-κB signaling pathways.

Importance

Our findings indicate that sepsis can lead to a disruption of the gut microbiota, an increase in pathogenic bacteria such as Escherichia-Shigella and Bacteroides, and that metabolites derived from the gut microbiota can modulate the lung inflammatory response through the gut-lung axis. Notably, Pro-Leu, a metabolite produced by the gut microbiota, was found to aggravate sepsis-induced ALI by activating the C/EBP-β/NOD2/NF-κB signaling pathways.