Intestinal Bacterial Dysbiosis and Liver Fibrosis in Mice Through Gut-Liver Axis and NLRP3 Inflammatory Pathway Caused by Fine Particulate Matter

Abstract

Fine particulate matter (PM_2.5) is associated with risks of liver diseases and intestinal bacterial dysbiosis, in which the gut-liver axis regulation mechanisms induced by PM_2.5 exposure are still limited so far. In this study, after 12 weeks of exposure to atmospheric PM_2.5 (64 μg/m³) and clean air in winter in Taiyuan, China, we collected liver and intestinal tissues and serum in male mice to perform toxicology experiments. The results showed that PM_2.5 significantly exacerbated the pathological injury in the liver and intestine and liver fibrosis in mice, along with elevated levels of pro-inflammatory cytokines and lipopolysaccharide (LPS) levels in the serum. PM_2.5 caused abnormal liver function and activated TLR4/NF-κB/NLRP3 pathway in mouse liver. PM_2.5 also significantly inhibited the expression of intestinal mucosal tight junction proteins such as ZO-1 and occludin. Besides, from 16S rRNA gene sequencing results in intestinal and fecal samples, we found that PM_2.5 decreased the diversity and abundance of intestinal bacteria, along with reducing Shannon, Chao1 and Ace indices and increasing Simpson indices. Principal component analysis (PCA) showed that mice's intestinal bacterial composition and β-diversity in the PM_2.5-exposed group significantly differed from the control group. KEGG pathway analyzed key functional genes and metabolic pathways in important mouse bacterial communities in the PM_2.5-exposed group. It suggested that PM_2.5 exposure exacerbates liver fibrosis in mice via the NLRP3 pathway. PM_2.5 caused intestinal mucosal injury, intestinal bacterial disorders and increased LPS levels, leading to the activation of inflammatory pathways, which can exacerbate liver fibrosis via the gut-liver axis.