Abstract
Accumulating evidence indicates that gut microbiota participates in the pathogenesis and progression of liver diseases. The severity of immune-mediated liver injury is associated with different microbial communities. Akkermansia muciniphila can regulate immunologic and metabolic functions. However, little is known about its effects on gut microbiota structure and function. This study investigated the effect of A. muciniphila on immune-mediated liver injury and potential underlying mechanisms. Twenty-two C57BL/6 mice were assigned to three groups (N = 7–8 per group) and continuously administrated A. muciniphila MucT or PBS by oral gavage for 14 days. Mouse feces were collected for gut microbiota analysis on the 15th day, and acute liver injury was induced by Concanavalin A (Con A, 15 mg/kg) injection through the tail vein. Samples (blood, liver, ileum, colon) were assessed for liver injury, systemic inflammation, and intestinal barrier function. We found that oral administration of A. muciniphila decreased serum ALT and AST and alleviated liver histopathological damage induced by Con A. Serum levels of pro-inflammatory cytokines and chemokines (IL-2, IFN-γ, IL-12p40, MCP-1, MIP-1a, MIP-1b) were substantially attenuated. A. muciniphila significantly decreased hepatocellular apoptosis; Bcl-2 expression increased, but Fas and DR5 decreased. Further investigation showed that A. muciniphila enhanced expression of Occludin and Tjp-1 and inhibited CB1 receptor, which strengthened intestinal barriers and reduced systemic LPS level. Fecal 16S rRNA sequence analysis indicated that A. muciniphila increased microbial richness and diversity. The community structure of the Akk group clustered distinctly from that of mice pretreated with PBS. Relative abundance of Firmicutes increased, and Bacteroidetes abundance decreased. Correlation analysis showed that injury-related factors (IL-12p40, IFN-γ, DR5) were negatively associated with specific genera (Ruminococcaceae_UCG_009, Lachnospiraceae_UCG_001, Akkermansia), which were enriched in mice pretreated with A. muciniphila. Our results suggested that A. muciniphila MucT had beneficial effects on immune-mediated liver injury by alleviating inflammation and hepatocellular death. These effects may be driven by the protective profile of the intestinal community induced by the bacteria. The results provide a new perspective on the immune function of gut microbiota in host diseases.
Highlights
Hepatitis and its complications are still a worldwide health burden
Acute autoimmune liver injury was established by Concanavalin A (Con A) injection, as shown by elevated serum ALT and aspartate transaminase (AST) (Figure 1B)
We found expression of Cannabinoid Receptor 1 (CB1) was significantly increased after Con A injection, while in A. muciniphila pretreated-mice it remained similar to Normal group
Summary
Hepatitis and its complications are still a worldwide health burden. Numerous environmental insults can cause hepatic damage, and viral infections and autoimmune activation are major causative factors. Hepatitis pathogenesis is associated with T cell stimulation and immunologic injury (Li et al, 2016a). Emerging evidence has shown a strong linkage between intestinal flora and liver diseases (Tilg et al, 2016). Different microbial communities may participate in the onset and progression of liver diseases, with strikingly varied microbial compositions reported (Lozupone et al, 2012; Celaj et al, 2014; Llopis et al, 2016). These findings suggest that modulating the composition and function of intestinal flora may be a potential intervention for liver injury. Studies on the relationship between microbiota and immune-mediated liver injury are rare
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