Abstract
Objective: Inflammatory bowel disease (IBD) is characterized by gut microbiota dysbiosis, which is also frequently observed in patients with non-alcoholic fatty liver disease. Whether gut microbiota dysbiosis in IBD patients promotes the development of non-alcoholic steatohepatitis (NASH) remains unclear. We aimed to explore the role of gut microbiota dysbiosis in the development of NASH in mice with dextran sulfate sodium salt (DSS) induced colitis.Design: Dextran sulfate sodium salt was used to induce colitis, and high fat (HF), in combination with a high-fructose diet, was used to induce NASH in C57BL/6J male mice. Mice were treated with (1%) DSS to induce colitis in cycles, and each cycle consisted of 7 days of DSS administration followed by a 10-day interval. The cycles were repeated throughout the experimental period of 19 weeks. Pathological alterations in colitis and NASH were validated by hematoxylin and eosin (H&E), oil red O, Sirius red staining, and immunofluorescence. Gut microbiota was examined by 16S rRNA sequencing, and gene expression profiles of hepatic non-parenchymal cells (NPCs) were detected by RNA sequencing.Results: Dextran sulfate sodium salt administration enhanced the disruption of the gut–vascular barrier and aggravated hepatic inflammation and fibrosis in mice with NASH. DSS-induced colitis was accompanied by gut microbiota dysbiosis, characterized by alteration in the core microbiota composition. Compared with the HF group, the abundance of p_Proteobacteria and g_Bacteroides increased, while that of f_S24-7 decreased in the DSS + HF mice. Specifically, gut microbiota dysbiosis was characterized by enrichment of lipopolysaccharide producing bacteria and decreased abundance of short-chain fatty acid-producing bacteria. Gene expression analysis of liver NPCs indicated that compared with the HF group, genes related to both inflammatory response and angiocrine signaling were altered in the DSS + HF group. The expression levels of inflammation-related and vascular development genes correlated significantly with the abundance of p_Proteobacteria, g_Bacteroides, or f_S24-7 in the gut microbiota, implying that gut microbiota dysbiosis induced by DSS might aggravate hepatic inflammation and fibrosis by altering the gene expression in NPCs.Conclusion: Dextran sulfate sodium salt-induced colitis may promote the progression of liver inflammation and fibrosis by inducing microbiota dysbiosis, which triggers an inflammatory response and disrupts angiocrine signaling in liver NPCs. The abundance of gut microbiota was associated with expression levels of inflammation-related genes in liver NPCs and may serve as a potential marker for the progression of NASH.
Highlights
Non-alcoholic steatohepatitis (NASH) is an inflammatory form of non-alcoholic fatty liver disease (NAFLD)
We explored the association between DSSinduced gut microbiota dysbiosis and liver injury in mice with NASH
As g_Proteobacteria was related to the production of LPS, whereas f_S24-7, g_Bacteroides, and p_Bacteroidetes were related to the production of short chain fatty acids (SCFAs), we further examined the expression of short-chain fatty acids (SCFAs) receptors, such as GPR41, G-protein-coupled receptor 43 (GPR43), and GPR109A, and that of toll like receptor 4 (TLR4), which is the receptor of LPS
Summary
Non-alcoholic steatohepatitis (NASH) is an inflammatory form of non-alcoholic fatty liver disease (NAFLD). The pathogenesis of NASH can be explained by the “multiple hit hypothesis,” which considers risk factors, such as insulin resistance, hormones, nutritional factors, gut microbiota, and genetic factors (Buzzetti et al, 2016). Previous studies indicate that the gut microbiota plays an essential role in the development of NASH (Buzzetti et al, 2016; Leung et al, 2016; Lang and Schnabl, 2020). Inflammatory bowel disease (IBD), which has been correlated with the pathogenesis of NAFLD, is characterized by intestinal bacterial overgrowth and imbalance (Cheng et al, 2018). The relationship between NASH and IBD has received considerable attention
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