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Updated: Jun 5, 2026
An Advanced Murine Model for Nonalcoholic Steatohepatitis in Association with Type 2 Diabetes
Published on: April 26, 2019
Alteration of small intestinal microbiota in diet-induced steatohepatitis mice
Go Soma1, Shogo Kawaguchi2, Nobuto Omura3
1Department of Gastroenterology, Hematology, and Clinical Immunology, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori, 036-8562, Japan.
Objective:
Dysbiosis is an important factor that exacerbate metabolic dysfunction-associated steatohepatitis (MASH) via the gut-liver axis. The alterations in the small intestinal microbiota and their contribution to MASH pathogenesis remain largely unexplored. The present study aimed to clarify the alteration of small intestinal microbiota and the gene expression in a diet-induced mouse model of MASH.
Methods:
C57BL6/J mice were fed a choline-deficient L-amino acid-defined high-fat diet (CDAHFD) to induce MASH. qRT-PCR was performed to evaluate the gene expression in liver and ileal tissues. Gut microbiota analysis of small intestinal contents was conducted by 16 S rRNA gene sequencing. The profiles of lamina propria mononuclear cells in the ileum were investigated by flow cytometry analysis. Intestinal mucosal permeability and epithelial expression of Zonula occludens-1 (ZO-1) protein were analyzed by FITC-dextran assay and immunofluorescence, respectively.
Results:
Significant fat accumulation was observed at 3 weeks after the start of CDAHFD, and clusters of F4/80-positive cells were observed at 6 weeks. Three weeks of CDAHFD feeding significantly altered the composition of the intestinal microbiota, characterized by a decrease in the abundance of Lactobacillus and Candidatus Arthromitus. Concurrently, mRNA expression of IL-10 and IL-17 A was significantly downregulated in the ileum, accompanied by a reduction in lamina propria IL-17 A+ T cells. At 6 weeks, the mucosal permeability was significantly increased, and the epithelial ZO-1 expression was decreased.
Conclusion:
Dysbiosis and impaired gut immune system occur in the small intestine during the early phase of MASH development. Small intestinal dysbiosis may be a promising therapeutic target for the progression of MASH.
Insights
Small intestinal dysbiosis and immune changes occur early in metabolic dysfunction-associated steatohepatitis (MASH) development. Targeting these gut alterations may offer new therapeutic strategies for MASH progression.
Area of Science:
- Gastroenterology
- Immunology
- Microbiology
Background:
- Metabolic dysfunction-associated steatohepatitis (MASH) is a growing health concern.
- The gut-liver axis plays a crucial role in MASH pathogenesis.
- Small intestinal microbiota alterations in MASH are not well understood.
Purpose of the Study:
- To investigate small intestinal microbiota changes in a diet-induced MASH mouse model.
- To examine the impact of these changes on gene expression and gut immunity.
- To clarify the role of small intestinal dysbiosis in MASH development.
Main Methods:
- MASH was induced in C57BL6/J mice using a choline-deficient L-amino acid-defined high-fat diet (CDAHFD).
- Small intestinal microbiota composition was analyzed using 16S rRNA gene sequencing.
- Gene expression (IL-10, IL-17A), immune cell profiles, intestinal permeability, and ZO-1 protein expression were evaluated.
Main Results:
- CDAHFD feeding led to significant MASH development, characterized by fat accumulation and inflammation.
- Small intestinal microbiota composition was altered, with decreased Lactobacillus and Candidatus Arthromitus.
- Downregulation of IL-10 and IL-17A mRNA and reduced IL-17A+ T cells were observed.
- Increased intestinal permeability and decreased epithelial ZO-1 expression occurred at later stages.
Conclusions:
- Early-stage MASH involves small intestinal dysbiosis and gut immune system impairment.
- Small intestinal dysbiosis is implicated in the pathogenesis of MASH.
- Targeting small intestinal dysbiosis presents a potential therapeutic avenue for MASH.
