Scholarlink

Background <p>Western diet (WD) fed Melanocortin 4 receptor-knockout (MC4R-KO) mice develop a phenotype resembling human metabolic dysfunction-associated steatohepatitis (MASH). Despite its clinical relevance, the role of the gut–liver axis in MASH pathogenesis remains unclear. We investigated the gut-liver axis through microbiomic and metabolomic analyses of WD-fed MC4R-KO mice, and we examined their association with MASH pathology. </p> Methods <p>We performed an integrated microbiome and metabolome analysis of the liver, small intestinal contents, large intestinal contents, and plasma of wild-type (WT) and MC4R-KO mice fed either a normal diet or WD. Markers of hepatic inflammation, fibrosis, and steatosis measured in this study were used to assess MASH severity and to correlate microbiome and metabolite alterations.</p> Results <p>WD-fed MC4R-KO mice exhibited significant hepatic steatosis, inflammation, and fibrosis. The abundance of certain microbiota, including Muribaculaceae and <i>Allobaculum</i>, negatively correlated with MASH severity, whereas increased levels of Desulfovibrionaceae and <i>Bacteroides</i> positively correlated with hepatic lipid accumulation, steatosis, and inflammation. Metabolomic profiling revealed increased triglyceride and diglyceride levels in the liver and a concomitant decrease in free fatty acids and monoglycerides in the intestines. Additionally, plasma taurine-conjugated bile acids were elevated in WD-fed MC4R-KO mice, which correlated with the reduced hepatic transport of bile salts from pathway enrichment analysis. These findings highlight substantial alterations in the gut microbiota and lipid and bile acid metabolism, indicating a mechanistic dysregulation of the gut–liver axis that may contribute to MASH progression.</p> Conclusion <p>The observed gut microbial and metabolic alterations, particularly bile acid and lipid metabolism dysregulation, offer insights into potential therapeutic targets aimed at modulating the gut–liver axis to treat or prevent MASH.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Cross-organ multi-omics profiling of microbiome and metabolome along the gut–liver axis in MASH model mice induced by western diet and MC4R knockout

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年2月25日

查看全文
  • Mitsuharu Matsumoto,
  • Osamu Miura,
  • Takeo Moriya,
  • Hitomi Ogino,
  • Megumi Hirayama,
  • Akira Mitsui,
  • Takaharu Hirayama,
  • Yukihiko Ebisuno,
  • Manami Kaneko,
  • Yoshinori Satomi,
  • Yasunori Nio

摘要

Background

Western diet (WD) fed Melanocortin 4 receptor-knockout (MC4R-KO) mice develop a phenotype resembling human metabolic dysfunction-associated steatohepatitis (MASH). Despite its clinical relevance, the role of the gut–liver axis in MASH pathogenesis remains unclear. We investigated the gut-liver axis through microbiomic and metabolomic analyses of WD-fed MC4R-KO mice, and we examined their association with MASH pathology.

Methods

We performed an integrated microbiome and metabolome analysis of the liver, small intestinal contents, large intestinal contents, and plasma of wild-type (WT) and MC4R-KO mice fed either a normal diet or WD. Markers of hepatic inflammation, fibrosis, and steatosis measured in this study were used to assess MASH severity and to correlate microbiome and metabolite alterations.

Results

WD-fed MC4R-KO mice exhibited significant hepatic steatosis, inflammation, and fibrosis. The abundance of certain microbiota, including Muribaculaceae and Allobaculum, negatively correlated with MASH severity, whereas increased levels of Desulfovibrionaceae and Bacteroides positively correlated with hepatic lipid accumulation, steatosis, and inflammation. Metabolomic profiling revealed increased triglyceride and diglyceride levels in the liver and a concomitant decrease in free fatty acids and monoglycerides in the intestines. Additionally, plasma taurine-conjugated bile acids were elevated in WD-fed MC4R-KO mice, which correlated with the reduced hepatic transport of bile salts from pathway enrichment analysis. These findings highlight substantial alterations in the gut microbiota and lipid and bile acid metabolism, indicating a mechanistic dysregulation of the gut–liver axis that may contribute to MASH progression.

Conclusion

The observed gut microbial and metabolic alterations, particularly bile acid and lipid metabolism dysregulation, offer insights into potential therapeutic targets aimed at modulating the gut–liver axis to treat or prevent MASH.