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<p>The incidence of inflammatory bowel disease (IBD) is notably increased in patients with nonalcoholic fatty liver disease (NAFLD). The high-fat diet (HFD), a common dietary intervention linked to NAFLD development, disrupts intestinal homeostasis and exacerbates colitis. However, the underlying mechanisms remains unknown. We hypothesized that hepatic lipid metabolism contributes to IBD pathogenesis via disruption of the liver‑gut axis. Here, we established a dextran sulfate sodium (DSS)-induced colitis in mice fed with HFD and investigated the mechanisms by which HFD exacerbates colitis. Our results revealed that an HFD markedly reduced intestinal barrier proteins (Claudin1, E-cadherin) and notably increased Escherichia coli levels. Furthermore, it upregulated the hepatic enzyme Cyp7b1 and suppressed key colonic autophagy markers (LC3-II, Beclin1, ATG5), while elevating P62. An approach combining data available in public domain and in-house RNA-seq revealed a significant correlation between hepatic Cyp7b1 and colonic autophagy. Treatment with Cyp7b1-derived chenodeoxycholic acid (CDCA) led to decreased levels of Claudin1, Occludin, LC3-II, Beclin1, and ATG5, accompanied by an increase in P62, suggesting that CDCA impairs both the epithelial barrier and autophagic flux in the colon. In conclusion, our findings indicated that HFD exacerbated colitis by upregulating hepatic Cyp7b1, which in turn suppresses colonic autophagy and promotes IBD pathogenesis. These findings contribute to a deeper understanding of the NAFLD‑IBD interplay and provide novel mechanistic insights for targeted therapeutic strategies in patients with NAFLD and IBD.</p>

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High-fat diet perturbs hepatic lipid metabolism and impairs colonic autophagy to exacerbate experimental colitis

  • 期刊论文

  • 发表日期：

    2026年4月28日

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  • Tian Xu,
  • Juan Shi,
  • Jing Ji,
  • Chongyang Ma,
  • Jingnan Li

摘要

The incidence of inflammatory bowel disease (IBD) is notably increased in patients with nonalcoholic fatty liver disease (NAFLD). The high-fat diet (HFD), a common dietary intervention linked to NAFLD development, disrupts intestinal homeostasis and exacerbates colitis. However, the underlying mechanisms remains unknown. We hypothesized that hepatic lipid metabolism contributes to IBD pathogenesis via disruption of the liver‑gut axis. Here, we established a dextran sulfate sodium (DSS)-induced colitis in mice fed with HFD and investigated the mechanisms by which HFD exacerbates colitis. Our results revealed that an HFD markedly reduced intestinal barrier proteins (Claudin1, E-cadherin) and notably increased Escherichia coli levels. Furthermore, it upregulated the hepatic enzyme Cyp7b1 and suppressed key colonic autophagy markers (LC3-II, Beclin1, ATG5), while elevating P62. An approach combining data available in public domain and in-house RNA-seq revealed a significant correlation between hepatic Cyp7b1 and colonic autophagy. Treatment with Cyp7b1-derived chenodeoxycholic acid (CDCA) led to decreased levels of Claudin1, Occludin, LC3-II, Beclin1, and ATG5, accompanied by an increase in P62, suggesting that CDCA impairs both the epithelial barrier and autophagic flux in the colon. In conclusion, our findings indicated that HFD exacerbated colitis by upregulating hepatic Cyp7b1, which in turn suppresses colonic autophagy and promotes IBD pathogenesis. These findings contribute to a deeper understanding of the NAFLD‑IBD interplay and provide novel mechanistic insights for targeted therapeutic strategies in patients with NAFLD and IBD.