Gut epithelial TSC1/mTOR controls RIPK3-dependent necroptosis in intestinal inflammation and cancer

Area of Science:

• Gastroenterology
• Immunology
• Metabolic pathways

Background:

• Western diet and gut dysbiosis are linked to inflammatory bowel diseases (IBDs).
• Host factors and cellular mechanisms underlying IBD pathogenesis are not fully understood.

Purpose of the Study:

• To investigate the role of the TSC1/mTOR pathway in the gut epithelium as a metabolic and immune checkpoint.
• To elucidate the cellular mechanisms linking diet, microbiota, and intestinal inflammation.

Main Methods:

• Utilized genetic models (Tsc1 ablation) and dietary interventions (Western diet).
• Investigated epithelial necroptosis, barrier function, and susceptibility to colitis and colon cancer.
• Examined the TSC1/mTOR pathway's regulation of RIPK3 expression and activation via ubiquitination and autophagy.
• Assessed the impact of microbiota depletion (antibiotics, gnotobiotics) on necroptosis and colitis.

Main Results:

• mTOR hyperactivation, induced by Western diet or Tsc1 loss, caused epithelial necroptosis, barrier disruption, and increased susceptibility to colitis and colon cancer.
• TSC1/mTOR restrains RIPK3 expression and activation through TRIM11-mediated degradation.
• Microbiota depletion ameliorated mTOR-driven necroptosis and colitis.
• Hyperactive mTOR and aberrant necroptosis were observed in human IBD samples.

Conclusions:

• The TSC1/mTOR pathway serves as a critical metabolic and immune checkpoint in the gut epithelium.
• Aberrant mTOR signaling and RIPK3-mediated necroptosis are key drivers of intestinal inflammation and cancer, linked to diet and microbiota.