High-fat diet exacerbates experimental colitis by inhibiting lysosomal function via the STAT3-TFEB Axis

Area of Science:

• Gastroenterology and Molecular Biology
• Cell Biology
• Immunology

Background:

• High-fat diet (HFD) intake is linked to increased inflammatory bowel disease (IBD) risk, but mechanisms are unclear.
• The lysosome and autophagy-lysosome pathway (ALP) are crucial for intestinal epithelial barrier integrity.
• Dysfunction in these pathways contributes to IBD pathogenesis.

Purpose of the Study:

• To investigate the molecular mechanisms by which HFD impairs intestinal barrier function and exacerbates inflammation.
• To elucidate the role of the STAT3-TFEB signaling axis in HFD-induced gut inflammation.
• To identify potential therapeutic targets for diet-associated IBD.

Main Methods:

• In vivo studies using dextran sulfate sodium (DSS)-induced colitis in mice.
• In vitro studies with lipopolysaccharide (LPS)-treated NCM460 cells.
• Molecular analyses including STAT3 and TFEB activation, lysosomal function assays, and gene silencing/knockout experiments.

Main Results:

• HFD and palmitic acid (PA) impaired epithelial barrier function and increased inflammation by suppressing lysosomal function and ALP.
• HFD/PA activated STAT3, which inhibited TFEB transcription and promoted its phosphorylation, hindering nuclear translocation.
• This cascade led to lysosomal membrane permeabilization (LMP), impaired acidification, and reduced degradative capacity.
• STAT3 knockout or TFEB activation restored lysosomal function, repaired the barrier, and ameliorated colitis.

Conclusions:

• HFD disrupts lysosomal function and the intestinal barrier through the STAT3-TFEB signaling axis.
• This pathway is a critical mediator of diet-associated gut inflammation.
• The STAT3-TFEB axis represents a promising therapeutic target for inflammatory bowel disease.