Gut bacterial metabolites modulate endoplasmic reticulum stress

Area of Science:

• Cell Biology
• Microbiology
• Gastroenterology

Background:

• The endoplasmic reticulum (ER) is vital for cellular homeostasis, and its stress response is implicated in inflammatory bowel disease (IBD).
• While gut microbiota and their metabolites are linked to ER stress, mechanisms involving non-pathogenic bacteria remain unclear.
• Existing knowledge on microbial metabolite effects on ER stress signaling is limited.

Purpose of the Study:

• To screen microbiome-related metabolites for their ability to modulate the ER stress pathway.
• To identify specific classes of metabolites that induce or suppress ER stress.
• To elucidate the molecular mechanisms by which these metabolites affect ER stress signaling.

Main Methods:

• Screening of 399 microbiome-related metabolites using an XBP1s-GFP reporter colorectal epithelial cell line.
• Characterization of metabolite activity on ER stress gene transcription and translation.
• Investigating mechanisms including protease inhibition and lipid metabolism interference.

Main Results:

• Identification of ER stress inducers (acylated dipeptide aldehydes, bisindole methane derivatives) and a suppressor (soraphen A).
• Demonstration of metabolite-induced modulation of ER stress gene expression.
• Evidence that these metabolites act via protease inhibition or lipid metabolism interference.

Conclusions:

• Discovery of novel connections between gut microbe-derived metabolites and the ER stress response.
• Highlighting the potential of these metabolites in maintaining gut ER homeostasis.
• Providing molecular insights into how gut microbes impact intestinal epithelial cell homeostasis.