Gut bacterial metabolites modulate endoplasmic reticulum stress

Xiaobo Ke,Ramnik J Xavier,Daniel B Graham,Kwontae You,Matthieu Pichaud,Jeffrey A Porter,Henry J Haiser,Hera Vlamakis

doi:10.1186/s13059-021-02496-8

Abstract

BackgroundThe endoplasmic reticulum (ER) is a membranous organelle that maintains proteostasis and cellular homeostasis, controlling the fine balance between health and disease. Dysregulation of the ER stress response has been implicated in intestinal inflammation associated with inflammatory bowel disease (IBD), a chronic condition characterized by changes to the mucosa and alteration of the gut microbiota. While the microbiota and microbially derived metabolites have also been implicated in ER stress, examples of this connection remain limited to a few observations from pathogenic bacteria. Furthermore, the mechanisms underlying the effects of bacterial metabolites on ER stress signaling have not been well established.ResultsUtilizing an XBP1s-GFP knock-in reporter colorectal epithelial cell line, we screened 399 microbiome-related metabolites for ER stress pathway modulation. We find both ER stress response inducers (acylated dipeptide aldehydes and bisindole methane derivatives) and suppressors (soraphen A) and characterize their activities on ER stress gene transcription and translation. We further demonstrate that these molecules modulate the ER stress pathway through protease inhibition or lipid metabolism interference.ConclusionsOur study identified novel links between classes of gut microbe-derived metabolites and the ER stress response, suggesting the potential for these metabolites to contribute to gut ER homeostasis and providing insight into the molecular mechanisms by which gut microbes impact intestinal epithelial cell homeostasis.

Highlights

The endoplasmic reticulum (ER) is a membranous organelle that maintains proteostasis and cellular homeostasis, controlling the fine balance between health and disease
An XBP1s-GFP screen to identify microbiome molecules with unfolded-protein response (UPR)-modulating activity Gut metabolites are jointly derived from diet, modified human metabolites and microbially derived compounds that act as key mediators between the gut microbiome and host biology
Short chain fatty acids (SCFAs) such as butyrate, acetate, and propionate are produced by gut bacteria and modulate host cell functions such as histone deacetylase (HDAC) activity, gene expression, cell proliferation, and immune response

Summary

Introduction

The endoplasmic reticulum (ER) is a membranous organelle that maintains proteostasis and cellular homeostasis, controlling the fine balance between health and disease. Dysregulation of the ER stress response has been implicated in intestinal inflammation associated with inflammatory bowel disease (IBD), a chronic condition characterized by changes to the mucosa and alteration of the gut microbiota. While the microbiota and microbially derived metabolites have been implicated in ER stress, examples of this connection remain limited to a few observations from pathogenic bacteria. Endoplasmic reticulum (ER) stress contributes to various human diseases including inflammatory conditions, cancer, neurodegeneration, fibrosis, diabetes, and metabolic disorders [1,2,3]. Accumulation of misfolded proteins and ER stress can derive from excessive secretory demands, loss of calcium balance, lipid toxicity, and expression of disease-related mutant proteins. To counteract ER stress, cells engage in the unfolded-protein response (UPR). The UPR consists of three parallel signaltransduction cascades that reprogram the cell to augment ER chaperone expression, facilitate misfolded protein elimination, and halt general protein translation

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