Lactobacillus johnsonii-derived extracellular vesicles carrying GAPDH protect against ulcerative colitis through modulating macrophage polarization

Abstract

Introduction

Ulcerative colitis (UC) is a major inflammatory condition worldwide.

Objectives

The purpose of this study was to investigate the potential contribution of Lactobacillus johnsonii against UC from the perspective of gut microbiota-macrophage-host interactions.

Methods

L. johnsonii abundance in UC patients and colitis mice was evaluated by genomic sequencing. SPF and macrophage-depleted mice were employed to explore the effects of L. johnsonii and its products on colitis. An in vitro macrophage and intestinal epithelial cell co-culture system was constructed. Proteins in extracellular vesicles (EVs) were identified by proteomic analyses, and host signaling pathways were analyzed with transcriptomic analyses.

Results

L. johnsonii abundance was found to be associated with macrophage polarization and intestinal barrier function in human UC patients and mice of a colitis model. L. johnsonii and its derived EVs alleviate colitis in mice in a macrophage-dependent manner. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH), a protein in EVs derived from L. johnsonii, counteracts colitis in vitro and in vivo by regulating macrophage phenotype. GAPDH enhances anti-inflammatory macrophage polarization by inhibiting the MAPK-STAT3 axis. Macrophage-secreted EVs enhances intestinal barrier function in colitis mice by blocking the TLR4 pathway. Protein components in macrophage-derived EVs contribute to colitis remission and intestinal barrier protection.

Conclusion

GAPDH originating in L. johnsonii-derived EVs alleviates colitis and improves intestinal barrier by inhibiting STAT3 in macrophages. EVs created from L. johnsonii are a potential novel treatment strategy for UC.