Fucosylated TLR‐4 signaling mediates microbial induction of intestinal fut2 expression

Abstract

Toll‐like‐receptor (TLR) binding by specific microbial pattern‐recognition molecule leads to a cascade of innate immune response by activating NF‐κB and/or IRF‐dependent inflammatory signaling pathways. Bacterial‐colonization is also known to stimulate mucosal fucosylation in the gut without activating inflammatory responses, however, it is not known whether this non‐inflammatory response is mediated by a specific TLR. The goal of this study is to determine, if a specific TLR mediates colonization‐dependent intestinal fucosylation. Induction of high fucosylated phenotype of the mature gut occurs in the wildtype mice, but not in the TLR4−/− mice. In the absence of microbiota, a novel and previously unreported form of fucosylated‐TLR4 is generated in the colonocytes. A TLR4 specific ligand, LPS, or monocolonization by a gram‐negative bacterium, Bacteroides fragilis, is sufficient to induce intestinal fucosylation without activating inflammatory responses. This novel fucosylated TLR4 is also activated by a specific α1,2‐fucosylated epitope binding ligand, UEA1, that generated a signaling pathway that is non‐inflammatory and NF‐κB and IRF3 independent. The ERK and JNK‐dependent signaling by the gut microbiota by activating this novel fucosylated TLR4 result in transcriptional induction of the secretor (fucosyltransferase 2; fut2) gene in the epithelium that leads to elevation of fut2 mRNA and FucT II activity. The resultant mucosal fucosylation creates a niche that facilitates colonization by a distinct fucose‐utilizing microbiota and this type of interkingdom communication between the microbiome and the epithelium seems to be central to establishing a protective microbial ecosystem in the gut. This may help explain of a significant association between lack of secretor gene expression and intestinal inflammatory diseases such as necrotizing enterocolitis and Crohn's disease.Supported by HD013021, AI075563, and DK070260.