Data_Sheet_1_Fucosylated TLR4 mediates communication between mutualist fucotrophic microbiota and mammalian gut mucosa.doc

ObjectiveThe glycans on the mucosa of suckling mice are predominantly sialylated; upon weaning, fucosylated glycans preponderate. This manifestation of mutualism between fucotrophic bacteria and the mature host utilizes a sentinel receptor in the intestinal mucosa; this receptor was isolated to distinguish its structural and functional features.
DesignProvisional identification of the sentinel gut receptor as fuc-TLR4 was through colonization of germ-free mutant mice. Conventional mice whose microbiota was depleted with a cocktail of antibiotics were used to further define the nature and functions of fuc-TLR4 sentinel, and to define the role of the fucotrophic microbiota in gut homeostasis and recovery from insult. The nature of the sentinel was confirmed in cultured human HEL cells.
ResultsFuc-TLR4 activity is distinct from that of TLR4. Activated mucosal fuc-TLR4 induces a fuc-TLR4 dependent non-inflammatory (ERK and JNK dependent, NF-κB independent) signaling cascade, initiating induction of fucosyltransferase 2 (secretor) gene transcription. In vitro, either defucosylation or TLR4 knockdown abrogates FUT2 induction, indicating that fuc-TLR4 activity requires both the peptide and glycan moieties. In vivo, fucose-utilizing bacteria and fucose-binding ligands induce mucosal fucosylation. Activation of this pathway is essential for recovery from chemically induced mucosal injury in vivo.
ConclusionIn mature mice, fucosyl-TLR4 mediated gut fucosylation creates a niche that supports the healthy fucose-dependent mutualism between the mammalian gut and its fucotrophic microbes. Such microbiota-induced Fuc-TLR4 signaling supports initial colonization of the secretor gut, recovery from dysbiosis, and restoration or preservation of intestinal homeostasis.