Nanthakumar Nanda N, Meng Di, Newburg David S
Department of Pediatrics, Harvard Medical School and GI Unit, Massachusetts General Hospital, Boston, MA, United States.
Front Med (Lausanne). 2023 Mar 16;10:1070734. doi: 10.3389/fmed.2023.1070734. eCollection 2023.
The 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.
Provisional 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.
Fuc-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. , either defucosylation or TLR4 knockdown abrogates induction, indicating that fuc-TLR4 activity requires both the peptide and glycan moieties. , fucose-utilizing bacteria and fucose-binding ligands induce mucosal fucosylation. Activation of this pathway is essential for recovery from chemically induced mucosal injury .
In 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.
乳鼠黏膜上的聚糖主要是唾液酸化的；断奶后，岩藻糖基化聚糖占优势。岩藻糖营养型细菌与成熟宿主之间这种共生关系的表现利用了肠黏膜中的一种哨兵受体；分离出该受体以区分其结构和功能特征。
通过无菌突变小鼠的定殖初步鉴定肠道哨兵受体为岩藻糖基化 Toll 样受体 4（fuc-TLR4）。使用用抗生素混合物耗尽微生物群的常规小鼠进一步确定 fuc-TLR4 哨兵的性质和功能，并确定岩藻糖营养型微生物群在肠道稳态和从损伤中恢复的作用。在培养的人 HEL 细胞中证实了哨兵的性质。
Fuc-TLR4 的活性与 TLR4 不同。活化的黏膜 fuc-TLR4 诱导一种依赖 fuc-TLR4 的非炎症性（依赖细胞外信号调节激酶和应激活化蛋白激酶，不依赖核因子κB）信号级联反应，启动岩藻糖基转移酶 2（分泌型）基因转录的诱导。岩藻糖基化缺失或 TLR4 敲低均消除诱导作用，表明 fuc-TLR4 活性需要肽和聚糖部分。岩藻糖利用细菌和岩藻糖结合配体诱导黏膜岩藻糖基化。该途径的激活对于化学诱导的黏膜损伤的恢复至关重要。
在成熟小鼠中，岩藻糖基化 TLR4 介导的肠道岩藻糖基化创造了一个生态位，支持哺乳动物肠道与其岩藻糖营养型微生物之间健康的岩藻糖依赖性共生关系。这种微生物群诱导的 Fuc-TLR4 信号支持分泌型肠道的初始定殖、从生态失调中恢复以及肠道稳态的恢复或维持。
