Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston MA 02115.
Broad Institute of MIT and Harvard, Cambridge, MA 02142.
Proc Natl Acad Sci U S A. 2019 Jun 25;116(26):12672-12677. doi: 10.1073/pnas.1904099116. Epub 2019 Jun 10.
A substantial and increasing number of human diseases are associated with changes in the gut microbiota, and discovering the molecules and mechanisms underlying these associations represents a major research goal. Multiple studies associate , a prevalent gut microbe, with Crohn's disease, a major type of inflammatory bowel disease. We have found that synthesizes and secretes a complex glucorhamnan polysaccharide with a rhamnose backbone and glucose sidechains. Chemical and spectroscopic studies indicated that the glucorhamnan was largely a repeating unit of five sugars with a linear backbone formed from three rhamnose units and a short sidechain composed of two glucose units. The rhamnose backbone is made from 1,2- and 1,3-linked rhamnose units, and the sidechain has a terminal glucose linked to a 1,6-glucose. This glucorhamnan potently induces inflammatory cytokine (TNFα) secretion by dendritic cells, and TNFα secretion is dependent on toll-like receptor 4 (TLR4). We also identify a putative biosynthetic gene cluster for this molecule, which has the four biosynthetic genes needed to convert glucose to rhamnose and the five glycosyl transferases needed to build the repeating pentasaccharide unit of the inflammatory glucorhamnan.
大量且不断增加的人类疾病与肠道微生物群的变化有关,发现这些关联背后的分子和机制是一个主要的研究目标。多项研究将 ,一种常见的肠道微生物,与克罗恩病(一种主要的炎症性肠病)联系起来。我们发现 合成并分泌一种具有鼠李糖主链和葡萄糖侧链的复杂葡甘聚糖多糖。化学和光谱研究表明,葡甘聚糖主要是由五个糖组成的重复单元,线性主链由三个鼠李糖单元组成,短侧链由两个葡萄糖单元组成。鼠李糖主链由 1,2-和 1,3-连接的鼠李糖单元组成,侧链有一个末端葡萄糖与 1,6-葡萄糖相连。这种葡甘聚糖强烈地诱导树突状细胞分泌炎症细胞因子(TNFα),而 TNFα 的分泌依赖于 Toll 样受体 4(TLR4)。我们还鉴定了这个分子的一个假定生物合成基因簇,该基因簇具有将葡萄糖转化为鼠李糖所需的四个生物合成基因,以及构建炎症性葡甘聚糖重复五糖单元所需的五个糖基转移酶。