Defining the role of S1p and myeloid cells during enterotoxigenic B. fragilis infection

产肠毒素脆弱类杆菌(ETBF)与急性腹泻有关， 炎症性肠病和结直肠癌。ETBF的致癌作用需要 协调其毒素、BFT和炎症反应的行动，以协调招募 但ETBF如何招募结肠髓系细胞仍知之甚少。S1P动作 作为生物活性的鞘磷脂信使，影响髓系细胞的迁移和调节 结肠炎。然而，ETBF是否整合鞘磷脂代谢物来确定 结肠髓系细胞的新陈代谢有待进一步研究。最近的证据表明 髓系细胞代谢的重塑是诱导先天免疫反应的核心。 我们发现ETBF感染改变了鞘氨醇激酶的活性，这与代谢有关 髓系细胞的重塑、组蛋白乙酰化和前列腺素E_2的产生。两个集成的特定 目标1将决定ETBF感染如何调节炎症 髓样细胞聚集在结肠内。目标2将确定乙酰辅酶A的ETBF是否发生改变 通过激活PPARγ促进髓系细胞的代谢重塑。更深入的理解 鞘磷脂及其酶在控制肠道免疫中的适当作用 并在促进结肠炎的发病和进展中产生新的 “以鞘磷脂为中心”的治疗策略的发展前景 ETBF诱导的肠道炎症的发生和持续。

Enterotoxigenic Bacteroides fragilis (ETBF) has been associated with acute diarrheal, inflammatory bowel disease, and colorectal cancer (CRC). ETBF oncogenesis requires the coordinated action of its toxin, BFT, and an inflammatory response to orchestrate the recruitment of myeloid cells, but how ETBF recruits colonic myeloid cells remains poorly understood. S1p acts as bioactive sphingolipid messengers, influencing the myeloid cells migration and regulating colonic inflammation. However, whether ETBF integrates sphingolipid metabolites to determine the metabolism of colonic myeloid cells needs to be explored. Recent evidence indicates that remodeling of myeloid cells metabolism is central to the induction of innate immune response. We found ETBF infection alters the activity of sphingosine kinase, which is linked to metabolic remodeling, histone acetylation and PGE2 production in myeloid cells. Two integrated specific aims are proposed to test: Aim 1 will determine how ETBF infection regulates inflammatory myeloid cells accumulation in the colon. Aim 2 will determine if ETBF alteration of acetyl-CoA contributes to metabolic remodeling in myeloid cells via PPARγ activation. Deeper understanding of the proper role of sphingolipids and their enzymes in controlling the intestinal immune properties and in promoting the pathogenesis and progression of colitis will generate new perspectives in the development of “sphingolipid-centered” therapeutic strategies that control the onset and perpetuation of the ETBF-induced gut inflammation.