Dehydrolithocholic acid (3-Oxo-5β-cholanoic acid; 3-oxoLCA; DLA) is a bile acid metabolite that inhibits T helper cell 17 (Th17) differentiation by interacting with retinoic acid receptor associated orphan receptor (RORγt) [1]. Bile acids are natural surfactants derived from cholesterol, which are crucial for lipid digestion and glucose metabolism, protecting the intestinal epithelium and endowing the mammalian gut with resistance to pathogens[2]. Dehydrolithocholic acid can be a potential candidate drug for the treatment of inflammatory bowel disease[1].
In vitro, use Dehydrolithocholic acid (5µM; 24 hours) can activate the TGR 5-ERK 1/2 pathway on the surface of bronchial epithelial cells (HBEpC) and increase the expression of cathelicidin in the cells[3]. Use Dehydrolithicholic Acid (20µM; 48 hours) treatment with primary CD4+T cells can inhibit Th 17 differentiation and reduce IL-17 α expression levels, but does not affect T cell differentiation into Th 1 or Th 2 cells[4]. MKN 45 was cultured in serum-free medium and treated with 10ng/mL LIF alone or in combination with Dehydrolithocholic acid (1, 3, 10, and 20μM) to reverse LIF induced cell growth at the lowest concentration of 1μM[5].
In vivo, Jax-B6 mice were fed with fecal slurry containing SFB (segmented filamentous bacteria from C57 BL/6 NTac mice) and fed with a control diet or a diet containing 0.3% (w/w) Dehydrolithocholic acid for one week. Treatment with Dehydrolithocholic acid significantly reduced the percentage of Th17 cells in the mouse gut[4]. The rat MCAO model was treated with Dehydrolithocholic acid (pre ischemic administration; 10mg/kg; ip.), which significantly promoted neuronal death in primary culture after OGD injury by downregulating PLOD 2 levels and increasing PTEN expression[6].
References:
[1] Hang S, Paik D, Yao L, et al. Bile acid metabolites control T(H)17 and T(reg) cell differentiation[J]. Nature, 2019, 576(7785): 143-148.
[2] Cheng W, Zhou X, Jin C, et al. Acid-base transformative HADLA micelles alleviate colitis by restoring adaptive immunity and gut microbiome[J]. J Control Release, 2023, 364: 283-296.
[3] Iwona T Myszor, Kornelia Lapka, et al. Bile acid metabolites enhance expression of cathelicidin antimicrobial peptide in airway epithelium through activation of the TGR5-ERK1/2 pathway. Sci Rep. 2024 Mar 21;14(1):6750.
[4] Saiyu Hang, Donggi Paik, et al. Bile acid metabolites control Th17 and Treg cell differentiation. Nature. 2019 Dec;576(7785):143-148.
[5] Cristina Di Giorgio, Elva Morretta, et al. Bile acids serve as endogenous antagonists of the Leukemia inhibitory factor (LIF) receptor in oncogenesis. Biochem Pharmacol. 2024 May:223:116134.
[6] Xiangyi Kong, Xujin Yao, et al. tDCS Regulates ASBT-3-OxoLCA-PLOD2-PTEN Signaling Pathway to Confer Neuroprotection Following Rat Cerebral Ischemia-Reperfusion Injury. Mol Neurobiol. 2023 Nov;60(11):6715-6730.
Dehydrolithocholic Acid（脱氢石胆酸；3-Oxo-5β-cholanoic acid；3-oxoLCA；DLA）是一种胆汁酸代谢产物，通过与维甲酸受体相关孤儿受体（RORγt）相互作用可抑制T辅助细胞17（Th17）分化[1]。胆汁酸是胆固醇衍生的天然表面活性剂，对脂质消化和葡萄糖代谢至关重要，保护肠道上皮并赋予对哺乳动物肠道对病原体的抵抗力[2]。Dehydrolithocholic Acid可作为治疗炎症性肠病的潜在候选药物[1]。
在体外，使用Dehydrolithocholic Acid（5µM；24h）能够激活支气管上皮细胞（HBEpC）表面TGR 5-ERK 1/2途径，增加细胞中cathelicidin的表达[3]。使用Dehydrolithocholic Acid（20µM；48h）处理原代CD 4+T细胞能够抑制细胞的Th 17分化，降低IL-17 α表达水平，但不影响T细胞分化为Th 1或Th 2细胞[4]。将MKN 45在无血清培养基中培养，单独使用10ng/mL LIF或与Dehydrolithocholic Acid（1、3、10 和 20μM）共同处理细胞，Dehydrolithocholic Acid在1μM的最低浓度下能够逆转LIF诱导的细胞生长[5]。
在体内，使用含SFB（分节丝状细菌，来自C57 BL/6 NTac小鼠）的粪浆管饲Jax-B6小鼠，并给这些动物喂食对照饮食或含0.3%（w/w）Dehydrolithocholic Acid的食物一周，Dehydrolithocholic Acid处理显著降低了小鼠回肠Th 17细胞的百分比[4]. 使用Dehydrolithocholic Acid（缺血前给药；10mg/kg；ip.）处理大鼠MCAO 模型，Dehydrolithocholic Acid通过下调PLOD 2水平和增加PTEN表达显著促进了OGD损伤后原代培养的神经元死亡[6]。