Complex chemical signals dictate Ah receptor activation through the gut-lung axis
Complex chemical signals dictate Ah receptor activation through the gut-lung axis
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DOI：
10.1096/fj.202300703r
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发表时间：
2023-07-01
期刊：
影响因子：
4.8
通讯作者：
Perdew, Gary H.
中科院分区：
文献类型：
--
作者：
Dong, Fangcong;Murray, Iain A.;Perdew, Gary H.
芳烃受体（AHR）介导肠道屏障稳态。许多 AHR 配体也是 CYP1A1/1B1 底物，可导致肠道内快速清除，限制全身暴露和随后的 AHR 激活。这使我们得出这样的假设：CYP1A1/1B1 的膳食底物可以在功能上延长有效 AHR 配体的半衰期。我们研究了尿石素 A (UroA)（一种鞣花单宁的肠道细菌代谢物）作为 CYP1A1/1B1 底物增强体内 AHR 活性的潜力。在体外竞争测定中，UroA 是 CYP1A1/1B1 的竞争性底物。含西兰花的饮食可促进胃中形成强效疏水性 AHR 配体和 CYP1A1/1B1 底物 5,11-二氢吲哚并[3,2-b]咔唑 (ICZ)。在小鼠中，摄入 10% 西兰花饮食中的 UroA 会导致十二指肠、心脏和肺 AHR 活性协调增加，但肝脏活性没有增加。因此，CYP1A1 饮食竞争性底物可以导致肠道的全身 AHR 配体分布增强，可能通过淋巴系统，从而增加关键屏障组织中的 AHR 激活。最后，该报告将导致对饮食中存在的其他疏水性化学物质的分布动态进行重新评估。
The aryl hydrocarbon receptor (AHR) mediates intestinal barrier homeostasis. Many AHR ligands are also CYP1A1/1B1 substrates, which can result in rapid clearance within the intestinal tract, limiting systemic exposure and subsequent AHR activation. This led us to the hypothesis that there are dietary substrates of CYP1A1/1B1 that functionally increase the half-life of potent AHR ligands. We examined the potential of urolithin A (UroA), a gut bacterial metabolite of ellagitannins, as a CYP1A1/1B1 substrate to enhance AHR activity in vivo. UroA is a competitive substrate for CYP1A1/1B1 in an in vitro competition assay. A broccoli-containing diet promotes the gastric formation of the potent hydrophobic AHR ligand and CYP1A1/1B1 substrate, 5,11-dihydroindolo[3,2-b]carbazole (ICZ). In mice, dietary exposure to UroA in a 10% broccoli diet led to a coordinated increase in duodenal, cardiac, and pulmonary AHR activity, but no increase in activity in the liver. Thus, CYP1A1 dietary competitive substrates can lead to enhanced systemic AHR ligand distribution from the gut, likely through the lymphatic system, increasing AHR activation in key barrier tissues. Finally, this report will lead to a reassessment of the dynamics of distribution of other hydrophobic chemicals present in the diet.