Complex chemical signals dictate Ah receptor activation through the gut–lung axis

Abstract

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.

Induction of AHR Signaling in Response to the Indolimine Class of Microbial Stress Metabolites

“…The supernatants were dried under vacuum and reconstituted in 60 μL 50% methanol ( v / v ). After centrifugation, supernatants were transferred to autosampler vials for LC-MS/MS analysis, as previously described [ 19 ].…”

“…These mixtures were kept at −20 • C for 30 min followed by centrifugation at 12,000× g for 20 min at 4 • C. The supernatants were dried under vacuum and reconstituted in 60 µL 50% methanol (v/v). After centrifugation, supernatants were transferred to autosampler vials for LC-MS/MS analysis, as previously described [19].…”

Increased Glycolytic Activity Is Part of Impeded M1(LPS) Macrophage Polarization in the Presence of Urolithin A

“…In vitro , UroA has been shown to reduce proinflammatory signaling in macrophages, osteoclasts, neutrophils, and T cells 9 , 10 , 11 . Reported molecular modes of action of UroA include binding to cytochrome P450 (Cyp) 1A1, activation of the aryl hydrocarbon receptor (AhR) or nuclear factor E2-related factor 2 (Nrf2), and inhibition of nuclear factor (NF)- κ B or mechanistic target of rapamycin (mTOR) signaling; the latter is closely linked to induction of macroautophagy, in particular mitophagy, which is considered one prime mechanism underlying the bioactivities of UroA 12 , 13 , 14 , 15 .…”