Assessing the Intestinal Permeability and Anti-Inflammatory Potential of Sesquiterpene Lactones from Chicory

Abstract

Cichorium intybus L. has recently gained major attention due to large quantities of health-promoting compounds in its roots, such as inulin and sesquiterpene lactones (SLs). Chicory is the main dietary source of SLs, which have underexplored bioactive potential. In this study, we assessed the capacity of SLs to permeate the intestinal barrier to become physiologically available, using in silico predictions and in vitro studies with the well-established cell model of the human intestinal mucosa (differentiated Caco-2 cells). The potential of SLs to modulate inflammatory responses through modulation of the nuclear factor of activated T-cells (NFAT) pathway was also evaluated, using a yeast reporter system. Lactucopicrin was revealed as the most permeable chicory SL in the intestinal barrier model, but it had low anti-inflammatory potential. The SL with the highest anti-inflammatory potential was 11β,13-dihydrolactucin, which inhibited up to 54% of Calcineurin-responsive zinc finger (Crz1) activation, concomitantly with the impairment of the nuclear accumulation of Crz1, the yeast orthologue of human NFAT.

Supercritical CO2 Extraction as a Tool to Isolate Anti-Inflammatory Sesquiterpene Lactones from Cichorium intybus L. Roots

“…In the presence of a stimulus (MnCl 2 ), Crz1 dephosphorylates from calcineurin and migrates towards the nucleus, thus promoting the expression of calcineurin dependent response element (CDRE) regulated genes similarly to human NFAT. SFE extract is rich in SLs, which have been already demonstrated to possess anti-inflammatory potential in a previous study [ 34 ]. However, this extract contains unexplored SLs such as the 8-deoxylactucin and 11β,13-dihydro-8-deoxylactuin, whose anti-inflammatory activity was not previously described towards the calcineurin/Crz1 pathway.…”

“…As mentioned above, other pure SLs present in the SFE extract, such as lactucin, lactucopicrin, 11β,13-dihydrolactucin and 11β,13-dihydrolactucopicrin, all of which are commercially available, were already investigated for their anti-inflammatory potential in our previous study [ 34 ]. Therefore, we decided to explore the potential of this novel purified fraction containing a mixture of 8-deoxylactucin and 11β,13-dihydro-8-deoxylactucin.…”

“…In a previous study, chicory SL 11β,13-dihydrolactucin, lacking the α-methylene-γ-lactone ring, was able to modulate the activation of calcineurin/Crz1 pathway due to the presence of α,β-unsaturated carbonyl groups [ 34 ]. In addition, 11β,13-dihydro-8-deoxylactucin also does not contain the α-methylene-γ-lactones group, but it contains other functional groups such as α,β-unsaturated carbonyl, similarly to 11β,13-dihydrolactucin, possibly still being able to modulate the calcineurin/Crz1 pathway acting as a potential anti-inflammatory compound [ 34 ].…”

“…Cell viability was monitored as previously described [34]. Briefly, 100 µL of cultures diluted to a final OD600 = 0.025 ± 0.0025 were placed into 96-well microplates; 10 µL of cell titer blue reagent (Promega, WI, USA) were added, and the plates were incubated for 3 h at 30 • C. Fluorescence was measured in 30 min intervals at emission wavelength 580 nm using the Biotek Power Wave XS Microplate Spectrophotometer (Biotek ® Instruments, Winooski, VT, USA).…”

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“…Chicory root, known for its high content of fibers (galacto-oligosaccharides and fructans, such as inulin) and beneficial for the MGB axis modulation [ 64 , 177 , 200 ], recently also has received attention due to its sesquiterpene lactones (a class of sesquiterpenoids that contain a lactone ring) [ 201 ]. Interestingly, it has been shown that different sesquiterpene lactones from chicory root have the potential to influence anti-inflammatory responses through modulation of the nuclear factor of the activated T-cells pathway [ 201 ].…”