Ready-to-use blueberry extract modulates the hypothalamic-pituitary-adrenal axis and alleviates post-stress anxiety linked to antibiotic-induced gut dysbiosis

This study investigated, for the first time, the effects of crude blueberry extracts obtained using natural deep eutectic solvent (CE-NADES) or a conventional organic solvent (CE-SORG) on anxiety- and depression-related parameters in a rat model of intestinal dysbiosis induced by antibiotics. CE-NADES is a ready-to-use extract that does not require solvent removal prior to administration, while CE-SORG was reconstituted in water after solvent removal. Oral administration of blueberry extracts (10 mg of phenolic compounds/kg b.w./day) for 11 days showed that CE-NADES significantly reduced plasma adrenocorticotropic hormone (13.2% vs. control dysbiosis; p < 0.01) and corticosterone (22.5% vs. control dysbiosis; p < 0.0001) levels, and attenuated anxiety-like behavior after acute restraint stress in the elevated plus maze test (85.1% increased time in open arms and 10.4% decreased anxiety index vs. control dysbiosis; p < 0.005). In contrast, CE-SORG reduced only corticosterone levels (15% vs. control dysbiosis; p < 0.0001) and did not produce an anxiolytic behavioral effect. These results indicate that while both extracts modulated the hypothalamic-pituitary-adrenal (HPA) axis, CE-NADES was more effective than CE-SORG. Only CE-NADES mitigated post-stress anxiety associated with antibiotic-induced gut dysbiosis, supporting an anxiolytic effect for this ready-to-use extract. NADES solvent/delivery system was a key determinant of the anxiolytic efficacy of blueberry extract, associated with HPA axis modulation at both the pituitary and adrenal levels. • Blueberry extracts (CE) mitigate activation of HPA axis in a gut dysbiosis model. • CE-NADES is more effective than CE-SORG to downregulate HPA axis in gut dysbiosis. • CE-NADES reduces anxiety-like behavior induced by acute stress in a dysbiosis model. • CE-SORG has no anxiolytic behavior effect in a dysbiosis model. • CE-NADES is ready-to-use, while CE-SORG requires solvent removal before oral intake.