The water extract of Aloe vera prevents fluoxetine-induced multiple-drug resistance of E. coli by inhibiting reactive oxygen species formation and membrane permeability

The medication of synthetic chemical is one of the main treatments for depressive disorders. Different lines of evidence reveal that a long-term exposure to anti-depressants, e.g., fluoxetine, is causing multiple-drug resistance (MDR) of gut microbiomes. The MDR bacterial strains in gut pose a threat to intestinal balance and treatment of future microbial infection. Effective strategies are thus in urgent need to prevent the anti-depressant-mediated MDR of gut microbes.We aimed to investigate the potential role of Aloe vera (L.) Burm. f. (aloe; Liliaceae family) to prevent MDR of E. coli being co-cultured with fluoxetine.The extract of A. vera was co-cultured with E. coli and fluoxetine to analyze the preventive effect of MDR. To figure out the mechanistic action, the formation of reactive oxygen species (ROS) and the expression of key biomarkers, including outer membrane proteins (OmpF and OmpC), superoxidative stress activator (SoxS) and efflux pumps (AcrA/B-TolC), were determined in E. coli being treated with fluoxetine and aloe extract. In addition, the genetic mutation of transcriptional factors of these biomarkers was determined in the fluoxetine-treated E. coli.The water extract of A. vera showed considerable potential to reduce the number of fluoxetine-mediated MDR colonies. The extract robustly suppressed the formation of ROS in E. coli. However, thiourea and N-acetylcysteine, two well-known antioxidants, showed no activity in preventing the formation of bacterial MDR. Additionally, A. vera extract directly affected the fluoxetine-triggered early stress response of E. coli and the expression of downstream genes. Meanwhile, A. vera extract was able to inhibit the genetic mutation of SoxR gene in E. coli, as induced by co-cultured with fluoxetine. By fractionation of the aloe extract, the ethanol precipitate, composing mainly polysaccharides, showed robust activity in preventing the fluoxetine-mediated MDR.This study therefore suggested that the extract of A. vera could be an adjuvant agent to combat bacterial MDR during anti-depressant treatment.