الفهرس 
Title : A Study of the Effects of selected Human Targeted Non-Antimicrobial Drugs on Members of the Gut Microbiota
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Abstract
Many studies have reported the influence of human-targeted drugs on the composition of the gut microbiota and the effect of the microbiota on drug effectiveness. However, the underlying mechanisms of these interactions are still under study. Therefore, this study aimed to evaluate the possible changes in selected members of gut bacteria exposed to oral drugs. The selected gut bacteria were Bacteroides fragilis, Bifidobacterium longum, Escherichia coli, and Limosilactobacillus reuteri representing Bacteroidetes, Actinobacteria, Proteobacteria, and Firmicutes phyla, respectively. Oral antihistamines and hormones were selected as oral drugs used for long terms with potential effects on gut microbiota. Antihistamines were represented by cyproheptadine, desloratadine, and fexofenadine; while oral hormones were represented by ethinyl estradiol, progesterone, and thyroxine. The effect of intestinal concentrations of these drugs on the selected bacterial growth, biofilm formation, and adherence to colorectal cancer cell lines coculture Caco-2/HT-29 (90:10) was assessed. In addition, drugs’ effects on the production of short-chain fatty acids (SCFAs) were assayed using High-Performance Liquid chromatography. Antihistamines showed variable effects on bacterial growth as fexofenadine caused a significant increase in the growth of all tested bacteria except B. longum, which significantly reduced its growth. Meanwhile, desloratadine and cyproheptadine caused a significant reduction in the growth of all tested bacteria. Oral hormones caused a significant increase in the growth of B. fragilis and E. coli while causing a significant reduction in the growth of B. longum. Hormones exerted a variable effect on L. reuteri growth where progesterone and ethinyl estradiol significantly increased its growth while thyroxine significantly reduced its growth. For biofilm formation, desloratadine and cyproheptadine significantly reduced the biofilm formation of B. fragilis, B. longum, and L. reuteri. While fexofenadine significantly increased the biofilm formation by Gram-positive bacteria, it significantly reduced the biofilm formation of B. fragilis. Progesterone showed significant antibiofilm activity against Gram-positive bacteria while it notably increased the biofilm formation by Gram-negative bacteria. Moreover, thyroxine and ethinyl estradiol exhibited significant antibiofilm activity against L. reuteri, while thyroxine significantly increased the ability of E. coli to form a biofilm. The adherence of E. coli to Caco-2/HT-29 coculture was increased in presence of cyproheptadine despite its negligible effect on biofilm formation by the bacterium. In presence of progesterone, the adherence of both B. fragilis and L. reuteri to the cell lines coculture was increased; conversely, it decreased the ability of L. reuteri to form biofilm. The adherence of B. longum to the cell lines coculture was increased in presence of ethinyl estradiol while it had no significance on its ability to form biofilm. The metabolic activity of B. fragilis and B. longum was altered in the presence of hormones. Progesterone reduced the amount of SCFAs produced by both bacteria. The use of ethinyl estradiol and thyroxine increased the amount of lactic and acetic acid produced by B. longum; however, they decreased the amount of the same acids produced by B. fragilis under the same conditions. The elevated levels of propionic acid were only observed after incubating B. fragilis with ethinyl estradiol and thyroxine, while progesterone decreased the detected levels of the same acid. In conclusion, our results showed that alteration in gut microbiota composition upon consumption of some antihistamines and hormones could be the result of the direct effect of these drugs on bacterial growth, and adherence in addition to their effect on the production of SCFAs, which could contribute to some of the side effects of these drugs beside the effect of these drugs on the host at the tissue targets.