Comparative Impacts of Oral Amoxicillin, Azithromycin, and Clindamycin on Gut Microbiota and Intestinal Homeostasis

<b>Background</b>: Amoxicillin, clindamycin and azithromycin are the most frequently prescribed antibiotics for odontogenic infections, but their comparative effects on gut microbiota and intestinal homeostasis remain insufficiently understood. Disruption of gut microbiota, short-chain fatty acid (SCFA) production, and mucosal barrier integrity may contribute to gastrointestinal symptoms. We aimed to compare the impacts of these antibiotics on gut microbiota, SCFA levels, and colonic goblet cells. <b>Methods</b>: C57BL/6N mice were treated with oral amoxicillin, clindamycin, or azithromycin at clinically relevant dosages. Cecal index, fecal water content, and diarrhea index were assessed during treatment and recovery. Gut microbiota composition and absolute bacterial abundance were determined using 16S rRNA amplicon absolute quantification sequencing. SCFAs in cecal contents were quantified by gas chromatography-mass spectrometry. Goblet cell abundance and <i>Muc2</i> mRNA expression in colon tissues were evaluated using Alcian blue staining and RT-PCR. <b>Results</b>: Amoxicillin caused moderate increases in cecal index, reduced <i>Ligilactobacillus</i> abundance, increased <i>Escherichia-Shigella</i>, lowered SCFA levels, and decreased goblet cells and <i>Muc2</i> expression, with partial recovery after two weeks. Clindamycin induced more severe dysbiosis, including sustained Proteobacteria expansion, persistent loss of beneficial taxa, 86-90% reduction in SCFA production, and lasting decreases in goblet cells and <i>Muc2</i> expression without recovery during the observation period. Azithromycin caused mild and reversible changes across all parameters. <b>Conclusions</b>: Among the three antibiotics, azithromycin had the least detrimental effects on gut microbiota, SCFA production, and mucosal barrier function, whereas clindamycin caused profound and persistent intestinal disruption. These findings provide comparative evidence to inform antibiotic selection in clinical practices.