Multi-Species Synbiotic Supplementation After Antibiotics Promotes Recovery of Microbial Diversity and Function, and Increases Gut Barrier Integrity: A Randomized, Placebo-Controlled Trial

<b>Background</b>: Antibiotics are essential for treating infections; however, they disrupt the microbiome and key microbiome-dependent functions. Clinical evidence is mixed for probiotic supplementation following antibiotics due to product heterogeneity and inconsistencies in evaluating biological mechanisms that drive clinical consequences. Accordingly, this study investigates the effects of a multi-species synbiotic on gut microbiome composition and function, and gut barrier integrity, during and following antibiotics. <b>Methods</b>: In a randomized, placebo-controlled trial designed to assess proof-of-mechanism, healthy adult participants received a daily synbiotic (53.6 billion AFU multi-species probiotic and 400 mg Indian pomegranate extract; DS-01) or matching placebo for 91 days. All participants also received ciprofloxacin (500 mg orally twice daily) and metronidazole (500 mg orally three times daily) for the first 7 days. Samples were collected at baseline and Days 7, 14, 49, and 91. Endpoints included fecal microbiome composition, fecal acetate and butyrate levels, urinary Urolithin A (UroA), serum <i>p</i>-cresol sulfate (pCS), gut barrier integrity, and safety. <b>Results</b>: The multi-species synbiotic significantly increased the alpha-diversity of <i>Bifidobacterium</i> and <i>Lactobacillus</i> at all timepoints compared to placebo, including short-term (Day 7, <i>p</i> < 0.0001) and end-of-study (Day 91, <i>p</i> < 0.001). The multi-species synbiotic enhanced recovery of native beneficial microbes, including butyrate-producing species and a novel <i>Oscillospiraceae</i> species (UMGS1312 sp900550625, <i>p</i> < 0.001). Beneficial microbiome-dependent metabolites increased, including fecal butyrate (119%, <i>p</i> < 0.05), fecal acetate (62%, <i>p</i> < 0.01), and UroA (13,008%, <i>p</i> < 0.05), whereas detrimental metabolite pCS decreased (68%, <i>p</i> < 0.05) compared to placebo. Functionally, the multi-species synbiotic improved gut barrier integrity rapidly (Day 7; 305%, <i>p</i> < 0.05) and over the long-term (Day 91; 161%, <i>p</i> < 0.05) compared to placebo. <b>Conclusions</b>: During and after antibiotics, this multi-species synbiotic promotes recovery of gut microbiome diversity and native beneficial microbes, microbiome metabolite recovery, and gut barrier function, all of which underpin antibiotic-associated gastrointestinal symptoms.