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Knowledge of the biotransformation of tetrabromobisphenol A (TBBPA) and its related contaminants by human gut microbiota (GM) remains unexplored. Here, TBBPA and its four analogs were incubated with mixed GM strains, and nine rhamnosylated or debrominated transformation products (TPs) were discovered. Remarkably, rhamnosylation was identified as a common and unique microbial transformation pathway for these contaminants, and six of the seven rhamnosylated TPs were reported for the first time. Additionally, a kinetic transformation study also showed a rapid and strong bioaccumulation of TBBPA and TPs by Clostridium manihotivorum. Genomic analysis and phylogenetic studies identified C1.1_02053 as the gene encoding the C. manihotivorumworking rhamnosyltransferase (CmRT), showing elevated gene expression with higher TBBPA exposure. Molecular docking identified five critical amino acid residues in CmRT that catalyze TBBPA rhamnosylation, and molecular dynamics simulations further confirmed the stability of the CmRT-TBBPA complex. Dynamic metabolomics analysis showed microbial growth-dependent disturbing effects in C. manihotivorumupon TBBPA exposure, and key metabolic pathways related to rhamnosyltransferase showed changes closely related to the transformation process. These findings provide insights into the unique transformation of environmental contaminants by the GM and highlight the disturbing effects of exogenous chemicals on the GM, as well as the potential impacts on overall human health.