Lactiplantibacillus plantarum CCFM8661 and hyaluronic acid synergistically alleviate Pb toxicity via promoting Pb excretion and gut microbiota restoration

• Synbiotic supplementation reduces tissue Pb burden comparable to DMSA while restoring antioxidant capacity • L. plantarum CCFM8661 eliminates Pb while HA restores essential microbial taxa ( Bacteroides and Ruminococcaceae ) • Synbiotics restore gut metabolism via S-adenosylmethionine and pantothenate pathways • Novel bifunctional strategy facilitates concurrent Pb elimination and microbiome restoration Lead (Pb) as a ubiquitous environmental hazard, can enter the human body through multiple routes, inducing systemic toxic responses and constituting a significant global public health challenge. Conventional therapeutic modalities inadequately address the intricate nexus between heavy metal toxicity and microbiome dysregulation. Here, we demonstrate that a synbiotic combination of Lactiplantibacillus plantarum CCFM8661 and hyaluronic acid (HA) provides comprehensive protection against lead toxicity through complementary mechanisms. In lead-exposed mice, this synbiotic intervention markedly reduced tissue Pb burden comparable to DMSA chela while restoring antioxidant capacity and tissue integrity. Notably, CCFM8661 facilitated lead elimination while HA enhanced microbiota resilience by restoring key bacterial taxa ( Bacteroides and Ruminococcaceae ). Metabolomic profiling revealed that synbiotic administration normalized lead-disrupted methylation, energy metabolism, and detoxification pathways, with network analysis identifying S-adenosylmethionine and pantothenic acid as pivotal metabolic hubs mediating microbiome-host recovery. Therefore, this bifunctional synbiotic targeting heavy metal elimination and microbiome restoration presents a novel dietary intervention for mitigating industrial contaminant toxicity.