Associations of low-level multi-metal exposure with peripheral blood-based inflammatory indices and the mediating role of gut microbiota: evidence from lifestyle-standardized men.

With improving environmental regulation and pollution control, low-level multi-metal exposure and its potential health impacts have received increasing attention. However, evidence on metal-related immune-inflammatory phenotypes and mechanisms at low-exposure ranges remains limited. We therefore evaluated the associations between low-level multi-metal exposure and peripheral blood-based inflammatory indices and further explored the mediation roles of gut microbiota. We enrolled 98 men from a centrally managed setting with relatively standardized diets and daily routines. After measuring plasma concentrations of multiple metals, we selected 8 immune-inflammatory-related non-essential metals. We calculated systemic immune-inflammation index (SII), systemic inflammation response index (SIRI), neutrophil-to-lymphocyte ratio (NLR), and derived NLR (dNLR) based on complete blood counts. Fecal microbial composition and functional potential were profiled using full-length 16S ribosomal RNA sequencing and shotgun metagenomics. We found that within low-exposure range, lead (Pb) and cadmium (Cd) were inversely associated with SII, NLR, and dNLR (β ≤ -0.22; PFDR ≤ 0.040), and the overall metal mixture was also inversely associated with these indices (β = -0.37, P = 0.020). Pb was associated with a lower abundance of Agathobaculum butyriciproducens SR79 (β = -0.48; PFDR = 0.026), which mediated 17-21% of the inverse associations of Pb with SII, NLR, and dNLR (PFDR ≤ 0.030). Metagenomic analyses further linked SR79 to signatures of polyamine biosynthesis (β ≥ 0.39; PFDR ≤ 0.032) and GDP-manno-heptose biosynthesis (β = 0.30; PFDR = 0.012). Overall, these results suggested that even at low-exposure range, Pb and Cd were associated with lower peripheral blood-based inflammatory indices, potentially reflecting altered peripheral inflammatory profiles. Gut microbiota features may partly mediate the associations between low-level Pb exposure and peripheral blood-based inflammatory indices.