Cadmium toxicity to the human gut microbiome varies depending on composition

ABSTRACT Cadmium (Cd) is a toxic heavy metal with detrimental impacts on the gut microbiota. We investigated the compositional and functional effects of acute Cd exposure on human fecal microbiotas using 24-hour in vitro cultures from 21 healthy adult donors. Regression analysis of butyrate production in the absence (Cd−) versus presence (Cd+) of Cd identified three categories of microbial responses: sensitive, intermediate, and resilient. Under Cd stress, sensitive microbiomes exhibited significant decreases in butyrate [-3.22±0.96 log 2 (Cd+/Cd−), p=0.001] coupled with elevated acetate [1.53±1.83 log 2 (Cd+/Cd−), p=0.003] and lactate [1.86±0.95 log 2 (Cd+/Cd−), p=0.001] production. In contrast, resilient microbiomes did not show significant changes in butyrate [0.22±0.43 log 2 (Cd+/Cd−), p=0.59] or acetate [-0.18±0.35 log 2 (Cd+/Cd−), p=0.26] and exhibited attenuated increases in lactate compared with sensitive microbiomes [0.45±0.43 versus 1.86±0.95 log 2 (Cd+/Cd−), p=0.002]. Sensitive microbiomes had a larger shift in global microbiota composition under Cd stress than resilient microbiomes (weighted UniFrac distance: 0.098±0.026 versus 0.073±0.035, p=0.04). Several genera were significantly different between sensitive and resilient communities after exposure to Cd, but the most striking was Anaerostipes (7.15 centered-log-ratio difference, Cd+/Cd−, q<0.001). Network analysis revealed a significantly greater disruption of microbial interactions in sensitive communities compared with resilient (χ 2 = 9.21, p = 0.002). Multivariable Association with Linear Models revealed that, in resilient communities, butyrate production was primarily associated with Faecalibacterium in the absence of Cd (q<0.001) and Anaerostipes in the presence of Cd (q=0.005). These findings highlight distinct gut microbial responses to acute Cd exposure and provide a foundation to investigate microbiota features underlying Cd sensitivity or resilience. IMPORTANCE Cadmium is a widespread environmental contaminant that reaches the human intestine, where it can disrupt the gut microbial community and negatively impact digestive and systemic health. However, this study demonstrates that human gut microbiomes vary in their responses to cadmium exposure: sensitive communities exhibit losses of beneficial organisms, particularly butyrate-producing taxa that contribute to intestinal integrity and metabolic balance, whereas resilient communities retain microorganisms with this key functional capacity. This work advances our understanding of how gut microbial functions may mitigate the adverse effects of cadmium exposure by identifying the compositional features that distinguish sensitive from resilient microbiomes. These findings highlight the importance of elucidating microbiome-mediated mechanisms that help sustain host health and lay the groundwork for deeper mechanistic studies aimed at mitigating cadmium toxicity.