Ingestion of subtoxic doses of cadmium induces persistent dysbiosis and enhances susceptibility to DSS-induced colitis long after exposure

Abstract Health officials often focus on the effect of high doses of heavy metal pollutants. However, most people will more likely be exposed to subtoxic doses via contaminated water or food. We addressed the effects exposure to subtoxic doses of heavy metal pollutants could have on the gut immune homeostasis. We report that chronic ingestion of environmentally relevant subtoxic doses of cadmium does not impair the barrier function of the intestine in mice. On the other hand, chronic exposure to subtoxic doses of this heavy metal stimulates the growth of intestinal epithelial cells including Paneth cells, and increased production of antimicrobial peptides by Paneth cells. We also found that subtoxic doses of cadmium induce a dysbiosis of the gut microbiota that persist months after the end of the exposure. Importantly, 12–14 months after exposure to cadmium, the cadmium-exposed mice weighted more and had more fat content than age-matched controls suggesting that these mice have developed a state of chronic inflammation. Cadmium is also known to accumulates in soft tissues with a half-life of 10–20 years. Thus, to investigate the long-term effect of exposure to subtoxic doses of cadmium, control and post-menopausal mice (> 15 months old) previously exposed to cadmium were treated with dextran sodium sulfate (DSS) in drinking water. Post-menopausal mice previously exposed to cadmium developed more severe signs of DSS-induced colitis including weight loss, shortened large intestine. Furthermore, they exhibited enhanced Th17 responses in mucosal tissues. Our results provide new insights the impact of chronic exposure to subtoxic doses of cadmium, and possibly other heavy metals on gut homeostasis and colitis or colon cancer.