Curcumin attenuates cadmium-induced atherosclerosis by regulating trimethylamine-N-oxide synthesis and macrophage polarization through remodeling the gut microbiota

Studies have shown that cadmium (Cd) exposure primarily occurs through diet, and Cd ingestion is a risk factor for atherosclerosis (AS). However, the underlying mechanism remains unclear. As a target organ, the gastrointestinal tract may play a key role in Cd-induced AS. Additionally, as curcumin is insoluble in water but stable in the stomach of acidic pH, it may play regulative roles in the gut.We assess the effect of Cd exposure on gut flora, trimethylamine-N-oxide (TMAO) metabolism and macrophage polarization, further investigate whether curcumin protects against Cd-induced AS by remodeling gut microbiota.The results of 16 S rRNA sequencing show that Cd exposure causes diversity reduction and compositional alteration of the microbial community, resulting in the increasing TMAO synthesis, the imbalance of lipid metabolism, and the M1-type macrophage polarization in the mouse model (ApoE-/-) of AS. As a result, the plaque area is increased with Cd exposure, shown by oil red O staining. TMAO synthesis is positively correlated with the concentration of blood Cd, and the dynamics of specific bacteria in this process were revealed at the phylum to genus levels. Moreover, the effects of intestinal flora and TMAO on Cd-induced AS are further confirmed via microbial transplantation from a mouse model not exposed to Cd, as the transplantation decreases plaque area. Finally, the gavage with curcumin reverses the Cd-induced pathological progression via gut flora restoration.We first demonstrate that Cd exposure worsens the progression of AS via intestinal flora imbalance and increased TMAO synthesis. Curcumin was verified as a potential novel intervention for preventing Cd-induced AS via remodeling gut microbiota. This study elucidates a new approach for treating AS in regions with significant Cd exposure.