Microbiota‐derived 3‐Methyl‐L‐histidine mediates the proatherogenic effect of high chicken protein diet

Diet rich in chicken protein has gained a widespread popularity for its profound effect on weight loss and glycemic control; however, its long-term effect on cardiovascular health and the underlying mechanisms remains obscure. Here, we demonstrated that higher intake of chicken protein was an independent risk factor for sub-clinical atherosclerosis. Adherence to high chicken protein diet (HCD) alleviated excessive weight gain and glycemic control regardless of the presence of gut microbiota in apolipoprotein E-deficient mice. In contrast, long-term HCD administration enhanced intestinal cholesterol absorption and accelerated atherosclerotic plaque formation in a gut microbiota-dependent manner. Integrative analysis of 16S rDNA sequencing and metabolomics profiling identified 3-Methyl-L-histidine (3-MH), resulting from an enrichment of <i>Lachnospiraceae</i>, as the key microbial effector to the atherogenic effect of HCD. Mechanistically, 3-MH facilitated the binding of hepatocyte nuclear factor 1A (HNF1A) to the promoter of NPC1-like intracellular cholesterol transporter 1 (NPC1L1), whereas inhibition of HNF1A-NPC1L1 axis abolished the atherogenic effect of 3-MH. Our findings uncovered a novel link between microbiota-derived 3-MH and disturbed cholesterol homeostasis, which ultimately accelerated atherosclerosis, and argued against the recommendation of HCD as weight loss regimens considering its adverse role in vascular health.