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

## TL;DR

A diet high in chicken protein may increase atherosclerosis risk through gut microbes producing 3-Methyl-L-histidine, which affects cholesterol absorption.

## Contribution

Identifies 3-Methyl-L-histidine as a microbiota-derived mediator linking high chicken protein diets to atherosclerosis.

## Key findings

- High chicken protein diet (HCD) accelerates atherosclerosis via gut microbiota-dependent mechanisms.
- 3-Methyl-L-histidine (3-MH) enhances cholesterol absorption by promoting NPC1L1 expression through HNF1A binding.
- Inhibition of the HNF1A–NPC1L1 axis negates the atherogenic effect of 3-MH.

## Abstract

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 Lachnospiraceae, 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.

Schematic summary illustrates the potential mechanism, whereby high chicken protein diet promoted the progression of atherosclerosis. Long‐term adherence to a diet rich in chicken protein accelerated atherosclerosis through an enhanced microbial production of 3‐Methyl‐L‐histidine, which in turn facilitated NPC1L1‐mediated intestinal cholesterol absorption.