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A lysine-restricted diet ameliorates obesity via enrichment of Parabacteroides goldsteinii and 1,4-methylimidazoleacetic acid

Feng Zhao,Zhen Zou,Zhaoyi Liu,Jiao Wang,Yuehua Wu,Jun Zhang,Qin Liu,Weijuan Liang,Jinwen Yao,Xuejun Jiang,Michael N. Routledge,Ahmad Khan,Hongyang Zhang,Jingfu Qiu,Chengzhi Chen

Published 2025 in Nature Communications

ABSTRACT

The effects of dietary amino acid restriction on obesity may be related to the gut microbiome, but its role and mechanism in lysine-restricted diet (LRD) on childhood obesity is largely undefined. Herein, we show that blood lysine levels are elevated in children with obesity compared to healthy controls. Using young mice, we show that LRD ameliorates obesity via gut microbiota modulation. We further identify Parabacteroides goldsteinii (P. goldsteinii) as a candidate contributor and validate that its supplementation reduces obesity phenotype. Metabolomics reveals that P. goldsteinii increases 1,4-methylimidazoleacetic acid (MIAA), a metabolite linked to decreased body weight in animal models. Mechanistically, we show that MIAA inhibits the expression of the demethylase FTO, leading to increased m6A modifications on Slc2a4 mRNA via the reader protein YTHDC1. Collectively, these findings suggest a role for P. goldsteinii and its metabolite MIAA on LRD-mediated obesity reduction, potentially via the FTO-SLC2A4 axis to restrict adipose tissue expansion. Here, using a mouse model, the authors show that a lysine-restricted diet counteracts obesity via the enrichment of Parabacteroides goldsteinii and its metabolite MIAA, which in turn leads to suppressed fat accumulation by modulating the FTO-YTHDC1-SLC2A4 pathway.

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