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

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 revealed 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.

膳食氨基酸限制对肥胖的影响可能与肠道微生物组（gut microbiome）相关，但赖氨酸限制膳食（lysine-restricted diet, LRD）在儿童肥胖中的作用与机制仍尚未明确。本研究发现，肥胖儿童的血液赖氨酸水平较健康对照者升高。通过幼年小鼠模型实验，我们证实赖氨酸限制膳食可通过调控肠道菌群改善肥胖。我们进一步鉴定出戈登副杆菌（Parabacteroides goldsteinii, P. goldsteinii）为潜在效应菌株，并验证其补充干预可减轻肥胖表型。代谢组学分析显示，戈登副杆菌可上调1,4-甲基咪唑乙酸（1,4-methylimidazoleacetic acid, MIAA）的水平，该代谢产物在动物模型中与体重降低密切相关。机制层面，我们发现MIAA可抑制去甲基化酶FTO的表达，进而通过m6A识别蛋白（reader protein）YTHDC1增强Slc2a4 mRNA的m6A修饰水平。综上，本研究结果表明，戈登副杆菌及其代谢产物MIAA可介导赖氨酸限制膳食的减重抗肥胖效应，其潜在通路为通过FTO-SLC2A4轴抑制脂肪组织扩张。