Low-dose epigallocatechin gallate combined with L-theanine effectively alleviate obesity and metabolic dysfunction-associated steatotic liver disease.

Low-dose epigallocatechin gallate combined with L-theanine effectively alleviate obesity and metabolic dysfunction-associated steatotic liver disease by remodeling gut homeostasis and avoiding its hepatotoxicity.

Gaolong Zuo, Yujie Shen, Ling Wang, Yu Gao, Chenyi Luo, Juanshu Wen, Jie Li, Jian-An Huang, Zhonghua Liu, Yong Lin

Phytomedicine

May 31, 2026

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Abstract

BACKGROUND: High-dose epigallocatechin gallate (EGCG) treats obesity and metabolic dysfunction-associated steatotic liver disease but causes hepatotoxicity, limiting its application. OBJECTIVE: To determine whether low-dose EGCG combined with L-theanine (LTA) can reproduce the metabolic benefits of high-dose EGCG without hepatotoxicity, and to clarify the role of the gut microbiota. METHODS: Diet-induced obese C57BL/6J mice were treated with L-EGCG (80 mg/kg/d), H-EGCG (160 mg/kg/d), LTA (80 mg/kg/d), or L-EGCG+LTA for 12 weeks. Metabolic parameters, liver function, oxidative stress, and gut barrier integrity, were evaluated. 16S rRNA sequencing and fecal microbiota transplantation (FMT) confirmed the causal role of microbiota remodeling in the observed therapeutic effects. RESULTS: Although H-EGCG effectively reduced body weight and adiposity, it induced liver injury and gut dysbiosis with depletion of commensal butyrate producers and enrichment of polyphenol-metabolizing taxa, collectively exacerbating hepatic oxidative stress and mitochondrial injury. In contrast, L-EGCG+LTA achieved weight- and lipid-lowering effects comparable to H-EGCG while significantly attenuating hepatic oxidative stress and conferring hepatoprotective effects. Two-way ANOVA confirmed that the combined effects were predominantly additive, with both agents contributing independently. The combination additively remodeled the gut microbiota, markedly enriching beneficial taxa such as Bacteroides uniformis and Oscillospiraceae. FMT from combination-treated donors recapitulated metabolic benefits to HFD-fed recipient mice. CONCLUSIONS: Co-administration of low-dose EGCG and L-theanine additively improves metabolic health by remodeling the gut microbiota, offering a promising strategy to enhance the safety and translational potential of EGCG-based interventions.