<i>Phyllanthus emblica</i> L. polysaccharides mitigate obesity <i>via</i> modulation of lipid metabolism and gut microbiota in high-fat diet-fed mice

<i>Phyllanthus emblica</i> L. polysaccharides (PEP) have been shown to ameliorate colitis through their antioxidant, anti-inflammatory, and gut microbiota-modulating properties. However, the potential of PEP in combating obesity remains unexplored. This study aimed to investigate the physicochemical characteristics of PEP and its mechanisms in modulating lipid metabolism in C57BL/6 mice treated with a high-fat diet (HFD). PEP is a high molecular weight, non-crystalline, sheet-like, heat-stable, α-acidic pyran polysaccharide rich in galactose and galacturonic acid. <i>In vivo</i> experiments demonstrated that administering PEP and atorvastatin (positive control) significantly reversed weight gain, adipose tissue hypertrophy, hyperlipidemia, liver steatosis, oxidative stress, and inflammation induced by a HFD. Mechanistically, PEP counteracted obesity by upregulating gene expression related to lipolysis (ATGL, HSL, and AMPKα), β-oxidation (SIRT1, PGC-1α, PPARα, CPT-1A, and MCAD), and cholesterol metabolism (LXRα and LXRβ), while downregulating the <i>de novo</i> lipogenesis axis (C/EBPα, PPARγ, SREBP1, ACC1, and FAS) and HMGCR, thereby enhancing fecal lipid excretion. Remarkably, PEP treatment decreased obesity-promoting bacteria (<i>Anaeroplasma</i> and <i>Clostridia_vadinBB60_group</i>) while increasing obesity-repressed flora (<i>Clostridium_sensu_stricto_1</i>, <i>Lactobacillus</i>, <i>Muribaculaceae</i>, <i>Romboutsia</i>, and <i>Turicibacter</i>). These changes correlated with increased production of short-chain fatty acids (SCFAs), which inhibited NF-κB <i>via</i> binding to GPR41/43. In summary, PEP promotes lipid metabolism and fecal fat excretion and exerts anti-inflammatory and antioxidant effects that are strongly linked to gut microbiota manipulation. These findings reveal the potential of PEP as a functional food ingredient for obesity prevention.