| Summary: | Supplementation of polysaccharides is a promising gut microbiota-targeted therapeutic method for obesity and metabolic diseases. Biological activities of <i>Cordyceps militaris</i> polysaccharides have been well reported, but the effect of selenium (Se)-rich <i>C. militaris</i> polysaccharides (SeCMP) on obesity and associated metabolic disorder and gut microbiota composition has been rarely studied. This study aimed to investigate the anti-obesity and gut microbiota modulatory effect of crude polysaccharides separated from Se-rich <i>C. militaris</i> on a high-fat diet (HFD)-fed C57BL/6J mice model. Mice were treated with a normal diet (CHOW), HFD alone, HFD plus <i>C. militaris</i> polysaccharides (CMP), or low/medium/high dosage of SeCMP for 8 weeks. Body weight, fat content, serum lipid, appetite hormone, lipid gene expression, inflammation cytokines, thermogenic protein, short-chain fatty acids (SCFAs), and gut microbiota structure of the mice were determined. Compared with HFD-fed mice, the serum triglyceride and low-density lipoprotein cholesterol (LDL-C) in the SeCMP-200 group were decreased by 51.5% and 44.1%, respectively. Furthermore, serum lipopolysaccharide-binding proteins (LBP), adiponectin level, and pro-inflammation gene expression in the colon and subcutaneous fat were inhibited, whereas anti-inflammation gene expression was improved, reflecting SeCMP-200 might mitigate obese-induced inflammation. Meanwhile, SeCMP-200 promoted satiety and thermogenesis of obese mice. It also significantly decreased gut bacteria, such as <i>Dorea</i>, <i>Lactobacillus</i>, <i>Clostridium</i>, <i>Ruminococcus,</i> that negatively correlated with obesity traits and increased mucosal beneficial bacteria <i>Akkermansia</i>. There was no significant difference between CMP and SeCMP-100 groups. Our results revealed a high dose of SeCMP could prevent HFD-induced dyslipidemia and gut microbiota dysbiosis and was potential to be used as functional foods.
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