Polysaccharide from Agrocybe cylindracea prevents diet-induced obesity through inhibiting inflammation mediated by gut microbiota and associated metabolites

Polysaccharide from Agrocybe cylindracea (ACP) has been demonstrated with various health benefits, but its anti-obesity effect and underlying mechanisms remain poorly understood. This study aimed to investigate the beneficial effects of ACP in high-fat diet (HFD)-induced obese mice by targeting gut microbiota and metabolites. 9-week ACP supplementation in HFD-fed mice reduced body weight, adipose accumulation, impaired insulin resistance, lipid levels, and liver injuries, which were negatively correlated to the pro-inflammatory factors, particularly tumor necrosis factor-alpha (TNF-α) and interleukin- 6 (IL-6). Moreover, ACP not only restored HFD-induced gut disorder, as indicated by the depletion of Desulfovibrio and Oscillibacter and the enrichment of the Bacteroides, Parabacteroides, Butyricimonas, and Dubosiella, but also positively regulated gut metabolites such as solavetivone and N-acetylneuraminic acid. Spearman's correlation analysis revealed that the ACP-altered microbes and metabolites were highly correlated with inflammation-related indexes. Notably, ACP greatly lowered the obesity-related TNF-α- and IL-6-levels partially by reducing Desulfovibrio and increasing Parabacteroides abundances, together with the associated decrease of solavetivone level. These findings suggest that ACP may be used as a prebiotic agent to prevent diet-induced obesity, and target-specific microbiota and metabolites may have unique therapeutic promise for inflammation-related diseases.