Administration of guava polysaccharides in C57BL/6 mice reduced weight gain and energy intake, restored lipid metabolism, reduced blood glucose and glucose intolerance, improved liver function, reduced hepatic steatosis and TNF-α level, restored AMPKα phosphorylation, prevented abnormal lipogenesis, and decreased adipose tissue inflammation. It decreased Firmicutes to Bacteroidetes ratio and abundance of Mucispirillum genus, and restored the total SCFA concentration in the feces. Here, TNF is linked to fatty liver disease.