Fructose is a common ingredient of food industry in the form of sucrose and high fructose corn sirup (HFCS). Due to its unique metabolic properties, excessive intake of fructose has been linked to various diseases, including obesity, nonalcoholic fatty liver disease (NAFLD), cardiovascular disease (CVD), chronic renal insufficiency, and even increase the risk of death. Interestingly, although high fructose intake may induce gout, it does not cause hyperuricemia, and the underlying molecular mechanisms remain debated. While previous studies focused on the liver as the primary site of fructose metabolism, recent evidence has suggested a crucial role for the intestine-hepatic axis in fructose metabolism. Low dose fructose is mainly metabolized in the small intestine. Only when the intake exceeds the intestine's metabolic capacity fructose spills over to be metabolized in the liver. High fructose diets also have a significant impact on the diversity of the gut microbiota, leading to alterations in the metabolic byproducts produced by these gut bacteria and thereby inducing endotoxemia. This paper provides a comprehensive review of the epidemiological and pathological studies conducted in recent years, describing the metabolic differences between fructose and glucose and the possible mechanisms underlying the link between excessive fructose intake and chronic metabolic diseases.