Letter to the editor: The multiple mechanisms of fructose disrupt gut‐liver axis and metabolic regulation
Authors: Hsien‐Hui Chung
Journal: Hepatology (2022)

To the editor, From the latest article published by Cho et al.,[1] the researchers have demonstrated that fructose drinking disrupted gut functions and induced liver fibrosis through elevated plasma bacterial endotoxin levels and decreased intestinal tight junction and adherent junction proteins as well as cytochrome P450‐2E1 (CYP2E1)‐mediated oxidative and nitrative stress. Nevertheless, I have some insights for the pathological mechanisms of fructose in the gut‐liver axis and systemic metabolism. First, the current study did not explain the influence of fructose metabolism on gut dysfunction in detail. The metabolic enzymes involved in fructose metabolism that interfere with glucose metabolism were worthy of being investigated, including aldolase B, ketohexokinase (KHK), phosphofructokinase, and ATP depletion in glycolysis and acetyl‐CoA carboxylase and fatty acid synthase in de novo lipogenesis. Based on the previous evidence, intestinal tumor growth and grade were enhanced by high‐fructose corn syrup because the conversion from fructose to fructose‐1‐phosphate by KHK further contributed to the activation of glycolysis and increased synthesis of fatty acids.[2] Thus, modulation of the KHK pathway provides a novel direction for the attenuation of fructose‐induced gut dysfunction. Second, the crosslink for fructose and gut‐liver systemic metabolism seemed insufficient. Fructose promoted the prevalence of NAFLD and metabolic dysfunction (hepatic and adipose insulin resistance) linked to hepatic lipogenesis through citrate cleavage in hepatocytes and the generation of gut microbiota–derived acetate through hepatic portal vein circulation.[3] Notably, short‐chain fatty acids (SCFAs) from the gut microbiota had a beneficial action in host energy metabolism and the hormono‐neuro‐immuno system linked to the switch between saccharolytic and proteolytic fermentation,[4] but fructose for the alteration of SCFAs in the current study was not adequately mentioned. Third, cellular metabolic pathways for increased inflammatory cytokine production were reprogrammed by fructose to trigger glutaminolysis and oxidative metabolism. Moreover, the modulation of CYP2E1 is associated with fructose exposure and ethanol induction, suggesting CYP2E1 as the therapeutic target in fructose‐ or ethanol‐induced gut‐liver diseases. Interestingly, controlling fructose ingestion by central neuronal regulation and metabolic hormone biosynthesis from gut microbiota involved in the gut‐liver axis and systemic metabolism should be considered in the current study. Collectively, dietary composition and microbial intervention (probiotic, prebiotic, and antibiotic) have critical effects on gut microbiota, and how to clarify the underlying mechanisms regarding the role of fructose in gut dysbiosis and metabolic dysfunction is promising for us to find efficient strategies to attenuate metabolism‐related digestive disorders. CONFLICT OF INTEREST Nothing to report. AUTHOR CONTRIBUTIONS Hsien‐Hui Chung was responsible for conceptualization, wrote and reviewed the whole manuscript.