Age- and Sex-dependent Effects of High-fructose, High-fat Diets on Small Bowel Inflammation and Hepatic Steatosis in F344 Rats.

BACKGROUND/AIMS: The liver and small bowel are closely interrelated, and their diet-induced metabolic dysfunction-associated steatotic liver disease (MASLD) may also be influenced by age and sex. Therefore, this study aims to investigate the effects of age and sex on hepatic steatosis and small bowel inflammation induced by a high-fructose and high-fat diet (HFHFD) in rats. METHODS: Male and female rats, aged 6 weeks (young) and 2 years (aged), were used. The HFHFD groups were provided with a high-fat diet and high-fructose water for 8 weeks. Liver and small bowel tissues were histologically analyzed. Tight junction protein expression in jejunal mucosa was analyzed, and immunohistochemistry was performed to detect claudin-2 (Cldn-2). RESULTS: The histological inflammation scores of the old control groups were higher than those of the young control groups, regardless of sex. The jejunal villus/crypt ratio in the young rats was decreased in the male HFHFD group (P = 0.045). In contrast, in aged rats, the villus/crypt ratio decreased in the female HFHFD group (P = 0.076). Hepatic steatosis was higher for the male HFHFD groups (young, P = 0.003; aged, P = 0.005) and in the aged female HFHFD groups (P = 0.003). The correlation of jejunal inflammation scores with hepatic steatosis (P < 0.001) and Cldn-2 mRNA expression (P = 0.047) was significant, with the highest expression observed in aged female HFHFD rats. CONCLUSION: MASLD may be associated with HFHFD-induced jejunal damage. In addition, the upregulation of Cldn-2 may contribute to MASLD in aged female rats.