Effects of Low Methionine Intake on Gastric Ulcer in Patients and Mice: Role of the NNMT Pathway.

Excessive methionine intake exacerbates gastrointestinal toxicity in mice. Conversely, dietary methionine restriction (MR) suppressed the invasiveness and spread of gastric cancer cells. However, its effects on gastric ulcers (GU) remain unclear. This study aimed to reveal the relationship between methionine intake and GU risk and the role and regulatory mechanism of MR in mice with GU. Logistic regression analysis of the population data showed a significant positive correlation between higher methionine intake and elevated GU risk in adults aged 18-50 years (OR = 1.016, 95% Confidence Interval (CI): 1.005-1.028, p = 0.024). Patients showed notably higher methionine intake levels than healthy controls. GU model mice (Male C57BL/6 mice, 11 weeks old, n = 6/group) treated with MR exhibited significant alleviation of gastric bleeding, edema, and inflammation, a reduction in the ulcer index, and 62.65% inhibition of GU. Furthermore, based on the unique metabolic pathway of methionine, this study demonstrated that MR inhibited gastric nicotinamide N-methyltransferase (NNMT) expression and elevated the NAD+/NADH ratio and Sirtuin 3 (SIRT3) protein expression, thereby lowering IL-1β and IL-6 levels and normalizing the levels of proapoptotic proteins. MR alleviated GU through the NNMT/NAD+/SIRT3 pathway.