Dietary Isoflavones Intake and Gastric Cancer

Introduction: Gastric cancer (GC) is the fifth cause of death from cancer globally and also remains a frequent. cancer in Italy. Although GC mostly affects countries with low or middle-income economies, particularly in Asia, this malignancy caused approximately 50,000 deaths in Europe in 2022 and will cause over 8200 deaths in Italy in 2024. Infection with Helicobacter pylori (H. pylori), tobacco smoking, heavy alcohol consumption and selected dietary habits are strongly associated with the risk of GC. In particular, high consumption of red meats and salt-preserved foods, and low consumption of fruit have been associated with excess GC risk. Isoflavones are a class of flavonoids mainly, but not exclusively, found in legumes. Various biological mechanisms mediate the effect of isoflavones on GC, including their antioxidant and antiproliferative activities. Genistein lowered GC cell stem-like properties by downregulating Gli1 and CD44 expression. as well as other stem cell markers including OCT-4, Sox2 and Nanog. Additionally, by suppressing COX-2 and upregulating the tumor suppressor PTEN, it inhibited proliferation of GC cells. Daidzein, genistein and isoflavones’ aglycones induced cytostasis in transplanted human GC cells and a reduction in cachexia in mice. The favorable effect on GC can also be linked to the interplay between isoflavones and gut microbiota. In GC patients, the short chain fatty acid (SCFA) production is decreased. In in vivo models and in the Simulator of the Human Intestinal Microbial Ecosystem, isoflavones enhanced the SCFA production. Equol levels also have been related to the presence of butyrate and propionate. Moreover, genistein inhibited the proliferation of H. pylori, a major GC risk factor. In epidemiological studies, isoflavone intakes have been inversely related to GC risk, but the association is still debated. We estimated the content of isoflavones from the European database VENUS on data from an Italian case–control study in order to investigate the relationship between dietary isoflavones and GC risk. Materials and Methods: We used data from a case–control study on GC conducted in the greater Milan area, Italy. The cases featured 230 individuals aged 22–80 years (median age 63 years) with incident, histologically confirmed GC who were admitted to general and major teaching hospitals. The controls were 547 individuals aged 22–80 years (median age 63 years) with no history of cancer. They were enrolled in the same hospitals as cases for non-neoplastic acute conditions, unrelated to risk factors for GC or to long-term modification of diet. Less than 5% of the contacted subjects refused to participate. The participants were interviewed during their hospital stay by trained interviewers using a structured questionnaire. Dietary habits were assessed through a valid and reproducible food frequency questionnaire (FFQ). The FFQ included questions on the weekly consumption of 78 foods items in the 2 years preceding the diagnosis (for cases) or the hospital admission (for controls). In each section, open questions were used to assess the intake of food items that were not included in the FFQ. Daily energy intake was estimated using an Italian food composition database, and data on isoflavone intake were derived from the VENUS database and other sources when needed. We derived the odds ratios (ORs) of GC and the corresponding 95% confidence intervals (CIs) according to tertiles (on the distribution of controls) of isoflavone intake using logistic regression models. The models included terms for sex, age, years of education, year of interview, tobacco smoking status and total energy intake. In addition, we analyzed the ORs of GC by the strata of sex, age, education and smoking, and we evaluated the heterogeneity by the likelihood ratio test. Results: The mean intake was 21.8 µg/day for daidzein, 24.4 µg/day for genistein and 46.2 µg/day for total isoflavones. Comparing the third versus the first tertile, the OR was 0.65 (95%CI = 0.44–0.97, p for trend = 0.04) for daidzein, 0.75 (95%CI = 0.54–1.11, p for trend = 0.15) for genistein and 0.66 (95%CI = 0.45–0.99, p for trend = 0.05) for total isoflavones. Stratified analyses by sex, age, education, and smoking showed no heterogeneity. Conclusions: This study provides findings from an Italian population, where isoflavone intake derives from multiple food sources and information on the role of isoflavones on GC risk is still scant. Isoflavones, mainly derived from non-soy legumes, appear to exert a favourable impact on GC risk. This supports the message that a diet rich in legumes has a protective effect on gastric carcinogenesis.