Consumption of a western diet leads to reduced intestinal Cl secretion and impaired intestinal epithelial barrier, with increased inflammation: proposed benefits of dietary genistein and/or exercise.

Chronic consumption of a western diet (high fat with high sugar, HFHS) is associated with type 2 diabetes, inflammation. Genistein is a naturally occurring isoflavone known to exert anti‐inflammatory properties and improve insulin sensitivity. Similar benefits have also been associated with moderate exercise. This study aimed to determine whether dietary genistein (600 mg genistein/kg diet, Gen) or moderate exercise (Ex), or both (Gen+Ex) would reduce the obese‐diabetic phenotype and thus mitigate the intestinal dysfunction induced by chronic consumption of a HFHS “western diet”, in C57BL/6J male and female mice. C57BL/6J mice (6 weeks old) were randomly assigned to one of the following groups (n=10/group): lean control, HFHS, HFHS+Gen, HFHS+Ex, and HFHS+Gen+Ex. The HF diet consisted of 60% saturated fat, 20% carbohydrate, 20% protein. The HS drinking water contained sucrose and fructose. Moderate exercise comprised daily treadmill running for 150 minutes/week for 12 weeks. We characterized jejunum function in this clinically relevant mouse model. We measured transepithelial short circuit current (Isc, a measure of chloride secretion), across freshly isolated segments of jejunum from the mice. Basal Isc was decreased 3‐fold in the HFHS males (19.3±1.7 μA/cm 2 , n=5, P<0.05) compared to leans (66.8±8.1 μA/cm 2 , n=5). Basal Isc was decreased 4‐fold in the HFHS females (16.9±5.4 μA/cm 2 , n=5, P<0.05) compared to leans (67.1±6.2 μA/cm 2 , n=5). Exercise alone significantly increased basal Isc for both sexes. We evaluated several key proteins involved in regulating Isc and/or intestinal motility: (1) expression of the adenosine receptor, A2BR was increased in HFHS females (5‐fold, P<0.05) and males (25‐fold, P<0.05) compared to lean controls. While there was no treatment effect in males, in females A2BR expression was reduced with Gen and Gen+Ex to ‘lean‐like’ levels. (2) expression of K Ca (needed to create the driving force for chloride secretion) was decreased in HFHS males (3.7‐fold, P<0.05) compared to leans controls. Evaluation of tight junction proteins (essential for intestinal epithelial barrier integrity) indicated that desmoglein‐1a, claudin‐1 and desmocollin were all significantly decreased in HFHS females compared to leans, and treatments were without effect. Levels of claudin‐1 were also decreased in HFHS males with recovery by Gen+Ex: indicating that intestinal barrier integrity is likely improved. These benefits are associated with improvements in serum levels of TNFα and IL‐6 (additional cytokines are under evaluation). A comparison of jejunum morphology including assessment of Edu positive proliferative cells (i.e. villi length, number of goblet cells/villi, crypt depth, number of goblet cells/crypt, number of EdU cells/crypt) is in progress. These data suggest that jejunum Cl secretion and intestinal barrier function is markedly dysregulated by consumption of HFHS and may explain the gastrointestinal disturbances associated with diet‐induced diabetic obesity. We find that genistein supplementation and/or moderate exercise (or both) can afford sex‐dependent benefits. Support or Funding Information Midwestern‐Arizona Alzheimer’s Association