Grape Polyphenols Attenuate Diet-Induced Obesity and Hepatic Steatosis in Mice in Association With Reduced Butyrate and Increased Markers of Intestinal Carbohydrate Oxidation

Abstract

A Western Diet (WD) low in fiber but high in fats and sugars contributes to obesity and non-alcoholic fatty liver disease (NAFLD). Supplementation with grape polyphenols (GPs) rich in B-type proanthocyanidins (PACs) can attenuate symptoms of cardiometabolic disease and alter the gut microbiota and its metabolites. We hypothesized that GP-mediated metabolic improvements would correlate with altered microbial metabolites such as short chain fatty acids (SCFAs). To more closely mimic a WD, C57BL/6J male mice were fed a low-fiber diet high in sucrose and butterfat along with 20% sucrose water to represent sugary beverages. This WD was supplemented with 1% GPs (WD-GP) to investigate the impact of GPs on energy balance, SCFA profile, and intestinal metabolism. Compared to WD-fed mice, the WD-GP group had higher lean mass along with lower fat mass, body weight, and hepatic steatosis despite consuming more calories from sucrose water. Indirect and direct calorimetry revealed that reduced adiposity in GP-supplemented mice was likely due to their greater energy expenditure, which resulted in lower energy efficiency compared to WD-fed mice. GP-supplemented mice had higher abundance of Akkermansia muciniphila, a gut microbe reported to increase energy expenditure. Short chain fatty acid measurements in colon content revealed that GP-supplemented mice had lower concentrations of butyrate, a major energy substrate of the distal intestine, and reduced valerate, a putrefactive SCFA. GP-supplementation also resulted in a lower acetate:propionate ratio suggesting reduced hepatic lipogenesis. Considering the higher sucrose consumption and reduced butyrate levels in GP-supplemented mice, we hypothesized that enterocytes would metabolize glucose and fructose as a replacement energy source. Ileal mRNA levels of glucose transporter-2 (GLUT2, SLC2A2) were increased indicating higher glucose and fructose uptake. Expression of ketohexokinase (KHK) was increased in ileum tissue suggesting increased fructolysis. A GP-induced increase in intestinal carbohydrate oxidation was supported by: (1) increased gene expression of duodenal pyruvate dehydrogenase (PDH), (2) a decreased ratio of lactate dehydrogenase a (LDHa): LDHb in jejunum and colon tissues, and (3) decreased duodenal and colonic lactate concentrations. These data indicate that GPs protect against WD-induced obesity and hepatic steatosis by diminishing portal delivery of lipogenic butyrate and sugars due to their increased intestinal utilization.

Evaluation of the Effects of a Short Supplementation With Tannins on the Gut Microbiota of Healthy Subjects

“…In view of this, attention is being focused on finding strategies to promote a healthier environment in the colonic ecosystem, in order to restore a balanced control over the immune-metabolic axis ( Cires et al, 2019 ; Mezhibovsky et al, 2021 ). While pharmacological strategies have resulted mostly ineffective to this aim, several studies have reported the efficacy of polyphenol-rich diets for promoting a healthy gut environment.…”

Cannabidiol-Treated Ovariectomized Mice Show Improved Glucose, Energy, and Bone Metabolism With a Bloom in Lactobacillus

“…Uterus and liver were weighed. Ileum and colon segments were dissected as previously described ( Tveter et al, 2020 ; Mezhibovsky et al, 2021 ) and then flushed with ice-cold, sterile PBS (pH 7.4) to collect luminal contents for targeted metabolomics. Samples were placed in cryogenic tubes, snap frozen in liquid nitrogen, and stored at −80°C until analysis.…”

“…Body composition was measured using an EchoMRI body composition analyzer (EMR-129, Echo Medical Systems, Houston, TX) at 0, 4, 7, 10, 14, and 18 weeks post-treatment. After 9 weeks of treatment, an oral glucose tolerance test was performed as previously described ( Tveter et al, 2020 ; Mezhibovsky et al, 2021 ). During the 9th and 10th week post-treatment, indirect calorimetry was performed on 9 mice per group using a Comprehensive Laboratory Animal Monitoring System with temperature and light control enclosure (CLAMS, Columbus Instruments, Columbus, Ohio) as previously described ( Mezhibovsky et al, 2021 ).…”

“…RNA from ileum and colon tissues (30–35 mg) were extracted as previously described ( Tveter et al, 2020 ; Mezhibovsky et al, 2021 ). Each femur bone sample (stored at −80°C) was ground to powder with a mortar and pestle (pre-chilled in −20°C freezer) containing liquid nitrogen.…”

Diet and Gut Microbiota Interaction-Derived Metabolites and Intrahepatic Immune Response in NAFLD Development and Treatment

“…Supplementation with grape polyphenols reduced Western diet (WD)-induced adiposity and hepatic steatosis in mice by increasing the abundance of Akkermansia muciniphila and butyrate and sugar expenditure in the distal intestine [ 50 ].…”