Changes in gut microbiome may improve blood glucose levels in obese
Resveratrol is a stilbenoid, a type of polyphenol produced by several plants in response to injury or pathogenic attack. Its efficacy is not research proven, but it has shown promising results in exerting antidiabetic effects. The low bioavailability of its oral formulation allows it to reach the colon mainly unmetabolized and, thus, it is suspected to interact with the gut microbiome to exert its antidiabetic effects. Moreover, it has been studied in obese mice and associated with improved insulin sensitivity with changes in the gut microbiome by decreasing relative abundance of Turicibacteraceae, Moryella, Lachnospiraceae, and Akkermansia, and increasing relative abundance of Bacteroides and Parabacteroides.
Prof. Jason Dyck at the University of Alberta revealed resveratrol’s potential to treat diabetes, in addition to reduction in blood pressure and heart health. The impact of resveratrol on the microbiome in the gut of obese mice over a period of 6 weeks altered the microbiome in their intestines with improvement in glucose tolerance. In a second experiment conducted over 8 weeks, fecal waste was collected from resveratrol-fed mice and transplanted into the obese mice with insulin resistance. This led to the rapid effects and dramatic results versus giving the resveratrol orally. Apparently, the fecal material was more potent and efficacious than the resveratrol itself as the blood glucose levels dropped within normal range in prediabetic obese mice within two weeks. Although Dyck was unsure of the key component, he was certain that an unknown metabolite in the fecal matter had caused the improvement in glucose homeostasis.
The study included obtained male mice, 8 weeks of age (n = 40) from Charles Rivers Laboratories that were randomly assigned into four groups and fed: (1) chow, (2) chow plus + 0.4% resveratrol, (3) HFHS, and (4) HFHS + 0.4% resveratrol. They were single housed to avoid confounding effects on microbiota due to cohousing. Glucose levels were checked from the tail tip blood prior to and at 10, 20, 30, 60, 90, and 120 minutes after injections. Fresh fecal matter from group (2) were collected and aliquots of pooled fecal sample was stored at -80°C until used for fecal microbiota transplantation (FMT) in group (3) every second day for a total of three FMTs. Aliquots of fecal matter from 10 mice from the group (3) and (4) were frozen and stored at -80°C for further use. Gut microbial profiling from cecum samples from all groups was used to extract genomic DNA. The serum samples were analyzed using the combined direct flow injection and liquid chromatography-tandem mass spectrometry compound identification and quantification.
Univariate analysis of serum metabolites was performed by unpaired two-tailed Student t-test and Wilcoxon Mann-Whitney test (P-value with W-value). Linear regression between bacterial taxon and the area under the curve from the glucose tolerance test showed no significant correlation between the bacterial groups. Resveratrol dose was intentionally chosen to align with prior studies that had proven its effectiveness. The results were consistent with previous reports as obese mice administered with resveratrol had significantly improved glucose tolerance and it did not alter body mass in HFHS-fed mice, but it significantly decreased the fat mass in resveratrol-fed obese mice. The 16S RNA-based bacterial profiling showed that resveratrol administration altered the commensal gut microbial community in the cecum of obese mice. Resveratrol fed obese mice showed higher ratio of Bacteroides to Firmicutes compared to vehicle treated. The glucose lowering effects of this nutritional was significantly associated with modification of gut microbial composition and predicted functional pathways in obese mice.
After resveratrol + FMT or chow + FMT, four clusters of metabolites that associated with changes in glut flora were identified. Decrease in proteobacteria was more evident in resveratrol + FMT group. Since gut fermentation yields metabolites, they are believed to play a crucial role in the maintenance of energy homeostasis and insulin sensitivity. Improved glucose homeostasis was seen in mice receiving FMT from resveratrol-fed donor mice. The data suggested that resveratrol induced changes in gut microbiome with improvement in glucose homeostasis in obese mice. The consistency of resveratrol effects with previous studies was not tested, thus it cannot be definitively stated as effective. However, studies have shown that it has some role in reducing tissue inflammation, endotoxemia, correct obesity-related alterations in gut microbiota, and metabolic endotoxemia. It is unclear whether the resveratrol effectiveness is due to the changes in the gut microbial community in conjunction with the drug, the drug’s metabolite, or a bacteria-derived metabolite induced by the drug. Thus, more research needs to be done to understand the contents and to address the effectiveness of the drug in depth.
- Oral administration of resveratrol is able to improve glucose homeostasis in obese individuals.
- The study shows that feeding resveratrol to obese mice over a period of 6 weeks altered the makeup of the bacteria in their intestines, improving glucose tolerance.
- Fecal transplantation from healthy resveratrol-fed donor mice has shown higher potency and efficacy than the resveratrol itself in improvement of glucose homeostasis.
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- Sung MM, Kim TT, Denou E, Soltys CM, Hamza SM, Byrne NJ, et al. Improved glucose homeostasis in obese mice treated with resveratrol is associated with alterations in the gut microbiome. Diabetes. 2017;66:418–425. DOI: 10.2337/db16-0680
Mark T. Lawrence, RPh, PharmD Candidate, University of Colorado-Denver, School of Pharmacy NTPD