Objective: The increasing prevalence of obesity and type 2 diabetes (T2D) demonstrates the failure of conventional treatments to curb these diseases. The gut microbiota has been put forward as a key player in the pathophysiology of diet-induced T2D. Importantly, cranberry (Vaccinium macrocarpon Aiton) is associated with a number of beneficial health effects. We aimed to investigate the metabolic impact of a cranberry extract (CE) on high fat/high sucrose (HFHS)-fed mice and to determine whether its consequent antidiabetic effects are related to modulations in the gut microbiota. Design: C57BL/6J mice were fed either a chow or a HFHS diet. HFHS-fed mice were gavaged daily either with vehicle (water) or CE (200 mg/kg) for 8 weeks. The composition of the gut microbiota was assessed by analysing 16S rRNA gene sequences with 454 pyrosequencing. Results: CE treatment was found to reduce HFHS-induced weight gain and visceral obesity. CE treatment also decreased liver weight and triglyceride accumulation in association with blunted hepatic oxidative stress and inflammation. CE administration improved insulin sensitivity, as revealed by improved insulin tolerance, lower homeostasis model assessment of insulin resistance and decreased glucose-induced hyperinsulinaemia during an oral glucose tolerance test. CE treatment was found to lower intestinal triglyceride content and to alleviate intestinal inflammation and oxidative stress. Interestingly, CE treatment markedly increased the proportion of the mucin-degrading bacterium Akkermansia in our metagenomic samples. Conclusions: CE exerts beneficial metabolic effects through improving HFHS diet-induced features of the metabolic syndrome, which is associated with a proportional increase in Akkermansia spp. population.

Objective: The consumption of fruits is strongly associated with better health and higher bacterial diversity in the gut microbiota (GM). Camu camu ( Myrciaria dubia ) is an Amazonian fruit with a unique phytochemical profile, strong antioxidant potential and purported anti-inflammatory potential. Design: By using metabolic tests coupled with 16S rRNA gene-based taxonomic profiling and faecal microbial transplantation (FMT), we have assessed the effect of a crude extract of camu camu (CC) on obesity and associated immunometabolic disorders in high fat/high sucrose (HFHS)-fed mice. Results: Treatment of HFHS-fed mice with CC prevented weight gain, lowered fat accumulation and blunted metabolic inflammation and endotoxaemia. CC-treated mice displayed improved glucose tolerance and insulin sensitivity and were also fully protected against hepatic steatosis. These effects were linked to increased energy expenditure and upregulation of uncoupling protein 1 mRNA expression in the brown adipose tissue (BAT) of CC-treated mice, which strongly correlated with the mRNA expression of the membrane bile acid (BA) receptor TGR5. Moreover, CC-treated mice showed altered plasma BA pool size and composition and drastic changes in the GM (eg, bloom of Akkermansia muciniphila and a strong reduction of Lactobacillus ). Germ-free (GF) mice reconstituted with the GM of CC-treated mice gained less weight and displayed higher energy expenditure than GF-mice colonised with the FM of HFHS controls. Conclusion: Our results show that CC prevents visceral and liver fat deposition through BAT activation and increased energy expenditure, a mechanism that is dependent on the GM and linked to major changes in the BA pool size and composition.

Previous studies have reported that polyphenol-rich extracts from various sources can prevent obesity and associated gastro-hepatic and metabolic disorders in diet-induced obese (DIO) mice. However, whether such extracts can reverse obesity-linked metabolic alterations remains unknown. In the present study, we aimed to investigate the potential of a polyphenol-rich extract from cranberry (CE) to reverse obesity and associated metabolic disorders in DIO-mice. Mice were pre-fed either a Chow or a High Fat-High Sucrose (HFHS) diet for 13 weeks to induce obesity and then treated either with CE (200 mg/kg, Chow + CE, HFHS + CE) or vehicle (Chow, HFHS) for 8 additional weeks. CE did not reverse weight gain or fat mass accretion in Chow- or HFHS-fed mice. However, HFHS + CE fully reversed hepatic steatosis and this was linked to upregulation of genes involved in lipid catabolism (e.g., PPARα) and downregulation of several pro-inflammatory genes (eg, COX2, TNFα) in the liver. These findings were associated with improved glucose tolerance and normalization of insulin sensitivity in HFHS + CE mice. The gut microbiota of HFHS + CE mice was characterized by lower Firmicutes to Bacteroidetes ratio and a drastic expansion of Akkermansia muciniphila and, to a lesser extent, of Barnesiella spp, as compared to HFHS controls. Taken together, our findings demonstrate that CE, without impacting body weight or adiposity, can fully reverse HFHS diet-induced insulin resistance and hepatic steatosis while triggering A. muciniphila blooming in the gut microbiota, thus underscoring the gut-liver axis as a primary target of cranberry polyphenols.

Berries are rich in polyphenols and plant cell wall polysaccharides (fibers), including cellulose, hemicellulose, arabinans and arabino-xyloglucans rich pectin. Most of polyphenols and fibers are known to be poorly absorbed in the small intestine and reach the colon where they interact with the gut microbiota, conferring health benefits to the host. This study assessed the contribution of polyphenol-rich whole cranberry and blueberry fruit powders (CP and BP), and that of their fibrous fractions (CF and BF) on modulating the gut microbiota, the microbial functional profile and influencing metabolic disorders induced by high-fat high-sucrose (HFHS) diet for 8 weeks. Lean mice-associated taxa, including Akkermansia muciniphila, Dubosiella newyorkensis, and Angelakisella, were selectively induced by diet supplementation with polyphenol-rich CP and BP. Fiber-rich CF also triggered polyphenols-degrading families Coriobacteriaceae and Eggerthellaceae. Diet supplementation with polyphenol-rich CP, but not with its fiber-rich CF, reduced fat mass depots, body weight and energy efficiency in HFHS-fed mice. However, CF reduced liver triglycerides in HFHS-fed mice. Importantly, polyphenol-rich CP-diet normalized microbial functions to a level comparable to that of Chow-fed controls. Using multivariate association modeling, taxa and predicted functions distinguishing an obese phenotype from healthy controls and berry-treated mice were identified. The enterotype-like clustering analysis underlined the link between a long-term diet intake and the functional stratification of the gut microbiota. The supplementation of a HFHS-diet with polyphenol-rich CP drove mice gut microbiota from Firmicutes/Ruminococcus enterotype into an enterotype linked to healthier host status, which is Prevotella/Akkermansiaceae. This study highlights the prebiotic role of polyphenols, and their contribution to the compositional and functional modulation of the gut microbiota, counteracting obesity.