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 HFHSfed 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.

The consumption of plant-based bioactive compounds modulates the gut microbiota and interacts with the innate and adaptive immune responses associated with metabolic disorders. The present study aimed to evaluate the effect of cranberry polyphenols (CP), rich in flavonoids, and agavins (AG), a highly branched agave-derived neo-fructans, on cardiometabolic response, gut microbiota composition, metabolic endotoxemia, and mucosal immunomodulation of C57BL6 male mice fed an obesogenic high-fat and high-sucrose (HFHS) diet for 9 weeks. Interestingly, CP+AG-fed mice had improved glucose homeostasis. Oral supplementation with CP selectively and robustly (five-fold) increases the relative abundance of Akkermansia muciniphila, a beneficial bacteria associated with metabolic health. AG, either alone or combined with CP (CP+AG), mainly stimulated the glycan-degrading bacteria Muribaculum intestinale, Faecalibaculum rodentium, Bacteroides uniformis, and Bacteroides acidifaciens. This increase of glycan-degrading bacteria was consistent with a significantly increased level of butyrate in obese mice receiving AG, as compared to untreated counterparts. CP+AG-supplemented HFHS-fed mice had significantly lower levels of plasma LBP than HFHS-fed controls, suggesting blunted metabolic endotoxemia and improved intestinal barrier function. Gut microbiota and derived metabolites interact with the immunological factors to improve intestinal epithelium barrier function. Oral administration of CP and AG to obese mice contributed to dampen the pro-inflammatory immune response through different signaling pathways. CP and AG, alone or combined, increased toll-like receptor (TLR)-2 (Tlr2) expression, while decreasing the expression of interleukin 1ß (ILß1) in obese mice. Moreover, AG selectively promoted the anti-inflammatory marker Foxp3, while CP increased the expression of NOD-like receptor family pyrin domain containing 6 (Nlrp6) inflammasome. The intestinal immune system was also shaped by dietary factor recognition. Indeed, the combination of CP+AG significantly increased the expression of aryl hydrocarbon receptors (Ahr). Altogether, both CP and AG can shape gut microbiota composition and regulate key mucosal markers involved in the repair of epithelial barrier integrity, thereby attenuating obesity-associated gut dysbiosis and metabolic inflammation and improving glucose homeostasis.