It is widely recognized that diet is an essential determinant of health. The Western diet, characterized by high fat, high sugar, and low fiber content, is one of the major factors contributing to the etiology of societal chronic disorders.
It is now clear that this unhealthy diet impacts metabolic responses and causes perturbations in the host–microbiota community structure, i.e., dysbiosis. Such an imbalance of the gut microbiota has consequences on the intestinal barrier integrity such as alteration of the immunological function and increase of the permeability, also called “leaky gut”. Certain dietary constituents specifically shape the gut microbiota through a prebiotic action.
Polyphenols are a good candidates for shaping the gut microbiota. Indeed, 90%–95% of dietary polyphenols reach the colon intact where they interact with the microbiota and are degraded to potential bioactive metabolites conferring health benefits.
The International Scientific Association for Probiotics and Prebiotics (ISAPP) consensus statement, published in Nature Reviews Gastroenterology & Hepatology, defines prebiotic as “a substrate that is selectively utilized by host microorganisms conferring a health benefit” and lists phenolic compounds as prebiotic good candidates. (Gibson et al., 2017)
* The figure shows candidate as well as accepted prebiotics in that levels of evidence currently vary, with FOS and GOS being the most researched prebiotics, and phenolics and phytochemicals components as good candidates.
CLA, conjugated linoleic acid; PUFA, polyunsaturated fatty acid; FOS, fructooligosaccharides; GOS, galactooligosaccharides; MOS, mannanoligosaccharide; XOS, xylooligosaccharide.
In 2018, Symrise supported, together with the Institute of Nutrition and Functional foods (INAF) and the Natural Science and Engineering Research Council of Canada (NSERC), the creation of a 5-year Industrial Partnership Chair on the potential prebiotic effects of fruit polyphenols.
This research program led by Pr. Yves Desjardins, has investigated how polyphenols can modulate the gut microbiome and affect the intestinal barrier function, the main cause of metabolic endotoxemia and low-grade inflammation associated with the onset of many chronic diseases.
— Symrise: The outcome of a 5-year research program chair on prebiotic potential of fruit polyphenols
Well known for its benefits in supporting urinary health, cranberry (Vaccinium macrocarpon) is a fruit originating from North America, traditionally used by Native Americans to relieve a variety of ailments.
Cranberries are high in polyphenols, supporting various health benefits of which urinary health but also cardiometabolic health or antioxidant properties.
Symrise has a long history in the processing and extraction of cranberry polyphenols. Thanks to its dedicated extraction facility located in the Quebec province of Canada, in the heart of the cranberry production area, Symrise has a unique access to local cranberry farmers and carefully selects the most concentrated in polyphenols varieties.
Prebiocran™ is an ingredient obtained by extracting the natural phenolic compounds of cranberries. It has been designed to offer all the variety of polyphenols that are present in the cranberry fruit. It is standardized to feature no less than 30% total polyphenols (Folin-Ciocalteu method).
Phenolic acids Anthocyanins
Flavonols Flavan-3-ols
The INAF Research Program Chair outcomes support Prebiocran™ benefits for gut health: in a systemic approach, Prebiocran™ has been shown to modulate the gut microbiota composition and function, which is associated with metabolic health improvement. Moreover, this unprecedented scientific program produced cutting-edge research combining efficacy and underlying mechanisms evaluation:
Prebiocran™ modulated the microbiota beta-diversity in a short-term human clinical study. This was further confirmed in an ex vivo gut model that mimics the entire gastrointestinal tract, but also in animal models.
In-depth investigations to understand the mechanisms and functions specifically showed an increase of bacteria associated with health benefits, enhancing a favorable ecosystem and health-related metabolites production. Additional results highlighted the capacity of Prebiocran™ to improve the gut health barrier function and metabolic health, supporting its prebiotic potential.
Lessard-Lord, unpublished
In a human clinical trial, 39 healthy participants consumed 480 mg of Prebiocran™ daily for 4 days. A 7-day washout period preceded the intervention, with strict limitation of polyphenols-containing food. Biological samples were collected before and after the treatment. Fecal DNA has been sequenced to study the gut microbiota evolution.
Results showed that Prebiocran™:
• Modulates the basal human gut microbiota beta-diversity in a shortterm period
• Notably induces a bloom of Bifidobacterium, a bacteria associated with gut health (Chen et al., 2021)
These results highlight the short-term clinical efficacy of Prebiocran™ and have been confirmed in ex vivo and animal studies in a longer term (2 weeks and 12 weeks).
Each dot represents a unique human microbiota analyzed by 16S rRNA gene amplicon sequencing. The distance-based redundancy analysis here clearly discriminates the gut microbiota after 4 days of Prebiocran™ treatment.
Cattero, unpublished
In this study, researchers inoculated fecal material of six healthy subjects in individual M-SHIME® systems. After weeks of stabilization to allow a suitable adaptation period for the microbiome to adapt, they administrated 480 mg Prebiocran™ for two weeks of treatment and analyzed the gut microbiota composition and function in the ascendant and transverse colon.
The Simulator of the Human Intestinal Microbial Ecosystem (SHIME®) is one of the few gut models that mimics the entire gastrointestinal tract. It is a semi-dynamic model with multi-stage compartment reactors, each of them respectively displaying defined conditions (pH, nutritional medium etc.) according to the intestinal region they represent. The M-SHIME, i.e., Mucosal-SHIME, is an extension of this model which also mimics the mucosal microbiome. It incorporates mucin-covered microcosms, allowing better understanding of the host-microbe interaction. Molly et al., 1993 & Van de Wiele et al., 2015.
Consistent with the clinical study, Prebiocran™ significantly and gradually modulated the microbiota composition throughout the 2-week dietary treatment in all the gut compartments (lumen and mucus of the ascendant and transverse colons).
More specifically, Prebiocran™ was shown to promote in both lumen and mucin, the growth of:
• Bacteria known to metabolize proanthocyanidins (PACs) into smaller bioactive metabolites: Eggerthella, Flavonifactor and Lactiplantibacillus. (Corrêa et al., 2019 ; Gaur et al., 2023)
• Bacteria associated with gut barrier protection and health: Akkermansia and Faecalibacterium (Cani et al., 2022 ; Leylabadlo et al., 2020)
Anhê et al., 2015 ; Rodríguez-Daza et al., 2020 ; Daoust et al. 2021 ; Medina-Larqué et al., 2022
In several male and female mouse studies, Prebiocran™ was administrated at a dose of 200 mg/kg of body weight during 8 to 12 weeks.
In all the studies, Prebiocran™ modulated the mice microbiota diversity in a long-term period, often associated with a bloom of Akkermansia
The gut microbiota was analyzed in all the compartments of the M-SHIME system. Here are selected bacteria (Akkermansia, Faecalibaterium) with a significant increase in relative abundance according to the duration of Prebiocran™ treatment.
Metataxonomic analysis of the mice fecal microbiota, with significant difference of relative abundance after 9 weeks of Prebiocran™ treatment.
Anhê, F.F. et al. (2015)
Anhê et al., 2015 ; Anhê et al., 2017 ; Daoust et al. 2021 ; Medina-Larqué et al., 2022 ; Feldman et al., 2023
Prebiocran™ was added to a high-fat high-sucrose diet at a daily dose of 200 mg/kg of body weight during 8 to 12 weeks in several mouse studies. Results included a prevention of endotoxemia (i.e., levels of plasma lipopolysaccharide) and intestinal inflammation, and a promotion of intestinal barrier strength, with:
- A decrease of jejunal inflammation markers (COX2, TNF-α, NF-κB) gene expression
- An increase of mucin production
- An increase of the expression of genes involved in Goblet cells differentiation
Denis et al., 2015; Koudoufio et al., 2021; Tinoco-Mar, unpublished data
Two cellular models were used to highlight the specific action of proanthocyanidins (PACs) isolated from Prebiocran™ on the gut barrier composition and function: mouse organoids and Caco-2/15 cell lines.
The mouse organoid is a complex multicellular in vitro system mimicking a mini-intestine. A fraction of Prebiocran™, purified in PACs, was incubated with organoids to measure the impact on gut endothelium composition. Results showed that Prebiocran™ PACs, in a complex in vitro system, time and dose-dependently increases Muc2 and Klf4, some key biomarkers of intestinal strengthening involved in Goblet cells differentiation and mucin production.
Caco-2/15 fully differentiated intestinal cell line was also used with PACs isolated from Prebiocran™ to demonstrate its effect of the gut barrier function. Prebiocran™ fraction was shown in vitro to protect against inflammation and oxidation, improve lipid homeostasis and modulate gut insulin signaling pathway.
M-SHIME® MODEL
Cattero et Lessard-Lord, unpublished
The M-SHIME® study showed that Prebiocran™ promotes not only the growth of individual bacteria, but also the growth of specific guild of bacteria, enhancing a favorable ecosystem associated with metabolic protection:
• Shift in production of short chain fatty acids (SCFAs) in favor of butyrate production
• Shift in cholesterol-derived bile acids, notably:
- Decrease of DCA (deoxycholic acid), associated with negative effects on metabolic health
- Increase of UDCA (ursodeoxycholic acid), associated with positive effects on metabolic health
Anhê et al., 2015 ; Anhê et al., 2017 ; Rodríguez-Daza et al., 2020 ; Daoust et al. 2021 ; Medina-Larqué et al., 2022
In our various mouse models of obesity and type 2 diabetes, Prebiocran™ (200 mg/kg of body weight daily for 8 to 12 weeks) significantly demonstrated several metabolic health improvements:
• Prevention of body weight gain, glucose homeostasis alteration and hepatic steatosis in mice fed a high-fat high-sucrose diet
Anhê et al. are the pioneers in demonstrating the prebiotic potential of a high in polyphenols cranberry extract and its cardiometabolicassociated benefits. This reference article has been cited more than 900 times.
Metabolomics analyses were performed in the transverse colon.
On the left, short chain fatty acids (SCFAs) quantification showed that Prebiocran™ induced a shift from acetate (yellow) to butyrate (black) production since the first days of treatment.
On the right, the heatmap displays bile acids levels and shows that Prebiocran™ progressively induced an increase of UDCA concomitant to a decrease of DCA.
Our results suggest the role of Prebiocran™ at a low dose of 480 mg, in supporting gut and metabolic health.
Conclusion
Prebiocran™ is a 100% cranberry extract in powder, designed to fit most of dietary supplement applications thanks to a low dosage: only 480 mg daily!
Standardized to minimum 30% total polyphenols (Folin-Ciocalteu) Spray dried powder
Highly soluble
Sourced and extracted locally in Canada from high polyphenol cranberry varieties
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