Clinical trials investigating the health effects of flavan-3-ols yield heterogeneous results due to interindividual variability in the gut microbiota metabolism. In fact, different groups in the population have similar metabolic profiles following (-)-epicatechin and (+)-catechin gut microbial metabolism and can be regrouped into so-called metabotypes. In this study, the capacity of 34 donors to metabolize polymeric B-type flavan-3-ols from aronia and oligomeric A-type flavan-3-ols from cranberry is investigated by in vitro fecal batch fermentations. Less than 1% of the flavan-3-ols from both sources are converted into microbial metabolites, such as phenyl-gamma-valerolactones (PVLs). To further confirm this result, gut microbial metabolites from flavan-3-ols are quantified in urine samples collected from participants, before and after a 4-day supplementation of cranberry extract providing 82.3 mg of flavan-3-ols per day. No significant difference is observed in the urinary excretion of flavan-3-ols microbial metabolites. Hence, it demonstrates by both in vitro and in vivo approaches that flavan-3-ols from aronia and cranberry are poorly degraded by the gut microbiota. The beneficial health impacts of these molecules likely stem from their capacity to affect gut microbiota and their interactions with the gut epithelium, rather than from their breakdown into smaller metabolites.

Cranberries contain proanthocyanidins with different interflavan bond types and degrees of polymerization. These chemical differences may impact the metabolism of proanthocyanidins by the intestinal microbiome. In our previous study, we found that healthy microbiomes produced higher concentrations of the phenolic acid metabolites 5-(3',4'-dihydroxyphenyl)-g-valerolactone and 3-hydroxyphenylacetic acid from the cranberry extract in comparison to ulcerative colitis (UC) microbiomes ex vivo. To understand this difference, LC-ESI-MS/MS was utilized to characterize the metabolism of the precursor proanthocyanidins. Healthy microbiomes metabolized procyanidin A2, procyanidin B2, and procyanidin dimeric intermediates but not A-type trimers, to a greater extent than UC microbiomes. The metabolism of procyanidin A2 and procyanidin B2 by fecal microorganisms was then compared to identify their derived phenolic acid metabolites. 5-(3',4'-Dihydroxyphenyl)-g-valerolactone and 3-hydroxyphenylacetic acid were identified as unique metabolites of procyanidin B2. Based on these results, the metabolism of procyanidin B2 contributed to the differential metabolism observed between healthy and UC microbiomes.

Cranberry is associated with multiple health benefits, which are mostly attributed to its high content of (poly)phenols, particularly flavan-3-ols. However, clinical trials attempting to demonstrate these positive effects have yielded heterogeneous results, partly due to the high inter-individual variability associated with gut microbiota interaction with these molecules. In fact, several studies have demonstrated the ability of these molecules to modulate the gut microbiota in animal and in vitro models, but there is a scarcity of information in human subjects. In addition, it has been recently reported that cranberry also contains high concentrations of oligosaccharides, which could contribute to its bioactivity. Hence, the aim of this study was to fully characterize the (poly)phenolic and oligosaccharidic contents of a commercially available cranberry extract and evaluate its capacity to positively modulate the gut microbiota of 28 human subjects. After only four days, the (poly)phenols and oligosaccharides-rich cranberry extract, induced a strong bifidogenic effect, along with an increase in the abundance of several butyrate-producing bacteria, such as Clostridium and Anaerobutyricum. Plasmatic and fecal short-chain fatty acids profiles were also altered by the cranberry extract with a decrease in acetate ratio and an increase in butyrate ratio. Finally, to characterize the inter-individual variability, we stratified the participants according to the alterations observed in the fecal microbiota following supplementation. Interestingly, individuals having a microbiota characterized by the presence of Prevotella benefited from an increase in Faecalibacterium with the cranberry extract supplementation.

Cranberry (poly)phenols may have potential health benefits. Circulating (poly)phenol metabolites can act as mediators of these effects, but they are subjected to an extensive inter-individual variability. This study aimed to quantify both plasma and urine (poly)phenol metabolites following a 12-week intake of a cranberry powder in healthy older adults, and to investigate inter-individual differences by considering the existence of urinary metabotypes related to dietary (poly)phenols. Up to 13 and 67 metabolites were quantified in plasma and urine respectively. Cranberry consumption led to changes in plasma metabolites, mainly hydroxycinnamates and hippuric acid. Individual variability in urinary metabolites was assessed using different data sets and a combination of statistical models. Three phenolic metabotypes were identified, colonic metabolism being the main driver for subject clustering. Metabotypes were characterized by quali-quantitative differences in the excretion of some metabolites such as phenyl-y-valerolactones, hydroxycinnamic acids, and phenylpropanoic acids. Metabotypes were further confirmed when applying a model only focused on flavan-3-ol colonic metabolites. 5-(3',4'- dihydroxyphenyl)-y-valerolactone derivatives were the most relevant metabolites for metabotyping. Metabotype allocation was well preserved after 12-week intervention. This metabotyping approach for cranberry metabolites represents an innovative step to handle the complexity of (poly)phenol metabolism in free-living conditions, deciphering the existence of metabotypes derived from the simultaneous consumption of different classes of (poly)phenols. These results will help contribute to studying the health effects of cranberries and other (poly) phenol-rich foods, mainly considering gut microbiota-driven individual differences.

Background & aims: Patients with Chronic Kidney Disease (CKD) have an imbalance in the gut microbiota that can lead to increase levels of lipopolysaccharides (LPS) and uremic toxins such as indoxyl sulfate (IS), p-cresyl sulfate (p-CS), and indole-3 acetic acid (IAA). Among the therapeutic options for modulating gut microbiota are the bioactive compounds such as polyphenols present in cranberry, fruit with potential antioxidant and anti-inflammatory effects. This clinical trial focuses on evaluating the effects of supplementation with a dry extract of cranberry on plasma levels of LPS and uremic toxins in non-dialysis CKD patients. Methods: It was a randomized, double-blind, placebo-controlled study. Patients were randomized into two groups: the cranberry group received 500 mg of dry cranberry extract (2 times daily), and the placebo group received 500 mg of corn starch (2 times daily) for two months. LPS plasma levels were evaluated by enzyme-linked immunosorbent assay (ELISA) and uremic toxins (IS, p-CS, and IAA) by high-performance liquid chromatography-fluorescence detection. Anthropometric measurements and food intake using the 24-h food recall technique were also evaluated before and after the intervention. Results: Twenty-five participants completed two months of supplementation: 12 patients in the cranberry group (8 women, 56.7 +or- 7.5 years, estimated glomerular filtration rate (eGFR) of 39.2 +or- 21.9 mL/min); 13 patients in the placebo group (9 women, 58.8 +or- 5.1 years, eGFR of 39.7 +or- 12.9 mL/min). As expected, there was a negative association between glomerular filtration rate and p-CS and IS plasma levels at the baseline. No change was observed in the uremic toxins and LPS levels. Conclusion: Cranberry dry extract supplementation for two months did not reduce the LPS and uremic toxins plasma levels produced by the gut microbiota in non-dialysis CKD patients.

Polyphenol-rich cranberry extracts decrease intestinal inflammation, alter gut microbiota, and decrease intestinal permeability in obese mice, but the effect has not been investigated in adults who are obese. The purpose of this randomized double-blind, cross-over feeding study in obese (BMI = 37.4 +or- 1.2 kg/m2) but otherwise healthy adults (n = 36) 35.4 +or- 1.3 years was to determine the effects of consuming 480 mL of a high polyphenolic cranberry or control beverage daily for 2 weeks on gastrointestinal permeability, markers of inflammation and immune function, and gut microbiota. An acute aspirin challenge was administered prior to assessing intestinal permeability to determine resistance to barrier function compromise. The cranberry beverage did not affect markers of gastrointestinal permeability, inflammation, or immune function. However, fecal Faecalibacterium prausnitzii and Eggerthella lenta increased with consumption of the cranberry beverage. Data suggest that the intervention impacted bacterial communities. A longer intervention may be required to observe beneficial effects on inflammation and gastrointestinal barrier function.