Cranberry consumption has numerous health benefits, with experimental reports showing its anti-inflammatory and anti-tumor properties. Importantly, microbiome research has demonstrated that the gastrointestinal bacterial community modulates host immunity, raising the question of whether the cranberry-derived effect may be related to its ability to modulate the microbiome. Only a few studies have investigated the effect of cranberry products on the microbiome to date. Especially because cranberries are rich in dietary fibers, the extent of microbiome modulation by polyphenols, particularly proanthocyanidins (PACs), remains to be shown. Since previous work has only focused on long-term effects of cranberry extracts, in this study we investigated the effect of a water-soluble, PAC-rich cranberry juice extract (CJE) on the short-term dynamics of a human-derived bacterial community in a gnotobiotic mouse model. CJE characterization revealed a high enrichment in PACs (57%), the highest ever utilized in a microbiome study. In a 37-day experiment with a ten-day CJE intervention and 14-day recovery phase, we profiled the microbiota via 16S rRNA sequencing and applied diverse time-series analytics methods to identify individual bacterial responses. We show that daily administration of CJE induces distinct dynamic patterns in bacterial abundances during and after treatment, before recovering resiliently to pre-treatment levels. Specifically, we observed an increase of Akkermansia muciniphila and Clostridium hiranonis at the expense of Bacteroides ovatus after the offset of the selection pressure imposed by the PAC-rich CJE. This demonstrates that termination of an intervention with a cranberry product can induce changes of a magnitude as high as the intervention itself.

Cranberry (Vaccinium macrocarpon) is known for urinary tract health benefits associated with reducing the adhesion of E. coli bacteria. This property has been linked to cranberry polyphenols known as proanthocyanidins. Staphylococcus bacteria are a growing public health concern due to development of resistant strains. Identification of agents that inhibit biofilm formation by these bacteria may provide a new route to reduce infection in clinical settings. Fruit and leaves of North American cranberry (Vaccinium macrocarpon) and cranberry juice were fractionated and screened for their ability to prevent biofilm formation by several strains of S. aureus and S. epidermidis bacteria. MALDI-TOF MS analysis of the most bioactive fractions identified the major constituents as proanthocyanidin oligomers (PACs) with A-type linkages, ranging in size from 2-12 degrees of polymerization. Further characterization by NMR is underway. The polyphenol-rich fractions from cranberry leaf, fruit and juice inhibited biofilm formation by strains of S. aureus and S. epidermidis, with MBIC as low as 3.1 μg/mL, and without significant bacteriocidal activity. Thus, compounds from cranberry fruit, plant material and juice may be useful in reducing Staphylococcus biofilms without promoting resistance.

The potential ability of dietary cranberry to inhibit colon carcinogenesis is under investigation. Compounds isolated from locally grown cranberry fruit (Vaccinium macrocarpon) have been shown in vitro to decrease proliferation of colon cancer cells, in part by induction of apoptosis. These compounds include oligomeric polyphenols known as proanthocyanidins (PACs) containing two or more epicatechin units with different types of linkages. To further elucidate the mechanism by which PACs induce cell death, we transcriptionally profiled cells treated with PACs. HCT116 and HT29 colon cancer cells were exposed to a cranberry proanthocyanidin (PACs) fraction isolated from Early Black variety cranberry fruit, at time intervals of 6, 12, 18 and 24 hours. Total RNA was extracted from PAC-treated and untreated control cells. Transcriptional profiling was performed using an Illumina microarray bead system. Microarray results revealed that expression of several members of the mitogen activated protein kinase family (MAPK) was significantly altered in the presence of PACs, leading to decreased transcription of genes in the nucleus and decreased tumor cell growth. Quantitative (Q)-PCR was used to confirm microarray data showing gene expression changes in some key apoptotic pathways. Western blotting was used to confirm the up- regulation or down-regulation of key proteins involved in the MAPK pathway. Significant changes in p53, APAF and VEGF protein expression were seen as early as eighteen hours. Flow cytometry was employed to identify changes in the cell cycle due to exposure to PACs. HCT116 and HT29 colon cancer cells showed a significant change in granularity and a significant increase in G2 arrest compared to control when exposed to PACs for as little as six hours. This study has provided insight into mechanisms by which cranberry PACs may inhibit colon cancer.