**Background:** Metabolic syndrome (MS) is a cluster of interrelated metabolic factors—insulin resistance, hyperglycemia, atherogenic dyslipidemia, central obesity, and hypertension—that constitutes a major public health problem. The harmonizing diagnostic criterion requires at least three of five parameters: large waist circumference, triglycerides ≥150 mg/dL, HDL-cholesterol <40 mg/dL (men) or <50 mg/dL (women), blood pressure ≥130/85 mmHg, and fasting glucose ≥100 mg/dL. Consumption of high-fat diets (HFD) disrupts intestinal homeostasis by altering gut microbiota composition (increasing the Firmicutes/Bacteroidetes ratio), impairing the intestinal barrier, and promoting metabolic endotoxemia via lipopolysaccharide (LPS) translocation. Proanthocyanidins (PAs), the second most abundant group of phenolic compounds in Western diets, are found in legumes, cereals, nuts, cocoa, tea, wine, and fruits. They are poorly bioavailable—only oligomers (dimers, trimers, possibly tetramers) can be absorbed in the small intestine via passive diffusion, while polymers reach the colon where gut microbiota ferment them into low-molecular-weight phenolic acids and phenylvalerolactones. This review systematically evaluates the intestinal effects of PAs in diet-induced MS models, distinguishing between preventive strategies (PAs introduced before or simultaneously with the HFD) and treatment strategies (PAs introduced after MS is established).
**Methods:** The authors conducted a narrative review of rodent experiments and clinical trials examining PA supplementation in the context of diet-induced MS. They searched ClinicalTrials.gov for completed clinical trials using terms including "gut microbiota," "proanthocyanidins," and "metabolic syndrome," later expanded to "flavonoids," "polyphenols," "grape," and "type 2 diabetes mellitus." The review focuses on three experimental designs: (1) PAs introduced before starting the MS-inducing diet (t < 0, prevention); (2) PAs introduced simultaneously with the MS-inducing diet (t = 0, prevention); and (3) PAs introduced after the pathology is established (t > 0, treatment). The authors analyzed changes in gut microbiota composition, short-chain fatty acid profiles, mucus and antimicrobial peptide production, intestinal wall morphology, permeability, and inflammatory/oxidative stress markers.
**Key Results:** Across rodent studies, PA consumption consistently increased beneficial bacteria. Akkermansia muciniphila increased in both preventive and treatment strategies—Anhê et al. (t < 0, red cranberry PAs 300 mg/kg), Rodríguez-Daza et al. (t = 0, wild blueberry PAs 200 mg/kg), and Anhê et al. (t > 0, cranberry extract PAs 200 mg/kg)—though changes were more pronounced with preventive use. Butyrate-producing bacteria including Roseburia spp., Allobaculum sp., and Faecalibacterium prausnitzii increased in preventive strategies (t = 0). Lactobacillus and Bifidobacterium increased in preventive studies (Lee et al., Macho-González et al., Zhu et al.) but results were mixed in treatment strategies—Macho-González et al. found no change when PAs were introduced 3 weeks after HFD, while Xu et al. found increases when Pyracantha fortuneana was introduced 2 weeks after HFD. Bacteria considered deleterious—Desulfovibrionaceae, Enterobacteriaceae, Enterococcus, Lactococcus, and the Firmicutes phylum—were reduced by PA supplementation in both prevention and treatment. The Firmicutes/Bacteroidetes ratio decreased in both preventive (Zheng et al., Zhu et al.) and treatment strategies (Anhê et al., Xu et al.). Regarding intestinal barrier integrity, preventive PA supplementation increased goblet cell numbers and Muc2 expression (Lee et al., Rodríguez-Daza et al., Macho-González et al.), while treatment studies showed no significant differences. Antimicrobial peptide genes (Defb2, lysozyme-1, Reg3γ) were upregulated in preventive studies. PA consumption reduced intestinal permeability in both prevention (Gil-Cardoso et al., Feldman et al., Gao et al.) and treatment (González-Quilen et al., Liu et al.) strategies, with lower serum LPS levels reported. Anti-inflammatory effects included reduced TNF-α, IL-1β, IL-6, COX-2, and iNOS in both preventive and treatment designs. Antioxidant mechanisms included radical scavenging, inhibition of myeloperoxidase activity, and activation of the NRF2 pathway. Of 13 completed clinical trials identified on ClinicalTrials.gov, only two have published gut microbiota results. The Direct-plus trial (NCT03020186) found that a Mediterranean diet rich in polyphenols increased Prevotella spp. and decreased Bifidobacterium spp., but the isolated effect of PAs could not be determined. The other trial (NCT03076463) found that grape pomace supplementation reduced plasma insulin and HOMA index in responders but produced no change in gut microbiota composition.
**Clinical Implications:** The authors conclude that preventive consumption of PAs is more effective than treatment strategies for managing MS-associated dysbiosis and intestinal dysfunction. They suggest that the greatest benefit of PA consumption is likely in patients at risk of developing MS who do not yet meet three diagnostic criteria, as established dysbiosis may partially impair the prebiotic effects of PAs. The review highlights the need for standardized experimental protocols—including specification of PA type and dose, timing of introduction, and confirmation of MS before treatment—to enable meaningful comparisons across studies. The authors urge publication of non-significant results from clinical trials to avoid duplication and advance knowledge. They also recommend that future studies include female animals, use colon-derived fecal samples, and prioritize measurement of key bacterial taxa (Akkermansia muciniphila, Bifidobacterium, Desulfovibrionaceae, F. prausnitzii, Lactobacillus, Lactococcus, and Roseburia).