SCOPE: This multi-omic study investigates the bidirectional interactions between gut microbiota and silymarin metabolism, highlighting the differential effects across various age groups. Silymarin, the extract from Silybum marianum (milk thistle), is commonly used for its hepatoprotective effects. METHODS AND RESULTS: An in vitro fermentation colon model was used with microbiota from 20 stool samples obtained from healthy donors divided into two age groups. A combination of three analytical advanced techniques, namely proton nuclear magnetic resonance (1H NMR), next-generation sequencing (NGS), and liquid chromatography-mass spectrometry (LC-MS) was used to determine silymarin microbial metabolites over 24 h, overall metabolome, and microbiota composition. Silymarin at a low diet-relevant dose of 50 µg mL-1 significantly altered gut microbiota metabolism, reducing short-chain fatty acid (acetate, butyrate, propionate) production, glucose utilization, and increasing alpha-diversity. Notably, the study reveals age-related differences in silymarin catabolism. Healthy elderly donors (70-80 years) exhibited a significant increase in a specific catabolite associated with Oscillibacter sp., whereas healthy young donors (12-45 years) showed a faster breakdown of silymarin components, particularly isosilybin B, which is associated with higher abundance of Faecalibacterium and Erysipelotrichaceae UCG-003. CONCLUSION: This study provides insights into microbiome functionality in metabolizing dietary flavonolignans, highlighting implications for age-specific nutritional strategies, and advancing our understanding of dietary (poly)phenol metabolism.

• Keywords
• age‐related differences, gut microbiota, multi‐Omics analysis, polyphenols, silymarin metabolism,
• MeSH
• Child MeSH
• Adult MeSH
• Feces microbiology   MeSH
• Fermentation MeSH
• Colon * microbiology   metabolism   drug effects   MeSH
• Fatty Acids, Volatile metabolism   MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Silymarin * pharmacology   MeSH
• Gastrointestinal Microbiome * drug effects   physiology   MeSH
• Healthy Volunteers MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Fatty Acids, Volatile MeSH
• Silymarin * MeSH

Stilbenoids are interesting natural compounds with pleiotropic in vitro and in vivo activity. Their well-documented biological properties include anti-inflammatory effects, anticancer effects, effects on longevity, and many others. Therefore, they are nowadays commonly found in foods and dietary supplements, and used as a part of treatment strategy in various types of diseases. Bioactivity of stilbenoids strongly depends on different types of factors such as dosage, food composition, and synergistic effects with other plant secondary metabolites such as polyphenols or vitamins. In this review, we summarize the existing in vitro, in vivo, and clinical data from published studies addressing the optimization of bioavailability of stilbenoids. Stilbenoids face low bioavailability due to their chemical structure. This can be improved by the use of novel drug delivery systems or enhancers, which are discussed in this review. Current in vitro and in vivo evidence suggests that both approaches are very promising and increase the absorption of the original substance by several times. However, data from more clinical trials are required.

• Keywords
• bioavailability, bioenhancers, metabolism, resveratrol,
• MeSH
• Biological Availability MeSH
• Drug Delivery Systems MeSH
• Humans MeSH
• Dietary Supplements MeSH
• Resveratrol chemistry   pharmacokinetics   therapeutic use   MeSH
• Stilbenes chemistry   pharmacokinetics   therapeutic use   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Resveratrol MeSH
• Stilbenes MeSH

Stilbenoids are dietary phenolics with notable biological effects on humans. Epidemiological, clinical, and nutritional studies from recent years have confirmed the significant biological effects of stilbenoids, such as oxidative stress protection and the prevention of degenerative diseases, including cancer, cardiovascular diseases, and neurodegenerative diseases. Stilbenoids are intensively metabolically transformed by colon microbiota, and their corresponding metabolites might show different or stronger biological activity than their parent molecules. The aim of the present study was to determine the metabolism of six stilbenoids (resveratrol, oxyresveratrol, piceatannol, thunalbene, batatasin III, and pinostilbene), mediated by colon microbiota. Stilbenoids were fermented in an in vitro faecal fermentation system using fresh faeces from five different donors as an inoculum. The samples of metabolized stilbenoids were collected at 0, 2, 4, 8, 24, and 48 h. Significant differences in the microbial transformation among stilbene derivatives were observed by liquid chromatography mass spectrometry (LC/MS). Four stilbenoids (resveratrol, oxyresveratrol, piceatannol and thunalbene) were metabolically transformed by double bond reduction, dihydroxylation, and demethylation, while batatasin III and pinostilbene were stable under conditions simulating the colon environment. Strong inter-individual differences in speed, intensity, and pathways of metabolism were observed among the faecal samples obtained from the donors.

• Keywords
• bacteria colon model, fecal fermentation, liquid chromatography high resolution mass spectrometry, metabolites, phenolics, polyphenols, stilbenoids,
• MeSH
• Chromatography, Liquid MeSH
• Feces microbiology   MeSH
• Phenols chemistry   metabolism   MeSH
• Fermentation MeSH
• Mass Spectrometry MeSH
• Colon metabolism   microbiology   MeSH
• Humans MeSH
• Microbiota * MeSH
• Resveratrol chemistry   metabolism   MeSH
• Stilbenes chemistry   metabolism   MeSH
• Tandem Mass Spectrometry MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• 3,3',4,5'-tetrahydroxystilbene MeSH Browser
• batatasin-III MeSH Browser
• Phenols MeSH
• pinostilbene MeSH Browser
• Resveratrol MeSH
• Stilbenes MeSH