Editorial - Natural Products and Gut Microbiome Metabolism in Hepatobiliary Gastrointestinal Diseases

Abstract

The gut microbiome, recognized as a pivotal metabolic organ, engages in intricate crosstalk with the intestine and liver, profoundly influencing the pathogenesis and progression of various diseases, particularly hepatobiliary and gastrointestinal disorders. Natural products are extensively metabolized by the gut microbiota, generating bioactive metabolites with potential therapeutic benefits or adverse effects. This Special Collection highlights the latest advances in unraveling these complex host–microbiome interactions, offering novel insights into therapeutic strategies for the prevention and management of diverse diseases, with a special focus on hepatobiliary and gastrointestinal conditions.

Introduction

The gut microbiome, often regarded as an “invisible organ” in mammals, plays vital physiopathological roles in collaboration with the host, particularly within the enterohepatic circulation system. ¹ Its close connection with both the intestine and liver makes it a key player in hepatobiliary and gastrointestinal health. ² Increasing evidence shows that many natural products are not only metabolized by the human body but also by the gut microbiome in the liver and gastrointestinal tract. ³ Interestingly, certain metabolites produced by the gut microbiome from herbal compounds, such as compound K from Ginseng and equol from Pueraria lobata, demonstrate enhanced therapeutic effects, while some may also have adverse impacts.^4,5

Given the growing importance of this interplay, this Special Collection titled “Natural Products and Gut Microbiome Metabolism in Hepatobiliary Gastrointestinal Diseases” aims to gather cutting-edge research articles exploring how gut microbiome-derived metabolites of natural products influence the onset, progression, and treatment of hepatobiliary and gastrointestinal diseases. This collection seeks to promote deeper understanding and foster new ideas for therapeutic strategies targeting these complex interactions.

Contributions of Collections

Firstly, Lu et al demonstrated that Nelumbo nucifera extract (LLAE) mitigates high-fat diet-induced hyperlipidemia in rats by modulating gut microbiota composition and diversity. ⁶ LLAE reduces serum lipid levels, alleviates hepatic steatosis, and regulates key microbial taxa, offering potential therapeutic insights into gut microbiota-mediated interventions for dyslipidemia and hepatobiliary disorders. ⁶

As a herbal formula, SH003 consisting of Astragalus membranaceus, Angelica gigas, and Trichosanthes kirilowii Maximowicz, can induce death receptors-mediated, caspase-dependent apoptosis in cancer cells by inhibiting AKT survival signaling. ⁷ Herein, caspase activation and AKT downregulation are key mechanisms, while ERK plays a limited role. In addition, the gut microbiota can regulate host cell caspase activation and AKT signaling pathways through specific microbial metabolites, such as short-chain fatty acids, bile acids, and indole derivatives.^8,9

Manizione et al summarized the phytochemistry and pharmacological activities of Pinus mugo Turra, highlighting its antioxidant, anti-inflammatory, antimicrobial, and anticancer effects. ¹⁰ Preclinical studies support its potential in respiratory and urinary diseases and cancer therapy. This revew emphasizes P. mugo as a promising candidate for future drug development.

Lin et al demonstrated that Jiedu Huayu granule (JDHY), a Chinese-modified herbal formula from Yin Chen decoction, mitigates D-GalN/LPS-induced acute liver failure by enhancing GPX4 expression, reducing lipid peroxidation, and inhibiting ferroptosis. ¹¹ JDHY modulates iron metabolism and suppresses LOX/PTGS-mediated inflammation, promoting antioxidant capacity in hepatocytes and alleviating liver injury. These findings highlight JDHY as a promising therapeutic candidate targeting ferroptosis and oxidative stress in acute liver failure.

Ahmadi et al revealed that gut microbiota-derived urolithins significantly enhance radiotherapy efficacy in gastric adenocarcinoma cells by synergistically reducing cell viability and targeting checkpoint kinase 1 (CHK1)-mediated DNA damage response pathways. ¹² Molecular docking confirmed the interaction between urolithins and CHK1, suggesting their potential application as natural radiosensitizers to overcome radio-resistance in gastric cancer treatment.

Sammari et al investigated Crataegus azarolus leaves and fruits for phytochemical composition, antioxidant capacity, and in vitro ruminal digestibility in goats. ¹³ Leaves exhibited higher phenolic content, antioxidant activity, and nutrient digestibility than fruits, enhancing volatile fatty acid production and metabolizable energy, indicating their superior potential as feed additives. These findings support Crataegus azarolus leaves as a valuable natural supplement to improve nutrition and digestion efficiency.

Yadav et al demonstrated that Bacillus subtilis-fermented Cynanchum atratum attenuated lipid accumulation, hepatic steatosis, inflammation, and metabolic dysfunction in high-fat, high-fructose diet-induced obese mice. ¹⁴ BSCA restored gut microbiota diversity and peripheral serotonin levels, improving metabolic profiles. This study highlights the potential of Cynanchum atratum as a therapeutic herbal candidate for fatty liver disease and metabolic syndrome.

Conclusion

Collectively, these studies underscore the multifaceted therapeutic potential of natural products and microbiota-targeted interventions across metabolic, hepatic, oncologic, and veterinary domains. Plant-derived compounds such as Nelumbo nucifera and Cynanchum atratum modulate gut microbiota, ameliorate lipid disorders, and attenuate liver injury. SH003 and microbiota-derived urolithins demonstrate promising anticancer activities through apoptosis induction and enhanced radiosensitivity. Pinus mugo offers broad pharmacological properties, while Crataegus azarolus improves nutrition and digestive efficiency. These findings highlight the emerging role of natural bioactives in disease prevention and therapy, supporting their further development in clinical and translational applications.