Study sheds light on the link between gut microbiota, isoflavones, and geniposide hepatotoxicity

A recent study published in Engineering has shed light on the relationship between gut microbiota, isoflavones, and geniposide hepatotoxicity. Geniposide, a key ingredient in Fructus gardeniae used in many traditional Chinese medicine prescriptions, has shown potential hepatotoxic effects due to its metabolite genipin. This research focused on exploring whether isoflavones in soy products, with the help of gut microbiota, could mitigate this risk.

The researchers first investigated the metabolic profile of geniposide in vivo. Using ultra high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC-Q/TOF-MS), they identified 24 metabolites of geniposide in rat plasma, urine, feces, and bile samples. Two main metabolic pathways were discovered. One pathway involved the demethylation, glucuronic acid reaction, and hydroxylation of geniposide, while the other involved the removal of glucose to form genipin, which then underwent further reactions such as conjugation with taurine, sulfate, and glucuronide.

In the study, isoflavones' impact on geniposide metabolism was examined. In a pseudo-sterile rat model, isoflavones were found to alter geniposide metabolism by mediating specific enzymes, including β-glucosidase (β-GC) and sulfotransferase (SULT). Molecular virtual docking analysis showed that geniposide and β-GC, as well as genipin and SULT, had strong docking capabilities. Enzyme inhibitor experiments further confirmed that isoflavones regulated geniposide metabolism by changing the levels of these enzymes.

The effect of isoflavones on gut microbiota was also a key part of the research. Oral administration of isoflavones to rats changed the gut microbiota's diversity and structure. The relative abundance of beneficial bacteria like Lactobacillus and Bifidobacterium increased, while that of harmful bacteria like Desulfovibrio decreased. Fecal microbiota transplantation (FMT) experiments demonstrated the crucial role of gut microbiota in regulating metabolic enzymes and geniposide metabolism. When gut microbiota was disrupted by antibiotics, geniposide metabolism was inhibited. However, FMT could restore the levels of metabolic enzymes and promote geniposide metabolism.

Clinical trials on human volunteers further verified these findings. Volunteers with a soy-product-rich diet had different gut microbiota compositions and higher levels of intestinal metabolic enzymes β-GC and SULT compared to those with a soy-product-free diet. In addition, Lactobacillus spp. were found to play a significant role in preventing geniposide-induced liver injury in rats. Pretreatment with Lactobacillus spp. could reduce the increase in liver injury markers such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin (TBIL) caused by geniposide.

This study comprehensively demonstrated that isoflavones in soy products regulate geniposide metabolism through gut microbiota, especially Lactobacillus spp. These findings provide valuable insights into preventing drug-induced liver injury and suggest that a soy-product-rich diet may be a potential strategy to reduce geniposide hepatotoxicity. Future research could explore more specific mechanisms and applications based on these results.