Gut microbiota-derived tryptophan metabolites alleviate liver injury via AhR/Nrf2 activation in pyrrolizidine alkaloids-induced sinusoidal obstruction syndrome

Abstract

Background and aims Hepatic sinusoidal obstruction syndrome (HSOS) is caused by toxic injury, such as pyrrolizidine alkaloids, to the liver sinusoidal endothelial cells, and the gut microbiota may be involved. However, the specific role and underlying mechanism of gut microbiota in HSOS is unknown. Methods HSOS model was established by gavage of monocrotaline (MCT) in rats. Fecal microbiota transplantation (FMT) with HSOS-derived or healthy gut flora was also conducted to validate the role of gut microflora in MCT-induced liver injury. The microbial 16 s rRNA analysis and untargeted metabolomics analysis in the faeces were performed to identify HSOS-related flora and metabolites. Finally, by supplementation with specific tryptophan metabolites, such as indole-3-acetaldehyde (IAAld) and indole acetic acid (IAA), we further confirmed the role of tryptophan metabolism in HSOS and the role of the AhR/Nrf2 pathway in MCT-induced liver injury. Results MCT induced HSOS-like liver injury in rats with significantly altered gut microbiota. Particularly, some tryptophan-metabolizing bacteria reduced in MCT-treated rats, such as Bacteroides, Bifidobacterium, Lactobacillus and Clostridium, and accompanied by a decrease in microbial tryptophan metabolic activity and a series of tryptophan derivatives. Restoring the gut microbiota via FMT improved MCT-induced liver damage, while HSOS-derived gut microbiota aggravated the liver injury induced by MCT. Supplementation with microbial tryptophan derivatives (IAAld or IAA), or 6-formylindolo(3,2-b)carbazole (Ficz, an AhR agonist) could activate the AhR/Nrf2 signaling pathway, thereby attenuating the MCT-induced liver oxidative stress and liver sinusoidal endothelial cells injury. Conclusions Gut microbiota plays a critical role in MCT-induced HSOS, with inadequate microbial tryptophan metabolism in the gut and consequently a lower activity of the AhR/Nrf2 signaling pathway in the liver, which should be a potential target for the management of HSOS.

Pyrrolizidine Alkaloids—Pros and Cons for Pharmaceutical and Medical Applications

“…The gut microbiota is believed to play a crucial role in the development of various acute and chronic liver diseases, e.g., (non-)alcoholic liver disease, hepatitis virus infection, and chemical-or drug-induced liver injuries [75]. One of the potential causes of hepatotoxicity is gut dysbiosis and microbial metabolites.…”

“…Due to the insufficient microbiome-derived tryptophan metabolism within the gut lumen resulting in decreased activity of AhR (aryl hydrocarbon receptor)/Nrf2 (nuclear transcription factor) signaling in the liver, HSOS was induced by the applied PA. The suggested therapeutic approach for treating the PA-induced HSOS is to restore or enrich the population of specific bacteria by supplementation with specific tryptophan metabolites (AhR ligands), or to directly administer with pharmacological AhR agonists [75].…”

Gut microbiota promotes macrophage M1 polarization in hepatic sinusoidal obstruction syndrome via regulating intestinal barrier function mediated by butyrate

“…Evidence has revealed that the microbiota in PA-HSOS animals is different from that of healthy individuals, and the abundance of potentially pathogenic bacteria is significantly increased. 19 , 20 However, the involvement of the gut bacterial flora in the development of PA-HSOS has not been fully elucidated, particularly short-chain fatty acids (SCFAs), which are thought to mediate the health benefits of the intestinal microbiome. In this study, we observed gut microbiota dysbiosis and impairment of the gut barrier in PA-HSOS patients and mice and that gut microbiota dysbiosis further resulted in enhanced M1 macrophage polarization via alteration of intestinal barrier function mediated by butyrate, aggravating the progression of PA-HSOS.…”