Bacterial and metabolic phenotypes associated with inadequate response to ursodeoxycholic acid treatment in primary biliary cholangitis.

Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease with ursodeoxycholic acid (UDCA) as first-line treatment. Poor response to UDCA is associated with a higher risk of progressing to cirrhosis, but the underlying mechanisms are unclear. UDCA modulates the composition of primary and bacterial-derived bile acids (BAs). We characterized the phenotypic response to UDCA based on BA and bacterial profiles of PBC patients treated with UDCA. Patients from the UK-PBC cohort (n = 419) treated with UDCA for a minimum of 12-months were assessed using the Barcelona dynamic response criteria. BAs from serum, urine, and feces were analyzed using Ultra-High-Performance Liquid Chromatography-Mass Spectrometry and fecal bacterial composition measured using 16S rRNA gene sequencing. We identified 191 non-responders, 212 responders, and a subgroup of responders with persistently elevated liver biomarkers (n = 16). Responders had higher fecal secondary and tertiary BAs than non-responders and lower urinary bile acid abundances, with the exception of 12-dehydrocholic acid, which was higher in responders. The sub-group of responders with poor liver function showed lower alpha-diversity evenness, lower abundance of fecal secondary and tertiary BAs than the other groups and lower levels of phyla with BA-deconjugation capacity (Actinobacteriota/Actinomycetota, Desulfobacterota, Verrucomicrobiota) compared to responders. UDCA dynamic response was associated with an increased capacity to generate oxo-/epimerized secondary BAs. 12-dehydrocholic acid is a potential biomarker of treatment response. Lower alpha-diversity and lower abundance of bacteria with BA deconjugation capacity might be associated with an incomplete response to treatment in some patients.

Gut microbiome and tissue metabolomics reveal the compatibility effects of Xiaoyaosan on depression based on "gut-liver-kidney" axis.

BACKGROUND: Depression affects not only the central nervous system, but also the peripheral system. Xiaoyaosan (XYS), a classical traditional Chinese medicine (TCM) prescription, exhibits definite anti-depression effects demonstrated both clinically and experimentally. However, its compatibility has not been entirely revealed due partly to the complex compositions of herbs contained. AIM: Based on the strategy of "Efficacy Group", this study aimed to reveal the compatibility of XYS from the perspective of "gut-liver-kidney" axis. METHODS: Firstly, XYS was divided into two efficacy groups, i.e. Shugan (SG) and Jianpi (JP) groups. Classic behaviors of rats were measured to confirm the anti-depression effects of XYS and its two efficacy groups. On top of this, gut microbiota analysis and kidney metabolomics were performed by 16S rRNA sequencing and 1H NMR, respectively. RESULTS: We found that XYS and its efficacy groups significantly regulated the abnormalities of behaviors and kidney metabolism of depressed rats, as well as intestinal disorders, but to different degrees. The regulatory effects of XYS and its efficacy groups on behaviors and kidney metabolomics of depressed rats had the same order, i.e. XYS > SG > JP, while the order of regulating gut microbiota was XYS > JP > SG. Both XYS and its efficacy groups significantly ameliorated gut microbiota disturbed, especially significant modulation of Peptostreptococcaceae. XYS significantly regulated nine kidney metabolites, while SG and JP regulated four and five differential metabolites, respectively, indicating that the two efficacy groups synergistically exhibited anti-depression effects, consequently contributing to the overall anti-depression effects of XYS. CONCLUSION: The current findings not only innovatively demonstrate the anti-depression effects and compatibility of XYS from the perspective of "gut-liver-kidney" axis, comprehensively using "Efficacy Group" strategy, macro behavioristics, metabolome and microbiome, and also provide a new perspective, strategy, and methodology for studying complex diseases and the compatibility of TCMs.

Integrated gut microbiota and serum metabolomics reveal the protective effect of oleanolic acid on liver and kidney-injured rats induced by Euphorbia pekinensis.

Euphorbia pekinensis (EP) is a commonly used Chinese medicine treating edema with potential hepatorenal toxicity. However, its toxic mechanism and prevention are remained to be explored. Oleanolic acid (OA) is a triterpene acid with potential hepatorenal protective activities. We investigated the protective effect and potential mechanism of OA on EP-induced hepatorenal toxicity. In this study, rats were given total diterpenes from EP (TDEP, 16 mg/kg) combined with OA (10, 20, 40 mg/kg) by gavage for 4 weeks. The results showed that TDEP administration could lead to a 3-4-fold increasement in hepatorenal biochemical parameters with histopathological injuries, while OA treatment could ameliorate them in a dose-dependent manner. At microbial and metabolic levels, intestinal flora and host metabolism were perturbed after TDEP administration. The disturbance of bile acid metabolism was the most significant metabolic pathway, with secondary bile acids increasing while conjugated bile acids decreased. OA treatment can improve the disorder of intestinal flora and metabolic bile acid spectrum. Further correlation analysis screened out that Escherichia-Shigella, Phascolarctobacterium, Acetatifactor, and Akkermansia were closely related to the bile acid metabolic disorder. In conclusion, oleanolic acid could prevent hepatorenal toxicity induced by EP by regulating bile acids metabolic disorder via intestinal flora improvement.

Progress in understanding hepatic fibrosis and renal fibrosis based on the gut-liver-kidney axis / 药学学报

Fibrosis is a pathological process of abnormal hyperplasia and excessive deposition of extracellular matrix during the process of repair after tissue and organ damage. Injury/inflammation caused by variously chronic diseases is a major trigger for fibrogenesis. Fibrosis of the liver and kidney is a common organ fibrosis. Recently, the intestinal microbiota has been shown to be extensively involved in the development of liver and kidney diseases, which may follow from changes in the intestinal microbial composition and intestinal integrity. This promotes the development of liver and/or kidney fibrosis through endocrine, cell signaling and other pathways. This paper reviews the research progress in understanding liver fibrosis and kidney fibrosis based on the gut-liver-kidney axis, which may be helpful for providing new strategies and theoretical basis for the diagnosis and treatment of hepatic and renal fibrosis.