Lei Zhang

Cholestatic liver diseases are a heterogeneous group of hepatobiliary disorders caused by impaired bile formation, secretion, or excretion, leading to hepatocyte injury, biliary inflammation, fibrosis, and eventually cirrhosis. Traditional studies have largely focused on isolated mechanisms, including bile acid toxicity, immune dysregulation, and genetic susceptibility. However, recent advances in metagenomics, metabolomics, and immunology have highlighted the critical role of the gut and biliary microbiota in disease pathogenesis. This review proposes the core concept of a “tripartite interplay among bile composition, biliary microbiome, and host immunity,” integrating the dynamic crosstalk among these three axes in cholestatic liver diseases. Bile composition shapes microbial communities and modulates immune responses through receptors such as FXR and TGR5. In turn, the biliary microbiome regulates bile acid metabolism and immune activity through microbial metabolites. Meanwhile, the host immune system senses microbial signals via pattern-recognition receptors, triggering inflammatory pathways and influencing microbial colonization and metabolism. These reciprocal interactions form complex feedback loops that drive disease progression from early inflammation to chronic fibrosis and cirrhosis. Based on this framework, emerging diagnostic approaches combine microbial signatures, bile acid profiles, and immune markers into multidimensional biomarker systems. Therapeutically, integrated strategies targeting the microbiome, bile acid metabolism, and immune pathways may offer synergistic benefits. Despite challenges including sampling difficulty, interindividual variability, and limitations of current models, future technologies such as single-cell sequencing, spatial transcriptomics, and multi-omics integration may enable precision diagnosis and targeted therapy.

Effective diagnoses and treatments for liver fibrosis (LF) are lacking. The gut microbiota (GM)–bile acid (BA) axis is critically associated with LF

Metabolic syndrome (MetS) was linked to poor cancer outcomes, but its impact on perihilar cholangiocarcinoma (pCCA) survival postresection was unclear. In

High-altitude environments, characterized by hypobaric and hypoxic conditions, induce acute hypoxia, resulting in decreased blood oxygen saturation. This hypoxic stress perturbs gut microecological homeostasis, significantly contributing to the pathogenesis of acute mountain sickness. Consequently, elucidating the mechanisms by which high altitude affects gut homeostasis is crucial for developing effective interventions.

Hypobaric hypoxia exposure occurs at high altitudes, including plateaus, and affects normal intestinal function and microbiota composition. Exposure induces an intestinal inflammatory response and oxidative stress injury, ultimately disrupting intestinal homeostasis and causing barrier damage. Thus, due to its anti-inflammatory, antioxidative, and intestinal microbiota-regulating properties, Bifidobacterium longum is a potentially effective probiotic intervention to protect the intestinal barrier during low-pressure hypoxia on plateaus. However, its mechanism of action is not fully defined. In this study, we investigate the mechanism by which B. longum intervenes in intestinal barrier damage caused by plateau low-pressure hypoxia. To this end, an in vivo model is established by exposing rats to a simulated low-pressure hypoxic plateau environment. The experimental rats were subsequently supplemented with a B. longum strain (JBLC-141) extracted from the feces of healthy adults in Bama, Guangxi. B. longum JBLC-141 mitigates the effects of plateau low-pressure hypoxia on the rat intestinal barrier. This is achieved by activating the intestinal Kelch-like ECH-associated protein 1 (KEAP1)/nuclear factor erythroid 2-related factor 2 (NRF2) pathway, alleviating plateau hypoxia-induced intestinal oxidative stress injury. B. longum JBLC-141 also attenuates the inflammatory response and upregulates the expression of the tight junction proteins claudin-1, occludin, and zonula occludens-1. Furthermore, it reduces intestinal permeability, effectively ameliorating and repairing the barrier histological damage induced by the plateau low-pressure hypoxic environment. In addition, B. longum JBLC-141 positively regulates the intestinal microbiota, increasing the relative abundance of beneficial bacteria while reducing that of pathogenic bacteria and maintaining intestinal flora homeostasis in rats.

Few studies have explored the biological mechanism by which probiotics alleviate adverse reactions to chemotherapy drugs after local hepatic chemotherapy perfusion by regulating the intestinal flora. This study investigates the effects of Combined Live Bifidobacterium, Lactobacillus, Enterococcus, and Bacillus Cereus Tablets on the intestinal microbial structure and intestinal barrier function, as well as the potential mechanism in rabbits after local hepatic chemotherapy infusion. Eighteen New Zealand White rabbits were randomly divided into a control group, a hepatic local chemotherapy perfusion group, and a hepatic local chemotherapy perfusion + Combined Live Bifidobacterium, Lactobacillus, Enterococcus, and Bacillus Cereus Tablets group to assess the effects of Combined Live Bifidobacterium, Lactobacillus, Enterococcus, and Bacillus Cereus Tablets on the adverse reactions. The administration of Combined Live Bifidobacterium, Lactobacillus, Enterococcus, and Bacillus Cereus Tablets alleviated the intestinal flora disorder caused by local hepatic perfusion chemotherapy, promoted the growth of beneficial bacteria, and inhibited the growth of harmful bacteria. The Combined Live Bifidobacterium, Lactobacillus, Enterococcus, and Bacillus Cereus Tablets also reduced the levels of serum pro-inflammatory cytokines and liver injury factors induced by local hepatic perfusion chemotherapy. Our findings indicate that Combined Live Bifidobacterium, Lactobacillus, Enterococcus, and Bacillus Cereus Tablets can ameliorate the toxicity and side effects of chemotherapy by regulating intestinal flora, blocking pro-inflammatory cytokines, reducing liver injury factors, and repairing the intestinal barrier. Probiotics may be used as a potential alternative therapeutic strategy to prevent the adverse reactions caused by chemotherapy with local hepatic perfusion.

The gut microbiota (GM) are closely related to hepatocellular carcinoma (HCC) occurrence and development. Furthermore, patients with HCC who have received transcatheter arterial chemoembolization (TACE) treatment often experience adverse gastrointestinal reactions, which may be related to changes in the GM caused by the chemotherapeutic drugs used in TACE. Therefore, we conducted animal experiments to investigate these changes. We analyzed changes in the GM of New Zealand white rabbits treated with hepatic arterial chemotherapy by measuring the levels of serological and colonic tissue markers. Simultaneously, we evaluated the correlation between the GM and these markers to explore the mechanism by which chemotherapy affects the GM. Following transarterial chemotherapy with epirubicin, the Firmicutes abundance decreased, whereas that of Proteobacteria increased. The relative abundance of beneficial bacteria, such as Muribaculaceae, Enterococcus, Ruminococcus, and Clostridia, decreased in the experimental group compared with those in the control group. However, the relative abundance of harmful bacteria, such as Bacteroides and Escherichia (Shigella), was higher in the experimental group than in the control group. Following chemotherapy, the GM of rabbits showed a dynamic change over time, first aggravating and then subsiding. The changes were most notable on the fourth day after surgery and recovered slightly on the seventh day. The changes in the host’s GM before and after arterial chemotherapy are evident. Hepatic arterial chemotherapy induces dysbiosis of the intestinal microbiota, disrupts intestinal barrier function, damages the integrity of the intestinal mucosa, increases intestinal permeability, facilitates excessive passage of harmful substances through the gut–liver axis communication between the liver and intestine, and triggers activation of inflammatory pathways such as LPS-TLR-4-pSTAT3, ultimately leading to an inflammatory response. This study provides a theoretical basis for combining TACE with targeted GM intervention to treat HCC and reduce adverse gastrointestinal reactions.

Residents of the Qinghai-Tibet Plateau might experience shifts in their gut microbiota composition as a result of the plateau environment. For example, high altitudes can increase the abundance of obligate anaerobic bacteria, decrease the number of aerobic bacteria and facultative anaerobic bacteria, increase probiotics, and decrease pathogenic bacteria. This study aimed to determine the structure and metabolic differences in intestinal microbial communities among the Tibetan and Han populations on the Qinghai-Xizang Plateau and shed light on the factors that influence the abundance of the microbial communities in the gut. The structural characteristics of intestinal microorganisms were detected from blood and fecal samples using 16S rRNA sequencing. Metabolic characteristics were detected using gas chromatography–time-of-flight mass spectrometry (GC–TOFMS). The influencing factors were analyzed using Spearman’s correlation analysis. Bacteroides and Bifidobacterium were dominant in the intestinal tract of the Han population, while Bacteroides and Prevotella were dominant in that of the Tibetan population, with marked differences in Pseudomonas, Prevotella, and other genera. Ferulic acid and 4-methylcatechol were the main differential metabolites between the Tibetan and Han ethnic groups. This may be the reason for the different adaptability of Tibetan and Han nationalities to the plateau. Alanine aminotransferase and uric acid also have a high correlation with different bacteria and metabolites, which may play a role. These results reveal notable disparities in the compositions and metabolic characteristics of gut microbial communities in the Tibetan and Han people residing on the Qinghai-Tibet Plateau and may provide insights regarding the mechanism of plateau adaptability.