No-Observed Adverse Effect Levels of Deoxynivalenol and Aflatoxin B1 in Combination Induced Immune Inhibition and Apoptosis in vivo and in vitro.

Mycotoxins are toxic metabolites produced by fungal species, commonly exist in animal feeds, and pose a serious risk to human as well as animal health. But limited studies have focused on combined effects of no-observed adverse effect levels. In vivo study, 6 weeks old twenty-four mice were individually exposed to Deoxynivalenol (DON) at 0.1 mg/kg BW, Aflatoxin B1 (AFB1) at 0.01 mg/kg BW, and mixture of DON and AFB1 (0.1 mg/kg BW and 0.01 mg/kg BW, respectively) for 28 days. Then, DON at 0.5 µg/mL, AFB1 at 0.04 µg /mL, and mixtures of DON and AFB1 (0.5 µg /mL, 0.04 µg /mL, respectively) were applied to porcine alveolar macrophages (PAMs) in vitro study. Our in vivo results revealed that the combined no-observed adverse effect levels of DON and AFB1 administration decreased IgA and IgG levels in the serum, the splenic TNF-α, IFN-γ, IL-2 and IL-6 mRNA expression and T-lymphocyte subset levels (CD4+ and CD8+) in the spleen. Additionally, the combined administration increased caspase-3, caspase-9, Bax, Cyt-c, and decreased Bcl-2 protein expression. Taken together, the combined no-observed adverse effect levels of DON and AFB1 could induce immunosuppression, which may be related to apoptosis. This study provides new insights into the combined immune toxicity (DON and AFB1).

Optimizing differential expression analysis for proteomics data via high-performing rules and ensemble inference.

Identification of differentially expressed proteins in a proteomics workflow typically encompasses five key steps: raw data quantification, expression matrix construction, matrix normalization, missing value imputation (MVI), and differential expression analysis. The plethora of options in each step makes it challenging to identify optimal workflows that maximize the identification of differentially expressed proteins. To identify optimal workflows and their common properties, we conduct an extensive study involving 34,576 combinatoric experiments on 24 gold standard spike-in datasets. Applying frequent pattern mining techniques to top-ranked workflows, we uncover high-performing rules that demonstrate optimality has conserved properties. Via machine learning, we confirm optimal workflows are indeed predictable, with average cross-validation F1 scores and Matthew's correlation coefficients surpassing 0.84. We introduce an ensemble inference to integrate results from individual top-performing workflows for expanding differential proteome coverage and resolve inconsistencies. Ensemble inference provides gains in pAUC (up to 4.61%) and G-mean (up to 11.14%) and facilitates effective aggregation of information across varied quantification approaches such as topN, directLFQ, MaxLFQ intensities, and spectral counts. However, further development and evaluation are needed to establish acceptable frameworks for conducting ensemble inference on multiple proteomics workflows.

CGRWDL: alignment-free phylogeny reconstruction method for viruses based on chaos game representation weighted by dynamical language model.

Traditional alignment-based methods meet serious challenges in genome sequence comparison and phylogeny reconstruction due to their high computational complexity. Here, we propose a new alignment-free method to analyze the phylogenetic relationships (classification) among species. In our method, the dynamical language (DL) model and the chaos game representation (CGR) method are used to characterize the frequency information and the context information of k-mers in a sequence, respectively. Then for each DNA sequence or protein sequence in a dataset, our method converts the sequence into a feature vector that represents the sequence information based on CGR weighted by the DL model to infer phylogenetic relationships. We name our method CGRWDL. Its performance was tested on both DNA and protein sequences of 8 datasets of viruses to construct the phylogenetic trees. We compared the Robinson-Foulds (RF) distance between the phylogenetic tree constructed by CGRWDL and the reference tree by other advanced methods for each dataset. The results show that the phylogenetic trees constructed by CGRWDL can accurately classify the viruses, and the RF scores between the trees and the reference trees are smaller than that with other methods.

High-power polarization-maintaining LP11-mode fiber laser based on long-period fiber grating for precise welding.

An LP11-mode output all-fiber laser was presented, utilizing long-period fiber gratings (LPFGs) and polarization-maintaining optical fiber (PMF). The LPFG was designed and fabricated, achieving a 90.56% efficiency in LP01 to LP11 mode conversion. Furthermore, the transmission stability of LP11-mode in the PMF was also explored, with the spatial mode overlap ratio exceeding 0.95. Ultimately, the high-power polarization-maintaining (PM) fiber laser, capable of the LP11 mode output, was constructed, with the output power of 600 W and the beam quality M2 of 2.84. During the process of welding a thick Al-plate, the LP11 fiber laser exhibits a notable 1.88 times greater depth of fusion compared to the commercial single-mode fiber laser, when operating at the laser welding head speed of 100 mm/s. For applications demanding non-circular symmetric high-order modes, this research holds substantial potential for widespread adoption within the field of industrial processing.

RNA editing factor SlORRM2 regulates the formation of fruit pointed tips in tomato.

Domestication of tomato (Solanum lycopersicum) has led to large variation in fruit size and morphology. The development of the distal end of the fruit is a critical factor in determining its overall shape. However, the intricate mechanisms underlying distal fruit development require further exploration. This study aimed to investigate the regulatory role of an organelle RNA recognition motif (RRM)-containing protein SlORRM2 in tomato fruit morphology development. Mutant plants lacking SlORRM2 exhibited fruits with pointed tips at the distal end. However, this phenotype could be successfully restored through the implementation of a "functional complementation" strategy. Our findings suggest that the formation of pointed tips in the fruits of the CR-slorrm2 mutants is linked to alterations in the development of the ovary and style. We observed a substantial decrease in the levels of indole-3-acetic acid (IAA) and altered expression of IAA-related response genes in the ovary and style tissues of CR-slorrm2. Moreover, our data demonstrated that SlORRM2 plays a role in regulating mitochondrial RNA editing sites, particularly within genes encoding various respiratory chain subunits. Additionally, the CR-slorrm2 mutants exhibited modified organellar morphology and increased levels of reactive oxygen species (ROS). These findings provide valuable insights into the mechanisms underlying the formation of fruit pointed tips in tomato and offer genetic resources for tomato breeding.

Comparative metabolic profiling of different pakchoi cultivars reveals nutritional diversity via widely targeted metabolomics.

Pakchoi (Brassica rapa ssp. chinensis) is cultivated for its high nutritional value; however, the nutritional diversity of different pakchoi cultivars is rarely investigated. Herein, we performed widely targeted metabolic profiling analyses of five popular pakchois. A total of 670 metabolites were detected, which could be divided into 13 categories. The accumulation patterns of main nutritional metabolites among the five pakchois were significantly different and complementary. Moreover, the pakchoi cultivar 'QYC' showed quite different metabolomic profiles compared with other pakchois. The Venn diagram showed that the 75 differential metabolites were shared among the comparison groups ('QYC' vs. 'MET'/ 'NBC'/ 'PPQ'/ 'XQC'), of which 52 metabolites were upregulated in 'QYC'. The phenolic acids had the largest variations between 'QYC' and the other pakchoi cultivars. These findings expand metabolomic information on different pakchoi cultivars and further provide new insights into the selection and breeding of excellent pakchoi cultivars.

[Visualization of mitochondrial dynamics in tomato based on green fluorescent protein].

This study aimed to visualize the morphological features and dynamic changes of tomato mitochondria to provide a basis for the study of its mitochondrial functions. In this study, transgenic tomatoes expressing mitochondria-localized green fluorescent protein (mitochondria-GFP, Mt-GFP) were obtained by Agrobacterium-mediated genetic transformation. The color, hardness, soluble solids, acidity content, respiration rate, and ethylene production of the transgenic Mt-GFP tomato fruits were determined at the stage of mature green, breaker, and 3, 6, 9 days after breaker, while the wild-type tomato fruits were used as a control. As expected, Mt-GFP recombinant protein did not affect the ripening process, but induced the increased acidity of tomato fruits. The accumulations of Mt-GFP protein in tomato leaves and fruits were successfully verified by Western blotting. The morphological characteristics of mitochondria in flower, leaf and fruit cells as well as the dynamic changes of mitochondria in flower cells were clearly observed and studied under confocal laser microscope. The development of transgenic Mt-GFP tomato plants helps the visualization of tomato mitochondria and provides good research materials for the study of mitochondrial function during tomato development and fruit ripening.

The role of Rab GTPase in Plant development and stress.

Small GTPase is a type of crucial regulator in eukaryotes. It acts as a molecular switch by binding with GTP and GDP in cytoplasm, affecting various cellular processes. Small GTPase were divided into five subfamilies based on sequence, structure and function: Ras, Rho, Rab, Arf/Sar and Ran, with Rab being the largest subfamily. Members of the Rab subfamily play an important role in regulating complex vesicle transport and microtubule system activity. Plant cells are composed of various membrane-bound organelles, and vesicle trafficking is fundamental to the existence of plants. At present, the function of some Rab members, such as RabA1a, RabD2b/c and RabF2, has been well characterized in plants. This review summarizes the role of Rab GTPase in regulating plant tip growth, morphogenesis, fruit ripening and stress response, and briefly describes the regulatory mechanisms involved. It provides a reference for further alleviating environmental stress, improving plant resistance and even improving fruit quality.

Quantitative immunochromatographic assay for rapid and cost-effective on-site detection of benzo[a]pyrene in oilfield chemicals.

Contamination of oilfield chemicals (OFCs) by benzo[a]pyrene (B[a]P) is increasingly becoming a severe environmental security issue. There is an urgent need to develop a rapid and accurate method for B[a]P detection in OFCs. In this study, B[a]P hapten was designed using computer aided molecular design. A high-affinity, specific, and matrix-insensitive monoclonal antibody (mAb) with IC50 values of 6.77 ng/mL was obtained. Based on this mAb, we developed a rapid gold nanoparticle-based immunochromatographic strip assay (GICA) with double T-line mode for on-site detection of B[a]P in OFCs samples. The GICA exhibited excellent detection performance in OFCs samples with strong acidity, strong alkalinity, and deep color. Under optimal conditions, the proposed method detected B[a]P in OFCs at 0.42-300 mg/kg, and limit of detection was 0.23-1.07 mg/kg. The recovery rate was 88-106% with a coefficient of variation of 1.46-6.35%. Confirmed by natural positive OFCs samples and high-performance liquid chromatography, this GICA is accurate and reliable, with great potential for rapid and cost-effective on-site detection.

Rapid and sensitive quantitation of amitraz in orange, tomato, and eggplant samples using immunochromatographic assay.

Amitraz (AMT) is a broad-spectrum formamidine insecticide and acaricide. In this study, we produced an anti-AMT monoclonal antibody (mAb) with high performance. The half-maximal inhibitory concentration of the anti-AMT mAb was 4.418 ng/mL, the cross reactivity with other insecticides was negligible, and an affinity constant was 2.06 × 109 mmol/L. Additionally, we developed an immunochromatographic assay for the rapid detection of AMT residues in oranges, tomatoes, and eggplants. The cut-off values were 2000 µg/kg in oranges and tomato samples and 1000 µg/kg in eggplant samples and the calculated limits of detection were 14.521 µg/kg, 6.281 µg/kg, and 3.518 µg/kg in oranges, tomatoes, and eggplants, respectively, meeting the detection requirements for AMT in fruits and vegetables. The recovery rates ranged between 95.8 % and 105.2 %, consistent with the recovery rates obtained via LC-MS/MS. Our developed immunochromatographic assay can effectively, accurately, and rapidly determine AMT residues in oranges, tomatoes, and eggplants.

M-type refractive index profile erbium-doped fiber for high-efficiency multicore EDFA.

Cladding-pumped multicore erbium-doped fiber is an important element for future spatial division multiplexing (SDM) amplification. We propose an M-type erbium-doped multicore fiber to achieve high-efficiency SDM amplification. The performance of cladding-pumped erbium-doped fiber with a central refractive index depression has been investigated, and the M-type fiber has better amplification performance than conventional fibers by reducing the signal mode overlap with the doped region. The experiment results show that the M-type 4-core erbium-doped fiber has a gain improvement of 2.8 dB compared with conventional 4-core fiber. The pump conversion efficiency (PCE) has been enhanced from 4.47% to 8.01%. For a 7.0 W pump power at 976 nm, the M-type fiber exhibits an average gain of 20.0 dB and an average noise fiber of 6.8 dB at the L-band. The core-to-core gain variation is less than 1.6 dB.

SARF: Aliasing Relation-Assisted Self-Supervised Learning for Few-Shot Relation Reasoning.

Few-shot relation reasoning on knowledge graphs (FS-KGR) is an important and practical problem that aims to infer long-tail relations and has drawn increasing attention these years. Among all the proposed methods, self-supervised learning (SSL) methods, which effectively extract the hidden essential inductive patterns relying only on the support sets, have achieved promising performance. However, the existing SSL methods simply cut down connections between high-frequency and long-tail relations, which ignores the fact, i.e., the two kinds of information could be highly related to each other. Specifically, we observe that relations with similar contextual meanings, called aliasing relations (ARs), may have similar attributes. In other words, the ARs of the target long-tail relation could be in high-frequency, and leveraging such attributes can largely improve the reasoning performance. Based on the interesting observation above, we proposed a novel Self-supervised learning model by leveraging Aliasing Relations to assist FS-KGR, termed . Specifically, we propose a graph neural network (GNN)-based AR-assist module to encode the ARs. Besides, we further provide two fusion strategies, i.e., simple summation and learnable fusion, to fuse the generated representations, which contain extra abundant information underlying the ARs, into the self-supervised reasoning backbone for performance enhancement. Extensive experiments on three few-shot benchmarks demonstrate that achieves state-of-the-art (SOTA) performance compared with other methods in most cases.

High bismuth-doped germanosilicate fiber for efficient E + S-band amplification.

Bismuth-doped germanosilicate fiber (BGSF), the active media of fiber amplifiers, has attracted widespread attention. Here, we report a BGSF with a high bismuth concentration of 0.075 wt. % and achieve high-efficiency E + S-band amplification, which was prepared by the modified chemical vapor deposition (MCVD) process. The small signal absorption (SSA) and unsaturated loss (UL) of BGSF at 1310 nm are 1.32 and 0.11 dB/m, respectively. The results show a record with only 45 m BGSF was created, to the best of our knowledge, which provides a maximum gain of 39.24 dB with an NF of 6.2 dB at 1430 nm under -20 dBm input signal power.

Tissue adhesive, ROS scavenging and injectable PRP-based 'plasticine' for promoting cartilage repair.

Platelet-rich plasma (PRP) that has various growth factors has been used clinically in cartilage repair. However, the short residence time and release time at the injury site limit its therapeutic effect. The present study fabricated a granular hydrogel that was assembled from gelatin microspheres and tannic acid through their abundant hydrogen bonding. Gelatin microspheres with the gelatin concentration of 10 wt% and the diameter distribution of 1-10 µm were used to assemble by tannic acid to form the granular hydrogel, which exhibited elasticity under low shear strain, but flowability under higher shear strain. The viscosity decreased with the increase in shear rate. Meanwhile, the granular hydrogel exhibited self-healing feature during rheology test. Thus, granular hydrogel carrying PRP not only exhibited well-performed injectability but also performed like a 'plasticine' that possessed good plasticity. The granular hydrogel showed tissue adhesion ability and reactive oxygen species scavenging ability. Granular hydrogel carrying PRP transplanted to full-thickness articular cartilage defects could integrate well with native cartilage, resulting in newly formed cartilage articular fully filled in defects and well-integrated with the native cartilage and subchondral bone. The unique features of the present granular hydrogel, including injectability, plasticity, porous structure, tissue adhesion and reactive oxygen species scavenging provided an ideal PRP carrier toward cartilage tissue engineering.

Different expression levels of interleukin-36 in asthma phenotypes.

Interleukin (IL)-36 family is closely associated with inflammation and consists of IL-36α, IL-36ß, IL-36γ, and IL-36Ra. The role of IL-36 in the context of asthma and asthmatic phenotypes is not well characterized. We examined the sputum IL-36 levels in patients with different asthma phenotypes in order to unravel the mechanism of IL-36 in different asthma phenotypes. Our objective was to investigate the induced sputum IL-36α, IL-36ß, IL-36γ, and IL-36Ra concentrations in patients with mild asthma, and to analyze the relationship of these markers with lung function and other cytokines in patients with different asthma phenotypes. Induced sputum samples were collected from patients with mild controlled asthma (n = 62, 27 males, age 54.77 ± 15.49) and healthy non-asthmatic controls (n = 16, 10 males, age 54.25 ± 14.60). Inflammatory cell counts in sputum were determined. The concentrations of IL-36 and other cytokines in the sputum supernatant were measured by ELISA and Cytometric Bead Array. This is the first study to report the differential expression of different isoforms of IL-36 in different asthma phenotypes. IL-36α and IL-36ß concentrations were significantly higher in the asthma group (P = 0.003 and 0.031), while IL-36Ra concentrations were significantly lower (P < 0.001) compared to healthy non-asthmatic controls. Sputum IL-36α and IL-36ß concentrations in the neutrophilic asthma group were significantly higher than those in paucigranulocytic asthma (n = 24) and eosinophilic asthma groups (n = 23). IL-36α and IL-36ß showed positive correlation with sputum neutrophils and total cell count (R = 0.689, P < 0.01; R = 0.304, P = 0.008; R = 0.689, P < 0.042; R = 0.253, P = 0.026). In conclusion, IL-36α and IL-36ß may contribute to asthma airway inflammation by promoting neutrophil recruitment in airways. Our study provides insights into the inflammatory pathways of neutrophilic asthma and identifies potential therapeutic target.

[Effects of Polystyrene Microplastics Combined with Cadmium Contamination on Soil Physicochemical Properties and Physiological Ecology of Lactuca sativa].

Contaminants such as microplastics (MPs) and heavy metals are commonly found in soils, both of which are extremely difficult to degrade and can easily form compound contamination, altering the physicochemical properties of the soil and thus potentially changing the growth and physiological and ecological characteristics of plants. In order to study the effects of the combined contamination of soil MPs and heavy metals on soil properties and plant growth, polystyrene microplastics (PS-MPs) with a particle size of 3 µm and the heavy metal cadmium were selected in the study. The changes in the physicochemical properties of soil and their effects on lettuce (Lactuca sativa) seed germination and seedling growth were studied at various exposure concentrations of PS-MPs (0, 10, 50, 100, 200, and 400 mg·kg-1) and combined with different Cd contamination concentrations (0, 1.2, and 6.0 mg·kg-1), respectively. The results showed that soil organic matter (SOM), available phosphorus (AP), alkali-hydrolysable nitrogen (AHN), and available kalium (AK) showed significant decreases as the intensity of PS-MPs combined with Cd contamination increased. Simultaneously, PS-MPs combined with Cd contamination also significantly reduced the germination rate of lettuce seeds, but low concentrations of PS-MPs slowed down the effect of Cd (6.0 mg·kg-1) contamination on lettuce seeds, and high concentrations of PS-MPs enhanced the effect of Cd (6.0 mg·kg-1). The fresh weight, dry weight, and plant height of lettuce seedlings showed an increasing and then decreasing trend with increasing exposure to PS-MPs. Chlorophyll content, superoxide dismutase (SOD), catalase (CAT), and peroxidase (POD) showed a decreasing trend, whereas malondialdehyde (MDA) content showed an overall increasing trend under different Cd concentrations. The main physicochemical indicators of the soil were negatively correlated with MDA of lettuce seedlings, whereas other indicators of the seedlings were positively correlated. The combined contamination of PS-MPs and Cd could affect the germination of plant seeds and the physiological and ecological characteristics of seedlings by changing the physicochemical properties of the soil. Both exposure to single PS-MPs contaminants and the combination of PS-MPs with Cd inhibited the germination of lettuce seeds and affected the physiological activities of their seedlings, and the inhibition was significantly increased with increasing exposure. Low exposure to PS-MPs or the combination of PS-MPs with Cd contamination exhibited a promotive effect on lettuce seedling growth. High exposure to PS-MPs combined with Cd contamination exhibited significant ecological effects on lettuce seedlings, and high exposure to PS-MPs exacerbated the ecotoxicological effects of Cd contaminants on lettuce seedlings, and PS-MPs and Cd exhibited synergistic effects. The results can provide some reference for assessing the ecological effects of MPs and heavy metal pollution in soil-plant systems.

Wild imitating vs greenhouse cultivated Dendrobium huoshanense: Chemical quality differences.

Dendrobium huoshanense (D. huoshanense) has been used as functional food supplements and herbal medicines for preventing and managing diseases with a long history in China. Due to its endangered natural resources and huge demand, people tend to cultivate D. huoshanense to protect this species. However, the quality of wild and cultivated herbs of the same species may change. This work quantified and compared the main quality traits and chemical components of wild imitating and greenhouse cultivated D. huoshanense with different growth years. As a result, wild and cultivated D. huoshanense had similar chemical composition, but there are significant differences in the content of many ingredients (polysaccharides, flavonoids, nucleosides, bibenzyls, lignans and volatile compounds). And the contents of many of these components increased with growing years. In addition, multivariate statistical analyses have been applied to classify and evaluate samples from different cultivation modes according to these components. In conclusion, our results demonstrated that the overall quality of greenhouse cultivated D. huoshanense was not as good as wild-grown, but this mode can be a promising and sustainable way of producing D. huoshanense.

Non-targeted metabolomics strategy reveals the role of Geng-Nian-Shu in regulating ferroptosis in perimenopausal syndrome.

Ovariectomy (OVX) is usually accompanied by the occurrence of metabolic syndrome. Previous studies have shown that Geng-Nian-Shu (GNS) plays an important regulatory role in perimenopausal syndrome (PMS) rats. GNS is a traditional Chinese medicine (TCM) prescription which composed of Suanzaoren Decoction and Ganmai Dazao Decoction in "Jingui Yaolue" and Siwu Decoction in "Heji Jufang". Recently, metabolomics analysis has been used to identify slight changes in the metabolic profile and to help understand disease progression and therapeutic interventions in PMS. However, the mechanism of GNS in the treatment of PMS is still unknown. We purposed to study the metabolic characteristics of PMS by serum and fecal metabolomics, and revealed the internal mechanism of GNS regulating ferroptosis against PMS. The PMS model was established by surgical removal of 4/5 ovaries of rats. HPLC-Q-TOF/MS was used to analyze the metabolomics of rat plasma and feces to explore the potential mechanism of GNS in PMS. The expression of ferroptosis-related proteins in rat ovaries was detected by tissue Prussian blue staining, Elisa kit and Western blotting. Cluster analysis of differential metabolites in plasma and feces between the control group and the model group showed that organic acids and their derivatives, lipids and lipid molecules were mainly disturbed during PMS in rats. After GNS administration, 17 differential metabolites were adjusted, involving several major pathways, such as the tricarboxylic acid (TCA) cycle, biosynthesis of amino acids and biosynthesis of unsaturated fatty acids. Further, we found that GNS affected ferroptosis in ovarian cells by regulating endogenous substances in OVX rats. Our study provides new insights into the mechanism of OVX-induced metabolic syndrome based on non-targeted metabolomics. It provides new ideas for the development and application of GNS and the diagnosis and treatment of PMS.

Hypothalamic CRF neurons facilitate brain reward function.

Aversive stimuli activate corticotropin-releasing factor (CRF)-expressing neurons in the paraventricular nucleus of hypothalamus (PVNCRF neurons) and other brain stress systems to facilitate avoidance behaviors. Appetitive stimuli also engage the brain stress systems, but their contributions to reward-related behaviors are less well understood. Here, we show that mice work vigorously to optically activate PVNCRF neurons in an operant chamber, indicating a reinforcing nature of these neurons. The reinforcing property of these neurons is not mediated by activation of the hypothalamic-pituitary-adrenal (HPA) axis. We found that PVNCRF neurons send direct projections to the ventral tegmental area (VTA), and selective activation of these projections induced robust self-stimulation behaviors, without activation of the HPA axis. Similar to the PVNCRF cell bodies, self-stimulation of PVNCRF-VTA projection was dramatically attenuated by systemic pretreatment of CRF receptor 1 or dopamine D1 receptor (D1R) antagonist and augmented by corticosterone synthesis inhibitor metyrapone, but not altered by dopamine D2 receptor (D2R) antagonist. Furthermore, we found that activation of PVNCRF-VTA projections increased c-Fos expression in the VTA dopamine neurons and rapidly triggered dopamine release in the nucleus accumbens (NAc), and microinfusion of D1R or D2R antagonist into the NAc decreased the self-stimulation of these projections. Together, our findings reveal an unappreciated role of PVNCRF neurons and their VTA projections in driving reward-related behaviors, independent of their core neuroendocrine functions. As activation of PVNCRF neurons is the final common path for many stress systems, our study suggests a novel mechanism underlying the positive reinforcing effect of stressful stimuli.

Melatonin improves cholestatic liver disease via the gut-liver axis.

Cholestatic liver disease is characterized by disturbances in the intestinal microbiota and excessive accumulation of toxic bile acids (BA) in the liver. Melatonin (MT) can improve liver diseases. However, the underlying mechanism remains unclear. This study aimed to explore the mechanism of MT on hepatic BA synthesis, liver injury, and fibrosis in 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-fed and Mdr2-/- mice. MT significantly improved hepatic injury and fibrosis with a significant decrease in hepatic BA accumulation in DDC-fed and Mdr2-/- mice. MT reprogramed gut microbiota and augmented fecal bile salt hydrolase activity, which was related to increasing intestinal BA deconjugation and fecal BA excretion in both DDC-fed and Mdr2-/- mice. MT significantly activated the intestinal farnesoid X receptor (FXR)/fibroblast growth factor 15 (FGF-15) axis and subsequently inhibited hepatic BA synthesis in DDC-fed and Mdr2-/- mice. MT failed to improve DDC-induced liver fibrosis and BA synthesis in antibiotic-treated mice. Furthermore, MT provided protection against DDC-induced liver injury and fibrosis in fecal microbiota transplantation mice. MT did not decrease liver injury and fibrosis in DDC-fed intestinal epithelial cell-specific FXR knockout mice, suggesting that the intestinal FXR mediated the anti-fibrosis effect of MT. In conclusion, MT ameliorates cholestatic liver diseases by remodeling gut microbiota and activating intestinal FXR/FGF-15 axis-mediated inhibition of hepatic BA synthesis and promotion of BA excretion in mice.