Metabolic-associated fatty liver disease (MAFLD) has become an increasingly prevalent liver disorder worldwide, being closely associated with obesity, metabolic syndrome, and insulin resistance. Bile acids (BAs), beyond their traditional role in lipid digestion, play a pivotal part in regulating lipid and glucose metabolism as well as inflammatory responses. Recent investigations have recognized BAs as key factors in the onset and progression of MAFLD, mainly via their interactions with nuclear receptors such as the farnesoid X receptor (FXR) and the G protein-coupled bile acid receptor (TGR5). Additionally, active compounds derived from traditional Chinese medicine (TCM) have shown promising potential in the treatment of MAFLD. This study systematically reviews and analyzes the molecular mechanisms and recent progress in the application of TCM active ingredients for MAFLD treatment, with a focus on their regulation of BAs. These active ingredients, including saponins, flavonoids, polysaccharides, and sterols, exert therapeutic effects through diverse mechanisms, such as modulating BA synthesis and mediating receptor-signaling pathways, and are expected to restore metabolic homeostasis.

The purpose of this research was to investigate how different bile acids impact lipid metabolism and carcass characteristics in finishing pigs, along with the potential mechanisms involved. Twenty-one finishing pigs (Duroc×Landrace×Yorkshire [DLY]; average BW = 144.38 ± 8.92 kg) were assigned to three dietary treatments, with each treatment containing seven replicates, each consisting of one pig. The three dietary treatments included: a basic diet, a basic diet supplemented with 500 mg/kg of hyodeoxycholic acid (HDCA), and a basic diet supplemented with 500 mg/kg of lithocholic acid (LCA). The trial lasted for 28 d. Hyodeoxycholic acid was used in the in vitro experiments and added to mature 3T3-L1 adipocytes for 4 d to elucidate the mechanism by which bile acids regulate lipid metabolism. The results suggested that HDCA tended to decrease backfat thickness in finishing pigs (P = 0.094) and reduced the size of lipid droplets in 3T3-L1 adipocytes (P = 0.012), whereas LCA increased backfat thickness (P = 0.016) and induced larger lipid droplets in the abdominal adipose tissue (P = 0.003). Furthermore, HDCA enhanced the expression of Takeda G-protein-coupled receptor 5 protein and hormone-sensitive lipase (HSL) gene in backfat of pigs (P < 0.05) and increased the protein expression of phosphorylated HSL (p-HSL) in vitro (P = 0.093). Compared to HDCA, LCA addition increased the gene and protein expression of peroxisome proliferator activated receptor gamma in backfat of pigs (P < 0.05) and enhanced the expression of hepatic genes sterol regulatory element-binding protein-1c and fatty acid synthase (P < 0.05). In conclusion, HDCA enhanced lipolysis and partially decreased backfat thickness in finishing pigs, while LCA promoted lipid synthesis and increased backfat thickness of pigs. The variations in the effects of various bile acids on bile acid receptors could explain these functional differences.

Bile acids, derived from cholesterol in the liver, consist a steroidal core. Primary bile acids and secondary bile acids metabolized by the gut microbiota make up the bile acid pool, which modulate nuclear hormone receptors to regulate immunity. Disruptions in the crosstalk between bile acids and the gut flora are intimately associated with the development and course of gastrointestinal inflammation.

This review provides an extensive summary of bile acid production, transport and metabolism. It also delves into the impact of bile acid metabolism on the body and explores the involvement of bile acid-microbiota interactions in various disease states. Furthermore, the potential of targeting bile acid signaling as a means to prevent and treat inflammatory bowel disease is proposed.

In this review, we primarily address the functions of bile acid-microbiota crosstalk in diseases. Firstly, we summarize bile acid signalling and the factors influencing bile acid metabolism, with highlighting the immune function of microbially conjugated bile acids and the unique roles of different receptors. Subsequently, we emphasize the vital role of bile acids in maintaining a healthy gut microbiota and regulating the intestinal barrier function, energy metabolism and immunity. Finally, we explore differences of bile acid metabolism in different disease states, offering new perspectives on restoring the host's health and the gastrointestinal ecosystem by targeting the gut microbiota-bile acid-bile acid receptor axis.

The purpose of this study is to investigate the effects and mechanisms of Acanthopanax senticosus polysaccharides (ASPS) on lipopolysaccharide (LPS)-induced intestinal injury and growth performance in piglets. Our results indicated that ASPS improved the growth performance in LPS-challenged piglets, including the increase in average daily gain (ADG), average daily feed intake (ADFI), and the feed to gain ratio (F/G). ASPS alleviated LPS-induced intestinal inflammation in piglets, accompanied by the increase in the villus height to crypt depth ratio (VCR) and the decreased in the expression levels of IL-1β, IL-6, and TNF-α. 16S rRNA sequencing results showed that ASPS improved gut microbiota dysbiosis and increased Lactobacillus_sp._L_YJ abundance. The combined analysis of untargeted metabolomics of intestinal contents and serum showed that ASPS significantly increased the levels of hyodeoxycholic acid (HDCA), DHA ethyl ester, and alanylalanine, and the level of HDCA is the highest among all metabolites, suggesting that ASPS regulated the metabolites of intestinal contents and serum to alleviate LPS-induced intestinal inflammation in piglets, and HDCA might play a significant role during this process. Furthermore, we investigated the effects of HDCA on growth performance and intestinal inflammation in LPS-challenged piglets. The results indicated that HDCA alleviated LPS-induced intestinal inflammation and improved the growth performance in piglets. In conclusion, ASPS could alleviate LPS-induced intestinal inflammation in piglets by gut microbiota and hyodeoxycholic acid regulation. These findings might provide strong evidence for ASPS as a feed additive to improve piglet diarrhea, and reveal the therapeutic potential of hyodeoxycholic acid in preventing intestinal inflammation in piglets.

Crossbreeding has emerged as a strategy to combine desirable traits from different sheep breeds, with the goal of enhancing productivity, disease resistance, and growth rates. This study compares the immune responses, rumen microbiomes, and serum metabolites of Hu sheep, East Friesian (EF) sheep, and crossbred Hu × EF (DH) sheep to explore the effects of crossbreeding on productivity and disease resistance. Hu sheep exhibited significantly higher lymphocyte counts (p < 0.05) and white blood cell (WBC) counts (p < 0.05) compared to EF and DH sheep, indicating stronger basal immune responses. DH sheep showed superior immune responses, with a higher cluster of differentiation 4+/cluster of differentiation 8+ (CD4+/CD8+) T cell ratio (p < 0.05) compared to EF sheep. Rumen microbiome analysis revealed distinct microbial profiles; DH sheep exhibited higher relative abundances of Prevotella (p < 0.05), which is associated with improved growth and disease resistance. Metabolomic analysis revealed significant differences in bile acid profiles: DH sheep exhibited higher levels of 6-keto lithocholic acid (6-ketoLCA), cholic acid and chenodeoxycholic acid (CDCA), and 3β-hyodeoxycholic acid (3β-HDCA) (p < 0.05), which is associated with improved immune function and gut health. These results indicate that crossbreeding improves immune resilience and metabolic efficiency, which has implications for breeding strategies designed to enhance livestock productivity and disease resistance.

Nonalcoholic fatty liver disease (NAFLD), a prevalent chronic liver disease, poses a substantial global health burden. Metformin is known for its protective effects in NAFLD, but the role of gut microbiota in the underlying mechanisms remains unclear. In this study, metformin was found to mitigate methionine-choline deficient (MCD) -diet induced NAFLD through reshaping the gut microbiota to increase ursodeoxycholic acid (UDCA) level, thereby inhibiting farnesoid X receptor (FXR) accompanied with activated autophagy. Specifically, using dirty cage experiments and 16S rRNA sequencing, it identified that metformin could reshape microbiota to release liver injury as confirmed by the results of histopathology and biochemical index detection. Furthermore, the bile acids were found to be altered by metformin, in which, the UDCA, a FXR natural inhibitor, was observed a significantly increase. Meanwhile, the inhibited FXR and activated autophagy in metformin-treated mice were captured using western blot, qRT-PCR and immunofluorescence analysis. In addition, the benefit of UDCA against NAFLD was demonstrated in UDCA treated mice. Further investigation with FXR siRNA introduced to HepG2 cells revealed that inhibiting FXR can reduce oleic acids induced cell injury with the autophagy activation. In conclusion, this study highlights metformin's potential to ameliorate NAFLD by reshaping gut microbiota, thereby upregulating UDCA in the liver and restoring cholesterol synthesis capacity, possibly via inhibiting FXR to activate autophagy.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a highly prevalent condition that can progress to fibrosis, steatohepatitis, and hepatocellular carcinoma. This review examines recent advances concerning the role of gut microbiota in MASLD and microbiota-focused interventions to positively impact disease outcome.

Dysbiotic microbiota and a compromised gut barrier facilitate the translocation of microbial-associated molecular patterns and harmful metabolites into the portal circulation and liver, where they exacerbate inflammatory and fibrogenic processes. Conversely, other bacterial metabolites have protective effects in the liver. Therefore, microbiota homeostasis is essential for maintaining liver health.

Levels of harmful bacterial metabolites including ethanol, NH3, trimethylamine-L-oxide, 2-oleylglycerol, and litocholic acid are often increased in patients with MASLD. Conversely, short-chain fatty acids, indole derivatives, histidine, and the acids taurodeoxycholic, 3-succinylcholic, and hyodeoxycholic are decreased. The main aim of current interventions/treatments is to reduce harmful metabolites and increase beneficial ones. These interventions include drugs (pemafibrate, metformin, obeticholic acid), natural compounds (silymarin, lupeol, dietary fiber, peptides), exogenous bacteria (probiotics, gut symbionts), special diets (Mediterranean diet, time-restricted feeding), as well as microbiota transplantation, and phage therapy. Most improve gut permeability, liver inflammation, and fibrosis through microbiota regulation, and are promising alternatives for MASLFD management. However, most results come from animal studies, while clinical trials in MASLD patients are lacking. Further research is therefore needed in this area.

Recent studies have indicated that Lactococcus petauri LZys1 (L. petauri LZys1), isolated from healthy human feces, exhibits a promising probiotic profile in vitro. However, its impact on the physiological status of the host in vivo remains uncertain. The objective of our study was to investigate the effects and mechanisms of orally administering L. petauri LZys1 on gut microbiota and liver function in mice. We administered L. petauri LZys1 through daily oral gavage to C57BL/6 male mice. Subsequently, we analyzed changes in gut microbiota composition using 16S rRNA sequencing and quantified alterations in hepatic-intestinal bile acid (BA) profile. Serum biochemical parameters were assessed to evaluate liver function. Our findings revealed that L. petauri LZys1 led to an increase in body weight, liver mass, and serum aminotransferase levels. Oral administration altered the gut microbiota composition, resulting in reduced diversity and abundance of intestinal bacteria. Additionally, the profiles of BAs were suppressed across organs, associated with the downregulation of the ileum's farnesoid X receptor (FXR)/fibroblast growth factor 15 (FGF15) signaling pathway. The decrease in circulating FGF15 mediated the downregulation of hepatic fibroblast growth factor receptor 4 (FGFR4)/FXR, disrupting BA metabolism and fatty acid oxidation. Our findings suggest that L. petauri LZys1 may impact liver function by influencing the gut microbiota-mediated ileal FXR-FGF15 axis and inhibiting hepatic bile acid metabolism.

This work elucidated the impact of L. petauri LZys1 on host gut microbiota metabolism and hepatic physiological metabolism. We observed that L. petauri LZys1 administration induced liver weight gain and biochemical parameters changes, in addition to a altered gut microbiota and suppressed bile acid (BA) profiles. Furthermore, we propose that changes in liver status are related to the enterohepatic farnesoid X receptor-fibroblast growth factor axis, which alters bile acid metabolism and disrupts liver function. The above findings suggest that attention should be paid to the effect of probiotics on liver function.

Intratumoral microbiota has been found to be a crucial component of hepatocellular carcinoma (HCC). Due to insufficient recognition, technical limitations, and low biomass of intratumoral microbiota, it is poorly understood. Intratumoral microbiota exhibit significant diversity in HCC tissues. It is involved in the development of HCC through several mechanisms, such as remodeling the immunosuppressive microenvironment, metabolic reprogramming, and genetic alterations. Moreover, intratumoral microbiota is associated with the metastasis of HCC cells. Herein, we reviewed the history of intratumoral microbiota, applied biotechnology to depict the signatures of intratumoral microbiota, investigated the potential sources of intratumoral microbiota, and assessed their functions, mechanisms, and heterogeneity. Furthermore, in this review, we summarized the development of therapeutics that can be used in the treatment of HCC and proposed future perspectives for research in this field.

To explore the correlation of dietary index for gut microbiota (DI-GM) with non-alcoholic fatty liver disease (NAFLD).

Data of 6,711 participants were extracted from the National Health and Nutrition Examination Survey (NHANES) during 2007-2018. A weighted logistic regression analysis was employed for assessment of the correlation of DI-GM with NAFLD, and a restricted cubic spline (RCS) analysis was implemented to examine potential non-linear associations. Subgroup analyses were conducted to identify particularly susceptible groups. Additionally, the synergistic effects of different DI-GM components on NAFLD risk was assessed by weighted quantile sum (WQS) regression.

The DI-GM exhibited statistically significant correlation with NAFLD [OR (95%CI):0.91 (0.85, 0.98), p = 0.015]. The results of the RCS analysis indicated a linear correlation of DI-GM and NAFLD (p = 0.810 for non-linearity). Further stratified analyses indicated that the negative correlation of DI-GM with NAFLD were significant and consistent for all subgroups. The results of WQS regression revealed that soybean (27%), refined grains (17%), coffee (16%), and red meat (9%) had the highest contribution weights to NAFLD.

As an important tool for assessment of the influences of diet on gut microbiota, DI-GM is negatively correlated with NAFLD risk factors. Soybean, refined grains, coffee, and red meat are key factors influencing NAFLD. The direct correlation of DI-GM with NAFLD shall be explored and the effectiveness of prevention and treatment of NAFLD shall be evaluated by improving DI-GM scores via dietary interventions.

Torularhodin, a unique carotenoid, confers beneficial effects on nonalcoholic fatty liver disease (NAFLD). However, the precise mechanism underlying its therapeutic effects remains unknown. Here, we report that torularhodin alleviates NAFLD in male mice by modulating the gut microbiota. Additionally, transplanting fecal microbiota from torularhodin-treated mice to germ-free mice also improves NAFLD. Mechanistically, torularhodin specifically enriches the abundance of Akkermansia muciniphila, which alleviates NAFLD by promoting the synthesis of adenosylcobalamin. Utilizing a human gastrointestinal system and a colonic organoid model, we further demonstrate that adenosylcobalamin confers protective effects against NAFLD through reducing ceramides, a well-known liver damaging compound, and this effect is mediated by inhibition of the hypoxia-inducible factor 2α pathway. Notably, we construct electrospun microsphere-encapsulated torularhodin, which facilitates the slow release of torularhodin in the colon. Together, our findings indicate the therapeutic potential of microbial utilization of carotenoids, such as torularhodin, for treating NAFLD.

Type 2 diabetes mellitus is a complex disorder associated with insulin resistance and hyperinsulinaemia that is insufficient to maintain normal glucose metabolism. Changes in insulin signalling and insulin levels are thought to directly explain many of the metabolic abnormalities that occur in diabetes mellitus, such as impaired glucose disposal. However, molecules that are directly affected by abnormal insulin signalling might subsequently go on to cause secondary metabolic effects that contribute to the pathology of type 2 diabetes mellitus. In the past several years, evidence has linked insulin resistance with the concentration, composition and distribution of bile acids. As bile acids are known to regulate glucose metabolism, lipid metabolism and energy balance, these findings suggest that bile acids are potential mediators of metabolic distress in type 2 diabetes mellitus. In this Review, we highlight advances in our understanding of the complex regulation of bile acids during insulin resistance, as well as how bile acids contribute to metabolic control.

Metabolic dysfunction-associated steatohepatitis (MASH) is an advanced form of liver disease with adverse outcomes. Manipulating interorgan communication is considered a promising strategy for managing metabolic disease, including steatohepatitis. Here, we report that remote limb ischemic conditioning (RIC), a clinically validated therapy for distant organ protection by transient muscle ischemia, significantly alleviated steatohepatitis in different mouse models. The beneficial effect of limb ischemic conditioning was mediated by muscle-to-liver transfer of small extracellular vesicles (sEVs) and their cargo microRNAs, leading to elevation of miR-181d-5p in the liver. Hepatic miR-181d-5p overexpression faithfully mirrored the molecular and histological benefits of limb ischemic conditioning by suppressing nuclear receptor 4A3 (NR4A3). Furthermore, circulating EVs from human volunteers undergoing limb ischemic conditioning improved steatohepatitis and transcriptomic perturbations in primary human hepatocytes and animal models. Our data underscore the translational potential of limb ischemic conditioning for steatohepatitis management and extend our understanding of muscle-liver crosstalk.

The study aims to investigate the mechanism of Farnesoid X receptor (FXR) activation in sepsis-induced abnormal bile acid metabolism and the metabolism status of each bile acid type.

The sepsis mouse model was developed via lipopolysaccharide intraperitoneal injection and confirmed via hematoxylin and eosin (H&E) staining. FXR agonist activated the FXR/fibroblast growth factor (FGF)15/FGFR pathway via quantitative real-time polymerase chain reaction and Western blot. Consequently, metabolomics and bioinformatics analysis were conducted to identify the alterations in each kind of bile acid content following FXR agonist/inhibitor intervention.

The H&E staining indicated that FXR activation alleviates the liver injury of the sepsis mouse model. The increased FGF15 and FXFR expression levels and decreased CYP7A1 demonstrated FXR/FGF15/FGFR pathway activation following FXR agonist treatment. Furthermore, total bile acid, interleukin (IL)-6, and tumor necrosis factor-α concentrations were downregulated after FXR activation, whereas IL-10 concentration was upregulated, indicating the alleviated effect of FXR agonist in sepsis. Consequently, metabolomics and bioinformatics analysis determined that T-a-MCA were downregulated in both FXR agonist and inhibitor groups, whereas six bile acid types were altered in the control group.

FXR activation was crucial in alleviating sepsis-induced hepatic injury and cholestasis through the FGF15/FGFR signaling pathway, and FXR may act as a potential preventive and intervention target of sepsis.

Metabolic-associated fatty liver disease (MAFLD) has become increasingly widespread. The intestine is the primary site of lipid absorption and is important for the homeostasis of lipid metabolism. However, the mechanism underlying the participation of the intestinal tract in the development of MAFLD requires additional investigation. In this study, analysis of the single-cell transcriptome of intestinal tissue from cynomolgus monkeys found that hepatic leukemia factor (HLF) participated in the genetic regulation of intestinal lipid absorption. Results obtained from normal and intestine-specific Hlf-knockout mice confirmed that HLF alleviated intestinal barrier disorders by inhibiting peroxisome proliferator-activated receptor alpha (PPARα) expression. The HLF/PPARα axis alleviated MAFLD by mediating gut microbiota-derived extracellular vesicles (fEVs), thereby inhibiting hepatocyte ferroptosis. Lipidomics and functional experiments verified that taurochenodeoxycholic acid (TCDCA), a conjugated bile acid contained in the fEVs, had a key role in the process. In conclusion, intestinal HLF activity was mediated by fEVs and identified as a novel therapeutic target for MAFLD.

The accumulation of abdominal fat and the metabolic dysfunction-associated fatty liver disease (MAFLD) are prevalent problems in the poultry industry, and seriously compromise broiler health and reduce economic benefits. Echinocystic acid (EA), a natural product with anti-inflammatory and antioxidant effects, has been demonstrated to reduce abdominal fat deposition and improve intestinal inflammation in mice. However, it has not been reported in poultry research. In this study, we employed chicken hepatocytes (Leghorn male hepatoma cells, LMHs) to construct an oleic acid and palmitic acid (OA/PA)-induced MAFLD model in vitro and 60 male K90 chickens were induced MAFLD by a high-fat diet (HFD) to examine the impact of EA on liver-lipid metabolism and abdominal fat deposition. Moreover, metabolomic analysis, 16S rDNA gene sequencing, and transcriptomic profiling were performed to determine the mechanism of EA. The results showed that EA (10 μM) significantly reduced triglyceride (TG) and total cholesterol (TC) levels in vitro. Moreover, EA reduced abdominal fat deposition without affecting growth performance. EA significantly decreased TC, TG, and low-density lipoprotein-cholesterol (LDL-C) levels, and increased high-density lipoprotein-cholesterol (HDL-C) levels in the blood. Additionally, EA supplementation altered the composition of the intestinal microbiota, particularly by decreasing the ratio of Firmicutes to Bacteroidetes. Furthermore, liver metabolomics analysis revealed that EA increased the abundance of metabolites related to arginine metabolism and mitochondrial oxidation pathways, and these metabolites were predicted to be positively correlated with the gut genera enriched by EA. EA also altered the expression patterns of genes related to liver lipid metabolism and inflammation, particularly CYP7A1, CYP7B1, CYP3A5, and ACAT, which are enriched in the PPAR signaling pathway and steroid hormone metabolism. Moreover, correlation analysis revealed that there was a close correlation between differential gut microbiota, metabolites, and gene expression profiles. Collectively, the results indicated that EA may alleviate MAFLD by regulating steroid hormone metabolism and modulating the gut microbiota. EA may be a candidate feed additive to prevent abdominal fat deposition and MAFLD in the broiler industry.

Nonalcoholic fatty liver disease (NAFLD) manifests as chronic hepatic steatosis, occurring variably across people due to racial and genetic diversity. It represents a stage in the development of chronic liver disease, marked by fat accumulation, inflammatory responses, oxidative stress in the endoplasmic reticulum, and fibrosis as primary concerns. Understanding its underlying mechanisms remains a challenging and pivotal area of study. In the past, acute liver injury-related diseases were commonly treated with methods such as liver transplantation. However, the emergence of artificial liver has shifted focus to stem cell therapies. Unlike conventional drugs, stem cell therapies are continuously evolving. Despite being classified as drugs, stem cells demonstrated significant efficacy after multiple injections. Mesenchymal stem cells, unlike other types of stem cells, do not have the risk of tumor formation and low immunogenicity, reducing the hypersensitivity reactions associated with liver transplantation. Increasingly, studies suggest that mesenchymal stem cells hold promise in the treatment of chronic liver injury diseases. This review focuses on investigating the role of mesenchymal stem cells in chronic metabolic liver diseases, such as non-alcoholic fatty liver disease, and delves into their specific functions.

Queen bee larvae (QBL) have been consumed as both a traditional food and medicine in China for thousands of years; however, their specific benefits for human health, particularly their potential anti-obesity property, remain underexplored. This study investigated the anti-obesity effect of QBL freeze-dried powder (QBLF) on high-fat diet (HFD) induced obesity in mice and explored the underlying mechanisms. Our findings showed that QBLF effectively reduced body weight, fasting blood glucose levels, lipid accumulation, and inflammation in HFD mice. 16S rRNA sequencing revealed that QBLF significantly modulated the gut microbiota disrupted by an HFD, notably increasing the relative abundance of beneficial microbes such as Ileibacterium, Clostridium sensu stricto 1, Incertae sedis, Streptococcus, Lactococcus, Clostridia UCG-014, and Lachnospiraceae UCG-006, which were inversely associated with obesity-related phenotypes in the mice. RNA sequencing analysis further demonstrated that QBLF intervention upregulated the expression of genes involved in liver lipid metabolism, including Pck1, Cyp4a10, Cyp4a14, and G6pc, while downregulating genes associated with the inflammatory response, such as Cxcl10, Ccl2, Traf1, Mapk15, Lcn2, and Fosb. These results suggested that QBLF can ameliorate HFD-induced obesity through regulating the gut microbiota, promoting liver lipid metabolism, and reducing inflammatory response.

Yi Mai granule (YMG) is a traditional Chinese medicine (TCM) herbal decoction consisting of two TCM formulas: Gua-Lou-Ban-Xia decoction and Si-Jun-Zi decoction. YMG has shown clinical benefit in the treatment of nonalcoholic fatty liver disease (NAFLD), which may be due to its regulatory effects on lipid metabolism. Previous studies have highlighted the importance of the gut microbiota and its metabolites in the use of TCM. However, the effect of YMG on the gut microbiota in the treatment of NAFLD remains unclear. In this study, we established an NAFLD model in ApoE-/- mice and treated them with YMG. High-performance liquid chromatography was adopted to identify the chemical components of YMG. By mapping the candidate targets using network pharmacology, we found that the targets of the main components of YMG were significantly enriched in NAFLD-related pathways. Moreover, 16S rRNA gene sequencing revealed that YMG affected the constitution and metabolism of the gut microbiota in NAFLD model mice, including lipid and carbohydrate metabolism. Similarly, metabolites related to lipid and carbohydrate metabolism in mouse serum were significantly altered by YMG. The correlation heat map and network analyses showed that the gut microbiota and metabolites affected by YMG were closely related to the blood lipid content. Collectively, YMG may exert therapeutic effects by affecting the metabolism of gut microbiota, thus regulating lipid and carbohydrate metabolism. These findings offer novel insight into the pharmacological mechanism of YMG in the treatment of NAFLD and provide theoretical bases for its clinical applications.

Lactobacillus johnsonii is a microbial biomarker associated with lipid deposition, but the mechanism by which it accelerates fatty acid absorption and deposition remains unclear. In this study, we isolated a strain of L. johnsonii MS0621 from the feces of Ningxiang pigs, an obese animal model, and evaluated its probiotic properties with high resistance to temperature and intestinal fluids. Colonization by L. johnsonii MS0621 increased the abundance of gut Lactobacillus in lean DLY pigs, concomitant with increases in fatty acid absorption in the intestine and lipid depositions in the fat and muscle tissues. The lipid absorption-promoting effect was further detected in IPEC-J2 cells treated with live L. johnsonii MS0621 and the bacteria-free supernatants, as evidenced by high triglyceride synthesis and the expression of CD36, a key lipid transporter. Metabolomics analysis showed that (R)-leucic acid is a potential metabolite targeting CD36 expression to guarantee lipid absorption and deposition. The mechanism might involve direct interaction with CD36, as molecular docking and inhibition of CD36 blocked L. johnsonii MS0621 or derived metabolite-mediated lipid absorption. In conclusion, we uncovered an important role of L. johnsonii MS0621 derived (R)-leucic acid in regulating the absorption and deposition of intestinal fatty acids via regulation of CD36 expression.

Inflammatory bowel disease (IBD) compromises the intestinal barrier and disrupts gut microbiota, impacting liver function via the gut-liver axis, which in turn influences the intestinal microbiota through lipid metabolites exacerbating IBD. This study introduced a probiotic-based treatment using Lactobacillus acidophilus encapsulated in tungsten ion-loaded mesoporous polydopamine (LA@WMPDA) to ameliorate colitis and balance enterohepatic homeostasis. After oral administration, the encapsulation could protect Lactobacillus acidophilus, scavenge reactive oxygen/nitrogen species, and the released tungsten ions would inhibit abnormal Enterobacteriaceae growth during colitis, consequently restoring the intestinal barrier and regulating the gut microbiota. Nontargeted metabolomics and transcriptomics analyses showed increased short-chain fatty acids and indole derivatives, and decreased hepatic lipid metabolism. Pathways associated with immune response, cell migration and death, and response to bacterium showed significant down-regulation in the colon and liver transcriptome analysis. Thus, this study provided a pioneered paradigm for IBD treatment and highlighted the regulation of liver-related metabolic functions via the gut-liver axis.

Herbal medicine has become an area of growing global scientific interest. The prime objective of this study was to investigate the protective role of Edgeworthia gardneri (Wall.) Meisn (EGM polysaccharide) against carbon tetrachloride (CCl4)-induced liver injury in mice. Forty-five ICR mice were randomly divided into three groups (n = 15): IC, IM, and IT. The IT group received EGM polysaccharide solution (50 mg/kg) daily, while the IC and IM groups were administered an equivalent volume of normal saline. The IT and IM groups were intraperitoneally injected with a mixture of CCl4 and olive oil at 1:1 (v/v) (2 mL/kg) every 3 days. Our results showed that EGM polysaccharide significantly (p < 0.05) reduced pathological hepatic alterations and an increased liver index caused by CCl4. Moreover, EGM polysaccharide therapy significantly (p < 0.001) increased levels of antioxidant enzymes, such as glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), and total antioxidant capacity (T-AOC) and reduced malondialdehyde (MDA) content in a dose-dependent manner. Notably, EGM polysaccharide alleviated the inflammatory cascades as evidenced by decreased serum levels of interleukin-6 (IL-6), interleukin-1β (IL-1β), and tumor necrosis factor- α (TNF-α) under CCl4 administration. Furthermore, 16 s rRNA gene sequencing results exhibited that EGM polysaccharide increased the abundance of probiotics bacteria, such as Unclassified_Lachnospiraceae, and decreased the abundance of pathogenic bacterial texas like Brevundimonas and Candidatus_Nitrocosmicu. Conclusively, EGM polysaccharide protects against CCl4-induced oxidative stress and inflammation in the liver and alleviates hepatic injury through beneficial gut microbiota modulations. The current study suggests that EGM polysaccharide is an effective agent in counteracting CCl4-induced hepatic damage.

The duodenum plays a significant role in metabolic regulation, and thickened mucous membranes are associated with insulin resistance. Duodenal mucosal resurfacing (DMR), a new-style endoscopic procedure using hydrothermal energy to ablate this thickened layer, shows promise for enhancing glucose and lipid metabolism in type 2 diabetes (T2D) patients. However, the mechanisms driving these improvements remain largely unexplored.

To investigate the mechanisms by which DMR improves metabolic disorders using a rat model.

Rats with T2D underwent a revised DMR procedure via a gastric incision using a specialized catheter to abrade the duodenal mucosa. The duodenum was evaluated using histology, immunofluorescence, and western blotting. Serum assays measured glucose, lipid profiles, lipopolysaccharide, and intestinal hormones, while the gut microbiota and metabolomics profiles were analyzed through 16S rRNA gene sequencing and ultra performance liquid chromatography-mass spectrum/mass spectrum, severally.

DMR significantly improved glucose and lipid metabolic disorders in T2D rats. It increased the serum levels of cholecystokinin, gastric inhibitory peptide, and glucagon-like peptide 1, and reduced the length and depth of duodenal villi and crypts. DMR also enhanced the intestinal barrier integrity and reduced lipopolysaccharide translocation. Additionally, DMR modified the gut microbiome and metabolome, particularly affecting the Blautia genus. Correlation analysis revealed significant links between the gut microbiota, metabolites, and T2D phenotypes.

This study illustrates that DMR addresses metabolic dysfunctions in T2D through multifaceted mechanisms, highlighting the potential role of the Blautia genus on T2D pathogenesis and DMR's therapeutic impact.

Effect of liver specific oxysterol 7α-hydroxylase (CYP7B1) overexpression on the Western diet (WD)-induced metabolic dysfunction-associated steatotic liver disease (MASLD) progression was studied in mice. Among various hepatic genes impacted during MASLD development, CYP7B1 is consistently suppressed in multiple MASLD mouse models and in human MASLD cohorts. CYP7B1 enzyme suppression leads to accumulations of bioactive oxysterols such as (25R)26-hydroxycholesterol (26HC) and 25-hydroxycholesterol (25HC). We challenged liver specific CYP7B1 transgenic (CYP7B1hep.tg) overexpressing mice with ad libitum WD feeding. Unlike their WT counterparts, WD-fed CYP7B1hep.tg mice developed no significant hepatotoxicity as evidenced by liver histology, lipid quantifications, and serum biomarker analyses. Hepatic 26HC and 25HC levels were maintained at the basal levels. The comparative gene expression/lipidomic analyses between WT and CYP7B1hep.tg mice revealed that chronically accumulated 26HC initiates LXR/PPAR-mediated hepatic fatty acid uptake and lipogenesis which surpasses fatty acid metabolism and export; compromising metabolic functions. In addition, major pathways related to oxidative stress, inflammation, and immune system including retinol metabolism, arachidonic acid metabolism, and linoleic acid metabolism were significantly impacted in the WD-fed WT mice. All pathways were unaltered in CYP7B1hep.tg mice liver. Furthermore, the nucleus of WT mouse liver but not of CYP7B1hep.tg mouse liver accumulated 26HC and 25HC in response to WD. These data strongly suggested that these two oxysterols are specifically important in nuclear transcriptional regulation for the described cytotoxic pathways. In conclusion, this study represents a "proof-of-concept" that maintaining normal mitochondrial cholesterol metabolism with hepatic CYP7B1 expression prevents oxysterol-driven liver toxicity; thus attenuating MASLD progression.

The liver regenerative capacity is crucial for patients with end-stage liver disease following partial hepatectomy (PHx). The specific bacteria and mechanisms regulating liver regeneration post-PHx remain unclear. This study demonstrated dynamic changes in the abundance of Parabacteroides distasonis (P. distasonis) post-PHx, correlating with hepatocyte proliferation. Treatment with live P. distasonis significantly promoted hepatocyte proliferation and liver regeneration after PHx. Targeted metabolomics revealed a significant positive correlation between P. distasonis and β-hydroxybutyric acid (BHB), as well as hyodeoxycholic acid and 3-hydroxyphenylacetic acid in the gut after PHx. Notably, treatment with BHB, but not hyodeoxycholic acid or 3-hydroxyphenylacetic acid, significantly promoted hepatocyte proliferation and liver regeneration in mice after PHx. Moreover, STAT3 inhibitor Stattic attenuated the promotive effects of BHB on cell proliferation and liver regeneration both in vitro and in vivo. Mechanistically, P. distasonis upregulated the expression of fatty acid oxidation-related proteins, and increased BHB levels in the liver, and then BHB activated the STAT3 signaling pathway to promote liver regeneration. This study, for the first time, identifies the involvement of P. distasonis and its associated metabolite BHB in promoting liver regeneration after PHx, providing new insights for considering P. distasonis and BHB as potential strategies for promoting hepatic regeneration.

The prevalence of metabolic associated fatty liver disease (MAFLD) is high. However, there are few studies on the effects of time-restricted feeding (TRF) and caloric restriction (CR) in MAFLD.

To investigate the efficacy and mechanism of 4 h TRF and 60% CR in MAFLD.

Twelve male Sprague-Dawley rats were randomly assigned to the Normal group (normal diet, 10 kcal% fat), while the remaining 38 rats were assigned to the MAFLD group (high-fat diet, 60 kcal% fat). 10 weeks later, the MAFLD group was randomly divided into the 4 h TRF, 60% CR, 4 h TRF + 60% CR, and Model groups; all rats were then given normal diet. After 4 weeks, weight, blood lipid, and other indicators were detected.

After the high-fat diet was discontinued, the liver lipid levels in the rat with MAFLD significantly reduced, while the body weight was not significantly changed. The rats in the Model group were heavier than those in the other four groups (p < 0.01). The triglyceride levels were higher in the TRF + CR group compared with the Model group (p < 0.01). Compared with the Model group, 110 metabolites were decreased in the TRF + CR group, and 83 metabolites were elevated in liver. Kyoto Encyclopedia of Genes and Genomes revealed that the mechanism involved the proliferator-activated receptor alpha signaling pathway, metabolic pathway, and so on. We observed differences in silent information regulator transcript 1 (SIRT1) mRNA levels in all five groups (p = 0.003).

4 h TRF and 60% CR significantly reduced body weight and liver lipid in rats with MAFLD. 4 h TRF can improve MAFLD, and there is no need to excessively restrict food intake.

Preclinical literature and behavioral human data suggest that diet profoundly impacts the human gut microbiome and energy absorption-a key determinant of energy balance. To determine whether these associations are causal, domiciled controlled feeding studies with precise measurements of dietary intake and energy balance are needed. Metabolomics-a functional readout of microbiome modulation-can help identify putative mechanisms mediating these effects. We previously demonstrated that a high-fiber, minimally processed Microbiome Enhancer Diet (MBD) fed at energy balance decreased energy absorption and increased microbial biomass relative to a calorie-matched fiber-poor, highly processed Western Diet (WD).

To identify metabolic signatures distinguishing MBD from WD feeding and potential metabolomic mechanisms mediating the MBD-induced negative energy balance.

We deployed global metabolomics in feces, serum, and urine using samples collected at the end of a randomized crossover controlled feeding trial delivering 22 days of an MBD and a WD to 17 persons without obesity. Samples were collected while participants were domiciled on a metabolic ward and analyzed using Ultrahigh Performance Liquid Chromatography-Tandem Mass Spectroscopy. Linear mixed effects models tested metabolite changes by diet. Weighted gene network correlation analysis identified metabolite modules correlated with energy balance phenotypes.

Numerous metabolites consistently altered in the feces, fasting serum, and/or urine may serve as putative dietary biomarkers of MBD feeding. Fecal diet-microbiota co-metabolites decreased by an MBD correlated with reduced energy absorption and increased microbial biomass. An MBD shifted the urinary metabolome from sugar degradation to ketogenesis-evidence of negative energy balance.

Precisely controlled diets disparate in microbiota-accessible substrates led to distinct metabolomic signatures in feces, fasting serum, and/or urine. These diet-microbiota co-metabolites may be biomarkers of a "fed" (MBD) or "starved" (WD) gut microbiota associated with energy balance. These findings lay the foundation for unveiling causal pathways linking diet-microbiota co-metabolism to energy absorption.

Cholestatic liver fibrosis is a common pathological feature of various biliary tract diseases. The underlying pathological mechanisms are not fully understood, posing significant obstacles to the discovery of new drug targets. The aims of the current study were to evaluate protective effects of hyodeoxycholic acid (HDCA) against cholestatic liver fibrosis and to ascertain whether ETV4 is a novel anti-fibrotic target involved in the therapeutic effects of HDCA.

The therapeutic effect of HDCA was verified using bile duct ligation and Abcb4-/- mouse models. Etv4-/- mice were subjected to bile duct ligation to investigate the role of ETV4 in liver fibrogenesis and the therapeutic effects of HDCA. The N6-methyladenosine (m6A) modification was investigated using methylated m6A RNA immunoprecipitation-qPCR and immunofluorescence/fluorescence in situ hybridization techniques.

HDCA levels were decreased in both cholestatic patients and mice, while HDCA supplementation significantly ameliorated cholestatic liver fibrosis. By inducing ETV4 expression in cholangiocytes, HDCA induced MMP9 secretion, facilitating extracellular matrix degradation. Findings in patients with cholestatic fibrosis and Etv4-/- mice further revealed a promising role of ETV4 in improving liver fibrosis and in mediating the therapeutic effects of HDCA. Mechanistically, HDCA promoted m6A modification of ETV4 mRNA, which thereby promotes IGF2BP1 recognition and PABPC1 recruitment to inhibit ETV4 mRNA deadenylation, leading to increased mRNA stability, storage in P-bodies, and prolonged translation. Mutation of the m6A site on ETV4 mRNA or knockdown of critical genes involved in m6A modification significantly abolished the therapeutic effects of HDCA.

The present study underscores ETV4 as a novel anti-fibrotic target and demonstrates that HDCA remodels extracellular matrix by facilitating m6A-regulated ETV4 expression, offering potential therapeutic approaches for cholestatic liver fibrosis.

This study delves into the underlying mechanisms of cholestatic liver fibrosis and reveals potential therapeutic targets. The research highlights ETV4 as a novel anti-fibrotic target that is essential for the therapeutic effects of hyodeoxycholic acid against cholestatic liver fibrosis. These findings are important for both the scientific community and patients with cholestatic liver diseases, offering valuable insights for future therapeutic strategies that focus on regulating m6A-dependent epigenetic modifications of anti-fibrotic targets like ETV4 and developing new interventions utilizing hyodeoxycholic acid.

Metabolites derived from the intestinal microbiota, including bile acids (BA), extensively modulate vertebrate physiology, including development1, metabolism2-4, immune responses5-7 and cognitive function8. However, to what extent host responses balance the physiological effects of microbiota-derived metabolites remains unclear9,10. Here, using untargeted metabolomics of mouse tissues, we identified a family of BA-methylcysteamine (BA-MCY) conjugates that are abundant in the intestine and dependent on vanin 1 (VNN1), a pantetheinase highly expressed in intestinal tissues. This host-dependent MCY conjugation inverts BA function in the hepatobiliary system. Whereas microbiota-derived free BAs function as agonists of the farnesoid X receptor (FXR) and negatively regulate BA production, BA-MCYs act as potent antagonists of FXR and promote expression of BA biosynthesis genes in vivo. Supplementation with stable-isotope-labelled BA-MCY increased BA production in an FXR-dependent manner, and BA-MCY supplementation in a mouse model of hypercholesteraemia decreased lipid accumulation in the liver, consistent with BA-MCYs acting as intestinal FXR antagonists. The levels of BA-MCY were reduced in microbiota-deficient mice and restored by transplantation of human faecal microbiota. Dietary intervention with inulin fibre further increased levels of both free BAs and BA-MCY levels, indicating that BA-MCY production by the host is regulated by levels of microbiota-derived free BAs. We further show that diverse BA-MCYs are also present in human serum. Together, our results indicate that BA-MCY conjugation by the host balances host-dependent and microbiota-dependent metabolic pathways that regulate FXR-dependent physiology.

Cisplatin (CP), a widely used antineoplastic agent, is a leading cause of drug-induced liver injury (DILI) due to its hepatotoxic effects. Licorice (GC), an established remedy in traditional Chinese medicine (TCM), has shown promise in addressing liver diseases and DILI. Nonetheless, the specific active components and underlying mechanisms of GC in mitigating CP-induced liver injury remain inadequately investigated.

This study examined the active components and efficacy of GC in addressing CP-induced hepatotoxicity, focusing on its mechanisms related to bile acid metabolism and gut microbiota regulation.

Utilizing a CP-induced rat liver injury model, this study evaluated changes in liver coefficient, liver function indices, and pathological morphology while assessing the efficacy of GC for both prevention and treatment of CP-induced liver injury. Subsequently, UPLC-Q-TOF-MS qualitatively analyzed GC's blood-entering components, elucidating its pharmacodynamic material basis. Network pharmacology analysis identified potential pathways and targets of GC's blood components in relation to CP-induced liver injury. Furthermore, metabolomics and 16S rRNA sequencing were employed to clarify the pharmacodynamic mechanisms of GC in modulating bile acid metabolism and gut microbiota, offering insights into its preventive and therapeutic roles.

The pharmacodynamic results revealed that GC significantly reduced liver function biomarkers and improved pathological changes in liver tissue. UPLC-Q-TOF-MS analysis identified 16 blood-entering components as potential pharmacodynamic agents of GC for preventing and treating CP-induced liver injury. Network pharmacology analysis suggested a link between GC's efficacy and the bile acid metabolic pathway. Furthermore, metabolomics analysis, immunoblotting, and 16S rRNA sequencing demonstrated that GC regulated bile acid metabolites in both liver and feces, enhanced FXR and BSEP expressions in the liver, and decreased CYP27A1 expression. Additionally, GC mitigated CP-induced intestinal dysbiosis by altering the abundance of gut microbiota.

UPLC-Q-TOF-MS performed a qualitative analysis of 16 blood-entering components linked to GC, providing a basis for further exploration of the pharmacodynamic material underpinning GC. The protective role of GC in CP-induced liver injury appears connected to enhanced bile acid metabolism and restoration of gut microbiota balance.

Non-alcoholic fatty liver disease (NAFLD) is a multisystem metabolic disorder, marked by abnormal lipid accumulation and intricate inter-organ interactions, which contribute to systemic metabolic imbalances. NAFLD may progress through several stages, including simple steatosis (NAFL), non-alcoholic steatohepatitis (NASH), cirrhosis, and potentially liver cancer. This disease is closely associated with metabolic disorders driven by overnutrition, with key pathological processes including lipid dysregulation, impaired lipid autophagy, mitochondrial dysfunction, endoplasmic reticulum (ER) stress, and local inflammation. While hepatic lipid metabolism in NAFLD is well-documented, further research into inter-organ communication mechanisms is crucial for a deeper understanding of NAFLD progression. This review delves into intrahepatic networks and tissue-specific signaling mediators involved in NAFLD pathogenesis, emphasizing their impact on distal organs.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a common multi-factorial liver disease, and its incidence is gradually increasing worldwide. Many reports have revealed that intestinal flora plays a crucial role for the occurrence and development of MASLD, through mechanisms such as flora translocation, endogenous ethanol production, dysregulation of choline metabolism and bile acid, and endotoxemia. Here, we review the relationship between intestinal flora and MASLD, as well as interventions for MASLD, such as prebiotics, probiotics, synbiotics, and intestinal flora transplantation. Intervention strategies targeting the intestinal flora along with its metabolites may be new targets for preventing and treating MASLD.

The high morbidity and mortality rates of colorectal cancer (CRC) have been a public health concern globally, and the search for additional therapeutic options is imminent. Hyodeoxycholic acid (HDCA) has been receiving attention in recent years and has demonstrated potent efficacy in several diseases. Nonetheless, the antitumor effects and molecular pathways of HDCA in CRC remain largely unexplored.

In this study, we investigated how HDCA influences the growth potential of CRC cells using techniques such as flow cytometry, Edu assay, CCK-8, colony formation assay, Western blot analysis, and animal experiments.

It was found that HDCA treatment of CRC cells was able to significantly inhibit the proliferative capacity of the cells. Furthermore, it was discovered that HDCA primarily stimulated Farnesoid X Receptor (FXR) rather than Takeda G protein coupled receptor 5 (TGR5) to suppress CRC growth. It was also confirmed that HDCA inhibited the Epiregulin (EREG)/Epidermal Growth Factor Receptor (EGFR) pathway by activating FXR, and a negative correlation between FXR and EREG was analyzed in CRC tissue samples. Finally, in vivo animal studies confirmed that HDCA inhibited CRC proliferation without hepatotoxicity.

Our findings indicate that HDCA suppresses the EREG/EGFR signaling route by activating FXR, thereby hindering the growth of CRC cells and demonstrating a tumor-inhibiting effect in CRC. This study may provide a new therapeutic strategy to improve the prognosis of CRC.

Metabolites produced as intermediaries or end-products of microbial metabolism provide crucial signals for health and diseases, such as metabolic dysfunction-associated steatotic liver disease (MASLD). These metabolites include products of the bacterial metabolism of dietary substrates, modification of host molecules (such as bile acids [BAs], trimethylamine-N-oxide, and short-chain fatty acids), or products directly derived from bacteria. Recent studies have provided new insights into the association between MASLD and the risk of developing chronic kidney disease (CKD). Furthermore, alterations in microbiota composition and metabolite profiles, notably altered BAs, have been described in studies investigating the association between MASLD and the risk of CKD. This narrative review discusses alterations of specific classes of metabolites, BAs, fructose, vitamin D, and microbiota composition that may be implicated in the link between MASLD and CKD.

Although diabetes is now a global epidemic, China has the highest number of affected people, presenting profound public health and socioeconomic challenges. In China, rapid ecological and lifestyle shifts have dramatically altered diabetes epidemiology and risk factors. In this Review, we summarize the epidemiological trends and the impact of traditional and emerging risk factors on Chinese diabetes prevalence. We also explore recent genetic, metagenomic and metabolomic studies of diabetes in Chinese, highlighting their role in pathogenesis and clinical management. Although heterogeneity across these multidimensional areas poses major analytic challenges in classifying patterns or features, they have also provided an opportunity to increase the accuracy and specificity of diagnosis for personalized treatment and prevention. National strategies and ongoing research are essential for improving diabetes detection, prevention and control, and for personalizing care to alleviate societal impacts and maintain quality of life.

Incidence of a number of liver diseases has increased. Gut microbiota serves a role in the pathogenesis of hepatitis, cirrhosis and liver cancer. Gut microbiota is considered 'a new virtual metabolic organ'. The interaction between the gut microbiota and liver is termed the gut‑liver axis. The gut‑liver axis provides a novel research direction for mechanism of liver disease development. The present review discusses the role of the gut‑liver axis and how this can be targeted by novel treatments for common liver diseases.

The objective of this study is to investigate the ability of Ramulus Mori (Sangzhi) alkaloid tablets (SZ-A) to ameliorate obesity and lipid metabolism disorders in rats subjected to a high-fat diet (HFD) through metagenomics, untargeted lipidomics, targeted metabolism of bile acid (BA), and BA pathways, providing a novel perspective on the management of metabolic disorders.

In this research, HFD-fed rats were concurrently administered SZ-A orally. We measured changes in body weight (BW), blood lipid profiles, and liver function to assess therapeutic effects. Liver lipid status was visualized through H&E and Oil Red O. Gut microbiota composition was elucidated using metagenomics. The LC-MS-targeted metabolomics approach was utilized to define the fecal BA profiles. Furthermore, the lipid metabolomics of adipose tissue samples was investigated using an LC-MS analysis platform. The expression levels of the BA receptor were determined by western blotting. Additionally, serum insulin (INS), glucagon-like peptide-1 (GLP-1), and inflammatory cytokines were quantified using an ELISA kit. The integrity of the colonic epithelial barrier was assessed using immunofluorescence.

SZ-A notably decreased BW and blood lipid levels in obese rats while also alleviating liver injury. Additionally, SZ-A reduced the serum levels of leptin (LEP), INS, and GLP-1, indicating its potential to modulate key metabolic hormones. Most notably, SZ-A substantially improved gut microbiota composition. Specifically, it reshaped the gut microbiota structure in HFD-fed rats by increasing the relative abundance of beneficial bacteria, such as Bacteroides, while decreasing the populations of potentially harmful bacteria, such as Dorea and Blautia. At the BA level, SZ-A decreased the levels of harmful BAs, including hyodeoxycholic acid (HDCA), deoxycholic acid (DCA), 12-keto lithocholic acid (12-KLCA), lithocholic acid (LCA), and muricholic acid (MDCA). Between the model group and SZ-A, 258 differentially abundant metabolites were detected, with 72 upregulated and 186 downregulated. Furthermore, these BAs are implicated in the activation of the FXR-FGF15 and TGR5-GLP-1 pathways in the intestine. This activation helps to alleviate HFD-fed intestinal inflammation and restore intestinal barrier damage by modulating inflammatory cytokines and bolstering the intestinal barrier's capabilities.

Our findings indicate that SZ-A effectively modulates BW, serum lipid profiles, and liver function in HFD-fed rats. Moreover, SZ-A exerts a positive influence on inflammatory cytokines, thereby mitigating inflammation and promoting the restoration of the intestinal barrier. Significantly, our research indicates that adjusting the gut microbiome and BA levels could serve as an effective approach for both preventing and treating obesity and related metabolic dyslipidemia.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a major public health threat globally. Management of patients afflicted with MASLD and research in this domain are limited by the lack of robust well-established non-invasive biomarkers for diagnosis, prognostication, and monitoring. The circulating metabolome reflects both the systemic metabo-inflammatory milieu and changes in the liver in affected individuals. In this review we summarize the available literature on changes in the different components of the metabolome in MASLD with a focus on changes that are linked to the presence of underlying steatohepatitis, severity of disease activity, and fibrosis stage. We further summarize the existing literature around biomarker panels that are derived from interrogation of the metabolome. Their relevance to disease biology and utility in practice are also discussed. We further highlight potential direction for future studies particularly to ensure they are fit for purpose and suitable for widespread use.

Metabolic dysfunction-associated steatotic liver disease (MASLD) represents a global health concern, affecting over 30 % of adults. It is a principal driver in the development of cirrhosis and hepatocellular carcinoma. The complex pathogenesis of MASLD involves an excessive accumulation of lipids, subsequently disrupting lipid metabolism and prompting inflammation within the liver. This review synthesizes the recent research progress in understanding the mechanisms contributing to MASLD progression, with particular emphasis on metabolic disorders and interorgan crosstalk. We highlight the molecular mechanisms linked to these factors and explore their potential as novel targets for pharmacological intervention. The insights gleaned from this article have important implications for both the prevention and therapeutic management of MASLD.