The gut microbiome is altered after bariatric surgery and is associated with weight loss. However, the commensal bacteria involved and the underlying mechanism remain to be determined. We performed shotgun metagenomic sequencing in obese subjects before and longitudinally after sleeve gastrectomy (SG), and found a significant enrichment in microbial species in Clostridia and bile acid metabolizing genes after SG treatment. Bile acid profiling further revealed decreased primary bile acids (PBAs) and increased conjugated secondary bile acids (C-SBAs) after SG. Specifically, glycodeoxycholic acid (GDCA) and taurodeoxycholic acid (TDCA) were increased at different follow-ups after SG, and were associated with the increased abundance of Clostridia and body weight reduction. Fecal microbiome transplantation with post-SG feces increased SBA levels, and alleviated body weight gain in the recipient mice. Furthermore, both Clostridia-enriched spore-forming bacteria and GDCA supplementation increased the expression of genes responsible for lipolysis and fatty acid oxidation in adipose tissue and reduced adiposity via Takeda G-protein-coupled receptor 5 (TGR5) signaling. Our findings reveal post-SG gut microbiome and C-SBAs as contributory to SG-induced weight loss, in part via TGR5 signaling, and suggest SBA-producing gut microbes as a potential therapeutic target for obesity intervention.

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.

The gut microbiota is closely associated with the onset and development of type 2 diabetes mellitus (T2DM), characterized by insulin resistance (IR) and chronic low-grade inflammation. However, despite the widespread use of first-line antidiabetic drugs, IR in diabetes and its complications continue to rise. The gut microbiota and its metabolic products may promote the development of T2DM by exacerbating IR. Therefore, regulating the gut microbiota has become a promising therapeutic strategy, with particular attention given to probiotics, prebiotics, synbiotics, and fecal microbiota transplantation. This review first examines the relationship between gut microbiota and IR in T2DM, summarizing the research progress of microbiota-based therapies in modulating IR. We then delve into how gut microbiota-related metabolic products contribute to IR. Finally, we summarize the research findings on the role of traditional Chinese medicine in regulating the gut microbiota and its metabolic products to improve IR. In conclusion, the gut microbiota and its metabolic products play a crucial role in the pathophysiological process of T2DM by modulating IR, offering new insights into potential therapeutic strategies for T2DM.

Obesity is a major global public health challenge, affecting billions and serving as a primary risk factor for many chronic diseases. Certain probiotics have shown promise in regulating energy balance and enhancing fat metabolism, offering potential strategies for managing obesity. In this study, we evaluated three strains of Bifidobacterium adolescentis and identified B. adolescentis FJSSZ23M10 as the most effective in alleviating high-fat diet (HFD)-induced obesity. This strain significantly reduced weight gain, improved abnormal serum biochemical indicators, decreased lipid accumulation in adipocytes, and enhanced energy expenditure. Furthermore, B. adolescentis FJSSZ23M10 treatment modulated the gut microbiota, notably increasing the abundance of Bifidobacterium and Faecalibaculum. Untargeted metabolomic analysis revealed that B. adolescentis FJSSZ23M10 uniquely upregulated beneficial metabolites, such as butyrate and pyruvic acid, suggesting its superior metabolic impact. Genomic analysis indicated that B. adolescentis FJSSZ23M10 harbored the highest abundance of unassigned genes and carbohydrate-active enzymes (CAZymes) compared to the other strains, highlighting its superior functional potential. Combining the shared and unique modifications in gut microbiota, metabolites, and genomic annotations, the study highlights that genomic differences among probiotics could shape their effects on gut microbiota and metabolites. Conclusively, the study underscores the critical role of probiotic genomic characteristics in determining their functional efficacy and suggests that the intake of the B. adolescentis FJSSZ23M10 strain with enriched genomic features, such as CAZymes, could represent a novel genomic-based strategy for alleviating obesity through gut microbiota modulation and metabolic regulation.

Time-restricted feeding (TRF) is a lifestyle intervention that aims to maintain a consistent daily cycle of feeding and fasting to support robust circadian rhythms. Recently, it has gained scientific, medical, and public attention due to its potential to enhance body composition, extend lifespan, and improve overall health, as well as induce autophagy and alleviate symptoms of diseases like cardiovascular diseases, type 2 diabetes, neurodegenerative diseases, cancer, and ischemic injury. However, there is still considerable debate on the primary factors that contribute to the health benefits of TRF. Despite not imposing strict limitations on calorie intake, TRF consistently led to reductions in calorie intake. Therefore, while some studies suggest that the health benefits of TRF are primarily due to caloric restriction (CR), others argue that the key advantages of TRF arise not only from CR but also from factors like the duration of fasting, the timing of the feeding period, and alignment with circadian rhythms. To elucidate the roles and mechanisms of TRF beyond CR, this review incorporates TRF studies that did not use CR, as well as TRF studies with equivalent energy intake to CR, which addresses the previous lack of comprehensive research on TRF without CR and provides a framework for future research directions.

FXR, encoded by Nh1r4, is a nuclear receptor crucial in regulating bile acid, lipid, and glucose metabolism. Prior research has indicated that activating FXR in the liver and small intestine may offer protection against obesity and metabolic diseases. This study demonstrates the essential role of the FXR-ApoC2 pathway in promoting the browning of white adipose tissue (WAT). Increased FXR by treatment with the FXR agonist farnesol upregulated beige adipocyte markers, including UCP1, PGC1α, and PRDM16, and increased the FXR target gene, ApoC2, in beige adipocytes and cold-exposed mice. However, these effects were not observed in mature white adipocytes. Remarkably, the knockdown of FXR results in a significantly reduced expression of UCP1, PGC1α, PRDM16, and ApoC2 in beige adipocytes. While studying the interaction between the nuclear receptor RXRα and FXR in transcription regulation, it was found that the knockdown of RXRα did not control the expression of FXR under beige adipogenesis. We further investigated whether the expression of beige-related markers could be altered under ApoC2 overexpression to ascertain the mechanism of action of FXR in relation to ApoC2 regulation. The overexpression of ApoC2 in both preadipocytes and beige adipocytes led to a significant increase in the expression of UCP1 and PGC1α. These results indicate that the FXR-mediated ApoC2 pathway is essential in the browning of WAT by inducing beige adipogenesis from preadipocytes.

Inflammatory bowel disease (IBD) is a global disease with limited therapy. It is reported that sedanolide exerts anti-oxidative and anti-inflammatory effects as a natural phthalide, but its effects on IBD remain unclear.

In this study, we investigated the impacts of sedanolide on dextran sodium sulfate (DSS)-induced colitis in mice.

The mice were administered sedanolide or vehicle followed by DSS administration, after which colitis symptoms, inflammation levels, and intestinal barrier function were evaluated. Transcriptome analysis, 16S rRNA sequencing, and targeted metabolomics analysis of bile acids and lipids were performed.

Sedanolide protected mice from DSS-induced colitis, suppressed the inflammation, restored the weakened epithelial barrier, and modified the gut microbiota by decreasing bile salt hydrolase (BSH)-expressing bacteria. The downregulation of BSH activity by sedanolide increased the ratio of conjugated/unconjugated bile acids (BAs), thereby inhibiting the intestinal farnesoid X receptor (FXR) pathway. The roles of the FXR pathway and gut microbiota were verified using an intestinal FXR-specific agonist (fexaramine) and germ-free mice, respectively. Furthermore, we identified the key effector ceramide, which is regulated by sphingomyelin phosphodiesterase 3 (SMPD3). The protective effects of ceramide (d18:1/16:0) against inflammation and the gut barrier were demonstrated in vitro using the human cell line Caco-2.

Sedanolide could reshape the intestinal flora and influence BA composition, thus inhibiting the FXR-SMPD3 pathway to stimulate the synthesis of ceramide, which ultimately alleviated DSS-induced colitis in mice. Overall, our research revealed the protective effects of sedanolide against DSS-induced colitis in mice, which indicated that sedanolide may be a clinical treatment for colitis. Additionally, the key lipid ceramide (d18:1/16:0) was shown to mediate the protective effects of sedanolide, providing new insight into the associations between colitis and lipid metabolites.

Chronic diseases such as obesity, hypertension, and metabolic syndrome are major health concerns worldwide. Ursodeoxycholic acid (UDCA) is a bile acid that is naturally produced in the liver and has been used for the treatment of various liver disorders. In this systematic review and meta-analysis, we investigated how UDCA might affect inflammation, blood pressure, and obesity.

Five major databases were searched from inception to August 2024. The investigated outcomes included body mass index (BMI), systolic blood pressure (SBP), diastolic blood pressure (DBP), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α). A random effect was carried out to estimate pooled weighted mean difference (WMD) with 95% confidence intervals (CI). The registration code is CRD42023428064.

Of the 7912 articles in the initial search, 12 were included in the systematic review and meta-analysis. UDCA consumption significantly decreased BMI (WMD: -0.29 kg/m2, 95% CI: -0.58, -0.01, P = 0.044), and DBP (WMD: -2.16 mmHg, 95% CI: -3.66, -0.66, P = 0.005). It also increased SBP (WMD: 5.50 mmHg, 95% CI: 3.65, 7.35, P < 0.001); however, it was not associated with weight loss (WMD: -0.3 kg, 95% CI: -1.3, 0.71, P = 0.561). Our systematic review showed that UDCA consumption has no effect on IL-6 and TNF-α.

This systematic review and meta-analysis suggest that UDCA supplementation may improve BMI and DBP, whereas it may increase SBP and have no effect on weight or inflammation. Further long-term and well-designed RCTs are needed to further assess and confirm these results.

Hyperlipidemia is a lipid metabolism disorder that, in severe cases, can lead to conditions such as hypertension, coronary heart disease, and cirrhosis. Previous studies have identified Ilicis Rotundae Cortex (IRC) crude extract as having the potential to regulate blood lipids. However, whether the triterpenoids therein are the principal agents responsible for hypolipidemic effects and their specific mechanisms of action remain unexplored. This study aimed to investigate the effects of total triterpenoids (TT) extract derived from IRC on hyperlipidemia and to elucidate their potential mechanisms.

TT extract was first prepared and characterized to assess their hypolipidemic activity in cell models. A hyperlipidemia mouse model was established by using C57BL/6 J mice fed a high-fat, high-sugar, and high-cholesterol diet for 8 weeks. TT extract was administered as a prophylactic intervention for 4 weeks to evaluate its impact on blood lipid levels, liver lipid metabolism, and liver function. Based on progressive analysis, this study integrated serum non-targeted metabolomics analysis strategy and bile acids-targeted metabolomics analysis strategy. It was combined with modern molecular biology techniques to reveal the mechanism by which TT extract ameliorated the symptoms of hyperlipidemia through a cascade approach.

TT extract treatment significantly reduced lipid levels in hyperlipidemic mice. Notably, TT extract down-regulated bile acid levels, particularly bile acids as FXR antagonists such as T-β-MCA, β-MCA, TUDCA, and UDCA. This effect is likely mediated through alterations in the hepatic FXR-SHP and ileal FXR-FGF15 signaling pathways. TT extract administration led to decreased expression of CYP7A1 and CYP7B1, resulting in reduced bile acid levels in vivo. Additionally, FXR expression was upregulated in both the liver and ileum, potentially activating FGF15 in the ileum, which in turn transmits signals to the liver and modulates SHP and BSEP expression. These changes contribute to the regulation of bile acid synthesis, metabolism, and excretion. In vitro experiments also demonstrated that TT extract influenced the protein expression of FXR and FGF19.

Our findings demonstrate that TT extract from IRC has hypolipidemic effects. This study is the first to reveal the mechanism by which TT extract improves hyperlipidemia from the perspective of the hepatic-intestinal axis and bile acid metabolism. Its underlying mechanism is related to activating the intestinal FXR-FGF15/19 signaling pathway, which transmits signals to the liver, thereby affecting the hepatic FXR-SHP signaling pathway. This results in improved bile acid metabolism, ultimately reducing hepatic injury and ileal inflammation to exert hypolipidemic effects.

The transition in terminology from fatty liver disease to metabolic dysfunction-associated steatotic liver disease (MASLD) marks a considerable evolution in diagnostic standards. This new definition focuses on liver fat accumulation in the context of overweight/obesity, type 2 diabetes, or metabolic dysfunction, without requiring the exclusion of other concurrent liver diseases. The new definition also provides clear guidelines for defining alcohol consumption in relation to the disease. MASLD is currently acknowledged as the most widespread liver disorder globally, affecting ~25% of the population. Despite the extensive array of clinical trials conducted in recent years, the number of approved treatments for metabolic dysfunction-associated fatty liver disease is very limited. In the review critically evaluates the results of clinical trials of related drugs and assesses the future directions for drug development trials. The renaming of MASLD presents new challenges and opportunities for the design of clinical trials and the selection of target populations for drug development.

A high-fat diet (HFD) is often associated with hepatic lipid metabolism disorders, leading to dysfunction in multiple body systems. Ginsenosides derived from Panax ginseng have been reported to possess potential effects in ameliorating lipid metabolism disorders; however, their underlying mechanisms remain insufficiently explored. This study aims to investigate the bioactivities of ginsenosides in combating lipid metabolism disorders and obesity, with a focus on their mechanisms involving the cholesterol metabolism signaling pathway and gut microbiota. Our results demonstrated that ginsenoside treatment significantly reduced overall body weight, body weight changes, liver weight, and eWAT weight, as well as alleviated hepatic steatosis and dyslipidemia in HFD-fed rats, without affecting food intake. These effects were dose-dependent. Furthermore, 16S rRNA sequencing revealed that ginsenosides significantly increased the relative abundance of Akkermansia muciniphila, Blautia, Eisenbergiella, Clostridium clusters XI, XVIII, and III, while decreasing the relative abundance of Clostridium subcluster XIVa and Dorea. In addition, ginsenoside treatment significantly regulated the expression of hepatic genes and proteins involved in the cholesterol metabolism signaling pathway (FXR, CYP7A1, CYP7B1, CYP27A1, ABCG5, ABCG8, Insig2, and Dhcr7), potentially inhibiting hepatic cholesterol biosynthesis while promoting cholesterol transport to HDL and its excretion via bile and feces. Notably, levels of 7-dehydrocholesterol (7-DHC) and 27-hydroxycholesterol (27-OHC) were reduced, while 5β,6β-epoxycholesterol (5,6β-epoxy) levels were elevated following ginsenoside treatment, indicating significant modulation of oxysterols by ginsenosides. Moreover, bile acid enterohepatic circulation was regulated through the enhancement of hepatic FXR-CYP7A1 signaling and intestinal FXR-FGF15 signaling in HFD-fed rats treated with ginsenosides, which was closely linked to gut microbiota composition. Collectively, our findings suggest that ginsenosides alleviate hepatic lipid metabolism disorders by modulating gut microbiota and the cholesterol metabolism signaling pathway in HFD-fed rats.

Obesity and its associated intestinal inflammatory responses represent a significant global challenge. (IF) is a dietary intervention demonstrating various health benefits, including weight loss, enhanced metabolic health, and increased longevity. However, its effect on the intestinal inflammation induced by high-fat diet (HFD) is still not fully comprehended. Thirty-four male Sprague-Dawley rats were randomized into three groups: Control (fed standard chow diet for 24 weeks); the HFD group (fed HFD for 24 weeks); and the HFD + IF group (fed HFD for 12 weeks, followed by an alternate day regimen of fasting and HFD for 12 weeks). The results revealed that IF significantly reduced body weight, food intake, and blood glucose levels compared to the HFD group. Furthermore, rats undergoing the intermittent fasting regimen exhibited a significant reduction in resting time, along with increased durations of grooming and exploration when compared to those on HFD. IF significantly reduced HFD-induced intestinal oxidative stress by lowering malondialdehyde levels and substantially increasing intestinal total antioxidant capacity, consistent with histopathological findings of gastric and intestinal tissues. The investigation of the underlying mechanisms revealed that IF significantly increased the intestinal expression of Farnesoid X receptor (FXR), glucagon-like peptide 1 (GLP-1), and melanocortin-4 receptors (MC4R), with a significant decrease in gastrointestinal peroxisome proliferator-activated receptor-γ (PPAR-γ) compared to the HFD group. The findings indicate that IF can mitigate HFD-induced intestinal inflammation via the FXR/GLP-1/MC4R/ PPAR-γ pathway. This highlights the need for further research to elucidate these mechanisms.

Inflammatory bowel disease (IBD) is a chronic condition affecting the gastrointestinal tract, primarily manifesting as ulcerative colitis (UC) or Crohn's disease (CD). Both inflammation and disruption of the intestinal epithelial barrier are key factors in IBD pathogenesis. Substantial evidence has revealed a significant association between aberrant immune responses and impairment of the intestinal epithelial barrier in IBD pathogenesis. The components of the intestinal epithelium, particularly goblet cells and Paneth cells, are crucial to gut homeostasis, as they secrete mucin, antimicrobial peptides (AMPs), and cytokines. Furthermore, impairment of epithelial integrity, which is regulated by tight junctions, is a hallmark of IBD pathology. While common treatments for IBD, such as anti-inflammatory drugs, target various signaling pathways with varying efficacies, therapeutic approaches focused on mucosal and epithelial barrier healing have been largely neglected. Moreover, high costs, side effects, and insufficient or inconsistent therapeutic outcomes remain major drawbacks of conventional anti-IBD drugs. Recent studies on epithelial barrier regeneration and permeability reduction have introduced promising therapeutic targets, including farnesoid X receptor (FXR), urokinase-type plasminogen activator (uPA)-urokinase-type plasminogen activator receptor (uPAR) interaction, fecal microbiota transplantation (FMT), and insulin receptor (INSR). Notably, the simultaneous targeting of intestinal inflammation and promotion of epithelial barrier healing shows promise for efficient IBD treatment. Future research should explore targeted therapies and combination treatments, including natural remedies, microbiota colonization, stem cell approaches, and computer-aided drug design. It is also crucial to focus on accurate prognosis and developing a thorough understanding of IBD development mechanisms.

Hepatocellular carcinoma (HCC) is a relevant complication occurring in individuals with advanced Metabolic dysfunction-Associated Steatotic Liver Disease (MASLD). Recent epidemiological data suggest an alarming increase in the HCC burden worldwide, with a relevant proportion attributable to MASLD (up to 38 %), either in cirrhotic or non-cirrhotic livers. In view of the changing landscape of metabolic syndrome as "silent pandemic", this narrative review aims to provide an updated picture of the burden of HCC in individuals with MASLD. In the complex pathophysiological pathways linking insulin resistance to MASLD and cardiometabolic syndrome, metabolic inflammation appears a relevant driver of systemic as well as organ-specific complications. Novel insights from the field of immunology, gut-derived liver damage, and association with extra-hepatic cancers will be discussed. Finally, strategies for risk-based HCC surveillance (circulating biomarkers, prognostic models and polygenic risk scores) will be provided and the potential impact of novel drug targeting fibrosing Metabolic dysfunction-Associated Steatohepatitis (MASH) on incident HCC will be discussed.

High sugar, high-fat diets and unhealthy lifestyles have led to an epidemic of obesity and obesity-related metabolic diseases, seriously placing a huge burden on socio-economic development. A deeper understanding and elucidation of the specific molecular biological mechanisms underlying the onset and development of obesity has become a key to the treatment of metabolic diseases. Recent studies have shown that the changes of bile acid composition are closely linked to the development of metabolic diseases. Bile acids can not only emulsify lipids in the intestine and promote lipid absorption, but also act as signaling molecules that play an indispensable role in regulating bile acid homeostasis, energy expenditure, glucose and lipid metabolism, immunity. Disorders of bile acid metabolism are therefore important risk factors for metabolic diseases. The farnesol X receptor, a member of the nuclear receptor family, is abundantly expressed in liver and intestinal tissues. Bile acids act as endogenous ligands for the farnesol X receptor, and erroneous FXR signaling triggered by bile acid dysregulation contributes to metabolic diseases, including obesity, non-alcoholic fatty liver disease and diabetes. Activation of FXR signaling can reduce lipogenesis and inhibit gluconeogenesis to alleviate metabolic diseases. It has been found that intestinal FXR can regulate hepatic FXR in an organ-wide manner. The crosstalk between intestinal FXR and hepatic FXR provides a new idea for the treatment of metabolic diseases. This review focuses on the relationship between bile acids and metabolic diseases and the current research progress to provide a theoretical basis for further research and clinical applications.

The failure of the fight against obesity makes us turn to new goals in its treatment. Now, brown adipose tissue has attracted attention as a promising target for the treatment of obesity and associated metabolic disorders such as insulin resistance, dyslipidemia, and glucose tolerance disorders. Meanwhile, the expansion of our knowledge has led to awareness about two rather different subtypes: classic brown and beige (inducible brown) adipose tissue. These subtypes have different origin, differences in the expression of individual genes but also a lot in common. Both tissues are thermogenic, which means that, by increasing energy consumption, they can improve their balance with excess intake. Both tissues are activated in response to specific inducers (cold, beta-adrenergic receptor activation, certain food and drugs), but beige adipose tissue transdifferentiates back into white adipose tissue after the cessation of inducing action, while classic brown adipose tissue persists, but its activity decreases. In this review, we attempted to understand whether there are differences in the effects of different groups of thermogenesis-affecting drugs on these tissues. The analysis showed that this area of research is rather sparse and requires close attention in further studies.

This comprehensive review explores the intricate relationship between gut microbiota, diet, and insulin resistance, emphasizing the novel roles of diet-induced microbial changes in influencing metabolic health. It highlights how diet significantly influences gut microbiota composition, with different dietary patterns fostering diverse microbial communities. These diet-induced changes in the microbiome impact human metabolism by affecting inflammation, energy balance, and insulin sensitivity, particularly through microbial metabolites like short-chain fatty acids (SCFAs). Focusing the key mediators like endotoxemia and systemic inflammation, and introduces personalized microbiome-based therapeutic strategies, it also investigates the effects of dietary components-fiber, polyphenols, and lipids-on microbiota and insulin sensitivity, along with the roles of protein intake and amino acid metabolism. The study compares the effects of Western and Mediterranean diets on the microbiota-insulin resistance axis. Therapeutic implications, including probiotics, fecal microbiota transplantation (FMT), and personalized diets, are discussed. Key findings reveal that high-fat diets, especially those rich in saturated fats, contribute to dysbiosis and increased intestinal permeability, while high-fiber diets promote beneficial bacteria and SCFAs. The review underscores the future potential of food and microbiota interventions for preventing or managing insulin resistance.

Scavenger receptor class B, member 2 (SCARB2) is linked to Gaucher disease and Parkinson's disease. Deficiency in the SCARB2 gene causes progressive myoclonus epilepsy (PME), a rare group of inherited neurodegenerative diseases characterized by myoclonus. We found that Scarb2 deficiency in mice leads to age-dependent dietary lipid malabsorption, accompanied with vitamin E deficiency. Our investigation revealed that Scarb2 deficiency is associated with gut dysbiosis and an altered bile acid pool, leading to hyperactivation of FXR in intestine. Hyperactivation of FXR impairs epithelium renewal and lipid absorption. Patients with SCARB2 mutations have a severe reduction in their vitamin E levels and cannot absorb dietary vitamin E. Finally, inhibiting FXR or supplementing vitamin E ameliorates the neuromotor impairment and neuropathy in Scarb2 knockout mice. These data indicate that gastrointestinal dysfunction is associated with SCARB2 deficiency-related neurodegeneration, and SCARB2-associated neurodegeneration can be improved by addressing the nutrition deficits and gastrointestinal issues.

Mulberry leaf polysaccharides (MLP) are integral components of Mulberry leaves that confer hypoglycemic and hypolipidemic properties. This study investigated the efficacy of MLP in treating Type 2 Diabetes Mellitus (T2DM) and the underlying mechanisms related to gut microbiota-bile acids metabolism in T2DM rats. The findings revealed that MLP apparently reduced fasting blood glucose and lipid levels, ameliorated disorders in glucose and lipid metabolism, and mitigated insulin resistance. MLP enhanced the abundance of Prevotella, Ruminococcus, and Lactobacillus, thereby rectifying the gut microbiota dysbiosis in rats, which effectively restored gut microbiota homeostasis and composition. Furthermore, the data demonstrated that MLP modulated bile acid metabolism, as evidenced by reduced serum cholesterol levels, enhanced mRNA expression of hepatic cholesterol 7α- hydroxylase (Cyp7a1) and cholesterol 12α- hydroxylase (Cyp8b1), and ileal G protein-coupled bile acid receptor (Tgr5), while suppressing hepatic and ileal farnesoid X receptor (Fxr) mRNA expression in T2DM rats. Additionally, MLP upregulated the protein expression of hepatic CYP7A1 and CYP8B1, and ileal TGR5, while inhibiting FXR protein levels in the liver and ileum of T2DM rats. These results suggest that MLP can rectify disorders in glucose and lipid metabolism via the gut microbiota-bile acids metabolic pathway.

Iron overload is a common complication in various chronic liver diseases, including non-alcoholic fatty liver disease (NAFLD). Lipid and bile acid metabolism disorders are regarded as crucial hallmarks of NAFLD. However, effects of iron accumulation on lipid and bile acid metabolism are not well understood. Ferulic acid (FA) can chelate iron and regulate lipid and bile acid metabolism, but its potential to alleviate lipid and bile acid metabolism disorders caused by iron overload remains unclear. Here, in vitro experiments, iron overload induced oxidative stress, apoptosis, genomic instability, and lipid deposition in AML12 cells. FA reduced lipid and bile acid synthesis while increasing fatty acid β-oxidation and bile acid export, as indicated by increased mRNA expression of PPARα, Acox1, Adipoq, Bsep, and Shp, and decreased mRNA expression of Fasn, Acc, and Cyp7a1. In vivo experiments, FA mitigated liver injury in mice caused by iron overload, as indicated by reduced AST and ALT activities, and decreased iron levels in both serum and liver. RNA-seq results showed that differentially expressed genes were enriched in biological processes related to lipid metabolism, lipid biosynthesis, lipid storage, and transport. Furthermore, FA decreased cholesterol and bile acid contents, downregulated lipogenesis protein FASN, and bile acid synthesis protein CYP7A1. In conclusion, FA can protect the liver from lipid and bile acid metabolism disorders caused by iron overload by targeting FASN and CYP7A1. Consequently, FA, as a dietary supplement, can potentially prevent and treat chronic liver diseases related to iron overload by regulating lipid and bile acid metabolism.

Silicon as a functional ingredient of restructured meat (RM) shows antidiabetic and hypocholesterolemic effects in a type 2 diabetes mellitus (T2DM) rat model. The present paper investigated the mechanisms involved in this cholesterol-lowering effect by studying the impact of silicon-RM consumption on bile acid (BA) and cholesterol metabolism. In addition, the main effects of cecal BA and short-chain fatty acids derived from the microbiota on intestinal barrier integrity were also tested. Rats were fed an RM high-saturated-fat, high-cholesterol diet (HSFHCD) combined with a low dose of streptozotocin plus nicotinamide injection (LD group) and for an 8 wk. period. Silicon-RM was included in the HSFHCD as a functional food (LD-Si group). An early-stage T2DM group fed a high-saturated-fat diet (ED group) was used as a reference. Silicon decreased the BA pool with a higher hydrophilic BA profile and a lower ability to digest fat and decreased the damaging effects, increasing the occludin levels and the integrity of the intestinal barrier. The ileal BA uptake and hepatic BA synthesis through CYP7A1 were reduced by FXR/FGF15 signaling activation. The silicon up-regulated the hepatic and ileal FXR and LXRα/β, improving transintestinal cholesterol (TICE), biliary BA and cholesterol effluxes. The inclusion of silicon in meat products could be used as a new therapeutic nutritional tool in the treatment of diabetic dyslipidemia.

The gut microbiome has a significant impact on human wellness, contributing to the emergence and progression of a range of health issues including inflammatory and autoimmune conditions, metabolic disorders, cardiovascular problems, and psychiatric disorders. Notably, clinical observations have revealed that these illnesses can display differences in incidence and presentation between genders. The present study aimed to evaluate whether the composition of gut microbiota is associated with sex-specific differences and to elucidate the mechanism.

16S-rRNA-sequencing technology, hormone analysis, gut microbiota transplantation, gonadectomy, and hormone treatment were employed to investigate the correlation between the gut microbiome and sex or sex hormones. Meanwhile, genes and proteins involved bile acid signaling pathway were analyzed both in the liver and ileum tissues.

The composition and diversity of the microbiota from the jejunum and feces and the level of sex hormones in the serum differed between the sexes in young and middle-aged Sprague Dawley (SD) rats. However, no similar phenomenon was found in geriatric rats. Interestingly, whether in young, middle-aged, or old rats, the composition of the microbiota and bacterial diversity differed between the jejunum and feces in rats. Gut microbiota transplantation, gonadectomy, and hormone replacement also suggested that hormones, particularly testosterone (T), influenced the composition of the gut microbiota in rats. Meanwhile, the mRNA and protein level of genes involved bile acid signaling pathway (specifically SHP, FXR, CYP7A1, and ASBT) exhibited gender-specific differences, and T may play a significant role in mediating the expression of this pathway.

Sex-specific differences in the structure of the gut microbiota are mediated by T through the bile acid signaling pathway, pointing to potential targets for disease prevention and management techniques by indicating that sex differences and T levels may alter the composition of the gut microbiota via the bile acid signaling pathway.

The prevalence of obesity in the United States has continued to increase over the past several decades. Understanding how diet-induced obesity modulates mucosal immunity is of clinical relevance. We previously showed that consumption of a high fat, high sugar "Western" diet (WD) reduces the density and function of small intestinal Paneth cells, a small intestinal epithelial cell type with innate immune function. We hypothesized that obesity could also result in repressed gut adaptive immunity. Using small intestinal intraepithelial lymphocytes (IEL) as a readout, we found that in non-inflammatory bowel disease (IBD) subjects, high body mass index correlated with reduced IEL density. We recapitulated this in wild type (WT) mice fed with WD. A 4-week WD consumption was able to reduce IEL but not splenic, blood, or bone marrow lymphocytes, and the effect was reversible after another 2 weeks of standard diet (SD) washout. Importantly, WD-associated IEL reduction was not dependent on the presence of gut microbiota, as WD-fed germ-free mice also showed IEL reduction. We further found that WD-mediated Farnesoid X Receptor (FXR) activation in the gut triggered IEL reduction, and this was partially mediated by intestinal phagocytes. Activated FXR signaling stimulated phagocytes to secrete type I IFN, and inhibition of either FXR or type I IFN signaling within the phagocytes prevented WD-mediated IEL loss. Therefore, WD consumption represses both innate and adaptive immunity in the gut. These findings have significant clinical implications in the understanding of how diet modulates mucosal immunity.

Shengmai San Formula (SMS) is a traditional Chinese medicine (TCM) that has been used to treat wasting-thirst regarded as diabetes mellitus, which occurs disproportionately in obese patients. Therefore, we investigated whether SMS could be used to treat obesity, and explored possible mechanisms by which it might improve glucose and fat metabolism.

To investigate the effects of SMS on a high-fat diet (HFD)-induced obesity (DIO) model, we studied glucose metabolism via glucose tolerance testing (GTT) and insulin tolerance testing (ITT). Browning of white adipose tissue (WAT) was evaluated using H&E staining, along with browning-related gene and protein expression. Changes in bile acid (BA) levels in serum, liver, ileum, and inguinal white adipose tissue were detected by Ultra performance liquid chromatography tandem quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS). In addition, antimicrobial mixture (ABX) and fecal microbial transplantation (FMT) experiments were used to verify the role of gut flora in the effects produced by SMS on HFD-induced obesity model.

SMS ameliorated diet-induced dyslipidemia in a dose-dependent manner and reduced glucose intolerance and insulin resistance in DIO mice, helping to restore energy metabolism homeostasis. SMS significantly altered the structure of intestinal microbiome composition, decreasing the abundance of Lactobacillus carrying bile salt hydrolase (BSH) enzymes and thereby increasing the level of conjugated BAs in the blood, ileum, and iWAT. Increased TCA content promoted the secretion of Slit3 from M2 macrophages in iWAT, which activates the protein kinase A/calmodulin-dependent protein kinase II (PKA/CaMKII) signaling pathway in sympathetic neurons via the roundabouts receptor 1(ROBO1). This pathway promotes the synthesis and release of norepinephrine (NE), inducing cyclic adenosine monophosphate (cAMP) release in adipose tissue that activates the cyclic adenosine monophosphate/protein kinase A/phosphorylated hormone-sensitive lipase (cAMP/PKA/pHSL) pathway and enhances WAT browning. ABX treatment eliminated SMS effects on glucose and lipid metabolism in DIO mice, whereas glucose and lipid metabolism in obese mice improved following SMS-FMT and increased the level of serum bile acids.

SMS affects intestinal flora and bile acid composition in vivo and increased TCA promotes M2 macrophage polarization and Slit3 release in adipose tissue. This induces NE release and increases WAT browning in obese mice, which may be a mechanism by which SMS could be used to treat obesity.

AMP-activated protein kinase (AMPK) regulates overall energy consumption and energy intake through cytokines. Ligusticum striatum DC (CX) combined with Gastrodia elata Blume (TM) has been used for migraine treatment for millennia. When used alone in clinical practice, CX causes symptoms of thirst, irritability, and yellow urine and has influenced the levels of cytokines such as AMP that activate the AMPK pathway of energy metabolism. However, relationships between this compatibility prescription, integral biological energy metabolism, and the AMPK pathway remain unclear. Studies were performed by treating normal rats with physiological saline, CX extract, CX coupled TM extract, and TM extracts separately for 4 weeks. Food intake, water intake, urine output, stool output, and body weight were monitored once a week by the metabolic cage method. Values of FBG, BUN, TP, TC and TG in blood samples were detected approaching the whole blood automatic detector from 1 to 4 weeks. Na+-K+-ATPase, Ca2+-Mg2+-ATPase, cAMP, and cGMP activity were determined by the enzyme-linked immunosorbent assay (ELISA); the biological samples that were obtained at 1, 2, 3, and 4 weeks after drug administration were tested by GC-TOF-MS. Then real-time PCR and Western Blot were applied to detect changes in expression of some substances involved in energy metabolism. The results demonstrated that administering CX alone increased energy input, mobility, and respiratory exchange ratio, accelerated energy consumption, and caused inflammatory infiltration in the liver. CX coupled with TM led to lower energy metabolism and liver damage in comparison with CX used alone. Moreover, CX-treated rats harbored higher levels of differential metabolites (including pyrophosphate, oxaloacetic acid, and galactinol). Glycerophospholipid metabolism and the citrate cycle are closely related to the differential metabolites above. In addition, CX-induced unbalanced energy metabolism depends on cAMP activation mediated by the AMPK/PGC-1α pathway in rats. Our findings suggest that CX-induced energy metabolism imbalance was corrected after coupling with TM by mediating the AMPK/PGC-1α pathway.

Many kidney transplant recipients continue to experience high symptom burden despite restoration of kidney function. High symptom burden is a significant driver of quality of life. In the post-transplant setting, high symptom burden has been linked to negative outcomes including medication non-adherence, allograft rejection, graft loss, and even mortality. Symbiotic bacteria (microbiota) in the human gastrointestinal tract critically interact with the immune, endocrine, and neurological systems to maintain homeostasis of the host. The gut microbiome has been proposed as an underlying mechanism mediating symptoms in several chronic medical conditions including irritable bowel syndrome, chronic fatigue syndrome, fibromyalgia, and psychoneurological disorders via the gut-brain-microbiota axis, a bidirectional signaling pathway between the enteric and central nervous system. Post-transplant exposure to antibiotics, antivirals, and immunosuppressant medications results in significant alterations in gut microbiota community composition and function, which in turn alter these commensal microorganisms' protective effects. This overview will discuss the current state of the science on the effects of the gut microbiome on symptom burden in kidney transplantation and future directions to guide this field of study.

The intestine constantly encounters and adapts to the external environment shaped by diverse dietary nutrients. However, whether and how gut adaptability to dietary challenges is compromised in ulcerative colitis is incompletely understood. Here, we show that a transient high-fat diet exacerbates colitis owing to inflammation-compromised bile acid tolerance. Mechanistically, excessive tumor necrosis factor (TNF) produced at the onset of colitis interferes with bile-acid detoxification through the receptor-interacting serine/threonine-protein kinase 1/extracellular signal-regulated kinase pathway in intestinal epithelial cells, leading to bile acid overload in the endoplasmic reticulum and consequent apoptosis. In line with the synergy of bile acids and TNF in promoting gut epithelial damage, high intestinal bile acids correlate with poor infliximab response, and bile acid clearance improves infliximab efficacy in experimental colitis. This study identifies bile acids as an "opportunistic pathogenic factor" in the gut that would represent a promising target and stratification criterion for ulcerative colitis prevention/therapy.

Bile acid metabolism is partially regulated through the activity of the gut microbiota. Primary bile acids can be deconjugated and modified by bacteria expressing bile salt hydrolase and other enzymes, changing bile acid recycling by changing the interactions between enterocytes and hepatocytes. The modified bile acids can also activate signalling in cells regulating metabolism including colonic L-cells, skeletal muscle cells and brown adipocytes. In pregnancy, both bile acid metabolism and gut microbiota composition are altered. In women with intrahepatic cholestasis of pregnancy, the changes in bile acid metabolism are exacerbated and there is some evidence that the gut microbiota composition is also altered. Here we review the crosstalk between the liver and the gut especially in women with intrahepatic cholestasis of pregnancy, with a focus on the role of the gut microbiota in this crosstalk.

Tissue-specific analysis of the transcriptome is critical to elucidating the molecular basis of complex traits, but central tissues are often not accessible. We propose a methodology, Multi-mOdal-based framework to bridge the Transcriptome between PEripheral and Central tissues (MOTPEC).

Multi-modal regulatory elements in peripheral blood are incorporated as features for gene expression prediction in 48 central tissues. To demonstrate the utility, we apply it to the identification of BMI-associated genes and compare the tissue-specific results with those derived directly from surrogate blood.

MOTPEC models demonstrate superior performance compared with both baseline models in blood and existing models across the 48 central tissues. We identify a set of BMI-associated genes using the central tissue MOTPEC-predicted transcriptome data. The MOTPEC-based differential gene expression (DGE) analysis of BMI in the central tissues (including brain caudate basal ganglia and visceral omentum adipose tissue) identifies 378 genes overlapping the results from a TWAS of BMI, while only 162 overlapping genes are identified using gene expression in blood. Cellular perturbation analysis further supports the utility of MOTPEC for identifying trait-associated gene sets and narrowing the effect size divergence between peripheral blood and central tissues.

The MOTPEC framework improves the gene expression prediction accuracy for central tissues and enhances the identification of tissue-specific trait-associated genes.

This research is supported by the National Natural Science Foundation of China 82204118 (D.Z.), the seed funding of the Key Laboratory of Intelligent Preventive Medicine of Zhejiang Province (2020E10004), the National Institutes of Health (NIH) Genomic Innovator Award R35HG010718 (E.R.G.), NIH/NHGRI R01HG011138 (E.R.G.), NIH/NIA R56AG068026 (E.R.G.), NIH Office of the Director U24OD035523 (E.R.G.), and NIH/NIGMS R01GM140287 (E.R.G.).

Bile acids (BAs) are an important metabolite produced by cholesterol catabolism. It serves important roles in glucose and lipid metabolism and host-microbe interaction. Recent research has shown that different gut-microbiota can secrete different metabolic-enzymes to mediate the deconjugation, dehydroxylation and epimerization of BAs. In addition, microbes mediate BAs transformation and exert physiological functions in metabolic diseases may have a potentially close relationship with diet. Therefore, elaborating the pathways by which gut microbes mediate the transformation of BAs through enzymatic reactions involved are principal to understand the mechanism of effects between dietary patterns, gut microbes and BAs, and to provide theoretical knowledge for the development of functional foods to regulate metabolic diseases. In the present review, we summarized works on the physiological function of BAs, as well as the classification and composition of BAs in different animal models and its organs. In addition, we mainly focus on the bidirectional interactions of gut microbes with BAs transformation, and discuss the effects of diet on microbial transformation of BAs. Finally, we raised the question of further in-depth investigation of the food-gut microbial-BAs relationship, which might contribute to the improvement of metabolic diseases through dietary interventions in the future.

Bile acids serve as endogenous ligands for nuclear and cell membrane receptors and play a crucial role in bile acid and lipid metabolism. These detergent-like compounds promote bile flow and aid in the absorption of dietary fats and fat-soluble vitamins in the intestine. Synthesized in the liver as end products of cholesterol catabolism, bile acids exhibit a chemical structure comprising a nucleus and a side chain featuring a carboxyl group, with diverse steric arrangements and potential polar substituents. Critical interactions occur between bile acid species and various nuclear and cell membrane receptors, including the farnesoid X receptor and G-protein-coupled bile acid receptor 1. This research aimed to review the literature on bile acids and their roles in treating different diseases. Currently, numerous investigations are concentrating on specific bile acid species that target nuclear receptors in the gastrointestinal system, aiming to improve the treatment of conditions such as nonalcoholic fatty liver disease. Given the global attention this topic has garnered from research groups, it is considered relatively new, thus anticipating some gaps or incomplete data. Bile acid species have a significant therapeutic promise, especially in their ability to activate or inhibit nuclear receptors, such as farnesoid X receptor. This research provides to offer essential information for scientists and medical practitioners interested in discovering new studies that underscore the importance of bile acids in ameliorating and impeding the progression of disorders. Furthermore, it opens avenues for previously overlooked bile acid-based therapies.

The main objective of this study was to analyze the changes of intestinal microflora and how bile acid metabolic pathways affect lipid metabolism in T2DM through the gut-liver axis.

Firstly, 16S rRNA sequencing, metabolomics and transcriptomic sequencing were performed on plasma and feces of clinical subjects to determine the changes of intestinal flora and its metabolites. Finally, T2DM mice model was verified in vivo.

T2DM patients have significant intestinal flora metabolism disorders. The differential fecal metabolites were mainly enriched in primary bile acid biosynthesis and cholesterol metabolism pathways in T2DM patients. After verification, the changes in gut microbiota and metabolites in T2DM patients (including up-regulated bacteria associated with BA metabolism, such as lactobacillus and bifidobacterial, and down-regulated bacteria capable of producing SCFAs such as Faecalibacterium, Bacteroides, Romboutsia and Roseburia); and the changes in the flora and metabolites that result in impairment of intestinal barrier function and changes of protein expression in the blood, intestine and liver of T2DM patients (including FGFR4↑, TRPM5↑ and CYP27A1↓, which are related to BA and lipid metabolism homeostasis, and TLR6↑, MYD88↑ and NF-κB↑, which are related to inflammatory response). These aspects together contribute to the development of further disorders of glucolipid metabolism and systemic inflammation in T2DM patients.

Changes in intestinal flora and its metabolites may affect lipid metabolism and systemic inflammatory response in T2DM patients through the gut-liver axis mediated by bile acids.

Emerging evidence shows that disrupted gut microbiota-bile acid (BA) axis is critically involved in the development of neurodegenerative diseases. However, the alterations in spatial distribution of BAs among different brain regions that command important functions during aging and their exact roles in aging-related neurodegenerative diseases are poorly understood. Here, we analyzed the BA profiles in cerebral cortex, hippocampus, and hypothalamus of young and natural aging mice of both sexes. The results showed that aging altered brain BA profiles sex- and region- dependently, in which TβMCA was consistently elevated in aging mice of both sexes, particularly in the hippocampus and hypothalamus. Furthermore, we found that aging accumulated-TβMCA stimulated microglia inflammation in vitro and shortened the lifespan of C. elegans, as well as behavioral impairment and neuroinflammation in mice. In addition, metagenomic analysis suggested that the accumulation of brain TβMCA during aging was partially attributed to reduction in BSH-carrying bacteria. Finally, rejuvenation of gut microbiota by co-housing aged mice with young mice restored brain BA homeostasis and improved neurological dysfunctions in natural aging mice. In conclusion, our current study highlighted the potential of improving aging-related neuro-impairment by targeting gut microbiota-brain BA axis.

Introduction: Obesity, a global epidemic, is caused by an imbalance between energy intake and expenditure. The induction of white adipose browning to increase heat production has emerged as a potential effective strategy to address obesity. Ling-gui-zhu-gan (LGZG), a traditional Chinese medicine formula, has been proved to achieve promising results to combat obesity and related metabolic diseases, yet the mechanisms remain largely unexplored. This study aimed to elucidate the anti-obesity properties and the mechanisms of LGZG by investigating its browning effect on 3T3-L1 adipocytes. Methods: LGZG-containing serum obtained by oral administration of LGZG to animals was added to 3T3-L1 adipocytes to simulate in vivo conditions. Results: The results showed that 49 compounds were identified in LGZG-containing serum by UHPLC-Q-Orbitrap HRMS, including compounds such as atractylenolides and polyporenic acid C, etc. LGZG-containing serum alleviated the lipid accumulation and decreased both intracellular and extracellular triglyceride contents in a dose-dependent manner. This reduction is accompanied by enhanced mitochondrial respiratory and heat production function. Mechanistically, LGZG-containing serum led to a decrease in miR-27b expression and an increase in the mRNA and protein levels of browning-related markers, including UCP1, PRDM16, PGC-1α, PPARγ, CTBP1, and CTBP2. Further investigation using miR-27b mimic transfection confirmed that miR-27b/PRDM16 pathway might be a potential mechanism by which LGZG-containing serum promotes browning of 3T3-L1 adipocytes. Discussion: These results underscore the therapeutic potential of LGZG in addressing obesity and its associated metabolic disorders through the promotion of adipose browning.