RESUMEN
Objective: This study aims to investigate the pathogenesis of hyperglycemia and its associated vasculopathy using multiomics analyses in diabetes and impaired glucose tolerance, and validate the mechanism using the cell experiments. Methods: In this study, we conducted a comprehensive analysis of the metagenomic sequencing data of diabetes to explore the key genera related to its occurrence. Subsequently, participants diagnosed with impaired glucose tolerance (IGT), and healthy subjects, were recruited for fecal and blood sample collection. The dysbiosis of the gut microbiota (GM) and its associated metabolites were analyzed using 16S rDNA sequencing and liquid chromatograph mass spectrometry, respectively. The regulation of gene and protein expression was evaluated through mRNA sequencing and data-independent acquisition technology, respectively. The specific mechanism by which GM dysbiosis affects hyperglycemia and its related vasculopathy was investigated using real-time qPCR, Western blotting, and enzyme-linked immunosorbent assay techniques in HepG2 cells and neutrophils. Results: Based on the published data, the key alterable genera in the GM associated with diabetes were identified as Blautia, Lactobacillus, Bacteroides, Prevotella, Faecalibacterium, Bifidobacterium, Ruminococcus, Clostridium, and Lachnoclostridium. The related metabolic pathways were identified as cholate degradation and L-histidine biosynthesis. Noteworthy, Blautia and Faecalibacterium displayed similar alterations in patients with IGT compared to those observed in patients with diabetes, and the GM metabolites, tauroursodeoxycholic acid (TUDCA) and carnosine (CARN, a downstream metabolite of histidine and alanine) were both found to be decreased, which in turn regulated the expression of proteins in plasma and mRNAs in neutrophils. Subsequent experiments focused on insulin-like growth factor-binding protein 3 and interleukin-6 due to their impact on blood glucose regulation and associated vascular inflammation. Both proteins were found to be suppressed by TUDCA and CARN in HepG2 cells and neutrophils. Conclusion: Dysbiosis of the GM occurred throughout the entire progression from IGT to diabetes, characterized by an increase in Blautia and a decrease in Faecalibacterium, leading to reduced levels of TUDCA and CARN, which alleviated their inhibition on the expression of insulin-like growth factor-binding protein 3 and interleukin-6, contributing to the development of hyperglycemia and associated vasculopathy.
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Carnosina , Disbiosis , Heces , Microbioma Gastrointestinal , Humanos , Disbiosis/microbiología , Carnosina/metabolismo , Masculino , Heces/microbiología , Intolerancia a la Glucosa/metabolismo , Inflamación/metabolismo , Células Hep G2 , Metagenómica , Femenino , Persona de Mediana Edad , Ácido Tauroquenodesoxicólico/metabolismo , Ácido Tauroquenodesoxicólico/farmacología , Hiperglucemia/metabolismo , Neutrófilos/metabolismo , ARN Ribosómico 16S/genética , Bacterias/clasificación , Bacterias/metabolismo , Bacterias/genéticaRESUMEN
Tauroursodeoxycholic acid (TUDCA) is a synthetic bile salt that has demonstrated efficacy in the management of hepatobiliary disorders. However, its specific mechanism of action in preventing and treating nonalcoholic fatty liver disease (NAFLD) remains incompletely understood. This research revealed that TUDCA treatment can reduce obesity and hepatic lipid buildup, enhance intestinal barrier function and microbial balance, and increase the presence of Allobaculum and Bifidobacterium in NAFLD mouse models. TUDCA can influence the activity of farnesoid X receptor (FXR) and cholesterol 7α-hydroxylase (CYP7A1), resulting in higher hepatic bile acid levels and increased expression of sodium taurocholate cotransporting polypeptide (NTCP), leading to elevated concentrations of liver-bound bile acids in mice. Furthermore, TUDCA can inhibit the expression of FXR and fatty acid transport protein 5 (FATP5), thereby reducing fatty acid absorption and hepatic lipid accumulation. This investigation provides new insights into the potential of TUDCA for preventing and treating NAFLD.
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Ácidos y Sales Biliares , Microbioma Gastrointestinal , Ratones Endogámicos C57BL , Enfermedad del Hígado Graso no Alcohólico , Ácido Tauroquenodesoxicólico , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Animales , Ácido Tauroquenodesoxicólico/farmacología , Ácido Tauroquenodesoxicólico/metabolismo , Microbioma Gastrointestinal/efectos de los fármacos , Ratones , Masculino , Humanos , Ácidos y Sales Biliares/metabolismo , Hígado/metabolismo , Hígado/efectos de los fármacos , Bacterias/metabolismo , Bacterias/clasificación , Bacterias/genética , Bacterias/efectos de los fármacos , Bacterias/aislamiento & purificación , Receptores Citoplasmáticos y Nucleares/metabolismo , Receptores Citoplasmáticos y Nucleares/genética , Colesterol 7-alfa-Hidroxilasa/metabolismo , Colesterol 7-alfa-Hidroxilasa/genética , Simportadores/metabolismo , Simportadores/genética , Transportadores de Anión Orgánico Sodio-Dependiente/metabolismo , Transportadores de Anión Orgánico Sodio-Dependiente/genéticaRESUMEN
AIMS: Estradiol 17ß-d-glucuronide (E217G) induces cholestasis by triggering endocytosis and further intracellular retention of the canalicular transporters Bsep and Mrp2, in a cPKC- and PI3K-dependent manner, respectively. Pregnancy-induced cholestasis has been associated with E217G cholestatic effect, and is routinely treated with ursodeoxycholic acid (UDCA). Since protective mechanisms of UDCA in E217G-induced cholestasis are still unknown, we ascertained here whether its main metabolite, tauroursodeoxycholate (TUDC), can prevent endocytosis of canalicular transporters by counteracting cPKC and PI3K/Akt activation. MAIN METHODS: Activation of cPKC and PI3K/Akt was evaluated in isolated rat hepatocytes by immunoblotting (assessment of membrane-bound and phosphorylated forms, respectively). Bsep/Mrp2 function was quantified in isolated rat hepatocyte couplets (IRHCs) by assessing the apical accumulation of their fluorescent substrates, CLF and GS-MF, respectively. We also studied, in isolated, perfused rat livers (IPRLs), the status of Bsep and Mrp2 transport function, assessed by the biliary excretion of TC and DNP-SG, respectively, and Bsep/Mrp2 localization by immunofluorescence. KEY FINDINGS: E217G activated both cPKC- and PI3K/Akt-dependent signaling, and pretreatment with TUDC significantly attenuated these activations. In IRHCs, TUDC prevented the E217G-induced decrease in apical accumulation of CLF and GS-MF, and inhibitors of protein phosphatases failed to counteract this protection. In IPRLs, E217G induced an acute decrease in bile flow and in the biliary excretion of TC and DNP-SG, and this was prevented by TUDC. Immunofluorescence studies revealed that TUDC prevented E217G-induced Bsep/Mrp2 endocytosis. SIGNIFICANCE: TUDC restores function and localization of Bsep/Mrp2 impaired by E217G, by preventing both cPKC and PI3K/Akt activation in a protein-phosphatase-independent manner.
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Colestasis , Endocitosis , Estradiol , Hepatocitos , Fosfatidilinositol 3-Quinasas , Transducción de Señal , Ácido Tauroquenodesoxicólico , Animales , Colestasis/metabolismo , Colestasis/inducido químicamente , Colestasis/prevención & control , Ratas , Transducción de Señal/efectos de los fármacos , Estradiol/metabolismo , Estradiol/farmacología , Estradiol/análogos & derivados , Hepatocitos/metabolismo , Hepatocitos/efectos de los fármacos , Endocitosis/efectos de los fármacos , Ácido Tauroquenodesoxicólico/farmacología , Ácido Tauroquenodesoxicólico/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Miembro 11 de la Subfamilia B de Transportador de Casetes de Unión al ATP/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas Wistar , Femenino , Masculino , Proteína Quinasa C/metabolismo , Transportadoras de Casetes de Unión a ATP/metabolismoRESUMEN
Genetic factors, diet, lifestyle, and other factors lead to various complications in the body, such as obesity and other chronic diseases. The inflammatory state caused by excessive accumulation of body fat affects the pathways related to the control of glycemic homeostasis, leading to a high demand for insulin, to subsequent failure of stressed ß cells, and development of type 2 diabetes mellitus (T2DM). The study of new endocrine signalers, such as bile acids (BAs), becomes necessary as it allows the development of alternatives for T2DM treatment. In this work, a methodology was developed to quantify tauroursodeoxycholic BA (TUDCA) in liver cells of the HepG2 strain treated in hyperlipidic medium. This BA helps to improve insulin clearance by increasing the expression of the insulin-degrading enzyme, restoring sensitivity to this hormone, and making it viable for treating T2DM. Herein, a targeted metabolomic method for TUDCA determination in extracellular medium of hepatocyte matrices by micellar electrokinetic chromatography-UV was optimized, validated, and applied. The optimized background electrolyte was composed of 40 mmol/L sodium cholate and 30 mmol/L sodium tetraborate at pH 9.0. The following figures of merit were evaluated: linearity, limit of quantification, limit of detection, accuracy, and precision. Data obtained with the validated electrophoretic method showed a self-stimulation of TUDCA production in media supplemented only with BA. On the other hand, TUDCA concentration was reduced in the hyperlipidic medium. This suggests that, in these media, the effect of TUDCA is reduced, such as self-stimulated production and consequent regulation of glycemic homeostasis. Therefore, the results reinforce the need for investigating TUDCA as a potential T2DM biomarker as well as its use to treat several comorbidities, such as obesity and diabetes mellitus.
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Cromatografía Capilar Electrocinética Micelar , Diabetes Mellitus Tipo 2 , Obesidad , Ácido Tauroquenodesoxicólico , Ácido Tauroquenodesoxicólico/farmacología , Ácido Tauroquenodesoxicólico/análisis , Ácido Tauroquenodesoxicólico/metabolismo , Humanos , Obesidad/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Células Hep G2 , Cromatografía Capilar Electrocinética Micelar/métodos , Hepatocitos/metabolismo , Hepatocitos/efectos de los fármacos , Reproducibilidad de los Resultados , Metabolómica/métodos , Modelos Lineales , Límite de DetecciónRESUMEN
Bile acids, such as taurochenodeoxycholic acid (TCDCA), are considered as functional small molecules involved in nutrition regulation or acting with adjuvant therapeutic effects against metabolic or immune diseases. The homeostasis of the intestinal epithelium depends on the conventional cellular proliferation and apoptosis of cells. Herein, mice and normal intestinal epithelial cells (IPEC-J2, a widely used normal intestinal epithelial cell line derived from porcine) were used as models to explore the regulatory effect of TCDCA on the proliferation of intestinal epithelial cells (IECs). In the mouse study, the oral gavage of TCDCA led to a significant reduction in weight gain, small intestinal weight, and the villus height of the intestinal epithelium while inhibiting the gene expression of Ki-67 in the intestinal epithelial crypts of mice (P < 0.05). TCDCA significantly downregulated the expression of the farnesoid X receptor (FXR) and upregulated the expression of caspase-9 in the jejunum (P < 0.05). The results of real-time quantitative PCR (RT-qPCR) suggested that TCDCA significantly inhibited the expression of tight junction proteins zonula occludens (ZO)-1, occludin, claudin-1, and mucin-2 (P < 0.05). In terms of apoptosis-related genes, TCDCA significantly inhibited the expression of Bcl2 and increased the expression of caspase-9 (P < 0.05). At the protein level, TCDCA decreased the expression of Ki-67 and PCNA, as well as FXR (P < 0.05). Caspase inhibitor Q-VD-OPh and guggulsterone, an FXR antagonist, significantly improved the inhibition of TCDCA-induced cell proliferation. Moreover, guggulsterone enhanced TCDCA-induced cell late apoptosis through flow cytometry and significantly lowered the TCDCA-induced up-regulated gene expression of caspase 9, despite both TCDCA and guggulsterone down-regulating the expression of FXR (P < 0.05). Overall, the effect of TCDCA on the induction of apoptosis is not dependent on FXR, whereas it would function via the activation of the caspase system. This provides a new perspective for the application of TCDCA or bile acid as functional small molecules in food, additives, and medicine.
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Mucosa Intestinal , Ácido Tauroquenodesoxicólico , Ratones , Animales , Porcinos , Ácido Tauroquenodesoxicólico/farmacología , Ácido Tauroquenodesoxicólico/metabolismo , Caspasa 9/metabolismo , Antígeno Ki-67/metabolismo , Proliferación Celular , Mucosa Intestinal/metabolismo , Ácidos y Sales Biliares/metabolismo , ApoptosisRESUMEN
OBJECTIVE: Multiple sclerosis (MS) is an immune regulatory disease that affects the central nervous system (CNS). The main pathological features include demyelination and neurodegeneration, and the pathogenesis is associated with astrocytic neuroinflammation. Taurochenodeoxycholic acid (TCDCA) is one of the conjugated bile acids in animal bile, and it is not clear whether TCDCA could improve MS by inhibiting the activation of astrocytes. This study was aimed to evaluate the effects of TCDCA on experimental autoimmune encephalomyelitis (EAE)-a classical animal model of MS, and to probe its mechanism from the aspect of suppressing astrocytic neuroinflammation. It is expected to prompt the potential application of TCDCA for the treatment of MS. RESULTS: TCDCA effectively alleviated the progression of EAE and improved the impaired neurobehavior in mice. It mitigated the hyperactivation of astrocytes and down-regulated the mRNA expression levels of inducible nitric oxide synthase (iNOS), cyclooxygenase 2 (COX2), tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß) and IL-6 in the brain cortex. In the C6 astrocytic cell line induced by lipopolysaccharide (LPS), TCDCA treatment dose-dependently decreased the production of NO and the protein expression of iNOS and glial fibrillary acidic protein (GFAP). TCDCA consistently inhibited the mRNA expressions of COX2, iNOS and other inflammatory mediators. Furthermore, TCDCA decreased the protein expression of phosphorylated serine/threonine kinase (AKT), inhibitor of NFκB α (IκBα) and nuclear factor κB (NFκB). And TCDCA also inhibited the nuclear translocation of NFκB. Conversely, as an inhibitor of the G-protein coupled bile acid receptor Gpbar1 (TGR5), triamterene eliminated the effects of TCDCA in LPS-stimulated C6 cells. CONCLUSION: TCDCA improves the progress of EAE by inhibiting the astrocytic neuroinflammation, which might be exerted by the regulation of TGR5 mediated AKT/NFκB signaling pathway. These findings may prompt the potential application of TCDCA for MS therapy by suppressing astrocyte inflammation.
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Encefalomielitis Autoinmune Experimental , Ratones , Animales , Astrocitos/metabolismo , Astrocitos/patología , Ácido Tauroquenodesoxicólico/metabolismo , Ácido Tauroquenodesoxicólico/farmacología , Enfermedades Neuroinflamatorias , Proteínas Proto-Oncogénicas c-akt/metabolismo , Lipopolisacáridos/farmacología , Ciclooxigenasa 2/metabolismo , Ciclooxigenasa 2/farmacología , FN-kappa B/metabolismo , ARN Mensajero/genética , Ratones Endogámicos C57BL , Receptores Acoplados a Proteínas G/metabolismoRESUMEN
Adipose tissue is an organ with metabolic and endocrine activity. White, brown and ectopic adipose tissues have different structure, location, and function. Adipose tissue regulates energy homeostasis, providing energy in nutrient-deficient conditions and storing it in high-supply conditions. To attend to the high demand for energy storage during obesity, the adipose tissue undergoes morphological, functional and molecular changes. Endoplasmic reticulum (ER) stress has been evidenced as a molecular hallmark of metabolic disorders. In this sense, the ER stress inhibitor tauroursodeoxycholic acid (TUDCA), a bile acid conjugated to taurine with chemical chaperone activity, has emerged as a therapeutic strategy to minimize adipose tissue dysfunction and metabolic alterations associated with obesity. In this review, we highlight the effects of TUDCA and receptors TGR5 and FXR on adipose tissue in the setting of obesity. TUDCA has been demonstrated to limit metabolic disturbs associated to obesity by inhibiting ER stress, inflammation, and apoptosis in adipocytes. The beneficial effect of TUDCA on perivascular adipose tissue (PVAT) function and adiponectin release may be related to cardiovascular protection in obesity, although more studies are needed to clarify the mechanisms. Therefore, TUDCA has emerged as a potential therapeutic strategy for obesity and comorbidities.
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Adiposidad , Ácido Tauroquenodesoxicólico , Humanos , Ácido Tauroquenodesoxicólico/farmacología , Ácido Tauroquenodesoxicólico/uso terapéutico , Ácido Tauroquenodesoxicólico/metabolismo , Tejido Adiposo/metabolismo , Obesidad/tratamiento farmacológico , Obesidad/metabolismoRESUMEN
Duyun compound green tea (DCGT) is a healthy beverage with lipid-lowering effect commonly consumed by local people, but its mechanism is not very clear. We evaluated the effect of DCGT treatment on bile acids (BA) metabolism of mice with high-fat diet (HFD) - induced hyperlipidaemia by biochemical indexes and metabolomics and preliminarily determined the potential biomarkers and metabolic pathways of hyperlipidaemia mice treated with DCGT as well as investigated its lipid-lowering mechanism. The results showed that DCGT treatment could reduce HFD - induced gain in weight and improve dyslipidaemia. In addition, a total of ten types of BA were detected, of which seven changed BA metabolites were observed in HFD group mice. After DCGT treatment, glycocholic acid, tauroursodeoxycholic acid and taurochenodeoxycholic acid were significantly down-regulated, while hyodeoxycholic acid, deoxycholic acid and chenodeoxycholic acid were markedly up-regulated. These results demonstrated that DCGT treatment was able to make the BA metabolites in the liver of hyperlipidaemia mice normal and alleviate hyperlipidaemia by regulating the metabolites such as glycocholic acid, tauroursodeoxycholic acid and taurochenodeoxycholic, as well as the BA metabolic pathway and cholesterol metabolic pathway involved.
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Hiperlipidemias , Enfermedades Metabólicas , Ratones , Animales , Dieta Alta en Grasa/efectos adversos , Ácido Tauroquenodesoxicólico/farmacología , Ácido Tauroquenodesoxicólico/metabolismo , Hígado/metabolismo , Colesterol/metabolismo , Té/química , Hiperlipidemias/tratamiento farmacológico , Hiperlipidemias/etiología , Hiperlipidemias/metabolismo , Extractos Vegetales/farmacología , Extractos Vegetales/metabolismo , Ácido Glicocólico/metabolismo , Ácidos y Sales Biliares/metabolismo , Metabolismo de los Lípidos , Ratones Endogámicos C57BLRESUMEN
It has been reported that aging-generated gut microecosystem may promote host hepatic lipid dysmetabolism through shaping the pattern of secondary bile acids (BAs). Then as an oral drug, melatonin (Mel)-mediated beneficial efforts on the communication between gut microbiota and aging host are still not clearly. Here, we show that aging significantly shapes the pattern of gut microbiota and BAs, whereas Mel treatment reverses these phenotypes (P < 0.05), which is identified to depend on the existence of gut microbiota. Mechanistically, aging-triggered high-level expression of ileac farnesoid X receptor (FXR) is significantly decreased through Mel-mediated inhibition on Campylobacter jejuni (C. jejuni)-induced deconjugation of tauroursodeoxycholic acid (TUDCA) and glycoursodeoxycholic acid (GUDCA) (P < 0.05). The aging-induced high-level of serum taurine chenodeoxycholic acid (TCDCA) activate trimethylamine-N-oxide (TMAO)-triggered activating transcriptional factor 4 (ATF4) signaling via hepatic FXR, which further regulates hepatic BAs metabolism, whereas TUDCA inhibits aging-triggered high-level of hepatic ATF4. Overall, Mel reduces C. jejuni-mediated deconjugation of TUDCA to inhibit aging-triggered high-level expression of hepatic FXR, which further decreases hepatic TMAO production, to relieve hepatic lipid dysmetabolism.
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Microbioma Gastrointestinal , Melatonina , Ácidos y Sales Biliares/metabolismo , Microbioma Gastrointestinal/fisiología , Lípidos , Hígado/metabolismo , Melatonina/metabolismo , Melatonina/farmacología , Metilaminas , Óxidos/metabolismo , Receptores Citoplasmáticos y Nucleares/metabolismo , Ácido Tauroquenodesoxicólico/metabolismo , Ácido Tauroquenodesoxicólico/farmacologíaRESUMEN
Most neurodegenerative disorders are diseases of protein homeostasis, with misfolded aggregates accumulating. The neurodegenerative process is mediated by numerous metabolic pathways, most of which lead to apoptosis. In recent years, hydrophilic bile acids, particularly tauroursodeoxycholic acid (TUDCA), have shown important anti-apoptotic and neuroprotective activities, with numerous experimental and clinical evidence suggesting their possible therapeutic use as disease-modifiers in neurodegenerative diseases. Experimental evidence on the mechanisms underlying TUDCA's neuroprotective action derives from animal models of Alzheimer's disease, Parkinson's disease, Huntington's diseases, amyotrophic lateral sclerosis (ALS) and cerebral ischemia. Preclinical studies indicate that TUDCA exerts its effects not only by regulating and inhibiting the apoptotic cascade, but also by reducing oxidative stress, protecting the mitochondria, producing an anti-neuroinflammatory action, and acting as a chemical chaperone to maintain the stability and correct folding of proteins. Furthermore, data from phase II clinical trials have shown TUDCA to be safe and a potential disease-modifier in ALS. ALS is the first neurodegenerative disease being treated with hydrophilic bile acids. While further clinical evidence is being accumulated for the other diseases, TUDCA stands as a promising treatment for neurodegenerative diseases.
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Esclerosis Amiotrófica Lateral , Enfermedades Neurodegenerativas , Animales , Ácidos y Sales Biliares/uso terapéutico , Enfermedades Neurodegenerativas/tratamiento farmacológico , Ácido Tauroquenodesoxicólico/metabolismo , Ácido Tauroquenodesoxicólico/farmacología , Ácido Tauroquenodesoxicólico/uso terapéuticoRESUMEN
Taurochenodeoxycholic acid (TCDCA) is one of the main components of bile acids (BAs). TCDCA has been reported as a signaling molecule, exerting anti-inflammatory and immunomodulatory functions. However, it is not well known whether those effects are mediated by TGR5. This study aimed to elucidate the interaction between TCDCA and TGR5. To achieve this aim, first, the TGR5 eukaryotic vector was constructed. The expression level of TGR5 in 293T cells was determined by immunofluorescence, real-time quantitative PCR (RT-PCR, qPCR), and Western blot. The luciferase assay, fluorescence microscopy, and enzyme-linked immunosorbent assay (ELISA) were recruited to check the interaction of TCDCA with TGR5. TCDCA treatment in 293T cells resulted in TGR5 internalization coupled with a significant increase in cAMP luciferase expression. Our results demonstrated that TCDCA was able to bind to the TGR5 receptor and activate it. These results provide an excellent potential therapeutic target for TCDCA research. Moreover, these findings also provide theoretical evidence for further TCDCA research.
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Antiinflamatorios/metabolismo , Antiinflamatorios/farmacología , AMP Cíclico/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Transducción de Señal/efectos de los fármacos , Ácido Tauroquenodesoxicólico/metabolismo , Ácido Tauroquenodesoxicólico/farmacología , Membrana Celular/metabolismo , Células HEK293 , Humanos , Ligandos , Plásmidos/genética , Unión Proteica , Receptores Acoplados a Proteínas G/genética , TransfecciónRESUMEN
Probiotics, including Lactobacillus rhamnosus GG ATCC53103 and Lactobacillus plantarum JL01, can improve growth performance and immunity of piglets, and relieve weaning stress-related immune disorders such as intestinal infections and inflammation. This study aimed to evaluate the ability of co-administration of the probiotics L. rhamnosus GG ATCC53103 and L. plantarum JL01 to stimulate immune responses and improve gut health during the critical weaning period in piglets. Forty-eight weaned piglets were randomly divided into four groups, and fed daily for 28 days either without, or with the two probiotics independently, or in combination. On day 28, we analyzed the cytokine and bacterial changes in intestinal mucosa and the hepatic portal vein blood metabolites of the weaned piglets. Our results showed that combined L. rhamnosus GG ATCC53103 and L. plantarum JL01 significantly increased (p < 0.05) the growth performance and expression of IL-10 and TGF-ß1 mRNAs. In contrast, this treatment significantly decreased (p < 0.05) IL-1ß mRNA level in the jejunum, ileum, and cecum. Furthermore, the secretion of IL-6 in the cecum, IL-1ß in the jejunum, ileum, and cecum, and TNF-α in the jejunum and ileum was significantly decreased (p < 0.05). The relative abundance of Prevotella_9 and Enterococcus in ileum and cecum was significantly increased (p < 0.05). The relative abundance of Ruminococcus_1 and Ruminococcaceae_UCG-005 in cecum was significantly decreased (p < 0.05). Prevotella_9 and Enterococcus may increase the accumulation of (4Z,7Z,10Z,13Z,16Z,19Z)-4,7,10,13,16,19-docosahexaenoic acid (DHA) and tauroursodeoxycholic acid (TCDA) in portal vein blood, while Ruminococcus_1 and Ruminococcaceae_UCG-005 may decrease the accumulation of succinic and palmitic acids. These results indicate that L. rhamnosus GG ATCC53103 and L. plantarum JL01 may regulate cytokine levels by reducing the accumulation of succinic and palmitic acids and increasing the accumulation of TCDA and DHA, thereby enhancing the immunity of weaned piglets.
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Citocinas/metabolismo , Lacticaseibacillus rhamnosus , Lactobacillus plantarum , Probióticos , Porcinos/metabolismo , Animales , Citocinas/genética , Ácidos Docosahexaenoicos/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Mucosa Intestinal/metabolismo , Ácidos Palmíticos/metabolismo , Distribución Aleatoria , Ácido Succínico/metabolismo , Ácido Tauroquenodesoxicólico/metabolismo , DesteteRESUMEN
Bile salt hydrolase (BSH)-producing bacteria are negatively related to the body weight gain and energy storage of the host. We aimed to obtain a novel BSH-producing strain with excellent anti-obesity effect and explained its mechanism. Here, we selected a strain named Lactiplantibacillus plantarum H-87 (H-87) with excellent ability to hydrolyze glycochenodeoxycholic acid (GCDCA) and tauroursodeoxycholic acid (TUDCA) in vitro from 12 lactobacilli, and evaluated its anti-obesity effect in high-fat diet (HFD)-fed C57BL/6J mice. The results suggested that H-87 could inhibit HFD-induced body weight gain, fat accumulation, liver lipogenesis and injury, insulin resistance and dyslipidemia. In addition, H-87 could colonize in the ileum and hydrolyze GCDCA and TUDCA, reflected as changes in the concentrations of GCDCA, TUDCA, CDCA and UDCA in the ileum or liver. Furthermore, the study identified that H-87 reduced TUDCA and GCDCA levels in the ileum, which decreased the GLP-1 secretion by L cells to alleviate insulin resistance in HFD-fed mice. Furthermore, H-87 increased the CDCA level in the ileum and liver to activate FXR signaling pathways to inhibit liver lipogenesis in HFD-fed mice. In addition, the decrease of intestinal conjugated bile acids (TUDCA and GCDCA) also increased fecal lipid content and decreased intestinal lipid digestibility. In conclusion, H-87 could inhibit liver fat deposition, insulin resistance and lipid digestion by changing bile acid enterohepatic circulation, and eventually alleviate HFD-induced obesity.
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Dieta Alta en Grasa/efectos adversos , Lactobacillus plantarum/metabolismo , Obesidad/microbiología , Obesidad/prevención & control , Animales , Ácidos y Sales Biliares/metabolismo , Dislipidemias/microbiología , Dislipidemias/prevención & control , Ácido Glicoquenodesoxicólico/metabolismo , Resistencia a la Insulina , Metabolismo de los Lípidos , Hígado/metabolismo , Hepatopatías/microbiología , Hepatopatías/prevención & control , Masculino , Ratones , Ratones Endogámicos C57BL , Obesidad/etiología , Ácido Tauroquenodesoxicólico/metabolismoRESUMEN
OBJECTIVES: In this study, we study the transplantation of tauroursodeoxycholic acid (TUDCA)-induced M2-phenotype (M2) macrophages and their ability to promote anti-neuroinflammatory effects and functional recovery in a spinal cord injury (SCI) model. METHODS: To this end, compared to the granulocyte-macrophage colony-stimulating factor (GM-CSF), we evaluated whether TUDCA effectively differentiates bone marrow-derived macrophages (BMDMs) into M2 macrophages. RESULTS: The M2 expression markers in the TUDCA-treated BMDM group were increased more than those in the GM-CSF-treated BMDM group. After the SCI and transplantation steps, pro-inflammatory cytokine levels and the mitogen-activated protein kinase (MAPK) pathway were significantly decreased in the TUDCA-induced M2 group more than they were in the GM-CSF-induced M1 group and in the TUDCA group. Moreover, the TUDCA-induced M2 group showed significantly enhanced tissue volumes and improved motor functions compared to the GM-CSF-induced M1 group and the TUDCA group. In addition, biotinylated dextran amine (BDA)-labelled corticospinal tract (CST) axons and neuronal nuclei marker (NeuN) levels were increased in the TUDCA-induced M2 group more than those in the GM-CSF-induced M1 group and the TUDCA group. CONCLUSIONS: This study demonstrates that the transplantation of TUDCA-induced M2 macrophages promotes an anti-neuroinflammatory effect and motor function recovery in SCI. Therefore, we suggest that the transplantation of TUDCA-induced M2 macrophages represents a possible alternative cell therapy for SCI.
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Macrófagos/trasplante , Traumatismos de la Médula Espinal/terapia , Ácido Tauroquenodesoxicólico/metabolismo , Animales , Células Cultivadas , Femenino , Inflamación/metabolismo , Inflamación/fisiopatología , Inflamación/terapia , Macrófagos/metabolismo , Ratas , Ratas Sprague-Dawley , Recuperación de la Función , Traumatismos de la Médula Espinal/metabolismo , Traumatismos de la Médula Espinal/fisiopatologíaRESUMEN
Bear bile has been used in Traditional Chinese Medicine for thousands of years due to its therapeutic potential and clinical applications. The tauroursodeoxycholic acid (TUDCA), one of the acids found in bear bile, is a hydrophilic bile acid and naturally produced in the liver by conjugation of taurine to ursodeoxycholic acid (UDCA). Several studies have shown that TUDCA has neuroprotective action in several models of neurodegenerative disorders (ND), including Alzheimer's disease, Parkinson's disease, and Huntington's disease, based on its potent ability to inhibit apoptosis, attenuate oxidative stress, and reduce endoplasmic reticulum stress in different experimental models of these illnesses. Our research extends the knowledge of the bile acid TUDCA actions in ND and the mechanisms and pathways involved in its cytoprotective effects on the brain, providing a novel perspective and opportunities for treatment of these diseases.
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Enfermedades Neurodegenerativas/tratamiento farmacológico , Ácido Tauroquenodesoxicólico/farmacología , Enfermedad de Alzheimer/tratamiento farmacológico , Animales , Apoptosis/efectos de los fármacos , Bilis/metabolismo , Ácidos y Sales Biliares/metabolismo , Estrés del Retículo Endoplásmico/efectos de los fármacos , Humanos , Medicina Tradicional China/métodos , Ácido Tauroquenodesoxicólico/metabolismo , Ácido Ursodesoxicólico/metabolismo , Ácido Ursodesoxicólico/farmacologíaRESUMEN
OBJECTIVE: The mechanism of nutrient sensing in the upper small intestine (USI) and ileum that regulates glucose homeostasis remains elusive. Short-term high-fat (HF) feeding increases taurochenodeoxycholic acid (TCDCA; an agonist of farnesoid X receptor (FXR)) in the USI and ileum of rats, and the increase of TCDCA is prevented by transplantation of microbiota obtained from the USI of healthy donors into the USI of HF rats. However, whether changes of TCDCA-FXR axis in the USI and ileum alter nutrient sensing remains unknown. METHODS: Intravenous glucose tolerance test was performed in rats that received USI or ileal infusion of nutrients (i.e., oleic acids or glucose) via catheters placed toward the lumen of USI and/or ileum, while mechanistic gain- and loss-of-function studies targeting the TCDCA-FXR axis or bile salt hydrolase activity in USI and ileum were performed. RESULTS: USI or ileum infusion of nutrients increased glucose tolerance in healthy but not HF rats. Transplantation of healthy microbiome obtained from USI into the USI of HF rats restored nutrient sensing and inhibited FXR via a reduction of TCDCA in the USI and ileum. Further, inhibition of USI and ileal FXR enhanced nutrient sensing in HF rats, while inhibiting USI (but not ileal) bile salt hydrolase of HF rats transplanted with healthy microbiome activated FXR and disrupted nutrient sensing in the USI and ileum. CONCLUSIONS: We reveal a TCDCA-FXR axis in both the USI and ileum that is necessary for the upper small intestinal microbiome to govern local nutrient-sensing glucoregulatory pathways in rats.
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Intestino Delgado/metabolismo , Nutrientes , Ácido Tauroquenodesoxicólico/metabolismo , Animales , Ácidos y Sales Biliares , Microbioma Gastrointestinal , Glucosa/metabolismo , Prueba de Tolerancia a la Glucosa , Homeostasis , Íleon/metabolismo , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
OBJECTIVE: Conjugated bile acids are metabolised by upper small intestinal microbiota, and serum levels of taurine-conjugated bile acids are elevated and correlated with insulin resistance in people with type 2 diabetes. However, whether changes in taurine-conjugated bile acids are necessary for small intestinal microbiome to alter insulin action remain unknown. DESIGN: We evaluated circulating and specifically brain insulin action using the pancreatic-euglycaemic clamps in high-fat (HF) versus chow fed rats with or without upper small intestinal healthy microbiome transplant. Chemical and molecular gain/loss-of-function experiments targeting specific taurine-conjugated bile acid-induced changes of farnesoid X receptor (FXR) in the brain were performed in parallel. RESULTS: We found that short-term HF feeding increased the levels of taurochenodeoxycholic acid (TCDCA, an FXR ligand) in the upper small intestine, ileum, plasma and dorsal vagal complex (DVC) of the brain. Transplantation of upper small intestinal healthy microbiome into the upper small intestine of HF rats not only reversed the rise of TCDCA in all reported tissues but also enhanced the ability of either circulating hyperinsulinaemia or DVC insulin action to lower glucose production. Further, DVC infusion of TCDCA or FXR agonist negated the enhancement of insulin action, while genetic knockdown or chemical inhibition of FXR in the DVC of HF rats reversed insulin resistance. CONCLUSION: Our findings indicate that FXR in the DVC is sufficient and necessary for upper small intestinal microbiome-mediated changes of TCDCA to alter insulin action in rats, and highlight a previously unappreciated TCDCA-FXR axis linking gut microbiome and host insulin action.
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Tronco Encefálico/fisiología , Microbioma Gastrointestinal/fisiología , Resistencia a la Insulina , Intestino Delgado/microbiología , Receptores Citoplasmáticos y Nucleares/metabolismo , Ácido Tauroquenodesoxicólico/metabolismo , Animales , Encéfalo/metabolismo , Química Encefálica , Tronco Encefálico/metabolismo , Dieta Alta en Grasa , Trasplante de Microbiota Fecal , Técnicas de Silenciamiento del Gen , Técnica de Clampeo de la Glucosa , Resistencia a la Insulina/fisiología , Intestino Delgado/metabolismo , Ratas , Receptores Citoplasmáticos y Nucleares/análisis , Ácido Tauroquenodesoxicólico/análisisRESUMEN
Hepatic cytochrome P450 reductase (EC 1.6.2.4, POR) deficient mice provide a useful means of investigating liver-related CYP450 drug metabolism. However, the organ-wide inactivation of CYP450s has wide ranging effects on liver physiology. Untargeted UHPLC-MS metabolic and lipid profiling of aqueous and organic solvent extracts has been employed to compare the metabolic phenotypes of livers obtained from either wild type (C57Bl6) or hepatic P450 reductase null (HRNTM) mice. The metabolic phenotyping of polar aqueous extracts revealed differences between wild type and HRNTM mice for bile acids with taurochendeoxycholic acid, and tauroursodeoxycholic acid increased in proportion in the latter and taurocholic acid reduced. Lipidomic profiling demonstrated that there were numerous differences in the lipidome, particularly relating to phospholipid synthesis with significant changes in the relative amounts of phosphatidylcholines (PC) and phosphatidylethanolamines (PE). These results illustrate the wide ranging disruptive effects on the normal hepatic phenotype that result from POR-deficiency in the the HRNTM animals.
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Lipidómica , Hígado/metabolismo , Metabolómica , NADPH-Ferrihemoproteína Reductasa/genética , Animales , Cromatografía Líquida de Alta Presión , Hígado/enzimología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Fenotipo , Fosfatidilcolinas/metabolismo , Fosfatidiletanolaminas/metabolismo , Ácido Tauroquenodesoxicólico/metabolismoRESUMEN
Multiple sclerosis (MS) is an inflammatory demyelinating disorder of the CNS. Bile acids are cholesterol metabolites that can signal through receptors on cells throughout the body, including in the CNS and the immune system. Whether bile acid metabolism is abnormal in MS is unknown. Using global and targeted metabolomic profiling, we identified lower levels of circulating bile acid metabolites in multiple cohorts of adult and pediatric patients with MS compared with controls. In white matter lesions from MS brain tissue, we noted the presence of bile acid receptors on immune and glial cells. To mechanistically examine the implications of lower levels of bile acids in MS, we studied the in vitro effects of an endogenous bile acid, tauroursodeoxycholic acid (TUDCA), on astrocyte and microglial polarization. TUDCA prevented neurotoxic (A1) polarization of astrocytes and proinflammatory polarization of microglia in a dose-dependent manner. TUDCA supplementation in experimental autoimmune encephalomyelitis reduced the severity of disease through its effects on G protein-coupled bile acid receptor 1 (GPBAR1). We demonstrate that bile acid metabolism was altered in MS and that bile acid supplementation prevented polarization of astrocytes and microglia to neurotoxic phenotypes and ameliorated neuropathology in an animal model of MS. These findings identify dysregulated bile acid metabolism as a potential therapeutic target in MS.
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Astrocitos/metabolismo , Microglía/metabolismo , Esclerosis Múltiple/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Ácido Tauroquenodesoxicólico , Animales , Astrocitos/patología , Modelos Animales de Enfermedad , Humanos , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Inflamación/patología , Ratones , Microglía/patología , Esclerosis Múltiple/tratamiento farmacológico , Esclerosis Múltiple/patología , Ácido Tauroquenodesoxicólico/metabolismo , Ácido Tauroquenodesoxicólico/farmacologíaRESUMEN
Cognitive decline is one of the complications of type 2 diabetes (T2D). Intermittent fasting (IF) is a promising dietary intervention for alleviating T2D symptoms, but its protective effect on diabetes-driven cognitive dysfunction remains elusive. Here, we find that a 28-day IF regimen for diabetic mice improves behavioral impairment via a microbiota-metabolites-brain axis: IF enhances mitochondrial biogenesis and energy metabolism gene expression in hippocampus, re-structures the gut microbiota, and improves microbial metabolites that are related to cognitive function. Moreover, strong connections are observed between IF affected genes, microbiota and metabolites, as assessed by integrative modelling. Removing gut microbiota with antibiotics partly abolishes the neuroprotective effects of IF. Administration of 3-indolepropionic acid, serotonin, short chain fatty acids or tauroursodeoxycholic acid shows a similar effect to IF in terms of improving cognitive function. Together, our study purports the microbiota-metabolites-brain axis as a mechanism that can enable therapeutic strategies against metabolism-implicated cognitive pathophysiologies.