RESUMEN

Clostridioides difficile is a major nosocomial pathogen, causing significant morbidity and mortality worldwide. Antibiotic usage, a major risk factor for Clostridioides difficile infection (CDI), disrupts the gut microbiota, allowing C. difficile to proliferate and cause infection, and can often lead to recurrent CDI (rCDI). Fecal microbiota transplantation (FMT) and live biotherapeutic products (LBPs) have emerged as effective treatments for rCDI and aim to restore colonization resistance provided by a healthy gut microbiota. However, much is still unknown about the mechanisms mediating their success. Bile acids, extensively modified by gut microbes, affect C. difficile's germination, growth, and toxin production while also shaping the gut microbiota and influencing host immune responses. Additionally, microbial interactions, such as nutrient competition and cross-feeding, contribute to colonization resistance against C. difficile and may contribute to the success of microbiota-focused therapeutics. Bile acids as well as other microbial mediated interactions could have implications for other diseases being treated with microbiota-focused therapeutics. This review focuses on the intricate interplay between bile acid modifications, microbial ecology, and host responses with a focus on C. difficile, hoping to shed light on how to move forward with the development of new microbiota mediated therapeutic strategies to combat rCDI and other intestinal diseases.

Asunto(s)

Ácidos y Sales Biliares , Clostridioides difficile , Infecciones por Clostridium , Trasplante de Microbiota Fecal , Microbioma Gastrointestinal , Ácidos y Sales Biliares/metabolismo , Humanos , Clostridioides difficile/fisiología , Infecciones por Clostridium/terapia , Infecciones por Clostridium/microbiología , Animales

RESUMEN

Bile acids (BAs) are cholesterol derivatives synthesized in the liver and released into the digestive tract to facilitate lipid uptake during the digestion process. Most of these BAs are reabsorbed and recycled back to the liver. Some of these BAs progress to other tissues through the bloodstream. The presence of BAs in the central nervous system (CNS) has been related to their capacity to cross the blood-brain barrier (BBB) from the systemic circulation. However, the expression of enzymes and receptors involved in their synthesis and signaling, respectively, support the hypothesis that there is an endogenous source of BAs with a specific function in the CNS. Over the last decades, BAs have been tested as treatments for many CNS pathologies, with beneficial effects. Although they were initially reported as neuroprotective substances, they are also known to reduce inflammatory processes. Most of these effects have been related to the activation of the Takeda G protein-coupled receptor 5 (TGR5). This review addresses the new challenges that face BA research for neuroscience, focusing on their molecular functions. We discuss their endogenous and exogenous sources in the CNS, their signaling through the TGR5 receptor, and their mechanisms of action as potential therapeutics for neuropathologies.

Asunto(s)

Ácidos y Sales Biliares , Sistema Nervioso Central , Receptores Acoplados a Proteínas G , Humanos , Receptores Acoplados a Proteínas G/metabolismo , Ácidos y Sales Biliares/metabolismo , Animales , Sistema Nervioso Central/metabolismo , Transducción de Señal , Barrera Hematoencefálica/metabolismo

RESUMEN

Non-alcoholic fatty liver disease (NAFLD) is one of the most common metabolic diseases encountered in clinical practice, which is characterized by the excessive accumulation of triglycerides (steatosis), and a variety of metabolic abnormalities including lipid metabolism and bile acid metabolism are closely related to NAFLD. In China, Gynostemma pentaphyllum is used as functional food and Chinese medicine to treat various diseases, especially NAFLD, for a long time. However, the active components that exert the main therapeutic effects and their mechanisms remain unclear. In this study, Gypensapogenin A was isolated from the total saponins of G. pentaphyllum and prepared as a liposomal delivery system. Gypensapogenin A liposomes could activate FXR, inhibit the expression of CYP7A1 and CYP8B1, increase the expression of CYP27A1, modulate the ratio of CA and CDCA, decrease the content of CA, and increase the content of CDCA, thus forming a virtuous cycle of activating FXR to play a role in lowering blood lipid levels.

Asunto(s)

Gynostemma , Metabolismo de los Lípidos , Liposomas , Receptores Citoplasmáticos y Nucleares , Receptores Citoplasmáticos y Nucleares/metabolismo , Liposomas/química , Metabolismo de los Lípidos/efectos de los fármacos , Humanos , Animales , Gynostemma/química , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Saponinas/farmacología , Saponinas/química , Células Hep G2 , Ratones , Ácidos y Sales Biliares/metabolismo , Hepatocitos/metabolismo , Hepatocitos/efectos de los fármacos

RESUMEN

AIMS: Beyond the pivotal roles of the gut microbiome in initiating physiological processes and modulating genetic factors, a query persists: Can a single gene mutation alter the abundance of the gut microbiome community? Not only this, but the intricate impact of gut microbiome composition on skin pigmentation has been largely unexplored. METHODS AND RESULTS: Based on these premises, our study examines the abundance of lipase-producing gut microbes about differential gene expression associated with bile acid synthesis and lipid metabolism-related blood metabolites in red (whole wild) and white (whole white wild and SCARB1-/- mutant) Oujiang colour common carp. Following the disruption of the SCARB1 gene in the resulting mutant fish with white body colour (SCARB1-/-), there is a notable decrease in the abundance of gut microbiomes (Bacillus, Staphylococcus, Pseudomonas, and Serratia) associated with lipase production. This reduction parallels the downregulation seen in wild-type white body colour fish (WW), as contrasting to the wild-type red body colour fish (WR). Meanwhile, in SCARB1-/- fish, there was a downregulation noted not only at the genetic and metabolic levels but also a decrease in lipase-producing bacteria. This consistency with WW contrasts significantly with WR. Similarly, genes involved in the bile acid synthesis pathway, along with blood metabolites related to lipid metabolism, exhibited downregulation in SCARB1-/- fish. CONCLUSIONS: The SCARB1 knockout gene blockage led to significant alterations in the gut microbiome, potentially influencing the observed reduction in carotenoid-associated skin pigmentation. Our study emphasizes that skin pigmentation is not only impacted by genetic factors but also by the gut microbiome. Meanwhile, the gut microbiome's adaptability can be rapidly shaped and may be driven by specific single-gene variations.

Asunto(s)

Carpas , Microbioma Gastrointestinal , Pigmentación de la Piel , Animales , Carpas/microbiología , Pigmentación de la Piel/genética , Lipasa/genética , Lipasa/metabolismo , Mutación , Metabolismo de los Lípidos , Ácidos y Sales Biliares/metabolismo , Bacterias/genética , Bacterias/metabolismo , Bacterias/aislamiento & purificación , Bacterias/clasificación

RESUMEN

Breastfeeding provides infection protection for several pathogens but not for noroviruses. Mechanisms explaining this discrepancy have been unclear. In this issue of Cell Host & Microbe, Peiper et al. demonstrate that while breastmilk protects mice from intestinal damage, it promotes neonatal murine norovirus infection due to maternal-derived bile acids.1.

Asunto(s)

Ácidos y Sales Biliares , Infecciones por Caliciviridae , Leche Humana , Norovirus , Animales , Ácidos y Sales Biliares/metabolismo , Infecciones por Caliciviridae/virología , Ratones , Leche Humana/virología , Leche Humana/química , Humanos , Femenino , Lactancia Materna , Gastroenteritis/virología

RESUMEN

Cholestatic liver injury results from the accumulation of toxic bile acids in the liver, presenting a therapeutic challenge with no effective treatment available to date. Andrographolide (AP) has exhibited potential as a treatment for cholestatic liver disease. However, its limited oral bioavailability poses a significant obstacle to harnessing its potent therapeutic properties and restricts its clinical utility. This limitation is potentially attributed to the involvement of gut microbiota in AP metabolism. In our study, employing pseudo-germ-free, germ-free and strain colonization animal models, along with 16S rRNA and shotgun metagenomic sequencing analysis, we elucidate the pivotal role played by gut microbiota in the C-sulfonate metabolism of AP, a process profoundly affecting its bioavailability and anti-cholestatic efficacy. Subsequent investigations pinpoint a specific enzyme, adenosine-5'-phosphosulfate (APS) reductase, predominantly produced by Desulfovibrio piger, which catalyzes the reduction of SO42- to HSO3-. HSO3- subsequently interacts with AP, targeting its C=C unsaturated double bond, resulting in the formation of the C-sulfonate metabolite, 14-deoxy-12(R)-sulfo andrographolide (APM). Inhibition of APS reductase leads to a notable enhancement in AP bioavailability and anti-cholestatic efficacy. Furthermore, employing RNA sequencing analysis and farnesoid X receptor (FXR) knockout mice, our findings suggest that AP may exert its anti-cholestatic effects by activating the FXR pathway to promote bile acid efflux. In summary, our study unveils the significant involvement of gut microbiota in the C-sulfonate metabolism of AP and highlights the potential benefits of inhibiting APS reductase to enhance its therapeutic effects. These discoveries provide valuable insights into enhancing the clinical applicability of AP as a promising treatment for cholestatic liver injury.

Asunto(s)

Disponibilidad Biológica , Diterpenos , Microbioma Gastrointestinal , Animales , Microbioma Gastrointestinal/efectos de los fármacos , Diterpenos/metabolismo , Diterpenos/farmacología , Ratones , Colestasis/metabolismo , Colestasis/tratamiento farmacológico , Colestasis/microbiología , Masculino , ARN Ribosómico 16S/genética , Ácidos y Sales Biliares/metabolismo , Bacterias/metabolismo , Bacterias/clasificación , Bacterias/genética , Bacterias/efectos de los fármacos , Bacterias/aislamiento & purificación , Humanos , Ratones Endogámicos C57BL , Hígado/metabolismo , Hígado/efectos de los fármacos , Receptores Citoplasmáticos y Nucleares/metabolismo , Receptores Citoplasmáticos y Nucleares/genética , Modelos Animales de Enfermedad

RESUMEN

During pregnancy, the maternal body undergoes a series of adaptative physiological changes, leading to a slight increase in serum bile acid (BA) levels. Although the fetal liver can synthesize BAs since the first trimester through the alternative pathway, the BA metabolic system is immature in the fetus. Compared to adults, the fetus has a distinct composition of BA pool and limited expression of BA synthesis enzymes and transporters. Besides, the "enterohepatic circulation" of BAs is absent in fetus. Thus, fetal BAs need to be transported to the mother through the placenta for further metabolism and excretion, and maternal BAs can also be transported to the fetus. That is what we call the "fetal-placental-maternal BA circulation". Various BA transporters and nuclear receptors are essential for maintaining the balance of this BA circulation to ensure normal fetal development. However, prenatal adverse environments can alter fetal BA metabolism, resulting in intrauterine developmental abnormalities and susceptibility to a variety of adult chronic diseases. This review summarizes the current understanding of the fetal-placental-maternal BA circulation and discusses the effects of prenatal adverse environments on this particular BA circulation, aiming to provide a theoretical basis for exploring early prevention and treatment strategies for BA metabolism-associated adverse pregnancy outcomes and long-term impairments.

Asunto(s)

Ácidos y Sales Biliares , Homeostasis , Intercambio Materno-Fetal , Placenta , Embarazo , Femenino , Ácidos y Sales Biliares/metabolismo , Ácidos y Sales Biliares/sangre , Humanos , Placenta/metabolismo , Feto/metabolismo , Animales , Efectos Tardíos de la Exposición Prenatal , Exposición Materna/efectos adversos , Desarrollo Fetal , Exposición a Riesgos Ambientales/efectos adversos

RESUMEN

Gut microbiota dysbiosis is involved in cholestatic liver diseases. However, the mechanisms remain to be elucidated. The purpose of this study was to examine the effects and mechanisms of Lactobacillus acidophilus (L. acidophilus) on cholestatic liver injury in both animals and humans. Bile duct ligation (BDL) was performed to mimic cholestatic liver injury in mice and serum liver function was tested. Gut microbiota were analyzed by 16S rRNA sequencing. Fecal bacteria transplantation (FMT) was used to evaluate the role of gut microbiota in cholestasis. Bile acids (BAs) profiles were analyzed by targeted metabolomics. Effects of L. acidophilus in cholestatic patients were evaluated by a randomized controlled clinical trial (NO: ChiCTR2200063330). BDL induced different severity of liver injury, which was associated with gut microbiota. 16S rRNA sequencing of feces confirmed the gut flora differences between groups, of which L. acidophilus was the most distinguished genus. Administration of L. acidophilus after BDL significantly attenuated hepatic injury in mice, decreased liver total BAs and increased fecal total BAs. Furthermore, after L. acidophilus treatment, inhibition of hepatic Cholesterol 7α-hydroxylase (CYP7α1), restored ileum Fibroblast growth factor 15 (FGF15) and Small heterodimer partner (SHP) accounted for BAs synthesis decrease, whereas enhanced BAs excretion was attributed to the increase of unconjugated BAs by enriched bile salt hydrolase (BSH) enzymes in feces. Similarly, in cholestasis patients, supplementation of L. acidophilus promoted the recovery of liver function and negatively correlated with liver function indicators, possibly in relationship with the changes in BAs profiles and gut microbiota composition. L. acidophilus treatment ameliorates cholestatic liver injury through inhibited hepatic BAs synthesis and enhances fecal BAs excretion.

Asunto(s)

Ácidos y Sales Biliares , Colestasis , Microbioma Gastrointestinal , Lactobacillus acidophilus , Hígado , Ratones Endogámicos C57BL , Probióticos , Ácidos y Sales Biliares/metabolismo , Animales , Colestasis/metabolismo , Colestasis/microbiología , Ratones , Humanos , Masculino , Probióticos/farmacología , Probióticos/administración & dosificación , Hígado/metabolismo , Heces/microbiología , Colesterol 7-alfa-Hidroxilasa/metabolismo , Colesterol 7-alfa-Hidroxilasa/genética , Femenino , Factores de Crecimiento de Fibroblastos/metabolismo , Factores de Crecimiento de Fibroblastos/genética , Trasplante de Microbiota Fecal , Disbiosis/microbiología , Disbiosis/terapia , ARN Ribosómico 16S/genética , Persona de Mediana Edad , Adulto , Modelos Animales de Enfermedad , Íleon/microbiología , Íleon/metabolismo

RESUMEN

Objective: To summarize the clinical features and genetic characteristics of Congenital bile acid synthetic disorder type 3 (BASD3) disorder caused by CYP7B1 gene variation. Methods: This was a case series study. Clinical data and genetic results of 2 cases of congenital bile acid synthetic disorder type 3 caused by CYP7B1 gene variations in the Department of Infectious Diseases, Children's Hospital of Fudan University at Xiamen and Department of Pediatrics, Women and Children's Hospital, School of Medicine, Xiamen University from January 2021 to December 2023 were retrospectively collected and analyzed. Literature up to December 2023 was searched from electronic databases of China National Knowledge Infrastructure (CNKI), Wanfang Data and PubMed with the combined keywords of " Congenital bile acid synthetic disorder type 3""Oxysterol 7-alpha-hydroxylase""Oxysterol 7α-Hydroxylase Deficiency""BASD3" and "CYP7B1 liver" both in Chinese and English. The main clinical features and genetic characteristics of BASD3 disorder caused by CYP7B1 gene variations were summarized. Results: Two BASD3 patients, 1 male and 1 female, were admitted at the ages of 3 months and 18 days, and 2 months and 7 days, respectively. Both patients presented with neonatal cholestasis and hepatomegaly. Biochemical evidence indicated direct hyper-bilirubinemia with elevated aminotransferase levels, while gamma-glutamyltransferase (GGT) and total bile acid levels were normal or nearly normal. Patient 1 was a compound heterozygotes of the CYP7B1 gene variants c.525-526insCAAGTTGG(p.Asp176GInfs*15) and c.334C>T(p.Arg112Ter). Patient 1 jaundice resolved and liver function tests normalized after oral administration of chenodeoxycholic acid (CDCA). Patient 2 was homozygous for variant c.334C>T(p.Arg112Ter) in CYP7B1 gene. Patient 2 was in liver failure status already and not reactive to oral CDCA administration. Patient 2 received living-related liver transplantation for enhanced abdominal CT revealed a liver tumor likely vascular origin. Literature review revealed no cases of BASD3 reported in Chinese literature, including 2 patients in this study, while 12 patients (9 males and 3 females) were reported in 9 English literatures. All of the 12 manifested jaundice and hepatosplenomegaly in infancy, with cirrhosis, liver failure, kidney enlargement, hypoglycemia, and spontaneous bleeding in some cases, polycystic kidney disease was demonstrated in 5 cases of them. The c.334C>T (p.Arg112Ter) of the CYP7B1 gene was homozygous in 4 cases and compound heterozygous in 2 cases. Among the 12 children, 6 cases received CDCA treatment, while 6 cases not. Four survived with their native liver in the 6 cases who received CDCA therapy, while none in the 6 cases not received CDCA therapy. Conclusions: BASD3 is a rare hereditary cholestatic disorder. Markedly elevated levels of conjugated bilirubin and aminotransferases, with normal or nearly normal GGT and total bile acid levels can serve as diagnostic clue. c.334C>T is the most common pathogenic variant of the CYP7B1 gene. Timely administration of CDCA may save the liver.

Asunto(s)

Ácidos y Sales Biliares , Familia 7 del Citocromo P450 , Mutación , Humanos , Familia 7 del Citocromo P450/genética , Masculino , Femenino , Ácidos y Sales Biliares/metabolismo , Ácidos y Sales Biliares/sangre , Lactante , Estudios Retrospectivos , Recién Nacido , Hígado/metabolismo , Esteroide Hidroxilasas

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Cholestatic liver diseases (CLD) are liver disorders resulting from abnormal bile formation, secretion, and excretion from various causes. Due to the lack of suitable and safe medications, liver transplantation is the ultimate treatment for CLD patients. Isoastragaloside I (IAS I) is one of the main saponin found in Astragalus membranaceus (Fisch.) Bge. var. mongholicus (Bge.) Hsiao or Astragalus membranaceus (Fisch.) Bge, which has been demonstrated to obviously alleviate CLD. Nevertheless, the IAS I's specific anti-CLD mechanism remains undecipherable. AIM OF THE STUDY: This study's purpose was to elucidate the protective consequence of IAS I on 0.1% 3, 5-diethoxycarbonyl-1,4-dihydroxychollidine (DDC) diet-induced CLD mice, and to reveal its potential mechanism. MATERIALS AND METHODS: In this study, mice with CLD that had been fed a 0.1% DDC diet were distributed two doses of IAS I (20 mg/kg, 50 mg/kg). The effects of IAS I on CLD models were investigated by assessing blood biochemistry, liver histology, and Hyp concentrations. We investigated markers of liver fibrosis and ductular reaction using immunohistochemistry, Western blot, and qRT-PCR. Liver inflammation indicators, arachidonic acid (ARA), and ω-3 fatty acid (FA) metabolites were also analyzed. Quantitative determination of 39 bile acids (BAs) in different organs employing UHPLC-Q-Exactive Orbitrap HRMS technology. Additionally, the H&E and Western blot analysis were used to evaluate differences in intestinal barrier function in DDC-induced mice before and after administering IAS I. RESULTS: After treatment with IAS I, serum biochemical indicators and liver hydroxyproline (Hyp) increased in a dose-dependent manner in CLD mice. The IAS I group showed significant improvement in indicators of liver fibrosis and ductular response, including as α-smooth muscle actin (α-SMA) and cytokeratin 19 (CK19), and transforming growth factor-ß (TGF-ß)/Smads signaling pathway. And inflammatory factors: F4/80, tumor necrosis factor-α (TNF-α), Interleukin-1ß (IL-1ß), ARA and ω-3 FA metabolites showed significant improvement following IAS I treatment. Moreover, IAS I significantly ameliorated liver tau-BAs levels, particularly TCA, THCA, THDCA, TCDCA, and TDCA contents, which were associated with enhanced expression of hepatic farnesoid X receptor (FXR), small heterodimer partner (SHP), cholesterol 7α-hydroxylase (Cyp7a1), and bile-salt export pump (BSEP). Furthermore, IAS I significantly improved pathological changes and protein expression related to intestinal barrier function, including zonula occludens protein 1 (ZO-1), Muc2, and Occludin. CONCLUSIONS: IAS I alleviated cholestatic liver injury, relieved inflammation, improved the altered tau-BAs metabolism and restored intestinal barrier function to protect against DDC-induced cholestatic liver diseases.

Asunto(s)

Ácidos y Sales Biliares , Colestasis , Saponinas , Animales , Ácidos y Sales Biliares/metabolismo , Masculino , Ratones , Colestasis/tratamiento farmacológico , Colestasis/metabolismo , Colestasis/patología , Saponinas/farmacología , Saponinas/uso terapéutico , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Ratones Endogámicos C57BL , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Hepatopatías/tratamiento farmacológico , Hepatopatías/metabolismo , Hepatopatías/patología , Hepatopatías/prevención & control , Modelos Animales de Enfermedad , Medicamentos Herbarios Chinos

RESUMEN

5ß-Dihydrosteroids are produced by the reduction of Δ4-3-ketosteroids catalyzed by steroid 5ß-reductase (AKR1D1). By analogy with steroid 5α-reductase, genetic deficiency exists in AKR1D1 which leads to errors in newborn metabolism and in this case to bile acid deficiency. Also, like the 5α-dihydrosteroids (e.g., 5α-dihydrotestosterone), the 5ß-dihydrosteroids produced by AKR1D1 are not inactive but regulate ligand access to nuclear receptors, can act as ligands for nuclear and membrane-bound receptors, and regulate ion-channel opening. For example, 5ß-reduction of cortisol and cortisone yields the corresponding 5ß-dihydroglucocorticoids which are inactive on the glucocorticoid receptor (GR) and provides an additional mechanism of pre-receptor regulation of ligands for the GR in liver cells. By contrast, 5ß-pregnanes can act as neuroactive steroids at the GABAA and NMDA receptors and at low-voltage-activated calcium channels, act as tocolytic agents, have analgesic activity and act as ligands for PXR, while bile acids act as ligands for FXR and thereby control cholesterol homeostasis. The 5ß-androstanes also have potent vasodilatory properties and work through blockade of Ca2+ channels. Thus, a preference for 5ß-dihydrosteroids to work at the membrane level exists via a variety of mechanisms. This article reviews the field and identifies gaps in knowledge to be addressed in future research.

Asunto(s)

Ácidos y Sales Biliares , Humanos , Animales , Ácidos y Sales Biliares/metabolismo , Oxidorreductasas/metabolismo

RESUMEN

BACKGROUND: Bariatric surgery is an effective treatment option for obesity and provides long-term weight loss and positive effects on metabolism, but the underlying mechanisms are poorly understood. Alterations in bile acid metabolism have been suggested as a potential contributing factor, but comprehensive studies in humans are lacking. METHODS: In this study, we analysed the postprandial responses of bile acids, C4 and FGF19 in plasma, and excretion of bile acids in faeces, before and after bariatric surgery in patients (n = 38; 74% females) with obesity with or without type 2 diabetes from the BARIA cohort. FINDINGS: We observed that total fasting plasma bile acid levels increased, and faecal excretion of bile acids decreased after surgery suggesting increased reabsorption of bile acids. Consistent with increased bile acid levels after surgery we observed increased postprandial levels of FGF19 and suppression of the bile acid synthesis marker C4, suggesting increased FXR activation in the gut. We also noted that a subset of bile acids had altered postprandial responses before and after surgery. Finally, fasting plasma levels of 6α-hydroxylated bile acids, which are TGR5 agonists and associated with improved glucose metabolism, were increased after surgery and one of them, HDCA, covaried with diabetes remission in an independent cohort. INTERPRETATION: Our findings provide new insights regarding bile acid kinetics and suggest that bariatric surgery in humans alters bile acid profiles leading to activation of FXR and TGR5, which may contribute to weight loss, improvements in glucose metabolism, and diabetes remission. FUNDING: Novo Nordisk Fonden, Leducq Foundation, Swedish Heart-Lung Foundation, Knut and Alice Wallenberg Foundation, the ALF-agreement, ZonMw.

Asunto(s)

Cirugía Bariátrica , Ácidos y Sales Biliares , Diabetes Mellitus Tipo 2 , Factores de Crecimiento de Fibroblastos , Obesidad , Humanos , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/cirugía , Diabetes Mellitus Tipo 2/sangre , Ácidos y Sales Biliares/metabolismo , Ácidos y Sales Biliares/sangre , Cirugía Bariátrica/métodos , Femenino , Masculino , Obesidad/cirugía , Obesidad/metabolismo , Obesidad/sangre , Persona de Mediana Edad , Adulto , Factores de Crecimiento de Fibroblastos/sangre , Factores de Crecimiento de Fibroblastos/metabolismo , Periodo Posprandial , Biomarcadores , Heces/química , Cinética , Ayuno

RESUMEN

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is a major clinical and global public health issue, with no specific pharmacological treatment available. Currently, there is a lack of approved drugs for the clinical treatment of NAFLD. Large-leaf yellow tea polysaccharides (YTP) is a natural biomacromolecule with excellent prebiotic properties and significant therapeutic effects on multiple metabolic diseases. However, the specific mechanisms by which YTP regulates NAFLD remain unclear. PURPOSE: This study aims to explore the prebiotic effects of YTP and the potential mechanisms by which it inhibits hepatic cholesterol accumulation in NAFLD mice. METHODS: The effects of YTP on lipid accumulation were evaluated in NAFLD mice through obesity trait analysis and bile acids (BAs) metabolism assessment. Additionally, fecal microbiota transplantation (FMT) was performed, and high-throughput sequencing was employed to investigate the mechanisms underlying YTP's regulatory effects on gut microbiota and BA metabolism. RESULTS: Our study demonstrated that YTP altered the constitution of colonic BA, particularly increasing the levels of conjugated BA and non-12OH BA, which suppressed ileum FXR receptors and hepatic BA reabsorption, facilitated BA synthesis, and fecal BA excretion. The modifications were characterized by a decrease in the levels of FXR, FGF15, FGFR4, and ASBT proteins, and an increase in the levels of Cyp7a1 and Cyp27a1 proteins. YTP might affect enterohepatic circulation and by the activated the hepatic FXR-SHP pathway. Meanwhile, YTP reshaped the intestinal microbiome structure by decreasing BSH-producing genera and increasing taurine metabolism genera. The correlation analysis implied that Muribaculaceae, Pseudomonas, acterium_coprostanoligenes_group, Clostridiales, Lachnospiraceae_NK4A136_group, Delftia, Dubosiella, and Romboutsia were strongly correlated with specific BA monomers. CONCLUSIONS: YTP modulates bile salt hydrolase-related microbial genera to activate alternative bile acid synthesis pathways, thereby inhibiting NAFLD progression. These results suggest that YTP may serve as a potential probiotic formulation, offering a feasible dietary intervention for NAFLD.

Asunto(s)

Ácidos y Sales Biliares , Trasplante de Microbiota Fecal , Microbioma Gastrointestinal , Ratones Endogámicos C57BL , Enfermedad del Hígado Graso no Alcohólico , Polisacáridos , Té , Animales , Enfermedad del Hígado Graso no Alcohólico/prevención & control , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Microbioma Gastrointestinal/efectos de los fármacos , Ácidos y Sales Biliares/metabolismo , Polisacáridos/farmacología , Masculino , Ratones , Té/química , Hígado/efectos de los fármacos , Hígado/metabolismo , Prebióticos , Factores de Crecimiento de Fibroblastos/metabolismo , Receptores Citoplasmáticos y Nucleares/metabolismo , Amidohidrolasas/metabolismo

RESUMEN

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Asunto(s)

Ácidos y Sales Biliares , Dieta Alta en Grasa , Medicamentos Herbarios Chinos , Microbioma Gastrointestinal , Macrófagos , Ratones Endogámicos C57BL , Obesidad , Termogénesis , Animales , Dieta Alta en Grasa/efectos adversos , Microbioma Gastrointestinal/efectos de los fármacos , Obesidad/tratamiento farmacológico , Medicamentos Herbarios Chinos/farmacología , Masculino , Ácidos y Sales Biliares/metabolismo , Termogénesis/efectos de los fármacos , Ratones , Macrófagos/efectos de los fármacos , Tejido Adiposo Blanco/efectos de los fármacos , Prueba de Tolerancia a la Glucosa , Modelos Animales de Enfermedad

RESUMEN

BACKGROUND: Silymarin is recognized for its excellent hepato-protective properties. Recent clinical studies have examined the effects of silymarin on metabolic dysfunction-associated steatotic liver disease (MASLD), highlighting the necessity of further exploration into optimal dosages, active components, and mechanisms of action. METHODS AND RESULTS: This study assessed the anti-inflammatory activity of the principal constituents of silymarin at the cellular level. The therapeutic effects of varying silymarin doses and components on MASLD in mouse models induced by a high-fat diet (HFD) were also examined. These findings indicate the superior efficacy of 80 mg kg-1 silymarin in mitigating liver steatosis and reducing lipid accumulation compared to 30 mg kg-1 silymarin or a combination of silybin and isosilybin A. The mechanism of silymarin involves regulating gut microbiota homeostasis and influencing the TLR4/NF-κB signalling pathway through LPS. Bile acid-targeted metabolomics analysis revealed that silymarin significantly decreases the HFD-induced increase in 7-keto-deoxycholic acid (7-KDCA). Further investigations suggested that 7-KDCA as an antagonist targeted farnesoid X receptor (FXR) and that both silybin and isosilybin A could directly interact with FXR. CONCLUSION: These findings elucidate that 80 mg kg-1 of silymarin can exert therapeutic effects on MASLD mice and offer novel insights into the mechanism of silymarin in treating MASLD. Especially, it was found that silymarin could regulate bile acid metabolism, reduce the concentration of 7-KDCA, and thus perform negative feedback regulation on FXR.

Asunto(s)

Ácido Desoxicólico , Dieta Alta en Grasa , Microbioma Gastrointestinal , Ratones Endogámicos C57BL , Receptores Citoplasmáticos y Nucleares , Silimarina , Animales , Silimarina/farmacología , Receptores Citoplasmáticos y Nucleares/metabolismo , Masculino , Ratones , Ácido Desoxicólico/farmacología , Microbioma Gastrointestinal/efectos de los fármacos , Silibina/farmacología , Transducción de Señal/efectos de los fármacos , Humanos , FN-kappa B/metabolismo , Ácidos y Sales Biliares/metabolismo , Hígado Graso/tratamiento farmacológico , Ratones Obesos , Obesidad/tratamiento farmacológico , Obesidad/metabolismo , Receptor Toll-Like 4/metabolismo , Modelos Animales de Enfermedad , Hígado/efectos de los fármacos , Hígado/metabolismo , Células Hep G2

RESUMEN

We have with great interest read the recent review on the molecular mechanisms underlying bile acid diarrhea (BAD) by Yang et al [...].

Asunto(s)

Ácidos y Sales Biliares , Diarrea , Medicina de Precisión , Ácidos y Sales Biliares/metabolismo , Diarrea/diagnóstico , Diarrea/metabolismo , Diarrea/tratamiento farmacológico , Diarrea/terapia , Humanos , Medicina de Precisión/métodos

RESUMEN

A mechanistic understanding of host-microbe interactions in the gut microbiome is hindered by poorly annotated bacterial genomes. While functional genomics can generate large gene-to-phenotype datasets to accelerate functional discovery, their applications to study gut anaerobes have been limited. For instance, most gain-of-function screens of gut-derived genes have been performed in Escherichia coli and assayed in a small number of conditions. To address these challenges, we develop Barcoded Overexpression BActerial shotgun library sequencing (Boba-seq). We demonstrate the power of this approach by assaying genes from diverse gut Bacteroidales overexpressed in Bacteroides thetaiotaomicron. From hundreds of experiments, we identify new functions and phenotypes for 29 genes important for carbohydrate metabolism or tolerance to antibiotics or bile salts. Highlights include the discovery of a D-glucosamine kinase, a raffinose transporter, and several routes that increase tolerance to ceftriaxone and bile salts through lipid biosynthesis. This approach can be readily applied to develop screens in other strains and additional phenotypic assays.

Asunto(s)

Ácidos y Sales Biliares , Carbono , Microbioma Gastrointestinal , Carbono/metabolismo , Microbioma Gastrointestinal/genética , Ácidos y Sales Biliares/metabolismo , Antibacterianos/farmacología , Estrés Fisiológico/genética , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Bacteroides thetaiotaomicron/genética , Bacteroides thetaiotaomicron/metabolismo , Regulación Bacteriana de la Expresión Génica , Bacteroidetes/genética , Bacteroidetes/metabolismo , Metabolismo de los Hidratos de Carbono/genética , Humanos , Genes Bacterianos/genética , Escherichia coli/genética , Escherichia coli/metabolismo , Genoma Bacteriano

RESUMEN

Acute graft-versus-host disease (aGVHD) is primarily driven by allogeneic donor T cells associated with an altered composition of the host gut microbiome and its metabolites. The severity of aGVHD after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is not solely determined by the host and donor characteristics; however, the underlying mechanisms remain unclear. Using single-cell RNA sequencing, we decoded the immune cell atlas of 12 patients who underwent allo-HSCT: six with aGVHD and six with non-aGVHD. We performed a fecal microbiota (16SrRNA sequencing) analysis to investigate the fecal bacterial composition of 82 patients: 30 with aGVHD and 52 with non-aGVHD. Fecal samples from these patients were analyzed for bile acid metabolism. Through multi-omic analysis, we identified a feedback loop involving "immune cell-gut microbes-bile acid metabolites" contributing to heightened immune responses in patients with aGVHD. The dysbiosis of the gut microbiota and disruption of bile acid metabolism contributed to an exaggerated interleukin-1 mediated immune response. Our findings suggest that resistin and defensins are crucial in mitigating against aGVHD. Therefore, a comprehensive multi-omic atlas incorporating immune cells, gut microbes, and bile acid metabolites was developed in this study and used to propose novel, non-immunosuppressive approaches to prevent aGVHD.

Asunto(s)

Ácidos y Sales Biliares , Heces , Microbioma Gastrointestinal , Enfermedad Injerto contra Huésped , Ácidos y Sales Biliares/metabolismo , Humanos , Enfermedad Injerto contra Huésped/inmunología , Enfermedad Injerto contra Huésped/microbiología , Microbioma Gastrointestinal/inmunología , Femenino , Masculino , Heces/microbiología , Persona de Mediana Edad , Enfermedad Aguda , Adulto , Retroalimentación Fisiológica , Inmunidad , Metabolómica , Trasplante de Células Madre Hematopoyéticas , Multiómica

RESUMEN

The incidence of duodenal tumors (DTs) is increasing. However, the mechanisms underlying its development remain unclear. Environmental factors, including the microbiome and bile acids (BAs), are believed to influence tumor development. Therefore, we conducted a single-center, prospective, observational study to investigate the potential differences between patients with DTs and healthy controls (HCs) based on these factors. In addition, the BAs in the duodenal fluid were measured using liquid chromatography-tandem mass spectrometry. We recruited 41 patients and performed 16S rRNA-seq. There was no difference in the observed ASVs or PCoA plot of Bray-Curtis dissimilarity between the DTs and HCs. The lithocholic acid concentration was significantly lower in the DT group than in the control group. The ratio of CDCA to LCA was significantly higher in patients with DTs. No significant differences in microbiota were observed between DTs and HCs. In patients with DTs, the lithocholic acid concentration in duodenal was significantly lower than in HCs.

Asunto(s)

Ácidos y Sales Biliares , Neoplasias Duodenales , Duodeno , Microbioma Gastrointestinal , ARN Ribosómico 16S , Humanos , Masculino , Ácidos y Sales Biliares/metabolismo , Femenino , Estudios Prospectivos , Persona de Mediana Edad , Neoplasias Duodenales/microbiología , Neoplasias Duodenales/metabolismo , Duodeno/metabolismo , Duodeno/microbiología , Anciano , ARN Ribosómico 16S/genética , Adulto , Ácido Litocólico/metabolismo , Microbiota , Estudios de Casos y Controles

RESUMEN

Antibiotics cause collateral damage to resident microbes that is associated with various health risks. To date, studies have largely focused on the impacts of antibiotics on large intestinal and fecal microbiota. Here, we employ a gastrointestinal (GI) tract-wide integrated multiomic approach to show that amoxicillin (AMX) treatment reduces bacterial abundance, bile salt hydrolase activity, and unconjugated bile acids in the small intestine (SI). Losses of fatty acids (FAs) and increases in acylcarnitines in the large intestine (LI) correspond with spatially distinct expansions of Proteobacteria. Parasutterella excrementihominis engage in FA biosynthesis in the SI, while multiple Klebsiella species employ FA oxidation during expansion in the LI. We subsequently demonstrate that restoration of unconjugated bile acids can mitigate losses of commensals in the LI while also inhibiting the expansion of Proteobacteria during AMX treatment. These results suggest that the depletion of bile acids and lipids may contribute to AMX-induced dysbiosis in the lower GI tract.

Asunto(s)

Amoxicilina , Ácidos y Sales Biliares , Ácidos y Sales Biliares/metabolismo , Animales , Amoxicilina/farmacología , Ratones , Microbioma Gastrointestinal/efectos de los fármacos , Ratones Endogámicos C57BL , Antibacterianos/farmacología , Proteobacteria/metabolismo , Proteobacteria/efectos de los fármacos , Ácidos Grasos/metabolismo , Masculino , Microbiota/efectos de los fármacos