Molecular Basis of Bile Acid-FXR-FGF15/19 Signaling Axis

International Journal of Molecular Sciences, Год журнала: 2022, Номер 23(11), С. 6046 - 6046

Опубликована: Май 27, 2022

Bile acids (BAs) are a group of amphiphilic molecules consisting rigid steroid core attached to hydroxyl with varying number, position, and orientation, hydrophilic side chain. While BAs act as detergents solubilize lipophilic nutrients in the small intestine during digestion absorption, they also hormones. Farnesoid X receptor (FXR) is nuclear that forms heterodimer retinoid α (RXRα), activated by enterohepatic circulation reabsorbed via transporters ileum colon, plays critical role regulating gene expression involved cholesterol, BA, lipid metabolism liver. The FXR/RXRα exists distal regulates production fibroblast growth factor (FGF) 15/FGF19, hormone traveling activates hepatic FGF 4 (FGFR4)-β-klotho complex metabolism, well those cell proliferation. Agonists for FXR analogs FGF15/19 currently recognized promising therapeutic target metabolic syndrome cholestatic diseases.

Язык: Английский

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Bile acid metabolism and signaling in health and disease: molecular mechanisms and therapeutic targets

Signal Transduction and Targeted Therapy, Год журнала: 2024, Номер 9(1)

Опубликована: Апрель 25, 2024

Bile acids, once considered mere dietary surfactants, now emerge as critical modulators of macronutrient (lipid, carbohydrate, protein) metabolism and the systemic pro-inflammatory/anti-inflammatory balance. acid signaling pathways play a crucial role in protecting against, or if aberrant, inducing cardiometabolic, inflammatory, neoplastic conditions, strongly influencing health disease. No curative treatment exists for any bile influenced disease, while most promising well-developed therapeutic was recently rejected by FDA. Here, we provide bottom-up approach on mechanistically explaining their biochemistry, physiology, pharmacology at canonical non-canonical receptors. Using this mechanistic model explain how abnormal physiology drives disease pathogenesis, emphasizing ceramide synthesis may serve unifying pathogenic feature cardiometabolic diseases. We an in-depth summary pre-existing receptor modulators, shortcomings, propose solutions they be remedied. Lastly, rationalize novel targets further translational drug discovery future perspectives. Rather than dismissing therapeutics due to recent setbacks, believe that there is immense clinical potential high likelihood success therapeutics.

Язык: Английский

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The underappreciated diversity of bile acid modifications

Cell, Год журнала: 2024, Номер 187(7), С. 1801 - 1818.e20

Опубликована: Март 1, 2024

The repertoire of modifications to bile acids and related steroidal lipids by host microbial metabolism remains incompletely characterized. To address this knowledge gap, we created a reusable resource tandem mass spectrometry (MS/MS) spectra filtering 1.2 billion publicly available MS/MS for bile-acid-selective ion patterns. Thousands are distributed throughout animal human bodies as well cultures. We employed library identify polyamine amidates, prevalent in carnivores. They present humans, their levels alter with diet change from Mediterranean typical American diet. This work highlights the existence many more acid than previously recognized value leveraging public large-scale untargeted metabolomics data discover metabolites. availability modification-centric will inform future studies investigating roles health disease.

Язык: Английский

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The double-edged sword of probiotic supplementation on gut microbiota structure in Helicobacter pylori management

Gut Microbes, Год журнала: 2022, Номер 14(1)

Опубликована: Авг. 11, 2022

As Helicobacter pylori management has become more challenging and less efficient over the last decade, interest in innovative interventions is growing by day. Probiotic co-supplementation to antibiotic therapies reported several studies, presenting a moderate reduction drug-related side effects promotion positive treatment outcomes. However, significance of gut microbiota involvement competence probiotic emphasized few researchers, indicating alteration host gastrointestinal following drug uptake. Due lack long-term follow-up studies determine efficiency intervention H. eradication, delicate interaction with wellness, this review aims discuss predict comprehensive effectiveness oral administration.Abbreviations: acyl-CoA- acyl-coenzyme A; AMP- antimicrobial peptide; AMPK- AMP-activated protein kinase; AP-1- activator 1; BA- bile acid; BAR- acid receptor; BCAA- branched-chain amino C2- acetate; C3- propionate; C4- butyrate; C5- valeric CagA- Cytotoxin-associated gene cAMP- cyclic adenosine monophosphate; CD- Crohn's disease; CDI- C. difficile infection; COX-2- cyclooxygenase-2; DC- dendritic cell; EMT- epithelial-mesenchymal transition; FMO- flavin monooxygenases; FXR- farnesoid X GPBAR1- G-protein-coupled receptor GPR4- G protein-coupled 4; H2O2- hydrogen peroxide; HCC- hepatocellular carcinoma; HSC- hepatic stellate IBD- inflammatory bowel IBS- irritable syndrome; IFN-γ- interferon-gamma; IgA immunoglobulin IL- interleukin; iNOS- induced nitric oxide synthase; JAK1- janus kinase JAM-A- junctional adhesion molecule LAB- lactic bacteria; LPS- lipopolysaccharide; MALT- mucosa-associated lymphoid tissue; MAMP- microbe-associated molecular pattern; MCP-1- monocyte chemoattractant protein-1; MDR- multiple resistance; mTOR- mammalian target rapamycin; MUC- mucin; NAFLD- nonalcoholic fatty liver NF-κB- nuclear factor kappa B; NK- natural killer; NLRP3- NLR family pyrin domain containing 3; NOC- N-nitroso compounds; NOD- nucleotide-binding oligomerization domain; PICRUSt- phylogenetic investigation communities reconstruction unobserved states; PRR- pattern recognition RA- retinoic RNS- reactive nitrogen species; ROS- oxygen rRNA- ribosomal RNA; SCFA- short-chain acids; SDR- single SIgA- secretory STAT3- signal transducer transcription T1D- type 1 diabetes; T2D- 2 Th17- T helper 17; TLR- toll-like TMAO- trimethylamine N-oxide; TML- trimethyllysine; TNF-α- tumor necrosis factor-alpha; Tr1- regulatory Treg- UC- ulcerative colitis; VacA- Vacuolating toxin A.

Язык: Английский

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Dysbiosis of Gut Microbiota from the Perspective of the Gut–Brain Axis: Role in the Provocation of Neurological Disorders

Metabolites, Год журнала: 2022, Номер 12(11), С. 1064 - 1064

Опубликована: Ноя. 3, 2022

The gut-brain axis is a bidirectional communication network connecting the gastrointestinal tract and central nervous system. keeps track of activities integrates them to connect gut health higher cognitive parts brain. Disruption in this connection may facilitate various neurological problems. Neurodegenerative diseases are characterized by progressive dysfunction specific populations neurons, determining clinical presentation. Misfolded protein aggregates that cause cellular toxicity aid collapse proteostasis defining characteristic neurodegenerative proteinopathies. These disorders not only caused changes neural compartment but also due other factors non-neural origin. Mounting data reveal majority (GI) physiologies mechanics governed system (CNS). Furthermore, microbiota plays critical role regulation physiological function brain, although mechanism involved has yet been fully interpreted. One emerging explanations start progression many illnesses dysbiosis microbial makeup. present understanding literature surrounding relationship between intestinal emergence certain diseases, such as Alzheimer's disease, Parkinson's Huntington's multiple sclerosis, main emphasis review. potential entry pathway pathogen-associated secretions toxins into CNS explored article at outset neuropathology. We have included possible undelaying synergistic effect infections, their metabolites, interactions based on current understanding.

Язык: Английский

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Bile salt hydrolase acyltransferase activity expands bile acid diversity

Nature, Год журнала: 2024, Номер 626(8000), С. 852 - 858

Опубликована: Фев. 7, 2024

Язык: Английский

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The changing metabolic landscape of bile acids – keys to metabolism and immune regulation

Nature Reviews Gastroenterology & Hepatology, Год журнала: 2024, Номер 21(7), С. 493 - 516

Опубликована: Апрель 4, 2024

Язык: Английский

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Interaction between gut microbiota and sex hormones and their relation to sexual dimorphism in metabolic diseases

Biology of Sex Differences, Год журнала: 2023, Номер 14(1)

Опубликована: Фев. 7, 2023

Metabolic diseases, such as obesity, metabolic syndrome (MetS) and type 2 diabetes (T2D), are now a widespread pandemic in the developed world. These pathologies show sex differences their development prevalence, steroids, mainly estrogen testosterone, thought to play prominent role this sexual dimorphism. The influence of hormones on these is not only reflected between men women, but also women themselves, depending hormonal changes associated with menopause. observed gut microbiota composition have led multiple studies highlighting interaction steroid its ultimately pointing new therapy for diseases based manipulation microbiota. This review aims shed light prevalence focusing MetS T2D. We focus microbiota, particular aspects barrier integrity, inflammatory status, gut-brain axis, given relevance factors diseases.

Язык: Английский

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Herba Origani alleviated DSS-induced ulcerative colitis in mice through remolding gut microbiota to regulate bile acid and short-chain fatty acid metabolisms

Biomedicine & Pharmacotherapy, Год журнала: 2023, Номер 161, С. 114409 - 114409

Опубликована: Фев. 22, 2023

This study aimed to investigate the protective effect of Herba Origani, dried whole herb Origanum vulgare L., on dextran sodium sulfate (DSS)-induced ulcerative colitis in mice and explore its mechanisms action through analyzing intestinal microbiota cecum contents metabolites colonic tissues. HOEP alleviated symptoms, inflammation pathological injury as well repaired barrier function DSS-induced UC mice. The analysis showed that restored gut dysbiosis DSS-treated by increasing alpha diversity microbiota, abundance Bacteroidota community adjusting short-chain fatty acids (SCFAs), which maintain mucosal immunity barrier. Metabolomic revealed promoted bile absorption regulated metabolism intestine, thereby maintaining immune homeostasis. In addition, might also regulate system phosphatidylinositol signaling system. These findings suggested exerted promising protection against remolding acid SCFA metabolism, have a potential be utilized for treatment inflammatory diseases.

Язык: Английский

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Gut microbiota derived bile acid metabolites maintain the homeostasis of gut and systemic immunity

Frontiers in Immunology, Год журнала: 2023, Номер 14

Опубликована: Май 15, 2023

Bile acids (BAs) as cholesterol-derived molecules play an essential role in some physiological processes such nutrient absorption, glucose homeostasis and regulation of energy expenditure. They are synthesized the liver primary BAs cholic acid (CA), chenodeoxycholic (CDCA) conjugated forms. A variety secondary deoxycholic (DCA) lithocholic (LCA) their derivatives is intestine through involvement various microorganisms. In addition to functions, metabolites also involved differentiation functions innate adaptive immune cells macrophages (Macs), dendritic (DCs), myeloid derived suppressive (MDSCs), regulatory T (Treg), Breg cells, helper (Th)17 CD4 Th1 Th2 CD8 B NKT cells. Dysregulation affects development diseases inflammatory bowel diseases. We here summarize recent advances how maintain gut systemic homeostasis, including metabolism derivatives, function effects on immune-associated disorders.

Язык: Английский

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