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

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(11), P. 6046 - 6046

Published: May 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.

Language: Английский

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

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: April 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.

Language: Английский

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

Gut Microbes, Journal Year: 2022, Volume and Issue: 14(1)

Published: Aug. 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.

Language: Английский

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The role of the gut microbiota in health and cardiovascular diseases

Molecular Biomedicine, Journal Year: 2022, Volume and Issue: 3(1)

Published: Oct. 11, 2022

Abstract The gut microbiota is critical to human health, such as digesting nutrients, forming the intestinal epithelial barrier, regulating immune function, producing vitamins and hormones, metabolites interact with host. Meanwhile, increasing evidence indicates that has a strong correlation occurrence, progression treatment of cardiovascular diseases (CVDs). In patients CVDs corresponding risk factors, composition ratio have significant differences compared their healthy counterparts. Therefore, dysbiosis, microbiota-generated metabolites, related signaling pathway may serve explanations for some mechanisms about occurrence development CVDs. Several studies also demonstrated many traditional latest therapeutic treatments are associated its generated pathways. Given information, we summarized advances in current research regarding effect on main CVDs, highlighted roles several introduced promising microbiota. this review mainly focuses exploring role potential which eventually provide better solutions well prevention

Language: 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, Journal Year: 2022, Volume and Issue: 12(11), P. 1064 - 1064

Published: Nov. 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.

Language: Английский

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The underappreciated diversity of bile acid modifications

Cell, Journal Year: 2024, Volume and Issue: 187(7), P. 1801 - 1818.e20

Published: March 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.

Language: Английский

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Bile salt hydrolase acyltransferase activity expands bile acid diversity

Nature, Journal Year: 2024, Volume and Issue: 626(8000), P. 852 - 858

Published: Feb. 7, 2024

Language: 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, Journal Year: 2023, Volume and Issue: 14(1)

Published: Feb. 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.

Language: Английский

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

Nature Reviews Gastroenterology & Hepatology, Journal Year: 2024, Volume and Issue: 21(7), P. 493 - 516

Published: April 4, 2024

Language: 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, Journal Year: 2023, Volume and Issue: 161, P. 114409 - 114409

Published: Feb. 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.

Language: Английский

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