Mastné kyseliny s krátkým řetězcem a jejich soli, zejména butyrát, jsou metabolity vytvořené střevními bakteriemi z vlákniny a polysacharidů přijímaných v potravě. Spektrum účinků působení butyrátu na organismus je velmi široké. Reguluje tvorbu zánětlivých cytokinů, a tím může pozitivně ovlivnit zánětlivé onemocnění střeva, které je provázeno střevní dysbiózou v neprospěch bakterií vytvářejících butyrát. Butyrát je také schopen zvyšovat produkci antimikrobiálních peptidů hostitelem na obranu před patogenními mikroorganismy. Butyrát se tak stal za poslední desetiletí předmětem řady výzkumů, od základního výzkumu, přes preklinický výzkum až na úroveň klinických hodnocení. Butyrát je prokazatelně schopen in vitro indukovat apoptózu nebo zastavit proliferaci nádorových buněk prostřednictvím ovlivnění genové exprese. Vliv butyrátu na regulaci exprese různých genů má potenciál v budoucnu posloužit v prevenci, léčbě nebo zmírnění příznaků diabetu, kardiovaskulárních onemocnění a některých neurodegenerativních a vrozených onemocnění. K potvrzení těchto účinků je třeba provést další kontrolovaná klinická hodnocení.

Short-chain fatty acids and their salts, particularly butyrate, are metabolites produced by intestinal bacteria from dietary fibreand polysaccharides. The spectrum of effects of butyrate on the body is very broad. Butyrate controls the formation of inflammatorycytokines and may thus have a positive effect on inflammatory bowel disease that is accompanied by intestinal dysbiosisto the detriment of the butyrate-producing bacteria. It is also capable of increasing the production of antimicrobial peptides bythe host in defence against pathogenic microorganisms. Consequently, in the past decade, butyrate has become the subject ofmuch research, ranging from basic research to preclinical studies to clinical trials. Butyrate is demonstrably capable of inducingapoptosis in vitro or inhibiting the proliferation of tumour cells by affecting gene expression. The effect of butyrate on the regulationof expression of various genes has the potential to be used, in the future, for the prevention, treatment, or symptom reliefin diabetes, cardiovascu¬lar disease, and some neurodegenerative and congenital diseases. However, further controlled clinicaltrials are required to confirm these effects.

• MeSH
• butyráty * MeSH
• enteritida farmakoterapie   MeSH
• idiopatické střevní záněty MeSH
• klinické hodnocení nového léčiva MeSH
• klinické zkoušky jako téma MeSH
• lidé MeSH
• preklinické hodnocení léčiv MeSH
• střevní mikroflóra účinky léků   MeSH
• střevní nádory MeSH
• tlusté střevo patologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH

• MeSH
• butyráty * izolace a purifikace   metabolismus   terapeutické užití   MeSH
• diabetes mellitus farmakoterapie   prevence a kontrola   MeSH
• idiopatické střevní záněty farmakoterapie   prevence a kontrola   MeSH
• karcinom farmakoterapie   prevence a kontrola   terapie   MeSH
• kardiovaskulární nemoci farmakoterapie   prevence a kontrola   MeSH
• kyselina máselná * metabolismus   terapeutické užití   MeSH
• lidé MeSH
• metaanalýza jako téma MeSH
• nemoci tlustého střeva farmakoterapie   prevence a kontrola   MeSH
• neurodegenerativní nemoci farmakoterapie   prevence a kontrola   MeSH
• statistika jako téma MeSH
• střevní mikroflóra * fyziologie   imunologie   účinky léků   MeSH
• zánět farmakoterapie   prevence a kontrola   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH

• MeSH
• butyráty * izolace a purifikace   metabolismus   terapeutické užití   MeSH
• diabetes mellitus farmakoterapie   prevence a kontrola   MeSH
• idiopatické střevní záněty farmakoterapie   prevence a kontrola   MeSH
• karcinom farmakoterapie   prevence a kontrola   terapie   MeSH
• kardiovaskulární nemoci farmakoterapie   prevence a kontrola   MeSH
• kyselina máselná * metabolismus   terapeutické užití   MeSH
• lidé MeSH
• metaanalýza jako téma MeSH
• nemoci tlustého střeva farmakoterapie   prevence a kontrola   MeSH
• neurodegenerativní nemoci farmakoterapie   prevence a kontrola   MeSH
• statistika jako téma MeSH
• střevní mikroflóra * fyziologie   imunologie   účinky léků   MeSH
• zánět farmakoterapie   prevence a kontrola   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH

• MeSH
• butyráty MeSH
• virus Epsteinův-Barrové MeSH

Aryl hydrocarbon receptor (AhR) is a critical player in the crosstalk between the gut microbiota and its host. However, factors regulating AhR within the gut, which is a complex metabolomic environment, are poorly understood. This study investigates the effect of a combination of metabolites on the activation mechanism of AhR. AhR activity was evaluated using both a luciferase reporter system and mRNA levels of AhR target genes on human cell lines and human colonic explants. AhR activation was studied by radioligand-binding assay, nuclear translocation of AhR by immuofluorescence and protein co-immunoprecipitation of AhR with ARNT. Indirect activation of AhR was evaluated using several tests and inhibitors. The promoter of the target gene CYP1A1 was studied both by chromatin immunoprecipitation and by using an histone deacetylase HDAC inhibitor (iHDAC). Short-chain fatty acids, and butyrate in particular, enhance AhR activity mediated by endogenous tryptophan metabolites without binding to the receptor. This effect was confirmed in human intestinal explants and did not rely on activation of receptors targeted by SCFAs, inhibition of AhR degradation or clearance of its ligands. Butyrate acted directly on AhR target gene promoter to reshape chromatin through iHDAC activity. Our findings revealed that butyrate is not an AhR ligand but acts as iHDAC leading to an increase recruitment of AhR to the target gene promoter in the presence of tryptophan-derived AhR agonists. These data contribute to a novel understanding of the complex regulation of AhR activation by gut microbiota-derived metabolites.

• MeSH
• butyráty farmakologie   MeSH
• lidé MeSH
• ligandy MeSH
• receptory aromatických uhlovodíků * genetika   metabolismus   MeSH
• střevní mikroflóra * MeSH
• tryptofan MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Colonic mucosal protection is provided by the mucus gel, mainly composed of mucins. Several factors can modulate the formation and the secretion of mucins, and among them butyrate, an end-product of carbohydrate fermentation. However, the specific effect of butyrate on the various colonic mucins, and the consequences in terms of the mucus layer thickness are not known. Our aim was to determine whether butyrate modulates colonic MUC genes expression in vivo and whether this results in changes in mucus synthesis and mucus layer thickness. Mice received daily for 7 days rectal enemas of butyrate (100 mM) versus saline. We demonstrated that butyrate stimulated the gene expression of both secreted (Muc2) and membrane-linked (Muc1, Muc3, Muc4) mucins. Butyrate especially induced a 6-fold increase in Muc2 gene expression in proximal colon. However, butyrate enemas did not modify the number of epithelial cells containing the protein Muc2, and caused a 2-fold decrease in the thickness of adherent mucus layer. Further studies should help understanding whether this last phenomenon, i.e. the decrease in adherent mucus gel thickness, results in a diminished protective function or not.

• MeSH
• adhezivita MeSH
• aplikace rektální MeSH
• butyráty aplikace a dávkování   MeSH
• financování organizované MeSH
• klyzma MeSH
• kolon metabolismus   účinky léků   MeSH
• mucin 1 metabolismus   MeSH
• mucin 2 metabolismus   MeSH
• mucin 3 metabolismus   MeSH
• mucin 4 metabolismus   MeSH
• muciny genetika   metabolismus   MeSH
• myši inbrední BALB C MeSH
• myši MeSH
• střevní sliznice metabolismus   účinky léků   MeSH
• up regulace MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH

Butyrate helps to maintain colon homeostasis and exhibits chemopreventive effects in colon epithelium. We examined the interactive effects of butyrate and benzo[a]pyrene (BaP), dietary carcinogen, in regulation of expression of a panel of phase I and II xenobiotic metabolizing enzymes (XMEs) in human colon cells. In human colon carcinoma HCT-116 and HT-29 cell lines, butyrate alone increased mRNA levels of some enzymes, such as N-acetyltransferases (in particular NAT2). In combination with BaP, butyrate potentiated induction of cytochrome P450 family 1 enzymes (CYP1A1), aldo-keto reductases (AKR1C1) or UDP-glucuronosyltransferases (UGT1A1). There were some notable differences between cell lines, as butyrate potentiated induction of NAD(P)H:quinone oxidoreductase 1 (NQO1) and UGT1A4 only in HCT-116 cells, and it even repressed AKR1C3 induction in HT-29 cells. Butyrate also promoted induction of CYP1, NQO1, NAT2, UGT1A1 or UGT1A4 in human colon Caco-2 cells, in a differentiation-dependent manner. Differentiated Caco-2 cells exhibited a higher inducibility of selected XME genes than undifferentiated cells. Butyrate increased induction of enzymatic activities of NATs, NQO1 and UGTs by BaP in HCT-116 and HT29 cells, whereas in differentiated Caco-2 cells it helped to increase only enzymatic activity of NQO1 and UGTs. Together, the present data suggest that butyrate may modulate expression/activities of several enzymes involved in metabolism of carcinogens in colon. In some cases (NAT2, UGT1 A1), this was linked to inhibition of histone deacetylases (HDAC), as confirmed by using HDAC inhibitor trichostatin A. These results may have implications for our understanding of the role of butyrate in regulation of XMEs and carcinogen metabolism in colon.

• MeSH
• benzopyren toxicita   MeSH
• buněčné linie MeSH
• butyráty farmakologie   MeSH
• epitelové buňky účinky léků   metabolismus   MeSH
• karcinogeny toxicita   MeSH
• kolon cytologie   MeSH
• lidé MeSH
• oxidoreduktasy genetika   metabolismus   MeSH
• transferasy genetika   metabolismus   MeSH
• xenobiotika metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Modulation of gut microbiome composition seems to be a promising therapeutic strategy for a wide range of pathologic states. However, these microbiota-targeted interventions may affect production of microbial metabolites, circulating factors in the gut-liver axis influencing hepatic drug metabolism with possible clinical relevance. Butyrate, a short-chain fatty acid produced through microbial fermentation of dietary fibers in the colon, has well established anti-inflammatory role in the intestine, while the effect of butyrate on the liver is unknown. In this study, we have evaluated the effect of butyrate on hepatic AhR activity and AhR-regulated gene expression. We have showed that AhR and its target genes were upregulated by butyrate in dose-dependent manner in HepG2-C3 as well as in primary human hepatocytes. The involvement of AhR has been proved using specific AhR antagonists and siRNA-mediated AhR silencing. Experiments with AhR reporter cells have shown that butyrate regulates the expression of AhR target genes by modulating the AhR activity. Our results suggest also epigenetic action by butyrate on AhR and its repressor (AHRR) presumably through mechanisms based on HDAC inhibition in the liver. Our results demonstrate that butyrate may influence the drug-metabolizing ability of liver enzymes e.g., through the interaction with AhR-dependent pathways.

• MeSH
• butyráty * metabolismus   farmakologie   MeSH
• játra metabolismus   MeSH
• kolon metabolismus   MeSH
• kyseliny mastné těkavé metabolismus   MeSH
• lidé MeSH
• receptory aromatických uhlovodíků genetika   metabolismus   MeSH
• střevní mikroflóra * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Docosahexaenoic acid (DHA) and sodium butyrate (NaBt) exhibit a number of interactive effects on colon cancer cell growth, differentiation, or apoptosis; however, the molecular mechanisms responsible for these interactions and their impact on cellular lipidome are still not fully clear. Here, we show that both dietary agents together induce dynamic alterations of lipid metabolism, specific cellular lipid classes, and fatty acid composition. In HT-29 cell line, a model of differentiating colon carcinoma cells, NaBt supported incorporation of free DHA into non-polar lipids and their accumulation in cytoplasmic lipid droplets. DHA itself was not incorporated into sphingolipids; however, it significantly altered representation of individual ceramide (Cer) classes, in particular in combination with NaBt (DHA/NaBt). We observed altered expression of enzymes involved in Cer metabolism in cells treated with NaBt or DHA/NaBt, and exogenous Cer 16:0 was found to promote induction of apoptosis in differentiating HT-29 cells. NaBt, together with DHA, increased n-3 fatty acid synthesis and attenuated metabolism of monounsaturated fatty acids. Finally, DHA and/or NaBt altered expression of proteins involved in synthesis of fatty acids, including elongase 5, stearoyl CoA desaturase 1, or fatty acid synthase, with NaBt increasing expression of caveolin-1 and CD36 transporter, which may further promote DHA incorporation and its impact on cellular lipidome. In conclusion, our results indicate that interactions of DHA and NaBt exert complex changes in cellular lipidome, which may contribute to the alterations of colon cancer cell differentiation/apoptotic responses. The present data extend our knowledge about the nature of interactive effects of dietary fatty acids.

• MeSH
• apoptóza účinky léků   MeSH
• buněčná diferenciace účinky léků   MeSH
• butyráty farmakologie   MeSH
• HCT116 buňky MeSH
• kyseliny dokosahexaenové farmakologie   MeSH
• lidé MeSH
• membránové lipidy klasifikace   metabolismus   MeSH
• metabolismus lipidů účinky léků   MeSH
• nádory tračníku metabolismus   patologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Several studies have indicated the beneficial anti-inflammatory effect of butyrate in inflammatory bowel disease (IBD) therapy implying attempts to increase butyrate production in the gut through orally administered dietary supplementation. Through the gut-liver axis, however, butyrate may reach directly the liver and influence the drug-metabolizing ability of hepatic enzymes, and, indirectly, also the outcome of applied pharmacotherapy. The focus of our study was on the liver microsomal cytochrome P450 (CYP) 2A5, which is a mouse orthologue of human CYP2A6 responsible for metabolism of metronidazole, an antibiotic used to treat IBD. Our findings revealed that specific pathogen-free (SPF) and germ-free (GF) mice with dextran sulfate sodium (DSS)-induced colitis varied markedly in enzyme activity of CYP2A and responded differently to butyrate pre-treatment. A significant decrease (to 50%) of the CYP2A activity was observed in SPF mice with colitis; however, an administration of butyrate prior to DSS reversed this inhibition effect. This phenomenon was not observed in GF mice. The results highlight an important role of gut microbiota in the regulation of CYP2A under inflammatory conditions. Due to the role of CYP2A in metronidazole metabolism, this phenomenon may have an impact on the IBD therapy. Butyrate administration, hence, brings promising therapeutic potential for improving symptoms of gut inflammation; however, possible interactions with drug metabolism need to be further studied.

• MeSH
• antibakteriální látky škodlivé účinky   farmakologie   terapeutické užití   MeSH
• antiflogistika farmakologie   MeSH
• butyráty * farmakologie   MeSH
• metronidazol farmakologie   MeSH
• modely nemocí na zvířatech MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• síran dextranu škodlivé účinky   MeSH
• střevní mikroflóra * MeSH
• systém (enzymů) cytochromů P-450 metabolismus   MeSH
• ulcerózní kolitida * chemicky indukované   farmakoterapie   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH