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1.
Handb Exp Pharmacol ; 256: 19-49, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31302759

RESUMO

The BA-responsive GPCRs S1PR2 and TGR5 are almost ubiquitously expressed in human and rodent tissues. In the liver, S1PR2 is expressed in all cell types, while TGR5 is predominately found in non-parenchymal cells. In contrast to S1PR2, which is mainly activated by conjugated bile acids (BAs), all BAs serve as ligands for TGR5 irrespective of their conjugation state and substitution pattern.Mice with targeted deletion of either S1PR2 or TGR5 are viable and develop no overt phenotype. In liver injury models, S1PR2 exerts pro-inflammatory and pro-fibrotic effects and thus aggravates liver damage, while TGR5 mediates anti-inflammatory, anti-cholestatic, and anti-fibrotic effects. Thus, inhibitors of S1PR2 signaling and agonists for TGR5 have been employed to attenuate liver injury in rodent models for cholestasis, nonalcoholic steatohepatitis, and fibrosis/cirrhosis.In biliary epithelial cells, both receptors activate a similar signaling cascade resulting in ERK1/2 phosphorylation and cell proliferation. Overexpression of both S1PR2 and TGR5 was found in human cholangiocarcinoma tissue as well as in CCA cell lines, where stimulation of both GPCRs resulted in transactivation of the epidermal growth factor receptor and triggered cell proliferation as well as increased cell migration and invasiveness.This chapter will focus on the function of S1PR2 and TGR5 in different liver cell types and summarizes current knowledge on the role of these receptors in liver disease models.


Assuntos
Ácidos e Sais Biliares/fisiologia , Receptores Acoplados a Proteínas-G/fisiologia , Animais , Neoplasias dos Ductos Biliares , Colangiocarcinoma , Humanos , Fígado , Hepatopatias , Camundongos , Receptores de Lisoesfingolipídeo/fisiologia
2.
Handb Exp Pharmacol ; 256: 51-72, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31230143

RESUMO

Nuclear receptors (NRs) are ligand-dependent transcription factors that are involved in various biological processes including metabolism, reproduction, and development. Upon activation by their ligands, NRs bind to their specific DNA elements, exerting their biological functions by regulating their target gene expression. Bile acids are detergent-like molecules that are synthesized in the liver. They not only function as a facilitator for the digestion of lipids and fat-soluble vitamins but also serve as signaling molecules for several nuclear receptors to regulate diverse biological processes including lipid, glucose, and energy metabolism, detoxification and drug metabolism, liver regeneration, and cancer. The nuclear receptors including farnesoid X receptor (FXR), pregnane X receptor (PXR), constitutive androstane receptor (CAR), vitamin D receptor (VDR), and small heterodimer partner (SHP) constitute an integral part of the bile acid signaling. This chapter reviews the role of the NRs in bile acid homeostasis, highlighting the regulatory functions of the NRs in lipid and glucose metabolism in addition to bile acid metabolism.


Assuntos
Ácidos e Sais Biliares/fisiologia , Receptores Citoplasmáticos e Nucleares/fisiologia , Humanos , Metabolismo dos Lipídeos , Fígado , Receptores de Esteroides/fisiologia , Fatores de Transcrição
3.
Yi Chuan ; 41(5): 365-374, 2019 May 20.
Artigo em Chinês | MEDLINE | ID: mdl-31106772

RESUMO

Bile acids are a class of cholesterol derivatives that play important roles in cholesterol and energy homeostasis and intestinal nutrition absorption. Bile acids are mainly synthesized in the liver. During fasting, bile acids are secreted from the liver and stored in the gallbladder. After a meal, the stored bile acids are released into small intestines. In the intestine, about 95% of bile acids will be re-absorbed and travel back into the liver through port veins, which is called bile acid enterohepatic circulation. This enterohepatic circulation of bile acids plays important roles in the emulsification and intestinal absorption of lipids and other nutrition. On the other hand, bile acids function as ligands for a number of receptors, such as farnesoid X receptor (FXR), proterane X receptor (PXR), vitamin D receptor (VDR) and cell membrane surface receptor-G protein coupled receptor (TGR5), which play important roles from metabolic homeostasis to innate immunity. A number of cytokines such as hepatocyte growth factor (HGF), interleukin-1ß (IL-1ß) and tumor necrosis factor α (TNF-α) regulate the homeostasis of bile acids. In the current review, we will summarize the recent progress in the regulation of bile acid synthesis and its physiological and pathological functions from energy homeostasis to innate immunity and cancer progression to provide a reference for the study of bile acid metabolism.


Assuntos
Ácidos e Sais Biliares/biossíntese , Ácidos e Sais Biliares/fisiologia , Circulação Êntero-Hepática , Fígado/fisiologia , Transporte Biológico , Homeostase , Humanos
4.
Handb Exp Pharmacol ; 256: 95-108, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31119464

RESUMO

Primary bile acids (BAs) are generated in the liver as the end products of cholesterol catabolism; they are then conjugated and accumulated in the gallbladder. After a meal ingestion, BAs are reversed into the duodenum to facilitate the lipid absorption. At the intestinal level, the 95% of BAs are reabsorbed and redirected into enterohepatic circulation; indeed only a small amount of them are then subjected to chemical modifications by the intestinal microbiota, which plays a very important role in the generation of secondary bile acids and in regulating host's metabolism and activity of the immune system. Behind their role in nutrients absorption, bile acids act as signaling molecules, activating several receptors, known as bile acid-activated receptors (BARs), including the farnesoid-X-receptor (FXR) and the G protein-coupled bile acid receptor 1 (GPBAR1 or Takeda G-protein receptor 5). Both receptors appear to contribute to maintain the tolerogenic state of the liver and intestine immunity. In particular, FXR and GPBAR1 are highly expressed in cells of innate immunity including intestinal and liver macrophages, dendritic cells, and natural killer T cells. In this chapter, we provide an overview on mechanisms through which FXR and GPBAR1 modulate the signaling between microbiota and intestinal and liver innate immune system. This overview could help to explain beneficial effects exerted by GPBAR1 and FXR agonists in the treatment of metabolic and immuno-mediated diseases.


Assuntos
Ácidos e Sais Biliares/fisiologia , Imunidade Inata , Intestinos/fisiologia , Fígado/fisiologia , Transdução de Sinais , Microbioma Gastrointestinal , Humanos , Receptores Citoplasmáticos e Nucleares , Receptores Acoplados a Proteínas-G
5.
Food Funct ; 10(3): 1455-1464, 2019 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-30768114

RESUMO

The management of lead (Pb) exposure and toxicity remains a major public health priority worldwide. In our previous study, the probiotic strain Lactobacillus plantarum CCFM8661 prevented Pb absorption in mice via intestinal sequestration. This follow-up study aimed to evaluate the additional protective mechanism of L. plantarum CCFM8661 with a focus on its regulation of enterohepatic circulation. We first confirmed the relationship between the enterohepatic circulations of Pb and bile acid (BA) by administering a BA sequestrant, cholestyramine, to mice with a high Pb burden. Our data further showed that L. plantarum CCFM8661 significantly induced hepatic BA synthesis, enhanced bile flow and biliary glutathione output, and increased fecal BA excretion in the mice, which in turn increased biliary Pb output and enhanced fecal Pb excretion. This regulation was associated with the alterations in the expression of target genes in the enterohepatic farnesoid X receptor-fibroblast growth factor (FXR-FGF15) axis and could be reversed using an FXR agonist, GW4064. Pre-treatment with antibiotics also abolished the L. plantarum CCFM8661-induced effects on BA and Pb enterohepatic circulation. These results suggest that L. plantarum CCFM8661 induces fecal Pb excretion by regulating BA enterohepatic circulation. This regulation is associated with the down-regulation of the FXR-FGF15 axis and is partly dependent on the gut microbiota of mice.


Assuntos
Ácidos e Sais Biliares/fisiologia , Lactobacillus plantarum/classificação , Chumbo/farmacocinética , Fígado/efeitos dos fármacos , Fígado/fisiologia , Animais , Ácidos e Sais Biliares/química , Fezes/química , Regulação da Expressão Gênica/efeitos dos fármacos , Rim/química , Chumbo/sangue , Chumbo/química , Chumbo/metabolismo , Fígado/química , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Probióticos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Distribuição Aleatória
6.
Biochim Biophys Acta Mol Cell Biol Lipids ; 1864(3): 403-412, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-29883797

RESUMO

Bile acids exhibit strong antimicrobial activity as natural detergents, and are involved in lipid digestion and absorption. We investigated the mechanism of bile acid adaptation in Lactobacillus gasseri JCM1131T. Exposure to sublethal concentrations of cholic acid (CA), a major bile acid in humans, resulted in development of resistance to otherwise-lethal concentrations of CA by this intestinal lactic acid bacterium. As this adaptation was accompanied by decreased cell-membrane damage, we analyzed the membrane lipid composition of L. gasseri. Although there was no difference in the proportions of glycolipids (~70%) and phospholipids (~20%), adaptation resulted in an increased abundance of long-sugar-chain glycolipids and a 100% increase in cardiolipin (CL) content (to ~50% of phospholipids) at the expense of phosphatidylglycerol (PG). In model vesicles, the resistance of PG vesicles to solubilization by CA increased with increasing CL/PG ratio. Deletion of the two putative CL synthase genes, the products of which are responsible for CL synthesis from PG, decreased the CL content of the mutants, but did not affect their ability to adapt to CA. Exposure to CA restored the CL content of the two single-deletion mutants, likely due to the activities of the remaining CL synthase. In contrast, the CL content of the double-deletion mutant was not restored, and the lipid composition was modified such that PG predominated (~45% of total lipids) at the expense of glycolipids. Therefore, CL plays important roles in bile acid resistance and maintenance of the membrane lipid composition in L. gasseri.


Assuntos
Ácidos e Sais Biliares/metabolismo , Cardiolipinas/metabolismo , Ácidos e Sais Biliares/fisiologia , Cardiolipinas/fisiologia , Membrana Celular/metabolismo , Ácido Cólico/metabolismo , Glicolipídeos/metabolismo , Glicolipídeos/fisiologia , Lactobacillus gasseri/metabolismo , Lactobacillus gasseri/fisiologia , Lipídeos de Membrana/metabolismo , Proteínas de Membrana/metabolismo , Membranas/metabolismo , Fosfatidilgliceróis/metabolismo , Fosfolipídeos/metabolismo , Transferases (Outros Grupos de Fosfato Substituídos)/metabolismo
7.
Trends Endocrinol Metab ; 29(10): 686-698, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30197155

RESUMO

Altered nutritional behavior in Western societies has unleashed numerous metabolic disorders, intimately linked to profound disruptions of the immune system. Here we summarize how nutrition modulates innate immunity. We outline recent findings regarding nutrient signaling and we particularly focus on the collateral impact of nutrition on the microbiome and on the bile acid (BA) pool. We discuss how the integration of postprandial signals by the gut microbiota, along with the absorption routes of metabolites, differentially affects immune niches to orchestrate immune responses. Finally, we discuss the potential consequences of these signals in the light of trained immunity. A better understanding of nutrition signaling will permit the optimization of therapeutic and dietary strategies against the arising immune disorders.


Assuntos
Ácidos e Sais Biliares/fisiologia , Microbioma Gastrointestinal/fisiologia , Imunidade Inata/fisiologia , Fenômenos Fisiológicos da Nutrição/fisiologia , Transdução de Sinais/fisiologia , Humanos
8.
Aliment Pharmacol Ther ; 48(9): 961-974, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30144108

RESUMO

BACKGROUND: Intestinal microbiota plays an important role in bile acid homeostasis. AIM: To study the structure of the intestinal microbiota and its function in bile acid homeostasis in alcoholic patients based on the severity of alcoholic liver disease. METHODS: In this prospective study, we included four groups of active alcoholic patients (N = 108): two noncirrhotic, with (noCir_AH, n = 13) or without alcoholic hepatitis (noCir_noAH, n = 61), and two cirrhotic, with (Cir_sAH, n = 17) or without severe alcoholic hepatitis (Cir_noAH, n = 17). Plasma and faecal bile acid profiles and intestinal microbiota composition were assessed. RESULTS: Plasma levels of total bile acids (84.6 vs 6.8 µmol/L, P < 0.001) and total ursodeoxycholic acid (1.3 vs 0.3 µmol/L, P = 0.03) were higher in cirrhosis with severe alcoholic hepatitis (Cir_sAH) than Cir_noAH, whereas total faecal (2.4 vs 11.3, P = 0.01) and secondary bile acids (0.7 vs 10.7, P < 0.01) levels were lower. Cir_sAH patients had a different microbiota than Cir_noAH patients: at the phyla level, the abundance of Actinobacteria (9 vs 1%, P = 0.01) was higher and that of Bacteroidetes was lower (25 vs 40%, P = 0.04). Moreover, the microbiota of Cir_sAH patients showed changes in the abundance of genes involved in 15 metabolic pathways, including upregulation of glutathione metabolism, and downregulation of biotin metabolism. CONCLUSIONS: Patients with Cir_sAH show specific changes of the bile acid pool with a shift towards more hydrophobic and toxic species that may be responsible for the specific microbiota changes. Conversely, the microbiota may also alter the bile acid pool by transforming primary to secondary bile acids, leading to a vicious cycle.


Assuntos
Ácidos e Sais Biliares/fisiologia , Disbiose/epidemiologia , Microbioma Gastrointestinal/fisiologia , Hepatite Alcoólica/epidemiologia , Hepatite Alcoólica/microbiologia , Homeostase/fisiologia , Adulto , Idoso , Diarreia/diagnóstico , Diarreia/epidemiologia , Diarreia/microbiologia , Disbiose/diagnóstico , Fezes/microbiologia , Feminino , França/epidemiologia , Hepatite Alcoólica/diagnóstico , Humanos , Cirrose Hepática Alcoólica/diagnóstico , Cirrose Hepática Alcoólica/epidemiologia , Cirrose Hepática Alcoólica/microbiologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos
9.
Gastroenterology ; 155(6): 1741-1752.e5, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30144429

RESUMO

BACKGROUND & AIMS: Intestinal bacteria can modify the composition of bile acids and bile acids, which are regulated by the farnesoid X receptor, affect the survival and growth of gut bacteria. We studied the effects of obeticholic acid (OCA), a bile acid analogue and farnesoid X receptor agonist, on the intestinal microbiomes of humans and mice. METHODS: We performed a phase I study in 24 healthy volunteers given OCA (5, 10, or 25 mg/d for 17 days). Fecal and plasma specimens were collected at baseline (day 0) and on days 17 (end of dosing) and 37 (end of study). The fecal specimens were analyzed by shotgun meta-genomic sequencing. A Uniref90 high-stringency genomic analysis was used to assign specific genes to the taxonomic signature of bacteria whose abundance was associated with OCA. Male C57BL/6 mice were gavage fed daily with water, vehicle, or OCA (10 mg/kg) for 2 weeks. Small intestine luminal contents were collected by flushing with saline and fecal pellets were collected at baseline and day 14. Mouse samples were analyzed by 16S-tagged sequencing. Culture experiments were performed to determine the taxonomic-specific effects of bile acids and OCA on bacterial growth. RESULTS: Suppression of endogenous bile acid synthesis by OCA in subjects led to a reversible induction of gram-positive bacteria that are found in the small intestine and are components of the diet and oral microbiota. We found that bile acids decreased proliferation of these bacteria in minimum inhibitory concentration assays. In these organisms, there was an increase in the representation of microbial genomic pathways involved in DNA synthesis and amino acid metabolism with OCA treatment of subjects. Consistent with these findings, mice fed OCA had lower endogenous bile acid levels and an increased proportion of Firmicutes, specifically in the small intestine, compared with mice fed water or vehicle. CONCLUSIONS: In studying the effects of OCA in humans and mice, we found evidence for interactions between bile acids and features of the small intestinal microbiome. These findings indicate that farnesoid X receptor activation alters the intestinal microbiota and could provide opportunities for microbiome biomarker discovery or new approaches to engineering the human microbiome. ClinicalTrials.gov, NCT01933503.


Assuntos
Ácidos e Sais Biliares/fisiologia , Ácido Quenodesoxicólico/análogos & derivados , Microbioma Gastrointestinal/efeitos dos fármacos , Intestino Delgado/microbiologia , Receptores Citoplasmáticos e Nucleares/fisiologia , Adulto , Animais , Ácido Quenodesoxicólico/farmacocinética , Feminino , Voluntários Saudáveis , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL
10.
J Intern Med ; 284(5): 546-559, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29964306

RESUMO

BACKGROUND AND OBJECTIVES: Bile acids (BAs) traversing the enterohepatic circulation (EHC) influence important metabolic pathways. By determining individual serum BAs in relation to markers of metabolic activity, we explored how diurnal variations in their EHC relate to hepatic metabolism in normal humans. METHODS: Serum BAs, fibroblast growth factor 19 (FGF19), lipoproteins, glucose/insulin and markers of cholesterol and BA syntheses were monitored for 32 h in 8 healthy males. Studies were conducted at basal state and during initiation of cholestyramine treatment, with and without atorvastatin pretreatment. Time series cross-correlation analysis, Bayesian structural model and Granger causality test were applied. RESULTS: Bile acids synthesis dominated daytime, and cholesterol production at night. Conjugated BAs peaked after food intake, with subsequent FGF19 elevations. BA synthesis was reduced following conjugated BA and FGF19 peaks. Cholestyramine reduced conjugated BAs and FGF19, and increased BA and cholesterol production; the latter effects attenuated by atorvastatin. The relative importance of FGF19 vs. conjugated BAs in this feedback inhibition could not be discriminated. Unconjugated BAs displayed one major peak late at night/early morning that was unrelated to FGF19 and BA synthesis, and abolished by cholestyramine. The normal suppression of serum triglycerides, glucose and insulin observed at night was attenuated by cholestyramine. CONCLUSIONS: Conjugated and unconjugated BAs have asynchronous rhythms of EHC in humans. Postprandial transintestinal flux of conjugated BAs increases circulating FGF19 levels and suppresses BA synthesis. Unconjugated BAs peak late at night, indicating a non-postprandial diurnal change in human gut microflora, the physiological implications of which warrants further study.


Assuntos
Ácidos e Sais Biliares/metabolismo , Ritmo Circadiano , Redes e Vias Metabólicas , Adulto , Anticolesterolemiantes/farmacologia , Atorvastatina/farmacologia , Ácidos e Sais Biliares/sangue , Ácidos e Sais Biliares/fisiologia , Biomarcadores/sangue , Glicemia/análise , Resina de Colestiramina/farmacologia , Ritmo Circadiano/fisiologia , Fatores de Crescimento de Fibroblastos/sangue , Humanos , Insulina/sangue , Lipoproteínas/sangue , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Redes e Vias Metabólicas/efeitos dos fármacos , Redes e Vias Metabólicas/fisiologia , Pessoa de Meia-Idade , Adulto Jovem
11.
Drug Metab Dispos ; 46(9): 1310-1319, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29959134

RESUMO

Nonalcoholic steatohepatitis (NASH) is the progressive stage of nonalcoholic fatty liver disease that may ultimately lead to cirrhosis and liver cancer, and there are few therapeutic options for its treatment. Glycyrrhizin (GL), extracted from the traditional Chinese medicine liquorice, has potent hepatoprotective effects in both preclinical animal models and in humans. However, little is currently known about its effects and mechanisms in treating NASH. To explore the effects of GL on NASH, GL or its active metabolite glycyrrhetinic acid (GA) was administered to mice treated with a methionine- and choline-deficient (MCD) diet-induced NASH model, and histologic and biochemical analyses were used to measure the degree of lipid disruption, liver inflammation, and fibrosis. GL significantly improved MCD diet-induced hepatic steatosis, inflammation, and fibrosis and inhibited activation of the NLR family pyrin domain-containing 3 (NLRP3) inflammasome. GL significantly attenuated serum bile acid accumulation in MCD diet-fed mice partially by restoring inflammation-mediated hepatic farnesoid X receptor inhibition. In Raw 264.7 macrophage cells, both GL and GA inhibited deoxycholic acid-induced NLRP3 inflammasome-associated inflammation. Notably, both intraperitoneal injection of GL's active metabolite GA and oral administration of GL prevented NASH in mice, indicating that GL may attenuate NASH via its active metabolite GA. These results reveal that GL, via restoration of bile acid homeostasis and inhibition of inflammatory injury, can be a therapeutic option for treatment of NASH.


Assuntos
Anti-Inflamatórios/uso terapêutico , Ácidos e Sais Biliares/fisiologia , Ácido Glicirrízico/uso terapêutico , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Animais , Anti-Inflamatórios/farmacologia , Ácido Glicirrízico/farmacologia , Células Hep G2 , Humanos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/patologia , Células RAW 264.7 , Distribuição Aleatória
12.
Reproduction ; 156(3): 249-259, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29921626

RESUMO

The farnesoid X receptor alpha (FXR) is a bile acid sensor activated by binding to endogenous bile acids including chenodeoxycholic acid (CDCA). Although, FXR is expressed in male reproductive tissue, the relevance of the receptor on reproduction is scarcely known. Here, we demonstrated the FXR presence and its action on several human sperm features. Western blot and immunofluorescence assays evidenced the FXR expression in human spermatozoa and the localisation in the middle piece. CDCA increasing concentrations and GW4064, synthetic ligand of FXR, were used to study the FXR influence on sperm motility, survival, capacitation, acrosome reaction and on glucose as well as lipid metabolism. Interestingly, our data showed that increasing concentrations of CDCA negatively affected sperm parameters, while the receptor blockage by (Z)-Guggulsterone and by the anti-FXR Ab reversed the effects. Intriguingly, elevated CDCA levels increased triglyceride content, while lipase and G6PDH activities were reduced with respect to untreated samples, thus impeding the metabolic reprogramming typical of the capacitated sperm. In conclusion, in this study, we demonstrated for the first time a novel target for FXR and that the activated receptor alters the acquisition of sperm fertilising ability. We showed that sperm itself express the FXR and it is responsive to specific ligands of the receptor; therefore, bile acids influence this cell both in male and in female genital tracts. It might be hypothesized that bile acid levels could be involved in infertility with idiopathic origin as these compounds are not systematically measured in men undergoing medically assisted procreation.


Assuntos
Fertilização/fisiologia , Receptores Citoplasmáticos e Nucleares/fisiologia , Espermatozoides/fisiologia , Reação Acrossômica/efeitos dos fármacos , Ácidos e Sais Biliares/fisiologia , Sobrevivência Celular/efeitos dos fármacos , Ácido Quenodesoxicólico/farmacologia , Fertilização/efeitos dos fármacos , Expressão Gênica , Glucose/metabolismo , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Receptores Citoplasmáticos e Nucleares/análise , Receptores Citoplasmáticos e Nucleares/efeitos dos fármacos , Capacitação Espermática/efeitos dos fármacos , Motilidade Espermática/efeitos dos fármacos , Espermatozoides/química , Espermatozoides/efeitos dos fármacos
13.
Nat Rev Gastroenterol Hepatol ; 15(8): 479-496, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29760502

RESUMO

Infant colic is a commonly reported phenomenon of excessive crying in infancy with an enigmatic and distressing character. Despite its frequent occurrence, little agreement has been reached on the definition, pathogenesis or the optimal management strategy for infant colic. This Review aims to delineate the definitional entanglement with the Rome IV criteria, which were published in 2016, as the leading, most recent diagnostic criteria. Moreover, neurogenic, gastrointestinal, microbial and psychosocial factors that might contribute to the pathophysiology of infant colic are explored. This Review underlines that a comprehensive medical history and physical examination in the absence of alarm symptoms serve as guidance for the clinician to a positive diagnosis. It also highlights that an important aspect of the management of infant colic is parental education and reassurance. Management strategies, including behavioural, dietary, pharmacological and alternative interventions, are also discussed. Owing to a lack of large, high-quality randomized controlled trials, none of these therapies are strongly recommended. Finally, the behavioural and somatic sequelae of infant colic into childhood are summarized.


Assuntos
Cólica/terapia , Ácidos e Sais Biliares/fisiologia , Aleitamento Materno , Pré-Escolar , Vestuário , Cólica/diagnóstico , Cólica/etiologia , Terapias Complementares , Choro/fisiologia , Deficiências do Desenvolvimento/etiologia , Diagnóstico Diferencial , Relações Pai-Filho , Feminino , Microbioma Gastrointestinal/fisiologia , Humanos , Lactente , Fórmulas Infantis , Recém-Nascido , Masculino , Massagem/métodos , Anamnese/métodos , Relações Mãe-Filho , Poder Familiar , Pais/educação , Exame Físico/métodos , Probióticos/uso terapêutico , Fatores de Risco
14.
Nat Rev Gastroenterol Hepatol ; 15(8): 497-516, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29844587

RESUMO

The intestinal epithelium is a multicellular interface in close proximity to a dense microbial milieu that is completely renewed every 3-5 days. Pluripotent stem cells reside at the crypt, giving rise to transient amplifying cells that go through continuous steps of proliferation, differentiation and finally anoikis (a form of programmed cell death) while migrating upwards to the villus tip. During these cellular transitions, intestinal epithelial cells (IECs) possess distinct metabolic identities reflected by changes in mitochondrial activity. Mitochondrial function emerges as a key player in cell fate decisions and in coordinating cellular metabolism, immunity, stress responses and apoptosis. Mediators of mitochondrial signalling include molecules such as ATP and reactive oxygen species and interrelate with pathways such as the mitochondrial unfolded protein response (MT-UPR) and AMP kinase signalling, in turn affecting cell cycle progression and stemness. Alterations in mitochondrial function and MT-UPR activation are integral aspects of pathologies, including IBD and cancer. Mitochondrial signalling and concomitant changes in metabolism contribute to intestinal homeostasis and regulate IEC dedifferentiation-differentiation programmes in the context of diseases, suggesting that mitochondrial function as a cellular checkpoint critically contributes to disease outcome. This Review highlights mitochondrial function and MT-UPR signalling in epithelial cell stemness, differentiation and lineage commitment and illustrates mitochondrial function in intestinal diseases.


Assuntos
Células Epiteliais/fisiologia , Homeostase/fisiologia , Mucosa Intestinal/fisiologia , Mitocôndrias/fisiologia , Ácidos e Sais Biliares/fisiologia , Proliferação de Células/fisiologia , Ácidos Graxos Voláteis/fisiologia , Humanos , Mucosa Intestinal/citologia , Neoplasias Intestinais/etiologia , Neoplasias Intestinais/fisiopatologia , Síndrome do Intestino Irritável/etiologia , Síndrome do Intestino Irritável/fisiopatologia , Espécies Reativas de Oxigênio/metabolismo , Receptores de Reconhecimento de Padrão/fisiologia , Transdução de Sinais/fisiologia , Células-Tronco/fisiologia , Resposta a Proteínas não Dobradas/fisiologia
15.
Nat Prod Rep ; 35(6): 501-513, 2018 06 20.
Artigo em Inglês | MEDLINE | ID: mdl-29662986

RESUMO

Covering: up to 2018 Fish use a diverse collection of molecules to communicate with conspecifics. Since Karlson and Lüscher termed these molecules 'pheromones', chemists and biologists have joined efforts to characterize their structures and functions. In particular, the understanding of insect pheromones developed at a rapid pace, set, in part, by the use of bioassay-guided fractionation and natural product chemistry. Research on vertebrate pheromones, however, has progressed more slowly. Initially, biologists characterized fish pheromones by screening commercially available compounds suspected to act as pheromones based upon their physiological function. Such biology-driven screening has proven a productive approach to studying pheromones in fish. However, the many functions of fish pheromones and diverse metabolites that fish release make predicting pheromone identity difficult and necessitate approaches led by chemistry. Indeed, the few cases in which pheromone identification was led by natural product chemistry indicated novel or otherwise unpredicted compounds act as pheromones. Here, we provide a brief review of the approaches to identifying pheromones, placing particular emphasis on the promise of using natural product chemistry together with assays of biological activity. Several case studies illustrate bioassay-guided fractionation as an approach to pheromone identification in fish and the unexpected diversity of pheromone structures discovered by natural product chemistry. With recent advances in natural product chemistry, bioassay-guided fractionation is likely to unveil an even broader collection of pheromone structures and enable research that spans across disciplines.


Assuntos
Produtos Biológicos/farmacologia , Avaliação Pré-Clínica de Medicamentos/métodos , Peixes/fisiologia , Feromônios/farmacologia , Feromônios/fisiologia , Aminoácidos/fisiologia , Animais , Ácidos e Sais Biliares/fisiologia , Produtos Biológicos/química , Feminino , Masculino , Metabolômica/métodos , Feromônios/química , Esteroides/fisiologia
16.
Curr Gastroenterol Rep ; 20(3): 10, 2018 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-29582208

RESUMO

PURPOSE OF REVIEW: To provide an update on the prevalence, pathophysiology, disease associations, and treatment options for bile acid malabsorption (BAM). RECENT FINDINGS: •Molecular mechanisms-BAs prevent water reabsorption and increase water secretion by intracellular mediators, increasing aquaporin channels and intracellular permeability. •Inflammatory bowel disease-new molecular mechanisms of BAM are identified in patients without ileal disease, including changes in expression of ileal BA transporter and nuclear receptors involved in BA homeostasis. •Microscopic colitis-BAM is one of the mechanisms leading to microscopic colitis. •Diagnostic testing-new diagnostic tests have been launched in the USA (serum C4 and fecal 48-h BA excretion); stimulated FGF19 has higher detection of BAM compared to fasting sample alone. •Treatment-investigational FXR agonists may provide a daily, oral option for treatment of BAM instead of BA sequestrants. There is a greater appreciation of the biological role of bile acids across multiple fields of medicine, including gastrointestinal indications.


Assuntos
Ácidos e Sais Biliares/metabolismo , Síndromes de Malabsorção/diagnóstico , Síndromes de Malabsorção/terapia , Ácidos e Sais Biliares/fisiologia , Biomarcadores/sangue , Colecistectomia/efeitos adversos , Diarreia/etiologia , Diarreia/fisiopatologia , Fezes/química , Humanos , Doenças Inflamatórias Intestinais/complicações , Síndromes de Malabsorção/epidemiologia , Síndromes de Malabsorção/fisiopatologia , Lesões por Radiação/etiologia , Receptores Citoplasmáticos e Nucleares/agonistas , Sequestrantes/uso terapêutico , Esteatorreia/etiologia , Esteatorreia/fisiopatologia , Ácido Taurocólico/análogos & derivados
18.
Toxicol Appl Pharmacol ; 343: 48-61, 2018 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-29452137

RESUMO

The effects of the most potent aryl hydrocarbon receptor (AhR) agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on bile acid (BA) homeostasis was examined in male and female wild-type and AhR-null mice shortly after 4-day exposure, rather than at a later time when secondary non-AhR dependent effects are more likely to occur. TCDD had similar effects on BA homeostasis in male and female mice. TCDD decreased the concentration of total-(Σ) BAs in liver by approximately 50% (all major BA categories except for the non-6,12-OH BAs), without decreasing the expression of the rate limiting BA synthetic enzyme (Cyp7a1) or altering the major BA regulatory pathways (FXR) in liver and intestine. Even though the Σ-BAs in liver were markedly decreased, the Σ-BAs excreted into bile were not altered. TCDD decreased the relative amount of 12-OH BAs (TCA, TDCA, CA, DCA) in bile and increased the biliary excretion of TCDCA and its metabolites (TαMCA, TUDCA); this was likely due to the decreased Cyp8b1 (12α-hydroxylase) in liver. The concentration of Σ-BAs in serum was not altered by TCDD, indicating that serum BAs do not reflect BA status in liver. However, proportions of individual BAs in serum reflected the decreased expression of Cyp8b1. All these TCDD-induced changes in BA homeostasis were absent in AhR-null mice. In summary, through the AhR, TCDD markedly decreases BA concentrations in liver and reduces the 12α-hydroxylation of BAs without altering Cyp7a1 and FXR signaling. The TCDD-induced decrease in Σ-BAs in liver did not result in a decrease in biliary excretion or serum concentrations of Σ-BAs.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/fisiologia , Ácidos e Sais Biliares/fisiologia , Poluentes Ambientais/toxicidade , Homeostase/fisiologia , Dibenzodioxinas Policloradas/toxicidade , Receptores de Hidrocarboneto Arílico/fisiologia , Animais , Feminino , Homeostase/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , RNA Mensageiro/metabolismo
19.
Laryngoscope ; 128(9): 2029-2033, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29399801

RESUMO

OBJECTIVE: Gastroesophageal reflux is thought to be a risk factor for laryngotracheal stenosis. Bile acids are a component of gastric refluxate and have previously been implicated in the development of fibrosis in other airway subsites. There is clear evidence that bile acids reflux into the upper airway. We therefore investigated the potential role of bile acids in the pathophysiology of laryngotracheal fibrosis and stenosis, specifically investigating the highly conserved process of epithelial-mesenchymal transition (EMT). STUDY DESIGN: Translational research study. METHODS: Human primary tracheal epithelial cells (PTECs) were challenged with the four most common digestive bile acids (cholic, chenodeoxycholic, deoxycholic, and lithocholic). EMT markers transforming growth factor (TGF)-ß1, Matrix metalloproteinase (MMP)-9, and procollagen proteins were measured in the supernatant at 48 hours via enzyme-linked immunosorbent assay. Real-time polymerase chain reaction was also used to measure E-cadherin and fibronectin expression. RESULTS: Significantly greater concentrations of TGF-ß1 and MMP-9 were measured in the culture supernatants of cells treated with each bile acid at 10 µmol/L. Lithocholic acid and deoxycholic acid induced significantly increased expression of procollagen protein. Upregulation of fibronectin and downregulation of E-cadherin were observed with all bile acids, except for deoxycholic acid. CONCLUSION: This is the first proof of principle demonstration that physiologically relevant bile acid challenge induces EMT mechanisms in PTECs. This implies a potential role for bile acids in laryngotracheal scarring and airway remodeling of potential translational significance in laryngotracheal stenosis. LEVEL OF EVIDENCE: NA. Laryngoscope, 128:2029-2033, 2018.


Assuntos
Ácidos e Sais Biliares/fisiologia , Transição Epitelial-Mesenquimal , Laringoestenose/etiologia , Estenose Traqueal/etiologia , Antígenos CD/metabolismo , Caderinas/metabolismo , Técnicas de Cultura de Células , Células Epiteliais , Fibronectinas/metabolismo , Humanos , Laringoestenose/fisiopatologia , Metaloproteinase 9 da Matriz/metabolismo , Pró-Colágeno/metabolismo , Traqueia/citologia , Traqueia/metabolismo , Estenose Traqueal/fisiopatologia , Fator de Crescimento Transformador beta1/metabolismo , Pesquisa Médica Translacional
20.
Hepatology ; 68(1): 187-199, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29360145

RESUMO

Bile acids stimulate a bicarbonate-rich choleresis, in part, through effects on cholangiocytes. Because Cl- channels in the apical membrane of cholangiocytes provide the driving force for secretion and transmembrane member 16A (TMEM16A) has been identified as the Ca2+ -activated Cl- channel in the apical membrane of cholangiocytes, the aim of the present study was to determine whether TMEM16A is the target of bile-acid-stimulated Cl- secretion and to identify the regulatory pathway involved. In these studies of mouse, rat, and human biliary epithelium exposure to ursodeoxycholic acid (UDCA) or tauroursodeoxycholic acid (TUDCA) rapidly increased the rate of exocytosis, ATP release, [Ca2+ ]i , membrane Cl- permeability, and transepithelial secretion. Bile-acid-stimulated Cl- currents demonstrated biophysical properties consistent with TMEM16A and were inhibited by pharmacological or molecular (small-interfering RNA; siRNA) inhibition of TMEM16A. Bile acid-stimulated Cl- currents were not observed in the presence of apyrase, suramin, or 2-aminoethoxydiphenyl borate (2-APB), demonstrating that current activation requires extracellular ATP, P2Y, and inositol 1,4,5-trisphosphate (IP3) receptors. TUDCA did not activate Cl- currents during pharmacologic inhibition of the apical Na+ -dependent bile acid transporter (ASBT), but direct intracellular delivery of TUDCA rapidly activated Cl- currents. CONCLUSION: Bile acids stimulate Cl- secretion in mouse and human biliary cells through activation of membrane TMEM16A channels in a process regulated by extracellular ATP and [Ca2+ ]i . These studies suggest that TMEM16A channels may be targets to increase bile flow during cholestasis. (Hepatology 2018;68:187-199).


Assuntos
Anoctamina-1/metabolismo , Ácidos e Sais Biliares/fisiologia , Ductos Biliares/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Cálcio/metabolismo , Cloretos/metabolismo , Exocitose , Humanos , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Camundongos , Transportadores de Ânions Orgânicos Dependentes de Sódio/metabolismo , Cultura Primária de Células , Ratos , Receptores Purinérgicos P2Y/metabolismo , Via Secretória , Simportadores/metabolismo
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