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1.
Hepatology ; 78(1): 295-306, 2023 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-36811393

RESUMO

BACKGROUND AND AIMS: Patients with severe alcohol-associated hepatitis have high morbidity and mortality. Novel therapeutic approaches are urgently needed. The aims of our study were to confirm the predictive value of cytolysin-positive Enterococcus faecalis ( E. faecalis ) for mortality in patients with alcohol-associated hepatitis and to assess the protective effect of specific chicken immunoglobulin Y (IgY) antibodies against cytolysin in vitro and in a microbiota-humanized mouse model of ethanol-induced liver disease. APPROACH AND RESULTS: We investigated a multicenter cohort of 26 subjects with alcohol-associated hepatitis and confirmed our previous findings that the presence of fecal cytolysin-positive E. faecalis predicted 180-day mortality in those patients. After combining this smaller cohort with our previously published multicenter cohort, the presence of fecal cytolysin has a better diagnostic area under the curve, better other accuracy measures, and a higher odds ratio to predict death in patients with alcohol-associated hepatitis than other commonly used liver disease models. In a precision medicine approach, we generated IgY antibodies against cytolysin from hyperimmunized chickens. Neutralizing IgY antibodies against cytolysin reduced cytolysin-induced cell death in primary mouse hepatocytes. The oral administration of IgY antibodies against cytolysin decreased ethanol-induced liver disease in gnotobiotic mice colonized with stool from cytolysin-positive patients with alcohol-associated hepatitis. CONCLUSIONS: E. faecalis cytolysin is an important mortality predictor in alcohol-associated hepatitis patients, and its targeted neutralization through specific antibodies improves ethanol-induced liver disease in microbiota-humanized mice.


Assuntos
Etanol , Hepatite Alcoólica , Animais , Camundongos , Galinhas , Imunoglobulinas/uso terapêutico , Anticorpos , Citotoxinas , Hepatite Alcoólica/tratamento farmacológico
2.
J Adolesc ; 96(1): 70-80, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37750345

RESUMO

INTRODUCTION: In the post-COVID-19 era, small-scale and long-term recurrences of the pandemic can exacerbate future economic uncertainty. Previous studies have found that stressful situations are strongly associated with a controlling type of parenting. The relationship between parental perceptions of future economic uncertainty (PFEU) and helicopter parenting is currently unclear. This study aimed to examine the dyadic relationship between PFEU and helicopter parenting among Chinese parents in the postpandemic era and its underlying mechanisms from a family system perspective. METHODS: Questionnaire data were collected from 395 pairs of parents (Mfather = 43.65 ± 5.30, Mmother = 40.71 ± 5.16, Madolescent = 13.17 ± 0.87, 45.3% male) in Jiangxi Province, China in October 2021. An actor-partner interdependence mediation model was established. RESULTS: The results indicated that fathers' and mothers' PFEU were positively associated with their own helicopter parenting. Additionally, paternal parenting stress mediated the relationship between fathers' and mothers' PFEU and paternal helicopter parenting, whereas mothers' parenting stress mediated the association between mothers' PFEU and paternal and maternal helicopter parenting. CONCLUSIONS: The current research provides important insights for improving Chinese family education practices in the postpandemic era.


Assuntos
COVID-19 , Poder Familiar , Feminino , Adolescente , Masculino , Humanos , COVID-19/epidemiologia , Pais , Pai , Mães
3.
Gut ; 72(10): 1959-1970, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-36690432

RESUMO

OBJECTIVE: Alcohol-associated liver disease is accompanied by microbial dysbiosis, increased intestinal permeability and hepatic exposure to translocated microbial products that contribute to disease progression. A key strategy to generate immune protection against invading pathogens is the secretion of IgA in the gut. Intestinal IgA levels depend on the polymeric immunoglobulin receptor (pIgR), which transports IgA across the epithelial barrier into the intestinal lumen and hepatic canaliculi. Here, we aimed to address the function of pIgR during ethanol-induced liver disease. DESIGN: pIgR and IgA were assessed in livers from patients with alcohol-associated hepatitis and controls. Wild-type and pIgR-deficient (pIgR-/- ) littermates were subjected to the chronic-binge (NIAAA model) and Lieber-DeCarli feeding model for 8 weeks. Hepatic pIgR re-expression was established in pIgR-/- mice using adeno-associated virus serotype 8 (AAV8)-mediated pIgR expression in hepatocytes. RESULTS: Livers of patients with alcohol-associated hepatitis demonstrated an increased colocalisation of pIgR and IgA within canaliculi and apical poles of hepatocytes. pIgR-deficient mice developed increased liver injury, steatosis and inflammation after ethanol feeding compared with wild-type littermates. Furthermore, mice lacking pIgR demonstrated increased plasma lipopolysaccharide levels and more hepatic bacteria, indicating elevated bacterial translocation. Treatment with non-absorbable antibiotics prevented ethanol-induced liver disease in pIgR-/- mice. Injection of AAV8 expressing pIgR into pIgR-/- mice prior to ethanol feeding increased intestinal IgA levels and ameliorated ethanol-induced steatohepatitis compared with pIgR-/- mice injected with control-AAV8 by reducing bacterial translocation. CONCLUSION: Our results highlight that dysfunctional hepatic pIgR enhances alcohol-associated liver disease due to impaired antimicrobial defence by IgA in the gut.


Assuntos
Fígado Gorduroso , Hepatite , Hepatopatias Alcoólicas , Receptores de Imunoglobulina Polimérica , Camundongos , Animais , Etanol/metabolismo , Receptores de Imunoglobulina Polimérica/metabolismo , Translocação Bacteriana , Fígado/metabolismo , Hepatopatias Alcoólicas/prevenção & controle , Hepatopatias Alcoólicas/metabolismo , Fígado Gorduroso/metabolismo , Hepatite/metabolismo , Imunoglobulina A , Camundongos Endogâmicos C57BL
4.
Dig Dis Sci ; 68(7): 3059-3069, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-36807831

RESUMO

BACKGROUND: Alcohol-associated liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) are two of the most common etiologies of chronic liver disease worldwide. Changes in intestinal permeability and increased gut microbial translocation have been posited as important contributors to inflammation in both ALD and NAFLD. However, gut microbial translocation has not been compared between the two etiologies and can lead to better understanding of the differences in their pathogenesis to liver disease. METHODS: We compared serum and liver markers in the following five models of liver disease to understand the differences in the role of gut microbial translocation on liver disease progression caused by ethanol versus Western diet: (1) 8-week chronic ethanol feeding model. (2) 2-week chronic-plus-binge (National Institute on Alcohol Abuse and Alcoholism (NIAAA)) ethanol feeding model. (3) 2-week chronic-plus-binge (NIAAA) ethanol feeding model in microbiota-humanized gnotobiotic mice colonized with stool from patients with alcohol-associated hepatitis. (4) 20-week Western-diet-feeding model of NASH. (5) 20-week Western-diet-feeding model in microbiota-humanized gnotobiotic mice colonized with stool from NASH patients. RESULTS: Translocation of bacterial lipopolysaccharide to the peripheral circulation was seen in both ethanol-induced and diet-induced liver disease, but translocation of bacteria itself was restricted to only ethanol-induced liver disease. Moreover, the diet-induced steatohepatitis models developed more significant liver injury, inflammation, and fibrosis compared with ethanol-induced liver disease models, and this positively correlated with the level of lipopolysaccharide translocation. CONCLUSIONS: More significant liver injury, inflammation, and fibrosis are seen in diet-induced steatohepatitis, which positively correlates with translocation of bacterial components, but not intact bacteria.


Assuntos
Hepatite Alcoólica , Hepatopatias Alcoólicas , Hepatopatia Gordurosa não Alcoólica , Camundongos , Animais , Etanol/efeitos adversos , Hepatopatia Gordurosa não Alcoólica/patologia , Translocação Bacteriana , Lipopolissacarídeos , Fígado/patologia , Hepatopatias Alcoólicas/complicações , Hepatite Alcoólica/complicações , Inflamação/patologia , Dieta , Bactérias , Fibrose , Camundongos Endogâmicos C57BL , Modelos Animais de Doenças
5.
J Hepatol ; 76(4): 788-799, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-34896404

RESUMO

BACKGROUND & AIMS: Studies investigating the gut-liver axis have largely focused on bacteria, whereas little is known about commensal fungi. We characterized fecal fungi in patients with non-alcoholic fatty liver disease (NAFLD) and investigated their role in a fecal microbiome-humanized mouse model of Western diet-induced steatohepatitis. METHODS: We performed fungal internal transcribed spacer 2 sequencing using fecal samples from 78 patients with NAFLD, 16 controls and 73 patients with alcohol use disorder. Anti-Candida albicans (C. albicans) IgG was measured in blood samples from 17 controls and 79 patients with NAFLD. Songbird, a novel multinominal regression tool, was used to investigate mycobiome changes. Germ-free mice were colonized with feces from patients with non-alcoholic steatohepatitis (NASH), fed a Western diet for 20 weeks and treated with the antifungal amphotericin B. RESULTS: The presence of non-obese NASH or F2-F4 fibrosis was associated with a distinct fecal mycobiome signature. Changes were characterized by an increased log-ratio for Mucor sp./Saccharomyces cerevisiae (S. cerevisiae) in patients with NASH and F2-F4 fibrosis. The C. albicans/S. cerevisiae log-ratio was significantly higher in non-obese patients with NASH when compared with non-obese patients with NAFL or controls. We observed a different fecal mycobiome composition in patients with NAFLD and advanced fibrosis compared to those with alcohol use disorder and advanced fibrosis. Plasma anti-C. albicans IgG was increased in patients with NAFLD and advanced fibrosis. Gnotobiotic mice, colonized with human NASH feces and treated with amphotericin B were protected from Western diet-induced steatohepatitis. CONCLUSIONS: Non-obese patients with NAFLD and more advanced disease have a different fecal mycobiome composition to those with mild disease. Antifungal treatment ameliorates diet-induced steatohepatitis in mice. Intestinal fungi could be an attractive target to attenuate NASH. LAY SUMMARY: Non-alcoholic fatty liver disease is one of the most common chronic liver diseases and is associated with changes in the fecal bacterial microbiome. We show that patients with non-alcoholic fatty liver disease and more severe disease stages have a specific composition of fecal fungi and an increased systemic immune response to Candida albicans. In a fecal microbiome-humanized mouse model of Western diet-induced steatohepatitis, we show that treatment with antifungals reduces liver damage.


Assuntos
Microbioma Gastrointestinal , Micobioma , Hepatopatia Gordurosa não Alcoólica , Animais , Fezes/microbiologia , Humanos , Fígado , Camundongos , Hepatopatia Gordurosa não Alcoólica/etiologia , Saccharomyces cerevisiae
6.
Proc Natl Acad Sci U S A ; 116(30): 15184-15193, 2019 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-31289229

RESUMO

Fibroblast growth factor 21 (FGF21) is an endocrine hormone that regulates glucose, lipid, and energy homeostasis. While gene expression of FGF21 is regulated by the nuclear hormone receptor peroxisome proliferator-activated receptor alpha in the fasted state, little is known about the regulation of trafficking and secretion of FGF21. We show that mice with a mutation in the Yip1 domain family, member 6 gene (Klein-Zschocher [KLZ]; Yipf6KLZ/Y ) on a high-fat diet (HFD) have higher plasma levels of FGF21 than mice that do not carry this mutation (controls) and hepatocytes from Yipf6KLZ/Y mice secrete more FGF21 than hepatocytes from wild-type mice. Consequently, Yipf6KLZ/Y mice are resistant to HFD-induced features of the metabolic syndrome and have increased lipolysis, energy expenditure, and thermogenesis, with an increase in core body temperature. Yipf6KLZ/Y mice with hepatocyte-specific deletion of FGF21 were no longer protected from diet-induced obesity. We show that YIPF6 binds FGF21 in the endoplasmic reticulum to limit its secretion and specifies packaging of FGF21 into coat protein complex II (COPII) vesicles during development of obesity in mice. Levels of YIPF6 protein in human liver correlate with hepatic steatosis and correlate inversely with levels of FGF21 in serum from patients with nonalcoholic fatty liver disease (NAFLD). YIPF6 is therefore a newly identified regulator of FGF21 secretion during development of obesity and could be a target for treatment of obesity and NAFLD.


Assuntos
Fatores de Crescimento de Fibroblastos/genética , Fígado/metabolismo , Proteínas de Membrana/genética , Síndrome Metabólica/genética , Hepatopatia Gordurosa não Alcoólica/genética , Obesidade/genética , Animais , Temperatura Corporal , Vesículas Revestidas pelo Complexo de Proteína do Envoltório/genética , Vesículas Revestidas pelo Complexo de Proteína do Envoltório/metabolismo , Dieta Hiperlipídica/efeitos adversos , Retículo Endoplasmático/genética , Retículo Endoplasmático/metabolismo , Metabolismo Energético/genética , Fatores de Crescimento de Fibroblastos/sangue , Regulação da Expressão Gênica , Hepatócitos/metabolismo , Hepatócitos/patologia , Humanos , Lipólise/genética , Fígado/patologia , Proteínas de Membrana/metabolismo , Síndrome Metabólica/etiologia , Síndrome Metabólica/metabolismo , Síndrome Metabólica/patologia , Camundongos , Camundongos Knockout , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Obesidade/etiologia , Obesidade/metabolismo , Obesidade/patologia , Ligação Proteica , Transdução de Sinais , Termogênese/genética , Proteínas de Transporte Vesicular/genética , Proteínas de Transporte Vesicular/metabolismo
7.
J Hepatol ; 72(3): 391-400, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31606552

RESUMO

BACKGROUND & AIMS: Alcohol-associated liver disease is a leading indication for liver transplantation and a leading cause of mortality. Alterations to the gut microbiota contribute to the pathogenesis of alcohol-associated liver disease. Patients with alcohol-associated liver disease have increased proportions of Candida spp. in the fecal mycobiome, yet little is known about the effect of intestinal Candida on the disease. Herein, we evaluated the contributions of Candida albicans and its exotoxin candidalysin in alcohol-associated liver disease. METHODS: C. albicans and the extent of cell elongation 1 (ECE1) were analyzed in fecal samples from controls, patients with alcohol use disorder and those with alcoholic hepatitis. Mice colonized with different and genetically manipulated C. albicans strains were subjected to the chronic-plus-binge ethanol diet model. Primary hepatocytes were isolated and incubated with candidalysin. RESULTS: The percentages of individuals carrying ECE1 were 0%, 4.76% and 30.77% in non-alcoholic controls, patients with alcohol use disorder and patients with alcoholic hepatitis, respectively. Candidalysin exacerbates ethanol-induced liver disease and is associated with increased mortality in mice. Candidalysin enhances ethanol-induced liver disease independently of the ß-glucan receptor C-type lectin domain family 7 member A (CLEC7A) on bone marrow-derived cells, and candidalysin does not alter gut barrier function. Candidalysin can damage primary hepatocytes in a dose-dependent manner in vitro and is associated with liver disease severity and mortality in patients with alcoholic hepatitis. CONCLUSIONS: Candidalysin is associated with the progression of ethanol-induced liver disease in preclinical models and worse clinical outcomes in patients with alcoholic hepatitis. LAY SUMMARY: Candidalysin is a peptide toxin secreted by the commensal gut fungus Candida albicans. Candidalysin enhances alcohol-associated liver disease independently of the ß-glucan receptor CLEC7A on bone marrow-derived cells in mice without affecting intestinal permeability. Candidalysin is cytotoxic to primary hepatocytes, indicating a direct role of candidalysin on ethanol-induced liver disease. Candidalysin might be an effective target for therapy in patients with alcohol-associated liver disease.


Assuntos
Candida albicans/metabolismo , Exotoxinas/metabolismo , Proteínas Fúngicas/metabolismo , Hepatite Alcoólica/metabolismo , Hepatite Alcoólica/microbiologia , Hepatopatias Alcoólicas/metabolismo , Hepatopatias Alcoólicas/microbiologia , Adulto , Idoso , Animais , Estudos de Casos e Controles , Células Cultivadas , Modelos Animais de Doenças , Exotoxinas/análise , Exotoxinas/farmacologia , Fezes/microbiologia , Feminino , Proteínas Fúngicas/análise , Proteínas Fúngicas/farmacologia , Microbioma Gastrointestinal , Hepatite Alcoólica/mortalidade , Hepatócitos/efeitos dos fármacos , Humanos , Lectinas Tipo C/deficiência , Lectinas Tipo C/genética , Hepatopatias Alcoólicas/mortalidade , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Índice de Gravidade de Doença
8.
Alcohol Clin Exp Res ; 44(9): 1842-1851, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32628772

RESUMO

BACKGROUND: Fucosyltransferase 2 (Fut2)-mediated intestinal α1-2-fucosylation is important in maintaining a symbiotic host-microbiota relationship and can protect against several pathogens. Intestinal dysbiosis is an important factor for the progression of experimental ethanol (EtOH)-induced liver disease, but the role of Fut2 in modulating the intestinal glycocalyx during alcohol-associated liver disease is unknown. We investigated the role of Fut2-mediated intestinal α1-2-fucosylation for the development of alcohol-associated liver disease. METHODS: Immunohistochemistry staining was applied to evaluate α1-2-fucosylation in duodenal biopsies from patients with alcohol use disorder. Wild-type (WT) and Fut2-deficient littermate mice were subjected to Lieber-DeCarli models of chronic EtOH administration and the chronic-binge EtOH diet (NIAAA model). RESULTS: Intestinal α1-2-fucosylation was down-regulated in patients with alcohol use disorder. Lack of α1-2-fucosylation in Fut2-deficient mice exacerbates chronic EtOH-induced liver injury, steatosis, and inflammation without affecting EtOH metabolism. Dietary supplementation of the α1-2-fucosylated glycan 2'-fucosyllactose (2'-FL) ameliorates EtOH-induced liver disease in Fut2-deficient mice in the NIAAA model. Despite no direct effects on growth of Enterococcus faecalis in vitro, intestinal α1-2-fucosylation reduces colonization of cytolysin-positive E. faecalis in the intestine of EtOH-fed mice. CONCLUSIONS: Intestinal α1-2-fucosylation acts as a host-protective mechanism against EtOH-induced liver disease. 2'-FL is an oligosaccharide naturally present in human milk that could be considered as therapeutic agent for alcohol-associated liver disease.


Assuntos
Alcoolismo/metabolismo , Disbiose/genética , Fucosiltransferases/genética , Hepatopatias Alcoólicas/genética , Fígado/efeitos dos fármacos , Alcoolismo/genética , Alcoolismo/microbiologia , Animais , Depressores do Sistema Nervoso Central/toxicidade , Modelos Animais de Doenças , Disbiose/metabolismo , Disbiose/microbiologia , Etanol/toxicidade , Fucosiltransferases/metabolismo , Microbioma Gastrointestinal/efeitos dos fármacos , Glicocálix/efeitos dos fármacos , Glicocálix/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Fígado/metabolismo , Fígado/patologia , Hepatopatias Alcoólicas/metabolismo , Hepatopatias Alcoólicas/microbiologia , Camundongos , Galactosídeo 2-alfa-L-Fucosiltransferase
9.
Dig Dis Sci ; 65(12): 3592-3604, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32671585

RESUMO

BACKGROUND: Alcohol-associated liver disease accounts for half of cirrhosis-related deaths worldwide. The spectrum of disease varies from simple steatosis to fibrosis, cirrhosis and ultimately hepatocellular carcinoma. Understanding the disease on a molecular level helps us to develop therapeutic targets. AIM: We performed transcriptomic analysis in liver and ileum from chronic plus binge ethanol-fed mice, and we assessed the role of selected differentially expressed genes and their association with serum bile acids and gut microbiota. METHODS: Wild-type mice were subjected to a chronic Lieber-DeCarli diet model for 8 weeks followed by one binge of ethanol. RNA-seq analysis was performed on liver and ileum samples. Associations between selected differentially regulated genes and serum bile acid profile or fecal bacterial profiling (16S rDNA sequencing) were investigated. RESULTS: We provide a comprehensive transcriptomic analysis to identify differentially expressed genes, KEGG pathways, and gene ontology functions in liver and ileum from chronic plus binge ethanol-fed mice. In liver, we identified solute carrier organic anion transporter family, member 1a1 (Slco1a1; encoding for organic anion transporting polypeptides (OATP) 1A1), as the most down-regulated mRNA, and it is negatively correlated with serum cholic acid level. Prokineticin 2 (Prok2) mRNA, a cytokine-like molecule associated with gastrointestinal tract inflammation, was significantly down-regulated in ethanol-fed mice. Prok2 mRNA expression was negatively correlated with abundance of Allobaculum (genus), Coprococcus (genus), Lachnospiraceae (family), Lactococcus (genus), and Cobriobacteriaceae (family), while it positively correlated with Bacteroides (genus). CONCLUSIONS: RNA-seq analysis revealed unique transcriptomic signatures in the liver and intestine following chronic plus binge ethanol feeding.


Assuntos
Etanol/farmacologia , Hormônios Gastrointestinais/genética , Microbioma Gastrointestinal , Intestinos , Hepatopatias Alcoólicas/metabolismo , Fígado , Neuropeptídeos/genética , Proteínas de Transporte de Cátions Orgânicos/genética , Animais , Depressores do Sistema Nervoso Central/farmacologia , Ácido Cólico/análise , Correlação de Dados , Regulação para Baixo , Microbioma Gastrointestinal/efeitos dos fármacos , Microbioma Gastrointestinal/fisiologia , Perfilação da Expressão Gênica/métodos , Intestinos/efeitos dos fármacos , Intestinos/microbiologia , Intestinos/fisiologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Camundongos , Análise de Sequência de RNA/métodos
10.
Gut ; 68(8): 1504-1515, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30448775

RESUMO

OBJECTIVE: Antimicrobial C-type lectin regenerating islet-derived 3 gamma (REG3G) is suppressed in the small intestine during chronic ethanol feeding. Our aim was to determine the mechanism that underlies REG3G suppression during experimental alcoholic liver disease. DESIGN: Interleukin 22 (IL-22) regulates expression of REG3G. Therefore, we investigated the role of IL-22 in mice subjected to chronic-binge ethanol feeding (NIAAA model). RESULTS: In a mouse model of alcoholic liver disease, we found that type 3 innate lymphoid cells produce lower levels of IL-22. Reduced IL-22 production was the result of ethanol-induced dysbiosis and lower intestinal levels of indole-3-acetic acid (IAA), a microbiota-derived ligand of the aryl hydrocarbon receptor (AHR), which regulates expression of IL-22. Importantly, faecal levels of IAA were also found to be lower in patients with alcoholic hepatitis compared with healthy controls. Supplementation to restore intestinal levels of IAA protected mice from ethanol-induced steatohepatitis by inducing intestinal expression of IL-22 and REG3G, which prevented translocation of bacteria to liver. We engineered Lactobacillus reuteri to produce IL-22 (L. reuteri/IL-22) and fed them to mice along with the ethanol diet; these mice had reduced liver damage, inflammation and bacterial translocation to the liver compared with mice fed an isogenic control strain and upregulated expression of REG3G in intestine. However, L. reuteri/IL-22 did not reduce ethanol-induced liver disease in Reg3g-/- mice. CONCLUSION: Ethanol-associated dysbiosis reduces levels of IAA and activation of the AHR to decrease expression of IL-22 in the intestine, leading to reduced expression of REG3G; this results in bacterial translocation to the liver and steatohepatitis. Bacteria engineered to produce IL-22 induce expression of REG3G to reduce ethanol-induced steatohepatitis.


Assuntos
Disbiose , Etanol , Microbioma Gastrointestinal/fisiologia , Interleucinas/imunologia , Intestino Delgado/imunologia , Limosilactobacillus reuteri/imunologia , Hepatopatias Alcoólicas , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Modelos Animais de Doenças , Disbiose/complicações , Disbiose/etiologia , Disbiose/imunologia , Etanol/efeitos adversos , Etanol/metabolismo , Imunidade Inata , Ácidos Indolacéticos/metabolismo , Inflamação/metabolismo , Hepatopatias Alcoólicas/imunologia , Hepatopatias Alcoólicas/microbiologia , Hepatopatias Alcoólicas/terapia , Camundongos , Camundongos Knockout , Proteínas Associadas a Pancreatite/imunologia , Receptores de Hidrocarboneto Arílico/metabolismo , Interleucina 22
11.
Dig Dis Sci ; 64(7): 1878-1892, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31076986

RESUMO

BACKGROUND: Alcohol-related liver disease is one of the most prevalent chronic liver diseases worldwide. Mechanisms involved in the pathogenesis of alcohol-related liver disease are not well understood. Oxylipins play a crucial role in numerous biological processes and pathological conditions. Nevertheless, oxylipins are not well studied in alcohol-related liver disease. AIMS: (1) To characterize the patterns of bioactive ω-3 and ω-6 polyunsaturated fatty acid metabolites in alcohol use disorder and alcoholic hepatitis patients and (2) to identify associations of serum oxylipins with clinical parameters in patients with alcohol-related liver disease. METHODS: We performed a comprehensive liquid chromatography with tandem mass spectrometry (LC-MS/MS) analysis of serum and fecal oxylipins derived from ω-6 arachidonic acid, ω-3 eicosapentaenoic acid, and docosahexaenoic acid in a patient cohort with alcohol-related liver disease. RESULTS: Our results show profound alterations in the serum oxylipin profile of patients with alcohol use disorder and alcoholic hepatitis compared to nonalcoholic controls. Spearman correlation of the oxylipins with clinical parameters shows a link between different serum oxylipins and intestinal permeability, aspartate aminotransferase, bilirubin, albumin, international normalized ratio, platelet count, steatosis, fibrosis and model for end-stage liver disease score. Especially, higher level of serum 20-HETE was significantly associated with decreased albumin, increased hepatic steatosis, polymorphonuclear infiltration, and 90-day mortality. CONCLUSIONS: Patients with alcohol-related liver disease have different oxylipin profiles. Future studies are required to confirm oxylipins as disease biomarker or to connect oxylipins to disease pathogenesis.


Assuntos
Alcoolismo/sangue , Ácidos Graxos Ômega-3/sangue , Ácidos Graxos Ômega-6/sangue , Fezes/química , Hepatite Alcoólica/sangue , Oxilipinas/sangue , Adulto , Idoso , Alcoolismo/diagnóstico , Biomarcadores/sangue , Cromatografia Líquida de Alta Pressão , Cromatografia de Fase Reversa , Feminino , Hepatite Alcoólica/diagnóstico , Humanos , Masculino , Metabolômica/métodos , Pessoa de Meia-Idade , Espectrometria de Massas por Ionização por Electrospray , Espectrometria de Massas em Tandem
12.
Int J Mol Sci ; 17(11)2016 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-27834859

RESUMO

Acne dysbiosis happens when there is a microbial imbalance of the over-growth of Propionibacterium acnes (P. acnes) in the acne microbiome. In our previous study, we demonstrated that Staphylococcus epidermidis (S. epidermidis, a probiotic skin bacterium) can exploit glycerol fermentation to produce short-chain fatty acids (SCFAs) which have antimicrobial activities to suppress the growth of P. acnes. Unlike glycerol, sucrose is chosen here as a selective fermentation initiator (SFI) that can specifically intensify the fermentation activity of S. epidermidis, but not P. acnes. A co-culture of P. acnes and fermenting S. epidermidis in the presence of sucrose significantly led to a reduction in the growth of P. acnes. The reduction was abolished when P. acnes was co-cultured with non-fermenting S. epidermidis. Results from nuclear magnetic resonance (NMR) analysis revealed four SCFAs (acetic acid, butyric acid, lactic acid, and succinic acid) were detectable in the media of S. epidermidis sucrose fermentation. To validate the interference of S. epidermidis sucrose fermentation with P. acnes, mouse ears were injected with both P. acnes and S. epidermidis plus sucrose or phosphate buffered saline (PBS). The level of macrophage-inflammatory protein-2 (MIP-2) and the number of P. acnes in ears injected with two bacteria plus sucrose were considerably lower than those in ears injected with two bacteria plus PBS. Our results demonstrate a precision microbiome approach by using sucrose as a SFI for S. epidermidis, holding future potential as a novel modality to equilibrate dysbiotic acne.


Assuntos
Acne Vulgar/terapia , Antibiose , Disbiose/terapia , Fermentação/efeitos dos fármacos , Probióticos/farmacologia , Staphylococcus epidermidis/efeitos dos fármacos , Sacarose/farmacologia , Acne Vulgar/microbiologia , Acne Vulgar/patologia , Animais , Carga Bacteriana/efeitos dos fármacos , Biomarcadores/metabolismo , Quimiocina CXCL2/genética , Quimiocina CXCL2/metabolismo , Técnicas de Cocultura , Disbiose/microbiologia , Disbiose/patologia , Orelha/microbiologia , Orelha/patologia , Feminino , Expressão Gênica , Glicerol/metabolismo , Glicerol/farmacologia , Humanos , Camundongos , Camundongos Endogâmicos ICR , Microbiota , Probióticos/metabolismo , Propionibacterium acnes/efeitos dos fármacos , Propionibacterium acnes/crescimento & desenvolvimento , Propionibacterium acnes/patogenicidade , Pele/efeitos dos fármacos , Pele/microbiologia , Pele/patologia , Staphylococcus epidermidis/crescimento & desenvolvimento , Staphylococcus epidermidis/metabolismo , Sacarose/metabolismo
13.
Appl Microbiol Biotechnol ; 98(1): 411-24, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24265031

RESUMO

Increasing evidence demonstrates that commensal microorganisms in the human skin microbiome help fight pathogens and maintain homeostasis of the microbiome. However, it is unclear how these microorganisms maintain biological balance when one of them overgrows. The overgrowth of Propionibacterium acnes (P. acnes), a commensal skin bacterium, has been associated with the progression of acne vulgaris. Our results demonstrate that skin microorganisms can mediate fermentation of glycerol, which is naturally produced in skin, to enhance their inhibitory effects on P. acnes growth. The skin microorganisms, most of which have been identified as Staphylococcus epidermidis (S. epidermidis), in the microbiome of human fingerprints can ferment glycerol and create inhibition zones to repel a colony of overgrown P. acnes. Succinic acid, one of four short-chain fatty acids (SCFAs) detected in fermented media by nuclear magnetic resonance (NMR) analysis, effectively inhibits the growth of P. acnes in vitro and in vivo. Both intralesional injection and topical application of succinic acid to P. acnes-induced lesions markedly suppress the P. acnes-induced inflammation in mice. We demonstrate for the first time that bacterial members in the skin microbiome can undergo fermentation to rein in the overgrowth of P. acnes. The concept of bacterial interference between P. acnes and S. epidermidis via fermentation can be applied to develop probiotics against acne vulgaris and other skin diseases. In addition, it will open up an entirely new area of study for the biological function of the skin microbiome in promoting human health.


Assuntos
Acne Vulgar/microbiologia , Antibiose , Propionibacterium acnes/crescimento & desenvolvimento , Propionibacterium acnes/fisiologia , Staphylococcus epidermidis/metabolismo , Staphylococcus epidermidis/fisiologia , Acne Vulgar/terapia , Animais , Antibacterianos/metabolismo , DNA Bacteriano/química , DNA Bacteriano/genética , Fermentação , Glicerol/metabolismo , Humanos , Camundongos , Dados de Sequência Molecular , Probióticos/administração & dosagem , Propionibacterium acnes/efeitos dos fármacos , Análise de Sequência de DNA , Pele/microbiologia , Ácido Succínico/metabolismo
14.
Life (Basel) ; 14(3)2024 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-38541740

RESUMO

Wine grape quality is influenced by the variety and growing environment, and the quality of the grapes has a significant impact on the quality of the wine. Tannins are a crucial indicator of wine grape quality, and, therefore, rapid and non-destructive methods for detecting tannin content are necessary. This study collected spectral data of Pinot Noir and Chardonnay using a geophysical spectrometer, with a focus on the 500-1800 nm spectrum. The spectra were preprocessed using Savitzky-Golay (SG), first-order differential (1D), standard normal transform (SNV), and their respective combinations. Characteristic bands were extracted through correlation analysis (PCC). Models such as partial least squares (PLS), support vector machine (SVM), random forest (RF), and one-dimensional neural network (1DCNN) were used to model tannin content. The study found that preprocessing the raw spectra improved the models' predictive capacity. The SVM-RF model was the most effective in predicting grape tannin content, with a test set R2 of 0.78, an RMSE of 0.31, and an RE of 10.71%. These results provide a theoretical basis for non-destructive testing of wine grape tannin content.

15.
Methods Protoc ; 6(6)2023 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-37987354

RESUMO

Alcohol-associated liver disease (ALD) is a major global health issue, contributing significantly to morbidity and mortality worldwide. Among the ALD subtypes, alcohol-associated hepatitis poses a severe and urgent medical challenge with high short-term mortality rates. Despite extensive research, the current therapeutic approaches for alcohol-associated hepatitis have limited efficacy, necessitating novel interventions. Recent studies have highlighted the crucial role of the gut microbiota in ALD pathogenesis, particularly Enterococcus faecalis (E. faecalis) and its cytolysin exotoxin. This study presents the development of a standardized real-time quantitative polymerase chain reaction (RT-qPCR) assay to detect and quantify cytolysin in fecal samples from patients with alcohol-associated hepatitis. The diagnostic assay allows for an association analysis between cytolysin-positive E. faecalis and disease severity as well as mortality. This assay was developed to standardize the identification of cytolysin-positive patients who can be selected for clinical trials.

16.
Gut Microbes ; 15(1): 2236750, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37475473

RESUMO

The gastrointestinal microbiome plays a significant role in modulating numerous host processes, including metabolism. Prior studies show that when mice receive fecal transplants from obese donors on high-fat diets (HFD) (even when recipient mice are fed normal diets after transplantation), they develop obese phenotypes, demonstrating the prominent role that gut microbiota play in determining lean and obese phenotypes. While much of the credit has been given to gut bacteria, the impact of gut viruses on these phenotypes is understudied. To address this shortcoming, we gavaged mice with viromes isolated from donors fed HFD or normal chow over a 4-week study. By characterizing the gut bacterial biota via 16S rRNA amplicon sequencing and measuring mouse weights over time, we demonstrate that transplanted viruses affect the gut bacterial community, as well as weight gain/loss. Notably, mice fed chow but gavaged with HFD-derived viromes gained more weight than their counterparts receiving chow-derived viromes. The converse was also true: mice fed HFD but gavaged with chow-derived viromes gained less weight than their counterparts receiving HFD-derived viromes. Results were replicated in two independent experiments and phenotypic changes were accompanied by significant and identifiable differences in the fecal bacterial biota. Due to methodological limitations, we were unable to identify the specific bacterial strains responsible for respective phenotypic changes. This study confirms that virome-mediated perturbations can alter the fecal microbiome in vivo and indicates that such perturbations are sufficient to drive lean and obese phenotypes in mice.


Assuntos
Microbioma Gastrointestinal , Microbiota , Vírus , Camundongos , Animais , Transplante de Microbiota Fecal , Viroma , RNA Ribossômico 16S/genética , Obesidade/microbiologia , Dieta Hiperlipídica/efeitos adversos , Bactérias/genética , Fenótipo , Camundongos Endogâmicos C57BL
17.
Hepatol Commun ; 7(2): e0029, 2023 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-36706195

RESUMO

Chronic alcohol consumption is associated with intestinal fungal dysbiosis, yet we understand little about how alterations of intestinal fungi (mycobiota) contribute to the pathogenesis of alcohol-associated liver disease. By reanalyzing internal transcribed spacer 2 amplicon sequencing of fecal samples from a cohort of 66 patients with alcohol use disorder for presence (as opposed to relative abundance) of fungal species, we observed that the presence of Malassezia restricta was associated with increased markers of liver injury. M. restricta exacerbates ethanol-induced liver injury both in acute binge and chronic ethanol-feeding models in mice. Using bone marrow chimeric mice, we found that the disease exacerbating effect by M. restricta was mediated by C-type lectin domain family 4, member N on bone marrow-derived cells. M. restricta induces inflammatory cytokines and chemokines in Kupffer cells through C-type lectin domain family 4, member N signaling. Targeting fungal pathobionts might be a therapeutic strategy for alcohol-associated liver disease.


Assuntos
Doença Hepática Crônica Induzida por Substâncias e Drogas , Hepatopatias Alcoólicas , Animais , Camundongos , Etanol/efeitos adversos , Hepatopatias Alcoólicas/microbiologia , Lectinas Tipo C/genética
18.
bioRxiv ; 2023 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-36778328

RESUMO

Background: The gastrointestinal microbiome plays a significant role in numerous host processes and has an especially large impact on modulating the host metabolism. Prior studies have shown that when mice receive fecal transplants from obese donors that were fed high-fat diets (HFD) (even when recipient mice are fed normal diets after transplantation), they develop obese phenotypes. These studies demonstrate the prominent role that the gut microbiota play in determining lean and obese phenotypes. While much of the credit has been given to gut bacteria, studies have not measured the impact of gut viruses on these phenotypes. To address this shortcoming, we gavaged mice with viromes isolated from donors fed HFD or normal chow. By characterizing the mice’s gut bacterial biota and weight-gain phenotypes over time, we demonstrate that viruses can shape the gut bacterial community and affect weight gain or loss. Results: We gavaged mice longitudinally over 4 weeks while measuring their body weights and collecting fecal samples for 16S rRNA amplicon sequencing. We evaluated mice that were fed normal chow or high-fat diets, and gavaged each group with either chow-derived fecal viromes, HFD-derived fecal viromes, or phosphate buffered saline controls. We found a significant effect of gavage type, where mice fed chow but gavaged with HFD-derived viromes gained significantly more weight than their counterparts receiving chow-derived viromes. The converse was also true: mice fed HFD but gavaged with chow-derived viromes gained significantly less weight than their counterparts receiving HFD-derived viromes. These results were replicated in two separate experiments and the phenotypic changes were accompanied by significant and identifiable differences in the fecal bacterial biota. Notably, there were differences in Lachnospirales and Clostridia in mice fed chow but gavaged with HFD-derived fecal viromes, and in Peptostreptococcales, Oscillospirales, and Lachnospirales in mice fed HFD but gavaged with chow-derived fecal viromes. Due to methodological limitations, we were unable to identify specific bacterial species or strains that were responsible for respective phenotypic changes. Conclusions: This study confirms that virome-mediated perturbations can alter the fecal microbiome in an in vivo model and indicates that such perturbations are sufficient to drive lean and obese phenotypes in mice.

19.
Alcohol Clin Exp Res (Hoboken) ; 47(5): 856-867, 2023 May.
Artigo em Inglês | MEDLINE | ID: mdl-36871955

RESUMO

BACKGROUND AND PURPOSE: Gut bacteria metabolize tryptophan into indoles. Intestinal levels of the tryptophan metabolite indole-3-acetic acid are reduced in patients with alcohol-associated hepatitis. Supplementation of indole-3-acetic acid protects against ethanol-induced liver disease in mice. The aim of this study was to evaluate the effect of engineered bacteria producing indoles as Aryl-hydrocarbon receptor (Ahr) agonists. METHODS: C57BL/6 mice were subjected to chronic-plus-binge ethanol feeding and orally given PBS, control Escherichia coli Nissle 1917 (EcN) or engineered EcN-Ahr. The effects of EcN and EcN-Ahr were also examined in mice lacking Ahr in interleukin 22 (Il22)-producing cells. RESULTS: Through the deletion of endogenous genes trpR and tnaA, coupled with overexpression of a feedback-resistant tryptophan biosynthesis operon, EcN-Ahr were engineered to overproduce tryptophan. Additional engineering allowed conversion of this tryptophan to indoles including indole-3-acetic acid and indole-3-lactic acid. EcN-Ahr ameliorated ethanol-induced liver disease in C57BL/6 mice. EcN-Ahr upregulated intestinal gene expression of Cyp1a1, Nrf2, Il22, Reg3b, and Reg3g, and increased Il22-expressing type 3 innate lymphoid cells. In addition, EcN-Ahr reduced translocation of bacteria to the liver. The beneficial effect of EcN-Ahr was abrogated in mice lacking Ahr expression in Il22-producing immune cells. CONCLUSIONS: Our findings indicate that tryptophan metabolites locally produced by engineered gut bacteria mitigate liver disease via Ahr-mediated activation in intestinal immune cells.

20.
Cell Host Microbe ; 31(3): 389-404.e7, 2023 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-36893735

RESUMO

Alcohol-associated liver disease is accompanied by intestinal mycobiome dysbiosis, yet the impacts on liver disease are unclear. We demonstrate that Candida albicans-specific T helper 17 (Th17) cells are increased in circulation and present in the liver of patients with alcohol-associated liver disease. Chronic ethanol administration in mice causes migration of Candida albicans (C. albicans)-reactive Th17 cells from the intestine to the liver. The antifungal agent nystatin decreased C. albicans-specific Th17 cells in the liver and reduced ethanol-induced liver disease in mice. Transgenic mice expressing T cell receptors (TCRs) reactive to Candida antigens developed more severe ethanol-induced liver disease than transgene-negative littermates. Adoptively transferring Candida-specific TCR transgenic T cells or polyclonal C. albicans-primed T cells exacerbated ethanol-induced liver disease in wild-type mice. Interleukin-17 (IL-17) receptor A signaling in Kupffer cells was required for the effects of polyclonal C. albicans-primed T cells. Our findings indicate that ethanol increases C. albicans-specific Th17 cells, which contribute to alcohol-associated liver disease.


Assuntos
Candida albicans , Células Th17 , Camundongos , Animais , Candida , Camundongos Transgênicos , Etanol/toxicidade
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