An altered fecal microbiota profile in patients with non-alcoholic fatty liver disease (NAFLD) associated with obesity

Introduction: increasing evidence suggests a role of intestinal dysbiosis in obesity and non-alcoholic fatty liver disease (NAFLD). The advances in recent years with regard to the role of the gut microbiota raise the potential utility of new therapeutic approaches based on the modification of the microbiome. Objective: the aim of this study was to compare the bacterial communities in obese patients with or without NAFLD to those of healthy controls. Patients and methods: the fecal microbiota composition of 20 healthy adults, 36 obese patients with NAFLD and 17 obese patients without NAFLD was determined by 16S ribosomal RNA sequencing using the Illumina MiSeq system. Results: the results highlighted significant differences in the phylum Firmicutes between patients with and without NAFLD, which was a determining factor of the disease and supported its possible role as a marker of NAFLD. At the genus level, the relative abundance of Blautia, Alkaliphilus, Flavobacterium and Akkermansia was reduced in obese patients, both with or without NAFLD, compared to healthy controls. Furthermore, the number of sequences from the genus Streptococcus was significantly higher in patients with NAFLD in comparison with individuals without the disease, constituting another possible marker. Comparison of bacterial communities at the genus level by a principal coordinate analysis indicated that the bacterial communities of patients with NAFLD were dispersed and did not form a group. Conclusion: in conclusion, these results indicate the role of intestinal dysbiosis in the development of NAFLD associated with obesity. There was a differential microbiota profile between obese patients, with and without NAFLD. Thus, supporting gut microbiota modulation as a therapeutic alternative for the prevention and treatment of NAFLD

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An altered fecal microbiota profile in patients with non-alcoholic fatty liver disease (NAFLD) associated with obesity.

INTRODUCTION: increasing evidence suggests a role of intestinal dysbiosis in obesity and non-alcoholic fatty liver disease (NAFLD). The advances in recent years with regard to the role of the gut microbiota raise the potential utility of new therapeutic approaches based on the modification of the microbiome. OBJECTIVE: the aim of this study was to compare the bacterial communities in obese patients with or without NAFLD to those of healthy controls. PATIENTS AND METHODS: the fecal microbiota composition of 20 healthy adults, 36 obese patients with NAFLD and 17 obese patients without NAFLD was determined by 16S ribosomal RNA sequencing using the Illumina MiSeq system. RESULTS: the results highlighted significant differences in the phylum Firmicutes between patients with and without NAFLD, which was a determining factor of the disease and supported its possible role as a marker of NAFLD. At the genus level, the relative abundance of Blautia, Alkaliphilus, Flavobacterium and Akkermansia was reduced in obese patients, both with or without NAFLD, compared to healthy controls. Furthermore, the number of sequences from the genus Streptococcus was significantly higher in patients with NAFLD in comparison with individuals without the disease, constituting another possible marker. Comparison of bacterial communities at the genus level by a principal coordinate analysis indicated that the bacterial communities of patients with NAFLD were dispersed and did not form a group. CONCLUSION: in conclusion, these results indicate the role of intestinal dysbiosis in the development of NAFLD associated with obesity. There was a differential microbiota profile between obese patients, with and without NAFLD. Thus, supporting gut microbiota modulation as a therapeutic alternative for the prevention and treatment of NAFLD.

Functional Interactions between Gut Microbiota Transplantation, Quercetin, and High-Fat Diet Determine Non-Alcoholic Fatty Liver Disease Development in Germ-Free Mice.

SCOPE: Modulation of intestinal microbiota has emerged as a new therapeutic approach for non-alcoholic fatty liver disease (NAFLD). Herein, it is addressed whether gut microbiota modulation by quercetin and intestinal microbiota transplantation can influence NAFLD development. METHODS AND RESULTS: Gut microbiota donor mice are selected according to their response to high-fat diet (HFD) and quercetin in terms of obesity and NAFLD-related biomarkers. Germ-free recipients displayed metabolic phenotypic differences derived from interactions between microbiota transplanted, diets, and quercetin. Based on the evaluation of hallmark characteristics of NAFLD, it is found that gut microbiota transplantation from the HFD-non-responder donor and the HFD-fed donor with the highest response to quercetin results in a protective phenotype against HFD-induced NAFLD, in a mechanism that involves gut-liver axis alteration blockage in these receivers. Gut microbiota from the HFD-responder donor predisposed transplanted germ-free mice to NAFLD. Divergent protective and deleterious metabolic phenotypes exhibited are related to definite microbial profiles in recipients, highlighting the predominant role of Akkermansia genus in the protection from obesity-associated NAFLD development. CONCLUSIONS: The results provide scientific support for the prebiotic capacity of quercetin and the transfer of established metabolic profiles through gut microbiota transplantation as a protective strategy against the development of obesity-related NAFLD.

Protective effect of quercetin on high-fat diet-induced non-alcoholic fatty liver disease in mice is mediated by modulating intestinal microbiota imbalance and related gut-liver axis activation.

Gut microbiota is involved in obesity, metabolic syndrome and the progression of nonalcoholic fatty liver disease (NAFLD). It has been recently suggested that the flavonoid quercetin may have the ability to modulate the intestinal microbiota composition, suggesting a prebiotic capacity which highlights a great therapeutic potential in NAFLD. The present study aims to investigate benefits of experimental treatment with quercetin on gut microbial balance and related gut-liver axis activation in a nutritional animal model of NAFLD associated to obesity. C57BL/6J mice were challenged with high fat diet (HFD) supplemented or not with quercetin for 16 weeks. HFD induced obesity, metabolic syndrome and the development of hepatic steatosis as main hepatic histological finding. Increased accumulation of intrahepatic lipids was associated with altered gene expression related to lipid metabolism, as a result of deregulation of their major modulators. Quercetin supplementation decreased insulin resistance and NAFLD activity score, by reducing the intrahepatic lipid accumulation through its ability to modulate lipid metabolism gene expression, cytochrome P450 2E1 (CYP2E1)-dependent lipoperoxidation and related lipotoxicity. Microbiota composition was determined via 16S ribosomal RNA Illumina next-generation sequencing. Metagenomic studies revealed HFD-dependent differences at phylum, class and genus levels leading to dysbiosis, characterized by an increase in Firmicutes/Bacteroidetes ratio and in Gram-negative bacteria, and a dramatically increased detection of Helicobacter genus. Dysbiosis was accompanied by endotoxemia, intestinal barrier dysfunction and gut-liver axis alteration and subsequent inflammatory gene overexpression. Dysbiosis-mediated toll-like receptor 4 (TLR-4)-NF-κB signaling pathway activation was associated with inflammasome initiation response and reticulum stress pathway induction. Quercetin reverted gut microbiota imbalance and related endotoxemia-mediated TLR-4 pathway induction, with subsequent inhibition of inflammasome response and reticulum stress pathway activation, leading to the blockage of lipid metabolism gene expression deregulation. Our results support the suitability of quercetin as a therapeutic approach for obesity-associated NAFLD via its anti-inflammatory, antioxidant and prebiotic integrative response.

Factors Determining Colorectal Cancer: The Role of the Intestinal Microbiota.

The gastrointestinal tract, in particular the colon, holds a complex community of microorganisms, which are essential for maintaining homeostasis. However, in recent years, many studies have implicated microbiota in the development of colorectal cancer (CRC), with this disease considered a major cause of death in the western world. The mechanisms underlying bacterial contribution in its development are complex and are not yet fully understood. However, there is increasing evidence showing a connection between intestinal microbiota and CRC. Intestinal microorganisms cause the onset and progression of CRC using different mechanisms, such as the induction of a chronic inflammation state, the biosynthesis of genotoxins that interfere with cell cycle regulation, the production of toxic metabolites, or heterocyclic amine activation of pro-diet carcinogenic compounds. Despite these advances, additional studies in humans and animal models will further decipher the relationship between microbiota and CRC, and aid in developing alternate therapies based on microbiota manipulation.

[A review of diseases related to the intake of gluten]. / REVISIÓN DE LAS PATOLOGÍAS RELACIONADAS CON LA INGESTA DE GLUTEN.

Cereals are considered a basic food. Through the development of cooking, the human being has produced high- gluten-content food, so that it could make the most of its nutritional properties. Wheat is becoming one of the key elements of the Mediterranean diet. Amongst gluten- intake-related pathologies- gluten is present mainly in wheat, barley and rye- celiac disease (CD) is the most well-known. CD is a chronic inflammatory condition which affects gastrointestinal tract which develops in genetically predisposed individuals. The most common manifestation of CD is nutrients malabsorption. This protein trigger other pathology, wheat allergy (WA), which is an adverse immunological effect to gluten due to E immunoglobulin. A recent increased in non celiac gluten sensitivity (NCGS) has also been noticed, defined as the emergence of a range of gluten-intake related symptoms in patients for which celiac disease and wheat allergy have been ruled out. This article discusses these three conditions with their phatogenic mecanisms and the different clinic manifestations.

Los cereales han sido considerados un alimento fundamental de la dieta. A través del desarrollo de la cocina, el ser humano ha producido alimentos ricos en gluten, con el fin de aprovechar al máximo las propiedades nutricionales de este alimento. De tal manera que el trigo se ha convertido en uno de los elementos centrales de la dieta mediterránea. Entre las patologías relacionadas con la ingesta de gluten, contenido principalmente en el trigo, la cebada y el centeno, la enfermedad celíaca (EC) es la más conocida. La EC es una condición inflamatoria crónica que afecta al tracto gastrointestinal y que se desarrolla en sujetos genéticamente predispuestos. La manifestación más común es la malabsorción de nutrientes. Otra patología condicionada por esta proteína es la alergia al trigo (AT), que constituye una reacción inmunológica adversa al gluten mediada por la inmunoglobulina E. Recientemente está aumentando la sensibilidad al gluten no celíaca (SGNC), definida como la aparición de una variedad de manifestaciones relacionadas con la ingestión de gluten, en pacientes en los que la enfermedad celíaca y la alergia al trigo han sido excluidas. En este artículo se describen estas tres entidades con sus mecanismos patogénicos y las diferentes manifestaciones clínicas.

Revisión de las patologías relacionadas con la ingesta de gluten / A review of diseases related to the intake of gluten

Los cereales han sido considerados un alimento fundamental de la dieta. A través del desarrollo de la cocina, el ser humano ha producido alimentos ricos en gluten, con el fin de aprovechar al máximo las propiedades nutricionales de este alimento. De tal manera que el trigo se ha convertido en uno de los elementos centrales de la dieta mediterránea. Entre las patologías relacionadas con la ingesta de gluten, contenido principalmente en el trigo, la cebada y el centeno, la enfermedad celíaca (EC) es la más conocida. La EC es una condición inflamatoria crónica que afecta al tracto gastrointestinal y que se desarrolla en sujetos genéticamente predispuestos. La manifestación más común es la malabsorción de nutrientes. Otra patología condicionada por esta proteína es la alergia al trigo (AT), que constituye una reacción inmunológica adversa al gluten mediada por la inmunoglobulina E. Recientemente está aumentando la sensibilidad al gluten no celíaca (SGNC), definida como la aparición de una variedad de manifestaciones relacionadas con la ingestión de gluten, en pacientes en los que la enfermedad celíaca y la alergia al trigo han sido excluidas. En este artículo se describen estas tres entidades con sus mecanismos patogénicos y las diferentes manifestaciones clínicas (AU)

Cereals are considered a basic food. Through the development of cooking, the human being has produced high-gluten-content food, so that it could make the most of its nutritional properties. Wheat is becoming one of the key elements of the Mediterranean diet. Amongst gluten-intake-related pathologies- gluten is present mainly in wheat, barley and rye- celiac disease (CD) is the most well-known. CD is a chronic inflammatory condition which affects gastrointestinal tract which develops in genetically predisposed individuals. The most common manifestation of CD is nutrients malabsorption. This protein trigger other pathology, wheat allergy (WA), which is an adverse immunological effect to gluten due to E immunoglobulin. A recent increased in non celiac gluten sensitivity (NCGS) has also been noticed, defined as the emergence of a range of gluten-intake related symptoms in patients for which celiac disease and wheat allergy have been ruled out. This article discusses these three conditions with their phatogenic mecanisms and the different clinic manifestations (AU)

Quercetin ameliorates dysregulation of lipid metabolism genes via the PI3K/AKT pathway in a diet-induced mouse model of nonalcoholic fatty liver disease.

SCOPE: Flavonoids and related compounds seem to have favorable effects on nonalcoholic fatty liver disease (NAFLD) progression, although the exact mechanisms implicated are poorly understood. In this study, we aimed to investigate the effect of the flanovol quercetin on gene expression deregulation involved in the development of NAFLD, as well as the possible implication of phosphatidylinositol 3-kinase (PI3K)/AKT pathway modulation. METHODS AND RESULTS: We used an in vivo model based on methionine- and choline-deficient (MCD) diet-fed mice and an in vitro model consisting of Huh7 cells incubated with MCD medium. MCD-fed mice showed classical pathophysiological characteristics of nonalcoholic steatohepatitis, associated with altered transcriptional regulation of fatty acid uptake- and trafficking-related gene expression, with increased lipoperoxidation. PI3K/AKT pathway was activated by MCD and triggered gene deregulation causing either activation or inhibition of all studied genes as demonstrated through cell incubation with the PI3K-inhibitor LY294002. Treatment with quercetin reduced AKT phosphorylation, and oxidative/nitrosative stress, inflammation and lipid metabolism-related genes displayed a tendency to normalize in both in vivo and in vitro models. CONCLUSION: These results place quercetin as a potential therapeutic strategy for preventing NAFLD progression by attenuating gene expression deregulation, at least in part through PI3K/AKT pathway inactivation.

La poliquistosis hepática del adulto (PHA) en España: análisis de una encuesta estructurada analizando la experiencia y actitud de los especialistas de digestivo españoles / Polycystic liver in the adult (PLA) in Spain: Analysis of a structured survey analysing the experience and attitude of gastroenterologists in Spain

Antecedentes: la poliquistosis hepática del adulto (PHA) es una enfermedad rara caracterizada por el engrandecimiento crónico del hígado. Objetivo: analizar la implicación, experiencia y actitud de los especialistas españoles en el diagnóstico, seguimiento y tratamiento de los pacientes con PHA. Métodos: siete coordinadores del estudio contactaron cada uno con 15 especialistas de su entorno geográfico para participar en el estudio a través de una encuesta estructurada online. Resultados: de los 105 clínicos contactados, 88 completaron el cuestionario, siguiendo una mediana de 3 pacientes por consulta, aunque 6 clínicos realizan seguimiento a > 20 pacientes con PHA. El seguimiento se realiza mayoritariamente en el departamento de hepatología (81 %) y/o gastroenterología (33 %). La ecografía hepática se usa para el diagnóstico (98 %) y seguimiento (97 %) de la mayoría de los pacientes. En el momento del diagnóstico, 76 % de los pacientes tenían < 50 años predominando las mujeres. El objetivo principal del manejo de los pacientes es el control sintomático. Un 28 % de los médicos prescriben tratamiento farmacológico, principalmente análogos de somatostatina, seguidos por inhibidores de mTOR. Un tercio de los clínicos indicó que tenían pacientes que habían recibido trasplante hepático y/o cirugía. Conclusiones: la ecografía es la técnica de elección para el diagnóstico y seguimiento. Entre los clínicos que administran tratamiento farmacológico para el control sintomático, los análogos de somatostatina son los fármacos de elección. El uso poco frecuente de técnicas invasivas sugiere que los clínicos tienen una percepción bastante pobre de la utilidad de las distintas técnicas invasivas (AU)

Background: Polycystic liver in the adult (PLA) is a rare disease characterized by chronic liver enlargement. Objective: To analyse gastroenterologists’ involvement in, experience with, and attitude toward diagnosing, monitoring, and treating patients with PLA in Spain. Methods: Each of seven study coordinators contacted 15 specialists in their geographic area about participating in the study via an online structured survey. Results: Of the 105 clinics contacted, 88 completed the questionnaire, with a mean of 3 patients being followed per practice, although 6 clinics were following more than 20 patients with PLA. Patients were being followed mainly by the Department of Hepatology (81 %) and/or the Department of Gastroenterology (33 %). The majority of patients were diagnosed (98 %) and monitored (97 %) using liver ultrasound. When diagnosed, 76 % of patients were under 50 years of age, females predominating. The primary treatment objective for the patients was symptomatic management. Pharmacotherapy was prescribed by 28 % of physicians: Somatostatin analogues, primarily, followed by mTOR inhibitors. One-third of the clinics indicated that they had patients who had undergone liver transplant and/or surgery. Conclusions: Ultrasound is the diagnosing and monitoring method of choice. Among the clinics using pharmacotherapy for symptomatic management, somatostatin analogues were the drugs of choice. These clinics’ infrequent use of invasive procedures suggests that they perceive the various invasive techniques as not very effective (AU)

Enhanced expression of pro-inflammatory mediators and liver X-receptor-regulated lipogenic genes in non-alcoholic fatty liver disease and hepatitis C.

NAFLD (non-alcoholic fatty liver disease) is one of the most frequent chronic liver diseases worldwide. The metabolic factors associated with NAFLD are also determinants of liver disease progression in chronic HCV (hepatitis C virus) infection. It has been reported that, besides inducing hepatic fatty acid biosynthesis, LXR (liver X receptor) regulates a set of inflammatory genes. We aimed to evaluate the hepatic expression of LXRα and its lipogenic and inflammatory targets in 43 patients with NAFLD, 44 with chronic HCV infection and in 22 with histologically normal liver. Real-time PCR and Western blot analysis were used to determine hepatic expression levels of LXRα and related lipogenic and inflammatory mediators in the study population. We found that the LXRα gene and its lipogenic targets PPAR-γ (peroxisome-proliferator-activated receptor-γ), SREBP (sterol-regulatory-element-binding protein)-1c, SREBP-2 and FAS (fatty acid synthase) were overexpressed in the liver of NAFLD and HCV patients who had steatosis. Moreover, up-regulation of inflammatory genes, such as TNF (tumour necrosis factor)-α, IL (interleukin)-6, OPN (osteopontin), iNOS (inducible NO synthase), COX (cyclo-oxygenase)-2 and SOCS (suppressors of cytokine signalling)-3, was observed in NAFLD and HCV patients. Interestingly, TNF-α, IL-6 and osteopontin gene expression was lower in patients with steatohepatitis than in those with steatosis. In conclusion, hepatic expression of LXRα and its related lipogenic and inflammatory genes is abnormally increased in NAFLD and HCV patients with steatosis, suggesting a potential role of LXRα in the pathogenesis of hepatic steatosis in these chronic liver diseases.

Primary liver carcinoid tumour with a Zollinger Ellison syndrome - an unusual diagnosis: a case report.

Carcinoids are neuroendocrine tumours which may secrete hormones like gastrin, insulin, ACTH, etc. Liver is a common site for metastasis of carcinoid origin and an unusual site for a primary carcinoid tumour to arise.We present the case of a 51-year-old Caucasian man with diarrhoea, weight loss, duodenum ulcers and a liver mass in ultrasonography. A primary hepatic carcinoid tumour with a Zollinger Ellison syndrome was diagnosed. Surgery resection was performed and the patient remained free of symptoms two years after, with normalisation of gastrin levels.Primary hepatic carcinoid tumour represents an uncommon diagnosis, based on radiological and pathological features. The exclusion of different primary locations is necessary. Once associated with a Zollinger Ellison syndrome, diagnose may be more complicated and challenging since only 7 cases of hepatic carcinoids with gastrin secretion were reported in medical literature.A review of medical literature is performed and diagnoses tools that should be used for an accurate diagnosis and available treatment approaches are commented here.

Paciente con hiperaminotransferasemia y mononeuritis múltiple / Patient with hypertransaminasemia and mononeuritis multiplex

Se presenta el caso de un paciente de 57 años con hiperaminotransferasemia y mononeuritis múltiple. Tras los estudios realizados se le diagnosticó infección aguda por el virus de la hepatitis B, con panarteritis nodosa (PAN) asociada. La PAN, en general, cursa con signos y síntomas muy inespecíficos. La afectación del sistema nervioso en forma de mononeuritis múltiple puede ser una de las formas de presentación. La PAN es una de las manifestaciones extrahepáticas de la hepatitis B, pero desde la introducción de la vacuna para la hepatitis B su incidencia ha disminuido notablemente. Después de un año de seguimiento el paciente se encuentra asintomático tras recibir tratamiento con antivíricos y corticoides(AU)

We present the case of a 57-year-old man with mononeuritis multiplex and high transaminase levels. After investigations, the patient was diagnosed with acute hepatitis B infection and polyarteritis nodosa (PAN). The symptoms of PAN are nonspecific. Nervous system involvement in the form of mononeuritis multiplex can be one of the forms of presentation. PAN is one of the extrahepatic manifestations of hepatitis B, but since the introduction of the hepatitis B vaccine, its incidence has markedly declined. After 1 year of follow-up, the patient is asymptomatic following treatment with antiviral drugs and steroids(AU)

[Patient with hypertransaminasemia and mononeuritis multiplex]. / Paciente con hiperaminotransferasemia y mononeuritis múltiple.

We present the case of a 57-year-old man with mononeuritis multiplex and high transaminase levels. After investigations, the patient was diagnosed with acute hepatitis B infection and polyarteritis nodosa (PAN). The symptoms of PAN are nonspecific. Nervous system involvement in the form of mononeuritis multiplex can be one of the forms of presentation. PAN is one of the extrahepatic manifestations of hepatitis B, but since the introduction of the hepatitis B vaccine, its incidence has markedly declined. After 1 year of follow-up, the patient is asymptomatic following treatment with antiviral drugs and steroids.

Influence of insulin resistance and adipokines in the grade of steatosis of nonalcoholic fatty liver disease.

The objective of this work was to study the influence of insulin resistance and adipokines on the grade of steatosis in patients with NAFLD (nonalcoholic fatty liver disease) diagnosed by liver biopsy. A sample of 24 NAFLD patients was analyzed in a cross-sectional study. All patients with a two-week weight-stabilization period before recruitment were enrolled. A liver biopsy was realized. Weight, basal glucose, insulin, insulin resistance (HOMA), total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides, and adipokines blood levels were measured. A nutritional evaluation (dietary intake, indirect calorimetry, and bioimpedance) was performed. The mean age was 41.6 +/- 8.7 years and the mean body mass index (BMI) 29.4 +/- 4.7. Twelve patients had a low grade of steatosis (grade 1 of the Brunt classification) and 12 patients had a high grade of steatosis (grade 2 or 3). Only HOMA was higher in patients with a high grade of steatosis (1.4 +/- 0.5 vs. 2.8 +/- 1.7 units; P < 0.05). Anthropometric data and dietary intake were similar for both groups. Blood levels of adiponectin were higher in patients with a low grade of steatosis (37.7 +/- 22.5 vs. 24.2 +/- 33 ng mL(-1); P < 0.05). Blood levels of resistin were higher in patients with a high grade of steatosis (2.36 +/- 0.6 vs. 2.8 +/- 0.6 mg mL(-1); P < 0.05), without differences in TNF-alpha or leptin levels. In logistic regression analysis, the HOMA-IR remained in the model, with an odds ratio to develop high grade of steatosis of 7.8 (95% CI: 1.8-75) with each 1 unit of HOMA-IR adjusted by age, sex, BMI, and dietary intake. This study demonstrates that insulin resistance determined with the HOMA model is associated with a high grade of steatosis in patients with NAFLD.