Metabolic endotoxemia in obesity. Influence of dietary intervention and bariatric surgery.

Objetivos y resultados. En primer lugar nos propusimos estudiar si las comidas ricas en grasa favorecen la translocación de LPS en pacientes obesos. Para ello se analizaron los niveles de LPS antes y a las 3 horas de la ingesta de una comida exclusivamente grasa, observando que los niveles de LPS sólo aumentaban significativamente en aquellos pacientes que presentaban un alto incremento postprandial de triglicéridos, y que este aumento ocurría tanto en suero como en la fracción de quilomicrones estando estrechamente asociado a los niveles de triglicéridos. Sin embargo, no vimos relación entre los niveles de LPS y el grado de resistencia a la insulina. En segundo lugar, quisimos analizar si la endotoxemia metabólica podría afectar la función del TA en obesidad humana. Para ello se tomaron muestras de sangre en ayunas y de TA tanto visceral como subcutáneo durante la cirugía bariátrica de pacientes obesos. De esta forma, se comprobó que los pacientes con mayores niveles de LPS presentaban una menor expresión génica de factores lipogénicos y relacionados con la función del TA, así como una mayor inflamación. Esta relación fue confirmada por estudios in vitro llevados a cabo en explantes de TA y adipocitos diferenciados estimulados con LPS. Asimismo, analizamos el efecto del consumo moderado de vino tinto sobre la endotoxemia metabólica en voluntarios de mediana edad que se sometieron a tres intervenciones consistentes en consumo moderado de vino tinto, vino tinto desalcoholizado (para comprobar el efecto del vino tinto sin la fracción alcohólica) y la ginebra (para comprobar el efecto del alcohol sin la fracción polifenólica del vino tinto) durante 20 días. Así, se demostró que el consumo de vino tinto llevó a una disminución de la endotoxemia relacionada con el aumento de los grupos Bifidobacterium y Prevotella en la microbiota intestinal (cuya presencia se asocia a estados saludables). También estudiamos si acompañando una comida rica en grasa con estos tres tipos de bebidas se alteraba la respuesta postprandial de LPS, pero no se encontraron efectos significativos en dicha respuesta. Esto apoyaría la hipótesis de que la modulación de la endotoxemia metabólica por parte del vino tinto es debida a su efecto prebiótico. Por último quisimos analizar si la mejora metabólica temprana tras dos técnicas diferentes de cirugía bariátrica (derivación biliopancreática-DBP- y gastrectomía vertical-GV) podría estar relacionada con modificaciones en los niveles de LPS en los pacientes obesos mórbidos. Se analizaron los niveles de LPS y de la proteína de unión a LPS (LBP) antes de la cirugía y a los 15 y 90 días tras la misma. Sólo la GV en pacientes prediabéticos/diabéticos llevó a una disminución significativa de los niveles de LPS a los 90 días tras cirugía, pero dichos cambios no estuvieron relacionados con la mejora metabólica temprana. Sin embargo, sí se observó un efecto de la cirugía bariátrica sobre los niveles de LBP que fue paralelo a los cambios en las variables hepáticas e inflamatorias ocurridos tras la cirugía, y que además se relacionaron con los cambios en el índice de masa corporal. Conclusiones. En este estudio vimos por primera vez que en pacientes obesos las comidas ricas en grasa favorecen la translocación de LPS hacia la circulación, estando estrechamente asociada al metabolismo de los triglicéridos. Asimismo, dicha endotoxemia metabólica podría alterar la función del TA promoviendo una mayor inflamación y afectando a su capacidad de expansión en obesidad humana. Además, comprobamos que una intervención dietética con vino tinto mejora la endotoxemia metabólica probablemente debido a su efecto prebiótico. También vimos que los cambios de los niveles de LPS tras cirugía bariátrica a corto plazo, dependen tanto del tipo de cirugía empleado así como del estado glucémico previo del paciente.Antecedentes. Aunque la obesidad aparece frecuentemente asociada al desarrollo de enfermedades metabólicas, también existen sujetos obesos sin alteraciones metabólicas. La inflamación de bajo grado se ha propuesto como uno de los responsables del desarrollo de dichas enfermedades así como un tejido adiposo (TA) disfuncional con una capacidad de almacenamiento energético limitada. Los lipopolisacáridos (LPS) procedentes de bacterias Gram negativas de la microbiota intestinal se han postulado como uno de los desencadenantes de dicha inflamación. Comidas ricas en grasa favorecen la translocación de los LPS desde el lumen intestinal hacia la circulación en individuos delgados sanos, probablemente debido a que los LPS se asocian a las partículas de quilomicrones. Las concentraciones elevadas de LPS circulantes en ausencia de infección, que se relacionan con los desórdenes metabólicos y son dependientes de la composición de la dieta, es lo que se conoce como endotoxemia metabólica. En modelos animales la endotoxemia metabólica se asocia a una menor expresión de genes lipogénicos y adipogénicos en TA. Sin embargo, aun no se ha comprobado si estos fenómenos ocurren en pacientes obesos. Por otro lado, intervenciones que mejoran el estado metabólico como el consumo de vino tinto (el cual tiene además un efecto prebiótico), o la cirugía bariátrica (que consigue una mejora metabólica a corto plazo independiente a la pérdida de peso), podrían deber su efecto, al menos en parte, a una modificación en los niveles de LPS

8-oxoguanine DNA glycosylase 1 upregulation as a risk factor for obesity and colorectal cancer

DNA damage has been extensively studied as a potentially helpful tool in assessing and preventing cancer, having been widely associated with the deregulation of DNA damage repair (DDR) genes and with an increased risk of cancer. Adipose tissue and tumoral cells engage in a reciprocal interaction to establish an inflammatory microenvironment that enhances cancer growth by modifying epigenetic and gene expression patterns. Here, we hypothesize that 8-oxoguanine DNA glycosylase 1 (OGG1)—a DNA repair enzyme—may represent an attractive target that connects colorectal cancer (CRC) and obesity. In order to understand the mechanisms underlying the development of CRC and obesity, the expression and methylation of DDR genes were analyzed in visceral adipose tissue from CRC and healthy participants. Gene expression analysis revealed an upregulation of OGG1 expression in CRC participants (p < 0.005) and a downregulation of OGG1 in normal-weight healthy patients (p < 0.05). Interestingly, the methylation analysis showed the hypermethylation of OGG1 in CRC patients (p < 0.05). Moreover, expression patterns of OGG1 were found to be regulated by vitamin D and inflammatory genes. In general, our results showed evidence that OGG1 can regulate CRC risk through obesity and may act as a biomarker for CRC.Partial funding for open access charge: Universidad de Málag

Plasma Levels of Endocannabinoids and Their Analogues Are Related to Specific Fecal Bacterial Genera in Young Adults: Role in Gut Barrier Integrity

Objective: To investigate the association of plasma levels of endocannabinoids with fecal microbiota.Methods: Plasma levels of endocannabinoids, anandamide (AEA) and 2-arachidonoylglycerol (2-AG), as well as their eleven analogues, and arachidonic acid (AA), were measured using liquid chromatography-tandem mass spectrometry in 92 young adults. DNA extracted from stool samples was analyzed using 16S rRNA gene sequencing. Lipopolysaccharide levels were measured in plasma samples.Results: Plasma levels of endocannabinoids and their analogues were not related to beta or alpha diversity indexes. Plasma levels of AEA and related N-acylethanolamines correlated positively with the relative abundance of Faecalibacterium genus (all rho >= 0.26, p = 0.22, p = 0.24, p = 0.27, p Conclusion: Plasma levels of endocannabinoids and their analogues are correlated to specific fecal bacterial genera involved in maintaining gut barrier integrity in young adults. This suggests that plasma levels of endocannabinoids and their analogues may play a role in the gut barrier integrity in young adults.</p

Adipose Tissue Gene Expression of Factors Related to Lipid Processing in Obesity

BACKGROUND: Adipose tissue lipid storage and processing capacity can be a key factor for obesity-related metabolic disorders such as insulin resistance and diabetes. Lipid uptake is the first step to adipose tissue lipid storage. The aim of this study was to analyze the gene expression of factors involved in lipid uptake and processing in subcutaneous (SAT) and visceral (VAT) adipose tissue according to body mass index (BMI) and the degree of insulin resistance (IR). METHODS AND PRINCIPAL FINDINGS: VLDL receptor (VLDLR), lipoprotein lipase (LPL), acylation stimulating protein (ASP), LDL receptor-related protein 1 (LRP1) and fatty acid binding protein 4 (FABP4) gene expression was measured in VAT and SAT from 28 morbidly obese patients with Type 2 Diabetes Mellitus (T2DM) or high IR, 10 morbidly obese patients with low IR, 10 obese patients with low IR and 12 lean healthy controls. LPL, FABP4, LRP1 and ASP expression in VAT was higher in lean controls. In SAT, LPL and FABP4 expression were also higher in lean controls. BMI, plasma insulin levels and HOMA-IR correlated negatively with LPL expression in both VAT and SAT as well as with FABP4 expression in VAT. FABP4 gene expression in SAT correlated inversely with BMI and HOMA-IR. However, multiple regression analysis showed that BMI was the main variable contributing to LPL and FABP4 gene expression in both VAT and SAT. CONCLUSIONS: Morbidly obese patients have a lower gene expression of factors related with lipid uptake and processing in comparison with healthy lean persons

Metabolic and Endocrine Consequences of Bariatric Surgery.

Obesity is one of the most serious worldwide epidemics of the twenty-first century according to the World Health Organization. Frequently associated with a number of comorbidities, obesity threatens and compromises individual health and quality of life. Bariatric surgery (BS) has been demonstrated to be an effective treatment to achieve not only sustained weight loss but also significant metabolic improvement that goes beyond mere weight loss. The beneficial effects of BS on metabolic traits are so widely recognized that some authors have proposed BS as metabolic surgery that could be prescribed even for moderate obesity. However, most of the BS procedures imply malabsorption and/or gastric acid reduction which lead to nutrient deficiency and, consequently, further complications could be developed in the long term. In fact, BS not only affects metabolic homeostasis but also has pronounced effects on endocrine systems other than those exclusively involved in metabolic function. The somatotropic, corticotropic, and gonadal axes as well as bone health have also been shown to be affected by the various BS procedures. Accordingly, further consequences and complications of BS in the long term in systems other than metabolic system need to be addressed in large cohorts, taking into account each bariatric procedure before making generalized recommendations for BS. In this review, current data regarding these issues are summarized, paying special attention to the somatotropic, corticotropic, gonadal axes, and bone post-operative health

Gut Microbiota: The Missing Link Between Helicobacter pylori Infection and Metabolic Disorders?

Helicobacter pylori (H. pylori) is a gram-negative bacterium that infects approximately 4.4 billion individuals worldwide. Although the majority of infected individuals remain asymptomatic, this bacterium colonizes the gastric mucosa causing the development of various clinical conditions as peptic ulcers, chronic gastritis and gastric adenocarcinomas and mucosa-associated lymphoid tissue lymphomas, but complications are not limited to gastric ones. Extradigestive pathologies, including metabolic disturbances such as diabetes, obesity and nonalcoholic fatty liver disease, have also been associated with H. pylori infection. However, the underlying mechanisms connecting H. pylori with extragastric metabolic diseases needs to be clarified. Notably, the latest studies on the topic have confirmed that H. pylori infection modulates gut microbiota in humans. Damage in the gut bacterial community (dysbiosis) has been widely related to metabolic dysregulation by affecting adiposity, host energy balance, carbohydrate metabolism, and hormonal modulation, among others. Taking into account that Type 2 diabetic patients are more prone to be H. pylori positive, gut microbiota emerges as putative key factor responsible for this interaction. In this regard, the therapy of choice for H. pylori eradication, based on proton pump inhibitor combined with two or more antibiotics, also alters gut microbiota composition, but consequences on metabolic health of the patients has been scarcely explored. Recent studies from our group showed that, despite decreasing gut bacterial diversity, conventional H. pylori eradication therapy is related to positive changes in glucose and lipid profiles. The mechanistic insights explaining these effects should also be addressed in future research. This review will deal with the role of gut microbiota as the linking factor between H. pylori infection and metabolic diseases, and discussed the impact that gut bacterial modulation by H. pylori eradication treatment can also have in host's metabolism. For this purpose, new evidence from the latest human studies published in more recent years will be analyzed.GMM-N was supported by a Juan de la Cierva, Formación contract (FJCI-2017-34349; Ministerio de Ciencia, Innovación y Universidades; Spain). MC-P was recipient of a postdoctoralYe

The Role of Autophagy in White Adipose Tissue Function: Implications for Metabolic Health

White adipose tissue (WAT) is a highly adaptive endocrine organ that continuously remodels in response to nutritional cues. WAT expands to store excess energy by increasing adipocyte number and/or size. Failure in WAT expansion has serious consequences on metabolic health resulting in altered lipid, glucose, and inflammatory profiles. Besides an impaired adipogenesis, fibrosis and low-grade inflammation also characterize dysfunctional WAT. Nevertheless, the precise mechanisms leading to impaired WAT expansibility are yet unresolved. Autophagy is a conserved and essential process for cellular homeostasis, which constitutively allows the recycling of damaged or long-lived proteins and organelles, but is also highly induced under stress conditions to provide nutrients and remove pathogens. By modulating protein and organelle content, autophagy is also essential for cell remodeling, maintenance, and survival. In this line, autophagy has been involved in many processes affected during WAT maladaptation, including adipogenesis, adipocyte, and macrophage function, inflammatory response, and fibrosis. WAT autophagy dysregulation is related to obesity and diabetes. However, it remains unclear whether WAT autophagy alteration in obese and diabetic patients are the cause or the consequence of WAT malfunction. In this review, current data regarding these issues are discussed, focusing on evidence from human studies.M.C.P. was a recipient of a post-doctoral grant Juan de la Cierva Formación (FJCI-2017-32194) from the Ministerio de Ciencia, Innovación y Universidades (Spain). R.E.B. is under a contract from the ‘Nicolas Monarde’ (C-0030-2016) program from the Servicio Andaluz de Salud, Regional Ministry of Health of the Andalusian Government, Andalusia, Spain. This research was funded by Centros de Investigación Biomédica en Red (CIBER, CB06/03/0018) from the ISCIII, Madrid (Spain); RIC-0539-2018 and PI-0092-2017 from Consejería de Salud (Junta de Andalucía), Spain; PI18/01160 from the ISCIII (Madrid, Spain), and co-funded by the Fondo Europeo de Desarrollo Regional (FEDER).Ye

Helicobacter pylori Eradication Therapy Affect the Gut Microbiota and Ghrelin Levels

Background: Antibiotic therapy used to eradicate Helicobacter pylori has been associated with changes in plasma ghrelin and alterations in the gut microbiota. On the other hand, changes in ghrelin levels have been related to changes in gut microbiota composition. Our aim was to evaluate the relationship between changes in the gut microbiota and ghrelin levels in H. pylori infected patients who received antibiotic treatment for its eradication. Methods: A prospective case-control study that included forty H. pylori-positive patients who received eradication therapy (omeprazole, clarithromycin, and amoxicillin) and twenty healthy H. pylori antigen-negative participants. Patients were evaluated, including clinical, anthropometric and dietary variables, before and 2 months after treatment. Gut microbiota composition was analyzed through 16S rRNA amplicon sequencing (IlluminaMiSeq). Results: Changes in gut microbiota profiles and decrease in ghrelin levels were identified after H. pylori eradication treatment. Gut bacteria such as Bifidobacterium longum, Bacteroides, Prevotella, Parabacteroides distasonis, and RS045 have been linked to ghrelin levels fasting and/or post meals. Changes in the abundance of Lachnospiraceae, its genus Blautia, as well as Prevotella stercorea, and Megasphaera have been inversely associated with changes in ghrelin after eradication treatment. Conclusions: Eradication treatment for H. pylori produces changes in the composition of the intestinal microbiota and ghrelin levels. The imbalance between lactate producers such as Blautia, and lactate consumers such as Megasphaera, Lachnospiraceae, or Prevotella, could trigger changes related to ghrelin levels under the alteration of the eradication therapy used for H. pylori. In addition, acetate producing bacteria such as B. longum, Bacteroides, and P. distasonis could also play an important role in ghrelin regulation.GMM-N was supported by a Juan de la Cierva, Formación contract (FJCI-2017-34349) from the Spanish Ministry of Science, Innovation and Universities (Spain). IC-P was supported by Rio Hortega (CM 17/00169), and is now the recipient of a postdoctoral grant Juan Rodes from the Spanish Ministry of Economy and Competitiveness (ISCIII), and cofounded by Fondo Europeo de Desarrollo Regional-FEDER (JR 19/00054). MC-P was recipient of a postdoctoral grant Juan de la Cierva Formación (FJCI-2017-32194) from the Ministerio de Ciencia, Innovación y Universidades (Spain) and postdoctoral research grant (DOC_00448) from the Consejeria de Economía, Industria, Conocimiento y Universidades (PAIDI 2020, Junta de Andalucía), Spain, cofounded by the Fondo Europeo de Desarrollo Regional (FEDER). IM-I was supported by the MS type I program (CP16/00163) from the Instituto de Salud Carlos III and co-funded by Fondo Europeo de Desarrollo Regional FEDER. The funding organizations played no role in the present manuscript. This work was supported in part by a grant from the Instituto de Salud Carlos III co-funded by Fondo Europeo de Desarrollo Regional-FEDER, PI14/00082, PI15/01114, PI18/01160Madrid, Spain, and by the Centros de Investigación Biomédica en Red (CIBER) of the Institute of Health Carlos III (ISCIII) (CB06/03/0018).Ye