Estudios de trasplante de microbiota fecal en síndrome metabólico, obesidad y diabetes, ¿dónde nos encontramos?

Fundamento: El trasplante de microbiota fecal (FMT) consiste en la transferencia de las heces de un donante sano a otro paciente con el objetivo de cambiar o restablecer la composición y función de su microbiota. Su única aplicación clínica actualmente aceptada es el tratamiento de infección recurrente por Clostridium difficile. No obstante, se está estudiando su empleo en enfermedades como la enfermedad inflamatoria intestinal, el autismo y las enfermedades metabólicas. En este último grupo encontramos el síndrome metabólico, la obesidad y la diabetes tipo 2, tres enfermedades relacionadas entre sí y cada vez más prevalentes en nuestro tiempo. Las tres se caracterizan por cursar con una disbiosis de la microbiota intestinal y en este contexto surge la idea del empleo del FMT para su tratamiento. El objetivo de este Trabajo de Fin de Grado es conocer los estudios que se han realizado para evaluar el efecto del FMT con donantes humanos en síndrome metabólico, obesidad y diabetes. Metodología: Se ha llevado a cabo una revisión sistemática utilizando la base de datos PubMed, realizando tres búsquedas por términos MeSH relacionando “fecal microbiota transplantation” con “obesity”, “diabetes” y “metabolic syndrome” y aplicando las metodologías PRISMA y PICO para seleccionar los resultados de interés. Resultados: Se han valorado siete artículos de intervención que evalúan el efecto del FMT con donantes humanos y receptores humanos o animales. Existen pocos resultados concluyentes sobre el efecto del FMT en la microbiota del receptor, debido a que los artículos son heterogéneos y valoran parámetros diferentes. Conclusión: El FMT supone un avance en el conocimiento de la relación entre la microbiota y las enfermedades metabólicas y, conforme obtenemos más información de los estudios de intervención realizados, nos acercamos a la posibilidad de aplicar este procedimiento en el tratamiento de otras enfermedades además de la infección por Clostridium difficile.Background: The fecal microbiota transplantation (FMT) consists in the transfer of gastrointestinal microbiota from a healthy individual to another in order to change or restore the composition and function of the recipient’s microbiota. Nowadays this method is only accepted as a therapeutic option for Clostridium difficile infection. However, there are many studies evaluating its applicability in other diseases such as inflammatory bowel disease, irritable bowel syndrome, autism and metabolic disorders, like obesity, diabetes or metabolic syndrome. In this project we are focusing on these three metabolic diseases, which incidence has increased rapidly worldwide. They are characterized by a dysbiosis of the intestinal microbiota and that is the reason why the idea of fecal microbiota transplantation as a possible therapeutic option arises. The main objective of this project is to analyse the currently available studies that evaluate the effect of fecal microbiota transplantation, from humans to either humans or animals, in the physiopathology of obesity, diabetes and metabolic syndrome. Methodology: A systematic review was carried out using the PubMed database with three independent searches using MeSH terms relating “fecal microbiota transplantation” and “obesity”, “diabetes” and “metabolic syndrome”. PRISMA and PICO methodologies were applied to select the studies of interest. Results: Seven articles from intervention studies that evaluate FMT with human donors and human or animal recipients have been included in this systematic review. To date, there are few conclusive results due to the heterogeneity of the studies. Conclusion: New studies on FMT represent an advance in the knowledge of the relationship between the microbiota and metabolic disorders. As we obtain more information regarding the applicability of this technique and its effect, we approach the possibility of applying it in the treatment of other diseases a part from infection by Clostridium difficile

Implication of miR-612 and miR-1976 in the regulation of TP53 and CD40 and their relationship in the response to specific weight-loss diets

Background: Non-coding RNAs (i.e., miRNAs) play a role in the development of obesity and related comorbidities and the regulation of body weight. Objective: To identify candidate miRNA biomarkers throughout omics approaches in order to predict the response to specific weight-loss dietary treatments. Design: Genomic DNA and cDNA isolated from white blood cells of a subset from the RESMENA nutritional intervention study (Low-responders (LR) vs High-responders (HR)) was hybridized in Infinium Human Methylation450 BeadChip and in Illumina Human HT-12 v4 gene expression BeadChips arrays respectively. A bioinformatic prediction of putative target sites of selected miRNAs was performed by applying miRBase algorithms. HEK-293T cells were co-transfected with expression vectors containing the 3'-UTR of candidate genes to validate the binding of miRNAs to its target sites. Results: 134 miRNAs were differentially methylated between HR and LR in the methylation array, whereas 44 miRNAs were differentially expressed between both groups in the expression array. Specifically, miR-1237, miR-1976, miR-642, miR-636, miR-612 and miR-193B were simultaneously hypomethylated and overexpressed in HR. miR-612 and miR-1976 showed greatest differences in methylation and expression levels, respectively. The bioinformatic prediction revealed that TP53 was a putative target gene of miR-612 and CD40 of miR-1976. Moreover, TP53 was downregulated in the expression array when comparing HR vs LR expression levels adjusted by sex, diet, age and baseline weight, and CD40 showed a statistical trend. Furthermore, gene expression levels of TP53 and CD40 in white blood cells, when measured by qPCR, were also downregulated in HR. Finally, miR-612 and miR-1976 potently repressed TP53 and CD40 respectively by targeting its 3'-UTR regions. Conclusion: miR-612 and miR-1976 levels could be prospective biomarkers of response to specific weight-loss diets and might regulate the gene expression of TP53 and CD40

One-carbon metabolism and nonalcoholic fatty liver disease: The crosstalk between nutrients, microbiota, and genetics

The prevalence of nonalcoholic fatty liver disease (NAFLD) is increasing worldwide. Its etiology includes nutritional, genetic, and lifestyle factors. Several mechanisms may link onecarbon metabolism – the associated metabolic pathways of folate, methionine, and choline – to the onset of NAFLD. In this review, we attempted to assess how choline, folate, methionine, and betaine affect NAFLD development, mainly through their role in the secretion of very low-density lipoproteins (VLDL) from the liver. We also reviewed recent articles that have described the relation between microbiota metabolism and NAFLD progression. Moreover, we describe the effect of single-nucleotide polymorphisms (SNP) in genes related to one-carbon metabolism and disease prevalence. We additionally seek SNP identified by genome-wide associations that may increase the risk of this disease. Even though the evidence available is not entirely consistent, it seems that the concentrations of choline, methionine, folate, and betaine may affect the progression of NAFLD. Since there is no effective therapy for NAFLD, further investigations into the link between nutrition, gut microbiota, genetic factors, and NAFLD are still necessary, with a particular emphasis on methyl donors

Implication of Trimethylamine N-Oxide (TMAO) in disease: Potential biomarker or new therapeutic target

Trimethylamine N-oxide (TMAO) is a molecule generated from choline, betaine, and carnitine via gut microbial metabolism. The plasma level of TMAO is determined by several factors including diet, gut microbial flora, drug administration and liver flavin monooxygenase activity. In humans, recent clinical studies evidence a positive correlation between elevated plasma levels of TMAO and an increased risk for major adverse cardiovascular events. A direct correlation between increased TMAO levels and neurological disorders has been also hypothesized. Several therapeutic strategies are being explored to reduce TMAO levels, including use of oral broad spectrum antibiotics, promoting the growth of bacteria that use TMAO as substrate and the development of target-specific molecules. Despite the accumulating evidence, it is questioned whether TMAO is the mediator of a bystander in the disease process. Thus, it is important to undertake studies to establish the role of TMAO in human health and disease. In this article, we reviewed dietary sources and metabolic pathways of TMAO, as well as screened the studies suggesting possible involvement of TMAO in the etiology of cardiovascular and neurological disorders, underlying the importance of TMAO mediating inflammatory processes. Finally, the potential utility of TMAO as therapeutic target is also analyzed

Inhibition of serum cholesterol oxidation by dietary vitamin C and selenium intake in high fat fed rats

Cholesterol oxidation products (COPs) have been considered as specific in vivo markers of oxidative stress. In this study, an increased oxidative status was induced in Wistar rats by feeding them a high-fat diet (cafeteria diet). Another group of animals received the same diet supplemented with a combination of two different antioxidants, ascorbic acid (100 mg/kg rat/day) and sodium selenite (200 microg/kg rat/day) and a third group fed on a control diet. Total and individual COPs analysis of the different diets showed no differences among them. At the end of the experimental trial, rats were sacrificed and serum cholesterol, triglycerides and COPs were measured. None of the diets induced changes in rats body weight, total cholesterol and triglycerides levels. Serum total COPs in rats fed on the high-fat diet were 1.01 microg/ml, two times the amount of the control rats (0.47 microg/ml). When dietary antioxidant supplementation was given, serum total COPs concentration (0.44 microg/ml) showed the same levels than those of the rats on control diet. 7beta-hydroxycholesterol, formed non-enzymatically via cholesterol peroxidation in the presence of reactive oxygen species, showed slightly lower values in the antioxidant-supplemented animals compared to the control ones. This study confirms the importance of dietary antioxidants as protective factors against the formation of oxysterols

Interaction among sex, aging, and epigenetic processes concerning visceral fat, insulin resistance, and dyslipidaemia

The distribution of adipose tissue is influenced by gender and by age, shifting from subcutaneous to visceral depots with longevity, increasing the development of several aging-related diseases and manifestations such as obesity, metabolic syndrome, and insulin resistance. Epigenetics might have an important role in aging processes. The aim of this research was to investigate the interactions between aging and epigenetic processes and the role of visceral adipose tissue, insulin resistance, and dyslipidaemia. Two different study samples of 366 and 269 adult participants were analyzed. Anthropometric, biochemical (including the triglycerides-glucose (TyG) index), and blood pressure measurements were assessed following standardized methods. Body composition measurements by Dual-energy X-ray absorptiometry (DXA) were also performed for the second sample. Methylation data were assessed by Infinium Human Methylation BeadChip (Illumina) in peripheral white blood cells. Epigenetic age acceleration was calculated using the methods DNAmAge (AgeAcc) and GrimAge (AgeAccGrim). Age acceleration (AgeAccGrim) showed better correlations than AgeAcc with most of the measured variables (waist circumference, glucose, HOMA-IR, HDL-cholesterol, triglycerides, and TyG index) for the first sample. In the second sample, all the previous correlations were confirmed, except for HOMA-IR. In addition, many of the anthropometrical measurements assessed by DXA and C-reactive protein (CRP) were also statistically associated with AgeAccGrim. Associations separated by sex showed statistically significant correlations between AgeAccGrim and HDL-cholesterol or CRP in women, whereas, in men, the association was with visceral adipose tissue mass DXA, triglycerides and TyG index. Linear regression models (model 1 included visceral adipose tissue mass DXA and TyG index and model 2 included HDL-cholesterol and CRP) showed a significant association for men concerning visceral adipose tissue mass DXA and TyG index, while HDL-cholesterol and CRP were associated in women. Moreover, structural equation modeling showed that the TyG index was mediating the majority of the visceral adipose tissue mass action on age acceleration. Collectively, these findings showed that there are different mechanisms affecting epigenetic age acceleration depending on sex. The identified relationships between epigenetic age acceleration and disease markers will contribute to the understanding of the development of age-related diseases

Interaction between an adcy3 genetic variant and two weight-lowering diets affecting body fatness and body composition outcomes depending on macronutrient distribution: a randomized trial

The adenylate cyclase 3 (ADCY3) gene is involved in the regulation of several metabolic processes including the development and function of adipose tissue. The effects of the ADCY3 rs10182181 genetic variant on changes in body composition depending on the macronutrient distribution intake after 16 weeks of the dietary intervention were tested. The ADCY3 genetic variant was genotyped in 147 overweight or obese subjects, who were randomly assigned to one of the two diets varying in macronutrient content: a moderately-high-protein diet and a low-fat diet. Anthropometric and body composition measurements (DEXA scan) were recorded. Significant interactions between the ADCY3 genotype and dietary intervention on changes in weight, waist circumference, and body composition were found after adjustment for covariates. Thus, in the moderately-high-protein diet group, the G allele was associated with a lower decrease of fat mass, trunk and android fat, and a greater decrease in lean mass. Conversely, in the low-fat diet group carrying the G allele was associated with a greater decrease in trunk, android, gynoid, and visceral fat. Subjects carrying the G allele of the rs10182181 polymorphism may benefit more in terms of weight loss and improvement of body composition measurements when undertaking a hypocaloric low-fat diet as compared to a moderately-high-protein diet

A dual epigenomic approach for the search of obesity biomarkers: DNA methylation in relation to diet-induced weight loss

Epigenetics could help to explain individual differences in weight loss after an energy-restriction intervention. Here, we identify novel potential epigenetic biomarkers of weight loss, comparing DNA methylation patterns of high and low responders to a hypocaloric diet. Twenty-five overweight or obese men participated in an 8-wk caloric restriction intervention. DNA was isolated from peripheral blood mononuclear cells and treated with bisulfite. The basal and endpoint epigenetic differences between high and low responders were analyzed by methylation microarray, which was also useful in comparing epigenetic changes due to the nutrition intervention. Subsequently, MALDI-TOF mass spectrometry was used to validate several relevant CpGs and the surrounding regions. DNA methylation levels in several CpGs located in the ATP10A and CD44 genes showed statistical baseline differences depending on the weight-loss outcome. At the treatment endpoint, DNA methylation levels of several CpGs on the WT1 promoter were statistically more methylated in the high than in the low responders. Finally, different CpG sites from WT1 and ATP10A were significantly modified as a result of the intervention. In summary, hypocaloric-diet-induced weight loss in humans could alter DNA methylation status of specific genes. Moreover, baseline DNA methylation patterns may be used as epigenetic markers that could help to predict weight loss

Possible metabolic interplay between quality of life and fecal microbiota in a presenior population: Preliminary results

Objectives: The number of people aged 60 y is increasing worldwide, so establishing a relationship between lifestyle and health-associated factors, such as gut microbiota in an older population, is important. This study aimed to characterize the gut microbiota of a presenior population, and analyze the association between some bacteria and quality of life with the Short Form (SF) 36 questionnaire. Methods: Participants were adult men and women ages 50 to 80 y (n = 74). In addition to the SF-36 question- naire, fecal samples were collected in cryotubes, and 16S RNA gene sequencing was performed to character- ize microbial features. Participants were classified into two groups according to SF-36 punctuation. Linear and logistic regression models were performed to assess the possible association between any bacterial bowl and SF-36 score. Receiver operating characteristics curves were fitted to define the relative diagnostic strength of different bacterial taxa for the correct determination of quality of life. Results: A positive relationship was established between SF-36 score and Actinobacteria (P = 0.0310; R = 0.2510) compared with Peptostreptococcaceae (P = 0.0259; R = 0.2589), which increased with decreasing quality of life. Logistic regressions models and receiver operating characteristics curves showed that the rela- tive abundance of Actinobacteria and Peptostreptococcaceae may be useful to predict quality of life in a prese- nior population (area under the curve: 0.71). Conclusions: Quality of life may be associated with the relative abundance of certain bacteria, especially Acti- nobacteria and Peptostreptococcaceae, which may have a specific effect on certain markers and health care, which is important to improve quality of life in older populations

Biochemical profile, eating habits, and telomere length among Brazilian children and adolescents

Objectives: Lifestyle, obesity, and eating habits are emerging as determinants for the instability of telomeres. The increase in childhood and adolescent obesity and the association of biochemical profiles and dietary components with telomere length (TL) makes it an important issue in nutritional research. The aim of the present study was to investigate TL and its association with ethnic background, adiposity, clinical and biochemical parameters, and dietary patterns among Brazilian children and adolescents. Methods: A cross-sectional study encompassing 981 children and adolescents between 7 and 17 y of age was performed. Dietary intake habits, anthropometry, and clinical data were collected. TL analysis was performed by quantitative polymerase chain reaction. Results: Children presented significantly longer TL than adolescents (P = 0.046). Participants who self-declared as black, mulatto, or brown (P < 0.001) also showed longer TL than those who were white. Regarding biochemical parameters, individuals with altered glucose levels had shorter TL than normoglycemic participants in the total sample (P = 0.014). Such difference remained statistically significant in adolescents (P = 0.019). Participants who reported eating fruits and vegetables regularly had longer TL than those who did not (P < 0.001). Conclusion: The results suggested that both biochemical parameters and the intake of antioxidant-rich food, such as fruits and vegetables, are associated with the stability of telomere biology among young Brazilians