Amelia Marti

Interplay Between Weight Loss and Gut Microbiota Composition in Overweight Adolescents

The aim of this study was to determine the influence of an obesity treatment program on the gut microbiota and body weight of overweight adolescents. Thirty‐six adolescents (13–15 years), classified as overweight according to the International Obesity Task Force BMI criteria, were submitted to a calorie‐restricted diet (10–40%) and increased physical activity (15–23 kcal/kg body weight/week) program over 10 weeks. Gut bacterial groups were analyzed by quantitative real‐time PCR before and after the intervention. A group of subjects (n = 23) experienced >4.0 kg weight loss and showed significant BMI (P = 0.030) and BMI z‐score (P = 0.035) reductions after the intervention, while the other group (n = 13) showed <2.0 kg weight loss. No significant differences in dietary intake were found between both groups. In the whole adolescent population, the intervention led to increased Bacteroides fragilis group (P = 0.001) and Lactobacillus group (P = 0.030) counts, and to decreased Clostridium coccoides group (P = 0.028), Bifidobacterium longum (P = 0.031), and Bifidobacterium adolescentis (P = 0.044) counts. In the high weight–loss group, B. fragilis group and Lactobacillus group counts also increased (P = 0.001 and P = 0.007, respectively), whereas C. coccoides group and B. longum counts decreased (P = 0.001 and P = 0.044, respectively) after the intervention. Total bacteria, B. fragilis group and Clostridium leptum group, and Bifidobacterium catenulatum group counts were significantly higher (P < 0.001–0.036) while levels of C. coccoides group, Lactobacillus group, Bifidobacterium, Bifidobacterium breve, and Bifidobacterium bifidum were significantly lower (P < 0.001–0.008) in the high weight–loss group than in the low weight–loss group before and after the intervention. These findings indicate that calorie restriction and physical activity have an impact on gut microbiota composition related to body weight loss, which also seem to be influenced by the individuals microbiota.

Obesity and immune function relationships.

The immunological processes involved in the collaborative defence of organisms are affected by nutritional status. Thus, a positive chronic imbalance between energy intake and expenditure leads to situations of obesity, which may influence unspecific and specific immune responses mediated by humoral and cell mediated mechanisms. Furthermore, several lines of evidence have supported a link between adipose tissue and immunocompetent cells. This interaction is illustrated in obesity, where excess adiposity and impaired immune function have been described in both humans and genetically obese rodents. However, limited and often controversial information exist comparing immunity in obese and non‐obese subjects as well as about the cellular and molecular mechanisms implicated. In general terms, clinical and epidemiological data support the evidence that the incidence and severity of specific types of infectious illnesses are higher in obese persons as compared to lean individuals together with the occurrence of poor antibody responses to antigens in overweight subjects. Leptin might play a key role in linking nutritional status with T‐cell function. The complexities and heterogeneity of the host defences concerning the immune response in different nutritional circumstances affecting the energy balance require an integral study of the immunocompetent cells, their subsets and products as well as specific and unspecific inducer/regulator systems. In this context, more research is needed to clarify the clinical implications of the alterations induced by obesity on the immune function.

Shifts in clostridia, bacteroides and immunoglobulin-coating fecal bacteria associated with weight loss in obese adolescents

Objective:To evaluate the effects of a multidisciplinary obesity treatment programme on fecal microbiota composition and immunoglobulin-coating bacteria in overweight and obese adolescents and their relationship to weight loss.Design:Longitudinal intervention study based on both a calorie-restricted diet (calorie reduction=10–40%) and increased physical activity (calorie expenditure=15–23 kcal/kg body weight per week) for 10 weeks.Participants:Thirty-nine overweight and obese adolescents (BMI mean 33.1 range 23.7–50.4; age mean 14.8 range, 13.0–16.0).Measurements:BMI, BMI z-scores and plasma biochemical parameters were measured before and after the intervention. Fecal microbiota was analyzed by fluorescent in situ hybridization. Immunoglobulin-coating bacteria were detected using fluorescent-labelled F(ab′)2 antihuman IgA, IgG and IgM.Results:Reductions in Clostridium histolyticum and E. rectale-C. coccoides proportions significantly correlated with weight and BMI z-score reductions in the whole adolescent population. Proportions of C. histolyticum, C. lituseburense and E. rectale-C. coccoides dropped significantly whereas those of the Bacteroides-Prevotella group increased after the intervention in those adolescents who lost more than 4 kg. Total fecal energy was almost significantly reduced in the same group of adolescents but not in the group that lost less than 2.5 kg. IgA-coating bacterial proportions also decreased significantly in participants who lost more than 6 kg after the intervention, paralleled to reductions in C. histolyticum and E. rectale-C. coccoides populations. E. rectale-C. coccoides proportions also correlated with weight loss and BMI z-score reduction in participants whose weight loss exceeded 4 kg.Conclusions:Specific gut bacteria and an associated IgA response were related to body weight changes in adolescents under lifestyle intervention. These results suggest interactions between diet, gut microbiota and host metabolism and immunity in obesity.

In vivo nutrigenomic effects of virgin olive oil polyphenols within the frame of the Mediterranean diet: a randomized controlled trial

The aim of the study was to assess whether benefits associated with the traditional Mediterranean diet (TMD) and virgin olive oil (VOO) consumption could be mediated through changes in the expression of atherosclerosis‐related genes. A randomized, parallel, controlled clinical trial in healthy volunteers (n=90) aged 20 to 50 yr was performed. Threemonth intervention groups were as follows: 1) TMD with VOO (TMD+VOO), 2) TMD with washed virgin olive oil (TMD+WOO), and 3) control with participants’ habitual diet. WOO was similar to VOO, but with a lower polyphenol content (55 vs. 328 mg/kg, respectively). TMD consumption decreased plasma oxidative and inflammatory status and the gene expression related with both inflammation [INF‐γ (INFy), Rho GTPase‐activating protein15 (ARHGAP15), and interleukin‐7 receptor (IL7R)] and oxidative stress [adrenergic ß2‐receptor (ADRB2) and polymerase (DNA‐directed) κ (POLK)] in peripheral blood mononuclear cells. All effects, with the exception of the decrease in POLK expression, were particularly observed when VOO, rich in polyphenols, was present in the TMD dietary pattern. Our results indicate a significant role of olive oil polyphenols in the down‐regulation of proatherogenic genes in the context of a TMD. In addition, the benefits associated with a TMD and olive oil polyphenol consumption on cardiovascular risk can be mediated through nutrigenomic effects.—Konstantinidou, V., Covas, M.‐I., Mun˜oz‐Aguayo, D., Khymenets, O., de la Torre, R., Saez, G., del Carmen Tormos, M., Toledo, E., Marti, A., Ruiz‐Gutiérrez, V., Ruiz Mendez, M. V., Fito, M. In vivo nutrigenomic effects of virgin olive oil polyphenols within the frame of the Mediterranean diet: a randomized controlled trial. FASEBJ. 24, 2546–2557 (2010). www.fasebj.org

Eicosapentaenoic acid actions on adiposity and insulin resistance in control and high-fat-fed rats: role of apoptosis, adiponectin and tumour necrosis factor-α

n-3 PUFA have shown potential anti-obesity and insulin-sensitising properties. However, the mechanisms involved are not clearly established. The aim of the present study was to assess the effects of EPA administration, one of the n-3 PUFA, on body-weight gain and adiposity in rats fed on a standard or a high-fat (cafeteria) diet. The actions on white adipose tissue lipolysis, apoptosis and on several genes related to obesity and insulin resistance were also studied. Control and cafeteria-induced overweight male Wistar rats were assigned into two subgroups, one of them daily received EPA ethyl ester (1 g/kg) for 5 weeks by oral administration. The high-fat diet induced a very significant increase in both body weight and fat mass. Rats fed with the cafeteria diet and orally treated with EPA showed a marginally lower body-weight gain (P = 0.09), a decrease in food intake (P < 0.01) and an increase in leptin production (P < 0.05). EPA administration reduced retroperitoneal adipose tissue weight (P < 0.05) which could be secondary to the inhibition of the adipogenic transcription factor PPARgamma gene expression (P < 0.001), and also to the increase in apoptosis (P < 0.05) found in rats fed with a control diet. TNFalpha gene expression was significantly increased (P < 0.05) by the cafeteria diet, while EPA treatment was able to prevent (P < 0.01) the rise in this inflammatory cytokine. Adiposity-corrected adiponectin plasma levels were increased by EPA. These actions on both TNFalpha and adiponectin could explain the beneficial effects of EPA on insulin resistance induced by the cafeteria diet.

Interaction between genes and lifestyle factors on obesity.

Obesity originates from a failure of the body-weight control systems, which may be affected by changing environmental influences. Basically, the obesity risk depends on two important mutually-interacting factors: (1) genetic variants (single-nucleotide polymorphisms, haplotypes); (2) exposure to environmental risks (diet, physical activity etc.). Common single-nucleotide polymorphisms at candidate genes for obesity may act as effect modifiers for environmental factors. More than 127 candidate genes for obesity have been reported and there is evidence to support the role of twenty-two genes in at least five different populations. Gene-environment interactions imply that the synergy between genotype and environment deviates from either the additive or multiplicative effect (the underlying model needs to be specified to appraise the nature of the interaction). Unravelling the details of these interactions is a complex task. Emphasis should be placed on the accuracy of the assessment methods for both genotype and lifestyle factors. Appropriate study design (sample size) is crucial in avoiding false positives and ensuring that studies have enough power to detect significant interactions, the ideal design being a nested case-control study within a cohort. A growing number of studies are examining the influence of gene-environmental interactions on obesity in either epidemiological observational or intervention studies. Positive evidence has been obtained for genes involved in adiposity, lipid metabolism or energy regulation such as PPARgamma2 (Pro12Ala), beta-adrenoceptor 2 (Gln27Glu) or uncoupling proteins 1, 2 and 3. Variants on other genes relating to appetite regulation such as melanocortin and leptin receptors have also been investigated. Examples of some recently-identified interactions are discussed.

Genes, lifestyles and obesity

OBJECTIVE: To review the role of genes and lifestyle factors, particularly dietary habits and physical activity patterns, in obesity risk as well as their potential interactions.DESIGN AND MEASUREMENTS: A descriptive report of a number of genes definitely ascribed or potentially implicated in excessive fat accumulation leading to obesity as assessed by different research approaches (Mendelian transmission, genetic animal models, epidemiological association/linkage studies and genome-wide scans). Also, the involvement of macronutrient intake and composition (fat/carbohydrate) as well as the role of activity-linked energy expenditure in obesity onset is reviewed.RESULTS: Examples of the role of the genotype as well as of the dietary macronutrient composition/intake and sedentary/low energy cost of physical activities in obesity prevalence are reported.CONCLUSIONS: Both genes and everyday life environmental factors such as cultural and social mediated food intake and reduced domestic and living work activities are involved in the obesity pandemia. The occurrence of gene × gene and gene × environmental factors interactions makes it more difficult to interpret the specific roles of genetics and lifestyle in obesity risk.

Mediterranean Diet and Stroke: Objectives and Design of the SUN Project

Purpose: The Mediterranean diet has been postulated as a protective factor against different diseases including stroke. Thus, an epidemiological study in a Mediterranean country, such as Spain, focused on diet may offer new insights of the potential benefits of this nutritional pattern to prevent the onset of cerebrovascular diseases. Methods: The SUN (“Seguimiento Universidad de Navarra”) project is a prospective study among Spanish university alumni, aimed to identify the dietary determinants of stroke, coronary disease and other disorders. Two pilot studies have been developed. The first pilot study was focused on the understanding of the questionnaire. The second study used a random sample to assess the response proportion and the feasibility of using a mailing system for following-up the cohort. The first informative results are expected to be available after the first four years of following-up the cohort (2005). Here, we report the description of the baseline diet of the first participants in the cohort using data from 1587 men and 2260 women. Results: The outcome of our pilot studies ensure the feasibility of a mail-based cohort. In the baseline assessment, we found a high consumption of olive oil (18.5 g/person/day), red wine (28.8 g/person/day), legumes (102.5 g/person/day), vegetables (507.8 g/person/day) and fruits (316.7 g/person/day), with a great between-subject variability. Also, the values for cereals (170.4 g/person/day), dairy products (239.3 g/person/day) and meat and meat products consumption (186 g/person/day) in this cohort were estimated. The coefficients of variation ranged in women from 56 (for vegetables) to 240% (for red wine) and in men from 62 to 180% (for these same two items)/reflecting a wide heterogeneity in the diet of participants. Conclusions: Although the participation was not high (22% according to the estimates of the pilot study), it was comparable to the proportion found in large previous cohorts such as the Nurses-II Health Study (24%). The sharp contrast in dietary habits between the US and Spain together with the high between-subjects variability we have found in our Spanish cohort provides an exceptional opportunity to assess the aspects of the Mediterranean diet, which may be protective against stroke and other neurological disorders.

Noncoding RNAs, cytokines, and inflammation-related diseases

Chronic inflammation is involved in the onset and development of many diseases, including obesity, atherosclerosis, type 2 diabetes, osteoarthritis, autoimmune and degenerative diseases, asthma, periodontitis, and cirrhosis. The inflammation process is mediated by chemokines, cytokines, and different inflammatory cells. Although the molecules and mechanisms that regulate this primary defense mechanism are not fully understood, recent findings offer a putative role of noncoding RNAs, especially microRNAs (miRNAs), in the progression and management of the inflammatory response. These noncoding RNAs are crucial for the stability and maintenance of gene expression patterns that characterize some cell types, tissues, and biologic responses. Several miRNAs, such as miR‐126, miR‐132, miR‐146, miR‐155, and miR‐221, have emerged as important transcriptional regulators of some inflammation‐related mediators. Additionally, little is known about the involvement of long noncoding RNAs, long intergenic noncoding RNAs, and circular RNAs in inflammation‐mediated processes and the homeostatic imbalance associated with metabolic disorders. These noncoding RNAs are emerging as biomarkers with diagnosis value, in prognosis protocols, or in the personalized treatment of inflammation‐related alterations. In this context, this review summarizes findings in the field, highlighting those noncoding RNAs that regulate inflammation, with emphasis on recognized mediators such as TNF‐α, IL‐1, IL‐6, IL‐18, intercellular adhesion molecule 1, VCAM‐1, and plasminogen activator inhibitor 1. The down‐regulation or antagonism of the noncoding RNAs and the administration of exogenous miRNAs could be, in the near future, a promising therapeutic strategy in the treatment of inflammation‐related diseases.—Marques‐Rocha, J. L., Samblas, M., Milagro, F. I., Bressan, J., Martínez, J. A., Marti, A. Noncoding RNAs, cytokines, and inflammation‐related diseases. FASEB J. 29, 3595‐3611 (2015). www.fasebj.org

Differential DNA methylation patterns between high and low responders to a weight loss intervention in overweight or obese adolescents: the EVASYON study

In recent years, epigenetic markers emerged as a new tool to understand the influence of lifestyle factors on obesity phenotypes. Adolescence is considered an important epigenetic window over a humans lifetime. The objective of this work was to explore baseline changes in DNA methylation that could be associated with a better weight loss response after a multidisciplinary intervention program in Spanish obese or overweight adolescents. Overweight or obese adolescents (n=107) undergoing 10 wk of a multidisciplinary intervention for weight loss were assigned as high or low responders to the treatment. A methylation microarray was performed to search for baseline epigenetic differences between the 2 groups (12 subjects/group), and MALDI‐TOF mass spectrometry was used to validate (n=107) relevant CpG sites and surrounding regions. After validation, 5 regions located in or near AQP9, DUSP22, HIPK3, TNNT1, and TNNI3 genes showed differential methylation levels between high and low responders to the multidisciplinary weight loss intervention. Moreover, a calculated methylation score was significantly associated with changes in weight, BMI‐SDS, and body fat mass loss after the treatment. In summary, we have identified 5 DNA regions that are differentially methylated depending on weight loss response. These methylation changes may help to better understand the weight loss response in obese adolescents.—Moleres, A., Campión, J., Milagro, F. I., Marcos, A., Campoy, C., Garagorri, J. M., Gómez‐Martínez, S., Martínez, J. A., Azcona‐Sanjulián, M. C., Martí, A. Differential DNA methylation patterns between high and low responders to a weight loss intervention in overweight or obese adolescents: the EVASYON study. FASEB J. 27, 2504–2512 (2013). www.fasebj.org