The gut microbiota in obesity and metabolic disease - a novel therapeutic target

Obesity is sweeping the westernized world at a rate which far outstrips human genomic evolution, highlighting the importance of the obesogenic environment. Diet is an important component of this obesogenic environment, with certain diets (high fat, high refined carbohydrates and sugar) predisposing to overweight. On the other hand, there are also foods shown to protect against obesity and the diseases of obesity, including whole plant foods, dairy products, dietary fibre and functional foods like probiotics, prebiotics and phytochemicals. Interestingly, many of these foods mediate their health-promoting activities through the gut microbiota. The human gut microbiota itself has recently been identified as a contributory factor in this obesogenic environment, with differences observed between lean and obese. Evidence from human studies indicates that important groups of fermentative bacteria differ in abundance between lean and obese. Recently it has been suggested that anomalous microbiota composition in infancy can predispose to overweight in later life, highlighting the important role of optimal microbiota successional development, and that – as observed in laboratory animals – the gut microbiota may contribute to the aetiology of obesity. In this review we will introduce the gut microbiota, describe its interactions with major dietary components and the host, and then go on to discuss evidence indicating that the gut microbiota may contribute to the obesogenic environment. Finally, we will explore possible strategies for modulating the composition and activity of the human gut microbiota which may impact on obesity or the metabolic diseases associated with obesity. (Nutritional Therapy & Metabolism 2009; 27: 113-33)

The potential role of the intestinal gut microbiota in obesity and the metabolic syndrome

The incidence of obesity has reached alarming levels worldwide, thus increasing the risk of development of metabolic disorders (e.g. type 2 diabetes, coronary heart disease (CHD) and cancer). Among the causes of obesity, diet and lifestyle play a central role. Although the treatment of obesity may appear quite straightforward, by simply re-addressing the balance between energy intake and energy expenditure, practically it has been very challenging. In the search for new therapeutic targets for treatment of obesity and related disorders, the gut microbiota and its activities have been investigated in relation to obesity. The human gut microbiota has already been shown to influence total energy intake and lipid metabolism, particularly through colonic fermentation of undigestible dietary constituents and production of short chain fatty acids (SCFA). Recent studies have highlighted the contribution of the gut microbiota to mammalian metabolism and energy harvested from the diet. A dietary modulation of the gut microbiota and its metabolic output could positively influence host metabolism and, therefore, constitute a potential coadjutant approach in the management of obesity and weight loss.

Metabolic endotoxemia initiates obesity and insulin resistance

Diabetes and obesity are two metabolic diseases characterized by insulin resistance and a low-grade inflammation Seeking an inflammatory factor causative of the onset of insulin resistance, obesity, and diabetes, we have identified bacterial lipopolysaccharide (LPS) as a triggering factor. We found that normal endotoxemia increased or decreased during the fed or fasted state, respectively, on a nutritional basis and that a 4-week high-fat diet chronically increased plasma LPS concentration two to three times, a threshold that we have defined as metabolic endotoxemia. Importantly, a high-fat diet increased the proportion of an LPS-containing microbiota in the gut. When metabolic endotoxemia was induced for 4 weeks in mice through continuous subcutaneous infusion of LPS, fasted glycemia and insulinemia and whole-body, liver, and adipose tissue weight gain were increased to a similar extent as in highfat-fed mice. In addition, adipose tissue F4/80-positive cells and markers of inflammation, and liver triglyceride content, were increased. Furthermore, liver, but not wholebody, insulin resistance was detected in LPS-infused mice. CD14 mutant mice resisted most of the LPS and high-fat diet-induced features of metabolic diseases. This new finding demonstrates that metabolic endotoxemia dysregulates the inflammatory tone and triggers body weight gain and diabetes. We conclude that the LPS/CD14 system sets the tone of insulin sensitivity and the onset of diabetes and obesity. Lowering plasma LPS concentration could be a potent strategy for the control of metabolic diseases.

Childhood obesity: should primary school children be routinely screened? A systematic review and discussion of the evidence

Background: Population monitoring has been introduced in UK primary schools in an effort to track the growing obesity epidemic. It has been argued that parents should be informed of their child's results, but is there evidence that moving from monitoring to screening would be effective? We describe what is known about the effectiveness of monitoring and screening for overweight and obesity in primary school children and highlight areas where evidence is lacking and research should be prioritised. Design: Systematic review with discussion of evidence gaps and future research. Data sources: Published and unpublished studies ( any language) from electronic databases ( inception to July 2005), clinical experts, Primary Care Trusts and Strategic Health Authorities, and reference lists of retrieved studies. Review methods: We included any study that evaluated measures of overweight and obesity as part of a population-level assessment and excluded studies whose primary outcome measure was prevalence. Results: There were no trials assessing the effectiveness of monitoring or screening for overweight and obesity. Studies focussed on the diagnostic accuracy of measurements. Information on the attitudes of children, parents and health professionals to monitoring was extremely sparse. Conclusions: Our review found a lack of data on the potential impact of population monitoring or screening for obesity and more research is indicated. Identification of effective weight reduction strategies for children and clarification of the role of preventative measures are priorities. It is difficult to see how screening to identify individual children can be justified without effective interventions.

Endocannabinoid receptor antagonists: potential for obesity treatment

Obesity has been described as a global epidemic. Its increasing prevalence is matched by growing costs, not only to the health of the individual, but also to the medical services required to treat a range of obesity-related diseases. In most instances, obesity is a product of progressively less energetic lifestyles and the over-consumption of readily available, palatable, and highly caloric foods. Past decades have seen massive investment in the search for effective anti-obesity therapies, so far with limited success. An important part of the process of developing new pharmacologic treatments for obesity lies in improving our understanding of the psychologic and physiologic processes that govern appetite and bodyweight regulation. Recent discoveries concerning the endogenous cannabinoids are beginning to give greater insight into these processes. Current research indicates that endocannabinoids may be key to the appetitive and consummatory aspects of eating motivation, possibly mediating the craving for and enjoyment of the most desired, most fattening foods. Additionally, endocannabinoids appear to modulate central and peripheral processes associated with fat and glucose metabolism. Selective cannabinoid receptor antagonists have been shown to suppress the motivation to eat, and preferentially reduce the consumption of palatable, energy-dense foods. Additionally, these agents act to reduce adiposity through metabolic mechanisms that are independent of changes in food intake. Given the current state of evidence, we conclude that the endocannabinoids represent an exciting target for new anti-obesity therapies.

A systematic review of controlled trials of interventions to prevent childhood obesity and overweight: realistic synthesis of the evidence

Background: Preventing childhood overweight and obesity has become a major public health issue in developed and developing countries. Systematic reviews of this topic have not provided practice-relevant guidance because of the generally low quality of research and the heterogeneity of reported effectiveness. Aim: To present practice-relevant guidance on interventions to reduce at least one measure of adiposity in child populations that do or do not contain overweight or obese children. Design: Systematic review of eligible randomized, controlled trials or controlled trials using a novel approach to synthesizing the trial results through application of descriptive epidemiological and realistic evaluation concepts. Eligible trials involved at least 30 participants, lasted at least 12 weeks and involved non-clinical child populations. Results: Twenty-eight eligible trials were identified to 30 April 2006. Eleven trials were effective and 17 were ineffective in reducing adiposity. Blind to outcome, the main factor distinguishing effective from ineffective trials was the provision of moderate to vigorous aerobic physical activity in the former on a relatively 'compulsory' rather than 'voluntary' basis. Conclusions: By using a novel approach to synthesizing trials, a decisive role for the 'compulsory' provision of aerobic physical activity has been demonstrated. Further research is required to identify how such activity can be sustained and transformed into a personally chosen behaviour by children and over the life course. (C) 2007 The Royal Institute of Public Health. Published by Elsevier Ltd. All rights reserved.

Obesity and health in Europeans aged 50 years and older

Background: Obesity is increasing globally across all population groups. Limited data are available on how obesity patterns differ across countries. Objective: To document the prevalence of obesity and related health conditions for Europeans aged 50 years and older, and to estimate the association between obesity and health outcomes across 10 European countries. Methods: Data were obtained from the 2004 Survey of Health, Ageing and Retirement in Europe, a cross-national survey of 22 777 Continental Europeans over the age of 50 years. The health outcomes included self-reported health, disability, doctor-diagnosed chronic health conditions and depression. Multivariate regression analysis was used to predict health outcomes across weight classes (defined by body mass index [BMI] from self-reported weight and height) in the pooled sample and individually in each country. Results: The prevalence of obesity (BMI >= 30) ranged from 12.8% in Sweden to 20.2% in Spain for men and from 12.3% in Switzerland to 25.6% in Spain for women. Adjusting for compositional differences across countries changed little in the observed large heterogeneity in obesity rates throughout Europe. Compared with normal weight individuals, men and women with greater BMI had significantly higher risks for all chronic health conditions examined except heart disease in overweight men. Depression was linked to obesity in women only. Particularly pronounced risks of impaired health and chronic health conditions were found among severely obese people. The effects of obesity on health did not vary significantly across countries. Conclusions: Cross-country differences in the prevalence of obesity in older Europeans are substantial and exceed socio-demographic differentials in excessive body weight. Obesity is associated with significantly poorer health outcomes among Europeans aged 50 years and over, with effects similar across countries. Large heterogeneity in obesity throughout Europe should be investigated further to identify areas for effective public policy. (C) 2007 Published by Elsevier Ltd on behalf of The Royal Institute of Public Health.

Calories, obesity and health in OECD countries

Theoretical models suggest that decisions about diet, weight and health status are endogenous within a utility maximization framework. In this article, we model these behavioural relationships in a fixed-effect panel setting using a simultaneous equation system, with a view to determining whether economic variables can explain the trends in calorie consumption, obesity and health in Organization for Economic Cooperation and Development (OECD) countries and the large differences among the countries. The empirical model shows that progress in medical treatment and health expenditure mitigates mortality from diet-related diseases, despite rising obesity rates. While the model accounts for endogeneity and serial correlation, results are affected by data limitations.

Obesity and diabetes, the built environment, and the ‘local’ food economy in the United States, 2007

Obesity and diabetes are increasingly attributed to environmental factors, however, little attention has been paid to the influence of the ‘local’ food economy. This paper examines the association of measures relating to the built environment and ‘local’ agriculture with U.S. county-level prevalence of obesity and diabetes. Key indicators of the ‘local’ food economy include the density of farmers’ markets and the presence of farms with direct sales. This paper employs a robust regression estimator to account for non-normality of the data and to accommodate outliers. Overall, the built environment is associated with the prevalence of obesity and diabetes and a strong local’ food economy may play an important role in prevention. Results imply considerable scope for community-level interventions.

Impact of income on nutrient intakes: implications for undernourishment and obesity

The relationship between income and nutrient intake is explored. Nonparametric, panel, and quantile regressions are used. Engle curves for calories, fat, and protein are approximately linear in logs with carbohydrate intakes exhibiting diminishing elasticities as incomes increase. Elasticities range from 0.10 to 0.25, with fat having the highest elasticities. Countries in higher quantiles have lower elasticities than those in lower quantiles. Results predict significant cumulative increases in calorie consumption which are increasingly composed of fats. Though policies aimed at poverty alleviation and economic growth may assuage hunger and malnutrition, they may also exacerbate problems associated with obesity.