Influence of prebiotics on human gut microbiota LPS and markers of metabolic syndrome.

Obesity is fast becoming the greatest health challenge of the 21st century. Central to our ability to intervene in this situation is a clear understanding of the link between diet and obesity and the ability of industry to deliver food products capable of reducing risk. This project will lay down the scientific rational linking the gut microbiota with obesity, and provide a rational for using functional foods in the obese for improved health, targeted towards modulating the gut bacteria. Traditional risk factors for obesity and associated metabolic disorders are dietary, genetic and exercise linked. However, there is the contention that these cannot fully explain the explosive increase seen in recent years. This was given added significance in 2006 when the first reports appeared suggeted that gut bacterial profiles in obese and lean persons differed. It was hypothesised that the bacterial profiles variably affected calory extraction rates from food and that some of their metabolites could influence satiety. This is still an area of some debate (and it may be that the traditional risk factors themselves affect microflora profiles), however what is not in question is that the gut microbiota has a major role to play in human metabolism. This is because of the huge numbers that are present and their constant supply of nutrients (principally diet). Should the gut microbiota differences be a factor in obese related conditions, then this opens up the possibily of altering the situation by using dietary ingredients that have a selective fernentation in situ. Prebiotics are functional foods ingredients that exert major composition and metabolic changes in the human gut microbiota. Together with probiotics, they are attracting much attention for their ability to improve gastrointestinal health. New products are constantly being developed, with the main remit being improved digestion and wellbeing. Research on modulating the gut flora has largely targeted gut infections including links into chronic disorders like IBS and ulcerative colitis. Given the recent link between gut microflora and obesity, it makes sense to research whether prebiotics can exert a modulatory role. In this project, these have been chosen over probiotics as they are more efficacious in exerting change in bacterial populations within the gut. Our collaborative research in an animal models has shown that LPS, a cell wall constituent of Gram -ve bacteria, can exert a metabolic endotoxaemia which is characteristic of diabetes in humans. Prebiotics target Gram+ve flora (principally bifidobacteria). Further studies in the murine showed that the toxic effects of LPS could be reversed by repressing Gram -ves at the expense of bifidobacteria. Here, we aim to replicate these experiments in humans at risk of metabolic syndrome. We will use a proven prebiotic (BiMuno, a type of galactooligosaccharide GOS), that was originally developed in our laboratories and is now commercially availble, to target bifidobacteria in a human feeding study. Prior to this, food quality experitise will be applied towards assessing the most appropriate dietary delivery vehicle that maintains functionality of the ingredient and has optimal sensory qualities. A placebo will also be trialled. The outcomes will be an in vivo assessment of the capacity to alter gut microbiota and concomitant effects upon validated markers of metabolic syndrome. If the research is successful it will lead towards a dietary intervention product that positively affects the risks associated with obesity in a manner that changes the microflora influence. This would have much impact upon a major 21st century dietary problem and tally that with an extremely topical functional food approach. The outcome would also partly inform on the health attributes that can be expected from altering a person's gut microbiota and has relevance for both the probiotic and prebiotic industries.

A fat-enriched diet induces diabetes, obesity and vascular diseases. This is a societal problem with substantial and long lasting social and economic implications. Current pharmacological strategies appear ineffective since the number of diabetic and obese people continues to rise and is set to reach 600 million over the next two decades worldwide. Physical activity and lowered calorie diet can reduce the outcome of metabolic and vascular diseases. However, the level of compliance required by this dietary and life-style approach is often poor. Obesity is characterised by low grade inflammation which has been linked to insulin resistance, type II diabetes and cardiovascular disease. It has also been linked to a number of putative diet-related aetiologies associated with gut microbiota. Our previous collaborative research indicated that metabolic bacterial lipopolysaccharides (LPS) could onset the inflammatory process linking fat-enriched diet to metabolic/vascular diseases. In mice, the intestinal LPS content was increased by a fat-enriched diet. We have therefore shown that the LPS of G-ve gut bacteria is able to induce a toxic reaction in rats that resembles diabetes in humans. Importantly, this could be reversed by a dietary prebiotic, which increased G+ve numbers, principally bifidobacteria. We intend to extrapolate these findings to humans. Food processing characteristics will be carried out to ensure optimum prebiotic functionality and sensory qualities, testing a range of food vehicles. An acceptable product will be tested in humans to determine effects upon faecal microflora, LPS and markers of metabolic syndrome. The overall aim is to prevent and reverse metabolic inflammation, the cornerstone of metabolic and vascular diseases, by altering indigenous gut microbiota composition towards increased bifidobacteria. We will develop a prebiotic food that modifies the intestinal flora to reduce risk of of metabolic/vascular diseases related to LPS.

Obesity is arguably the single greatest global health challenge of the 21st century. In the UK the Department of Health attributes 58% of type 2 diabetes, 21% of heart disease, and between 8% and 42% of certain cancers (endometrial, breast and colon), to excess body fat, and estimate that obesity is responsible for 9,000 premature deaths annually in England alone. They also foresee an additional £7.7 billion in annual NHS costs for treating obesity by 2050. This figure reaches £49.9 billion per year when the wider societal costs are included. While the root causes are fairly well understood (a higher energy intake than expenditure over extended periods of time), less is know about the societal, life-style and other environmental factors comprising the obesogenic environment. There is likely to be a genetic component to obesity at least in some individuals but this does not account for the sudden rise in the incidence of obesity at the population level. Differences in gut microbiota composition and activity is a newly recognised contributor towards this obesogenic environment and the key hypothesis of this project is that the gut microbiota is a marker of obesity and can be modulated using prebiotics. Prebiotics are dietary ingredients (non-absorbed carbohydrates) that are selectively fermented by positive gut microbiotia components. By establishing the gut microbiota as a modifiable risk factor in obesity, this project aims to provide supportive evidence for the anti-obesity use of prebiotics which can be added to foods consumed by the population. The development of efficacious functional foods is critical to tackling this challenging health crises and the food industry will play a critical role in the design and scientific testing of these products. Direct beneficiaries are widespread: One principal beneficiary will be the partner company (Clasado) who will be able to develop novel products for the European and worldwide marketplace - ultimately leading to improved consumer health. In terms of user groups, the following may benefit from a successful project outcome: 1) Prebiotic consumers: who may be given straightforward dietary recommendations that help prophylactically manage, or even treat, gut disorder - with the focus here on obesity. 2) Food industry: information for generating new designer prebiotics. Peer review publications from the data could be used to consolidate new product developments. 3) Academia: who would access new information on further mechanisms underpinning prebiotic use. In terms of social benefits, there exists a number of different aspects: a) Prophylactic management of gut disease There remains an increase in gut bacterial dysfunction which may manifest as both acute (e.g. gastroenteritis) and chronic (e.g. inflammatory bowel disease) disorder. Many consumers experience symptoms of gut disease, without considering prior management through the diet. The route of using prebiotics to reduce the risk of disease is attractive as it is user friendly, inexpensive, simplistic and has no adverse host and/or environmental consequences. With recent evidence that gut flora may be involved in obesity and related metabolic aspects, this opens up a new area of prebiotic application that (if proven efficacious) will be of major benefit. b) Socio-economic The economic aspects prebiotic developments has social aspects where the prevention of disease risk adds towards better financial status through reduced expenditure on pharmaceuticals. This has particular relevance for obesity given the statistics quoted above. c) Quality of life Improved quality of life and social functioning are important human factors. Whiler management of obesity is feasible through dietary and exercise issues - targeting of gut microbiota in this regard is a new avenue. Activities to target the impact will include public lectures, project fliers, use of extensive media links, workshops, reviews and the internet.