MECNUT: Impact of dietary exposure to emulsifiers on the intestinal mucosa - implications for inflammatory bowel disease and metabolic syndrome

Emulsifiers have been increasingly used in processed foods over the past 50 years or more. They include naturally occurring substances such as lecithin present in egg yolk and soy but also synthetic compounds called Polysorbates. Previous research by the applicants showed that Polysorbate 80, commonly used in ice creams and confectionery, at very low concentrations plausibly present in the human distal small intestinal lumen, caused a marked leakiness of the intestinal wall that resulted in bacteria penetrating through the gut lining. It was speculated that this might account for the increased incidence of gut inflammation such as Crohn's disease, seen in association with wider consumption of a westernized diet. Further work from the USA confirmed these findings and showed that ingestion of polysorbate 80 caused not only intestinal inflammation but also metabolic syndrome in mice - the syndrome associated with obesity, type 2 diabetes, high blood cholesterol and risk for atheroma (fat build up in the arteries). These changes were associated with alterations in the gut bacteria that were shown to be essential for the gut inflammation and metabolic syndrome. Emulsifiers are detergents and this also raises the possibility that dishwashing detergents, if inadequately rinsed, might have a similar effect. In the studies proposed, we will assess a range of permitted food emulsifiers and detergents including naturally occurring lecithin and bile acids, and dishwashing detergents. Studies will be undertaken to assess the effects of these emulsifiers on bacterial translocation into intestinal tissue using cultured cells, mini-gut "organoids" and pieces of human bowel tissue isolated from endoscopic biopsies grown in the laboratory, plus studies looking at emulsifiers effects on promoting gut inflammation and metabolism, altering the balance and activity of the gut microbial community, and passage of intestinal bacteria/bacterial DNA into the blood circulation in mice. The naturally occurring food emulsifier lecithin will be tested at realistic dietary concentrations in a 6-week study in 25 adult human volunteers, again with circulating bacterial DNA as a measure of intestinal microbiota translocation but with additional measures of blood glucose and lipid concentrations plus faecal microbial community and metabolome characterisation. These studies should go a long way towards clarifying which emulsifiers and at what concentration are capable of inducing potentially harmful alterations in gut bacteria, inflammation, bacterial translocation to the circulation and human metabolism - all of which may be relevant to development of conditions such as type 2 diabetes, coronary artery disease and inflammatory bowel diseases, e.g. Crohn's disease.

We have shown that very low concentrations of food emulsifier Polysorbate 80 cause bacterial translocation across human ileal epithelium and that this occurs transcellularly across both M (microfold) cells and non-M epithelial cells. Subsequent mouse studies show that dietary polysorbate 80 induces bacterial translocation, intestinal inflammation and metabolic syndrome. This raises the possibility that dietary emulsifiers might be factors in conditions such as coronary artery disease, type 2 diabetes and Crohn's disease. It is not known whether this effect applies equally to all emulsifiers/detergents; e.g. including the natural emulsifier lecithin or possibly even conjugated bile acids present in the distal terminal ileum where bacteria may have refluxed through the ileo-caecal valve. The proposed studies will investigate effects of a wide range of permitted food emulsifiers, low concentrations of dishwashing detergent (sodium laureth sulphate), conjugated bile acids on bacterial translocation in cell monolayers and in murine and human intestinal organoids (small intestine and colon). At least 5 emulsifiers will then be assessed as dietary additives in mice with circulating bacterial DNA, intestinal inflammation and metabolic syndrome (body weight/blood glucose) as endpoints. An established collaboration (Linkoping, Sweden) will assess the impacts of at least 3 emulsifiers on bacterial (E. coli) translocation across cultured human terminal ileum explants. Co-investigators at Aberdeen University will examine dietary lecithin supplementation in a 6-week cross over study in 25 human volunteers with circulating bacterial DNA, fasting blood glucose, faecal calprotectin and balance and activity of the gut microbial community as endpoints.

These studies will clarify the health implications of exposure to these various dietary and washing detergent/emulsifiers and better inform the public and the food industry regarding healthy dietary and food processing practices.

This application addresses the call "Mechanistic Research in Nutrition" encouraging research that will increase mechanistic understanding of the role that foods and nutrients play in health and disease. The use of additives in food, particularly permitted emulsifiers (detergents), is a topic which continues to raise consumer concerns. The widespread use of such substances in processed foods could be a factor in the rising incidence of inflammatory bowel disease and metabolic syndrome. Work by the applicants, and others, has recently shown potentially harmful effects of the food emulsifier polysorbate 80, including increased enteric pathogen translocation and inflammation. It is also not yet known whether similar harm can be caused by other emulsifiers, including the very commonly ingested natural emulsifier lecithin. This application, using in vitro, ex vivo, mouse and human intervention studies, will serve to provide robust mechanistic understanding about potentially harmful effects of dietary exposure to emulsifiers and detergents on risk for intestinal inflammatory disease and metabolic syndrome.

The applicants pioneered the initial hypothesis and investigations in model systems that underpin the current proposal. They have a strong track record of translating previous research from the bench to the bedside and will apply their expertise to understand how these dietary components act at a molecular, cellular and systems level to influence physiological and pathological processes, determine cause-and-effect relationships and in the strategic need to develop healthier foods.

Overall, the outcomes of this research proposal should lead to awareness whether excessive exposure to emulsifiers in the food chain could be harmful to health, informing the key international Health and Food Safety regulatory authorities, and those working in the scientific food research community and in the food industry (both processing and additive formulation). Given the varying ranges of emulsifier intakes across populations and changes in consumption patterns world-wide, interventions which could include public health information (via Government education campaigns, the National Healthy Schools Programme, workplace 'healthy' canteen and food retailers traffic light food labelling) initiatives could then result in a significant health enhancement, possibly resulting in reduced incidence of inflammatory bowel diseases, e.g. Crohn's disease, and metabolic syndrome.