The Role of Dietary D-serine in Health and Disease

The importance of our diet on health is well established yet hard to properly assess. Many so called "health foods", "super foods" and "probiotics" make bold claims but rigorously evaluating their effects is challenging, especially for complex systems like humans and other animals. If we can understand how specific components of our diet affect our chances of being infected by food poisoning bugs then we can make good dietary decisions or tailor our food to provide an inherent resistance to infection.

The aim of our work is to understand how a specific D-amino acid (D-AA) affects susceptibility to, and recovery from, gastrointestinal infections. Wheres L-amino acids are the building blocks of proteins, D-amino acids can't be used in the same way so have largely been ignored by scientists. However, our work has shown that they play an important role in controlling the key weapons used by food poisoning bacteria. These D-amino acids are present is many processed food so it is now appropriate to look at how they affect our gut bacteria and how they affect gut pathogens.

We have exciting new results showing that one specific D-amino acid can help restore the balance of the normal gut bacteria following infection. We propose to investigate the mechanism underlying this result using a mouse model that allows us to test the interplay between the host diet, gut bacteria and host defences in the resistance to pathogens. The work is important because we believe it will lead to new dietary-based strategies to combat a range of gastrointestinal infections, both acute and chronic.

Sensing environmental stimuli is critically important for bacteria when faced with the multitude of adversities presented within the host. Responding appropriately to these signals and in turn integrating these responses into the regulatory network of the cell allows bacteria to control precisely when and where they should establish colonization. D-ser (D-ser) is an abundant metabolite of the human urinary tract but is a toxic metabolite for Escherichia coli that lack a D-ser tolerance locus. Enterohaemorrhagic E. coli (EHEC) cannot catabolize D-ser for this reason and colonize the large intestine specifically, an environment low in D-ser. EHEC can however use D-ser sensing to repress colonization thus signaling the presence of an unfavorable environment. We now want to develop this work and investigate how D-ser restores the balance of the normal microbiota following infection. We propose to investigate the mechanism underlying this result using a murine model that allows us to test the interplay between the host diet, microbiota and mucosal immunity in the resistance to pathogens. The work is important because we believe it will lead to new dietary-based strategies to combat a range of gastrointestinal infections, both acute and chronic.

The aims and objectives of the proposed research will contribute to advances in knowledge and understanding at the fundamental level. As our work on niche specificity develops, we will be able to more precisely define potential applications derived from this research. However, in the medium and long term this fundamental knowledge could have significant economic and societal impact as described below.
Food manufacturers: As we understand the importance of diet and its influence on infection, there will be the opportunity to develop formulated dietary programs that will require interfacing with food and healthcare manufacturers. This sector is very important across Europe, with over 1750 health-product manufacturers represented by the European Federation of Associations of Health Product Manufacturers (EHPM) alone. The UK has become a leading source of new foods with health propositions. In 2007, 36% of new health product launches in the European Union originated in the UK. Our work will help maintain this competitive advantage.
Antibiotics development industry: New mechanisms to combat hard to treat infection, particularly gram negative infections are a cross council priority area that still has been sorely neglected despite the urgency of the issue.
Health care providers and patients: understanding how these infections are influenced by host metabolism could have profound implications for prevention and treatment of these pathogens. For example, our prediction is that strains that can metabolise D-serine are more likely to cause specific infections of tissues abundant in this amino acid. One outcome might be that the diet of patients with a strong susceptibility to such infections (e.g. patients with catheters, women with recurrent infections) modulated be formulated to reduce the concentration of this amino acid in the urine. Furthermore, understanding the basis to how E. coli O157:H7 colonises disease in humans is very important. Children under five years of age have been shown to be particularly vulnerable to this organism with Shiga toxin (Stx) produced inducing hemolytic uremic syndrome (HUS), resulting in acute kidney injury in 50-70% of patients. Longer-term sequelae include ongoing chronic renal disease (usually requiring kidney replacement) and hypertension, as well as a variety of neuropsychiatric problems. There is no effective therapy that can alter progression from initial O157:H7 infection to HUS. Indeed, treatment with conventional antibiotics increases the likelihood of progression through the release of Stx. Our research will help in understanding the potential for this organism to colonise new sites and niches and the genetic factors involved.
Money saving to the economy and NHS: Research by the Centre for Foodborne Illness Research has found that, one-third of E. coli O157:H7 HUS survivors will suffer life-long medical problems, such as high blood pressure, diabetes, kidney failure and brain damage. These costs are estimated to be ten times greater than those associated with the initial infection alone. Based on data from Canadian studies we estimate that the cost to the UK health system is around £9 million per year. As our research progresses we will aim to develop partnerships with strategic partnerships with groups working on human metabolism to explore the relationship between diet formulation and levels of D-serine in the body. This push towards overall patient health through careful formulation of diets perfectly matches fits the BBSRC strategic priority "Food, Nutrition and Health".

Capacity building: the work will feed directly into training at the forefront of research (applied and basic) in respect of Food Security (a BBSRC priority area).