Identifying the Microbial Metabolome: The Missing Link Between Diet and Human Health

An accumulation of evidence indicates that the gut microbiota plays a vital role in inflammation and in the development of many diseases including diabetes, cardiovascular disease and cancer (Vijay-Kumar et al; 2010, Masklowski et al; 2009, Clarke et al 2010). Despite tremendous advances in the molecular approaches describing the composition of the human gut microbiota (Qin et al; 2012), to date relatively little is known about the functionality and role of even the most dominant commensal organisms within the human host. It is widely accepted that the products of microbial metabolism influence human health and disease, particularly regarding inflammation and immune responses. Despite this, many of the products of microbial metabolism of dietary compounds remain uncharacterised and consequently, their mechanisms of action unknown. As an enormous investment is being made to continue to characterise the microbiome and its interaction with the human immune system, there is now a critical requirement that the functional role of the microbiota is established. It is important that in addition to describing the microbial populations, the species are also defined by their function and metabolic outputs. This topic is exceptionally timely as there is increasing pressure to provide healthy food to a growing and increasingly unhealthy and aging population. Elucidating the products of microbial metabolism provides an essential and missing link between well-defined dietary intakes and the physiological effect of dietary constituents. Without this information, the nutritional value of food cannot be fully established, food claims effectively evaluated, nor the contribution of the gut microbiota to an overall aim of developing sustainable agricultural products beneficial for human health ascertained.

Diet, is a major factor shaping the composition of the colonic microbial community as well as a principal determinant of the gut metabolome. This is likely to explain why it is also a contributing factor in disease development and progression. Two related dietary factors appear to play a significant role in maintaining the equilibrium between health and disease. Firstly, the balance between different types of carbohydrate and protein is fundamental. Dietary fibre intake is strongly correlated with prevention of carcinogenesis and evidence that high protein-low carbohydrate diets are detrimental to health is increasing. Secondly, there is a large amount of literature suggesting that plant secondary metabolites have anti-cancer properties. In particular, almost all plant foods considered to have cancer-preventative properties are rich in non-nutrient compounds derived from the phenylpropanoid pathway. Much of the evidence for this however is obtained from in vitro data and there is very little evidence from both pre-clinical and human interventions to support their bioavailability and role in carcinogenesis. Data regarding the metabolism and bioavailability of phytochemicals is lacking, particularly with reference to transformation by the gut microbiota and absorption from the colon via the hepatic circulation. Additionally, the relationship between the main macronutrients (carbohydrate and protein) and non-nutrient phytochemicals is poorly understood. It is likely that it is a combination of these dietary factors that modulates both the gut bacteria and the overall metabolite profile, both in the gut and in the systemic circulation. This unique proposal will address the combined effects of the macro- and non-nutrient components of the diet, along with the gut microbial composition on the production of microbial metabolites.

Study Objectives

Specific objectives of the project are to:

• Fully characterise dietary substrates in terms of their macro-, micro- and non-nutrient phytochemicals, providing the basis for detailed in vitro work and rigorous human intervention studies.
• Identify the microbial metabolites which exhibit inflammatory activity at relevant in vivo concentrations. This will provide essential information, not currently available and will inform wider studies looking at the action of microbial metabolites on particular receptors and biomarkers of health.
• Determine the functionality of the bacterial species responsible in terms of metabolite production. In this context, this will also identify the extent of redundancy of certain species.
• Establish the role of major macronutrients in driving microbial metabolism, both in the production of phytochemical metabolites and the provision of carbohydrate and protein by-products.

Hypothesis Phytochemicals bound to plant polymers reach the colon largely intact and are metabolised and released by the gut microbiota where they can exert a direct anti-inflammatory action on the gut mucosa. Additionally mucosal uptake of these metabolites will suppress low-level chronic systemic inflammation. Furthermore, the source and type of polymer may improve or exacerbate the effect.

Inclusion criteria

Volunteers will be:

• healthy male or females
• aged between 18 and 55 years
• able to give informed consent.

Exclusion criteria

Volunteers will be excluded if they:

• are taking any medicines prescribed by their GP
• are taking drugs to lower high cholesterol levels or high blood pressure
• regularly take analgesics, antipyretic or anti-inflammatories
• regularly take nutritional supplements
• have taken antibiotics in the last three months
• have given a large blood donation in last three months