Host-Gut Microbiota Metabolic InteractionsThe gut microbiota co-evolves with its human host from birth or even in-utero. Factors such as the mode of birth, diet and other environmental stimuli influence the developing composition of the microbiome. Interaction between the human host and its’s microbiome is mediated via several axes of communication including the immune system, signalling and direct metabolic cross-talk that physiologically connect the gut with the brain, muscle and liver. A deeper understanding of these axes provides a new framework for developing novel therapeutic targets and optimising personalised interventions.

     

The missing link between stunted growth and diet

Kwashiorkor is a severe form of malnutrition commonly encountered in developing countries. Much effort has been placed on trying to find appropriate and low resource nutritional protocols for overcoming malnutrition. Gnotobiotic mice implanted with the faeces of Malawian infant twins discordant for kwashiorkor showed differences in growth in these animals with mice implanted with faeces from the healthy twin gaining more weight. These mice also demonstrated perturbations in amino acid, carbohydrate and TCA metabolism, which were apparent when the mice were placed on a traditional Malawian diet, but largely resolved when the mice were fed with a protein enriched diet. This research adds further weight to the literature emphasising the importance of the microbiome in processing of nutrients and recovery of energy from the diet.

    

Gut microbial influence in melamine toxicity is melamine toxicity.

The recent health scare in China, where there was an outbreak of renal injury leading to death in some infants following ingestion of melamine-tainted milk, was shown to be related to gut microbial activity. Cyanuric acid, responsible for forming renal stones in the renal tubules, is a product of bacterial conversion of melamine. Klebsiella terrigena, isolated from faeces of rats treated with melamine, was shown to directly convert melamine to cyanuric acid. The prevalence of Klebsiella in human infant faeces (ca 1%) approximately matches the percentage of adverse reactions to the melamine-contaminated milk product.

Surgical Metabonomics

By focusing multiple metabolic measuring technologies on the patient at any one moment during their surgical pathway, the quality and depth of prognostic or diagnostic information can also be increased. Several powerful spectroscopic techniques are suitable for surgical metabonomic implementation driven by improved analytical performance and size/cost reductions. We aim to use a combination of NMR and MS technologies to provide unique phenotypic information on the tissue state of the patient and to generate new in situbiomarker diagnostics to help the surgeon where there is an unmet medical need. Magic angle spinning (MAS) NMR spectroscopy is well suited to real-time surgical investigations as no sample preparation is required and allows collection of diagnostic information on pin-head size pieces of tissue biopsy material.

     

The Patient Journey

Metabolic phenotypes and profiles are modulated by interactions of genes, diet and symbiotic gut microorganismsand influence an individual’s recovery from any therapeutic intervention. Moreover, metabolic phenotypes are responsive to, and predictive of, interventional outcomes. These molecular signatures are data-rich and provide sensitive, specific and efficient vehicles for delivering metabolic phenotype information to aid clinical decision-making. Hence we are initiating a new paradigm for patient stratification based on modelling multi-level patient phenotypes, which could beneficially influence patient outcomes by improving optimisation of therapeutic strategies. Thus, we propose a new vision for improving the patient pathway (See figure), initially focussing on colon and breast cancer but later extending to other areas of oncology. This programme harmonises current scientific and clinical expertise across a range of disparate disciplines and projects, and will provide a vehicle for implementation of these translational molecular approaches in our clinical units.