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How do gut-derived tryptophan metabolites impact on muscle metabolism and physiology?

Primary Supervisor: Professor Warwick (Rick) Dunn, School of Biosciences

Secondary supervisors: Professor Gareth Lavery, University of Birmingham and Dr Robert Dallmann, University of Warwick

PhD project title: How do gut-derived tryptophan metabolites impact on muscle metabolism and physiology?

University of Registration: University of Birmingham

Project outline:

Tryptophan is an amazing amino acid. As an essential amino acid, all tryptophan in the human body is derived from dietary sources (e.g. chocolate) or supplements. Metabolism of tryptophan in the gut and subsequently in different tissues is wide ranging and includes the synthesis of serotonin (brain serotonin levels control our mood), kynurenine (which controls our response to inflammatory and immune stresses), melatonin (which controls our wake-sleep cycle) and nicotinamide adenine dinucleotide (NADH which is a cofactor involved in many redox-dependent metabolic processes). Gut microbes control the uptake of tryptophan from our diet and can metabolise tryptophan in to a wide range of different metabolites which through cross-talk between the gut microbiome and other organs control biological process and human physiology across the human body. For example, tryptophanase-containing gut bacteria help synthesis indole-3-propionic acid which can be transported to the brain and provides neuroprotective effect against cerebral ischemia and Alzheimer's disease.

Exercise and diet are important lifestyle choices which impact on how we age, how we feel physically and mentally and for treatment of human diseases including obesity. Exercise involves skeletal muscle which is the largest metabolic organ in the human body. Metabolic dysfunction occurring in skeletal muscle impacts whole-body nutrient homeostasis and gut microbiome-derived metabolites are believed to influence muscle health, function and physiology. Many tryptophan metabolites are derived from the gut microbiome in humans and the gut-muscle cross-talk axis is thought to play important roles in muscle ageing, metabolic homeostatis, circadian rhythm as well as a multitude of human diseases (cardiovascular disease, cancer and diabetes). The role of tryptophan and its gut-derived metabolites in skeletal muscle has not been studied in-depth and indeed some controversies exist as to whether supplementation is appropriate to increase tryptophan concentrations in the human body.

In this PhD programme you will apply a range of laboratory and computational approaches to study tryptophan metabolism in different mammalian tissues including the gut microbiome, liver and primarily muscle. In the laboratory you will apply in-vitro cell models and in-vivo animal models to determine the metabolic pathways in operation and then develop and apply a targeted metabolite assay to measure these metabolites in biological studies. You will also apply bioinformatics tools to help derive the metabolic pathways in operation, to analyse large-scale metabolomics data from open access data repositories and from data that you will collect as well as analyse 13C/15N tracer data applied to study tryptophan metabolism.

The PhD programme has the following hypothesis and objectives

Hypothesis: Higher concentrations of tryptophan and its metabolic products help maintain healthy function, metabolism and circadian rhythms in mammalian muscle.

Objective 1. To determine how tryptophan is metabolised in the gut and liver applying detailed literature reviews and in-vitro cell models as well as to develop a targeted metabolite assay to quantify tryptophan and its gut-derived and liver-derived metabolic products.

Objective 2. To determine which gut-derived metabolites are transported to and have an impact on muscle metabolism and function and to derive mechanisms using in-vitro cell models and animal models

Objective 3. To determine the circadian rhythm of gut-derived tryptophan metabolites in muscle and to determine how this rhythm mechanistically operates and impacts on muscle metabolism and function.

Recommended paper to read

[2] Roager, H.M., Licht, T.R. Microbial tryptophan catabolites in health and disease. Nat Commun 9, 3294 (2018). https://doi.org/10.1038/s41467-018-05470-4

BBSRC Strategic Research Priority: Understanding the Rules of Life: Systems Biology

    Techniques that will be undertaken during the project:

    You will be immersed in a multi-disciplinary research environment across three colleges at the Universities of Birmingham and Warwick which house three nationally/internationally recognised scientific centres to be used in the PhD programme (Phenome Centre Birmingham, Metabolic Tracer Analysis Core and Mouse Metabolic Phenotyping Core).The three supervisors provide complementary areas of expertise and research groups (PhD, post-doctoral researchers) to provide support in training and supervision in the following topics:(1) Personal development: the student will complete a Development Needs Analysis in year one to identify key areas for development in intellectual abilities, personal effectiveness, research organisation and engagement with impact. Both online training courses and face-to-face courses will be attended; (2) Metabolism, metabolomics, analytical chemistry and bioinformatics: the student will receive face-to-face training from the groups of Dunn and Lavery on many aspects of metabolism research in mammals including in metabolism/biochemistry, analytical chemistry and bioinformatics; (3) In-vitro cell models: the student will receive face-to-face training from the groups of Lavery and Dallmann on the design and operation of primary and immortalised human muscle cell culture; (4) chronobiology: the student will receive training in the biology of and how to measure circadian rhythms.

    Contact: Professor Warwick Dunn, University of Birmingham