Title: Dietary Protein and Skeletal Muscle in Older Twins - Targeting the Gut Microbiome to Overcome Anabolic Resistance
Funder: Department of Health and Social Care

Abstract: Research Question: Does the gut microbiome contribute to muscle anabolic resistance to protein supplementation in older adults? Background: Loss of skeletal muscle mass and strength occurs with increasing age and is associated with loss of function, disability, and the development of sarcopenia and frailty. Dietary protein is essential for skeletal muscle function, but older adults do not respond as well as younger people to protein, so called 'anabolic resistance'. The aetiology and molecular mechanisms for this are not understood, however a number have been proposed. The gut microbiome is known to play a key role in a number of these postulated mechanisms (Ni Lochlainn et al., 2018). This has led us to hypothesise that the gut microbiome may mediate anabolic resistance and could represent an exciting new target for ameliorating muscle loss in older adults. Aims and objectives:This trial aims to test whether the gut microbiome mediates anabolic resistance to protein in older adults. Investigate the relationship between the gut microbiome, dietary protein, metabolites and skeletal muscle function, within TwinsUK cohort Investigate whether the gut microbiome mediates response to protein intake, potentially indicating its implication in anabolic resistance Test whether modulation of the gut microbiome, in addition to protein supplementation, can improve skeletal muscle function versus protein supplementation aloneMethods: An initial exploratory epidemiology study will address objectives 1 and 2, using existing TwinsUK data. The relationship between the gut microbiome, dietary protein intake and skeletal muscle function will be tested, as well as faecal and plasma metabolites. This initial observational study will be used to inform our interventional study. The second part of this doctorate will assess objective 3, via a pilot interventional study. Volunteers will be recruited in twin pairs from TwinsUK cohort, for which extensive baseline data are available. The twin nature of the study allows for close genetic and environmental matching at baseline. Each pair will be randomised to either receive protein supplementation plus placebo or protein supplementation plus a gut microbiome modulator (prebiotic plus probiotic). Intervention period will be 12 weeks. Clinical and biochemical measures will be taken at 0, 6 and 12 weeks, with monthly contact. Gut microbiota composition will be measured, alongside a battery of physical assessments. Dual-energy X-ray absorptiometry measurements of muscle mass will be taken. Primary outcome will be muscle function measured using chair-rise time. Secondary outcomes include physical battery measurements, microbiome measures, and faecal/plasma metabolites. Conclusion: Anabolic resistance warrants further characterisation to guide future therapeutic interventions, especially considering its role in the development of disability, sarcopenia and frailty. Therapeutic options are badly needed, particularly for older adults who cannot undertake exercise programmes. Dissemination and Impact: Findings will be shared with volunteers, the public, health professionals and service commissioners via peer-reviewed journals, conferences; newsletter for volunteers; and videos via social media. If effective, the addition of simple microbome-modulating supplements to protein may be a game changer in preventing and treating age-associated muscle loss. This will have implications for a wide range of high-cost complications for our ageing population.

Lay abstract: Background:Muscle strength and mass decline with age. This can affect balance, walking and the ability to perform basic daily tasks. It is associated with the development of frailty. Frailty is a term used to describe a state of increased vulnerability, weakness and increased risk of poor health outcomes. It also costs the health service a lot of money. Older people have been found to need a larger amount of protein in their diet, in order to get the same muscle responses as younger people. This is termed anabolic resistance. This is thought to be part of the reason that older people lose muscle, leading to them becoming frail. Anabolic resistance has led to experts advising that older people have a higher daily allowance of protein than younger people. We do not understand exactly how or why anabolic resistance develops, however a number of suggestions have been proposed by researchers. The gut microbiome is the collection of microbes such as bacteria inside our guts. It has an active role in processing food we eat, and in many other bodily processes. It is involved in many of the suggested mechanisms for anabolic resistance. This study is designed to assess whether the gut microbiome has an effect on how the body uses the protein we get from our diet, to help us to see whether the gut microbiome could play a role in anabolic resistance. Aims: PhD Part 1: To study the relationship between dietary protein intake, muscle mass and strength, and the gut microbiome - using data already collected within TwinsUK study PhD Part 2: Dietary intervention trial to test whether targeting the gut microbiome with a probiotic can improve muscle response to protein supplements within older twins Methods: The trial will be carried out within TwinsUK, a large cohort of British Twins who volunteer to take part in various scientific studies. Volunteers with low protein intake will be recruited, in twin pairs. Within each twin pair, one twin will receive a supplement that is protein + probiotic, and the other will receive protein + placebo. These will be assigned at random. They will take these supplements for 12 weeks. All twins will be given advice to undertake resistance exercise training on a regular basis. All volunteers will have a weekly telephone reminder to take their supplements, and to exercise. At the beginning of the study a number of measurements will be performed, including measures of muscle strength and mass, and blood and stool samples will be taken. These will be repeated at the midpoint and when the study ends. Conclusion In comparison to other parts of the body, the gut microbiome can be changed and influenced from the outside, using diet and probiotic supplements. This means that there is potential to design new treatments. This study aims to answer the question: does the gut microbiome contribute to anabolic resistance to protein with ageing? Answering this question will help with the process of designing therapies for anabolic resistance going forward. As the population continues to age, and frailty becomes more common, it is becoming ever more important to tackle age-related muscle loss, to benefit all older adults, and reduce healthcare costs. Patient and public involvement: The TwinsUK Volunteer Advisory Panel and the Patient Advisory Group of the London NIHR Research Design Service have both been consulted in planning this study and will be involved throughout. Disseminations: Findings will be shared with volunteers, the public, health professionals and service commissioners via medical journals, conferences; TwinsUK newsletter; and videos via social media.

Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING;6.7 PHYSICAL
Health categories: MUSCULOSKELETAL;ORAL AND GASTROINTESTINAL