Abstract
As the population ages, physical and cognitive frailty is increasing in prevalence, with a clear need for new therapeutic options. There is a growing body of evidence linking the microbiota in the human gut and the metabolites they produce to a wide range of physiological systems including muscle and brain health. Animal and human studies have shown that inducing changes in the microbiota can alter muscle physiology and cognitive behaviour, indicating causative pathways. 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. Older people’s skeletal muscle displays anabolic resistance to dietary protein. The aetiology and molecular mechanisms for this are not well understood, however the gut microbiome is known to play a key role in several of the postulated mechanisms. I therefore hypothesised that the gut microbiome may mediate anabolic resistance and could represent an exciting new target for ameliorating muscle loss and frailty in older adults.The basis of this thesis was the exploration of this hypothesis, firstly via an observational study utilising existing data within the TwinsUK cohort to explore the relationship between dietary protein, skeletal muscle function, sarcopenia, and a range of other factors including gut microbiome features; and secondly via the PROMOTe (effect of PRebiotic and prOtein on Muscle in Older Twins) randomised controlled trial, which aimed to test whether modulation of the gut microbiome using a prebiotic supplement could improve muscle strength versus placebo.
The observational study utilised cross-sectional data from a study of 3302 community dwelling twins aged ≥60 years. Multivariable logistic regression and between- and within- twin pair regression modelling were used. High protein intake (>1.3g/kg/day) was associated with low muscle mass (OR 1.76; 95% CI 1.39-2.24; P<0.0001), while low protein intake was protective (OR 0.52; 95% CI 0.40-0.67; P<0.0001). High protein intake was associated with sarcopenia (OR 2.04; 95% CI 1.21-3.44; p=0.008), and this was robust to adjustment for demographic, anthropometric and dietary factors. The association between muscle strength and weight, body mass index, healthy eating index, protein intake, and alpha diversity, was not significantly influenced by shared twin factors, indicating greater amenability to interventions.
The PROMOTe trial was a double-blind, randomised, placebo-controlled, trial, which recruited 36 twin pairs from the TwinsUK cohort (72 individuals) to time and target. Each pair was randomised, so one twin received protein supplementation plus placebo and the other twin received protein supplementation plus a gut microbiome modulator (prebiotic) for 12 weeks. All participants were given resistance exercise advice. The trial was carried out remotely. The intervention was well tolerated, and the prebiotic did result in a changed gut microbiome [e.g., increased Bifidobacterium]. Overall, participants had significant improvements in muscle strength, gait speed, cognition, and physical activity levels over the course of the study, likely attributable to the protein and exercise intervention. There was no significant difference between prebiotic and placebo for the primary outcome of chair rise time (β=0.184; 95% CI -0.569-0.938; p=0.631). Prebiotic food supplementation improved cognition factor score versus placebo (β=0.482; 95% CI 0.823-0.141; p=0.014).
An exploratory metabolomic analysis was carried out using capillary blood samples from PROMOTe participants. No differences were found between the prebiotic and the placebo arms for the metabolites tested.
This thesis is the first to report that high protein intake can be associated with sarcopenia. While the findings are specific to healthy community-dwelling older adults with high animal-source protein intake, this finding highlights the importance of avoiding supplementation in replete populations, as this may cause harm. The PROMOTe study did not show a significant improvement in muscle strength in the prebiotic group versus placebo, however I illustrate the feasibility of the prebiotic intervention. Further, I demonstrated the efficacy of remotely delivered interventions for older people, which holds huge promise for future studies in ageing research. Larger trials with longer intervention periods can build on this to examine the role of the modulation of the gut microbiome in overcoming age-associated muscle loss and sarcopenia. Lastly, my results demonstrate that cheap, scaleable, and readily available gut microbiome interventions offer potential as avenues of research for improving cognitive frailty in our ageing population.
| Date of Award | 1 Sept 2023 |
|---|---|
| Original language | English |
| Awarding Institution |
|
| Supervisor | Claire Steves (Supervisor) & Kevin Whelan (Supervisor) |