A pilot study of alternative substrates in the critically Ill subject using a ketogenic feed.

Bioenergetic failure caused by impaired utilisation of glucose and fatty acids contributes to organ dysfunction across multiple tissues in critical illness. Ketone bodies may form an alternative substrate source, but the feasibility and safety of inducing a ketogenic state in physiologically unstable patients is not known. Twenty-nine mechanically ventilated adults with multi-organ failure managed on intensive care units were randomised (Ketogenic n = 14, Control n = 15) into a two-centre pilot open-label trial of ketogenic versus standard enteral feeding. The primary endpoints were assessment of feasibility and safety, recruitment and retention rates and achievement of ketosis and glucose control. Ketogenic feeding was feasible, safe, well tolerated and resulted in ketosis in all patients in the intervention group, with a refusal rate of 4.1% and 82.8% retention. Patients who received ketogenic feeding had fewer hypoglycaemic events (0.0% vs. 1.6%), required less exogenous international units of insulin (0 (Interquartile range 0-16) vs.78 (Interquartile range 0-412) but had slightly more daily episodes of diarrhoea (53.5% vs. 42.9%) over the trial period. Ketogenic feeding was feasible and may be an intervention for addressing bioenergetic failure in critically ill patients. Clinical Trials.gov registration: NCT04101071.

Metabolomics as an Important Tool for Determining the Mechanisms of Human Skeletal Muscle Deconditioning.

Muscle deconditioning impairs both locomotor function and metabolic health, and is associated with reduced quality life and increased mortality rates. Despite an appreciation of the existence of phenomena such as muscle anabolic resistance, mitophagy, and insulin resistance with age and disease in humans, little is known about the mechanisms responsible for these negative traits. With the complexities surrounding these unknowns and the lack of progress to date in development of effective interventions, there is a need for alternative approaches. Metabolomics is the study of the full array of metabolites within cells or tissues, which collectively constitute the metabolome. As metabolomics allows for the assessment of the cellular metabolic state in response to physiological stimuli, any chronic change in the metabolome is likely to reflect adaptation in the physiological phenotype of an organism. This, therefore, provides a holistic and unbiased approach that could be applied to potentially uncover important novel facets in the pathophysiology of muscle decline in ageing and disease, as well as identifying prognostic markers of those at risk of decline. This review will aim to highlight the current knowledge and potential impact of metabolomics in the study of muscle mass loss and deconditioning in humans and will highlight key areas for future research.

Metabolomics reveals diet-derived plant polyphenols accumulate in physiological bone.

Plant-derived secondary metabolites consumed in the diet, especially polyphenolic compounds, are known to have a range of positive health effects. They are present in circulation after ingestion and absorption and can be sequestered into cells within particular organs, but have rarely been investigated systematically in osteological tissues. However, a small number of polyphenols and similar molecules are known to bind to bone. For example alizarin, a plant derived anthraquinone and tetracycline (a naturally occurring antibiotic), are both absorbed into bone from circulation during bone formation and are used to monitor mineralization in osteological studies. Both molecules have also been identified serendipitously in archaeological human bones derived from natural sources in the diet. Whether an analogous mechanism of sequestration extends to additional diet-derived plant-polyphenols has not previously been systematically studied. We investigated whether a range of diet-derived polyphenol-like compounds bind to bone using untargeted metabolomics applied to the analysis of bone extracts from pigs fed an acorn-based diet. We analysed the diet which was rich in ellagitannins, extracts from the pig bones and surrounding tissue, post-mortem. We found direct evidence of multiple polyphenolic compounds in these extracts and matched them to the diet. We also showed that these compounds were present in the bone but not surrounding tissues. We also provide data showing that a range of polyphenolic compounds bind to hydroxyapatite in vitro. The evidence for polyphenol sequestration into physiological bone, and the range and specificity of polyphenols in human and animal diets, raises intriguing questions about potential effects on bone formation and bone health. Further studies are needed to determine the stability of the sequestered molecules post-mortem but there is also potential for (palaeo)dietary reconstruction and forensic applications.