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Diet has a pivotal role in shaping the composition, function and diversity of the gut microbiome, with various diets having a profound impact on the stability, functionality and diversity of the microbial community within our gut. Understanding the profound impact of varied diets on the microbiome is crucial, as it will enable us not only to make well-informed dietary decisions for better metabolic and intestinal health, but also to prevent and slow the onset of specific diet-related diseases that stem from suboptimal diets. In this Review, we explore how geographical location affects the gut microbiome and how different diets shape its composition and function. We examine the mechanisms by which whole dietary regimes, such as the Mediterranean diet, high-fibre diet, plant-based diet, high-protein diet, ketogenic diet and Western diet, influence the gut microbiome. Furthermore, we underscore the need for exhaustive studies to better understand the causal relationship between diet, host and microorganisms for the development of precision nutrition and microbiome-based therapies.In this Review, Stanton and colleagues examine the effect of different whole diets on the composition and function of the gut microbiome and explore how the diet–microbiome relationship influences human health and the progression of different chronic diseases.

Ketone bodies are crucial intermediate metabolites widely associated with treating metabolic diseases. Accumulating evidence suggests that ketone bodies may act as immunoregulators in humans and animals to attenuate pathological inflammation through multiple strategies. Although the clues are scattered and untrimmed, the elevation of these ketone bodies in the circulation system and tissues induced by ketogenic diets was reported to affect the immunological barriers, an important part of innate immunity. Therefore, beta-hydroxybutyrate, a key ketone body, might also play a vital role in regulating the barrier immune systems. In this review, we retrospected the endogenous ketogenesis in animals and the dual roles of ketone bodies as energy carriers and signal molecules focusing on beta-hydroxybutyrate. In addition, the research regarding the effects of beta-hydroxybutyrate on the function of the immunological barrier, mainly on the microbiota, chemical, and physical barriers of the mucosa, were outlined and discussed. As an inducible endogenous metabolic small molecule, beta-hydroxybutyrate deserves delicate investigations focusing on its immunometabolic efficacy. Comprehending the connection between ketone bodies and the barrier immunological function and its underlining mechanisms may help exploit individualised approaches to treat various mucosa or skin-related diseases.

Mitochondria control cellular fate by various mechanisms and are key drivers of cellular metabolism. Although the main function of mitochondria is energy production, they are also involved in cellular detoxification, cellular stabilization, as well as control of ketogenesis and glucogenesis. Conditions like neurodegenerative disease, insulin resistance, endocrine imbalances, liver and kidney disease are intimately linked to metabolic disorders or inflexibility and to mitochondrial dysfunction. Mitochondrial dysfunction due to a relative lack of micronutrients and substrates is implicated in the development of many chronic diseases. l-carnitine is one of the key nutrients for proper mitochondrial function and is notable for its role in fatty acid oxidation. l-carnitine also plays a major part in protecting cellular membranes, preventing fatty acid accumulation, modulating ketogenesis and glucogenesis and in the elimination of toxic metabolites. l-carnitine deficiency has been observed in many diseases including organic acidurias, inborn errors of metabolism, endocrine imbalances, liver and kidney disease. The protective effects of micronutrients targeting mitochondria hold considerable promise for the management of age and metabolic related diseases. Preventing nutrient deficiencies like l-carnitine can be beneficial in maintaining metabolic flexibility via the optimization of mitochondrial function. This paper reviews the critical role of l-carnitine in mitochondrial function, metabolic flexibility and in other pathophysiological cellular mechanisms.

The Internet has become the main source of health-related information including nutrition. The aim of this study was to rank the most popular diets among Google users globally and regionally in addition to secular and seasonal trends in the years 2004 to 2019. We used Google Trends (GT) to identify and analyze course over time and regional interest of 47 topics related to diets. We analyzed secular trends using the Seasonal Mann–Kendall test and seasonal variation using time-series decomposition. The topic “Mediterranean diet” (MedD) was used as a benchmark. We calculated the interest of all topics in proportion to the relative search volume (RSV) of MedD. Globally, Google users were particularly interested in veganism (19.54 times higher than MedD), vegetarianism (15.09 times higher than MedD), and gluten-free diet (11.11 times higher than MedD). Veganism was the most frequently searched diet type in 23 countries followed by vegetarianism (14), ketogenic diet (7), and low-carbohydrate diet (7). Whereas an increase of RSV over time was observed for 23 diets, a decrease was noted for 20. The most dynamic increase was found for FODMAP (6.12 RSV/year), gluten-free diet (5.95 RSV/year), and raw veganism (5.72 RSV/year). Sharp declines concerned negative-calorie food (–4.34 RSV/year), macrobiotic diet (–3.89 RSV/year), and cabbage soup diet (–3.50 RSV/year). The interest in most diets falls in December but peaks in January. Veganism, vegetarianism, and gluten-free diet attract the largest public interest globally. Both secular trends and seasonal variation shape the ever-changing landscape of diet popularity. GT holds promise as a valuable tool in local and international nutrition research. [Display omitted] •Public interest in various diets can be investigated using Google Trends.•Vegan, vegetarian, and gluten-free diets currently are the most popular.•Interest in most diets is subject to marked annual variation.•Dynamics of interest in less established diets are often remarkably high.

Alzheimer’s disease (AD) is a progressive, late-onset dementia with no effective treatment available. Recent studies suggest that AD pathology is driven by age-related changes in metabolism. Alterations in metabolism, such as placing patients on a ketogenic diet, can alter cognition by an unknown mechanism. One of the ketone bodies produced as a result of ketogenesis, β-hydroxybutyrate (BHB), is known to inhibit NLRP3 inflammasome activation. Therefore, we tested if BHB inhibition of the NLRP3 inflammasome reduces overall AD pathology in the 5XFAD mouse model of AD. Here, we find BHB levels are lower in red blood cells and brain parenchyma of AD patients when compared with non-AD controls. Furthermore, exogenous BHB administration reduced plaque formation, microgliosis, apoptosis-associated speck-like protein containing a caspase recruitment domain (Asc) speck formation, and caspase-1 activation in the 5XFAD mouse model of AD. Taken together, our findings demonstrate that BHB reduces AD pathology by inhibiting NLRP3 inflammasome activation. Additionally, our data suggest dietary or pharmacological approaches to increase BHB levels as promising therapeutic strategies for AD.

During starvation, fasting, or a diet containing little digestible carbohydrates, the circulating insulin levels are decreased. This promotes lipolysis, and the breakdown of fat becomes the major source of energy. The hepatic energy metabolism is regulated so that under these circumstances, ketone bodies are generated from β-oxidation of fatty acids and secreted as ancillary fuel, in addition to gluconeogenesis. Increased plasma levels of ketone bodies thus indicate a dietary shortage of carbohydrates. Ketone bodies not only serve as fuel but also promote resistance to oxidative and inflammatory stress, and there is a decrease in anabolic insulin-dependent energy expenditure. It has been suggested that the beneficial non-metabolic actions of ketone bodies on organ functions are mediated by them acting as a ligand to specific cellular targets. We propose here a major role of a different pathway initiated by the induction of oxidative stress in the mitochondria during increased ketolysis. Oxidative stress induced by ketone body metabolism is beneficial in the long term because it initiates an adaptive (hormetic) response characterized by the activation of the master regulators of cell-protective mechanism, nuclear factor erythroid 2-related factor 2 (Nrf2), sirtuins, and AMP-activated kinase. This results in resolving oxidative stress, by the upregulation of anti-oxidative and anti-inflammatory activities, improved mitochondrial function and growth, DNA repair, and autophagy. In the heart, the adaptive response to enhanced ketolysis improves resistance to damage after ischemic insults or to cardiotoxic actions of doxorubicin. Sodium-dependent glucose co-transporter 2 (SGLT2) inhibitors may also exert their cardioprotective action via increasing ketone body levels and ketolysis. We conclude that the increased synthesis and use of ketone bodies as ancillary fuel during periods of deficient food supply and low insulin levels causes oxidative stress in the mitochondria and that the latter initiates a protective (hormetic) response which allows cells to cope with increased oxidative stress and lower energy availability. Keywords Ketogenic diet, Ketone bodies, Beta hydroxybutyrate, Insulin, Obesity, Type 2 diabetes, Inflammation, Oxidative stress, Cardiovascular disease, SGLT2, Hormesis

An emerging body of data suggests that lipid metabolism has an important role to play in the aging process. Indeed, a plethora of dietary, pharmacological, genetic, and surgical lipid‐related interventions extend lifespan in nematodes, fruit flies, mice, and rats. For example, the impairment of genes involved in ceramide and sphingolipid synthesis extends lifespan in both worms and flies. The overexpression of fatty acid amide hydrolase or lysosomal lipase prolongs life in Caenorhabditis elegans, while the overexpression of diacylglycerol lipase enhances longevity in both C. elegans and Drosophila melanogaster. The surgical removal of adipose tissue extends lifespan in rats, and increased expression of apolipoprotein D enhances survival in both flies and mice. Mouse lifespan can be additionally extended by the genetic deletion of diacylglycerol acyltransferase 1, treatment with the steroid 17‐α‐estradiol, or a ketogenic diet. Moreover, deletion of the phospholipase A2 receptor improves various healthspan parameters in a progeria mouse model. Genome‐wide association studies have found several lipid‐related variants to be associated with human aging. For example, the epsilon 2 and epsilon 4 alleles of apolipoprotein E are associated with extreme longevity and late‐onset neurodegenerative disease, respectively. In humans, blood triglyceride levels tend to increase, while blood lysophosphatidylcholine levels tend to decrease with age. Specific sphingolipid and phospholipid blood profiles have also been shown to change with age and are associated with exceptional human longevity. These data suggest that lipid‐related interventions may improve human healthspan and that blood lipids likely represent a rich source of human aging biomarkers. A growing body of evidence suggests that lipid metabolism regulates aging. Various dietary, pharmacological, surgical, and genetic lipid‐related interventions have been shown to extend lifespan in model organisms. These lifespan studies have implicated several specific lipid pathways as regulators of aging and health. Current data suggest that lipid‐specific interventions have the potential to extend human healthspan. Moreover, blood‐based lipids represent a promising source of aging biomarkers.

Dietary interventions can change metabolite levels in the tumour microenvironment, which might then affect cancer cell metabolism to alter tumour growth 1 – 5 . Although caloric restriction (CR) and a ketogenic diet (KD) are often thought to limit tumour progression by lowering blood glucose and insulin levels 6 – 8 , we found that only CR inhibits the growth of select tumour allografts in mice, suggesting that other mechanisms contribute to tumour growth inhibition. A change in nutrient availability observed with CR, but not with KD, is lower lipid levels in the plasma and tumours. Upregulation of stearoyl-CoA desaturase (SCD), which synthesises monounsaturated fatty acids, is required for cancer cells to proliferate in a lipid-depleted environment, and CR also impairs tumour SCD activity to cause an imbalance between unsaturated and saturated fatty acids to slow tumour growth. Enforcing cancer cell SCD expression or raising circulating lipid levels through a higher-fat CR diet confers resistance to the effects of CR. By contrast, although KD also impairs tumour SCD activity, KD-driven increases in lipid availability maintain the unsaturated to saturated fatty acid ratios in tumours, and changing the KD fat composition to increase tumour saturated fatty acid levels cooperates with decreased tumour SCD activity to slow tumour growth. These data suggest that diet-induced mismatches between tumour fatty acid desaturation activity and the availability of specific fatty acid species determine whether low glycaemic diets impair tumour growth. Lien et al. show that low glycemic diets can reduce tumour growth by deregulating lipid metabolism.

High-fat, low-carbohydrate diets, known as ketogenic diets, have been used as a non-pharmacological treatment for refractory epilepsy. A key mechanism of this treatment is thought to be the generation of ketones, which provide brain cells (neurons and astrocytes) with an energy source that is more efficient than glucose, resulting in beneficial downstream metabolic changes, such as increasing adenosine levels, which might have effects on seizure control. However, some studies have challenged the central role of ketones because medium-chain fatty acids, which are part of a commonly used variation of the diet (the medium-chain triglyceride ketogenic diet), have been shown to directly inhibit AMPA receptors (glutamate receptors), and to change cell energetics through mitochondrial biogenesis. Through these mechanisms, medium-chain fatty acids rather than ketones are likely to block seizure onset and raise seizure threshold. The mechanisms underlying the ketogenic diet might also have roles in other disorders, such as preventing neurodegeneration in Alzheimer's disease, the proliferation and spread of cancer, and insulin resistance in type 2 diabetes. Analysing medium-chain fatty acids in future ketogenic diet studies will provide further insights into their importance in modified forms of the diet. Moreover, the results of these studies could facilitate the development of new pharmacological and dietary therapies for epilepsy and other disorders.

Anorexia and fasting are host adaptations to acute infection, and induce a metabolic switch towards ketogenesis and the production of ketone bodies, including β-hydroxybutyrate (BHB) 1 – 6 . However, whether ketogenesis metabolically influences the immune response in pulmonary infections remains unclear. Here we show that the production of BHB is impaired in individuals with SARS-CoV-2-induced acute respiratory distress syndrome (ARDS) but not in those with  influenza-induced ARDS. We found that BHB promotes both the survival of and the production of interferon-γ by CD4 + T cells. Applying a metabolic-tracing analysis, we established that BHB provides an alternative carbon source to fuel oxidative phosphorylation (OXPHOS) and the production of bioenergetic amino acids and glutathione, which is important for maintaining the redox balance. T cells from patients with SARS-CoV-2-induced ARDS were exhausted and skewed towards glycolysis, but could be metabolically reprogrammed by BHB to perform OXPHOS, thereby increasing their functionality. Finally, we show in mice that a ketogenic diet and the delivery of BHB as a ketone ester drink restores CD4 + T cell metabolism and function in severe respiratory infections, ultimately reducing the mortality of mice infected with SARS-CoV-2. Altogether, our data reveal that BHB is an alternative source of carbon that promotes T cell responses in pulmonary viral infections, and highlight impaired ketogenesis as a potential confounding factor in severe COVID-19. The ketone body β-hydroxybutyrate can be used as an alternative carbon source by T cells to maintain their function during severe respiratory viral infections, including infection with SARS-CoV-2.