Effects of Intermittent Fasting on Health and Aging Evidence is accumulating that eating in a 6-hour period and fasting for 18 hours can trigger a metabolic switch from glucose-based to ketone-base...

https://www.nejm.org/doi/pdf/10.1056/NEJMra1905136

Effects of Intermittent Fasting on Health, Aging, and Disease

The gut microbiome plays an important role in human health and influences the development of chronic diseases ranging from metabolic disease to gastrointestinal disorders and colorectal cancer. Of increasing prevalence in Western societies, these conditions carry a high burden of care. Dietary patterns and environmental factors have a profound effect on shaping gut microbiota in real time. Diverse populations of intestinal bacteria mediate their beneficial effects through the fermentation of dietary fiber to produce short-chain fatty acids, endogenous signals with important roles in lipid homeostasis and reducing inflammation. Recent progress shows that an individual’s starting microbial profile is a key determinant in predicting their response to intervention with live probiotics. The gut microbiota is complex and challenging to characterize. Enterotypes have been proposed using metrics such as alpha species diversity, the ratio of Firmicutes to Bacteroidetes phyla, and the relative abundance of beneficial genera (e.g., Bifidobacterium, Akkermansia) versus facultative anaerobes (E. coli), pro-inflammatory Ruminococcus, or nonbacterial microbes. Microbiota composition and relative populations of bacterial species are linked to physiologic health along different axes. We review the role of diet quality, carbohydrate intake, fermentable FODMAPs, and prebiotic fiber in maintaining healthy gut flora. The implications are discussed for various conditions including obesity, diabetes, irritable bowel syndrome, inflammatory bowel disease, depression, and cardiovascular disease.

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Gut Microbiome: Profound Implications for Diet and Disease

Conceptual scientific and medical advances have led to a recent realization that there may be no single, one-size-fits-all diet and that differential human responses to dietary inputs may rather be driven by unique and quantifiable host and microbiome features. Integration of these person-specific host and microbiome readouts into actionable modules may complement traditional food measurement approaches in devising diets that are of benefit to the individual. Although many host-derived factors are hardwired and difficult to modulate, the microbiome may be more readily reshaped by environmental factors such as dietary exposures and is increasingly recognized to potentially impact human physiology by participating in digestion, the absorption of nutrients, shaping of the mucosal immune response and the synthesis or modulation of a plethora of potentially bioactive compounds. Thus, diet-induced microbiota alterations may be harnessed in order to induce changes in host physiology, including disease development and progression. However, major limitations in ‘big-data’ processing and analysis still limit our interpretive and translational capabilities concerning these person-specific host, microbiome and diet interactions. In this Review, we describe the latest advances in understanding diet–microbiota interactions, the individuality of gut microbiota composition and how this knowledge could be harnessed for personalized nutrition strategies to improve human health. In this Review, Kolodziejczyk, Zheng and Elinav describe the latest advances in understanding diet–microbiota interactions, the individuality of gut microbiota composition and how this knowledge could be harnessed for personalized nutrition strategies to improve human health.

Diet–microbiota interactions and personalized nutrition

The interplay of gut microbiota, host metabolism, and metabolic health has gained increased attention. Gut microbiota may play a regulatory role in gastrointestinal health, substrate metabolism, and peripheral tissues including adipose tissue, skeletal muscle, liver, and pancreas via its metabolites short-chain fatty acids (SCFA). Animal and human data demonstrated that, in particular, acetate beneficially affects host energy and substrate metabolism via secretion of the gut hormones like glucagon-like peptide-1 and peptide YY, which, thereby, affects appetite, via a reduction in whole-body lipolysis, systemic pro-inflammatory cytokine levels, and via an increase in energy expenditure and fat oxidation. Thus, potential therapies to increase gut microbial fermentation and acetate production have been under vigorous scientific scrutiny. In this review, the relevance of the colonically and systemically most abundant SCFA acetate and its effects on the previously mentioned tissues will be discussed in relation to body weight control and glucose homeostasis. We discuss in detail the differential effects of oral acetate administration (vinegar intake), colonic acetate infusions, acetogenic fiber, and acetogenic probiotic administrations as approaches to combat obesity and comorbidities. Notably, human data are scarce, which highlights the necessity for further human research to investigate acetate’s role in host physiology, metabolic, and cardiovascular health.

The Short-Chain Fatty Acid Acetate in Body Weight Control and Insulin Sensitivity

The gut microbiome has emerged as a key regulator of host metabolism. Here we review the various mechanisms through which the gut microbiome influences the energy metabolism of its host, highlighting the complex interactions between gut microbes, their metabolites and host cells. Among the most important bacterial metabolites are short-chain fatty acids, which serve as a direct energy source for host cells, stimulate the production of gut hormones and act in the brain to regulate food intake. Other microbial metabolites affect systemic energy expenditure by influencing thermogenesis and adipose tissue browning. Both direct and indirect mechanisms of action are known for specific metabolites, such as bile acids, branched chain amino acids, indole propionic acid and endocannabinoids. We also discuss the roles of specific bacteria in the production of specific metabolites and explore how external factors, such as antibiotics and exercise, affect the microbiome and thereby energy homeostasis. Collectively, we present a large body of evidence supporting the concept that gut microbiota-based therapies can be used to modulate host metabolism, and we expect to see such approaches moving from bench to bedside in the near future.

Microbial regulation of organismal energy homeostasis.

Intermittent Fasting Promotes White Adipose Browning and Decreases Obesity by Shaping the Gut Microbiota

De Novo Sphingolipid Biosynthesis Is Required for Adipocyte Survival and Metabolic Homeostasis.

OBJECTIVES Beta-3 adrenergic receptors (β3-AR) stimulate lipolysis and thermogenesis in white and brown adipose tissue (WAT and BAT). Obesity increases oxidative stress and inflammation that attenuate AT β3-AR signaling. The objective of this study was to test the hypothesis that the combination of the β3-AR agonist CL-316,243 (CL) and the antioxidant alpha-lipoic acid (ALA) would lower inflammation in diet-induced obesity (DIO) and improve β3-AR function. METHODS A total of 40 DIO mice were separated into four groups: Control (per os and intraperitoneal [IP] vehicle); CL alone (0.01 mg/kg IP daily); ALA alone (250 mg/kg in drinking water); or ALA+CL combination, all for 5 weeks. RESULTS Food intake was similar in all groups; however, mice receiving ALA+CL showed improved body composition and inflammation as well as lower body weight (+1.7 g Control vs. -2.5 g ALA+CL [-7%]; p < 0.01) and percentage of body fat (-9%, p < 0.001). Systemic and epididymal WAT inflammation was lower with ALA+CL than all other groups, with enhanced recruitment of epididymal WAT anti-inflammatory CD206+ M2 macrophages. β3-AR signaling in WAT was enhanced in the combination-treatment group, with higher mRNA and protein levels of thermogenic uncoupling protein 1 and AT lipases. CONCLUSIONS Chronic treatment with ALA and a β3-AR agonist reduces DIO-induced inflammation. AT immune modulation could be a therapeutic target in patients with obesity.

Combining a β3 adrenergic receptor agonist with alpha-lipoic acid reduces inflammation in male mice with diet-induced obesity.

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Intermittent Fasting Promotes White Adipose Browning and Decreases Obesity by Shaping the Gut Microbiota

De Novo Sphingolipid Biosynthesis Is Required for Adipocyte Survival and Metabolic Homeostasis.

Combining a β3 adrenergic receptor agonist with alpha-lipoic acid reduces inflammation in male mice with diet-induced obesity.