Fatty acid-induced mitochondrial uncoupling elicits inflammasome-independent IL-1α and sterile vascular inflammation in atherosclerosis.

Chronic inflammation is a fundamental aspect of metabolic disorders such as obesity, diabetes and cardiovascular disease. Cholesterol crystals are metabolic signals that trigger sterile inflammation in atherosclerosis, presumably by activating inflammasomes for IL-1ß production. We found here that atherogenesis was mediated by IL-1α and we identified fatty acids as potent inducers of IL-1α-driven vascular inflammation. Fatty acids selectively stimulated the release of IL-1α but not of IL-1ß by uncoupling mitochondrial respiration. Fatty acid-induced mitochondrial uncoupling abrogated IL-1ß secretion, which deviated the cholesterol crystal-elicited response toward selective production of IL-1α. Our findings delineate a previously unknown pathway for vascular immunopathology that links the cellular response to metabolic stress with innate inflammation, and suggest that IL-1α, not IL-1ß, should be targeted in patients with cardiovascular disease.

Perspective: Leveraging the Gut Microbiota to Predict Personalized Responses to Dietary, Prebiotic, and Probiotic Interventions.

Humans often show variable responses to dietary, prebiotic, and probiotic interventions. Emerging evidence indicates that the gut microbiota is a key determinant for this population heterogeneity. Here, we provide an overview of some of the major computational and experimental tools being applied to critical questions of microbiota-mediated personalized nutrition and health. First, we discuss the latest advances in in silico modeling of the microbiota-nutrition-health axis, including the application of statistical, mechanistic, and hybrid artificial intelligence models. Second, we address high-throughput in vitro techniques for assessing interindividual heterogeneity, from ex vivo batch culturing of stool and continuous culturing in anaerobic bioreactors, to more sophisticated organ-on-a-chip models that integrate both host and microbial compartments. Third, we explore in vivo approaches for better understanding of personalized, microbiota-mediated responses to diet, prebiotics, and probiotics, from nonhuman animal models and human observational studies, to human feeding trials and crossover interventions. We highlight examples of existing, consumer-facing precision nutrition platforms that are currently leveraging the gut microbiota. Furthermore, we discuss how the integration of a broader set of the tools and techniques described in this piece can generate the data necessary to support a greater diversity of precision nutrition strategies. Finally, we present a vision of a precision nutrition and healthcare future, which leverages the gut microbiota to design effective, individual-specific interventions.

Decoding breast milk oligosaccharides.

Oligosaccharides represent a significant fraction of breast milk, reaching up to 20 g/l in early milk. Human milk oligosaccharides comprise close to 200 structures, which are not absorbed by the intestinal tissue and have no nutritional value for the breastfed infant. Early studies conducted around 1930 already attributed a prebiotic activity to milk oligosaccharides by showing their stimulatory effects on the growth of specific intestinal microbiota. In addition, milk oligosaccharides contribute to the defence against enteric pathogens by acting as soluble decoys preventing the adhesion of viruses and bacteria to their carbohydrate mucosal receptors. The structural complexity of milk oligosaccharides hampers the assignment of specific functions to single carbohydrates. The application of mouse models allows the investigation of unique milk oligosaccharides in the context of intestinal microbiota and mucosal immunity. In this respect, our recent work has demonstrated that uptake of the milk oligosaccharide 3-sialyllactose increases the inflammatory response observed in different colitis models. The proinflammatory action of 3-sialyllactose was attributed on the one hand to the modulation of intestinal bacterial groups, and on the other hand to a direct stimulatory effect on CD11c+ dendritic cells. The availability of pure oligosaccharides in large amounts will soon enable the study of these compounds in humans in the context of intestinal and metabolic disorders associated to various forms of dysbiosis.

Sugar-sweetened beverages with moderate amounts of fructose, but not sucrose, induce Fatty Acid synthesis in healthy young men: a randomized crossover study.

CONTEXT: The impact of sugar-sweetened beverages (SSB) on lipid metabolism when consumed in moderate amounts by normal weight subjects is debated. OBJECTIVE: The objective of the study was to investigate the effect of different types of sugars in SSB on fatty acid metabolism (ie, fatty acid synthesis and oxidation) in healthy young men. DESIGN: Thirty-four normal-weight men were studied in a randomized crossover study. Four isocaloric 3-week interventions with SSB were performed in random order: medium fructose (MF; 40 g/d); high fructose (HF; 80 g/d), high sucrose (HS; 80 g/d), and high glucose (HG; 80g/d). Fasting total plasma fatty acid composition was measured after each intervention. Acylcarnitines were measured in the fasting state and after a euglycemic hyperinsulinemic clamp in nine subjects. RESULTS: The relative abundance of palmitate (16:0) and the molar fatty acid ratio of palmitate to linoleic acid (16:0 to18:2) as markers of fatty acid synthesis were increased after HF [relative abundance of palmitate: 22.97% ± 5.51% (percentage of total fatty acids by weight ±SD)] and MF (26.1% ± 1.7%) compared with HS (19.40% ± 2.91%, P < .001), HG (19.43% ±3.12 %, P < .001), or baseline (19.40% ± 2.79%, P < .001). After HS and HG, the relative abundance of palmitate was equal to baseline. Fasting palmitoylcarnitine was significantly increased after HF and HS (HF and HS vs. HG: P = .005), decreasing after inhibition of lipolysis by insulin in the clamp. CONCLUSIONS: When consumed in moderate amounts, fructose but not sucrose or glucose in SSB increases fatty acid synthesis (palmitate), whereas fasting long-chain acylcarnitines are increased after both fructose and sucrose, indicating an impaired ß-oxidation flux.