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    Harnessing global fisheries to tackle micronutrient deficiencies. Hicks Christina C,Cohen Philippa J,Graham Nicholas A J,Nash Kirsty L,Allison Edward H,D'Lima Coralie,Mills David J,Roscher Matthew,Thilsted Shakuntala H,Thorne-Lyman Andrew L,MacNeil M Aaron Nature Micronutrient deficiencies account for an estimated one million premature deaths annually, and for some nations can reduce gross domestic product by up to 11%, highlighting the need for food policies that focus on improving nutrition rather than simply increasing the volume of food produced. People gain nutrients from a varied diet, although fish-which are a rich source of bioavailable micronutrients that are essential to human health-are often overlooked. A lack of understanding of the nutrient composition of most fish and how nutrient yields vary among fisheries has hindered the policy shifts that are needed to effectively harness the potential of fisheries for food and nutrition security. Here, using the concentration of 7 nutrients in more than 350 species of marine fish, we estimate how environmental and ecological traits predict nutrient content of marine finfish species. We use this predictive model to quantify the global spatial patterns of the concentrations of nutrients in marine fisheries and compare nutrient yields to the prevalence of micronutrient deficiencies in human populations. We find that species from tropical thermal regimes contain higher concentrations of calcium, iron and zinc; smaller species contain higher concentrations of calcium, iron and omega-3 fatty acids; and species from cold thermal regimes or those with a pelagic feeding pathway contain higher concentrations of omega-3 fatty acids. There is no relationship between nutrient concentrations and total fishery yield, highlighting that the nutrient quality of a fishery is determined by the species composition. For a number of countries in which nutrient intakes are inadequate, nutrients available in marine finfish catches exceed the dietary requirements for populations that live within 100 km of the coast, and a fraction of current landings could be particularly impactful for children under 5 years of age. Our analyses suggest that fish-based food strategies have the potential to substantially contribute to global food and nutrition security. 10.1038/s41586-019-1592-6
    Interactions Between Diet and the Intestinal Microbiota Alter Intestinal Permeability and Colitis Severity in Mice. Llewellyn Sean R,Britton Graham J,Contijoch Eduardo J,Vennaro Olivia H,Mortha Arthur,Colombel Jean-Frederic,Grinspan Ari,Clemente Jose C,Merad Miriam,Faith Jeremiah J Gastroenterology BACKGROUND & AIMS:It is not clear how the complex interactions between diet and the intestinal microbiota affect development of mucosal inflammation or inflammatory bowel disease. We investigated interactions between dietary ingredients, nutrients, and the microbiota in specific pathogen-free (SPF) and germ-free (GF) mice given more than 40 unique diets; we quantified individual and synergistic effects of dietary macronutrients and the microbiota on intestinal health and development of colitis. METHODS:C56BL/6J SPF and GF mice were placed on custom diets containing different concentrations and sources of protein, fat, digestible carbohydrates, and indigestible carbohydrates (fiber). After 1 week, SPF and GF mice were given dextran sulfate sodium (DSS) to induce colitis. Disease severity was determined based on the percent weight change from baseline, and modeled as a function of the concentration of each macronutrient in the diet. In unchallenged mice, we measured intestinal permeability by feeding mice labeled dextran and measuring levels in blood. Feces were collected and microbiota were analyzed by 16S rDNA sequencing. We collected colons from mice and performed transcriptome analyses. RESULTS:Fecal microbiota varied with diet; the concentration of protein and fiber had the strongest effect on colitis development. Among 9 fiber sources tested, psyllium, pectin, and cellulose fiber reduced the severity of colitis in SPF mice, whereas methylcellulose increased severity. Increasing dietary protein increased the density of the fecal microbiota and the severity of colitis in SPF mice, but not in GF mice or mice given antibiotics. Psyllium fiber reduced the severity of colitis through microbiota-dependent and microbiota-independent mechanisms. Combinatorial perturbations to dietary casein protein and psyllium fiber in parallel accounted for most variation in gut microbial density and intestinal permeability in unchallenged mice, as well as the severity of DSS-induced colitis; changes in 1 ingredient could be offset by changes in another. CONCLUSIONS:In an analysis of the effects of different dietary components and the gut microbiota on mice with and without DSS-induced colitis, we found complex mixtures of nutrients affect intestinal permeability, gut microbial density, and development of intestinal inflammation. 10.1053/j.gastro.2017.11.030
    Paradoxical Roles of Antioxidant Enzymes: Basic Mechanisms and Health Implications. Lei Xin Gen,Zhu Jian-Hong,Cheng Wen-Hsing,Bao Yongping,Ho Ye-Shih,Reddi Amit R,Holmgren Arne,Arnér Elias S J Physiological reviews Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are generated from aerobic metabolism, as a result of accidental electron leakage as well as regulated enzymatic processes. Because ROS/RNS can induce oxidative injury and act in redox signaling, enzymes metabolizing them will inherently promote either health or disease, depending on the physiological context. It is thus misleading to consider conventionally called antioxidant enzymes to be largely, if not exclusively, health protective. Because such a notion is nonetheless common, we herein attempt to rationalize why this simplistic view should be avoided. First we give an updated summary of physiological phenotypes triggered in mouse models of overexpression or knockout of major antioxidant enzymes. Subsequently, we focus on a series of striking cases that demonstrate "paradoxical" outcomes, i.e., increased fitness upon deletion of antioxidant enzymes or disease triggered by their overexpression. We elaborate mechanisms by which these phenotypes are mediated via chemical, biological, and metabolic interactions of the antioxidant enzymes with their substrates, downstream events, and cellular context. Furthermore, we propose that novel treatments of antioxidant enzyme-related human diseases may be enabled by deliberate targeting of dual roles of the pertaining enzymes. We also discuss the potential of "antioxidant" nutrients and phytochemicals, via regulating the expression or function of antioxidant enzymes, in preventing, treating, or aggravating chronic diseases. We conclude that "paradoxical" roles of antioxidant enzymes in physiology, health, and disease derive from sophisticated molecular mechanisms of redox biology and metabolic homeostasis. Simply viewing antioxidant enzymes as always being beneficial is not only conceptually misleading but also clinically hazardous if such notions underpin medical treatment protocols based on modulation of redox pathways. 10.1152/physrev.00010.2014
    Dietary Fructose and Microbiota-Derived Short-Chain Fatty Acids Promote Bacteriophage Production in the Gut Symbiont Lactobacillus reuteri. Oh Jee-Hwan,Alexander Laura M,Pan Meichen,Schueler Kathryn L,Keller Mark P,Attie Alan D,Walter Jens,van Pijkeren Jan-Peter Cell host & microbe The mammalian intestinal tract contains a complex microbial ecosystem with many lysogens, which are bacteria containing dormant phages (prophages) inserted within their genomes. Approximately half of intestinal viruses are derived from lysogens, suggesting that these bacteria encounter triggers that promote phage production. We show that prophages of the gut symbiont Lactobacillus reuteri are activated during gastrointestinal transit and that phage production is further increased in response to a fructose-enriched diet. Fructose and exposure to short-chain fatty acids activate the Ack pathway, involved in generating acetic acid, which in turn triggers the bacterial stress response that promotes phage production. L. reuteri mutants of the Ack pathway or RecA, a stress response component, exhibit decreased phage production. Thus, prophages in a gut symbiont can be induced by diet and metabolites affected by diet, which provides a potential mechanistic explanation for the effects of diet on the intestinal phage community. 10.1016/j.chom.2018.11.016
    Short-Term Fasting Reveals Amino Acid Metabolism as a Major Sex-Discriminating Factor in the Liver. Della Torre Sara,Mitro Nico,Meda Clara,Lolli Federica,Pedretti Silvia,Barcella Matteo,Ottobrini Luisa,Metzger Daniel,Caruso Donatella,Maggi Adriana Cell metabolism Sex impacts on liver physiology with severe consequences for energy metabolism and response to xenobiotic, hepatic, and extra-hepatic diseases. The comprehension of the biology subtending sex-related hepatic differences is therefore very relevant in the medical, pharmacological, and dietary perspective. The extensive application of metabolomics paired to transcriptomics here shows that, in the case of short-term fasting, the decision to maintain lipid synthesis using amino acids (aa) as a source of fuel is the key discriminant for the hepatic metabolism of male and female mice. Pharmacological and genetic interventions indicate that the hepatic estrogen receptor (ERα) has a key role in this sex-related strategy that is primed around birth by the aromatase-dependent conversion of testosterone into estradiol. This energy partition strategy, possibly the result of an evolutionary pressure enabling mammals to tailor their reproductive capacities to nutritional status, is most important to direct future sex-specific dietary and medical interventions. 10.1016/j.cmet.2018.05.021
    Dietary L-serine confers a competitive fitness advantage to Enterobacteriaceae in the inflamed gut. Kitamoto Sho,Alteri Christopher J,Rodrigues Michael,Nagao-Kitamoto Hiroko,Sugihara Kohei,Himpsl Stephanie D,Bazzi Malak,Miyoshi Mao,Nishioka Tatsuki,Hayashi Atsushi,Morhardt Tina L,Kuffa Peter,Grasberger Helmut,El-Zaatari Mohamad,Bishu Shrinivas,Ishii Chiharu,Hirayama Akiyoshi,Eaton Kathryn A,Dogan Belgin,Simpson Kenneth W,Inohara Naohiro,Mobley Harry L T,Kao John Y,Fukuda Shinji,Barnich Nicolas,Kamada Nobuhiko Nature microbiology Metabolic reprogramming is associated with the adaptation of host cells to the disease environment, such as inflammation and cancer. However, little is known about microbial metabolic reprogramming or the role it plays in regulating the fitness of commensal and pathogenic bacteria in the gut. Here, we report that intestinal inflammation reprograms the metabolic pathways of Enterobacteriaceae, such as Escherichia coli LF82, in the gut to adapt to the inflammatory environment. We found that E. coli LF82 shifts its metabolism to catabolize L-serine in the inflamed gut in order to maximize its growth potential. However, L-serine catabolism has a minimal effect on its fitness in the healthy gut. In fact, the absence of genes involved in L-serine utilization reduces the competitive fitness of E. coli LF82 and Citrobacter rodentium only during inflammation. The concentration of luminal L-serine is largely dependent on dietary intake. Accordingly, withholding amino acids from the diet markedly reduces their availability in the gut lumen. Hence, inflammation-induced blooms of E. coli LF82 are significantly blunted when amino acids-particularly L-serine-are removed from the diet. Thus, the ability to catabolize L-serine increases bacterial fitness and provides Enterobacteriaceae with a growth advantage against competitors in the inflamed gut. 10.1038/s41564-019-0591-6
    Remodeling of the Acetylproteome by SIRT3 Manipulation Fails to Affect Insulin Secretion or β Cell Metabolism in the Absence of Overnutrition. Peterson Brett S,Campbell Jonathan E,Ilkayeva Olga,Grimsrud Paul A,Hirschey Matthew D,Newgard Christopher B Cell reports SIRT3 is a nicotinamide adenine dinucleotide (NAD)-dependent mitochondrial protein deacetylase purported to influence metabolism through post-translational modification of metabolic enzymes. Fuel-stimulated insulin secretion, which involves mitochondrial metabolism, could be susceptible to SIRT3-mediated effects. We used CRISPR/Cas9 technology to manipulate SIRT3 expression in β cells, resulting in widespread SIRT3-dependent changes in acetylation of key metabolic enzymes but no appreciable changes in glucose- or pyruvate-stimulated insulin secretion or metabolomic profile during glucose stimulation. Moreover, these broad changes in the SIRT3-targeted acetylproteome did not affect responses to nutritional or ER stress. We also studied mice with global SIRT3 knockout fed either standard chow (STD) or high-fat and high-sucrose (HFHS) diets. Only when chronically fed HFHS diet do SIRT3 KO animals exhibit a modest reduction in insulin secretion. We conclude that broad changes in mitochondrial protein acetylation in response to manipulation of SIRT3 are not sufficient to cause changes in islet function or metabolism. 10.1016/j.celrep.2018.05.088
    Fasting-Refeeding Impacts Immune Cell Dynamics and Mucosal Immune Responses. Nagai Motoyoshi,Noguchi Ryotaro,Takahashi Daisuke,Morikawa Takayuki,Koshida Kouhei,Komiyama Seiga,Ishihara Narumi,Yamada Takahiro,Kawamura Yuki I,Muroi Kisara,Hattori Kouya,Kobayashi Nobuhide,Fujimura Yumiko,Hirota Masato,Matsumoto Ryohtaroh,Aoki Ryo,Tamura-Nakano Miwa,Sugiyama Machiko,Katakai Tomoya,Sato Shintaro,Takubo Keiyo,Dohi Taeko,Hase Koji Cell Nutritional status potentially influences immune responses; however, how nutritional signals regulate cellular dynamics and functionality remains obscure. Herein, we report that temporary fasting drastically reduces the number of lymphocytes by ∼50% in Peyer's patches (PPs), the inductive site of the gut immune response. Subsequent refeeding seemingly restored the number of lymphocytes, but whose cellular composition was conspicuously altered. A large portion of germinal center and IgA B cells were lost via apoptosis during fasting. Meanwhile, naive B cells migrated from PPs to the bone marrow during fasting and then back to PPs during refeeding when stromal cells sensed nutritional signals and upregulated CXCL13 expression to recruit naive B cells. Furthermore, temporal fasting before oral immunization with ovalbumin abolished the induction of antigen-specific IgA, failed to induce oral tolerance, and eventually exacerbated food antigen-induced diarrhea. Thus, nutritional signals are critical in maintaining gut immune homeostasis. 10.1016/j.cell.2019.07.047
    A post-ingestive amino acid sensor promotes food consumption in Drosophila. Yang Zhe,Huang Rui,Fu Xin,Wang Gaohang,Qi Wei,Mao Decai,Shi Zhaomei,Shen Wei L,Wang Liming Cell research Adequate protein intake is crucial for the survival and well-being of animals. How animals assess prospective protein sources and ensure dietary amino acid intake plays a critical role in protein homeostasis. By using a quantitative feeding assay, we show that three amino acids, L-glutamate (L-Glu), L-alanine (L-Ala) and L-aspartate (L-Asp), but not their D-enantiomers or the other 17 natural L-amino acids combined, rapidly promote food consumption in the fruit fly Drosophila melanogaster. This feeding-promoting effect of dietary amino acids is independent of mating experience and internal nutritional status. In vivo and ex vivo calcium imagings show that six brain neurons expressing diuretic hormone 44 (DH44) can be rapidly and directly activated by these amino acids, suggesting that these neurons are an amino acid sensor. Genetic inactivation of DH44 neurons abolishes the increase in food consumption induced by dietary amino acids, whereas genetic activation of these neurons is sufficient to promote feeding, suggesting that DH44 neurons mediate the effect of dietary amino acids to promote food consumption. Single-cell transcriptome analysis and immunostaining reveal that a putative amino acid transporter, CG13248, is enriched in DH44 neurons. Knocking down CG13248 expression in DH44 neurons blocks the increase in food consumption and eliminates calcium responses induced by dietary amino acids. Therefore, these data identify DH44 neuron as a key sensor to detect amino acids and to enhance food intake via a putative transporter CG13248. These results shed critical light on the regulation of protein homeostasis at organismal levels by the nervous system. 10.1038/s41422-018-0084-9
    Pyruvate-Carboxylase-Mediated Anaplerosis Promotes Antioxidant Capacity by Sustaining TCA Cycle and Redox Metabolism in Liver. Cappel David A,Deja Stanisław,Duarte João A G,Kucejova Blanka,Iñigo Melissa,Fletcher Justin A,Fu Xiaorong,Berglund Eric D,Liu Tiemin,Elmquist Joel K,Hammer Suntrea,Mishra Prashant,Browning Jeffrey D,Burgess Shawn C Cell metabolism The hepatic TCA cycle supports oxidative and biosynthetic metabolism. This dual responsibility requires anaplerotic pathways, such as pyruvate carboxylase (PC), to generate TCA cycle intermediates necessary for biosynthesis without disrupting oxidative metabolism. Liver-specific PC knockout (LPCKO) mice were created to test the role of anaplerotic flux in liver metabolism. LPCKO mice have impaired hepatic anaplerosis, diminution of TCA cycle intermediates, suppressed gluconeogenesis, reduced TCA cycle flux, and a compensatory increase in ketogenesis and renal gluconeogenesis. Loss of PC depleted aspartate and compromised urea cycle function, causing elevated urea cycle intermediates and hyperammonemia. Loss of PC prevented diet-induced hyperglycemia and insulin resistance but depleted NADPH and glutathione, which exacerbated oxidative stress and correlated with elevated liver inflammation. Thus, despite catalyzing the synthesis of intermediates also produced by other anaplerotic pathways, PC is specifically necessary for maintaining oxidation, biosynthesis, and pathways distal to the TCA cycle, such as antioxidant defenses. 10.1016/j.cmet.2019.03.014