2'-Fucosyllactose helps butyrate producers outgrow competitors in infant gut microbiota simulations.

A reduced capacity for butyrate production by the early infant gut microbiota is associated with negative health effects, such as inflammation and the development of allergies. Here, we develop new hypotheses on the effect of the prebiotic galacto-oligosaccharides (GOS) or 2'-fucosyllactose (2'-FL) on butyrate production by the infant gut microbiota using a multiscale, spatiotemporal mathematical model of the infant gut. The model simulates a community of cross-feeding gut bacteria in metabolic detail. It represents the community as a grid of bacterial populations that exchange metabolites, using 20 different subspecies-specific metabolic networks taken from the AGORA database. The simulations predict that both GOS and 2'-FL promote the growth of Bifidobacterium, whereas butyrate producing bacteria are only consistently abundant in the presence of propane-1,2-diol, a product of 2'-FL metabolism. In absence of prebiotics or in presence of only GOS, however, Bacteroides vulgatus and Cutibacterium acnes outcompete butyrate producers by consuming intermediate metabolites.

E-DES-PROT: A novel computational model to describe the effects of amino acids and protein on postprandial glucose and insulin dynamics in humans.

Current computational models of whole-body glucose homeostasis describe physiological processes by which insulin regulates circulating glucose concentrations. While these models perform well in response to oral glucose challenges, interaction with other nutrients that impact postprandial glucose metabolism, such as amino acids (AAs), is not considered. Here, we developed a computational model of the human glucose-insulin system, which incorporates the effects of AAs on insulin secretion and hepatic glucose production. This model was applied to postprandial glucose and insulin time-series data following different AA challenges (with and without co-ingestion of glucose), dried milk protein ingredients, and dairy products. Our findings demonstrate that this model allows accurate description of postprandial glucose and insulin dynamics and provides insight into the physiological processes underlying meal responses. This model may facilitate the development of computational models that describe glucose homeostasis following the intake of multiple macronutrients, while capturing relevant features of an individual's metabolic health.

Thyroidal and Extrathyroidal Requirements for Iodine and Selenium: A Combined Evolutionary and (Patho)Physiological Approach.

Iodide is an antioxidant, oxidant and thyroid hormone constituent. Selenoproteins are needed for triiodothyronine synthesis, its deactivation and iodine release. They also protect thyroidal and extrathyroidal tissues from hydrogen peroxide used in the 'peroxidase partner system'. This system produces thyroid hormone and reactive iodine in exocrine glands to kill microbes. Exocrine glands recycle iodine and with high urinary clearance require constant dietary supply, unlike the thyroid. Disbalanced iodine-selenium explains relations between thyroid autoimmune disease (TAD) and cancer of thyroid and exocrine organs, notably stomach, breast, and prostate. Seafood is iodine unconstrained, but selenium constrained. Terrestrial food contains little iodine while selenium ranges from highly deficient to highly toxic. Iodine vs. TAD is U-shaped, but only low selenium relates to TAD. Oxidative stress from low selenium, and infection from disbalanced iodine-selenium, may generate cancer of thyroid and exocrine glands. Traditional Japanese diet resembles our ancient seashore-based diet and relates to aforementioned diseases. Adequate iodine might be in the milligram range but is toxic at low selenium. Optimal selenoprotein-P at 105 µg selenium/day agrees with Japanese intakes. Selenium upper limit may remain at 300-400 µg/day. Seafood combines iodine, selenium and other critical nutrients. It brings us back to the seashore diet that made us what we currently still are.

A Multiscale Spatiotemporal Model Including a Switch from Aerobic to Anaerobic Metabolism Reproduces Succession in the Early Infant Gut Microbiota.

The human intestinal microbiota starts to form immediately after birth and is important for the health of the host. During the first days, facultatively anaerobic bacterial species generally dominate, such as Enterobacteriaceae. These are succeeded by strictly anaerobic species, particularly Bifidobacterium species. An early transition to Bifidobacterium species is associated with health benefits; for example, Bifidobacterium species repress growth of pathogenic competitors and modulate the immune response. Succession to Bifidobacterium is thought to be due to consumption of intracolonic oxygen present in newborns by facultative anaerobes, including Enterobacteriaceae. To study if oxygen depletion suffices for the transition to Bifidobacterium species, here we introduced a multiscale mathematical model that considers metabolism, spatial bacterial population dynamics, and cross-feeding. Using publicly available metabolic network data from the AGORA collection, the model simulates ab initio the competition of strictly and facultatively anaerobic species in a gut-like environment under the influence of lactose and oxygen. The model predicts that individual differences in intracolonic oxygen in newborn infants can explain the observed individual variation in succession to anaerobic species, in particular Bifidobacterium species. Bifidobacterium species became dominant in the model by their use of the bifid shunt, which allows Bifidobacterium to switch to suboptimal yield metabolism with fast growth at high lactose concentrations, as predicted here using flux balance analysis. The computational model thus allows us to test the internal plausibility of hypotheses for bacterial colonization and succession in the infant colon. IMPORTANCE The composition of the infant microbiota has a great impact on infant health, but its controlling factors are still incompletely understood. The frequently dominant anaerobic Bifidobacterium species benefit health, e.g., they can keep harmful competitors under control and modulate the intestinal immune response. Controlling factors could include nutritional composition and intestinal mucus composition, as well as environmental factors, such as antibiotics. We introduce a modeling framework of a metabolically realistic intestinal microbial ecology in which hypothetical scenarios can be tested and compared. We present simulations that suggest that greater levels of intraintestinal oxygenation more strongly delay the dominance of Bifidobacterium species, explaining the observed variety of microbial composition and demonstrating the use of the model for hypothesis generation. The framework allowed us to test a variety of controlling factors, including intestinal mixing and transit time. Future versions will also include detailed modeling of oligosaccharide and mucin metabolism.

Healthy aging and muscle function are positively associated with NAD+ abundance in humans.

Skeletal muscle is greatly affected by aging, resulting in a loss of metabolic and physical function. However, the underlying molecular processes and how (lack of) physical activity is involved in age-related metabolic decline in muscle function in humans is largely unknown. Here, we compared, in a cross-sectional study, the muscle metabolome from young to older adults, whereby the older adults were exercise trained, had normal physical activity levels or were physically impaired. Nicotinamide adenine dinucleotide (NAD+) was one of the most prominent metabolites that was lower in older adults, in line with preclinical models. This lower level was even more pronounced in impaired older individuals, and conversely, exercise-trained older individuals had NAD+ levels that were more similar to those found in younger individuals. NAD+ abundance positively correlated with average number of steps per day and mitochondrial and muscle functioning. Our work suggests that a clear association exists between NAD+ and health status in human aging.

Effect of high compared with low dairy intake on blood pressure in overweight middle-aged adults: results of a randomized crossover intervention study.

BACKGROUND: Observational studies suggest that high dairy intake is associated with a lower blood pressure (BP). OBJECTIVE: We aimed to investigate the effect of a high-dairy diet (HDD) as compared with a low-dairy diet (LDD) on BP in overweight middle-aged adults. METHODS: Fifty-two overweight men and women were included in a randomized crossover intervention study. Each subject consumed 2 isocaloric diets for 6 wk, an LDD (≤1 dairy portion per day) and an HDD (6 or 5 reduced-fat dairy portions for men and women, respectively), with a 4-wk washout period in between the diets during which the subjects consumed their habitual diet. BP was measured at the start and at the end of the intervention diets. The effect of the intervention study was evaluated by 2-sample t tests. Mixed-model analyses were used for adjustment for the potential influence of changes in dietary protein and mineral intake and risk factors for hypertension including body weight and plasma cholesterol. RESULTS: Consumption of an HDD as compared with an LDD resulted in a reduction of both systolic BP (mean ± SD: 4.6 ± 11.2 mm Hg, P < 0.01) and diastolic BP (3.0 ± 6.7 mm Hg, P < 0.01). In further analyses, these reductions appeared dependent on the concomitant increase in calcium intake. CONCLUSIONS: This intervention study shows that an HDD results in a reduction of both systolic and diastolic BP in overweight middle-aged men and women. If the results of our study are reproduced by other studies, advice for high dairy intake may be added to treatment and prevention of high BP. This trial was registered at trialregister.nl as NTR4899.

The effect of high compared with low dairy consumption on glucose metabolism, insulin sensitivity, and metabolic flexibility in overweight adults: a randomized crossover trial.

BACKGROUND: Dairy products contain many nutritious components that may benefit metabolic health. There are indications that glucose metabolism and insulin sensitivity, which are generally disturbed in overweight and obese individuals, may improve by increased dairy intake. This may also affect one's metabolic flexibility. OBJECTIVE: The aim of this study was to investigate the effects of high compared with low dairy intake on glucose metabolism, insulin sensitivity, and metabolic flexibility in overweight adults (aged 45-65 y). METHODS: In this randomized intervention study, subjects consumed a high- and a low-dairy diet [HDD (5-6 dairy portions) and LDD (≤1 dairy portion), respectively] for 6 wk in a crossover design, with a washout period of 4 wk. Dairy portions were 200 g semi-skimmed yoghurt, 30 g reduced-fat (30+) cheese, and 250 mL semiskimmed milk and buttermilk. After 6 wk, a 75-g oral-glucose-tolerance test (13C-labeled) and a subsequent fasting challenge were performed. Metabolic flexibility was studied by determining the respiratory quotient (RQ) using indirect calorimetry. Fasting and postprandial plasma concentrations of glucose and insulin were analyzed. The dual isotope technique enabled calculation of glucose kinetics. RESULTS: The study was completed by 45 overweight men and postmenopausal women [age 58.9 ± 4.3 y, BMI 27.9 ± 1.9 kg/m2 (mean ± SD)]. Fasting RQ and ΔRQ, reflecting metabolic flexibility, did not differ after both diets. Fasting glucose concentrations were similar, whereas fasting insulin concentrations were lower after the LDD (LDD: 8.1 ± 2.8 mU/L; HDD: 8.9 ± 3.3 mU/L; P = 0.024). This resulted in a higher HOMA-IR after the HDD (P = 0.027). Postprandial glucose and insulin responses as well as glucose kinetics were similar after both diets. CONCLUSIONS: The amount of dairy intake during a 6-wk period had a neutral effect on metabolic flexibility or postprandial glucose metabolism in middle-aged overweight subjects. More trials are needed to study the effects of specific dairy types and to differentiate between metabolic subgroups. This trial was registered at trialregister.nl as NTR4899.

Combining chemoinformatics with bioinformatics: in silico prediction of bacterial flavor-forming pathways by a chemical systems biology approach "reverse pathway engineering".

The incompleteness of genome-scale metabolic models is a major bottleneck for systems biology approaches, which are based on large numbers of metabolites as identified and quantified by metabolomics. Many of the revealed secondary metabolites and/or their derivatives, such as flavor compounds, are non-essential in metabolism, and many of their synthesis pathways are unknown. In this study, we describe a novel approach, Reverse Pathway Engineering (RPE), which combines chemoinformatics and bioinformatics analyses, to predict the "missing links" between compounds of interest and their possible metabolic precursors by providing plausible chemical and/or enzymatic reactions. We demonstrate the added-value of the approach by using flavor-forming pathways in lactic acid bacteria (LAB) as an example. Established metabolic routes leading to the formation of flavor compounds from leucine were successfully replicated. Novel reactions involved in flavor formation, i.e. the conversion of alpha-hydroxy-isocaproate to 3-methylbutanoic acid and the synthesis of dimethyl sulfide, as well as the involved enzymes were successfully predicted. These new insights into the flavor-formation mechanisms in LAB can have a significant impact on improving the control of aroma formation in fermented food products. Since the input reaction databases and compounds are highly flexible, the RPE approach can be easily extended to a broad spectrum of applications, amongst others health/disease biomarker discovery as well as synthetic biology.

Nutrigenomics: the impact of biomics technology on nutrition research.

The interaction between the human body and nutrition is an extremely complex process involving multi-organ physiology with molecular mechanisms on all levels of regulation (genes, gene expression, proteins, metabolites). Only with the recent technology push have nutritional scientists been able to address this complexity. Both the challenges and promises that are offered by the merge of 'biomics' technologies and mechanistic nutrition research are huge, but will eventually evolve in a new nutrition research concept: nutritional systems biology. This review describes the principles and technologies involved in this merge. Using nutrition research examples, including gene expression modulation by carbohydrates and fatty acids, this review discusses applications as well as limitations of genomics, transcriptomics, proteomics, metabolomics, and systems biology. Furthermore, reference is made to gene polymorphisms that underlie individual differences in nutrient utilization, resulting in, e.g., different susceptibility to develop obesity.

The Lactococcus lactis CodY regulon: identification of a conserved cis-regulatory element.

CodY of Lactococcus lactis MG1363 is a transcriptional regulator that represses the expression of several genes encoding proteins of the proteolytic system. DNA microarray analysis, comparing the expression profiles of L. lactis MG1363 and an isogenic strain in which codY was mutated, was used to determine the CodY regulon. In peptide-rich medium and exponentially growing cells, where CodY exerts strong repressing activity, the expression of over 30 genes was significantly increased upon removal of codY. The differentially expressed genes included those predominantly involved in amino acid transport and metabolism. In addition, several genes belonging to other functional categories were derepressed, stressing the pleiotropic role of CodY. Scrutinizing the transcriptome data with bioinformatics tools revealed the presence of a novel over-represented motif in the upstream regions of several of the genes derepressed in L. lactis MG1363DeltacodY. Evidence is presented that this 15-bp cis-sequence, AATTTTCWGAAAATT, serves as a high affinity binding site for CodY, as shown by electrophoretic mobility shift assays and DNase I footprinting analyses. The presence of this CodY-box is sufficient to evoke CodY-mediated regulation in vivo. A copy of this motif is also present in the upstream region of codY itself. It is shown that CodY regulates its own synthesis and requires the CodY-box and branched-chain amino acids to interact with its promoter.

Identification of the PPARA locus on chromosome 22q13.3 as a modifier gene in familial combined hyperlipidemia.

Familial combined hyperlipidemia (FCHL) is a common genetic lipid disorder that is present in 10% of patients with premature coronary artery disease (CAD). It was the objective of the present study to evaluate the possible involvement of the PPARA locus in the pathophysiology of FCHL. Mutation detection analyses of the six coding PPARA exons resulted in the identification of four novel variants, [C/T] intron 3, S234G, [G/A] intron 5, and [C/A] 3(') UTR in three FCHL probands, whereas no novel variants were identified in spouses. In a case-control study, markers D22S275 and D22S928 were shown not to be associated with FCHL. However, D22S928, mapped within 1Mb of the PPARA gene, was shown to have a modifying effect on plasma apoCIII concentrations (P=0.011) and the combined hyperlipidemic FCHL phenotype (P=0.038). In addition two PPARA polymorphisms in intron 2 and 7 were studied, but these were not associated with FCHL. The frequency of the L162V variant was less in FCHL probands (1.98%) compared to that in spouses (4.84%). These results clearly demonstrate the genetically complex nature of FCHL and identify the PPARA gene as a modifier of the FCHL phenotype.

Identification of differentially expressed genes in subcutaneous adipose tissue from subjects with familial combined hyperlipidemia.

Subjects with familial combined hyperlipidemia (FCHL) are characterized by a complex metabolic phenotype with hyperlipidemia, insulin resistance, and central obesity. FCHL is due to impaired adipose tissue function superimposed on hepatic overproduction of lipoproteins. We investigated adipose tissue as an interesting target tissue for differential gene expression in FCHL. Human cDNA expression array analyses, in which adipose tissue from five FCHL patients was compared with that from four age, gender, and BMI matched controls, resulted in the identification of 22 up-regulated and three down-regulated genes. The genes differentially expressed imply activation of the adipocyte cell cycle genes. Furthermore, the differential expression of the genes coding for tumor necrosis factor alpha, interleukin 6, and intracellular adhesion molecule 1 support a role for adipose tissue in insulin resistance in FCHL subjects. The observed changes represent a primary genetic defect, an adaptive response, or a contribution of both.