Higher compared with lower dietary protein during an energy deficit combined with intense exercise promotes greater lean mass gain and fat mass loss: a randomized trial.
Longland Thomas M,Oikawa Sara Y,Mitchell Cameron J,Devries Michaela C,Phillips Stuart M
The American journal of clinical nutrition
BACKGROUND:A dietary protein intake higher than the Recommended Dietary Allowance during an energy deficit helps to preserve lean body mass (LBM), particularly when combined with exercise. OBJECTIVE:The purpose of this study was to conduct a proof-of-principle trial to test whether manipulation of dietary protein intake during a marked energy deficit in addition to intense exercise training would affect changes in body composition. DESIGN:We used a single-blind, randomized, parallel-group prospective trial. During a 4-wk period, we provided hypoenergetic (~40% reduction compared with requirements) diets providing 33 ± 1 kcal/kg LBM to young men who were randomly assigned (n = 20/group) to consume either a lower-protein (1.2 g · kg(-1) · d(-1)) control diet (CON) or a higher-protein (2.4 g · kg(-1) · d(-1)) diet (PRO). All subjects performed resistance exercise training combined with high-intensity interval training for 6 d/wk. A 4-compartment model assessment of body composition was made pre- and postintervention. RESULTS:As a result of the intervention, LBM increased (P < 0.05) in the PRO group (1.2 ± 1.0 kg) and to a greater extent (P < 0.05) compared with the CON group (0.1 ± 1.0 kg). The PRO group had a greater loss of fat mass than did the CON group (PRO: -4.8 ± 1.6 kg; CON: -3.5 ± 1.4kg; P < 0.05). All measures of exercise performance improved similarly in the PRO and CON groups as a result of the intervention with no effect of protein supplementation. Changes in serum cortisol during the intervention were associated with changes in body fat (r = 0.39, P = 0.01) and LBM (r = -0.34, P = 0.03). CONCLUSIONS:Our results showed that, during a marked energy deficit, consumption of a diet containing 2.4 g protein · kg(-1) · d(-1) was more effective than consumption of a diet containing 1.2 g protein · kg(-1) · d(-1) in promoting increases in LBM and losses of fat mass when combined with a high volume of resistance and anaerobic exercise. Changes in serum cortisol were associated with changes in body fat and LBM, but did not explain much variance in either measure. This trial was registered at clinicaltrials.gov as NCT01776359.
Prevotella-to-Bacteroides ratio predicts body weight and fat loss success on 24-week diets varying in macronutrient composition and dietary fiber: results from a post-hoc analysis.
Hjorth Mads F,Blædel Trine,Bendtsen Line Q,Lorenzen Janne K,Holm Jacob B,Kiilerich Pia,Roager Henrik M,Kristiansen Karsten,Larsen Lesli H,Astrup Arne
International journal of obesity (2005)
BACKGROUND/OBJECTIVES:Individuals with high pre-treatment bacterial Prevotella-to-Bacteroides (P/B) ratio have been reported to lose more body weight on diets high in fiber than subjects with a low P/B ratio. Therefore, the aim of the present study was to examine potential differences in dietary weight loss responses between participants with low and high P/B. SUBJECTS/METHODS:Eighty overweight participants were randomized (52 completed) to a 500 kcal/d energy deficit diet with a macronutrient composition of 30 energy percentage (E%) fat, 52 E% carbohydrate and 18 E% protein either high (≈1500 mg calcium/day) or low ( ≤ 600 mg calcium/day) in dairy products for 24 weeks. Body weight, body fat, and dietary intake (by 7-day dietary records) were determined. Individuals were dichotomized according to their pre-treatment P/B ratio derived from 16S rRNA gene sequencing of collected fecal samples to test the potential modification of dietary effects using linear mixed models. RESULTS:Independent of the randomized diets, individuals with high P/B lost 3.8 kg (95%CI, 1.8,5.8; P < 0.001) more body weight and 3.8 kg (95% CI, 1.1, 6.5; P = 0.005) more body fat compared to individuals with low P/B. After adjustment for multiple covariates, individuals with high P/B ratio lost 8.3 kg (95% CI, 5.8;10.9, P < 0.001) more body weight when consuming above compared to below 30 g fiber/10MJ whereas this weight loss was 3.2 kg (95% CI, 0.8;5.5, P = 0.008) among individuals with low P/B ratio [Mean difference: 5.1 kg (95% CI, 1.7;8.6, P = 0.003)]. Partial correlation coefficients between fiber intake and weight change was 0.90 (P < 0.001) among individuals with high P/B ratio and 0.25 (P = 0.29) among individuals with low P/B ratio. CONCLUSIONS:Individuals with high P/B lost more body weight and body fat compared to individuals with low P/B, confirming that individuals with a high P/B are more susceptible to weight loss on a diet rich in fiber.
Innovation: Metabolomics: the apogee of the omics trilogy.
Patti Gary J,Yanes Oscar,Siuzdak Gary
Nature reviews. Molecular cell biology
Metabolites, the chemical entities that are transformed during metabolism, provide a functional readout of cellular biochemistry. With emerging technologies in mass spectrometry, thousands of metabolites can now be quantitatively measured from minimal amounts of biological material, which has thereby enabled systems-level analyses. By performing global metabolite profiling, also known as untargeted metabolomics, new discoveries linking cellular pathways to biological mechanism are being revealed and are shaping our understanding of cell biology, physiology and medicine.
Effects of Combined High-Protein Diet and Exercise Intervention on Cardiometabolic Health in Middle-Aged Obese Adults: A Randomized Controlled Trial.
Chen Chiao-Nan,Hsu Kuo-Jen,Chien Kuei-Yu,Chen Jeu-Jung
Frontiers in cardiovascular medicine
Obesity is the main risk factor of cardiovascular diseases (CVD) and metabolic diseases. The middle-aged population is the age group with the highest prevalence of obesity. Thus, improving cardiometabolic health is important to prevent CVD and metabolic diseases in middle-aged obese adults. The aim of this study was to examine the effects of exercise alone or in combination with a high-protein diet on markers of cardiometabolic health in middle-aged adults with obesity. Sixty-nine middle-aged adults with obesity were assigned randomly to the control group (C; = 23), exercise group (E; = 23), or exercise combined with high-protein diet group (EP; = 23). Individuals in the E and EP groups received supervised exercise training and individuals in the EP group received high-protein diet intervention. Body composition (assessed by dual-energy X-ray absorptiometry), oral glucose tolerance test (OGTT), lipid profiles, and inflammatory markers were determined before and after 12 weeks of intervention. Insulin sensitivity index (ISI) was calculated from values of fasting and 2-h insulin and glucose concentration of OGTT. Insulin-peak-time during the OGTT was recorded to reflect β-cell function. Analysis of covariance with baseline values as covariates was used to examine the effects of the intervention. The significant level was set at 0.05. After 12 weeks of intervention, the E group had a greater percentage of individuals with early insulin-peak-time during the OGTT than that in the C and EP groups ( = 0.031). EP group had lower total cholesterol and triglycerides than that in the C group ( = 0.046 and 0.014, respectively). Within-group comparisons showed that the 2-h glucose of OGTT and C-reactive protein decreased in the EP group ( = 0.013 and 0.008, respectively) but not in the E and C groups; insulin sensitivity improved in the EP group ( = 0.016) and had a trend to improve in the E group ( = 0.052); and abdominal fat mass and total body fat mass decreased in both intervention groups ( < 0.05). Combined high-protein diet and exercise intervention significantly decreased fat mass and improved lipid profiles, insulin sensitivity, glucose tolerance, and inflammation in middle-aged adults with obesity. Thai Clinical Trials Registry, TCTR20180913003, 13-09-2018.
Overweight, obesity, and risk of cardiometabolic multimorbidity: pooled analysis of individual-level data for 120 813 adults from 16 cohort studies from the USA and Europe.
Kivimäki Mika,Kuosma Eeva,Ferrie Jane E,Luukkonen Ritva,Nyberg Solja T,Alfredsson Lars,Batty G David,Brunner Eric J,Fransson Eleonor,Goldberg Marcel,Knutsson Anders,Koskenvuo Markku,Nordin Maria,Oksanen Tuula,Pentti Jaana,Rugulies Reiner,Shipley Martin J,Singh-Manoux Archana,Steptoe Andrew,Suominen Sakari B,Theorell Töres,Vahtera Jussi,Virtanen Marianna,Westerholm Peter,Westerlund Hugo,Zins Marie,Hamer Mark,Bell Joshua A,Tabak Adam G,Jokela Markus
The Lancet. Public health
BACKGROUND:Although overweight and obesity have been studied in relation to individual cardiometabolic diseases, their association with risk of cardiometabolic multimorbidity is poorly understood. Here we aimed to establish the risk of incident cardiometabolic multimorbidity (ie, at least two from: type 2 diabetes, coronary heart disease, and stroke) in adults who are overweight and obese compared with those who are a healthy weight. METHODS:We pooled individual-participant data for BMI and incident cardiometabolic multimorbidity from 16 prospective cohort studies from the USA and Europe. Participants included in the analyses were 35 years or older and had data available for BMI at baseline and for type 2 diabetes, coronary heart disease, and stroke at baseline and follow-up. We excluded participants with a diagnosis of diabetes, coronary heart disease, or stroke at or before study baseline. According to WHO recommendations, we classified BMI into categories of healthy (20·0-24·9 kg/m), overweight (25·0-29·9 kg/m), class I (mild) obesity (30·0-34·9 kg/m), and class II and III (severe) obesity (≥35·0 kg/m). We used an inclusive definition of underweight (<20 kg/m) to achieve sufficient case numbers for analysis. The main outcome was cardiometabolic multimorbidity (ie, developing at least two from: type 2 diabetes, coronary heart disease, and stroke). Incident cardiometabolic multimorbidity was ascertained via resurvey or linkage to electronic medical records (including hospital admissions and death). We analysed data from each cohort separately using logistic regression and then pooled cohort-specific estimates using random-effects meta-analysis. FINDINGS:Participants were 120 813 adults (mean age 51·4 years, range 35-103; 71 445 women) who did not have diabetes, coronary heart disease, or stroke at study baseline (1973-2012). During a mean follow-up of 10·7 years (1995-2014), we identified 1627 cases of multimorbidity. After adjustment for sociodemographic and lifestyle factors, compared with individuals with a healthy weight, the risk of developing cardiometabolic multimorbidity in overweight individuals was twice as high (odds ratio [OR] 2·0, 95% CI 1·7-2·4; p<0·0001), almost five times higher for individuals with class I obesity (4·5, 3·5-5·8; p<0·0001), and almost 15 times higher for individuals with classes II and III obesity combined (14·5, 10·1-21·0; p<0·0001). This association was noted in men and women, young and old, and white and non-white participants, and was not dependent on the method of exposure assessment or outcome ascertainment. In analyses of different combinations of cardiometabolic conditions, odds ratios associated with classes II and III obesity were 2·2 (95% CI 1·9-2·6) for vascular disease only (coronary heart disease or stroke), 12·0 (8·1-17·9) for vascular disease followed by diabetes, 18·6 (16·6-20·9) for diabetes only, and 29·8 (21·7-40·8) for diabetes followed by vascular disease. INTERPRETATION:The risk of cardiometabolic multimorbidity increases as BMI increases; from double in overweight people to more than ten times in severely obese people compared with individuals with a healthy BMI. Our findings highlight the need for clinicians to actively screen for diabetes in overweight and obese patients with vascular disease, and pay increased attention to prevention of vascular disease in obese individuals with diabetes. FUNDING:NordForsk, Medical Research Council, Cancer Research UK, Finnish Work Environment Fund, and Academy of Finland.
Obesity, inflammation, and liver cancer.
Sun Beicheng,Karin Michael
Journal of hepatology
Obesity has become a universal and major public health problem with increasing prevalence in both adults and children in the 21st century, even in developing countries. Extensive epidemiological studies reveal a strong link between obesity and development and progression of various types of cancers. The connection between obesity and liver cancer is particularly strong and obesity often results in liver diseases such as non-alcoholic fatty liver disease (NAFLD) and the more severe non-alcoholic steatohepatitis (NASH). NASH is characterized by fatty liver inflammation and is believed to cause fibrosis and cirrhosis. The latter is a known liver cancer risk factor. In fact due to its much higher prevalence obesity may be a more substantial contributor to overall hepatocellular carcinoma burden than infection with hepatitis viruses. Here we review and discuss recent advances in elucidation of cellular and molecular alterations and signaling pathways associated with obesity and liver inflammation and their contribution to hepatocarcinogenesis.
Gut Bifidobacteria Populations in Human Health and Aging.
Arboleya Silvia,Watkins Claire,Stanton Catherine,Ross R Paul
Frontiers in microbiology
The intestinal microbiota has increasingly been shown to have a vital role in various aspects of human health. Indeed, several studies have linked alterations in the gut microbiota with the development of different diseases. Among the vast gut bacterial community, Bifidobacterium is a genus which dominates the intestine of healthy breast-fed infants whereas in adulthood the levels are lower but relatively stable. The presence of different species of bifidobacteria changes with age, from childhood to old age. Bifidobacterium longum, B. breve, and B. bifidum are generally dominant in infants, whereas B. catenulatum, B. adolescentis and, as well as B. longum are more prevalent in adults. Increasingly, evidence is accumulating which shows beneficial effects of supplementation with bifidobacteria for the improvement of human health conditions ranging from protection against infection to different extra- and intra-intestinal positive effects. Moreover, bifidobacteria have been associated with the production of a number of potentially health promoting metabolites including short chain fatty acids, conjugated linoleic acid and bacteriocins. The aim of this mini-review is to describe the bifidobacteria compositional changes associated with different stages in life, highlighting their beneficial role, as well as their presence or absence in many disease states.
Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells.
Furusawa Yukihiro,Obata Yuuki,Fukuda Shinji,Endo Takaho A,Nakato Gaku,Takahashi Daisuke,Nakanishi Yumiko,Uetake Chikako,Kato Keiko,Kato Tamotsu,Takahashi Masumi,Fukuda Noriko N,Murakami Shinnosuke,Miyauchi Eiji,Hino Shingo,Atarashi Koji,Onawa Satoshi,Fujimura Yumiko,Lockett Trevor,Clarke Julie M,Topping David L,Tomita Masaru,Hori Shohei,Ohara Osamu,Morita Tatsuya,Koseki Haruhiko,Kikuchi Jun,Honda Kenya,Hase Koji,Ohno Hiroshi
Gut commensal microbes shape the mucosal immune system by regulating the differentiation and expansion of several types of T cell. Clostridia, a dominant class of commensal microbe, can induce colonic regulatory T (Treg) cells, which have a central role in the suppression of inflammatory and allergic responses. However, the molecular mechanisms by which commensal microbes induce colonic Treg cells have been unclear. Here we show that a large bowel microbial fermentation product, butyrate, induces the differentiation of colonic Treg cells in mice. A comparative NMR-based metabolome analysis suggests that the luminal concentrations of short-chain fatty acids positively correlates with the number of Treg cells in the colon. Among short-chain fatty acids, butyrate induced the differentiation of Treg cells in vitro and in vivo, and ameliorated the development of colitis induced by adoptive transfer of CD4(+) CD45RB(hi) T cells in Rag1(-/-) mice. Treatment of naive T cells under the Treg-cell-polarizing conditions with butyrate enhanced histone H3 acetylation in the promoter and conserved non-coding sequence regions of the Foxp3 locus, suggesting a possible mechanism for how microbial-derived butyrate regulates the differentiation of Treg cells. Our findings provide new insight into the mechanisms by which host-microbe interactions establish immunological homeostasis in the gut.
Introducing mothur: open-source, platform-independent, community-supported software for describing and comparing microbial communities.
Schloss Patrick D,Westcott Sarah L,Ryabin Thomas,Hall Justine R,Hartmann Martin,Hollister Emily B,Lesniewski Ryan A,Oakley Brian B,Parks Donovan H,Robinson Courtney J,Sahl Jason W,Stres Blaz,Thallinger Gerhard G,Van Horn David J,Weber Carolyn F
Applied and environmental microbiology
mothur aims to be a comprehensive software package that allows users to use a single piece of software to analyze community sequence data. It builds upon previous tools to provide a flexible and powerful software package for analyzing sequencing data. As a case study, we used mothur to trim, screen, and align sequences; calculate distances; assign sequences to operational taxonomic units; and describe the alpha and beta diversity of eight marine samples previously characterized by pyrosequencing of 16S rRNA gene fragments. This analysis of more than 222,000 sequences was completed in less than 2 h with a laptop computer.
UniFrac: a new phylogenetic method for comparing microbial communities.
Lozupone Catherine,Knight Rob
Applied and environmental microbiology
We introduce here a new method for computing differences between microbial communities based on phylogenetic information. This method, UniFrac, measures the phylogenetic distance between sets of taxa in a phylogenetic tree as the fraction of the branch length of the tree that leads to descendants from either one environment or the other, but not both. UniFrac can be used to determine whether communities are significantly different, to compare many communities simultaneously using clustering and ordination techniques, and to measure the relative contributions of different factors, such as chemistry and geography, to similarities between samples. We demonstrate the utility of UniFrac by applying it to published 16S rRNA gene libraries from cultured isolates and environmental clones of bacteria in marine sediment, water, and ice. Our results reveal that (i) cultured isolates from ice, water, and sediment resemble each other and environmental clone sequences from sea ice, but not environmental clone sequences from sediment and water; (ii) the geographical location does not correlate strongly with bacterial community differences in ice and sediment from the Arctic and Antarctic; and (iii) bacterial communities differ between terrestrially impacted seawater (whether polar or temperate) and warm oligotrophic seawater, whereas those in individual seawater samples are not more similar to each other than to those in sediment or ice samples. These results illustrate that UniFrac provides a new way of characterizing microbial communities, using the wealth of environmental rRNA sequences, and allows quantitative insight into the factors that underlie the distribution of lineages among environments.
Microbiome, trimethylamine N-oxide, and cardiometabolic disease.
Tang W H Wilson,Hazen Stanley L
Translational research : the journal of laboratory and clinical medicine
There is increasing appreciation that changes in microbiome composition and function can promote long-term susceptibility for cardiometabolic risk. Gut microbe-derived metabolites that are biologically active, such as trimethylamine N-oxide (TMAO), are now recognized as contributors to atherogenesis. This review summarizes our current understanding of the role of TMAO in the pathogenesis of cardiometabolic diseases and will discuss current findings, controversies, and further perspectives in this new area of investigation. Better appreciation of the interactions between dietary nutrient intake with gut microbiota-mediated metabolism may provide clinical insights into defining individuals at risk for disease progression in cardiometabolic diseases, as well as additional potential therapeutic targets for reducing risks for cardiometabolic disease progression.
Human insulin resistance is associated with increased plasma levels of 12α-hydroxylated bile acids.
Haeusler Rebecca A,Astiarraga Brenno,Camastra Stefania,Accili Domenico,Ferrannini Ele
Bile acids (BAs) exert pleiotropic metabolic effects, and physicochemical properties of different BAs affect their function. In rodents, insulin regulates BA composition, in part by regulating the BA 12α-hydroxylase CYP8B1. However, it is unclear whether a similar effect occurs in humans. To address this question, we examined the relationship between clamp-measured insulin sensitivity and plasma BA composition in a cohort of 200 healthy subjects and 35 type 2 diabetic (T2D) patients. In healthy subjects, insulin resistance (IR) was associated with increased 12α-hydroxylated BAs (cholic acid, deoxycholic acid, and their conjugated forms). Furthermore, ratios of 12α-hydroxylated/non-12α-hydroxylated BAs were associated with key features of IR, including higher insulin, proinsulin, glucose, glucagon, and triglyceride (TG) levels and lower HDL cholesterol. In T2D patients, BAs were nearly twofold elevated, and more hydrophobic, compared with healthy subjects, although we did not observe disproportionate increases in 12α-hydroxylated BAs. In multivariate analysis of the whole dataset, controlling for sex, age, BMI, and glucose tolerance status, higher 12α-hydroxy/non-12α-hydroxy BA ratios were associated with lower insulin sensitivity and higher plasma TGs. These findings suggest a role for 12α-hydroxylated BAs in metabolic abnormalities in the natural history of T2D and raise the possibility of developing insulin-sensitizing therapeutics based on manipulations of BA composition.
Plasma bile acids show a positive correlation with body mass index and are negatively associated with cognitive restraint of eating in obese patients.
Prinz Philip,Hofmann Tobias,Ahnis Anne,Elbelt Ulf,Goebel-Stengel Miriam,Klapp Burghard F,Rose Matthias,Stengel Andreas
Frontiers in neuroscience
Bile acids may be involved in the regulation of food intake and energy metabolism. The aim of the study was to investigate the association of plasma bile acids with body mass index (BMI) and the possible involvement of circulating bile acids in the modulation of physical activity and eating behavior. Blood was obtained in a group of hospitalized patients with normal weight (BMI 18.5-25 kg/m(2)), underweight (anorexia nervosa, BMI < 17.5 kg/m(2)) and overweight (obesity with BMI 30-40, 40-50 and >50 kg/m(2), n = 14-15/group) and plasma bile acid concentrations assessed. Physical activity and plasma bile acids were measured in a group of patients with anorexia nervosa (BMI 14.6 ± 0.3 kg/m(2), n = 43). Lastly, in a population of obese patients (BMI 48.5 ± 0.9 kg/m(2), n = 85), psychometric parameters related to disordered eating and plasma bile acids were assessed. Plasma bile acids showed a positive correlation with BMI (r = 0.26, p = 0.03) in the population of patients with broad range of BMI (9-85 kg/m(2), n = 74). No associations were observed between plasma bile acids and different parameters of physical activity in anorexic patients (p > 0.05). Plasma bile acids were negatively correlated with cognitive restraint of eating (r = -0.30, p = 0.008), while no associations were observed with other psychometric eating behavior-related parameters (p > 0.05) in obese patients. In conclusion, these data may point toward a role of bile acids in the regulation of body weight. Since plasma bile acids are negatively correlated with the cognitive restraint of eating in obese patients, this may represent a compensatory adaptation to prevent further overeating.
Benefits of polyphenols on gut microbiota and implications in human health.
Cardona Fernando,Andrés-Lacueva Cristina,Tulipani Sara,Tinahones Francisco J,Queipo-Ortuño María Isabel
The Journal of nutritional biochemistry
The biological properties of dietary polyphenols are greatly dependent on their bioavailability that, in turn, is largely influenced by their degree of polymerization. The gut microbiota play a key role in modulating the production, bioavailability and, thus, the biological activities of phenolic metabolites, particularly after the intake of food containing high-molecular-weight polyphenols. In addition, evidence is emerging on the activity of dietary polyphenols on the modulation of the colonic microbial population composition or activity. However, although the great range of health-promoting activities of dietary polyphenols has been widely investigated, their effect on the modulation of the gut ecology and the two-way relationship "polyphenols ↔ microbiota" are still poorly understood. Only a few studies have examined the impact of dietary polyphenols on the human gut microbiota, and most were focused on single polyphenol molecules and selected bacterial populations. This review focuses on the reciprocal interactions between the gut microbiota and polyphenols, the mechanisms of action and the consequences of these interactions on human health.
Branched-chain amino acid levels are associated with improvement in insulin resistance with weight loss.
Shah S H,Crosslin D R,Haynes C S,Nelson S,Turer C B,Stevens R D,Muehlbauer M J,Wenner B R,Bain J R,Laferrère B,Gorroochurn P,Teixeira J,Brantley P J,Stevens V J,Hollis J F,Appel L J,Lien L F,Batch B,Newgard C B,Svetkey L P
AIMS/HYPOTHESIS:Insulin resistance (IR) improves with weight loss, but this response is heterogeneous. We hypothesised that metabolomic profiling would identify biomarkers predicting changes in IR with weight loss. METHODS:Targeted mass spectrometry-based profiling of 60 metabolites, plus biochemical assays of NEFA, β-hydroxybutyrate, ketones, insulin and glucose were performed in baseline and 6 month plasma samples from 500 participants who had lost ≥4 kg during Phase I of the Weight Loss Maintenance (WLM) trial. Homeostatic model assessment of insulin resistance (HOMA-IR) and change in HOMA-IR with weight loss (∆HOMA-IR) were calculated. Principal components analysis (PCA) and mixed models adjusted for race, sex, baseline weight, and amount of weight loss were used; findings were validated in an independent cohort of patients (n = 22). RESULTS:Mean weight loss was 8.67 ± 4.28 kg; mean ∆HOMA-IR was -0.80 ± 1.73, range -28.9 to 4.82). Baseline PCA-derived factor 3 (branched chain amino acids [BCAAs] and associated catabolites) correlated with baseline HOMA-IR (r = 0.50, p < 0.0001) and independently associated with ∆HOMA-IR (p < 0.0001). ∆HOMA-IR increased in a linear fashion with increasing baseline factor 3 quartiles. Amount of weight loss was only modestly correlated with ∆HOMA-IR (r = 0.24). These findings were validated in the independent cohort, with a factor composed of BCAAs and related metabolites predicting ∆HOMA-IR (p = 0.007). CONCLUSIONS/INTERPRETATION:A cluster of metabolites comprising BCAAs and related analytes predicts improvement in HOMA-IR independent of the amount of weight lost. These results may help identify individuals most likely to benefit from moderate weight loss and elucidate novel mechanisms of IR in obesity.
Adiposity, gut microbiota and faecal short chain fatty acids are linked in adult humans.
Fernandes J,Su W,Rahat-Rozenbloom S,Wolever T M S,Comelli E M
Nutrition & diabetes
BACKGROUND/OBJECTIVES:High dietary fibre intakes may protect against obesity by influencing colonic fermentation and the colonic microbiota. Though, recent studies suggest that increased colonic fermentation contributes to adiposity. Diet influences the composition of the gut microbiota. Previous research has not evaluated dietary intakes, body mass index (BMI), faecal microbiota and short chain fatty acid (SCFA) in the same cohort. Our objectives were to compare dietary intakes, faecal SCFA concentrations and gut microbial profiles in healthy lean (LN, BMI⩽25) and overweight or obese (OWOB, BMI>25) participants. DESIGN:We collected demographic information, 3-day diet records, physical activity questionnaires and breath and faecal samples from 94 participants of whom 52 were LN and 42 OWOB. RESULTS:Dietary intakes and physical activity levels did not differ significantly between groups. OWOB participants had higher faecal acetate (P=0.05), propionate (P=0.03), butyrate (P=0.05), valerate (P=0.03) and total short chain fatty acid (SCFA; P=0.02) concentrations than LN. No significant differences in Firmicutes to Bacteroides/Prevotella (F:B) ratio was observed between groups. However, in the entire cohort, Bacteroides/Prevotella counts were negatively correlated with faecal total SCFA (r=-0.32, P=0.002) and F:B ratio was positively correlated with faecal total SCFA (r=0.42, P<0.0001). Principal component analysis identified distinct gut microbiota and SCFA-F:B ratio components, which together accounted for 59% of the variation. F:B ratio loaded with the SCFA and not with the microbiota suggesting that SCFA and F:B ratio vary together and may be interrelated. CONCLUSIONS:The results support the hypothesis that colonic fermentation patterns may be altered, leading to different faecal SCFA concentrations in OWOB compared with LN humans. More in-depth studies looking at the metabolic fate of SCFA produced in LN and OWOB participants are needed in order to determine the role of SCFA in obesity.
Gut Microbes and Health: A Focus on the Mechanisms Linking Microbes, Obesity, and Related Disorders.
Rastelli Marialetizia,Knauf Claude,Cani Patrice D
Obesity (Silver Spring, Md.)
The past decade has been characterized by tremendous progress in the field of the gut microbiota and its impact on host metabolism. Although numerous studies show a strong relationship between the composition of gut microbiota and specific metabolic disorders associated with obesity, the key mechanisms are still being studied. The present review focuses on specific complex pathways as well as key interactions. For instance, the nervous routes are explored by examining the enteric nervous system, the vagus nerve, and the brain, as well as the endocrine routes (i.e., glucagon-like peptide-1, peptide YY, endocannabinoids) by which gut microbes communicate with the host. Moreover, the key metabolites involved in such specific interactions (e.g., short chain fatty acids, bile acids, neurotransmitters) as well as their targets (i.e., receptors, cell types, and organs) are briefly discussed. Finally, the review highlights the role of metabolic endotoxemia in the onset of metabolic disorders and the implications for alterations in gut microbiota-host interactions and ultimately the onset of diseases.
Gut Microbiota in Obesity and Metabolic Abnormalities: A Matter of Composition or Functionality?
Moran-Ramos Sofia,López-Contreras Blanca E,Canizales-Quinteros Samuel
Archives of medical research
The obesity pandemic and the metabolic complications derived from it represent a major public health challenge worldwide. Although obesity is a multifactorial disease, research from the past decade suggests that the gut microbiota interacts with host genetics and diet, as well as with other environmental factors, and thus contributes to the development of obesity and related complications. Despite abundant research on animal models, substantial evidence from humans has only started to accumulate over the past few years. Thus, the aim of the present review is to discuss structural and functional characteristics of the gut microbiome in human obesity, challenges associated with multi-omic technologies, and advances in identifying microbial metabolites with a direct link to obesity and metabolic complications. To date, studies suggests that obesity is related to low microbial diversity and taxon depletion sometimes resulting from an interaction with host dietary habits and genotype. These findings support the idea that the depletion or absence of certain taxa leaves an empty niche, likely leading to compromised functionality and thus promoting dysbiosis. Although the role of altered gut microbiota as cause or consequence of obesity remains controversial, research on microbial genomes and metabolites points towards an increased extraction of energy from the diet in obesity and suggests that metabolites, such as trimethylamine-N-oxide or branched-chain amino acids, participate in metabolic complications. Future research should be focused on structural and functional levels to unravel the mechanism linking gut microbiota and obesity.
Meta-analyses of human gut microbes associated with obesity and IBD.
Walters William A,Xu Zech,Knight Rob
Recent studies have linked human gut microbes to obesity and inflammatory bowel disease, but consistent signals have been difficult to identify. Here we test for indicator taxa and general features of the microbiota that are generally consistent across studies of obesity and of IBD, focusing on studies involving high-throughput sequencing of the 16S rRNA gene (which we could process using a common computational pipeline). We find that IBD has a consistent signature across studies and allows high classification accuracy of IBD from non-IBD subjects, but that although subjects can be classified as lean or obese within each individual study with statistically significant accuracy, consistent with the ability of the microbiota to experimentally transfer this phenotype, signatures of obesity are not consistent between studies even when the data are analyzed with consistent methods. The results suggest that correlations between microbes and clinical conditions with different effect sizes (e.g. the large effect size of IBD versus the small effect size of obesity) may require different cohort selection and analysis strategies.
A taxonomic signature of obesity in the microbiome? Getting to the guts of the matter.
Finucane Mariel M,Sharpton Thomas J,Laurent Timothy J,Pollard Katherine S
Obesity is an important and intractable public health problem. In addition to the well-known risk factors of behavior, diet, and genetics, gut microbial communities were recently identified as another possible source of risk and a potential therapeutic target. However, human and animal-model studies have yielded conflicting results about the precise nature of associations between microbiome composition and obesity. In this paper, we use publicly available data from the Human Microbiome Project (HMP) and MetaHIT, both surveys of healthy adults that include obese individuals, plus two smaller studies that specifically examined lean versus obese adults. We find that inter-study variability in the taxonomic composition of stool microbiomes far exceeds differences between lean and obese individuals within studies. Our analyses further reveal a high degree of variability in stool microbiome composition and diversity across individuals. While we confirm the previously published small, but statistically significant, differences in phylum-level taxonomic composition between lean and obese individuals in several cohorts, we find no association between BMI and taxonomic composition of stool microbiomes in the larger HMP and MetaHIT datasets. We explore a range of different statistical techniques and show that this result is robust to the choice of methodology. Differences between studies are likely due to a combination of technical and clinical factors. We conclude that there is no simple taxonomic signature of obesity in the microbiota of the human gut.
Looking for a Signal in the Noise: Revisiting Obesity and the Microbiome.
Sze Marc A,Schloss Patrick D
UNLABELLED:Two recent studies have reanalyzed previously published data and found that when data sets were analyzed independently, there was limited support for the widely accepted hypothesis that changes in the microbiome are associated with obesity. This hypothesis was reconsidered by increasing the number of data sets and pooling the results across the individual data sets. The preferred reporting items for systematic reviews and meta-analyses guidelines were used to identify 10 studies for an updated and more synthetic analysis. Alpha diversity metrics and the relative risk of obesity based on those metrics were used to identify a limited number of significant associations with obesity; however, when the results of the studies were pooled by using a random-effect model, significant associations were observed among Shannon diversity, the number of observed operational taxonomic units, Shannon evenness, and obesity status. They were not observed for the ratio of Bacteroidetes and Firmicutes or their individual relative abundances. Although these tests yielded small P values, the difference between the Shannon diversity indices of nonobese and obese individuals was 2.07%. A power analysis demonstrated that only one of the studies had sufficient power to detect a 5% difference in diversity. When random forest machine learning models were trained on one data set and then tested by using the other nine data sets, the median accuracy varied between 33.01 and 64.77% (median, 56.68%). Although there was support for a relationship between the microbial communities found in human feces and obesity status, this association was relatively weak and its detection is confounded by large interpersonal variation and insufficient sample sizes. IMPORTANCE:As interest in the human microbiome grows, there is an increasing number of studies that can be used to test numerous hypotheses across human populations. The hypothesis that variation in the gut microbiota can explain or be used to predict obesity status has received considerable attention and is frequently mentioned as an example of the role of the microbiome in human health. Here we assessed this hypothesis by using 10 independent studies and found that although there is an association, it is smaller than can be detected by most microbiome studies. Furthermore, we directly tested the ability to predict obesity status on the basis of the composition of an individual's microbiome and found that the median classification accuracy is between 33.01 and 64.77%. This type of analysis can be used to design future studies and expanded to explore other hypotheses.
Metagenomic sequencing of the human gut microbiome before and after bariatric surgery in obese patients with type 2 diabetes: correlation with inflammatory and metabolic parameters.
Graessler J,Qin Y,Zhong H,Zhang J,Licinio J,Wong M-L,Xu A,Chavakis T,Bornstein A B,Ehrhart-Bornstein M,Lamounier-Zepter V,Lohmann T,Wolf T,Bornstein S R
The pharmacogenomics journal
Roux-en-Y gastric bypass (RYGB) has become a prominent therapeutic option for long-term treatment of morbid obesity and type 2 diabetes mellitus (T2D). Cross talk and pathogenetic consequences of RYGB-induced profound effects on metabolism and gut microbiome are poorly understood. The aim of the present study therefore was to characterize intra-individual changes of gut microbial composition before and 3 months after RYGB by metagenomic sequencing in morbidly obese patients (body mass index (BMI)>40 kg m(-)(2)) with T2D. Subsequently, metagenomic data were correlated with clinical indices. Based on gene relative abundance profile, 1061 species, 729 genera, 44 phyla and 5127 KO (KEGG Orthology) were identified. Despite high diversity, bacteria could mostly be assigned to seven bacterial divisions. The overall metagenomic RYGB-induced shift was characterized by a reduction of Firmicutes and Bacteroidetes and an increase of Proteobacteria. Twenty-two microbial species and 11 genera were significantly altered by RYGB. Using principal component analysis, highly correlated species were assembled into two common components. Component 1 consisted of species that were mainly associated with BMI and C-reactive protein. This component was characterized by increased numbers of Proteobacterium Enterobacter cancerogenus and decreased Firmicutes Faecalibacterium prausnitzii and Coprococcus comes. Functional analysis of carbohydrate metabolism by KO revealed significant effects in 13 KOs assigned to phosphotransferase system. Spearmen's Rank correlation indicated an association of 10 species with plasma total- or low-density lipoprotein cholesterol, and 5 species with triglycerides. F. prausnitzii was directly correlated to fasting blood glucose. This is the first clinical demonstration of a profound and specific intra-individual modification of gut microbial composition by full metagenomic sequencing. A clear correlation exists of microbiome composition and gene function with an improvement in metabolic and inflammatory parameters. This will allow to develop new diagnostic and therapeutic strategies based on metagenomic sequencing of the human gut microbiome.
Roux-en-Y Gastric Bypass and Vertical Banded Gastroplasty Induce Long-Term Changes on the Human Gut Microbiome Contributing to Fat Mass Regulation.
Tremaroli Valentina,Karlsson Fredrik,Werling Malin,Ståhlman Marcus,Kovatcheva-Datchary Petia,Olbers Torsten,Fändriks Lars,le Roux Carel W,Nielsen Jens,Bäckhed Fredrik
Bariatric surgery is currently the most effective procedure for the treatment of obesity. Given the role of the gut microbiota in regulating host metabolism and adiposity, we investigated the long-term effects of bariatric surgery on the microbiome of patients randomized to Roux-en-Y gastric bypass or vertical banded gastroplasty and matched for weight and fat mass loss. The two surgical procedures induced similar and durable changes on the gut microbiome that were not dependent on body mass index and resulted in altered levels of fecal and circulating metabolites compared with obese controls. By colonizing germ-free mice with stools from the patients, we demonstrated that the surgically altered microbiota promoted reduced fat deposition in recipient mice. These mice also had a lower respiratory quotient, indicating decreased utilization of carbohydrates as fuel. Our results suggest that the gut microbiota may play a direct role in the reduction of adiposity observed after bariatric surgery.
Comparison of the gut microbiota composition between obese and non-obese individuals in a Japanese population, as analyzed by terminal restriction fragment length polymorphism and next-generation sequencing.
Kasai Chika,Sugimoto Kazushi,Moritani Isao,Tanaka Junichiro,Oya Yumi,Inoue Hidekazu,Tameda Masahiko,Shiraki Katsuya,Ito Masaaki,Takei Yoshiyuki,Takase Kojiro
BACKGROUND:Obesity has become one of the most serious social problems in developed countries, including Japan. The relationship between the gut microbiota and obesity has recently attracted the attention of many researchers. Although the gut microbiota was long thought to contribute to obesity, the exact association remains largely unknown. We examined the human gut microbiota composition in a Japanese population in order to determine its relationship to obesity. METHODS:Stool samples from 23 non-obese subjects (body mass index [BMI] <20 kg/m(2)) and 33 obese subjects (BMI ≥25 kg/m(2)) were collected and DNA was extracted prior to colonoscopy. After terminal restriction fragment length polymorphism (T-RFLP) analysis, samples from 10 subjects (4 non-obese and 6 obese) were selected and subjected to next-generation sequencing for species-level analysis. RESULTS:T-RFLP analysis showed significantly reduced numbers of Bacteroidetes and a higher Firmicutes to Bacteroidetes ratio in obese subjects compared with non-obese subjects. Bacterial diversity was significantly greater in obese subjects compared with non-obese subjects. Next-generation sequencing revealed that obese and non-obese subjects had different gut microbiota compositions and that certain bacterial species were significantly associated with each group (obese: Blautia hydrogenotorophica, Coprococcus catus, Eubacterium ventriosum, Ruminococcus bromii, Ruminococcus obeum; non-obese: Bacteroides faecichinchillae, Bacteroides thetaiotaomicron, Blautia wexlerae, Clostridium bolteae, Flavonifractor plautii). CONCLUSION:Gut microbial properties differ between obese and non-obese subjects in Japan, suggesting that gut microbiota composition is related to obesity.
Linking long-term dietary patterns with gut microbial enterotypes.
Wu Gary D,Chen Jun,Hoffmann Christian,Bittinger Kyle,Chen Ying-Yu,Keilbaugh Sue A,Bewtra Meenakshi,Knights Dan,Walters William A,Knight Rob,Sinha Rohini,Gilroy Erin,Gupta Kernika,Baldassano Robert,Nessel Lisa,Li Hongzhe,Bushman Frederic D,Lewis James D
Science (New York, N.Y.)
Diet strongly affects human health, partly by modulating gut microbiome composition. We used diet inventories and 16S rDNA sequencing to characterize fecal samples from 98 individuals. Fecal communities clustered into enterotypes distinguished primarily by levels of Bacteroides and Prevotella. Enterotypes were strongly associated with long-term diets, particularly protein and animal fat (Bacteroides) versus carbohydrates (Prevotella). A controlled-feeding study of 10 subjects showed that microbiome composition changed detectably within 24 hours of initiating a high-fat/low-fiber or low-fat/high-fiber diet, but that enterotype identity remained stable during the 10-day study. Thus, alternative enterotype states are associated with long-term diet.
Enterotypes of the human gut microbiome.
Arumugam Manimozhiyan,Raes Jeroen,Pelletier Eric,Le Paslier Denis,Yamada Takuji,Mende Daniel R,Fernandes Gabriel R,Tap Julien,Bruls Thomas,Batto Jean-Michel,Bertalan Marcelo,Borruel Natalia,Casellas Francesc,Fernandez Leyden,Gautier Laurent,Hansen Torben,Hattori Masahira,Hayashi Tetsuya,Kleerebezem Michiel,Kurokawa Ken,Leclerc Marion,Levenez Florence,Manichanh Chaysavanh,Nielsen H Bjørn,Nielsen Trine,Pons Nicolas,Poulain Julie,Qin Junjie,Sicheritz-Ponten Thomas,Tims Sebastian,Torrents David,Ugarte Edgardo,Zoetendal Erwin G,Wang Jun,Guarner Francisco,Pedersen Oluf,de Vos Willem M,Brunak Søren,Doré Joel, ,Antolín María,Artiguenave François,Blottiere Hervé M,Almeida Mathieu,Brechot Christian,Cara Carlos,Chervaux Christian,Cultrone Antonella,Delorme Christine,Denariaz Gérard,Dervyn Rozenn,Foerstner Konrad U,Friss Carsten,van de Guchte Maarten,Guedon Eric,Haimet Florence,Huber Wolfgang,van Hylckama-Vlieg Johan,Jamet Alexandre,Juste Catherine,Kaci Ghalia,Knol Jan,Lakhdari Omar,Layec Severine,Le Roux Karine,Maguin Emmanuelle,Mérieux Alexandre,Melo Minardi Raquel,M'rini Christine,Muller Jean,Oozeer Raish,Parkhill Julian,Renault Pierre,Rescigno Maria,Sanchez Nicolas,Sunagawa Shinichi,Torrejon Antonio,Turner Keith,Vandemeulebrouck Gaetana,Varela Encarna,Winogradsky Yohanan,Zeller Georg,Weissenbach Jean,Ehrlich S Dusko,Bork Peer
Our knowledge of species and functional composition of the human gut microbiome is rapidly increasing, but it is still based on very few cohorts and little is known about variation across the world. By combining 22 newly sequenced faecal metagenomes of individuals from four countries with previously published data sets, here we identify three robust clusters (referred to as enterotypes hereafter) that are not nation or continent specific. We also confirmed the enterotypes in two published, larger cohorts, indicating that intestinal microbiota variation is generally stratified, not continuous. This indicates further the existence of a limited number of well-balanced host-microbial symbiotic states that might respond differently to diet and drug intake. The enterotypes are mostly driven by species composition, but abundant molecular functions are not necessarily provided by abundant species, highlighting the importance of a functional analysis to understand microbial communities. Although individual host properties such as body mass index, age, or gender cannot explain the observed enterotypes, data-driven marker genes or functional modules can be identified for each of these host properties. For example, twelve genes significantly correlate with age and three functional modules with the body mass index, hinting at a diagnostic potential of microbial markers.
The impact of the gut microbiota on human health: an integrative view.
Clemente Jose C,Ursell Luke K,Parfrey Laura Wegener,Knight Rob
The human gut harbors diverse microbes that play a fundamental role in the well-being of their host. The constituents of the microbiota--bacteria, viruses, and eukaryotes--have been shown to interact with one another and with the host immune system in ways that influence the development of disease. We review these interactions and suggest that a holistic approach to studying the microbiota that goes beyond characterization of community composition and encompasses dynamic interactions between all components of the microbiota and host tissue over time will be crucial for building predictive models for diagnosis and treatment of diseases linked to imbalances in our microbiota.
Structure, function and diversity of the healthy human microbiome.
Studies of the human microbiome have revealed that even healthy individuals differ remarkably in the microbes that occupy habitats such as the gut, skin and vagina. Much of this diversity remains unexplained, although diet, environment, host genetics and early microbial exposure have all been implicated. Accordingly, to characterize the ecology of human-associated microbial communities, the Human Microbiome Project has analysed the largest cohort and set of distinct, clinically relevant body habitats so far. We found the diversity and abundance of each habitat's signature microbes to vary widely even among healthy subjects, with strong niche specialization both within and among individuals. The project encountered an estimated 81-99% of the genera, enzyme families and community configurations occupied by the healthy Western microbiome. Metagenomic carriage of metabolic pathways was stable among individuals despite variation in community structure, and ethnic/racial background proved to be one of the strongest associations of both pathways and microbes with clinical metadata. These results thus delineate the range of structural and functional configurations normal in the microbial communities of a healthy population, enabling future characterization of the epidemiology, ecology and translational applications of the human microbiome.
A human gut microbial gene catalogue established by metagenomic sequencing.
Qin Junjie,Li Ruiqiang,Raes Jeroen,Arumugam Manimozhiyan,Burgdorf Kristoffer Solvsten,Manichanh Chaysavanh,Nielsen Trine,Pons Nicolas,Levenez Florence,Yamada Takuji,Mende Daniel R,Li Junhua,Xu Junming,Li Shaochuan,Li Dongfang,Cao Jianjun,Wang Bo,Liang Huiqing,Zheng Huisong,Xie Yinlong,Tap Julien,Lepage Patricia,Bertalan Marcelo,Batto Jean-Michel,Hansen Torben,Le Paslier Denis,Linneberg Allan,Nielsen H Bjørn,Pelletier Eric,Renault Pierre,Sicheritz-Ponten Thomas,Turner Keith,Zhu Hongmei,Yu Chang,Li Shengting,Jian Min,Zhou Yan,Li Yingrui,Zhang Xiuqing,Li Songgang,Qin Nan,Yang Huanming,Wang Jian,Brunak Søren,Doré Joel,Guarner Francisco,Kristiansen Karsten,Pedersen Oluf,Parkhill Julian,Weissenbach Jean, ,Bork Peer,Ehrlich S Dusko,Wang Jun
To understand the impact of gut microbes on human health and well-being it is crucial to assess their genetic potential. Here we describe the Illumina-based metagenomic sequencing, assembly and characterization of 3.3 million non-redundant microbial genes, derived from 576.7 gigabases of sequence, from faecal samples of 124 European individuals. The gene set, approximately 150 times larger than the human gene complement, contains an overwhelming majority of the prevalent (more frequent) microbial genes of the cohort and probably includes a large proportion of the prevalent human intestinal microbial genes. The genes are largely shared among individuals of the cohort. Over 99% of the genes are bacterial, indicating that the entire cohort harbours between 1,000 and 1,150 prevalent bacterial species and each individual at least 160 such species, which are also largely shared. We define and describe the minimal gut metagenome and the minimal gut bacterial genome in terms of functions present in all individuals and most bacteria, respectively.
Revised Estimates for the Number of Human and Bacteria Cells in the Body.
Sender Ron,Fuchs Shai,Milo Ron
Reported values in the literature on the number of cells in the body differ by orders of magnitude and are very seldom supported by any measurements or calculations. Here, we integrate the most up-to-date information on the number of human and bacterial cells in the body. We estimate the total number of bacteria in the 70 kg "reference man" to be 3.8·1013. For human cells, we identify the dominant role of the hematopoietic lineage to the total count (≈90%) and revise past estimates to 3.0·1013 human cells. Our analysis also updates the widely-cited 10:1 ratio, showing that the number of bacteria in the body is actually of the same order as the number of human cells, and their total mass is about 0.2 kg.
Metagenomic analysis of the human distal gut microbiome.
Gill Steven R,Pop Mihai,Deboy Robert T,Eckburg Paul B,Turnbaugh Peter J,Samuel Buck S,Gordon Jeffrey I,Relman David A,Fraser-Liggett Claire M,Nelson Karen E
Science (New York, N.Y.)
The human intestinal microbiota is composed of 10(13) to 10(14) microorganisms whose collective genome ("microbiome") contains at least 100 times as many genes as our own genome. We analyzed approximately 78 million base pairs of unique DNA sequence and 2062 polymerase chain reaction-amplified 16S ribosomal DNA sequences obtained from the fecal DNAs of two healthy adults. Using metabolic function analyses of identified genes, we compared our human genome with the average content of previously sequenced microbial genomes. Our microbiome has significantly enriched metabolism of glycans, amino acids, and xenobiotics; methanogenesis; and 2-methyl-d-erythritol 4-phosphate pathway-mediated biosynthesis of vitamins and isoprenoids. Thus, humans are superorganisms whose metabolism represents an amalgamation of microbial and human attributes.
Host-bacterial mutualism in the human intestine.
Bäckhed Fredrik,Ley Ruth E,Sonnenburg Justin L,Peterson Daniel A,Gordon Jeffrey I
Science (New York, N.Y.)
The distal human intestine represents an anaerobic bioreactor programmed with an enormous population of bacteria, dominated by relatively few divisions that are highly diverse at the strain/subspecies level. This microbiota and its collective genomes (microbiome) provide us with genetic and metabolic attributes we have not been required to evolve on our own, including the ability to harvest otherwise inaccessible nutrients. New studies are revealing how the gut microbiota has coevolved with us and how it manipulates and complements our biology in ways that are mutually beneficial. We are also starting to understand how certain keystone members of the microbiota operate to maintain the stability and functional adaptability of this microbial organ.
Role of the normal gut microbiota.
Jandhyala Sai Manasa,Talukdar Rupjyoti,Subramanyam Chivkula,Vuyyuru Harish,Sasikala Mitnala,Nageshwar Reddy D
World journal of gastroenterology
Relation between the gut microbiota and human health is being increasingly recognised. It is now well established that a healthy gut flora is largely responsible for overall health of the host. The normal human gut microbiota comprises of two major phyla, namely Bacteroidetes and Firmicutes. Though the gut microbiota in an infant appears haphazard, it starts resembling the adult flora by the age of 3 years. Nevertheless, there exist temporal and spatial variations in the microbial distribution from esophagus to the rectum all along the individual's life span. Developments in genome sequencing technologies and bioinformatics have now enabled scientists to study these microorganisms and their function and microbe-host interactions in an elaborate manner both in health and disease. The normal gut microbiota imparts specific function in host nutrient metabolism, xenobiotic and drug metabolism, maintenance of structural integrity of the gut mucosal barrier, immunomodulation, and protection against pathogens. Several factors play a role in shaping the normal gut microbiota. They include (1) the mode of delivery (vaginal or caesarean); (2) diet during infancy (breast milk or formula feeds) and adulthood (vegan based or meat based); and (3) use of antibiotics or antibiotic like molecules that are derived from the environment or the gut commensal community. A major concern of antibiotic use is the long-term alteration of the normal healthy gut microbiota and horizontal transfer of resistance genes that could result in reservoir of organisms with a multidrug resistant gene pool.
Composition and energy harvesting capacity of the gut microbiota: relationship to diet, obesity and time in mouse models.
Murphy E F,Cotter P D,Healy S,Marques T M,O'Sullivan O,Fouhy F,Clarke S F,O'Toole P W,Quigley E M,Stanton C,Ross P R,O'Doherty R M,Shanahan F
BACKGROUND AND AIMS:Increased efficiency of energy harvest, due to alterations in the gut microbiota (increased Firmicutes and decreased Bacteroidetes), has been implicated in obesity in mice and humans. However, a causal relationship is unproven and contributory variables include diet, genetics and age. Therefore, we explored the effect of a high-fat (HF) diet and genetically determined obesity (ob/ob) for changes in microbiota and energy harvesting capacity over time. METHODS:Seven-week-old male ob/ob mice were fed a low-fat diet and wild-type mice were fed either a low-fat diet or a HF-diet for 8 weeks (n=8/group). They were assessed at 7, 11 and 15 weeks of age for: fat and lean body mass (by NMR); faecal and caecal short-chain fatty acids (SCFA, by gas chromatography); faecal energy content (by bomb calorimetry) and microbial composition (by metagenomic pyrosequencing). RESULTS:A progressive increase in Firmicutes was confirmed in both HF-fed and ob/ob mice reaching statistical significance in the former, but this phylum was unchanged over time in the lean controls. Reductions in Bacteroidetes were also found in ob/ob mice. However, changes in the microbiota were dissociated from markers of energy harvest. Thus, although the faecal energy in the ob/ob mice was significantly decreased at 7 weeks, and caecal SCFA increased, these did not persist and faecal acetate diminished over time in both ob/ob and HF-fed mice, but not in lean controls. Furthermore, the proportion of the major phyla did not correlate with energy harvest markers. CONCLUSION:The relationship between the microbial composition and energy harvesting capacity is more complex than previously considered. While compositional changes in the faecal microbiota were confirmed, this was primarily a feature of high-fat feeding rather than genetically induced obesity. In addition, changes in the proportions of the major phyla were unrelated to markers of energy harvest which changed over time. The possibility of microbial adaptation to diet and time should be considered in future studies.
Correlations of Fecal Metabonomic and Microbiomic Changes Induced by High-fat Diet in the Pre-Obesity State.
Lin Hong,An Yanpeng,Hao Fuhua,Wang Yulan,Tang Huiru
Obesity resulting from interactions of genetic and environmental factors becomes a serious public health problem worldwide with alterations of the metabolic phenotypes in multiple biological matrices involving multiple metabolic pathways. To understand the contributions of gut microbiota to obesity development, we analyzed dynamic alterations in fecal metabonomic phenotype using NMR and fecal microorganism composition in rats using pyrosequencing technology during the high-fat diet (HFD) feeding for 81 days (pre-obesity state). Integrated analysis of these two phenotypic datasets was further conducted to establish correlations between the altered rat fecal metabonome and gut microbiome. We found that one-week HFD feeding already caused significant changes in rat fecal metabonome and such changes sustained throughout 81-days feeding with the host and gut microbiota co-metabolites clearly featured. We also found that HFD caused outstanding decreases in most fecal metabolites implying enhancement of gut absorptions. We further established comprehensive correlations between the HFD-induced changes in fecal metabonome and fecal microbial composition indicating contributions of gut microbiota in pathogenesis and progression of the HFD-induced obesity. These findings provided essential information about the functions of gut microbiota in pathogenesis of metabolic disorders which could be potentially important for developing obesity prevention and treatment therapies.
Obesity and the gut microbiome: Striving for causality.
Harley Isaac T W,Karp Christopher L
The gut microbiome has been proposed to play a causal role in obesity. Here, we review the historical context for this hypothesis, highlight recent key findings, and critically discuss issues central to further progress in the field, including the central epistemological problem for the field: how to define causality in the relationship between microbiota and obesity phenotypes. Definition of such will be critical for the field to move forward.
Myocardial Injury, Obesity, and the Obesity Paradox: The ARIC Study.
Pokharel Yashashwi,Sun Wensheng,Virani Salim S,Nambi Vijay,Hoogeveen Ron C,Chang Patricia P,Ndumele Chiadi E,Solomon Scott D,Bozkurt Biykem,Selvin Elizabeth,Ballantyne Christie M,Deswal Anita
JACC. Heart failure
OBJECTIVES:This study sought to determine whether pre-heart failure (HF) myocardial injury explains the differential mortality after HF across weight categories. BACKGROUND:Obesity is a risk factor for HF, but pre-HF obesity is associated with lower mortality after incident HF. High-sensitivity cardiac troponin T (hs-cTnT) is a sensitive marker of myocardial injury, and predicts incident HF and mortality. METHODS:Stratifying 1,279 individuals with incident HF hospitalizations by their pre-HF hs-cTnT levels (< and ≥ 14 ng/l), we examined the association of pre-HF body mass index (BMI) with mortality after incident HF hospitalization in the ARIC (Atherosclerosis Risk In Communities) study. RESULTS:Mean age at HF was 74 years (53% women, 27% black). Individuals with pre-HF hs-cTnT ≥14 ng/l had higher mortality after incident HF (hazard ratio [HR]: 1.46; 95% confidence interval [CI]: 1.18 to 1.80) compared to individuals with hs-cTnT <14 ng/l in an adjusted model including BMI. Compared with normal weight subjects, the mortality was lower in overweight (HR: 0.69, 95% CI 0.48-0.98) and obese individuals (HR: 0.50; 95% CI: 0.35 to 0.72) with hs-cTnT <14 ng/l; and in those with hs-cTnT ≥14 ng/l (overweight HR: 0.50; 95% CI: 0.30 to 0.83; obese HR: 0.56; 95% CI: 0.34 to 0.91; interaction: p = 0.154 between BMI and hs-cTnT). The lower mortality risk in obese and overweight subjects remained similar when log hs-cTnT was added as a continuous variable to a multivariable model, and in sensitivity analyses after further adjusting for left ventricular hypertrophy or high-sensitivity C-reactive protein. CONCLUSION:Although greater pre-existing subclinical myocardial injury was associated with higher mortality after incident HF hospitalization, it did not explain the obesity paradox in HF, which was observed irrespective of subclinical myocardial injury. (Atherosclerosis Risk In Communities [ARIC]; NCT00005131).
Predictive functional profiling of microbial communities using 16S rRNA marker gene sequences.
Langille Morgan G I,Zaneveld Jesse,Caporaso J Gregory,McDonald Daniel,Knights Dan,Reyes Joshua A,Clemente Jose C,Burkepile Deron E,Vega Thurber Rebecca L,Knight Rob,Beiko Robert G,Huttenhower Curtis
Profiling phylogenetic marker genes, such as the 16S rRNA gene, is a key tool for studies of microbial communities but does not provide direct evidence of a community's functional capabilities. Here we describe PICRUSt (phylogenetic investigation of communities by reconstruction of unobserved states), a computational approach to predict the functional composition of a metagenome using marker gene data and a database of reference genomes. PICRUSt uses an extended ancestral-state reconstruction algorithm to predict which gene families are present and then combines gene families to estimate the composite metagenome. Using 16S information, PICRUSt recaptures key findings from the Human Microbiome Project and accurately predicts the abundance of gene families in host-associated and environmental communities, with quantifiable uncertainty. Our results demonstrate that phylogeny and function are sufficiently linked that this 'predictive metagenomic' approach should provide useful insights into the thousands of uncultivated microbial communities for which only marker gene surveys are currently available.
Cytoscape: a software environment for integrated models of biomolecular interaction networks.
Shannon Paul,Markiel Andrew,Ozier Owen,Baliga Nitin S,Wang Jonathan T,Ramage Daniel,Amin Nada,Schwikowski Benno,Ideker Trey
Cytoscape is an open source software project for integrating biomolecular interaction networks with high-throughput expression data and other molecular states into a unified conceptual framework. Although applicable to any system of molecular components and interactions, Cytoscape is most powerful when used in conjunction with large databases of protein-protein, protein-DNA, and genetic interactions that are increasingly available for humans and model organisms. Cytoscape's software Core provides basic functionality to layout and query the network; to visually integrate the network with expression profiles, phenotypes, and other molecular states; and to link the network to databases of functional annotations. The Core is extensible through a straightforward plug-in architecture, allowing rapid development of additional computational analyses and features. Several case studies of Cytoscape plug-ins are surveyed, including a search for interaction pathways correlating with changes in gene expression, a study of protein complexes involved in cellular recovery to DNA damage, inference of a combined physical/functional interaction network for Halobacterium, and an interface to detailed stochastic/kinetic gene regulatory models.
Metagenomic biomarker discovery and explanation.
Segata Nicola,Izard Jacques,Waldron Levi,Gevers Dirk,Miropolsky Larisa,Garrett Wendy S,Huttenhower Curtis
This study describes and validates a new method for metagenomic biomarker discovery by way of class comparison, tests of biological consistency and effect size estimation. This addresses the challenge of finding organisms, genes, or pathways that consistently explain the differences between two or more microbial communities, which is a central problem to the study of metagenomics. We extensively validate our method on several microbiomes and a convenient online interface for the method is provided at http://huttenhower.sph.harvard.edu/lefse/.
Defining the healthy "core microbiome" of oral microbial communities.
Zaura Egija,Keijser Bart J F,Huse Susan M,Crielaard Wim
BACKGROUND:Most studies examining the commensal human oral microbiome are focused on disease or are limited in methodology. In order to diagnose and treat diseases at an early and reversible stage an in-depth definition of health is indispensible. The aim of this study therefore was to define the healthy oral microbiome using recent advances in sequencing technology (454 pyrosequencing). RESULTS:We sampled and sequenced microbiomes from several intraoral niches (dental surfaces, cheek, hard palate, tongue and saliva) in three healthy individuals. Within an individual oral cavity, we found over 3600 unique sequences, over 500 different OTUs or "species-level" phylotypes (sequences that clustered at 3% genetic difference) and 88 - 104 higher taxa (genus or more inclusive taxon). The predominant taxa belonged to Firmicutes (genus Streptococcus, family Veillonellaceae, genus Granulicatella), Proteobacteria (genus Neisseria, Haemophilus), Actinobacteria (genus Corynebacterium, Rothia, Actinomyces), Bacteroidetes (genus Prevotella, Capnocytophaga, Porphyromonas) and Fusobacteria (genus Fusobacterium).Each individual sample harboured on average 266 "species-level" phylotypes (SD 67; range 123 - 326) with cheek samples being the least diverse and the dental samples from approximal surfaces showing the highest diversity. Principal component analysis discriminated the profiles of the samples originating from shedding surfaces (mucosa of tongue, cheek and palate) from the samples that were obtained from solid surfaces (teeth).There was a large overlap in the higher taxa, "species-level" phylotypes and unique sequences among the three microbiomes: 84% of the higher taxa, 75% of the OTUs and 65% of the unique sequences were present in at least two of the three microbiomes. The three individuals shared 1660 of 6315 unique sequences. These 1660 sequences (the "core microbiome") contributed 66% of the reads. The overlapping OTUs contributed to 94% of the reads, while nearly all reads (99.8%) belonged to the shared higher taxa. CONCLUSIONS:We obtained the first insight into the diversity and uniqueness of individual oral microbiomes at a resolution of next-generation sequencing. We showed that a major proportion of bacterial sequences of unrelated healthy individuals is identical, supporting the concept of a core microbiome at health.
Multivariate analyses in microbial ecology.
FEMS microbiology ecology
Environmental microbiology is undergoing a dramatic revolution due to the increasing accumulation of biological information and contextual environmental parameters. This will not only enable a better identification of diversity patterns, but will also shed more light on the associated environmental conditions, spatial locations, and seasonal fluctuations, which could explain such patterns. Complex ecological questions may now be addressed using multivariate statistical analyses, which represent a vast potential of techniques that are still underexploited. Here, well-established exploratory and hypothesis-driven approaches are reviewed, so as to foster their addition to the microbial ecologist toolbox. Because such tools aim at reducing data set complexity, at identifying major patterns and putative causal factors, they will certainly find many applications in microbial ecology.
Quantitative and qualitative beta diversity measures lead to different insights into factors that structure microbial communities.
Lozupone Catherine A,Hamady Micah,Kelley Scott T,Knight Rob
Applied and environmental microbiology
The assessment of microbial diversity and distribution is a major concern in environmental microbiology. There are two general approaches for measuring community diversity: quantitative measures, which use the abundance of each taxon, and qualitative measures, which use only the presence/absence of data. Quantitative measures are ideally suited to revealing community differences that are due to changes in relative taxon abundance (e.g., when a particular set of taxa flourish because a limiting nutrient source becomes abundant). Qualitative measures are most informative when communities differ primarily by what can live in them (e.g., at high temperatures), in part because abundance information can obscure significant patterns of variation in which taxa are present. We illustrate these principles using two 16S rRNA-based surveys of microbial populations and two phylogenetic measures of community beta diversity: unweighted UniFrac, a qualitative measure, and weighted UniFrac, a new quantitative measure, which we have added to the UniFrac website (http://bmf.colorado.edu/unifrac). These studies considered the relative influences of mineral chemistry, temperature, and geography on microbial community composition in acidic thermal springs in Yellowstone National Park and the influences of obesity and kinship on microbial community composition in the mouse gut. We show that applying qualitative and quantitative measures to the same data set can lead to dramatically different conclusions about the main factors that structure microbial diversity and can provide insight into the nature of community differences. We also demonstrate that both weighted and unweighted UniFrac measurements are robust to the methods used to build the underlying phylogeny.
The SILVA ribosomal RNA gene database project: improved data processing and web-based tools.
Quast Christian,Pruesse Elmar,Yilmaz Pelin,Gerken Jan,Schweer Timmy,Yarza Pablo,Peplies Jörg,Glöckner Frank Oliver
Nucleic acids research
SILVA (from Latin silva, forest, http://www.arb-silva.de) is a comprehensive web resource for up to date, quality-controlled databases of aligned ribosomal RNA (rRNA) gene sequences from the Bacteria, Archaea and Eukaryota domains and supplementary online services. The referred database release 111 (July 2012) contains 3 194 778 small subunit and 288 717 large subunit rRNA gene sequences. Since the initial description of the project, substantial new features have been introduced, including advanced quality control procedures, an improved rRNA gene aligner, online tools for probe and primer evaluation and optimized browsing, searching and downloading on the website. Furthermore, the extensively curated SILVA taxonomy and the new non-redundant SILVA datasets provide an ideal reference for high-throughput classification of data from next-generation sequencing approaches.
VSEARCH: a versatile open source tool for metagenomics.
Rognes Torbjørn,Flouri Tomáš,Nichols Ben,Quince Christopher,Mahé Frédéric
BACKGROUND:VSEARCH is an open source and free of charge multithreaded 64-bit tool for processing and preparing metagenomics, genomics and population genomics nucleotide sequence data. It is designed as an alternative to the widely used USEARCH tool (Edgar, 2010) for which the source code is not publicly available, algorithm details are only rudimentarily described, and only a memory-confined 32-bit version is freely available for academic use. METHODS:When searching nucleotide sequences, VSEARCH uses a fast heuristic based on words shared by the query and target sequences in order to quickly identify similar sequences, a similar strategy is probably used in USEARCH. VSEARCH then performs optimal global sequence alignment of the query against potential target sequences, using full dynamic programming instead of the seed-and-extend heuristic used by USEARCH. Pairwise alignments are computed in parallel using vectorisation and multiple threads. RESULTS:VSEARCH includes most commands for analysing nucleotide sequences available in USEARCH version 7 and several of those available in USEARCH version 8, including searching (exact or based on global alignment), clustering by similarity (using length pre-sorting, abundance pre-sorting or a user-defined order), chimera detection (reference-based or ), dereplication (full length or prefix), pairwise alignment, reverse complementation, sorting, and subsampling. VSEARCH also includes commands for FASTQ file processing, i.e., format detection, filtering, read quality statistics, and merging of paired reads. Furthermore, VSEARCH extends functionality with several new commands and improvements, including shuffling, rereplication, masking of low-complexity sequences with the well-known DUST algorithm, a choice among different similarity definitions, and FASTQ file format conversion. VSEARCH is here shown to be more accurate than USEARCH when performing searching, clustering, chimera detection and subsampling, while on a par with USEARCH for paired-ends read merging. VSEARCH is slower than USEARCH when performing clustering and chimera detection, but significantly faster when performing paired-end reads merging and dereplication. VSEARCH is available at https://github.com/torognes/vsearch under either the BSD 2-clause license or the GNU General Public License version 3.0. DISCUSSION:VSEARCH has been shown to be a fast, accurate and full-fledged alternative to USEARCH. A free and open-source versatile tool for sequence analysis is now available to the metagenomics community.
Application of high-throughput sequencing in understanding human oral microbiome related with health and disease.
Chen Hui,Jiang Wen
Frontiers in microbiology
The oral microbiome is one of most diversity habitat in the human body and they are closely related with oral health and disease. As the technique developing, high-throughput sequencing has become a popular approach applied for oral microbial analysis. Oral bacterial profiles have been studied to explore the relationship between microbial diversity and oral diseases such as caries and periodontal disease. This review describes the application of high-throughput sequencing for characterization of oral microbiota and analyzing the changes of the microbiome in the states of health or disease. Deep understanding the knowledge of microbiota will pave the way for more effective prevent dentistry and contribute to the development of personalized dental medicine.
QIIME allows analysis of high-throughput community sequencing data.
Caporaso J Gregory,Kuczynski Justin,Stombaugh Jesse,Bittinger Kyle,Bushman Frederic D,Costello Elizabeth K,Fierer Noah,Peña Antonio Gonzalez,Goodrich Julia K,Gordon Jeffrey I,Huttley Gavin A,Kelley Scott T,Knights Dan,Koenig Jeremy E,Ley Ruth E,Lozupone Catherine A,McDonald Daniel,Muegge Brian D,Pirrung Meg,Reeder Jens,Sevinsky Joel R,Turnbaugh Peter J,Walters William A,Widmann Jeremy,Yatsunenko Tanya,Zaneveld Jesse,Knight Rob
Effect of storage conditions on the assessment of bacterial community structure in soil and human-associated samples.
Lauber Christian L,Zhou Nicholas,Gordon Jeffrey I,Knight Rob,Fierer Noah
FEMS microbiology letters
Storage conditions are considered to be a critical component of DNA-based microbial community analysis methods. However, whether differences in short-term sample storage conditions impact the assessment of bacterial community composition and diversity requires systematic and quantitative assessment. Therefore, we used barcoded pyrosequencing of bacterial 16S rRNA genes to survey communities, harvested from a variety of habitats [soil, human gut (feces) and human skin] and subsequently stored at 20, 4, -20 and -80 degrees C for 3 and 14 days. Our results indicate that the phylogenetic structure and diversity of communities in individual samples were not significantly influenced by the storage temperature or the duration of storage. Likewise, the relative abundances of most taxa were largely unaffected by temperature even after 14 days of storage. Our results indicate that environmental factors and biases in molecular techniques likely confer greater amounts of variation to microbial communities than do differences in short-term storage conditions, including storage for up to 2 weeks at room temperature. These results suggest that many samples collected and stored under field conditions without refrigeration may be useful for microbial community analyses.
abundant colonization in human gastrointestinal tract.
Wu Feifan,Guo Xianfeng,Zhang Jiachun,Zhang Min,Ou Zihao,Peng Yongzheng
Experimental and therapeutic medicine
can produce short-chain fatty acids, including acetate and propionate, and can be associated with the metabolic state and mood of the host. The present study investigated the colonization characteristics of in healthy individuals <1-80 years old in Southern China. A total of 150 fresh fecal samples were collected, and bacterial DNA was isolated from these samples for quantitative polymerase chain reaction analysis. demonstrated a high colonization rate and abundant colonization in the human gastrointestinal tract. The colonization rate varied between 43.33-93.33%, and the abundance of ranged between 3.22-5.76 log cells g-1 (<1 years old) and 3.06-9.33 log cells g-1 (>1 year old). The permillage of in total bacteria ranged between 0.004-1.479. There was presence of -like bacteria in younger individuals with a gradual increase in the number of bacteria maintained at a high level with increasing ages (between 1 and 60 years old), but with a decrease in elderly individuals (>60 years old). The results of the present study demonstrated that is abundantly colonized in the human gastrointestinal tract.
Oral treatment with γ-aminobutyric acid improves glucose tolerance and insulin sensitivity by inhibiting inflammation in high fat diet-fed mice.
Tian Jide,Dang Hoa N,Yong Jing,Chui Wing-Sheung,Dizon Matthew P G,Yaw Catherine K Y,Kaufman Daniel L
Adipocyte and β-cell dysfunction and macrophage-related chronic inflammation are critical for the development of obesity-related insulin resistance and type 2 diabetes mellitus (T2DM), which can be negatively regulated by Tregs. Our previous studies and those of others have shown that activation of γ-aminobutyric acid (GABA) receptors inhibits inflammation in mice. However, whether GABA could modulate high fat diet (HFD)-induced obesity, glucose intolerance and insulin resistance has not been explored. Here, we show that although oral treatment with GABA does not affect water and food consumption it inhibits the HFD-induced gain in body weights in C57BL/6 mice. Furthermore, oral treatment with GABA significantly reduced the concentrations of fasting blood glucose, and improved glucose tolerance and insulin sensitivity in the HFD-fed mice. More importantly, after the onset of obesity and T2DM, oral treatment with GABA inhibited the continual HFD-induced gain in body weights, reduced the concentrations of fasting blood glucose and improved glucose tolerance and insulin sensitivity in mice. In addition, oral treatment with GABA reduced the epididymal fat mass, adipocyte size, and the frequency of macrophage infiltrates in the adipose tissues of HFD-fed mice. Notably, oral treatment with GABA significantly increased the frequency of CD4(+)Foxp3(+) Tregs in mice. Collectively, our data indicated that activation of peripheral GABA receptors inhibited the HFD-induced glucose intolerance, insulin resistance, and obesity by inhibiting obesity-related inflammation and up-regulating Treg responses in vivo. Given that GABA is safe for human consumption, activators of GABA receptors may be valuable for the prevention of obesity and intervention of T2DM in the clinic.
Tryptophan Metabolic Pathways Are Altered in Obesity and Are Associated With Systemic Inflammation.
Cussotto Sofia,Delgado Inês,Anesi Andrea,Dexpert Sandra,Aubert Agnès,Beau Cédric,Forestier Damien,Ledaguenel Patrick,Magne Eric,Mattivi Fulvio,Capuron Lucile
Frontiers in immunology
Obesity is a condition with a complex pathophysiology characterized by both chronic low-grade inflammation and changes in the gut microbial ecosystem. These alterations can affect the metabolism of tryptophan (TRP), an essential amino acid and precursor of serotonin (5-HT), kynurenine (KYN), and indoles. This study aimed to investigate alterations in KYN and microbiota-mediated indole routes of TRP metabolism in obese subjects relatively to non-obese controls and to determine their relationship with systemic inflammation. Eighty-five obese adults (avg. BMI = 40.48) and 42 non-obese control individuals (avg. BMI = 24.03) were recruited. Plasma levels of TRP catabolites were assessed using Ultra High Performance Liquid Chromatography-ElectroSpray-Ionization-Tandem Mass Spectrometry. High-sensitive C-reactive protein (hsCRP) and high-sensitive interleukin 6 (hsIL-6) were measured in the serum as markers of systemic inflammation using enzyme-linked immunosorbent assay. Both KYN and microbiota-mediated indole routes of TRP metabolism were altered in obese subjects, as reflected in higher KYN/TRP ratio and lower 5-HT and indoles levels, relatively to non-obese controls. HsIL-6 and hsCRP were increased in obesity and were overall associated with TRP metabolic pathways alterations. These results indicate for the first time that KYN and indole TRP metabolic pathways are concomitantly altered in obese subjects and highlight their respective associations with obesity-related systemic inflammation.
GABA-stimulated adipose-derived stem cells suppress subcutaneous adipose inflammation in obesity.
Hwang Injae,Jo Kyuri,Shin Kyung Cheul,Kim Jong In,Ji Yul,Park Yoon Jeong,Park Jeu,Jeon Yong Geun,Ka Sojeong,Suk Sujin,Noh Hye Lim,Choe Sung Sik,Alfadda Assim A,Kim Jason K,Kim Sun,Kim Jae Bum
Proceedings of the National Academy of Sciences of the United States of America
Accumulating evidence suggests that subcutaneous and visceral adipose tissues are differentially associated with metabolic disorders. In obesity, subcutaneous adipose tissue is beneficial for metabolic homeostasis because of repressed inflammation. However, the underlying mechanism remains unclear. Here, we demonstrate that γ-aminobutyric acid (GABA) sensitivity is crucial in determining fat depot-selective adipose tissue macrophage (ATM) infiltration in obesity. In diet-induced obesity, GABA reduced monocyte migration in subcutaneous inguinal adipose tissue (IAT), but not in visceral epididymal adipose tissue (EAT). Pharmacological modulation of the GABA receptor affected the levels of ATM infiltration and adipose tissue inflammation in IAT, but not in EAT, and GABA administration ameliorated systemic insulin resistance and enhanced insulin-dependent glucose uptake in IAT, accompanied by lower inflammatory responses. Intriguingly, compared with adipose-derived stem cells (ADSCs) from EAT, IAT-ADSCs played key roles in mediating GABA responses that repressed ATM infiltration in high-fat diet-fed mice. These data suggest that selective GABA responses in IAT contribute to fat depot-selective suppression of inflammatory responses and protection from insulin resistance in obesity.
Impaired tricarboxylic acid cycle flux and mitochondrial aerobic respiration during isoproterenol induced myocardial ischemia is rescued by bilobalide.
Wang Zhe,Zhang Fan,Liu Wei,Sheng Ning,Sun Hua,Zhang Jinlan
Journal of pharmaceutical analysis
There is an urgent need to elucidate the pathogenesis of myocardial ischemia (MI) and potential drug treatments. Here, the anti-MI mechanism and material basis of L. extract (GBE) were studied from the perspective of energy metabolism flux regulation. Metabolic flux analysis (MFA) was performed to investigate energy metabolism flux disorder and the regulatory nodes of GBE components in isoproterenol (ISO)-induced ischemia-like cardiomyocytes. It showed that [U-C] glucose derived m+2 isotopologues from the upstream tricarboxylic acid (TCA) cycle metabolites were markedly accumulated in ISO-injured cardiomyocytes, but the opposite was seen for the downstream metabolites, while their total cellular concentrations were increased. This indicates a blockage of carbon flow from glycolysis and enhanced anaplerosis from other carbon sources. A Seahorse test was used to screen for GBE components with regulatory effects on mitochondrial aerobic respiratory dysfunction. It showed that bilobalide protected against impaired mitochondrial aerobic respiration. MFA also showed that bilobalide significantly modulated the TCA cycle flux, reduced abnormal metabolite accumulation, and balanced the demand of different carbon sources. Western blotting and PCR analysis showed that bilobalide decreased the enhanced expression of key metabolic enzymes in injured cells. Bilobalide's efficacy was verified by in vivo experiments in rats. This is the first report to show that bilobalide, the active ingredient of GBE, protects against MI by rescuing impaired TCA cycle flux. This provides a new mechanism and potential drug treatment for MI. It also shows the potential of MFA/Seahorse combination as a powerful strategy for pharmacological research on herbal medicine.
A high whey protein-, leucine-, and vitamin D-enriched supplement preserves muscle mass during intentional weight loss in obese older adults: a double-blind randomized controlled trial.
Verreijen Amely M,Verlaan Sjors,Engberink Mariëlle F,Swinkels Sophie,de Vogel-van den Bosch Johan,Weijs Peter J M
The American journal of clinical nutrition
BACKGROUND:Intentional weight loss in obese older adults is a risk factor for muscle loss and sarcopenia. OBJECTIVE:The objective was to examine the effect of a high whey protein-, leucine-, and vitamin D-enriched supplement on muscle mass preservation during intentional weight loss in obese older adults. DESIGN:We included 80 obese older adults in a double-blind randomized controlled trial. During a 13-wk weight loss program, all subjects followed a hypocaloric diet (-600 kcal/d) and performed resistance training 3×/wk. Subjects were randomly allocated to a high whey protein-, leucine-, and vitamin D-enriched supplement including a mix of other macro- and micronutrients (150 kcal, 21 g protein; 10×/wk, intervention group) or an isocaloric control. The primary outcome was change in appendicular muscle mass. The secondary outcomes were body composition, handgrip strength, and physical performance. Data were analyzed by using ANCOVA and mixed linear models with sex and baseline value as covariates. RESULTS:At baseline, mean ± SD age was 63 ± 5.6 y, and body mass index (in kg/m(2)) was 33 ± 4.4. During the trial, protein intake was 1.11 ± 0.28 g · kg body weight(-1) · d(-1) in the intervention group compared with 0.85 ± 0.24 g · kg body weight(-1) · d(-1) in the control group (P < 0.001). Both intervention and control groups decreased in body weight (-3.4 ± 3.6 kg and -2.8 ± 2.8 kg; both P < 0.001) and fat mass (-3.2 ± 3.1 kg and -2.5 ± 2.4 kg; both P < 0.001), with no differences between groups. The 13-wk change in appendicular muscle mass, however, was different in the intervention and control groups [+0.4 ± 1.2 kg and -0.5 ± 2.1 kg, respectively; β = 0.95 kg (95% CI: 0.09, 1.81); P = 0.03]. Muscle strength and function improved over time without significant differences between groups. CONCLUSION:A high whey protein-, leucine-, and vitamin D-enriched supplement compared with isocaloric control preserves appendicular muscle mass in obese older adults during a hypocaloric diet and resistance exercise program and might therefore reduce the risk of sarcopenia. This trial was registered at the Dutch Trial Register (http://www.trialregister.nl) as NTR2751.
Weight-loss diets and 2-y changes in circulating amino acids in 2 randomized intervention trials.
Zheng Yan,Ceglarek Uta,Huang Tao,Li Lerong,Rood Jennifer,Ryan Donna H,Bray George A,Sacks Frank M,Schwarzfuchs Dan,Thiery Joachim,Shai Iris,Qi Lu
The American journal of clinical nutrition
BACKGROUND:Circulating amino acids, such as branched-chain amino acids (BCAAs) and aromatic amino acids (AAAs), have been associated with diabetes risk; however, little is known about how a long-term dietary intervention for weight loss affects circulating amino acids. OBJECTIVES:We examined the effects of weight-loss diets on long-term changes in plasma amino acids and the associations of these changes with weight loss and the improvement of insulin resistance. DESIGN:We repeatedly measured plasma amino acid profiles over 2 y in overweight or obese participants from 2 randomized, dietary intervention, weight-loss trials [774 subjects from the POUNDS LOST (Preventing Overweight Using Novel Dietary Strategies Trial) and 318 subjects from the DIRECT (Dietary Intervention Randomized Controlled Trial)]. RESULTS:Intervention diets consistently lowered most of the amino acid concentrations, including BCAAs and AAAs, in both trials. In the POUNDS LOST, average-protein diets (15% of daily energy) showed stronger effects than did high-protein diets (25% of daily energy) on reducing concentrations of the diabetes-associated BCAA valine at 6 mo independent of the weight change. In both trials, weight loss was directly related to the concurrent reduction of the BCAAs leucine and isoleucine, the AAAs tyrosine and phenylalanine, and 4 other amino acids. For example, per kilogram of weight loss, there was a 0.04-SD decrease in log tyrosine (∼0.6 μmol/L) in both trials. In addition, we showed that reductions in alanine and the AAA tyrosine were significantly related to improved insulin resistance (measured with the use of the homeostasis model assessment of insulin resistance), independent of weight loss, in both trials (both P < 0.05). For example, per 1-SD decrease in log tyrosine (∼17 μmol/L), there was a 0.04-SD (∼3%) improvement in insulin resistance in the POUNDS LOST and a 0.13-SD (∼8%) improvement in insulin resistance in the DIRECT. CONCLUSION:Our findings underscore the potential importance of dietary interventions in improving amino acid profiles (i.e., reducing diabetes risk-enhancing amino acid concentrations) along with and beyond weight loss. The POUNDS LOST and the DIRECT were registered at clinicaltrials.gov as NCT00072995 and NCT00160108, respectively.
Molecular pathways behind acquired obesity: Adipose tissue and skeletal muscle multiomics in monozygotic twin pairs discordant for BMI.
van der Kolk Birgitta W,Saari Sina,Lovric Alen,Arif Muhammad,Alvarez Marcus,Ko Arthur,Miao Zong,Sahebekhtiari Navid,Muniandy Maheswary,Heinonen Sini,Oghabian Ali,Jokinen Riikka,Jukarainen Sakari,Hakkarainen Antti,Lundbom Jesper,Kuula Juho,Groop Per-Henrik,Tukiainen Taru,Lundbom Nina,Rissanen Aila,Kaprio Jaakko,Williams Evan G,Zamboni Nicola,Mardinoglu Adil,Pajukanta Päivi,Pietiläinen Kirsi H
Cell reports. Medicine
Tissue-specific mechanisms prompting obesity-related development complications in humans remain unclear. We apply multiomics analyses of subcutaneous adipose tissue and skeletal muscle to examine the effects of acquired obesity among 49 BMI-discordant monozygotic twin pairs. Overall, adipose tissue appears to be more affected by excess body weight than skeletal muscle. In heavier co-twins, we observe a transcriptional pattern of downregulated mitochondrial pathways in both tissues and upregulated inflammatory pathways in adipose tissue. In adipose tissue, heavier co-twins exhibit lower creatine levels; in skeletal muscle, glycolysis- and redox stress-related protein and metabolite levels remain higher. Furthermore, metabolomics analyses in both tissues reveal that several proinflammatory lipids are higher and six of the same lipid derivatives are lower in acquired obesity. Finally, in adipose tissue, but not in skeletal muscle, mitochondrial downregulation and upregulated inflammation are associated with a fatty liver, insulin resistance, and dyslipidemia, suggesting that adipose tissue dominates in acquired obesity.
The regulatory effects of whey retentate from bifidobacteria fermented milk on the microbiota of the Simulator of the Human Intestinal Microbial Ecosystem (SHIME).
Meddah A T,Yazourh A,Desmet I,Risbourg B,Verstraete W,Romond M B
Journal of applied microbiology
AIMS:To investigate the effects of whey retentate from Bifidobacteria fermented milk. METHODS AND RESULTS:The simulator of the human intestinal microbial ecosystem (SHIME) was used. The composition of the microbiota and its metabolic activities were analysed. Changes in the microbial composition became apparent within 15 days of the treatment in the vessels representing the ileum and the large intestine. The whey retentate favoured the growth of endogenous bifidobacteria and induced a decrease in Bacteroides fragilis and in sulphite-reducing clostridia, especially Clostridium perfringens. After the administration was stopped, these populations tended to revert to their original levels, except for the streptococci and the staphylococci populations. The treatment also led to an increase in acetic acid, CH4 and CO2 production, suggesting overgrowth of some anaerobic bacteria. Ammonium, generally considered as undesirable, declined. CONCLUSIONS:The whey retentate clearly altered the microbial community in the SHIME. SIGNIFICANCE AND IMPACT OF THE STUDY:Whey retentate appears to exert a beneficial effect on the in vitro gastrointestinal system; these findings warrant confirmation by in vivo studies.
Effect of a Protein Supplement on the Gut Microbiota of Endurance Athletes: A Randomized, Controlled, Double-Blind Pilot Study.
Moreno-Pérez Diego,Bressa Carlo,Bailén María,Hamed-Bousdar Safa,Naclerio Fernando,Carmona Manuel,Pérez Margarita,González-Soltero Rocío,Montalvo-Lominchar Maria Gregoria,Carabaña Claudia,Larrosa Mar
Nutritional supplements are popular among athletes to improve performance and physical recovery. Protein supplements fulfill this function by improving performance and increasing muscle mass; however, their effect on other organs or systems is less well known. Diet alterations can induce gut microbiota imbalance, with beneficial or deleterious consequences for the host. To test this, we performed a randomized pilot study in cross-country runners whose diets were complemented with a protein supplement (whey isolate and beef hydrolysate) ( = 12) or maltodextrin (control) ( = 12) for 10 weeks. Microbiota, water content, pH, ammonia, and short-chain fatty acids (SCFAs) were analyzed in fecal samples, whereas malondialdehyde levels (oxidative stress marker) were determined in plasma and urine. Fecal pH, water content, ammonia, and SCFA concentrations did not change, indicating that protein supplementation did not increase the presence of these fermentation-derived metabolites. Similarly, it had no impact on plasma or urine malondialdehyde levels; however, it increased the abundance of the phylum and decreased the presence of health-related taxa including , , and . Thus, long-term protein supplementation may have a negative impact on gut microbiota. Further research is needed to establish the impact of protein supplements on gut microbiota.
A High Protein Calorie Restriction Diet Alters the Gut Microbiome in Obesity.
Dong Tien S,Luu Kayti,Lagishetty Venu,Sedighian Farzaneh,Woo Shih-Lung,Dreskin Benjamin W,Katzka William,Chang Candace,Zhou Yi,Arias-Jayo Nerea,Yang Julianne,Ahdoot Aaron,Li Zhaoping,Pisegna Joseph R,Jacobs Jonathan P
BACKGROUND:High protein calorie restriction diets have shown clinical efficacy for obesity, but the mechanisms are not fully known. The intestinal microbiome is a mediator of obesity and preclinical data support an effect of high protein diet (HPD) on the gut microbiome of obesity, but there are few studies in humans. METHODS:To address this, we conducted a dietary intervention trial of 80 overweight and obese subjects who were randomized to a calorie-restricted high protein diet (HPD) (30% calorie intake) or calorie-restricted normal protein diet (NPD) (15%) for 8 weeks. Baseline dietary intake patterns were assessed by the Diet History Questionnaire III. Longitudinal fecal sampling was performed at baseline, week 1, week 2, week 4, week 6, and week 8, for a total of 365 samples. Intestinal microbiome composition was assessed by 16S rRNA gene sequencing. RESULTS:At baseline, microbial composition was associated with fiber and protein intake. Subjects on the HPD showed a significant increase in microbial diversity as measured by the Shannon index compared to those on the NPD. The HPD was also associated with significant differences in microbial composition after treatment compared to the NPD. Both diets induced taxonomic shifts compared to baseline, including enrichment of and and depletion of Conclusion: These findings provide evidence that weight loss diets alter the gut microbiome in obesity and suggest differential effects of HPDs compared to NPDs which may influence the clinical response to HPD.
Gut microbiota associations with common diseases and prescription medications in a population-based cohort.
Jackson Matthew A,Verdi Serena,Maxan Maria-Emanuela,Shin Cheol Min,Zierer Jonas,Bowyer Ruth C E,Martin Tiphaine,Williams Frances M K,Menni Cristina,Bell Jordana T,Spector Tim D,Steves Claire J
The human gut microbiome has been associated with many health factors but variability between studies limits exploration of effects between them. Gut microbiota profiles are available for >2700 members of the deeply phenotyped TwinsUK cohort, providing a uniform platform for such comparisons. Here, we present gut microbiota association analyses for 38 common diseases and 51 medications within the cohort. We describe several novel associations, highlight associations common across multiple diseases, and determine which diseases and medications have the greatest association with the gut microbiota. These results provide a reference for future studies of the gut microbiome and its role in human health.
A high-whey-protein diet reduces body weight gain and alters insulin sensitivity relative to red meat in wistar rats.
Belobrajdic Damien P,McIntosh Graeme H,Owens Julie A
The Journal of nutrition
A high-protein diet can reduce body weight and increase insulin sensitivity, but whether the type of dietary protein affects these outcomes is unknown. We hypothesized that feeding insulin-resistant rats a high-protein diet (32%) containing whey protein concentrate (WPC) would reduce body weight and tissue lipid levels and increase insulin sensitivity more than a diet containing red meat (RM). Rats were fed a high-fat diet (300 g fat/kg diet) for 9 wk, then switched to a diet containing either 80 or 320 g protein/kg diet, provided by either WPC or RM, for 6 wk (n = 8). The rats were then killed after overnight food deprivation. High dietary protein reduced energy intake (P < 0.001) and visceral (P < 0.001), subcutaneous (P < 0.001), and carcass fat (P < 0.05). Increasing the dietary density of WPC, but not of RM, reduced body weight gain by 4% (P < 0.001). Dietary WPC also reduced plasma insulin concentration by 40% (P < 0.05) and increased insulin sensitivity, compared to RM (P < 0.05). These findings support the conclusions that a high-protein diet reduces energy intake and adiposity and that whey protein is more effective than red meat in reducing body weight gain and increasing insulin sensitivity.
Effect of a high protein diet and/or resistance exercise on the preservation of fat free mass during weight loss in overweight and obese older adults: a randomized controlled trial.
Verreijen Amely M,Engberink Mariëlle F,Memelink Robert G,van der Plas Suzanne E,Visser Marjolein,Weijs Peter J M
BACKGROUND:Intentional weight loss in obese older adults is a risk factor for accelerated muscle mass loss. We investigated whether a high protein diet and/or resistance exercise preserves fat free mass (FFM) during weight loss in overweight and obese older adults. METHODS:We included 100 overweight and obese adults (55-80 year) in a randomized controlled trial (RCT) with a 2 × 2 factorial design and intention-to-treat analysis. During a 10-week weight loss program all subjects followed a hypocaloric diet. Subjects were randomly allocated to either a high protein (1.3 g/kg body weight) or normal protein diet (0.8 g/kg), with or without a resistance exercise program 3 times/week. FFM was assessed by air displacement plethysmography. RESULTS:At baseline, mean (±SD) BMI was 32 ± 4 kg/m. During intervention, protein intake was 1.13 ± 0.35 g/kg in the high protein groups vs. 0.98 ± 0.29 in the normal protein groups, which reflects a 16.3 ± 5.2 g/d higher protein intake in the high protein groups. Both high protein diet and exercise did not significantly affect change in body weight, FFM and fat mass (FM). No significant protein*exercise interaction effect was observed for FFM. However, within-group analysis showed that high protein in combination with exercise significantly increased FFM (+0.6 ± 1.3 kg, p = 0.011). CONCLUSION:A high protein diet, though lower than targeted, did not significantly affect changes in FFM during modest weight loss in older overweight and obese adults. There was no significant interaction between the high protein diet and resistance exercise for change in FFM. However, only the group with the combined intervention of high protein diet and resistance exercise significantly increased in FFM. TRIAL REGISTRATION:Dutch Trial Register, number NTR4556, date 05-01-2014.
Comparative effects of whey and casein proteins on satiety in overweight and obese individuals: a randomized controlled trial.
Pal S,Radavelli-Bagatini S,Hagger M,Ellis V
European journal of clinical nutrition
BACKGROUND/OBJECTIVE:Dairy protein seems to reduce appetite by increasing satiety and delaying the return of hunger and subsequently lowering energy intake compared with fat or carbohydrate. The aim of this study was to compare the effect of whey with that of casein proteins on satiety in overweight/obese individuals. METHODS/SUBJECTS:This was a randomized, parallel-design 12-week-long study. Seventy subjects with a body mass index between 25 and 40 kg/m(2) and aged 18-65 years were randomized into one of three supplement groups: glucose control (n=25), casein (n=20) or whey (n=25) protein. Before commencing the study, at weeks 6 and 12 of the treatment, a Visual Analogue Scale (VAS) was used to measure subjective sensations of appetite before lunch and before dinner. RESULTS:Rating for VAS (mm) at 6 and 12 weeks showed significantly higher satiety in the whey group compared with the casein (P=0.017 and P=0.025, respectively) or control (P=0.024 and P=0.032, respectively) groups when measured before lunch. Similarly, at 6 and 12 weeks, the score for fullness was also significantly higher in the whey group compared with both casein (P=0.038 and P=0.022, respectively) and control (P=0.020 and P=0.030, respectively) groups. However, these short-term effects on satiety from dairy whey proteins did not have any long-term effects on energy intake or body weight over 12 weeks compared with casein. CONCLUSIONS:Collectively, whey protein supplementation appears to have a positive and acute postprandial effect on satiety and fullness compared with casein and carbohydrate supplementation in overweight and obese individuals.
Metabolite profiling of obese individuals before and after a one year weight loss program.
Geidenstam N,Al-Majdoub M,Ekman M,Spégel P,Ridderstråle M
International journal of obesity (2005)
OBJECTIVE:We and others have previously characterized changes in circulating metabolite levels following diet-induced weight loss. Our aim was to investigate whether baseline metabolite levels and weight-loss-induced changes in these are predictive of or associated with changes in body mass index (BMI) and metabolic risk traits. METHODS:Serum metabolites were analyzed with gas and liquid chromatography/mass spectrometry in 91 obese individuals at baseline and after participating in a 1 year non-surgical weight loss program.ResultsA total of 137 metabolites were identified and semi-quantified at baseline (BMI 42.7±5.8, mean±s.d.) and at follow-up (BMI 36.3±6.6). Weight-loss-induced modification was observed for levels of 57 metabolites in individuals with ⩾10% weight loss. Lower baseline levels of xylitol was predictive of a greater decrease in BMI (β=0.06, P<0.01) and ⩾10% weight loss (odds ratio (OR)=0.2, confidence interval (CI)=0.07-0.7, P=0.01). Decreases in levels of isoleucine, leucine, valine and tyrosine were associated with decrease in BMI (β>0.1, P<0.05) and ⩾10% weight loss (isoleucine: OR=0.08, CI=0.01-0.3, leucine: OR=0.1, CI=0.01-0.6, valine: OR=0.1, CI=0.02-0.5, tyrosine: OR=0.1, CI=0.03-0.6, P<0.02). CONCLUSIONS:Diet-induced weight loss leads to mainly reduced levels of metabolites that are elevated in obese insulin resistant individuals. We identified multiple new associations with metabolic risk factors and validated several previous findings related to weight loss-mediated metabolite changes. Levels of specific metabolites, such as xylitol, may be predictive of the response to non-surgical weight loss already at baseline.
Weight loss predictability by plasma metabolic signatures in adults with obesity and morbid obesity of the DiOGenes study.
Stroeve Johanna H M,Saccenti Edoardo,Bouwman Jildau,Dane Adrie,Strassburg Katrin,Vervoort Jacques,Hankemeier Thomas,Astrup Arne,Smilde Age K,van Ommen Ben,Saris Wim H M
Obesity (Silver Spring, Md.)
OBJECTIVE:Aim is to predict successful weight loss by metabolic signatures at baseline and to identify which differences in metabolic status may underlie variations in weight loss success. METHODS:In DiOGenes, a randomized, controlled trial, weight loss was induced using a low-calorie diet (800 kcal) for 8 weeks. Men (N = 236) and women (N = 431) as well as groups with overweight/obesity and morbid obesity were studied separately. The relation between the metabolic status before weight loss and weight loss was assessed by stepwise regression on multiple data sets, including anthropometric parameters, NMR-based plasma metabolites, and LC-MS-based plasma lipid species. RESULTS:Maximally, 57% of the variation in weight loss success can be predicted by baseline parameters. The most powerful predictive models were obtained in subjects with morbid obesity. In these models, the metabolites most predictive for weight loss were acetoacetate, triacylglycerols, phosphatidylcholines, specific amino acids, and creatine and creatinine. This metabolic profile suggests that high energy metabolism activity results in higher amounts of weight loss. CONCLUSIONS:Possible predictive (pre-diet) markers were found for amount of weight loss for specific subgroups.
Human gut microbes impact host serum metabolome and insulin sensitivity.
Pedersen Helle Krogh,Gudmundsdottir Valborg,Nielsen Henrik Bjørn,Hyotylainen Tuulia,Nielsen Trine,Jensen Benjamin A H,Forslund Kristoffer,Hildebrand Falk,Prifti Edi,Falony Gwen,Le Chatelier Emmanuelle,Levenez Florence,Doré Joel,Mattila Ismo,Plichta Damian R,Pöhö Päivi,Hellgren Lars I,Arumugam Manimozhiyan,Sunagawa Shinichi,Vieira-Silva Sara,Jørgensen Torben,Holm Jacob Bak,Trošt Kajetan, ,Kristiansen Karsten,Brix Susanne,Raes Jeroen,Wang Jun,Hansen Torben,Bork Peer,Brunak Søren,Oresic Matej,Ehrlich S Dusko,Pedersen Oluf
Insulin resistance is a forerunner state of ischaemic cardiovascular disease and type 2 diabetes. Here we show how the human gut microbiome impacts the serum metabolome and associates with insulin resistance in 277 non-diabetic Danish individuals. The serum metabolome of insulin-resistant individuals is characterized by increased levels of branched-chain amino acids (BCAAs), which correlate with a gut microbiome that has an enriched biosynthetic potential for BCAAs and is deprived of genes encoding bacterial inward transporters for these amino acids. Prevotella copri and Bacteroides vulgatus are identified as the main species driving the association between biosynthesis of BCAAs and insulin resistance, and in mice we demonstrate that P. copri can induce insulin resistance, aggravate glucose intolerance and augment circulating levels of BCAAs. Our findings suggest that microbial targets may have the potential to diminish insulin resistance and reduce the incidence of common metabolic and cardiovascular disorders.
Whey Protein Hydrolysate and Pumpkin Pectin as Nutraceutical and Prebiotic Components in a Functional Mousse with Antihypertensive and Bifidogenic Properties.
Agarkova Evgeniya Yu,Kruchinin Alexandr G,Glazunova Olga A,Fedorova Tatyana V
Systematical consumption of functional products has a significant positive effect on health and can reduce the risk of diseases. The aim of this study was to investigate the possibility of using whey protein hydrolysate (WPH) and pumpkin pectin as ingredients in a functional mousse, to evaluate the mousse's antioxidant and hypotensive activities in vitro, and to evaluate the effect of the long-term intake of mousse samples on the progression of hypertension in spontaneously hypertensive rats (SHRs) and on the microbiome status in Wistar rats with antibiotic-induced dysbiosis. The experimental mousse's in vitro antioxidant activity (oxygen radical absorbance capacity) increased by 1.2 times. The hypotensive (angiotensin-1-converting enzyme inhibitory) activity increased by 6 times in comparison with a commercial mousse. Moreover, the addition of pectin allowed the elimination of the bitter aftertaste of WPH. In vivo testing confirmed the hypotensive properties of the experimental mousse. The systolic blood pressure in SHRs decreased by 18 mmHg and diastolic blood pressure by 12 mmHg. The experimental mousse also showed a pronounced bifidogenic effect. The spp. population increased by 3.7 times in rats orally administered with the experimental mousse. The results of these studies confirm that WPH and pumpkin pectin are prospective ingredients for the development of functional mousses.
Inulin-type fructans and whey protein both modulate appetite but only fructans alter gut microbiota in adults with overweight/obesity: A randomized controlled trial.
Reimer Raylene A,Willis Holly J,Tunnicliffe Jasmine M,Park Heekuk,Madsen Karen L,Soto-Vaca Adriana
Molecular nutrition & food research
SCOPE:Independently, prebiotics and dietary protein have been shown to improve weight loss and/or alter appetite. Our objective was to determine the effect of combined prebiotic and whey protein on appetite, body composition and gut microbiota in adults with overweight/obesity. METHODS AND RESULTS:In a 12 week, placebo-controlled, double-blind study, 125 adults with overweight/obesity were randomly assigned to receive isocaloric snack bars of: (1) Control; (2) Inulin-type fructans (ITF); (3) Whey protein; (4) ITF + Whey protein. Appetite, body composition and gut microbiota composition/genetic potential were assessed. Compared to Control, body fat was significantly reduced in the Whey protein group at 12 wks. Hunger, desire to eat and prospective food consumption were all lower with ITF, Whey protein and ITF + Whey protein compared to Control at 12 wks. Microbial community structure differed from 0 to 12 wks in the ITF and ITF +Whey Protein groups (i.e. increased Bifidobacterium) but not Whey Protein or Control. Changes in microbial genetic potential were seen between Control and ITF-containing treatments. CONCLUSION:Adding ITF, whey protein or both to snack bars improved several aspects of appetite control. Changes in gut microbiota may explain in part the effects of ITF but likely not whey protein.
In vitro modulation of gut microbiota by whey protein to preserve intestinal health.
Sánchez-Moya T,López-Nicolás R,Planes D,González-Bermúdez C A,Ros-Berruezo G,Frontela-Saseta C
Food & function
The effect of several types of whey milk - cow, sheep, goat and a mixture of them (60 : 20 : 20, respectively) - was assessed in the human gut microbiota. The prebiotic potential of these substrates was evaluated through in vitro gastrointestinal digestion following faecal batch culture fermentations (mimicking colonic fermentation) for 48 hours, using faeces from normal-weight (NW) and obese (OB) donors. Throughout the fermentation process, pH, gas production, short chain and branched fatty acids (SCFA-BCFA) were measured, as well as the changes of microbiota using qPCR. The pH decreased in all whey samples during the fermentation process. Gas production was higher in all whey samples than in controls, especially at 12 hours (p < 0.05). The diversity of SCFA and BCFA production was significantly different between the donors, in particular cow and mixed whey. Whey milk had a strong prebiotic effect on the gut microbiota of NW and OB donors, showing a significant increase of Bifidobacterium (p < 0.05) with cow, sheep and mixed whey and increase in the Lactobacillus group, particularly in OB donors. Bacteria associated with obesity did not show an increase in any of the groups of donors. Therefore, supplementing a diet with these types of whey can selectively stimulate the growth of probiotic bacteria, enhancing SCFA production, which could improve intestinal disorders. In addition, it may be an interesting approach to the prevention of overweight and obesity and related diseases. Whey milk has a potent prebiotic effect. It can selectively stimulate desirable bacteria and SCFA profile, in both OB and NW donors, contributing to improved intestinal health and reducing obesity.
Environment dominates over host genetics in shaping human gut microbiota.
Rothschild Daphna,Weissbrod Omer,Barkan Elad,Kurilshikov Alexander,Korem Tal,Zeevi David,Costea Paul I,Godneva Anastasia,Kalka Iris N,Bar Noam,Shilo Smadar,Lador Dar,Vila Arnau Vich,Zmora Niv,Pevsner-Fischer Meirav,Israeli David,Kosower Noa,Malka Gal,Wolf Bat Chen,Avnit-Sagi Tali,Lotan-Pompan Maya,Weinberger Adina,Halpern Zamir,Carmi Shai,Fu Jingyuan,Wijmenga Cisca,Zhernakova Alexandra,Elinav Eran,Segal Eran
Human gut microbiome composition is shaped by multiple factors but the relative contribution of host genetics remains elusive. Here we examine genotype and microbiome data from 1,046 healthy individuals with several distinct ancestral origins who share a relatively common environment, and demonstrate that the gut microbiome is not significantly associated with genetic ancestry, and that host genetics have a minor role in determining microbiome composition. We show that, by contrast, there are significant similarities in the compositions of the microbiomes of genetically unrelated individuals who share a household, and that over 20% of the inter-person microbiome variability is associated with factors related to diet, drugs and anthropometric measurements. We further demonstrate that microbiome data significantly improve the prediction accuracy for many human traits, such as glucose and obesity measures, compared to models that use only host genetic and environmental data. These results suggest that microbiome alterations aimed at improving clinical outcomes may be carried out across diverse genetic backgrounds.
Obesity, inflammation, and the gut microbiota.
Cox Amanda J,West Nicholas P,Cripps Allan W
The lancet. Diabetes & endocrinology
As the prevalence of obesity and associated disease continues to rise and concerns for the spiralling economic and social costs also escalate, innovative management strategies beyond primary prevention and traditional lifestyle interventions are urgently needed. The biological basis of disease is one avenue for further exploration in this context. Several key inflammatory markers have been consistently associated with both obesity and risk of adverse outcomes in obesity-associated diseases, which suggests that a persistent, low-grade, inflammatory response is a potentially modifiable risk factor. In this Review, we provide evidence supporting perturbation of the intestinal microbiota and changes in intestinal permeability as potential triggers of inflammation in obesity. Further characterisation of the mechanisms underpinning the triggers of such inflammatory responses in overweight and obese individuals could offer unique opportunities for intervention strategies to help ameliorate the risk of obesity-associated disease.
Whey protein hydrolysate and branched-chain amino acids downregulate inflammation-related genes in vascular endothelial cells.
Da Silva Marine S,Bigo Cyril,Barbier Olivier,Rudkowska Iwona
Nutrition research (New York, N.Y.)
A recent review of clinical studies reports that dairy products may improve inflammation, a key etiologic cardiovascular disease risk factor. Yet the impact of dairy proteins on inflammatory markers is controversial and could be mediated by a differential impact of whey proteins and caseins. In this study, we hypothesized that whey proteins may have a greater anti-inflammatory effect than caseins. A model of human umbilical vein endothelial cells, with or without TNF-α stimulation, was used to investigate the effect of several dairy protein compounds on inflammation. Specifically, the impact of whey proteins either isolate or hydrolysate, caseins, and their amino acids on expression of TNF, VCAM-1, SOD2, and eNOS was examined. After a 24-hour incubation period, whey protein hydrolysate, leucine, isoleucine, and valine attenuated the TNF-α-induced endothelial inflammation by normalizing TNF and eNOS gene expression. This effect was not observed in unstimulated cells. Oppositely, caseins, a whey protein/casein mixture (1:4 w/w), and glutamine aggravated the TNF-α-induced TNF and SOD2 gene expression. Yet caseins and whey protein/casein mixture decreased VCAM-1 expression in both unstimulated and stimulated human umbilical vein endothelial cells. Measurement of TNF-α in cell supernatants by immunoassay substantiates gene expression data without reaching statistical significance. Taken together, this study showed that whey proteins and their major amino acids normalize TNF-α-induced proinflammatory gene expression in endothelial cells.
A whey protein hydrolysate promotes insulinotropic activity in a clonal pancreatic β-cell line and enhances glycemic function in ob/ob mice.
Gaudel Celine,Nongonierma Alice B,Maher Samuel,Flynn Sarah,Krause Mauricio,Murray Brian A,Kelly Phillip M,Baird Alan W,FitzGerald Richard J,Newsholme Philip
The Journal of nutrition
Whey protein hydrolysates (WPHs) represent novel antidiabetic agents that affect glycemia in animals and humans, but little is known about their insulinotropic effects. The effects of a WPH were analyzed in vitro on acute glucose-induced insulin secretion in pancreatic BRIN-BD11 β cells. WPH permeability across Caco-2 cell monolayers was determined in a 2-tiered intestinal model. WPH effects on insulin resistance were studied in vivo following an 8-wk oral ingestion (100 mg/kg body weight) by ob/ob (OB-WPH) and wild-type mice (WT-WPH) compared with vehicle control (OB and WT groups) using a 2 × 2 factorial design, genotype × treatment. BRIN-BD11 cells showed a robust and reproducible dose-dependent insulinotropic effect of WPH (from 0.01 to 5.00 g/L). WPH bioactive constituents were permeable across Caco-2 cell monolayers. In the OB-WPH and WT-WPH groups, WPH administration improved glucose clearance after a glucose challenge (2 g/kg body weight), as indicated by differences in the area under curves (AUCs) (P ≤ 0.05). The basal plasma glucose concentration was not affected by WPH treatment in either genotype. The plasma insulin concentration was lower in the OB-WPH than in the OB group (P ≤ 0.005) but was similar between the WT and WT-WPH groups; the interaction genotype × treatment was significant (P ≤ 0.005). Insulin release from pancreatic islets isolated from the OB-WPH group was greater (P ≤ 0.005) than that from the OB group but did not differ between the WT-WPH and WT groups; the interaction genotype × treatment was not significant. In conclusion, an 8-wk oral administration of WPH improved blood glucose clearance, reduced hyperinsulinemia, and restored the pancreatic islet capacity to secrete insulin in response to glucose in ob/ob mice. Hence, it may be useful in diabetes management.
Effects of whey protein isolate on body composition, lipids, insulin and glucose in overweight and obese individuals.
Pal Sebely,Ellis Vanessa,Dhaliwal Satvinder
The British journal of nutrition
The health benefits currently associated with increased dairy intake may be attributable to the whey component of dairy proteins. The present study evaluated the effects of whey protein supplementation on body composition, lipids, insulin and glucose in comparison to casein and glucose (control) supplementation in overweight/obese individuals for 12 weeks. The subjects were randomised to whey protein, casein or glucose supplementation for 12 weeks according to a parallel design. Fasting blood samples and dual-energy X-ray absorptiometry measurements were taken. Seventy men and women with a mean age of 48.4 (SEM 0.86) years and a mean BMI of 31.3 (SEM 0.8) kg/m2 completed the study. Subjects supplemented with whey protein had no significant change in body composition or serum glucose at 12 weeks compared with the control or casein group. Fasting TAG levels were significantly lowered in the whey group compared with the control group at 6 weeks (P = 0.025) and 12 weeks (P = 0.035). There was a significant decrease in total cholesterol and LDL cholesterol at week 12 in the whey group compared with the casein (P = 0.026 and 0.045, respectively) and control groups (P < 0.001 and 0.003, respectively). Fasting insulin levels and homeostasis model assessment of insulin resistance scores were also significantly decreased in the whey group compared with the control group (P = 0.049 and P = 0.034, respectively). The present study demonstrated that supplementation with whey proteins improves fasting lipids and insulin levels in overweight and obese individuals.
Effect of a Whey Protein Supplement on Preservation of Fat Free Mass in Overweight and Obese Individuals on an Energy Restricted Very Low Caloric Diet.
Larsen Anne Ellegaard,Bibby Bo Martin,Hansen Mette
The obesity epidemic has caused a widespread interest in strategies to achieve a healthy "high quality" weight loss, where excess fat is lost, while fat free mass (FFM) is preserved. In this study, we aimed to examine the effect of whey protein supplementation given before night sleep on FFM preservation during a 4-week (wk) period on a very low caloric diet (VLCD). Twenty-nine obese subjects (body mass index (BMI) > 28 kg/m²) completed a 4-week intervention including a VLCD and a walking program (30 min walking × 5 times per week). Subjects were randomly assigned to either control (CON, n = 15) or a whey protein supplement (PRO, 0.4 g protein/kg/day, n = 14), ingested before bedtime. Body composition (dual-energy X-ray absorptiometry, DXA), blood analysis and physical test were performed pre and post intervention. We measured nitrogen excretion in three 24 h urine collections (Day 0, 7 and 28) to assess nitrogen balance. Changes in nitrogen balance (NB) after 7 and 28 days was different between treatment groups (interaction < 0.05). PRO was in NB after 7 days and in positive NB at day 28. In contrast, CON was in negative NB at day 7, but in NB at day 28. Nevertheless, no significant group differences were observed in the change in pre- and post-FFM measurements (-2.5 kg, [95% CI: 1.9; 3.1], = 0.65). In conclusion, ingestion of a whey protein supplement before bedtime during a 4-week period on a VLCD improved nitrogen balance, but did not lead to any significant improvement in the quality of the weight loss in regard to observed changes in body composition and health parameters compared with controls.
Protein, amino acids and obesity treatment.
Simonson Mathilde,Boirie Yves,Guillet Christelle
Reviews in endocrine & metabolic disorders
Dietary proteins have been used for years to treat obesity. Body weight loss is beneficial when it concerns fat mass, but loss of fat free mass - especially muscle might be detrimental. This occurs because protein breakdown predominates over synthesis, thus administering anabolic dietary compounds like proteins might counter fat free mass loss while allowing for fat mass loss.Indeed, varying the quantity of proteins will decrease muscle anabolic response and increase hyperphagia in rodents fed a low protein diet; but it will favor lean mass maintenance and promote satiety, in certain age groups of humans fed a high protein diet. Beyond protein quantity, protein source is an important metabolic regulator: whey protein and plant based diets exercize favorable effects on the risk of developing obesity, body composition, metabolic parameters or fat free mass preservation of obese patients. Specific amino-acids like branched chain amino acids (BCAA), methionine, tryptophan and its metabolites, and glutamate can also positively influence parameters and complications of obesity especially in rodent models, with less studies translating this in humans.Tuning the quality and quantity of proteins or even specific amino-acids can thus be seen as a potential therapeutic intervention on the body composition, metabolic syndrome parameters and appetite regulation of obese patients. Since these effects vary across age groups and much of the data comes from murine models, long-term prospective studies modulating proteins and amino acids in the human diet are needed.
Evaluation of Hypocaloric Diet With Protein Supplementation in Middle-Aged Sarcopenic Obese Women: A Pilot Study.
Sammarco Rosa,Marra Maurizio,Di Guglielmo Maria Luisa,Naccarato Marianna,Contaldo Franco,Poggiogalle Eleonora,Donini Lorenzo Maria,Pasanisi Fabrizio
OBJECTIVE:The aim of this study was to evaluate the efficacy of a nutritional program, which is characterized by a different modulation of proteins, in adult patients with sarcopenic obesity. METHODS:We studied 18 obese women aged 41-74 years. Obesity was diagnosed as fat mass > 34.8% and sarcopenia was defined when lean body mass was <90% of the subject's ideal fat free mass. All subjects were randomly assigned to different nutritional interventions: Hypocaloric diet plus placebo (A) and hypocaloric high-protein diet (1.2-1.4 g / kg body weight reference / day) (B). Anthropometric measurements, body composition, resting energy expenditure, handgrip test, Short Physical Performance Battery (SPPB), and SF-36 questionnaire were evaluated at baseline and after 4 months. RESULTS:Weight significantly decreased in both groups. Women with high-protein diet preserved lean body mass compared to low-calorie diet and improved significantly muscle strength; SPPB score did not change in both groups. SF-36 test showed a significant change for general health after 4 months in group B. CONCLUSIONS:In our study, sarcopenic obese patients with high-protein diet showed an improvement in muscle strength. Furthermore, dietary protein enrichment may represent a protection from the risk of sarcopenia following a hypocaloric diet.
Effects of dietary protein intake on body composition changes after weight loss in older adults: a systematic review and meta-analysis.
Kim Jung Eun,O'Connor Lauren E,Sands Laura P,Slebodnik Mary B,Campbell Wayne W
CONTEXT:The impact of dietary protein on body composition changes after older adults purposefully lose weight requires systematic evaluation OBJECTIVE:: This systematic review and meta-analysis assessed the effects of protein intake (< 25% vs ≥ 25% of energy intake or 1.0 g/kg/d) on energy restriction-induced changes in body mass, lean mass, and fat mass in adults older than 50 years. DATA SOURCES:PubMed, Cochrane, Scopus, and Google Scholar were searched using the keywords "dietary proteins," "body composition," "skeletal muscle," and "muscle strength." STUDY SELECTION:Two researchers independently screened 1542 abstracts. DATA EXTRACTION:Information was extracted from 24 articles. DATA SYNTHESIS:Twenty randomized control trials met the inclusion criteria. CONCLUSION:Older adults retained more lean mass and lost more fat mass during weight loss when consuming higher protein diets.
Weight loss in obese adults 65years and older: a review of the controversy.
Waters Debra L,Ward Aimee L,Villareal Dennis T
Obesity in older adults is ubiquitous in many developed countries and is related to various negative health outcomes, making it an important public health target for intervention. However, treatment approaches for obesity in older adults remain controversial due to concerns surrounding the difficulty of behavior change with advancing age, exacerbating the age-related loss of skeletal muscle and bone, and the feasibility of long-term weight maintenance and related health consequences. This review serves to systematically examine the evidence regarding weight loss interventions with a focus on obese (body mass index 30kg/m(2) and above) older adults (aged 65years and older) and some proposed mechanisms associated with exercise and caloric restriction (lifestyle intervention). Our findings indicate that healthy weight loss in this age group can be achieved through lifestyle interventions of up to a one-year period. Most interventions reviewed reported a loss of lean body mass and bone mineral density with weight loss. Paradoxically muscle quality and physical function improved. Inflammatory molecules and metabolic markers also improved, although the independent and additive effects of exercise and weight loss on these pathways are poorly understood. Using our review inclusion criteria, only one small pilot study investigating long-term weight maintenance and associated health implications was found in the literature. Future research on lifestyle interventions for obese older adults should address the loss of bone and lean body mass, inflammatory mechanisms, and include sufficient follow-up to assess long-term weight maintenance and health outcomes.
Effects of a High-Protein Diet Including Whole Eggs on Muscle Composition and Indices of Cardiometabolic Health and Systemic Inflammation in Older Adults with Overweight or Obesity: A Randomized Controlled Trial.
Wright Christian S,Zhou Jing,Sayer R Drew,Kim Jung Eun,Campbell Wayne W
Age-related increases in intermuscular adipose tissue (IMAT) impair muscle quality, decrease functional capacity, and promote several cardiometabolic and inflammatory disorders. Whether these age-related alterations in muscle composition improve by consuming a high-protein (HP) diet with whole eggs are unclear. This parallel-design, randomized-controlled trial assessed the effects of a 12-week eucaloric HP diet with three whole eggs per day (1.4 g protein kg day) versus a normal-protein diet void of eggs (NP, 0.8 g protein kg day) on muscle composition (IMAT), cardiometabolic health, and systemic inflammation in older adults with overweight or obesity (12 men and 10 women; age 70 ± 5 years, BMI 31.3 ± 3.2 kg/m², mean ± SD). No changes in muscle composition were observed over time, independent of protein intake. Total body weight was reduced in both groups (-3.3 ± 1.2%) and lean mass was preserved only with the HP diet. LDL concentration and hip circumference decreased only with the NP diet, while MCP-1 and HsCRP concentrations increased over time in both groups. A HP diet with whole eggs promotes lean mass retention with modest weight loss, but does not positively influence muscle composition, cardiometabolic health or systemic inflammation, compared to a NP diet void of eggs.
Epidemiology and determinants of obesity in China.
Pan Xiong-Fei,Wang Limin,Pan An
The lancet. Diabetes & endocrinology
Obesity has become a major public health issue in China. Overweight and obesity have increased rapidly in the past four decades, and the latest national prevalence estimates for 2015-19, based on Chinese criteria, were 6·8% for overweight and 3·6% for obesity in children younger than 6 years, 11·1% for overweight and 7·9% for obesity in children and adolescents aged 6-17 years, and 34·3% for overweight and 16·4% for obesity in adults (≥18 years). Prevalence differed by sex, age group, and geographical location, but was substantial in all subpopulations. Strong evidence from prospective cohort studies has linked overweight and obesity to increased risks of major non-communicable diseases and premature mortality in Chinese populations. The growing burden of overweight and obesity could be driven by economic developments, sociocultural norms, and policies that have shaped individual-level risk factors for obesity through urbanisation, urban planning and built environments, and food systems and environments. Substantial changes in dietary patterns have occurred in China, with increased consumption of animal-source foods, refined grains, and highly processed, high-sugar, and high-fat foods, while physical activity levels in all major domains have decreased with increasing sedentary behaviours. The effects of dietary factors and physical inactivity intersect with other individual-level risk factors such as genetic susceptibility, psychosocial factors, obesogens, and in-utero and early-life exposures. In view of the scarcity of research around the individual and collective roles of these upstream and downstream factors, multidisciplinary and transdisciplinary studies are urgently needed to identify systemic approaches that target both the population-level determinants and individual-level risk factors for obesity in China.