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Host-diet-gut microbiome interactions influence human energy balance: a randomized clinical trial.
Corbin, KD, Carnero, EA, Dirks, B, Igudesman, D, Yi, F, Marcus, A, Davis, TL, Pratley, RE, Rittmann, BE, Krajmalnik-Brown, R, et al
Nature communications. 2023;14(1):3161
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Composition of the human gut microbiome has been shown to be associated with chronic diseases such as obesity, however whether they have a causal effect in disease development or whether microbiota composition is a direct result of the disease is unclear. This randomised control trial of 17 individuals aimed to determine the effects of a diet designed to modulate the gut microbiome (MBD) on human energy balance compared to a typical Western style diet (WD). The MBD diet maximised fibre, resistant starch, and limited processed foods and resulted in a significant decrease in the amount of energy produced by individuals compared to the WD. It was also shown that the MBD increased the microbial composition and decreased nutrient breakdown. It was concluded that the MBD increased the amount of gut bacteria and altered the amount of energy produced by individuals on this diet. This study could be used by healthcare practitioners to understand that composition of the gut microbiome can affect the amount of energy gained from food. Diets high in fibre, starch and low in processed foods, which promote microbial diversity may help individuals to lose weight.
Abstract
The gut microbiome is emerging as a key modulator of human energy balance. Prior studies in humans lacked the environmental and dietary controls and precision required to quantitatively evaluate the contributions of the gut microbiome. Using a Microbiome Enhancer Diet (MBD) designed to deliver more dietary substrates to the colon and therefore modulate the gut microbiome, we quantified microbial and host contributions to human energy balance in a controlled feeding study with a randomized crossover design in young, healthy, weight stable males and females (NCT02939703). In a metabolic ward where the environment was strictly controlled, we measured energy intake, energy expenditure, and energy output (fecal and urinary). The primary endpoint was the within-participant difference in host metabolizable energy between experimental conditions [Control, Western Diet (WD) vs. MBD]. The secondary endpoints were enteroendocrine hormones, hunger/satiety, and food intake. Here we show that, compared to the WD, the MBD leads to an additional 116 ± 56 kcals (P < 0.0001) lost in feces daily and thus, lower metabolizable energy for the host (89.5 ± 0.73%; range 84.2-96.1% on the MBD vs. 95.4 ± 0.21%; range 94.1-97.0% on the WD; P < 0.0001) without changes in energy expenditure, hunger/satiety or food intake (P > 0.05). Microbial 16S rRNA gene copy number (a surrogate of biomass) increases (P < 0.0001), beta-diversity changes (whole genome shotgun sequencing; P = 0.02), and fermentation products increase (P < 0.01) on an MBD as compared to a WD along with significant changes in the host enteroendocrine system (P < 0.0001). The substantial interindividual variability in metabolizable energy on the MBD is explained in part by fecal SCFAs and biomass. Our results reveal the complex host-diet-microbiome interplay that modulates energy balance.
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Reprogramming the Human Gut Microbiome Reduces Dietary Energy Harvest.
Corbin, KD, Carnero, EA, Dirks, B, Igudesman, D, Yi, F, Marcus, A, Davis, TL, Pratley, RE, Rittmann, BE, Krajmalnik-Brown, R, et al
Research square. 2023
Abstract
The gut microbiome is emerging as a key modulator of host energy balance1. We conducted a quantitative bioenergetics study aimed at understanding microbial and host factors contributing to energy balance. We used a Microbiome Enhancer Diet (MBD) to reprogram the gut microbiome by delivering more dietary substrates to the colon and randomized healthy participants into a within-subject crossover study with a Western Diet (WD) as a comparator. In a metabolic ward where the environment was strictly controlled, we measured energy intake, energy expenditure, and energy output (fecal, urinary, and methane)2. The primary endpoint was the within-participant difference in host metabolizable energy between experimental conditions. The MBD led to an additional 116 ± 56 kcals lost in feces daily and thus, lower metabolizable energy for the host by channeling more energy to the colon and microbes. The MBD drove significant shifts in microbial biomass, community structure, and fermentation, with parallel alterations to the host enteroendocrine system and without altering appetite or energy expenditure. Host metabolizable energy on the MBD had quantitatively significant interindividual variability, which was associated with differences in the composition of the gut microbiota experimentally and colonic transit time and short-chain fatty acid absorption in silico. Our results provide key insights into how a diet designed to optimize the gut microbiome lowers host metabolizable energy in healthy humans.
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Glucagon-like peptide-1/glucagon receptor agonism associates with reduced metabolic adaptation and higher fat oxidation: A randomized trial.
Corbin, KD, Carnero, EA, Allerton, TD, Tillner, J, Bock, CP, Luyet, PP, Göbel, B, Hall, KD, Parsons, SA, Ravussin, E, et al
Obesity (Silver Spring, Md.). 2023;(2):350-362
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Abstract
OBJECTIVE This study tested the hypothesis that treatment with the glucagon-like peptide-1/glucagon receptor agonist SAR425899 would lead to a smaller decrease in sleeping metabolic rate (SMR; kilocalories/day) than expected from the loss of lean and fat mass (metabolic adaptation). METHODS This Phase 1b, double-blind, randomized, placebo-controlled study was conducted at two centers in inpatient metabolic wards. Thirty-five healthy males and females with overweight and obesity (age = 36.5 ± 7.1 years) were randomized to a calorie-reduced diet (-1000 kcal/d) and escalating doses (0.06-0.2 mg/d) of SAR425899 (n = 17) or placebo (n = 18) for 19 days. SMR was measured by whole-room calorimetry. RESULTS Both groups lost weight (-3.68 ± 1.37 kg placebo; -4.83 ± 1.44 kg SAR425899). Those treated with SAR425899 lost more weight, fat mass, and fat free mass (p < 0.05) owing to a greater achieved energy deficit than planned. The SAR425899 group had a smaller reduction in body composition-adjusted SMR (p = 0.002) as compared with placebo, but not 24-hour energy expenditure. Fat oxidation and ketogenesis increased in both groups, with significantly greater increases with SAR425899 (p < 0.05). CONCLUSIONS SAR425899 led to reduced selective metabolic adaptation and increased lipid oxidation, which are believed to be beneficial for weight loss and weight-loss maintenance.
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Sleep Disturbance and Changes in Energy Intake and Body Composition During Weight Loss in the POUNDS Lost Trial.
Li, A, Li, X, Zhou, T, Ma, H, Heianza, Y, Williamson, DA, Smith, SR, Bray, GA, Sacks, FM, Qi, L
Diabetes. 2022;(5):934-944
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Abstract
To examine associations between sleep disturbance and changes in weight and body composition and the mediating role of changes of appetite and food cravings in the Preventing Overweight Using Novel Dietary Strategies (POUNDS Lost) 2-year weight-loss diet intervention trial, this study included 810 overweight or obese individuals with baseline sleep disturbance assessment who were randomly assigned one of four diets varying in macronutrient composition. Changes in body weight and fat distribution were assessed by DEXA and computed tomography during the 2-year intervention. Participants were asked to provide sleep disturbance levels (no, slight, moderate, or great) at baseline and to recall their sleep disturbances since last visit at 6, 12, 18, and 24 months. Weight loss during the first 6 months was followed by 1.5 years of steady weight regain. Participants with greater sleep disturbance from baseline to 6 months showed significant losses of body weight (Ptrend <0.001) and waist circumference (Ptrend = 0.002) at 6 months, after multivariate adjustment. Compared with individuals without sleep disturbance at all from baseline to 6 months, those with slight, moderate, or great sleep disturbance showed an elevated risk of failure to lose weight (-5% or more loss) at 6 months, when the maximum weight loss was achieved, with an odds ratio of 1.24 (95% CI 0.87, 1.78), 1.27 (95% CI 0.75, 2.13), or 3.12 (95% CI 1.61, 6.03), respectively. In addition, we observed that the repeatedly measured levels of sleep disturbance over 2 years were inversely associated with the overall weight loss rate (weight changes per 6 months) (Ptrend <0.001). Further, sleep disturbances during weight loss from baseline to 6 months and weight regain from 6 months to 24 months were significantly predictive of total fat, total fat mass percent, and trunk fat percent changes during the 2 years. Our results also indicated that food cravings for carbohydrates/starches, fast food fats, and sweets; cravings, prospective consumption, hunger of appetite measurements; and dietary restraint, disinhibition, and hunger subscales measured at 6 months significantly mediated the effects of sleep disturbance on weight loss. In conclusion, our results suggested that more severe sleep disturbance during weight loss was associated with an elevated risk of failure to lose weight during the dietary intervention. Food cravings and eating behaviors may partly mediate these associations.
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Chemical Oxygen Demand Can Be Converted to Gross Energy for Food Items Using a Linear Regression Model.
Davis, TL, Dirks, B, Carnero, EA, Corbin, KD, Krakoff, J, Parrington, S, Lee, D, Smith, SR, Rittmann, BE, Krajmalnik-Brown, R, et al
The Journal of nutrition. 2021;(2):445-453
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Abstract
BACKGROUND Human and microbial metabolism are distinct disciplines. Terminology, metrics, and methodologies have been developed separately. Therefore, combining the 2 fields to study energetic processes simultaneously is difficult. OBJECTIVES When developing a mechanistic framework describing gut microbiome and human metabolism interactions, energy values of food and digestive materials that use consistent and compatible metrics are required. As an initial step toward this goal, we developed and validated a model to convert between chemical oxygen demand (COD) and gross energy (${E_g}$) for >100 food items and ingredients. METHODS We developed linear regression models to relate (and be able to convert between) theoretical gross energy (${E_g}^{\prime}$) and chemical oxygen demand (COD'); the latter is a measure of electron equivalents in the food's carbon. We developed an overall regression model for the food items as a whole and separate regression models for the carbohydrate, protein, and fat components. The models were validated using a sample set of computed ${E_g}^{\prime}$ and COD' values, an experimental sample set using measured ${E_g}$ and COD values, and robust statistical methods. RESULTS The overall linear regression model and the carbohydrate, protein, and fat regression models accurately converted between COD and ${E_g}$, and the component models had smaller error. Because the ratios of COD per gram dry weight were greatest for fats and smallest for carbohydrates, foods with a high fat content also had higher ${E_g}$ values in terms of kcal · g dry weight-1. CONCLUSION Our models make it possible to analyze human and microbial energetic processes in concert using a single unit of measure, which fills an important need in the food-nutrition-metabolism-microbiome field. In addition, measuring COD and using the regressions to calculate ${E_g}$ can be used instead of measuring ${E_g}$ directly using bomb calorimetry, which saves time and money.
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Effect of Overeating Dietary Protein at Different Levels on Circulating Lipids and Liver Lipid: The PROOF Study.
Bray, GA, Redman, LM, Rood, J, de Jonge, L, Smith, SR
Nutrients. 2020;(12)
Abstract
BACKGROUND During overeating, a low protein diet slowed the rate of weight gain and increased the energy cost of the added weight, suggesting that low protein diets reduced energy efficiency. The Protein Overfeeding (PROOF) study explored the metabolic changes to low and high protein diets, and this sub-study examined the changes in body composition and blood lipids when eating high and low protein diets during overeating. METHODS Twenty-three healthy volunteers (M = 14; F = 9) participated in an 8-week, parallel arm study where they were overfed by ~40% with diets containing 5% (LPD = low protein diet), 15% (NPD = normal protein diet), or 25% (HPD = high protein diet) protein. Dual energy X-ray absorptiometry (DXA) and computer tomography (CT) were used to quantify whole body and abdominal fat and intrahepatic lipid, respectively. Metabolites were measured by standard methods. RESULTS Protein intake and fat intake were inversely related since carbohydrate intake was fixed. Although overeating the LPD diet was associated with a significant increase in high density lipoprotein (HDL)-cholesterol (p < 0.001) and free fatty acids (p = 0.034), and a significant decrease in fat free mass (p < 0.0001) and liver density (p = 0.038), statistical models showed that dietary protein was the main contributor to changes in fat free mass (p = 0.0040), whereas dietary fat was the major predictor of changes in HDL-cholesterol (p = 0.014), free fatty acids (p = 0.0016), and liver fat (p = 0.0007). CONCLUSIONS During 8 weeks of overeating, the level of dietary protein intake was positively related to the change in fat free mass, but not to the change in HDL-cholesterol, free fatty acids, and liver fat which were, in contrast, related to the intake of dietary fat.
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Racial differences in body composition and cardiometabolic risk during the menopause transition: a prospective, observational cohort study.
Marlatt, KL, Redman, LM, Beyl, RA, Smith, SR, Champagne, CM, Yi, F, Lovejoy, JC
American journal of obstetrics and gynecology. 2020;(4):365.e1-365.e18
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Abstract
BACKGROUND Obesity disproportionately affects more women than men. The loss of ovarian function during the menopause transition coincides with weight gain, increases in abdominal adiposity, and impaired metabolic health. Racial differences in obesity prevalence that results from the menopause transition are not well understood. OBJECTIVE The purpose of the study was to assess longitudinal changes in body composition and cardiometabolic risk among black and white women during the menopausal transition. STUDY DESIGN In a secondary analysis of a prospective, observational cohort study (the Healthy Transitions study), 161 women ≥43 years old with a body mass index of 20-40 kg/m2 and who had not yet transitioned through menopause were enrolled at Pennington Biomedical Research Center. Women were seen annually for body composition by dual-energy X-ray absorptiometry, for abdominal adipose tissue distribution by computed tomography, for sex steroid hormones, and for cardiometabolic risk factors that include fasting glucose, insulin, and lipids. Surrogate measures of insulin sensitivity were also calculated. RESULTS Ninety-four women (25 black, 69 white) transitioned through menopause and were included within the analyses. At menopause onset, black women weighed more (77.8±3.0 vs 70.8±1.8 kg) and had a higher systolic (125±16 vs 118±14 mm Hg) and diastolic (80±8 vs 74±7 mm Hg) blood pressure compared with white women (all P≤.05). No other differences in body composition, sex steroid hormones, or cardiometabolic risk factors were observed at menopause onset. Before menopause, white women gained significant weight (3 kg), total body adiposity (6% percent body fat, 9% fat mass, 12% trunk fat mass) and abdominal adipose tissue (19% subcutaneous fat, 15% visceral fat, 19% total adipose tissue), which coincided with significant decreases in estradiol, sex hormone-binding globulin, and estrone sulfate and increases in follicle-stimulating hormone, total cholesterol, and low-density lipoprotein cholesterol. Conversely, black women had more abdominal adipose tissue before menopause, which was maintained across the menopause transition. Black women also had significant decreases in estrone sulfate and total testosterone and increases in follicle-stimulating hormone before menopause. In the postmenopausal years, abdominal subcutaneous adipose tissue, total adipose tissue, follicle-stimulating hormone, total cholesterol, and low-density and high-density lipoprotein cholesterol increased only in white women. CONCLUSION White women gained more abdominal adiposity during the menopause transition compared with black women, which, in part, may be due to differences in the pattern of sex steroid hormone changes between women of different racial backgrounds. The gains in abdominal adiposity in white women were observed in tandem with increased cardiometabolic risk factors. Future studies should consider comprehensive lifestyle approaches to target these increased gains in abdominal adiposity (ie, nutrition and physical activity coaching), while taking into account the potential interactions of race, body adiposity, sex steroid hormones, and their influence on cardiometabolic risk.
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Lorcaserin and Renal Outcomes in Obese and Overweight Patients in the CAMELLIA-TIMI 61 Trial.
Scirica, BM, Bohula, EA, Dwyer, JP, Qamar, A, Inzucchi, SE, McGuire, DK, Keech, AC, Smith, SR, Murphy, SA, Im, K, et al
Circulation. 2019;(3):366-375
Abstract
BACKGROUND Obesity is thought to increase renal hyperfiltration, thereby increasing albuminuria and the progression of renal disease. The effect of pharmacologically mediated weight loss on renal outcomes is not well-described. Lorcaserin, a selective serotonin 2C receptor agonist that promotes appetite suppression, led to sustained weight loss without any increased risk for major adverse cardiovascular (CV) events in the CAMELLIA-TIMI 61 trial (Cardiovascular and Metabolic Effects of Lorcaserin in Overweight and Obese Patients-Thrombolysis in Myocardial Infarction 61). METHODS CAMELLIA-TIMI 61 randomly assigned 12 000 overweight or obese patients with or at high risk for atherosclerotic CV disease to lorcaserin or placebo on a background of lifestyle modification. The primary renal outcome was a composite of new or worsening persistent micro- or macroalbuminuria, new or worsening chronic kidney disease, doubling of serum creatinine, end-stage renal disease, renal transplant, or renal death. RESULTS At baseline, 23.8% of patients had an estimated glomerular filtration rate (eGFR) <60 mL·min-1·1.73 m-2 and 19.0% had albuminuria (urinary albumin:creatinine ratio ≥30 mg/g). Lorcaserin reduced the risk of the primary renal composite outcome (4.2% per year versus 4.9% per year; hazard ratio [HR], 0.87; 95% confidence interval [CI], 0.79-0.96; P=0.0064). The benefit was consistent across subpopulations at increased baseline CV and renal risk. Lorcaserin improved both eGFR and urinary albumin:creatinune ratio within the first year after randomization. The effect of lorcaserin on weight, hemoglobin A1c, and systolic blood pressure was consistent regardless of baseline renal function. Likewise, there was no excess in cardiovascular events in patients assigned to lorcaserin in comparison with placebo, regardless of renal function. After adjustment for baseline characteristics, those with evidence of kidney disease were at increased risk of major CV events. Compared with patients with an eGFR ≥90 mL·min-1·1.73 m-2, those with an eGFR 60-90 and those <60 mL·min-1·1.73 m-2 had HRs of 1.25 (95% CI, 1.01, 1.56) and 1.51 (95% CI, 1.17, 1.95), respectively ( P for trend 0.0015). Likewise, compared with patients with no albuminuria (<30 mg/g), those microalbuminuria and those with macroalbuminuria had HRs of 1.46 (95% CI, 1.22, 1.74) and 2.10 (95% CI, 1.58, 2.80), respectively ( P for trend <0.0001). CONCLUSIONS Renal dysfunction was associated with increased CV risk in overweight and obese patients. When added to diet and lifestyle, lorcaserin reduced the rate of new-onset or progressive renal impairment in comparison with placebo. CLINICAL TRIAL REGISTRATION URL: https://www.clinicaltrials.gov . Unique identifier: NCT02019264.
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Albuminuria and Allograft Failure, Cardiovascular Disease Events, and All-Cause Death in Stable Kidney Transplant Recipients: A Cohort Analysis of the FAVORIT Trial.
Weiner, DE, Park, M, Tighiouart, H, Joseph, AA, Carpenter, MA, Goyal, N, House, AA, Hsu, CY, Ix, JH, Jacques, PF, et al
American journal of kidney diseases : the official journal of the National Kidney Foundation. 2019;(1):51-61
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RATIONALE & OBJECTIVE Cardiovascular disease (CVD) is common and overall graft survival is suboptimal among kidney transplant recipients. Although albuminuria is a known risk factor for adverse outcomes among persons with native chronic kidney disease, the relationship of albuminuria with cardiovascular and kidney outcomes in transplant recipients is uncertain. STUDY DESIGN Post hoc longitudinal cohort analysis of the Folic Acid for Vascular Outcomes Reduction in Transplantation (FAVORIT) Trial. SETTING & PARTICIPANTS Stable kidney transplant recipients with elevated homocysteine levels from 30 sites in the United States, Canada, and Brazil. PREDICTOR Urine albumin-creatinine ratio (ACR) at randomization. OUTCOMES Allograft failure, CVD, and all-cause death. ANALYTICAL APPROACH Multivariable Cox models adjusted for age; sex; race; randomized treatment allocation; country; systolic and diastolic blood pressure; history of CVD, diabetes, and hypertension; smoking; cholesterol; body mass index; estimated glomerular filtration rate (eGFR); donor type; transplant vintage; medications; and immunosuppression. RESULTS Among 3,511 participants with complete data, median ACR was 24 (Q1-Q3, 9-98) mg/g, mean eGFR was 49±18 (standard deviation) mL/min/1.73m2, mean age was 52±9 years, and median graft vintage was 4.1 (Q1-Q3, 1.7-7.4) years. There were 1,017 (29%) with ACR < 10mg/g, 912 (26%) with ACR of 10 to 29mg/g, 1,134 (32%) with ACR of 30 to 299mg/g, and 448 (13%) with ACR ≥ 300mg/g. During approximately 4 years, 282 allograft failure events, 497 CVD events, and 407 deaths occurred. Event rates were higher at both lower eGFRs and higher ACR. ACR of 30 to 299 and ≥300mg/g relative to ACR < 10mg/g were independently associated with graft failure (HRs of 3.40 [95% CI, 2.19-5.30] and 9.96 [95% CI, 6.35-15.62], respectively), CVD events (HRs of 1.25 [95% CI, 0.96-1.61] and 1.55 [95% CI, 1.13-2.11], respectively), and all-cause death (HRs of 1.65 [95% CI, 1.23-2.21] and 2.07 [95% CI, 1.46-2.94], respectively). LIMITATIONS No data for rejection; single ACR assessment. CONCLUSIONS In a large population of stable kidney transplant recipients, elevated baseline ACR is independently associated with allograft failure, CVD, and death. Future studies are needed to evaluate whether reducing albuminuria improves these outcomes.
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Cross-compartment metabolic coupling enables flexible photoprotective mechanisms in the diatom Phaeodactylum tricornutum.
Broddrick, JT, Du, N, Smith, SR, Tsuji, Y, Jallet, D, Ware, MA, Peers, G, Matsuda, Y, Dupont, CL, Mitchell, BG, et al
The New phytologist. 2019;(3):1364-1379
Abstract
Photoacclimation consists of short- and long-term strategies used by photosynthetic organisms to adapt to dynamic light environments. Observable photophysiology changes resulting from these strategies have been used in coarse-grained models to predict light-dependent growth and photosynthetic rates. However, the contribution of the broader metabolic network, relevant to species-specific strategies and fitness, is not accounted for in these simple models. We incorporated photophysiology experimental data with genome-scale modeling to characterize organism-level, light-dependent metabolic changes in the model diatom Phaeodactylum tricornutum. Oxygen evolution and photon absorption rates were combined with condition-specific biomass compositions to predict metabolic pathway usage for cells acclimated to four different light intensities. Photorespiration, an ornithine-glutamine shunt, and branched-chain amino acid metabolism were hypothesized as the primary intercompartment reductant shuttles for mediating excess light energy dissipation. Additionally, simulations suggested that carbon shunted through photorespiration is recycled back to the chloroplast as pyruvate, a mechanism distinct from known strategies in photosynthetic organisms. Our results suggest a flexible metabolic network in P. tricornutum that tunes intercompartment metabolism to optimize energy transport between the organelles, consuming excess energy as needed. Characterization of these intercompartment reductant shuttles broadens our understanding of energy partitioning strategies in this clade of ecologically important primary producers.