Plasma Acetate Concentrations Research Articles

Acetate derived from the intestinal tract has a critical role in maintaining skeletal muscle mass and strength in mice.

Acetate is a short-chain fatty acid (SCFA) that is produced by microbiota in the intestinal tract. It is an important nutrient for the intestinal epithelium, but also has a high plasma concentration and is used in the various tissues. Acetate is involved in endurance exercise, but its role in resistance exercise remains unclear. To investigate this, mice were administered either multiple antibiotics with and without oral acetate supplementation or fed a low-fiber diet. Antibiotic treatment for 2 weeks significantly reduced grip strength and the cross-sectional area (CSA) of muscle fiber compared with the control group. Intestinal concentrations of SCFAs were reduced in the antibiotic-treated group. Oral administration of acetate with antibiotics prevented antibiotic-induced weakness of skeletal muscle and reduced CSA of muscle fiber. Similarly, a low-fiber diet for 1 year significantly reduced the CSA of muscle fiber and fecal and plasma acetate concentrations. To investigate the role of acetate as an energy source, acetyl-CoA synthase 2 knockout mice were used. These mice had a shorter lifespan, reduced skeletal muscle mass and smaller CSA of muscle fiber than their wild type littermates. In conclusion, acetate derived from the intestinal microbiome can contribute to maintaining skeletal muscle performance.

Metabolomic profiling of maternal plasma identifies inverse associations of acetate and urea with anti-SARS-CoV-2 antibody titers following COVID-19 vaccination during pregnancy.

We conducted a comprehensive metabolomic analysis of plasma samples obtained from pregnant women who displayed varying post-vaccination antibody titers after receiving mRNA-1273-SARS-CoV-2 vaccines. The study involved 62 pregnant women, all of whom had been vaccinated after reaching 24weeks of gestation. To quantify post-vaccination plasma antibody titers, we employed binding antibody units (BAU) in accordance with the World Health Organization International Standard. Subsequently, we classified the study participants into three distinct BAU/mL categories: those with high titers (above 2000), medium titers (ranging from 1000 to 2000), and low titers (below 1000). Plasma metabolomic profiling was conducted using 1H nuclear magnetic resonance spectroscopy, and the obtained data were correlated with the categorized antibody titers. Notably, in pregnant women exhibiting elevated anti-SARS-CoV-2 antibody titers, reduced plasma concentrations of acetate and urea were observed. A significant negative correlation between these compounds and antibody titers was also evident. An analysis of metabolomics pathways revealed significant inverse associations between antibody titers and four distinct amino acid metabolic pathways: (1) biosynthesis of phenylalanine, tyrosine, and tryptophan; (2) biosynthesis of valine, leucine, and isoleucine; (3) phenylalanine metabolism; and (4) degradation of valine, leucine, and isoleucine. Additionally, an association between the synthesis and degradation pathways of ketone bodies was evident. In conclusion, we identified different metabolic pathways that underlie the diverse humoral responses triggered by COVID-19 mRNA vaccines during pregnancy. Our data hold significant implications for refining COVID-19 vaccination approaches in expectant mothers. KEY MESSAGES : Anti-SARS-CoV-2 antibody titers decline as the number of days since COVID-19 vaccination increases. Anti-SARS-CoV-2 antibody titers are inversely associated with acetate, a microbial-derived metabolite, and urea. Amino acid metabolism is significantly associated with SARS-CoV-2 antibody titers.

Targeted metabolomics reveals plasma short-chain fatty acids are associated with metabolic dysfunction-associated steatotic liver disease

BackgroundAlterations in the production of short-chain fatty acids (SCFAs) may reflect disturbances in the gut microbiota and have been linked to metabolic dysfunction-associated steatotic liver disease (MASLD). We assessed plasma SCFAs in patients with MASLD and healthy controls.MethodsFasting venous blood samples were collected and eight SCFAs were measured using gas chromatography-tandem mass spectrometry (GC-MS/MS). Relative between-group differences in circulating SCFA concentrations were estimated by linear regression, and the relation between SCFA concentrations, MASLD, and fibrosis severity was investigated using logistic regression.ResultsThe study includes 100 patients with MASLD (51% with mild/no fibrosis and 49% with significant fibrosis) and 50 healthy controls. Compared with healthy controls, MASLD patients had higher plasma concentrations of propionate (21.8%, 95% CI 3.33 to 43.6, p = 0.02), formate (21.9%, 95% CI 6.99 to 38.9, p = 0.003), valerate (35.7%, 95% CI 4.53 to 76.2, p = 0.02), and α-methylbutyrate (16.2%, 95% CI 3.66 to 30.3, p = 0.01) but lower plasma acetate concentrations (− 30.0%, 95% CI − 40.4 to − 17.9, p < 0.001). Among patients with MASLD, significant fibrosis was positively associated with propionate (p = 0.02), butyrate (p = 0.03), valerate (p = 0.03), and α-methylbutyrate (p = 0.02). Six of eight SCFAs were significantly increased in F4 fibrosis.ConclusionsIn the present study, SCFAs were associated with MASLD and fibrosis severity, but further research is needed to elucidate the potential mechanisms underlying our observations and to assess the possible benefit of therapies modulating gut microbiota.

81 Measuring biomarkers to assess the effect of diet on the mucosal integrity of the equine large intestine

Alterations in the integrity of the intestinal mucosa can lead to severe health issues, which can manifest as an increase in mucosal permeability and/or in malabsorption of nutrients. In horses, the hindgut acidosis and the disbalance of the intestinal microbiota caused by excessive starch intake may jeopardize mucosal integrity. In other species, studies suggest that polyphenols could play a protective role for maintaining mucosal integrity. Thus, the objective of this study was to evaluate the integrity of the mucosa of the large intestineby measuring biomarkers of intestinal permeability and absorption in horses fed either a high-fiber or a high-starch diet, combined with a polyphenol-rich plant (sainfoin) supplementation. Twelve adult geldings (7 ± 2 years old,515 ± 53 kg BW) were enrolled in a 4 periods × 4 diets Latin square design, including 4 21 d experimental periods separated by 21 d wash-out periods. The 4 iso-caloric and iso-nitrogenous rations included either high-fiber (HF; 18.5g DM hay/kg BW) or high-starch meals (HS; 8.0g DM hay+6.3g DM barley/kg BW; 1.9g starch/kg BW/meal), and were supplemented with ether control (CONT; 3.1g DM sunflower meal+hay/kg BW) or sainfoin pellets (SF; 3.1g DM Equifolia [Multifolia]/kg BW). Feces and blood were sampled at theend of each experimental period to measure fecal and plasma acetate concentrations, and plasma lipopolysaccharides (LPS) concentration. Mixed effect models were used to assess the effect of the diet (HF vs HS), supplementation (CONT vs SF), and their interaction on these parameters. When horses were fed the diet HS, higher concentration of fecal acetate (P < 0.001) and lower concentration of plasma acetate (P = 0.007) were observed compared with diet HF. This might indicate a decreased absorption capacity through the intestinal wall with diet HS. However, no significant effect of the diet was observed on plasma LPS concentration which suggests that the permeability of the intestinal mucosa is not modified after 21 d with these diets. Adding sainfoin to the ration did not alter the monitored parameters related to mucosal integrity. The next step would be to monitor mucosal permeability and absorption for longer periods of time (longer that the 21-d monitoring done here). This might allow to have a better insight on the effect of diet on mucosal integrity.

26 Hindgut microbiota fibrolytic efficiency may impact energetic metabolism and exercise performance in standardbred horses

Blood acetate originates from fiber degradation by the hindgut microbiota. In addition to glucose and fat, acetate represents an energy substrate for muscles during exercise. Compared with horses fed high-starch diets, it has been reported that high-fiber diets lead to higher plasma acetate concentrations prior and post-exercise, lower lactatemia during exercise, and lower glycogen depletion post-exercise. Fibrolytic efficiency of the hindgut microbiota could thus play a crucial role in energy metabolism during exercise by enhancing acetate availability, which could modulate performance. This study aimed at investigating the relationships between fibrolytic efficiency, energy metabolism, and exercise performance in Standardbred horses. Twenty-one elite 2-years old Standardbred horses (12 stallions, 9 mares) from Ecurie Hunter Valley with similar feeding (hay ad libitum + 6.8kg concentrates/day) and training regimen (3 very heavy works/week) were included in this experiment. An individual in vitro fermentation test was performed from fecal samples with hay as substrate. Gas production (GP) in the bottles was monitored during 48h and fitted to a generalized model using nonlinear regression. Dry matter (DM), cellulose, and hemicellulose were analyzed in substrate residues, and their disappearance was calculated. Two weeks after, horses performed an incremental exercise including 3 steps of 3 min duration at35km/h, 40km/h, and maximal velocity. Steps were separated by 1 min walking. Maximal speed was defined as the maximal velocity sustained for 1 min during the last step. Blood samples were collected before (T0), 5 min (T5), and 20 min (T20) after the incremental exercise to measure glucose, lactate, NEFA, and acetate concentrations. Maximal speed, blood parameters, and fermentation parameters were correlated with Pearson coefficients. No significant correlation was found between maximal speed and glycemia, lactatemia, or NEFA concentration. Maximal speed was correlated with asymptotic GP (P = 0.04; r = 0.46), DM (P = 0.01; r = 0.53) and cellulose (P = 0.02; r = 0.52) disappearance, and with acetate concentration measured at T5 (P = 0.03; r = 0.48). Higher in vitro fibrolytic activity of the hindgut ecosystem was associated with better performance, although resting acetate did not correlate significantly with maximal speed. These results suggest that the extra source of energy provided by fiber digestion could benefit muscle activity during high-intensity exercise in horses. Further work should monitor blood metabolites during exercise to evaluate acetate absorption from the hindgut and utilization by muscles.

Role of short-chain fatty acids in the pathogenesis of Parkinson’s disease

Parkinsons disease is tightly related to enteric nervous system dysfunction and gut microbiota dysbiosis. Short-chain fatty acids are the main metabolites produced by the gut bacteria fermentation of dietary fiber and are suggested to play a key role in gutbrain cross-talk. The article presents a review of the literature on the contribution of short-chain fatty acids to the pathogenesis of Parkinsons disease. Patients with Parkinsons disease have higher plasma concentrations of acetate, propionate, and butyrate than controls. These changes correlate with the severity of the clinical picture of Parkinsons disease, levels of pro-inflammatory gut bacteria and pro-inflammatory cytokines. The cause of these changes may be an over-population of the gut of Parkinsons disease patients with bacteria such as clostridia and ruminococci, leading to regulatory immune reactions, intestinal inflammation, increased permeability of the intestinal barrier, excessive intake primarily of propionate in the central nervous system, and activation of neuroinflammation. The importance of further study of the relationship between changes in gut metabiotic, its metabolome, and the immune system T-cell in patients with Parkinsons disease is demonstrated. Justified the study of blood plasma from patients with Parkinsons disease using gas chromatographymass spectrometry for the accurate, clinically relevant, assessment of the gutbrain crosstalk.

Fiber-like Action of d-Fagomine on the Gut Microbiota and Body Weight of Healthy Rats.

The goal of this work is to explore if the changes induced by d-fagomine in the gut microbiota are compatible with its effect on body weight and inflammation markers in rats. Methods: Sprague Dawley rats were fed a standard diet supplemented with d-fagomine (or not, for comparison) for 6 months. The variables measured were body weight, plasma mediators of inflammation (hydroxyeicosatetraenoic acids, leukotriene B4, and IL-6), and the concentration of acetic acid in feces and plasma. The composition and diversities of microbiota in cecal content and feces were estimated using 16S rRNA metabarcoding and high-throughput sequencing. We found that after just 6 weeks of intake d-fagomine significantly reduced body weight gain, increased the plasma acetate concentration, and reduced the plasma concentration of the pro-inflammatory biomarkers' leukotriene B4, interleukin 6 and 12 hydroxyeicosatetraenoic acids. These changes were associated with a significantly increased prevalence of Bacteroides and Prevotella feces and increased Bacteroides, Prevotella, Clostridium, and Dysgonomonas while reducing Anaerofilum, Blautia, and Oribacterium in cecal content. In conclusion, d-fagomine induced changes in the composition and diversity of gut microbiota similar to those elicited by dietary fiber and compatible with its anti-inflammatory and body-weight-reducing effects.

Effect of the timing of sodium acetate infusion on the daily rhythms of milk synthesis and plasma metabolites and hormones in Holstein cows.

Dairy cows have a daily pattern of feed intake which influences ruminal fermentation and nutrient absorption. Milk synthesis also exhibits a daily rhythm and is altered by the timing of feed availability. Nutrients can regulate physiological rhythms, but it is unclear which specific nutrients affect the rhythms of milk synthesis in the cow. The objective of this study was to determine the effect of the timing of acetate infusion on the daily rhythms of feed intake, milk synthesis, milk fatty acids, plasma insulin and metabolites, and core body temperature. Ten lactating ruminally cannulated Holstein cows (127 ± 24.6 d in milk; mean ± standard deviation) were arranged in a 3 × 3 Latin square design. Treatments were ruminal infusions of 600 g/d of acetate either continuously throughout the day (CON) or over 8 h/d during the day (day treatment, DT; 0900 to 1700 h) or the night (night treatment, NT; 2100 to 0500 h). Experimental periods were 14 d with a 7-d washout between periods. Cows were milked every 6 h during the final 7 d of each experimental period to determine the daily pattern of milk synthesis. Blood samples were taken to represent every 4 h across the day and plasma glucose, insulin, β-hydroxybutyrate, urea nitrogen, and acetate concentration were measured. An intravaginal temperature logger was used to measure core body temperature. Data were analyzed with cosinor-based rhythmometry to test the fit of a cosine function with a period of 24 h and to determine the acrophase (time at peak) and amplitude (peak to mean) of each rhythm. Milk yield fit a daily rhythm for all treatments and DT and NT phase-delayed the rhythm and DT increased the robustness of the rhythm. Milk protein concentration fit a daily rhythm for all treatments and DT increased robustness, whereas NT phase-delayed the rhythm. Plasma acetate concentration also fit a daily rhythm in all treatments. Plasma acetate peaked at ∼1600 h in CON and DT and at 0053 h in NT, reflecting the timing of treatment infusions. There was a daily rhythm in plasma β-hydroxybutyrate that reflected the plasma acetate rhythm. Core body temperature fit a rhythm for all treatments, but the amplitude of the rhythm was smaller than previously observed. In conclusion, the timing of acetate infusion influences peripheral rhythms of milk synthesis and plasma metabolites.

Association of Fecal and Plasma Levels of Short-Chain Fatty Acids With Gut Microbiota and Clinical Severity in Patients With Parkinson Disease.

Background and ObjectivesShort-chain fatty acids (SCFAs) are gut microbial metabolites that promote the disease process in a rodent model of Parkinson disease (PD), but fecal levels of SCFAs in patients with PD are reduced. Simultaneous assessments of fecal and plasma SCFA levels, and their interrelationships with the PD disease process, are scarce. We aimed to compare fecal and plasma levels of different SCFA subtypes in patients with PD and healthy controls to delineate their interrelations and link to gut microbiota changes and clinical severity of PD.MethodsA cohort of 96 patients with PD and 85 controls were recruited from National Taiwan University Hospital. Fecal and plasma concentrations of SCFAs were measured using chromatography and mass spectrometry. Gut microbiota was analyzed using metagenomic shotgun sequencing. Body mass index and medical comorbidities were evaluated and dietary information was obtained using a food frequency questionnaire. To assess motor and cognitive impairment, we used the Movement Disorder Society–Unified Parkinson's Disease Rating Scale (MDS-UPDRS) and the Mini-Mental Status Examination (MMSE).ResultsCompared with controls, patients with PD had lower fecal but higher plasma concentrations of acetate, propionate, and butyrate. After adjustment for age, sex, disease duration, and anti-PD medication dosage, MDS-UPDRS part III motor scores correlated with reduced fecal levels of acetate (ρ = −0.37, p = 0.012), propionate (ρ = −0.32, p = 0.036), and butyrate (ρ = −0.40, p = 0.004) and with increased plasma propionate concentrations (ρ = 0.26, p = 0.042) in patients with PD. MMSE scores negatively correlated with plasma levels of butyrate (ρ = −0.09, p = 0.027) and valerate (ρ = −0.032, p = 0.033) after adjustment for confounders. SCFAs-producing gut bacteria correlated positively with fecal levels of SCFAs in healthy controls but revealed no association in patients with PD. In the PD patient group, the abundance of proinflammatory microbes, such as Clostridiales bacterium NK3B98 and Ruminococcus sp AM07-15, significantly correlated with decreased fecal levels and increased plasma levels of SCFAs, especially propionic acid.DiscussionReductions in fecal SCFAs but increased plasma SCFAs were observed in patients with PD and corelated to specific gut microbiota changes and the clinical severity of PD.Classification of EvidenceThis study provides Class III evidence that gut metabolite SCFAs distinguish between patients with PD and controls and are associated with disease severity in patients with PD.

Lower Plasma Short-Chain Fatty Acids Are Associated With Increased Leg Muscle Fatigue in (Morbidly) Obese Adults

ObjectivesMany obese subjects have a lower muscle performance. Short-chain fatty acids (SCFAs; acetate, propionate, butyrate, valerate, and isovalerate) are derived from microbial fermentation of dietary fiber and are metabolic fuels for skeletal muscle during periods of sustained contraction. We compared plasma SCFA concentrations between obese and non-obese individuals in relation to muscle quality and fatigue. MethodsWe studied 141 subjects, divided into 2 BMI-based groups (cut-off point 30 kg/m2): 68 non-obese (26 males/42 females, age 52.3 [46.8, 57.9] yo and BMI 25.3 [24.7, 25.9] kg/m2) and 73 obese (29 males/44 females, age 55.7 [52.6, 58.8] yo and BMI 38.6 [37.1, 40.0] kg/m2). We collected blood samples in the postabsorptive state for SCFAs concentrations and analyzed them by GC-MS. We measured body composition by DXA, leg muscle strength (peak strength and endurance) using an isokinetic dynamometer and 24h dietary recall. Statistics were performed by ANCOVA and Pearson’s correlations adjusted for age, gender, and habitual fiber intake. Significance set at P < 0.05. Results expressed as mean [95% CI]. ResultsObese subjects reported a 18% lower (22.5 vs 18.4 gr; P = 0.0371) daily fiber intake and a 15% lower plasma concentration of acetate, propionate, and butyrate (P = 0.0460, P = 0.0074, and P = 0.0245, resp) and 33% lower plasma valerate (P = 0.0014). Maximal strength was comparable but obese subjects had a 14% lower (P = 0.0034) leg muscle quality and 50% higher (P = 0.0210) leg fatigue after endurance exercise. Increased leg fatigue strongly related to the lower plasma of all measured SCFAs with propionate (r: –0.61, P < 0.0001), isovalerate (r: –0.51, P = 0.0004), acetate (r = –0.46, P = 0.0017), butyrate (r: –0.38, P = 0.0101), and valerate (r: –0.38, P = 0.0114). ConclusionsWe hypothesize that impaired availability of SCFAs for contracting skeletal muscle contributes to the reduced capacity for physical activity in (morbid) obesity. Funding SourcesNone.

Comparison of the effects of short-term feeding of sodium acetate and sodium bicarbonate on milk fat production

Supplementation with sodium acetate (NaAcet) increases milk fat production through an apparent stimulation of de novo lipogenesis in the mammary gland. Sodium acetate increases acetate supply to the mammary gland, but it also increases dietary cation-anion difference, which can also increase milk fat yield. The objective of this study was to determine if the effect of NaAcet on milk fat production was due to an increase in acetate supply or an increase in dietary cation-anion difference. The study included 12 multiparous cows in a replicated 3 × 3 Latin square design balanced for carryover effects, with 14-d experimental periods. Treatments were a basal total mixed ration (31.8% neutral detergent fiber, 14.8% crude protein, 25.5% starch, and 4.4% fatty acids on a dry matter basis) as a no-supplement control, acetate supplemented at 3.25% of dry matter as NaAcet, and sodium bicarbonate (NaHCO3) providing an equal amount of sodium to the NaAcet treatment. The NaAcet and NaHCO3 were mixed into the basal diet before feeding. Milk samples were taken at each milking during the last 3 d of each period. Plasma samples were taken every 9 h during the last 3 d (a total of 8 times) to determine concentrations of plasma metabolites and hormones. Eating behavior was monitored during the last week of each period using an automated system. The NaAcet and NaHCO3 treatments increased milk fat concentration and yield compared to the no-supplement control. The NaAcet treatment increased milk fat production predominantly by increasing the yield of de novo and mixed-source fatty acids. The NaHCO3 treatment increased the yield of preformed and de novo fatty acids, suggesting different mechanisms for the 2 treatments. The NaAcet treatment increased plasma acetate concentration in a period of the day concurrent with the highest dry matter intake. The NaAcet treatment increased milk fat production by stimulating the production of de novo fatty acids, a mechanism consistent with previous reports, possibly by increasing acetate supply to the mammary gland. The NaHCO3 treatment increased milk fat production by increasing the production of all biological categories of fatty acids, except for odd and branched-chain fatty acids, possibly by increasing overall diet digestibility.

Intestinal function is impaired in patients with Chronic Obstructive Pulmonary Disease

Gastrointestinal symptoms are prevalent extrapulmonary systemic manifestations of Chronic Obstructive Pulmonary Disease (COPD), but have been rarely studied. We dissected the perturbations in intestinal function in human patients with COPD using comprehensive metabolic and physiological approaches. In this observational study, small intestinal membrane integrity and active carrier-mediated glucose transport were quantified by sugar permeability test in 21 clinically stable patients with moderate to severe COPD (mean FEV1, 41.2 (3.2) % of predicted) and 16 healthy control subjects. Protein digestion and absorption was analyzed using stable tracer kinetic methods. Plasma acetate, propionate, and butyrate concentrations were measured as markers of intestinal microbial metabolism. Compared with healthy controls, non carrier-mediated permeability was higher (0.062 (95% CI [0.046, 0.078]) vs. 0.037 (95% CI [0.029, 0.045]), P=0.009) and active glucose transport lower in COPD (31.4 (95% CI [23.4, 39.4])% vs. 48.0 (95% CI [37.8, 58.3])%, P=0.010). Protein digestion and absorption was lower in COPD (0.647 (95% CI [0.588, 0.705]) vs. 0.823 (95% CI [0.737, 0.909]), P=0007), and impairment greater in patients with dyspnea (P=0.038), exacerbations in preceding year (P=0.052), and reduced transcutaneous oxygen saturation (P=0.051), and was associated with reduced physical activity score (P=0.016) and lower quality of life (P=0.0007). Plasma acetate concentration was reduced in COPD (41.54 (95% CI [35.17, 47.91]) vs. 80.44 (95% CI [54.59, 106.30]) μmol/L, P=0.001) suggesting perturbed intestinal microbial metabolism. We conclude that intestinal dysfunction is present in COPD, worsens with increasing disease severity, and is associated with reduced quality of life.

Maternal Iron Deficiency Programs Offspring Cognition and Its Relationship with Gastrointestinal Microbiota and Metabolites.

Iron is an essential micronutrient for the brain development of the fetus. Altered intestinal microbiota might affect behavior and cognition through the so-called microbiota-gut-brain axis. We used a Sprague-Dawley rat model of a maternal low-iron diet to explore the changes in cognition, dorsal hippocampal brain-derived neurotrophic factor (BDNF) and related pathways, gut microbiota, and related metabolites in adult male offspring. We established maternal iron-deficient rats by feeding them a low-iron diet (2.9 mg/kg), while the control rats were fed a standard diet (52.3 mg/kg). We used a Morris water maze test to assess spatial learning and long-term memory. Western blot (WB) assays and a quantitative reverse-transcription polymerase chain reaction (qRT-PCR) were used to detect the BDNF concentration and related signaling pathways. We collected fecal samples for microbiota profiling and measured the concentrations of plasma short-chain fatty acids. The adult male offspring of maternal rats fed low-iron diets before pregnancy, during pregnancy and throughout the lactation period had (1) spatial deficits, (2) a decreased BDNF mRNA expression and protein concentrations, accompanied by a decreased TrkB protein abundance, (3) a decreased plasma acetate concentration, and (4) an enrichment of the Bacteroidaceae genus Bacteroides and Lachnospiraceae genus Marvinbryantia. Maternal iron deficiency leads to an offspring spatial deficit and is associated with alternations in gastrointestinal microbiota and metabolites.

The effects of increased acetate turnover on glucose-induced insulin secretion in lean and obese humans.

Increased endogenous acetate production (Ra) in rodents has been shown to activate the parasympathetic nervous system and thereby promote increased glucose-stimulated insulin secretion (GSIS), increased ghrelin secretion, hyperphagia and obesity. To examine whether rates of acetate turnover are different in lean versus obese humans and whether increased acetate turnover promotes increased GSIS and increased ghrelin secretion in humans. Basal acetate Ra was measured following an overnight fast in lean (BMI: 21.3 ± 1.1 Kg/m2) and obese (30.2 ± 0.9 Kg/m2, P = 0.00001) individuals. The subjects underwent two hyperglycemic (10 mmol/L) clamp studies to measure GSIS during a basal acetate infusion and during a high-dose acetate infusion increasing plasma acetate concentrations ∼5-fold. Basal acetate Ra was 30% higher in the lean compared to the obese subjects (257 ± 27 vs. 173 ± 18 μmol/min; P = 0.025). Basal plasma insulin concentrations were 4-fold higher in the obese than the lean subjects (P = 0.008) and increased 5-fold during hyperglycemia in both groups, independent of changes in plasma acetate concentrations. Fasting plasma ghrelin concentrations were 35% lower in the obese compared to the lean subjects (P = 0.015). During the hyperglycemic clamp, plasma ghrelin decreased by 42% in the lean group (P < 0.022 vs. basal) and did not change in the obese group. Rates of endogenous acetate turnover are ∼30% higher in the lean subjects compared to the obese subjects, and increasing plasma acetate turnover does not promote increased GSIS or ghrelin secretion in either group.

The prebiotic inulin improves substrate metabolism and promotes short-chain fatty acid production in overweight to obese men

Background and AimsHuman gut microbiota play an important role in maintaining human health. Dietary fibers, i.e. prebiotics, are fermented by human gut microbiota into the short-chain fatty acids (SCFAs) acetate, propionate, and butyrate. SCFAs promote fat oxidation and improve metabolic health. Therefore, the prebiotic inulin might be an effective dietary strategy to improve human metabolism. We aimed to investigate the acute metabolic effects of ingesting inulin compared with digestible carbohydrates and to trace inulin-derived SCFAs using stable isotope tracer methodology. MethodsIn a double-blind, randomized, placebo-controlled crossover design, 14 healthy, overweight to obese men consumed a high-fat milkshake containing A) 24 g inulin of which 0.5 g was U-13C-inulin (INU) or B) 24 g maltodextrin placebo (PLA), with a wash-out period of at least five days. Fat oxidation was measured via an open-circuit ventilated hood and blood samples were collected up to 7 h after ingestion. Plasma, breath, and fecal samples were collected, and appetite and satiety scores were assessed. ResultsFat oxidation increased in the early postprandial phase (0−3 h), and both plasma glucose and insulin were lower after INU ingestion compared with PLA (all P < 0.05). Plasma free fatty acids were higher in the early, and lower in the late postprandial period after INU ingestion. Inulin was fermented into SCFAs as indicated by higher plasma acetate concentrations after INU compared with PLA (P < 0.05). In addition, we found continuous increases in plasma 13C-SCFA enrichments (P < 0.05 from t = 120 onwards) and breath 13CO2 enrichments after INU intake. There were no effects on plasma triglycerides, free glycerol, satiety hormones GLP-1 and PYY, and appetite and satiety scores. ConclusionsIngestion of the prebiotic inulin improves fat oxidation and promotes SCFA production in overweight to obese men. Overall, replacing digestible carbohydrates with the fermentable inulin may favor human substrate metabolism. Clinical Trial RegistryThe trial was registered at clinicaltrials.gov under number NCT02009670.

Prebiotic attenuation of olanzapine-induced weight gain in rats: analysis of central and peripheral biomarkers and gut microbiota

Olanzapine is an effective antipsychotic drug but since it causes significant weight gain, it is not well tolerated by psychosis patients. The prebiotic, B-GOS®, attenuates metabolic dysfunction in obese subjects, and in rodents, alters central NMDA receptors and may affect serotonin receptors that are relevant in psychosis. We have determined whether B-GOS® influenced olanzapine-associated weight gain and central NMDA and serotonin receptors. Circulating acetate, IL-1β, IL-8 and TNFα, liver acetyl-CoA carboxylase (ACC), white adipose tissue (WAT) acetate receptor GPR43, and specific faecal bacteria genera were also measured to provide mechanistic information. Adult female Sprague-Dawley rats were administered a B-GOS® (0.5 g/kg/day) solution or water for 21 days, and received a single, daily, intraperitoneal injection of olanzapine or saline on days 8–21. The intake of B-GOS® significantly attenuated olanzapine-induced weight gain without altering frontal cortex 5-HT2AR blockade. Cortical GluN1 levels were elevated by olanzapine in the presence of B-GOS®. Plasma acetate concentrations increased following B-GOS® or olanzapine administration alone, but reduced when prebiotic and drug were administered in combination. This pattern was paralleled by hepatic ACC mRNA expression. The abundance of WAT GPR43 mRNA was reduced by olanzapine, only in the absence of B-GOS®. Co-administration of B-GOS® and olanzapine also elevated plasma TNFα, which is reported to influence lipid metabolism. Finally, B-GOS® elevated faecal Bifidobacterium spp. and reduced some bacteria in the Firmicutes phylum, whilst olanzapine treatment either alone or with B-GOS®, was without effect. These data suggest that inclusion of B-GOS® as an adjunct to olanzapine treatment in schizophrenia may prevent weight gain and have benefits on cognitive function in psychosis. The role of acetate in these effects requires further investigation.

P.1.015 - Influence of prebiotic intake on olanzapine-mediated weight gain, central receptors, peripheral biomarkers, and gut microbiota

Olanzapine is the first-line antipsychotic treatment for schizophrenia, but often leads to secondary health concerns such as metabolic syndrome and weight gain. Studies in rats have shown that chronic olanzapine administration induces weight gain [1] and reduces hippocampal glutamate N-methyl-D-Aspartate receptor (NMDAR) levels, the latter which may hinder the recovery of cognitive function in schizophrenia patients. We have shown that dietary augmentation of beneficial gut bacteria using the commercially available prebiotic Bimuno ™ galacto-oligosaccharides (B-GOS ® ) increases central levels of NMDAR subunits in rodents [2,3]. The aim of this study was to determine whether the effects of olanzapine on weight gain and peripheral effects are influenced by B-GOS® intake in rats. Adult female Sprague-Dawley rats were provided with a B-GOS ® (0.5g/kg/day) solution or water for 21 days, and received a single, daily, intraperitoneal injection of olanzapine or saline on days 8-21. Weight gain and water intake were monitored daily. We determined whether B-GOS ® influenced olanzapine-associated weight gain, and central NMDAR and serotonin receptor expression. Circulating levels of acetate, IL-1β, IL-8 and TNFα as well as liver acetyl-CoA Carboxylase (ACC), white adipose tissue acetate receptor GPR43, and specific faecal bacteria genera were also measured to provide mechanistic information. Two-way ANOVAs were used to analyse all data, with repeated measures included to explore weight gain. Olanzapine induced significant weight gain (p ® -fed rats. Significant effect of treatment was observed on hippocampal GluN1 mRNA abundance (p = 0.034), where olanzapine significantly increased (+17%) levels in the absence of B-GOS ® (p = 0.040). Plasma acetate concentrations increased following B-GOS ® or olanzapine administration alone, but reduced when prebiotic and drug were administered in combination. This pattern was paralleled by hepatic ACC mRNA expression. The abundance of WAT GPR43 mRNA was reduced by olanzapine, only in the absence of B-GOS ® . Co-administration of B-GOS ® and olanzapine also elevated plasma TNFα, which is reported to influence lipid metabolism. Finally, B-GOS ® elevated faecal Bifidobacterium Spp. and reduced some bacteria in the Firmicutes phylum, whilst olanzapine treatment either alone or with B-GOS ® , was without effect. The current study demonstrates a potential strategy to reduce olanzapine-mediated weight gain in schizophrenia without compromising a key central pharmacological action of this antipsychotic. We also demonstrate a NMDAR augmenting effect, supporting a potential pro-cognitive effect of the prebiotic. Our data also implies that elevated TNFα in B-GOS ® /olanzapine rats may contribute to the reduction in olanzapine-induced weight gain as pro-inflammatory TNFα is a recognised appetite suppressant. These data suggest that inclusion of B-GOS ® as an adjunct to olanzapine treatment in schizophrenia may prevent weight gain and have benefits on cognitive function in psychosis.

Effects of acetic acid or sodium acetate infused into the rumen or abomasum on feeding behavior and metabolic response of cows in the postpartum period

Effects of continuous isomolar infusions of acetic acid (AcA) or sodium acetate (NAc) infused into the rumen (RU) or into the abomasum (AB) on feeding behavior, dry matter intake (DMI), and metabolic response of cows in the early postpartum period were evaluated. Six rumen-cannulated multiparous Holstein cows (11.8 ± 3.9 d in milk; mean ± SD) were utilized in a 6 × 6 Latin square design experiment balanced for carryover effects with a 2 × 3 factorial arrangement of treatments. Treatments were AcA and NAc, with sodium chloride (CON) as a control, infused at a rate of ˜0.75 mol/h (0.5 L/h) into the RU or AB for the first 8 h following feeding, with a rest day between infusion days. Treatment sequences were assigned randomly to cows. Feeding behavior was recorded by a computerized data acquisition system and blood was sampled at 0, 4, and 8 h relative to the start of infusion. We hypothesized that AcA is more hypophagic than NAc, and that infusion into the AB is more hypophagic than infusion into the RU. Dry matter intakes (DMI) for the CON treatments were similar at 6.2 kg/8 h for RU and 6.1 kg/8 h for AB, and the AcA and NAc treatments interacted with site of infusion to affect DMI. The NAc-RU treatment did not reduce DMI (7.0 kg/8 h), whereas AcA-RU (2.6 kg/8 h), AcA-AB (3.7 kg/8 h), and NAc-AB (4.0 kg/8 h) decreased DMI compared with CON. Following infusions of AcA compared with NAc, there was a residual effect on DMI for the remainder of the day, but treatments did not affect DMI during the rest day. Treatments increased plasma acetate and β-hydroxybutyrate concentrations over time (interaction) and decreased plasma insulin concentration compared with CON. Plasma glucose concentration decreased over time after AcA-AB infusion compared with other treatments and CON. Plasma nonesterified fatty acid concentration increased over time for AcA compared with NAc and CON, suggesting an increase in lipolysis to compensate the decrease in DMI. In contrast to the other treatments, NAc-RU did not decrease DMI compared with control but we cannot determine the reason for this from the data available from the current study.

Road transport and diet affect metabolic response to exercise in horses.

This study investigated the effects of transport and diet on metabolic response during a subsequent race-like test in Standardbred horses in training fed a forage-only diet and a 50:50 forage:oats diet. Six trained and raced Standardbred trotter mares were used. Two diets, 1 forage-only diet (FONLY) and 1 diet with 50% of DM intake from forage and 50% from oats (FOATS), were fed for two 29-d periods in a crossover design. At Day 21, the horses were subjected to transport for 100 km before and after they performed an exercise test (transport test [TT]). At Day 26, the horses performed a control test (CT), in which they were kept in their stall before and after the exercise test. Blood samples were collected throughout the study, and heart rate and water intake were recorded. Heart rate and plasma cortisol, glucose, and NEFA concentrations were greater for the TT than for the CT (P = 0.008, P = 0.020, P = 0.010, and P = 0.0002, respectively) but were not affected by diet. Plasma acetate concentration was lower during the TT than during the CT (P = 0.034) and greater for the FONLY than for the FOATS (P = 0.003). There were no overall effects of the TT compared with the CT on total plasma protein concentration (TPP), but TPP was lower with the FONLY than with the FOATS (P = 0.016). There was no overall effect of the TT compared with the CT on water intake, but water intake was greater with the FONLY than the FOATS (P = 0.011). There were no overall effects of transport or diet on BW, plasma lactate, or plasma urea concentration. It was concluded that both transport and diet affect metabolic response during exercise in horses. Aerobic energy supply was most likely elevated by transportation and by the FONLY. The FONLY also decreased exercise-induced effects on extracellular fluid regulation. These results highlight the importance of experimental design in nutrition studies. If the aim is to examine how a diet affects exercise response in competition horses, transport should preferably be included in the experimental design, because horses are likely to be transported before a competition.

Addition of glycerol to lactating cow diets stimulates dry matter intake and milk protein yield to a greater extent than addition of corn grain.

The objective of this study was to determine if the addition of glycerol to the diet of dairy cows would stimulate milk protein yield in the same manner as the addition of corn grain. Twelve multiparous lactating dairy cows at 81 ± 5 d in milk were subjected to 3 dietary treatments in a replicated 3 × 3 Latin square design for 28-d periods. The diets were a 70% forage diet considered the basal diet, the basal diet with 19% ground and high-moisture corn replacing forages, and the basal diet with 15% refined glycerol and 4% added protein supplements to be isocaloric and isonitrogenous with the corn diet. Cows were milked twice a day and samples were collected on the last 7 d of each period for compositional analysis. Within each period, blood samples were collected on d 26 and 27, and mammary tissue was collected by biopsy on d 28 for Western blot analysis. Dry matter intake increased from 23.7 kg/d on the basal diet to 25.8 kg/d on the corn diet and 27.2 kg/d on the glycerol diet. Dry matter intake tended to be higher with glycerol than corn. Milk production increased from 39.2 kg/d on the basal diet to 43.8 kg/d on the corn diet and 44.2 kg/d on the glycerol diet. However, milk yield did not differ between corn and glycerol diets. Milk lactose yields were higher on the corn and glycerol diets than the basal diet. Milk fat yield significantly decreased on the glycerol diet compared with the basal diet and tended to decrease in comparison with the corn diet. Mean milk fat globule size was reduced by glycerol feeding. Milk protein yield increased 197 g/d with addition of corn to the basal diet and 263 g/d with addition of glycerol, and the glycerol effect was larger than the corn effect. The dietary treatments had no effects on plasma glucose concentration, but plasma acetate levels decreased 27% on the glycerol diet. Amino acid concentrations were not affected by dietary treatments, except for branched-chain amino acids, which decreased 22% on the glycerol diet compared with the corn diet. The decreases in plasma acetate and branched-chain amino acid concentrations with glycerol and the larger effects of glycerol than corn on milk protein and fat yields suggest that glycerol is more glucogenic for cows than corn grain.