Betaine may be a beneficial nutrient to add to a specialty enteral formula for obesity

The most appropriate enteral formula for the severely obese population has yet to be determined. The obese patient in the intensive care unit (ICU) creates numerous difficulties for managing care, one being the ability to deliver appropriate and timely nutrition. Access for nutrition therapy, either enteral or parenteral, can also create a challenge. Currently, no specific guidelines are available on a national or international scale to address the issues of how and when to feed the obese patient in the ICU. A bias against feeding these patients exists, secondary to the perception that an enormous quantity of calories is stored in adipose tissue. Making a specialty enteral formula for obesity from existing commercial formulas and other modular nutrient components is not practical, secondary to difficulty with solubility issues, dilution of the formula, and safety concerns. Using today's concepts and current metabolic data, a formula could be produced that would address many of the specific metabolic derangements noted in obesity. This formula should have a high-protein, low-carbohydrate content with at least a portion of the lipid source coming from fish oil. Specific nutrients that may be beneficial in obesity include arginine, glutamine, leucine, L-carnitine, lipoic acid, S-adenosylmethionine, and betaine. Certain trace minerals such as magnesium, zinc, and selenium may also be of value in the obese population. The concept of a specific bariatric formulation for the ICU setting is theoretically sound, is scientifically based, and could be delivered to patients safely.

Martindale, R. G., M. DeLegge, et al. (2011). "Nutrition Delivery for Obese ICU Patients." Journal of Parenteral and Enteral Nutrition 35(5 suppl): 80S-87S.

Betaine has a hepatoprotective effect by increasing glutathione levels and glutathione-related enzyme activities in rats

The effects of betaine supplementation on D-galactosamine-induced liver injury were examined in terms of hepatic and serum enzyme activities and of the levels of glutathione and betaine-derived intermediates. The rats induced with liver injury showed marked increases in serum enzyme activity, but those receiving dietary supplementation of 1% betaine showed enzyme activity levels similar to a control group without liver injury. Administration of betaine also increased both hepatic and serum glutathione levels, even following D-galactosamine injection. The activity of glutathione-related enzymes was markedly decreased following injection of D-galactosamine, but remained comparable to that of the control group in rats receiving 1% betaine. The concentrations of hepatic S-adenosyl methionine and cysteine showed similar trends to that observed for hepatic glutathione levels. These results indicate that 1% betaine has a hepatoprotective effect by increasing hepatic and serum glutathione levels along with glutathione-related enzyme activities in rats.

Okada, T., et al., Amelioration of D-galactosamine-induced acute liver injury in rats by dietary supplementation with betaine derived from sugar beet molasses. Biosci Biotechnol Biochem, 2011. 75(7): p. 1335-41.

Betaine prevents ethanol-induced oxidative stress and reduces total homocysteine in the rat cerebellum

Oxidative stress is a hypothesis for the association of reactive oxygen species with cerebrovascular and neurodegenerative diseases. Thus, we examined whether oral betaine can act as a preventive agent in ethanol-induced oxidative stress on the cerebellum of rats. Thirty-two adult male Sprague–Dawley rats were divided into four equal groups (control, ethanol, betaine, and betaine plus ethanol) with different dietary regimens and were followed up for 1 month. Total homocysteine (tHcy) of plasma and cerebellum homogenate was determined by an Axis® homocysteine EIA kit, and antioxidant enzyme (glutathione peroxidase (GPx), SOD, and CAT) activities of cerebellum homogenate were measured chemically by a spectrophotometer. Lipid peroxidation of cerebellum was shown by the measurement of thiobarbituric reactive substances (TBARS) via a spectrophotometer. Ethanol-induced hyperhomocysteinemia was manifested by an increase in the concentrations of tHcy in the plasma and cerebellum homogenates of the ethanol group, while ethanol-induced oxidative stress was indicated via an increase in lipid peroxidation marker (TBARS) in cerebellum homogenates of ethanol-treated rats. In contrast, betaine prevented hyperhomocysteinemia and oxidative stress in the betaine plus ethanol group as well as the betaine group. The results of the present investigation indicated that the protective effect of betaine is probably related to its ability to strengthen the cerebellum membrane cells by enhancement of antioxidant enzyme activity principally GPx, while the methyl donor effect of betaine to reduce hyperhomocysteinemia has been explained previously and confirmed in the present study.

Alirezaei, M., et al., Betaine prevents ethanol-induced oxidative stress and reduces total homocysteine in the rat cerebellum. J Physiol Biochem, 2011. 67(4): p. 605-12.

Women who developed gestational diabetes had lower plasma betaine

This work describes an exploratory NMR metabonomic study of second trimester maternal urine and plasma, in an attempt to characterize the metabolic changes underlying prenatal disorders and identify possible early biomarkers. Fetal malformations have the strongest metabolic impact in both biofluids, suggesting effects due to hypoxia (leading to hypoxanthine increased excretion) and a need for enhanced gluconeogenesis, with higher ketone bodies (acetone and 3-hydroxybutyric acid) production and TCA cycle demand (suggested by glucogenic amino acids and cis-aconitate overproduction). Choline and nucleotide metabolisms also seem affected and a distinct plasma lipids profile is observed for mothers with fetuses affected by central nervous system malformations. Urine from women who subsequently develop gestational diabetes mellitus exhibits higher 3-hydroxyisovalerate and 2-hydroxyisobutyrate levels, probably due to altered biotin status and amino acid and/or gut metabolisms (the latter possibly related to higher BMI values). Other urinary changes suggest choline and nucleotide metabolic alterations, whereas lower plasma betaine and TMAO levels are found. Chromosomal disorders and pre-preterm delivery groups show urinary changes in choline and, in the latter case, in 2-hydroxyisobutyrate. These results show that NMR metabonomics of maternal biofluids enables the noninvasive detection of metabolic changes associated to prenatal disorders, thus unveiling potential disorder biomarkers.

Diaz, S.O., et al., Metabolic biomarkers of prenatal disorders: an exploratory NMR metabonomics study of second trimester maternal urine and blood plasma. J Proteome Res, 2011. 10(8): p. 3732-42.

High dietary betaine intake associated with less advanced AMD

Objective
We evaluated monozygotic twin pairs with discordant age-related macular degeneration (AMD) phenotypes to assess differences in behavioral and nutritional factors.

Design
Case series.

Participants
Caucasian male twin pairs from the United States Twin Study of Macular Degeneration.

Methods
Twin pairs were genotyped to confirm monozygosity. Ocular characteristics were evaluated based on fundus photographs using the Wisconsin Grading System and a 5-grade Clinical Age-Related Maculopathy Staging System. We selected twin pairs discordant in each of the following phenotypic categories: Stage of AMD (n = 28), drusen area (n = 60), drusen size (n = 40), and increased pigment area (n = 56). The Wilcoxon signed-rank test and linear regression were used to assess associations between behavioral and nutritional characteristics and each phenotype within discordant twin pairs.

Main Outcome Measures
Differences in smoking and dietary factors within twin pairs discordant for stage of AMD, drusen area, drusen size, and pigment area.

Results
Representative fundus photographs depict the discordant phenotypes. Pack-years of smoking were higher for the twin with the more advanced stage of AMD (P = 0.05). Higher dietary intake of vitamin D was present in the twins with less severe AMD (P = 0.01) and smaller drusen size (P = 0.05) compared with co-twins, adjusted for smoking and age. Dietary intakes of betaine and methionine were significantly higher in the twin with lower stage of AMD (P = 0.009) and smaller drusen area (P = 0.03), respectively.

Conclusions
The twin with the more advanced stage of AMD, larger drusen area, drusen size, and pigment area tended to be the heavier smoker. The twin with the earlier stage of AMD, smaller drusen size and area, and less pigment tended to have higher dietary vitamin D, betaine, or methionine intake. Results suggest that behavioral and nutritional factors associated with epigenetic mechanisms are involved in the etiology of AMD, in addition to genetic susceptibility.

Seddon, J.M., et al., Smoking, dietary betaine, methionine, and vitamin D in monozygotic twins with discordant macular degeneration: epigenetic implications. Ophthalmology, 2011. 118(7): p. 1386-94.

Serum betaine concentration is decreased in patients after bariatric surgery

Bariatric surgery significantly reduces the risk of cardiovascular diseases but has no effects on hyperhomocysteinemia, the risk factor for atherogenesis. We hypothesize that the decrease in serum betaine (involved in homocysteine metabolism) concentrations, after bariatric surgery, impairs conversion of homocysteine to methionine, leading to hyperhomocysteinemia. If this is true, it may be desirable to supply patients after bariatric surgery with betaine. Serum betaine and homocysteine concentrations were measured by liquid chromatography/mass spectrometry, in 16 obese patients, before and 6 months after bariatric surgery. Ten healthy individuals with normal body mass index served as controls. Serum betaine concentrations decreased to the values lower than in controls after bariatric surgery, whereas serum homocysteine concentrations remained elevated. In patients supplemented with B(12) and folate, no effect of bariatric surgery on serum concentrations of vitamins involved in homocysteine metabolism was observed. These results suggest that betaine deficit could be responsible for maintenance of hyperhomocysteinemia after bariatric surgery. We postulate that supplementation with betaine could be of therapeutic value for the treatment of hyperhomocysteinemia after bariatric surgery.

Sledzinski, T., et al., Decreased serum betaine concentrations in patients after bariatric surgery. Obes Surg, 2011. 21(10): p. 1634-9.

Betaine improves performance under heat stress in rabbit model

The objective of this study was to determine the effects of dietary betaine supplementation on growth performance, carcass characteristics, rectal temperature, respiration rate and immune response of growing rabbits under high ambient temperature.

A total of 120 weaned New Zealand White male rabbits, 6 weeks old, were randomly divided into five experimental treatments (24 each). Animals were fed ad libitum the basal diet supplemented with 0 (control), 250, 500, 750 and 1000 mg betaine/kg diet from 6 to 12 weeks of age. Animals were provided with water freely. The average daily temperature and relative humidity inside the rabbitry were 30.3 ± 0.9 °C and 76.2 ± 2.5%, respectively. Under heat stress conditions, diet significantly increased the body weight and hot carcass weight and significantly reduced the feed conversion. Dietary 1000 and 750 mg betaine/kg increased (P < 0.05) final body weights (2529.1 and 2418.5 g, respectively) compared with the control (2110.3 g). Betaine supplementation ameliorated some of the adverse effects of heat stress on immune responsiveness, rectal temperature and respiration rate. Dietary 250, 500, 750 and 1000 mg betaine/kg led to a decrease in rectal temperature (40.03, 39.85, 39.63 and 39.53 °C, respectively) compared with the control (40.20 °C). The inclusion of 1000 mg betaine/kg in the growing rabbits' diets nearly doubled the humoral and immune responses compared to the controls (P < 0.05) and significantly reduced rectal temperature and respiration rate. Serum T3, T4, total protein, globulin and total lipids were significantly increased while serum glucose concentration was significantly decreased due to dietary betaine.

In conclusion, supplemental dietary betaine enhanced growth performance and humoral and cell-mediated immunity as well as reduced rectal temperature and respiration rate in growing rabbits subjected to heat stress. From an economic point of view, high levels of betaine are not recommended because betaine is reasonably effective at lower, less expensive, doses.

Hassan et al (2011). "Effect of dietary betaine supplementation on growth, carcass and immunity of New Zealand White rabbits under high ambient temperature." Livestock Science 135(2-3): 103-109.

Betaine alleviates heat stress in chickens

Exposing broilers to a high temperature increases water and electrolyte K(+) and Na(+) excretion, which negatively affects the heat dissipation capacity and acid-base homeostasis, resulting in losses in growth performance.

In this experiment, the efficacy of providing oral rehydration therapy and betaine on growth performance, acid-base balance, and water and electrolyte retention was evaluated. A total of 432 one-day-old broiler chicks (Cobb) were allocated to 72 metabolic cages and reared to 31 d of age under standard conditions. From 32 to 41 d of age, chicks were exposed to heat stress (ambient temperature, 32 degrees C) and high RH (80 to 100% RH) for 9 h daily. The ameliorative effects of a 3 x 3 factorial array of treatments administered via drinking water were evaluated in 8 replicates of 6 chicks per cage for each treatment. Two oral rehydration therapy (ORT) fluids, based on either citrate or bicarbonate salts, were added to tap water. In addition, betaine was added to tap water at an inclusion rate of 0, 500, or 1,000 mg/L to complete the array of 9 liquid-based treatments. Growth performance was assessed at 32, 35, and 41 d of age. From 32 to 35 d of age, chicks receiving ORT fluids exhibited improved growth performance, water balance, and electrolyte (K(+), Na(+)) retention. In addition, the physiological response to stress was attenuated, as indicated by lower heterophil-to-lymphocyte ratios and blood glucose concentrations relative to the negative controls. The addition of betaine at an inclusion rate of 500 mg/L improved BW gain. From d 36 to 41, treatments did not significantly influence growth performance, which suggests that chicks receiving tap water were able to compensate and adapt to the heat-stress conditions.

The results demonstrate that the beneficial effects of providing ORT fluids and 500 mg of betaine/L were observed only during the first 4 d of heat exposure. After this period, adaptation to the heat appears to occur, and none of the treatments was successful in improving growth performance.

Sayed and Downing (2011). "The effects of water replacement by oral rehydration fluids with or without betaine supplementation on performance, acid-base balance, and water retention of heat-stressed broiler chickens." Poult Sci 90(1): 157-67.

High dietary betaine reduces risk of Barrett's esophagus

Folate plays a key role in DNA synthesis and methylation. Limited evidence suggests high intake may reduce risks of esophageal cancer overall; however, associations with esophageal cancer subtypes and Barrett's esophagus (BE), a precancerous lesion, remain unexplored.

We evaluated the relation between intake of folate, B vitamins, and methyl-group donors (methionine, choline, betaine) from foods and supplements, polymorphisms in key folate-metabolizing genes, and risk of BE, esophageal adenocarcinoma (EAC), and esophageal squamous cell carcinoma (ESCC) in 2 population-based case-control studies in Australia. BE patients without (n = 266) or with (n = 101) dysplasia were compared with population controls (n = 577); similarly, EAC (n = 636) or ESCC (n = 245) patients were compared with population controls (n = 1507) using multivariable adjusted logistic regression. Increasing intake of folate from foods was associated with reduced EAC risk (P-trend = 0.01) and mitigated the increased risks of ESCC associated with smoking and alcohol consumption. In contrast, high intake of folic acid from supplements was associated with a significantly elevated risk of BE with dysplasia. High intakes of riboflavin and methionine from food were associated with increased EAC risk, whereas increasing betaine intake was associated with reduced risks of BE without (P-trend = 0.004) or with dysplasia (P-trend = 0.02). Supplemental thiamin, riboflavin, niacin, and vitamin B-12 were associated with increased EAC risk. There were no consistent associations between genetic polymorphisms studied and BE or EAC risk. High intake of folate-containing foods may reduce risk of EAC, but our data raise the possibility that folic acid supplementation may increase risks of BE with dysplasia and EAC.

Ibiebele, T.I., et al., High intake of folate from food sources is associated with reduced risk of esophageal cancer in an Australian population. J Nutr, 2011. 141(2): p. 274-83.

Consumption of wheat aleurone-rich foods increases fasting plasma betaine and modestly decreases fasting homocysteine and LDL-cholesterol

There is strong evidence that whole-grain foods protect against heart disease. Although underlying mechanisms and components are unclear, betaine, found at high levels in wheat aleurone, may play a role. We evaluated the effects of a diet high in wheat aleurone on plasma betaine and related measures.

In a parallel, single-blinded intervention study, 79 healthy participants (aged 45–65 y, BMI ≥ 25 kg/m2) incorporated either aleurone-rich cereal products (27 g/d aleurone) or control products balanced for fiber and macronutrients into their habitual diets for 4 wk. Fasting blood samples were taken at baseline and postintervention (4 wk) from participants. Compared with the control, the aleurone products provided an additional 279 mg/d betaine and resulted in higher plasma betaine (P < 0.001; intervention effect size: 5.2 μmol/L) and lower plasma total homocysteine (tHcy) (P = 0.010; −0.7 μmol/L). Plasma dimethylglycine and methionine, which are products of betaine-mediated homocysteine remethylation, were also higher (P < 0.001; P = 0.027) relative to control. There were no significant effects on plasma choline or B vitamins (folate, riboflavin, and vitamin B-6). However, LDL cholesterol was lower than in the control group (P = 0.037).

We conclude that incorporating aleurone-rich products into the habitual diet for 4 wk significantly increases plasma betaine concentrations and lowers tHcy, which is attributable to enhanced betaine-homocysteine methyltransferase-mediated remethylation of homocysteine. Although this supports a role for betaine in the protective effects of whole grains, concomitant decreases in LDL suggest more than one component or mechanism may be responsible.

Price et al (2010). "Consumption of Wheat Aleurone-Rich Foods Increases Fasting Plasma Betaine and Modestly Decreases Fasting Homocysteine and LDL-Cholesterol in Adults." The Journal of Nutrition 140(12): 2153-2157.

Betaine prevents ethanol induced oxidative stress through regulation of gene expression

There is a need for a nontoxic antioxidant agent to be identified which will prevent alcoholic liver disease (ALD) in alcoholic patients. We tested 4 candidate agents: quercetin, EGCG, catechin and betaine, all of which occur naturally in food. HepG2 cells overexpressing CYP2E1 were subjected to arachidonic acid, iron and 100 mM ethanol with or without the antioxidant agent. All the agents prevented oxidative stress and MDA/4HNE formation induced by ethanol, except for EGCG. Catechin prevented CYP2E1 induction by ethanol. All the agents tended to down-regulate the ethanol-induced increased expression of glutathionine peroxidase 4 (GPX4). All the agents, except catechin, tended to reduce the expression of SOD2 induced by ethanol. Heat shock protein 70 was up-regulated by ethanol alone and betaine tended to prevent this. All 4 agents down-regulated the expression of Gadd45b in the presence of ethanol, which could explain the mechanism of DNA demethylation associated with the up-regulation of the gene expression observed in experimental ALD.

In conclusion, the in vitro model of oxidative stress induced by ethanol provided evidence that all 4 agents tested prevented some aspect of liver cell injury caused by ethanol.

Oliva, J., et al., Protective effect of quercetin, EGCG, catechin and betaine against oxidative stress induced by ethanol in vitro. Exp Mol Pathol, 2011. 90(3): p. 295-9.

Plasma betaine is lower in children with cystic fibrosis

Choline is an important constituent of acetylcholine. Choline is needed for acetylcholine in the nonneuronal acetylcholine system that includes epithelial cells of the lung and intestine, endothelial cells, and immune cells. Plasma free choline concentrations are low in children with cystic fibrosis (CF), but the implications for acetylcholine are unknown.

We determined the relation between plasma free choline and related metabolites and leukocyte acetylcholine in children with CF and in a control group of healthy children without CF. This was a cross-sectional study in 34 children with CF who were pancreatic insufficient and taking pancreatic enzyme-replacement therapy and in 16 healthy children. Plasma free choline, betaine, dimethylglycine, methionine, homocysteine, and leukocyte acetylcholine concentrations were quantified by using isotope-dilution HPLC–tandem mass spectrometry. Mean (±SE) plasma free choline was 9.30 ± 0.37 and 6.54 ± 0.38 μmol/L (P < 0.05) and leukocyte acetylcholine was 1.21 ± 0.016 and 0.077 ± 0.011 pmol leukocyte acetylcholine/106 cells (P < 0.05) in control children and children with CF, respectively. Leukocyte acetylcholine was positively correlated with plasma free choline concentration in children with CF (r = 0.412, P < 0.05) but not in control children. Plasma betaine, dimethylglycine, and methionine concentrations were also lower in children with CF than in control children (P < 0.05).

A low free choline and methyl status in children with CF is associated with reduced acetylcholine in leukocytes. Whether these changes are explained by a mutation in the CF transmembrane conductance regulator or disturbances in choline metabolism and the implications for immune cell dysfunction in CF are unknown.

Innis et al (2011). "Plasma choline depletion is associated with decreased peripheral blood leukocyte acetylcholine in children with cystic fibrosis." The American Journal of Clinical Nutrition 93(3): 564-568

A whole-grain diet increases plasma betaine, and decreases total and LDL-cholesterol compared with a refined-grain diet

Epidemiological studies have repeatedly found that whole-grain (WG) cereal foods reduce the risk of several lifestyle-related diseases, though consistent clinical outcomes and mechanisms are elusive.

To compare the effects of a WG-rich diet with a matched refined-grain (RG) diet on plasma biomarkers and bowel health parameters, seventeen healthy subjects (eleven females and six males) completed an exploratory cross-over study with a 2-week intervention diet based on either WG- or RG-based foods, separated by a washout of at least 5 weeks. Both diets were the same except for the use of WG (150 g/d) or RG foods. Subjects undertook a 4 h postprandial challenge on day 8 of each intervention diet. After 2 weeks, the WG diet tended to decrease plasma total and LDL-cholesterol (both P = 0.09), but did not change plasma HDL-cholesterol, fasting glucose, C-reactive protein or homocysteine compared with the RG diet. Plasma betaine and alkylresorcinol concentrations were elevated after 1 week of the WG diet (P = 0.01 and P < 0.0001, respectively). Clostridium leptum populations in faeces were increased after the WG diet, along with a trend for decreased faecal water pH (P = 0.096) and increased stool frequency (P < 0.0001) compared with the RG diet. A short controlled intervention trial with a variety of commercially available WG-based products tended to improve biomarkers of CVD compared with a RG diet.

Changes in faecal microbiota related to increased fibre fermentation and increased plasma betaine concentrations point to both fibre and phytochemical components of WG being important in mediating any potential health effects.

Ross et al (2011). "A whole-grain cereal-rich diet increases plasma betaine, and tends to decrease total and LDL-cholesterol compared with a refined-grain diet in healthy subjects." Br J Nutr: 1-12.