Individuals with high plasma concentrations of methionine, choline, and betaine may be at reduced risk of colorectal cancer

BACKGROUND: Disturbances in one carbon-metabolism may contribute to carcinogenesis by affecting methylation and synthesis of DNA. Choline and its oxidation product betaine are involved in this metabolism and can serve as alternative methyl group donors when folate status is low.
SUBJECTS AND METHODS: We conducted a case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC), to investigate plasma concentrations of the methyl donors methionine, choline, betaine (trimethylglycine), and dimethylglycine (DMG) in relation to colorectal cancer (CRC) risk. Our study included 1,367 incident CRC cases (965 colon; 402 rectum) and 2,323 controls matched by gender, age group, and study center. Multivariate-adjusted odds ratios (OR) and 95% confidence intervals (CI) for CRC risk were estimated by conditional logistic regression comparing the fifth to the first quintile of plasma concentrations.
RESULTS: Overall, methionine (OR: 0.79, 95%CI: 0.63-0.99, P-trend=0.05), choline (OR: 0.77, 95%CI: 0.60-0.99, P-trend=0.07), and betaine (OR: 0.85, 95%CI: 0.66-1.09, P-trend=0.06) concentrations were inversely associated with CRC risk of borderline significance. In participants with folate concentration below the median of 11.3 nmol/L, high betaine concentration was associated with reduced CRC risk (OR: 0.71, 95%CI: 0.50-1.00, P-trend=0.02), which was not observed for those having a higher folate status. Among women, but not men, high choline concentration was associated with decreased CRC risk (OR: 0.62, 95%CI: 0.43-0.88, P-trend=0.01). Plasma DMG was not associated with CRC risk.
CONCLUSIONS: Individuals with high plasma concentrations of methionine, choline, and betaine may be at reduced risk of colorectal cancer.

Nitter, M., et al., Plasma Methionine, Choline, Betaine, and Dimethylglycine, in relation to Colorectal Cancer Risk in the European Prospective Investigation into Cancer and Nutrition (EPIC). Ann Oncol, 2014

Effects of betaine on performance and body composition: a review of recent findings and potential mechanisms

Betaine is a methyl derivative of glycine first isolated from sugar beets. Betaine consumed from food sources and through dietary supplements presents similar bioavailability and is metabolized to di-methylglycine and sarcosine in the liver. The ergogenic and clinical effects of betaine have been investigated with doses ranging from 500 to 9,000 mg/day. Some studies using animal models and human subjects suggest that betaine supplementation could promote adiposity reductions and/or lean mass gains. Moreover, previous investigations report positive effects of betaine on sports performance in both endurance- and resistance-type exercise, despite some conflicting results. The mechanisms underlying these effects are poorly understood, but could involve the stimulation of lipolysis and inhibition of lipogenesis via gene expression and subsequent activity of lipolytic-/lipogenic-related proteins, stimulation of autocrine/endocrine IGF-1 release and insulin receptor signaling pathways, stimulation of growth hormone secretion, increased creatine synthesis, increases in protein synthesis via intracellular hyper-hydration, as well as exerting psychological effects such as attenuating sensations of fatigue. However, the exact mechanisms behind betaine action and the long-term effects of supplementation on humans remain to be elucidated. This review aims to describe evidence for the use of betaine as an ergogenic and esthetic aid, and discuss the potential mechanisms underlying these effects.

Cholewa, J.M., L. Guimaraes-Ferreira, and N.E. Zanchi, Effects of betaine on performance and body composition: a review of recent findings and potential mechanisms. Amino Acids, 2014

Betaine supplementation protects against renal injury induced by cadmium intoxication in rats

Cadmium (Cd) is an environmental and industrial pollutant that can induce a broad spectrum of toxicological effects that affect various organs in humans and experimental animals. This study aims to investigate the effect of betaine supplementation on cadmium-induced oxidative impairment in rat kidney. The animals were divided into four groups (n=10 per group): control, cadmium, betaine and betaine+cadmium (1) saline control group; (2) cadmium group in which cadmium chloride (CdCl2) was given orally at a daily dose of 5mg/kg body weight for four weeks; (3) betaine group, in which betaine was given to rats at a dose of 250mg/kg/day, orally via gavage for six weeks; (4) cadmium+betaine group in which betaine was given at a dose of 250mg/kg/day, orally via gavage for two weeks prior to cadmium administration and concurrently during cadmium administration for four weeks. Cadmium nephrotoxicity was indicated by elevated blood urea nitrogen (BUN) and serum creatinine levels. Kidneys from cadmium-treated rats showed an increase in lipid peroxidation measured as thiobarbituric acid-reactive substances (TBARS) concentration and reductions in total antioxidant status (TAS), reduced glutathione (GSH) content, glutathione peroxidase (GSH-Px) activity, superoxide dismutase concentration (SOD) and catalase activity. Caspase-3 activity, a marker of DNA damage was also elevated in renal tissues of cadmium-treated rats. Pre-treatment of rats with betaine substantially attenuated the increase in BUN and serum creatinine levels. Betaine also inhibited the increase in TBARS concentration and reversed the cadmium-induced depletion in total antioxidant status, GSH, GSH-Px, SOD and catalase concentrations in renal tissues. Renal caspase-3 activity was also reduced with betaine supplementation. These data emphasize the importance of oxidative stress and caspase signaling cascade in cadmium nephrotoxicity and suggest that betaine pretreatment reduces severity of cadmium nephrotoxicity probably via antioxidant action and suppression of apoptosis.

Hagar, H. and W. Al Malki, Betaine supplementation protects against renal injury induced by cadmium intoxication in rats: Role of oxidative stress and caspase-3. Environ Toxicol Pharmacol, 2014. 37(2): p. 803-811

Dietary betaine may help prevent NTDs

BACKGROUND: Low maternal intake of dietary choline and betaine (a choline derivative) has recently been investigated as a possible risk factor for neural tube defects (NTDs)
METHODS: This case-control study examined the NTD risk associated with choline and betaine in 409 Mexican-American women who gave birth during 1995 to 2000 in the 14-county border region of Texas RESULTS: Using data from the food frequency questionnaire and the lowest quartiles of intake as the reference categories, a protective association was suggested between higher intakes of choline and betaine and NTD risk although the 95% confidence intervals for all risk estimates included 1.0. For choline intake in the second, third, and fourth quartiles, adjusted odds ratios were 1.2, 0.80, and 0.89, respectively. Betaine appeared more protective with odds ratios of 0.62, 0.73, and 0.61, respectively, for the second, third, and fourth quartiles of intake.
CONCLUSION: Study findings suggest that dietary betaine may help to prevent NTDs.

Lavery, A.M., et al., Dietary intake of choline and neural tube defects in Mexican Americans. Birth Defects Res A Clin Mol Teratol, 2014

Betaine suppressed amyloid-beta formation, a component of senile plaques related to Alzheimer disease

Betaine was an endogenous catabolite of choline, which could be isolated from vegetables and marine products. Betaine could promote the metabolism of homocysteine in healthy subjects and was used for hyperlipidemia, coronary atherosclerosis, and fatty liver in clinic. Recent findings shown that Betaine rescued neuronal damage due to homocysteine induced Alzheimer's disease (AD) like pathological cascade, including tau hyperphosphorylation and amyloid-beta (Abeta) deposition. Abeta was derived from amyloid precursor protein (APP) processing, and was a triggering factor for AD pathological onset. Here, we demonstrated that Betaine reduced Abeta levels by altering APP processing in N2a cells stably expressing Swedish mutant of APP. Betaine increased alpha-secretase activity, but decreased beta-secretase activity. Our data indicate that Betaine might play a protective role in Abeta production.

Liu, X.P., et al., Betaine suppressed Abeta generation by altering amyloid precursor protein processing. Neurol Sci, 2014

Prognostic value of choline and betaine depends on intestinal microbiota-generated metabolite TMAO

AIMS: Recent metabolomics and animal model studies show trimethylamine-N-oxide (TMAO), an intestinal microbiota-dependent metabolite formed from dietary trimethylamine-containing nutrients such as phosphatidylcholine (PC), choline, and carnitine, is linked to coronary artery disease pathogenesis. Our aim was to examine the prognostic value of systemic choline and betaine levels in stable cardiac patients. METHODS AND RESULTS: We examined the relationship between fasting plasma choline and betaine levels and risk of major adverse cardiac events (MACE = death, myocardial infraction, stroke) in relation to TMAO over 3 years of follow-up in 3903 sequential stable subjects undergoing elective diagnostic coronary angiography. In our study cohort, median (IQR) TMAO, choline, and betaine levels were 3.7 (2.4-6.2)muM, 9.8 (7.9-12.2)muM, and 41.1 (32.5-52.1)muM, respectively. Modest but statistically significant correlations were noted between TMAO and choline (r = 0.33, P < 0.001) and less between TMAO and betaine (r = 0.09, P < 0.001). Higher plasma choline and betaine levels were associated with a 1.9-fold and 1.4-fold increased risk of MACE, respectively (Quartiles 4 vs. 1; P < 0.01, each). Following adjustments for traditional cardiovascular risk factors and high-sensitivity C-reactive protein, elevated choline [1.34 (1.03-1.74), P < 0.05], and betaine levels [1.33 (1.03-1.73), P < 0.05] each predicted increased MACE risk. Neither choline nor betaine predicted MACE risk when TMAO was added to the adjustment model, and choline and betaine predicted future risk for MACE only when TMAO was elevated. CONCLUSION: Elevated plasma levels of choline and betaine are each associated with incident MACE risk independent of traditional risk factors. However, high choline and betaine levels are only associated with higher risk of future MACE with concomitant increase in TMAO.

Wang, Z., et al., Prognostic value of choline and betaine depends on intestinal microbiota-generated metabolite trimethylamine-N-oxide. Eur Heart J, 2014

Betaine supplementation improved high fructose- induced hyperuricemia, insulin resistance, dyslipidemia and systemic inflammation in rats

High fructose intake causes metabolic syndrome, being an increased risk of chronic kidney disease development in humans and animals. In this study, we examined the influence of betaine on high-fructose-induced renal damage involving renal inflammation, insulin resistance and lipid accumulation in rats and explored its possible mechanisms. Betaine was found to improve high-fructose-induced metabolic syndrome including hyperuricemia, dyslipidemia and insulin resistance in rats with systemic inflammation. Betaine also showed a protection against renal dysfunction and tubular injury with its restoration of the increased glucose transporter 9 and renal-specific transporter in renal brush bolder membrane and the decreased organic anion transporter 1 and adenosine-triphosphatebinding cassette transporter 2 in the renal cortex in this model. These protective effects were relevant to the anti-inflammatory action by inhibiting the production of inflammatory cytokines including interleukin (IL)-1â, IL-18, IL-6 and tumor necrosis factor-á in renal tissue of high-fructose-fed rat, being more likely to suppress renal NOD-like receptor superfamily, pyrin domain containing 3 inflammasome activation than nuclear factor êB activation. Subsequently, betaine with anti-inflammation ameliorated insulin signaling impairment by reducing the up-regulation of suppressor of cytokine signaling 3 and lipid accumulation partly by regulating peroxisome proliferator-activated receptor á/palmityltransferase 1/carnitine/organic cation transporter 2 pathway in kidney of high-fructose-fed rats. These results indicate that the inflammatory inhibition plays a pivotal role in betaine’s improvement of high-fructose-induced renal injury with insulin resistance and lipid accumulation in rats.

Fan, C.-Y., et al., Betaine supplementation protects against high-fructose-induced renal injury in rats. The Journal of Nutritional Biochemistry, 2014. 25(3): p. 353-62