Betaine might be applicable to the prevention of inflammation-associated colon carcinogenesis.

In this review, we will summarize the current understanding of modulation of colitis-associated colon tumorigenesis by two natural products, baicalein and betaine, which have anti-inflammatory activities. Baicalein and betaine have been shown to provide various health benefits to organism in many ways. Baicalein is a phenolic flavonoid derived originally from the root of Scutellaria baicalensis Georgi. From ancient times, baicalein has widely been used in oriental medicines as an anti-inflammatory and anti-cancer therapy. Betaine, trimethylglycine, is an essential biochemical molecule of the methionine/homocysteine cycle and is synthesized by conversion of choline. Betaine is an important human nutrient obtained from various foods including sugar beet and lycium. Betaine has provided various health benefits including disease prevention. However, the action mechanisms of their activity remain poorly understood. Recent studies reported the effects of baicalein and betaine on cytotoxicity against colon cancer cells and chemically induced colitis-associated colon tumorigenesis in mice. Administrations of baicalein and betaine containing diets significantly inhibited the incidence of tumors and hyperplasia with down-regulation of inflammation. Therefore, baicalein and betaine might be applicable to the prevention of inflammation-associated colon carcinogenesis.

Kim, D.H., et al., Modulation of Colitis-associated Colon Tumorigenesis by Baicalein and Betaine. J Cancer Prev, 2014. 19(3): p. 153-60

Betaine recovers hypothalamic neural injury by inhibiting astrogliosis and inflammation in fructose-fed rats

SCOPE:: Hypothalamic astrogliosis and inflammation cause neural injury, playing a critical role in metabolic syndrome development. This study investigated whether and how fructose caused hypothalamic astrogliosis and inflammation in vivo and in vitro. The inhibitory effects of betaine on hypothalamic neural injury, astrogliosis and inflammation were explored to address its improvement of fructose-induced metabolic syndrome.
METHODS AND RESULTS:: Rats or astrocytes were exposed to fructose and then treated with betaine. Neural injury, proinflammatory markers, toll-like receptor 4/nuclear factor-kappaB (TLR4/NF-kappaB) pathway and histone deacetylases (HDAC3) expression were evaluated. The reduction of pro-opiomelanocortin (POMC) and melanocortin 4 receptor (Mc4R) neurons in fructose-fed rats were ameliorated by betaine. Moreover, fructose induced astrogliosis and proinflammatory cytokines by increasing TLR4, MyD88 and NF-kappaB expression in rat hypothalamus and astrocytes. HDAC3 over-expression preserved the prolonged inflammation in fructose-stimulated astrocytes by regulating nuclear NF-kappaB-dependent transcription. Betaine suppressed TLR4/NF-kappaB pathway activation and HDAC3 expression, contributing to its inhibition of hypothalamic astrogliosis and inflammation in animal and cell models.
CONCLUSION:: These findings suggest that betaine inhibits fructose-caused astrogliosis and inflammation by the suppression of TLR4/NF-kappaB pathway activation and HDAC3 expression to protect against hypothalamic neural injury, which, at least partly, contributes to the improvement on fructose-induced metabolic syndrome.

Li, J.M., et al., Betaine recovers hypothalamic neural injury by inhibiting astrogliosis and inflammation in fructose-fed rats. Mol Nutr Food Res, 2014

Carnitine, erythritol and betaine may have efficacy in reducing innate inflammation in dry eye disease.

Purpose: To explore the effects of osmoprotectants on pro-inflammatory mediator production in primary human corneal epithelial cells (HCECs) exposed to hyperosmotic stress.
Methods: HCECs cultured in iso-osmolar medium (312 mOsM) were switched to hyperosmotic media with or without prior incubation with 2-20 mM of l-carnitine, erythritol or betaine for different time periods. The mRNA expression and protein production of pro-inflammatory markers in HCECs were evaluated by RT-qPCR and ELISA.
Results: Hyperosmolar media significantly stimulated the mRNA and protein expression of pro-inflammatory cytokines, TNF-alpha, IL-1beta and IL-6, and chemokines, IL-8, CCL2 and CCL20 in HCECs in an osmolarity dependent manner. The stimulated expression of these pro-inflammatory mediators was significantly but differentially suppressed by l-carnitine, erythritol or betaine. l-Carnitine displayed the greatest inhibitory effects and down-regulated 54-77% of the stimulated mRNA levels of TNF-alpha (down from 12.3-5.7 fold), IL-1beta (2.2-0.9 fold), IL-6 (7.3-2.9 fold), IL-8 (4.6-2.0 fold), CCL2 (15.3-3.5 fold) and CCL20 (4.1-1.5 fold) in HCECs exposed to 450 mOsM. The stimulated protein production of TNF-alpha, IL-1beta, IL-6 and IL-8 was also significantly suppressed by l-carnitine, erythritol and betaine. l-carnitine suppressed 49-79% of the stimulated protein levels of TNF-alpha (down from 81.3 to 17.4 pg/ml), IL-1beta (56.9-29.2 pg/ml), IL-6 (12.8-4.6 ng/ml) and IL-8 (21.2-10.9 ng/ml) by HCECs exposed to 450 mOsM. Interestingly, hyperosmolarity stimulated increase in mRNA and protein levels of TNF-alpha, IL-1beta and IL-6 were significantly suppressed by a transient receptor potential vanilloid channel type 1 (TRPV1) activation inhibitor capsazepine.
Conclusions: l-carnitine, erythritol and betaine function as osmoprotectants to suppress inflammatory responses via TRPV1 pathway in HCECs exposed to hyperosmotic stress. Osmoprotectants may have efficacy in reducing innate inflammation in dry eye disease.

Hua, X., et al., Effects of l-Carnitine, Erythritol and Betaine on Pro-inflammatory Markers in Primary Human Corneal Epithelial Cells Exposed to Hyperosmotic Stress. Curr Eye Res, 2014: p. 1-11.

Anti-inflammatory effects of betaine on AOM/DSS induced colon tumorigenesis in ICR male mice

Betaine is an important human nutrient obtained from various foods and studies in animals and humans have provided results suggesting their pathogenesis of various chronic diseases and points to a role in risk assessment and disease prevention. However, the molecular mechanisms of its activity remain poorly understood and warrant further investigation. This study was performed to investigate the anti-inflammation and tumor preventing capacity of betaine on colitis-associated cancer in mice. In in vivo experiments, we induced colon tumors in mice by azoxymethane (AOM) and dextran sulfate sodium (DSS) and evaluated the effects of betaine on tumor growth. Administration with betaine significantly decreased the incidence of tumor formation with downregulation of inflammation. Treatment with betaine inhibited ROS generation and GSSG concentration in colonic mucosa. Based on the qPCR data, administration of betaine inhibited inflammatory cytokines such TNF-alpha, IL-6, iNOS and COX-2. In in vitro experiments, LPS-induced NF-kappaB and inflammatory-related cytokines were inhibited by betaine treatment in RAW 264.7 murine macrophage cells. Our findings suggest that betaine is one of the candidates for the prevention of inflammation-associated colon carcinogenesis.

Kim, D.H., et al., Anti-inflammatory effects of betaine on AOM/DSSinduced colon tumorigenesis in ICR male mice. Int J Oncol, 2014. 45(3): p. 1250-6

Hepatoprotective effects of Lycium chinense Miller fruit and its constituent betaine in CCl-induced hepatic damage in rats.

The hepatoprotective activities of Lycium chinense Miller (LC) fruit extract and its component betaine were investigated under carbon tetrachloride (CCl4)-induced hepatotoxicity in rats. The treatment of LC fruit extract significantly suppressed the increase of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in the sera of CCl4 injured rats, and restored the decreased levels of anti-oxidant enzymes such as total antioxidant capacity (TAC), superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) and suppressed the expression of inflammatory mediators including inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-1 and -2. To visualize the potential activity of betaine, a component of LC fruit, betaine was substituted for LC extract in CCl4 injured rats. The biochemical profile in CCl4 injured rats co-treated with betaine matched those of LC fruit treated CCl4 injured rats. The ameliorative effects of LC extract, as well as betaine, were also confirmed by histopathological examination. Collectively, the present findings imply that LC fruit, via its component betaine, mitigate CCl4-induced hepatic injury by increasing antioxidative activity and decreasing inflammatory mediators including iNOS and COX-1/COX-2.

Ahn, M., et al., Hepatoprotective effects of Lycium chinense Miller fruit and its constituent betaine in CCl-induced hepatic damage in rats. Acta Histochem, 2014

Betaine protects against high-fat-diet-induced NAFLD and improves liver function

BACKGROUND AND OBJECTIVES: Previous studies have shown that betaine prevents alcohol-induced liver injury and improves liver function. The purpose of this study was to investigate the hepatoprotective effects of betaine on nonalcoholic fatty liver disease (NAFLD) and to observe changes of HMGB1/TLR4 signaling.
METHODS: Thirty rats were randomly divided into control, model, and betaine groups. The rats in the model and betaine groups were fed a high-fat diet for 12 weeks to induce an animal model of NAFLD. The rats in the betaine group were then intragastrically administered betaine solution at a dose of 400 mg/kg per day for four weeks. Liver histology was examined. Serum levels of ALT, AST, TC, TG, HDL-C, LDL-C, FFA, HMGB1, NF-kappaB, TLR4, and tHcy were determined and intrahepatic TC, TG, and Hcy levels were assayed. mRNA expression and protein levels of HMGB1, NF-kappaB, and TLR4 in liver tissue were also determined.
RESULTS: Compared with the control group, rats in the model group developed severe liver injury, accompanied by significant increases in serum levels of ALT, AST, TC, TG, LDL-C, FFA, HMGB1, NF-kappaB, and TLR4, intrahepatic TC, TG, and Hcy content, histological scores for steatosis, inflammation, and necrosis, and mRNA expression and protein levels of HMGB1, NF-kappaB, and TLR4, and a significant decrease in serum HDL-C (P < 0.05). Compared with the model group, all these indicators were significantly improved by administration of betaine (P < 0.05).
CONCLUSIONS: Betaine effectively protects against high-fat-diet-induced NAFLD and improves liver function; the mechanism is probably related to inhibition of HMGB1/TLR4 signaling pathways.

Zhang, W., et al., Betaine Protects Against High-Fat-Diet-Induced Liver Injury by Inhibition of High-Mobility Group Box 1 and Toll-Like Receptor 4 Expression in Rats. Dig Dis Sci, 2013

Betaine prevents vasculature remodeling and inflammatory response during vascular aging

We previously reported that lysophosphatidylcholine (LPC) is a mediator of endothelial dysfunction in expression of adhesion molecules (AMs) during aging. This study aimed at investigating the effects of betaine on LPC-related expression of AMs and the molecular modulation of nuclear factor-kappaB (NF-kappaB) activation in the aorta of aged rats and rat endothelial YPEN-1 cells. The experiment was performed on young (7months) and old (21months) rats; 2 groups of old rats were fed betaine (3 or 6mg*kg-1*day-1 for 10days). Betaine inhibited the expression of LPC-related AMs in the serum and tissue of aged rats, without affecting the elevated levels of serum LPC. Betaine also prevented the generation of reactive species, thereby maintaining the redox status via the enhancement of the thiol status during aging. Furthermore, betaine attenuated NF-kappaB activation via the dephosphorylation of IkappaB kinase (IKK) and mitogen-activated protein kinases (MAPKs) in aged aorta and LPC-treated YPEN-1 cells. Thus, betaine suppressed the LPC-related AM expression associated with NF-kappaB activation via the upregulation of IKK/MAPKs. Our findings provide insights into the prevention of vascular disorders and the development of interventions based on natural compounds, such as betaine.

Lee, E.K., et al., Betaine attenuates lysophosphatidylcholine-mediated adhesion molecules in aged rat aorta: Modulation of the nuclear factor-kappaB pathway. Exp Gerontol, 2013

Plasma betaine concentrations correlate with plasma cortisol but not with C-reactive protein in an elderly population

Background: Low plasma betaine concentrations are a feature of seriously ill patients. Increased dietary betaine intake has been associated with lowered systemic inflammation. We aimed to compare plasma cortisol (a stress marker) and C-reactive protein (an inflammation marker) as statistical predictors of plasma betaine concentrations.
Methods: Plasma carnitine, cortisol and C-reactive protein concentrations, other biochemical measures and urine betaine excretion, were compared with plasma betaine concentration by correlation and in multiple regression models, using morning blood and urine samples from 64 ambulant elderly subjects and from 55 patients admitted to hospital with hip fractures.
Results: In the ambulant elderly without acute trauma, plasma cortisol (with negative coefficients) and carnitine (with positive coefficients) statistically predicted plasma betaine concentrations. C-reactive protein was not a predictor. In the patients, the significant predictors were plasma carnitine (positive coefficient) and plasma homocysteine (negative coefficient) and C-reactive protein again was not a predictor. In regression models using combined patient and control data there were large ranges of both cortisol and especially C-reactive protein; cortisol and homocysteine (negative coefficients) and carnitine (positive coefficient) were significant predictors but C-reactive protein was not significant.
Conclusions: Stress rather than inflammation may affect plasma betaine concentrations.

Lever, M., et al., Plasma betaine concentrations correlate with plasma cortisol but not with C-reactive protein in an elderly population. Clin Chem Lab Med, 2012. 50(9): p. 1635-40

Betaine inhibits in vitro and in vivo angiogenesis through suppression of the NF-κB and Akt signaling pathways

Angiogenesis is defined as the formation of new blood vessels form existing vessels surrounding a tumor. The process of angiogenesis is an important step for tumor growth and metastasis, as is inflammation. Thus, angiogenesis inhibitors that suppress inflammation have been studied as an anticancer treatment. Recently, many research groups have investigated the anti-angiogenic activity of natural compounds since some have been demonstrated to have anticancer properties. Among many natural compounds, we focused on betaine, which is known to suppress inflammation. Betaine, trimethylglycine (TMG), was first discovered in the juice of sugar beets and was later shown to be present in wheat, shellfish and spinach. In Southeast Asia, betaine is used in traditional oriental medicine for the treatment of hepatic disorders. Here, we report the anti-angiogenic action of betaine. Betaine inhibited in vitro angiogenic cascade, tube formation, migration and invasion of human umbilical vein endothelial cells (HUVECs). Betaine also inhibited in vivo angiogenesis in the mouse Matrigel plug assay. The mRNA expression levels of basic fibroblast growth factor (bFGF), matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) in HUVECs were decreased by betaine treatment. In addition, betaine suppressed NF-kappaB and Akt activation.
Yi, E.Y. and Y.J. Kim, Betaine inhibits in vitro and in vivo angiogenesis through suppression of the NF-kappaB and Akt signaling pathways. Int J Oncol, 2012. 41(5): p. 1879-85

Dietary choline and betaine intakes and risk of cardiovascular diseases: review of epidemiological evidence

BACKGROUND: Cardiovascular diseases (CVD) are the most important causes of human mortality in the world. Higher intakes of choline and betaine have been shown to be associated with lower plasma homocysteine levels (the putative CVD risk factor). This study aimed to review the evidence on the association between dietary intakes of choline and betaine and traditional/novel CVD risk factors.

METHODS: We searched in PubMed website from 1990 to 2009, with the use of following keywords: "dietary choline and betaine, cardiovascular diseases, metabolic syndrome, inflammation". The cross-sectional and prospective studies as well as the clinical trials were recruited in this investigation.

RESULTS: Dietary intakes of “choline”/“choline and betaine” were not significantly associated with CVD risk; however, the higher intakes of choline and betaine were associated with higher serum concentrations of CRP, IL-6 and TNF-α. Individuals with high plasma choline levels were obese and had elevated plasma triglycerides, HDL and non-HDL cholesterol levels; whereas high plasma betaine levels were inversely associated with these biochemical markers. Both choline and betaine supplementation resulted in increased blood lipid profiles.

CONCLUSION: Although dietary intakes of choline and betaine were not significantly associated with CVD incidence, the long-term consumption of these nutrients have been shown to prevent CVD mortality by decreasing inflammation and other risk factors.

Rajaie, S. and A. Esmaillzadeh, Dietary choline and betaine intakes and risk of cardiovascular diseases: review of epidemiological evidence. ARYA Atheroscler, 2011. 7(2): p. 78-86

Betaine reduces the expression of inflammatory adipokines caused by hypoxia in human adipocytes

Obesity is characterised by a state of chronic low-grade inflammation and the elevated circulating and tissue levels of inflammatory markers, including inflammation-related adipokines, released from white adipose tissue. The expression and release of these adipokines generally rises as the adipose tissue expands and hypoxic conditions start to develop within the tissue. Here, the effect of betaine, a trimethylglycine having a biological role as an osmolyte and a methyl donor, on the expression of inflammation-related markers was tested in human adipocytes under hypoxia. Differentiated adipocytes were cultivated under low (1 %) oxygen tension for 8-20 h. The expression of different adipokines, including IL-6, leptin, PPARgamma, TNF-alpha and adiponectin, was measured by quantitative PCR by determining the relative mRNA level from the adipocytes. Hypoxia, in general, led to a decrease in the expression of PPARgamma mRNA in human adipocytes, whereas the expression levels of leptin and IL-6 mRNA were substantially increased by hypoxia. The cultivation of adipocytes under hypoxia also led to a reduction in the expression of TNF-alpha mRNA. The results showed that hypoxia increased the relative quantification of leptin gene transcription, and that betaine (250 mumol/l) reduced this effect, caused by low oxygen conditions. Under hypoxia, betaine also reduced the mRNA level of the pro-inflammatory markers IL-6 and TNF-alpha. These results demonstrate that the extensive changes in the expression of inflammation-related adipokines in human adipocytes caused by hypoxia can be diminished by the presence of physiologically relevant concentrations of betaine.
Olli, K., et al., Betaine reduces the expression of inflammatory adipokines caused by hypoxia in human adipocytes. Br J Nutr, 2012: p. 1-7.

Betaine improves liver function, histology and homocysteine levels in 1 yr study of NASH subjects

Introduction: Nonalcoholic steatohepatitis (NASH) is an important cause of cirrhosis and over the past decade has accounted for an increasing proportion of liver transplants in the United States. Unfortunately there is no treatment for NASH except for risk factor modification. The aims of our study were to assess the impact of betaine on liver function tests, homocysteine levels and hepatic fibrosis in a prospective cohort of NASH patients.

Materials and Methodology: Between July 2003 and June 2006, consecutive patients with NASH were screened to determine treatment eligibility. Eligibility criteria included elevated aminotransferases and a liver biopsy within twelve months of study entry satisfying the Brunt criteria for NASH. Patients were treated with betaine anhydrous 10 grams twice a day for one year. Liver function tests, homocysteine levels and liver biopsy were performed prior to and at the end of treatment. Outcomes were calculated using intention to treat analysis.

Results: 35 patients were eligible. 23 patients completed treatment, seven were intolerant and five dropped out and were lost to follow up. Improvement or normalization in aminotransferases occurred in 62.9% of patients and in homocysteine in 45.7%. Resolution or improvement in steatosis occurred in 57.1%, improvement or stabilization of inflammation in 60% and fibrosis in 62.9%.


Conclusion: Betaine appears to improve hepatic function tests, homocysteine levels and histology in this cohort of NASH patients. Large randomized studies with long-term follow up are required to assess the effect of betaine for this growing epidemic.

Mukherjee, M., et al., Impact of Betaine on Hepatic Fibrosis and Homocysteine in Nonalcoholic Steatohepatitis - A Prospective, Cohort Study. The Open Translational Medicine Journal, 2011. 3: p. 1-4.

Metabonomics in ulcerative colitis

Nuclear magnetic resonance (NMR) spectroscopy and appropriate multivariate statistical analyses have been employed on mucosal colonic biopsies, colonocytes, lymphocytes, and urine from patients with ulcerative colitis (UC) and controls in order to explore the diagnostic possibilities, define new potential biomarkers, and generate a better understanding of the pathophysiology.

Samples were collected from patients with active UC, quiescent UC, and from controls and analyzed by NMR spectroscopy. Significant differences between controls and active UC were discovered in the metabolic profiles of biopsies and colonocytes. In the biopsies from patients with active UC higher levels of antioxidants and of a range of amino acids, but lower levels of lipid, glycerophosphocholine (GPC), myo-inositol, and betaine were found, whereas the colonocytes only displayed low levels of GPC, myo-inositol and choline. Interestingly, 20% of inactive UC patients had similar profiles to those who were in an active state.

This study demonstrates the possibilities of metabonomics as a diagnostic tool in active and quiescent UC and provides new insight into pathophysiologic mechanisms.

Bjerrum et al (2009). "Metabonomics in ulcerative colitis: diagnostics, biomarker identification, and insight into the pathophysiology." J Proteome Res: Epub Oct.

Betaine reduces athersclerosis and inflammatory response

This study investigated the effect of betaine supplementation on atherosclerotic lesion in apolipoprotein (apo) E-deficient mice. Four groups of these mice were fed AIN-93G diets supplemented with 0, 1, 2, or 4 g betaine/100 g diet (no, 1, 2, and 4% betaine, respectively). Wild-type C57BL/6 J mice were fed AIN-93G diet (wild-type). Mice were sacrificed after 0, 7, or 14 weeks of the experimental diets. Atherosclerotic lesion area in the aortic sinus, levels of tumor necrosis factor (TNF)-α and monocyte chemoattractant protein (MCP)-1 in aorta and serum, serum lipids, and methylation status of TNF-α promoter in aorta were determined.

The results showed:

- compared with no-betaine mice after 14 weeks, mice receiving 1%, 2%, or 4% betaine had 10.8, 41, and 37% smaller lesion area, respectively.
- betaine supplementation reduced aortic expression of TNF-α in a dose-dependent way.
- betaine supplementation for 14 weeks led to higher concentrations of serum total cholesterol (P < 0.01), LDL cholesterol (P < 0.05), and lower body weight (P < 0.05).

The authors concluded that despite exacerbating hyperlipidemia in apoE-deficient mice, betaine may exert its anti-atherogenic effect by inhibiting aortic inflammatory response mediated by TNF-α.

Lv et al (2009). "Betaine supplementation attenuates atherosclerotic lesion in apolipoprotein E-deficient mice." Eur J Nutr 48(4): 205-12.

Betaine inhibits atherosclerosis via anti-inflammation

Five groups of mice were studied: ApoE-deficient (model group and three betaine groups) and wild-type mice as control. The control group and model group were fed AIN-93G diet. Three betaine groups were fed AIN-93G diet supplemented with 1, 2, 4 g betaine/100 g diet, respectively.

The study found:

- The percentage of aorta sinus plaque to lumen area of 1% and 2% betaine groups were 41% and 33% smaller than that of the model group.

- Serum TNF-alpha level of three betaine groups were lower than that of the model group, but there was no significant difference in the methylation status of TNF-alpha promotor among all five groups.

They concluded that betaine could inhibit the development of atherosclerosis via anti-inflammation.

Fan et al (2008). "Anti-atherosclerotic effect of betaine in apolipoprotein E-deficient mice." Zhonghua Yu Fang Yi Xue Za Zhi 42(10): 742-7.

Betaine reduces oxidative stress and inflammation

This study investigated the effects of betaine on the inflammatory process and the oxidative stress in rats with nonalcoholic steatohepatitis (NASH) using control, model, low and high dose betaine groups. Except control group, all rats were fed with high fat diet containing propylthioracil (PTU), a fatty liver-inducing drug, to construct NASH model, and those in low (200 mg/kg) and high (400 mg/kg) dose group received betaine solution intragastric gavage.

Compared with control group, model group rats had:

- increased liver damage
- enhanced expression of tumor necrosis factor-α (TNF-α), inflammatory factor interferon-γ (IEN-γ), and cytochrome-related factor CYP2E1 mRNA in liver
- decreased expression of IL-10 mRNA
- increased levels of malonaldehyde (MDA) and nitrogen monoxide (NO) in liver
- no significant change in cytochrome-related factor CYP3A2

Compared with that in the model group, high and low dose betaine groups had:

- less liver damage
- attenuated expression of TNF-α, TEN-γ, CYP2E1 and CYP3A2 mRNA in liver
- enhanced expression of IL-10 mRNA
- decreased levels of MDA and NO in liver

There was a significant difference in the above parameters between the two betaine treatment groups. Betaine has protective effects on liver injury in rats induced by a high fat diet. The mechanisms may involve improvement in oxidative stress and suppressed expression of inflammatory factors.

Zhang et al (2008). "Effects of betaine on oxidative stress and inflammatory factors in rats with nonalcoholic steatohepatitis." Wuhan Daxue Xuebao (Yixue Ban) 29(5): 587-91.

Betaine and Inflammation

An article by Detopoulou et al (2008). "Dietary choline and betaine intakes in relation to concentrations of inflammatory markers in healthy adults: the ATTICA study." showed that participants who consumed >360 mg/d of betaine had, on average:

- 10% lower concentrations of homocysteine
- 19% lower concentrations of C-reactive protein
- 12% lower concentrations of tumor necrosis factor

than did those who consumed <260 mg/d.

This was accompanied by an Editorial by Zeisel "Is there a new component of the Mediterranean diet that reduces inflammation?" and a letter to the editor of AJCN by Slow et al, entitled "Dietary betaine and inflammation". Zeisel draws the correlation between betaine/choline intake and the Mediterranean diet, whilst Slow et al stress the importance of the osmolyte function in addition to the methylation role of betaine. The reply to Slow et al is here.

Papers 2004-7:

Go et al (2005). "Betaine Suppresses Proinflammatory Signaling During Aging: The Involvement of Nuclear Factor-{kappa}B via Nuclear Factor-Inducing Kinase/I{kappa}B Kinase and Mitogen-Activated Protein Kinases."

Go et al (2007). "Betaine modulates age-related NF-kappaB by thiol-enhancing action."