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© 2007 American Society for Nutrition J. Nutr. 137:2224-2228, October 2007

Nutrient Physiology, Metabolism, and Nutrient-Nutrient Interactions

Betaine Can Partially Spare Choline in Chicks but Only When Added to Diets Containing a Minimal Level of Choline1

Ryan N. Dilger2, Timothy A. Garrow3,4 and David H. Baker2,4,*

Departments of 2 Animal Sciences and 3 Food Science and Human Nutrition and 4 Division of Nutritional Sciences, University of Illinois at Urbana-Champaign, Urbana, IL 61801

* To whom correspondence should be addressed. E-mail: dhbaker{at}uiuc.edu.


   ABSTRACT
TOP
 ABSTRACT
Introduction
 Materials and Methods
 Results
 Discussion
 LITERATURE CITED
 
The ability of betaine to serve as a methyl donor in chicks was assessed in 3 bioassays using a choline-free purified diet that contained adequate methionine (Met). In assay 1, choline and betaine were each supplemented at 300 mg/kg in a 2 x 2 factorial arrangement of diets. Supplemental choline improved (P < 0.05) growth performance over the 9-d growth period, whereas betaine alone had no effect. In assay 2, graded supplements of choline produced a linear increase (P < 0.05) in growth performance criteria over a 9-d growth period. Additionally, hepatic betaine-homocysteine (Hcy) methyltransferase (BHMT) activity decreased linearly (P < 0.05), whereas plasma total Hcy remained unchanged. Addition of 260 or 600 mg/kg betaine to the choline-free basal diet did not affect growth performance or BHMT activity, but 600 mg/kg betaine reduced (P < 0.05) plasma total Hcy. Assay 3 was designed to quantify the ability of betaine to spare choline. Minimal supplemental choline requirements of 20.8 ± 1.50 mg/d (722 mg/kg diet) and 10.5 ± 1.03 mg/d (412 mg/kg diet) were estimated in the absence and presence of 1000 mg/kg supplemental betaine, respectively. Based on these estimates, 50% of the dietary choline requirement must be supplied as choline per se, but the remaining 50% can be replaced by betaine. Collectively, these data suggest betaine and Met have minimal choline-sparing activity in chicks fed purified diets devoid of preformed choline. However, addition of betaine to diets containing minimal choline allows a marked reduction in the total dietary choline requirement.


   Introduction
TOP
 ABSTRACT
 Introduction
Materials and Methods
 Results
 Discussion
 LITERATURE CITED
 
Methylation of phosphatidylethanolamine, the first step in choline biosynthesis, allows methionine (Met) to donate a methyl group (via S-adenosyl-Met) and therefore spare choline in mammalian species (1,2). In contrast, avian species have limited capacity to carry out this initial biosynthetic step (3,4). Therefore, limited choline synthetic capacity translates into a relatively high dietary requirement for preformed choline in young chicks (5,6). Although the choline-Met interrelationship has been studied extensively, less emphasis has been placed on the link between choline and its oxidation product, betaine.

Betaine is a substrate for betaine-homocysteine (Hcy)5 methyltransferase (BHMT), which remethylates Hcy to form Met. Thus, the methyl moiety donated by betaine becomes a component of Met and is subsequently donated by S-adenosyl-Met to various acceptors (e.g. guanidinoacetate to form creatine). Choline can only supply methyl groups after it has been oxidized to betaine. Based on initial rate kinetics, dietary choline is preferentially used for biosynthesis of acetylcholine (i.e. neurotransmission) and phosphatidylcholine (i.e. cell membrane integrity) (7). Previous research suggested these 2 functions require choline per se and that betaine would have no sparing effect on this portion of the choline requirement (8–10). Both choline and betaine are commercially available products used to fortify foods and feeds. Thus, characterizing their interrelationship is important, especially in avian species.

Our primary objectives were to 1) assess the capacity of betaine to support chick growth when included in a choline-free purified diet, and 2) provide quantitative estimates of the choline requirement of chicks in the presence and absence of surfeit betaine. Thus, if betaine were able to spare choline, this effect would manifest as a reduction in the total dietary choline requirement.


   Materials and Methods
TOP
 ABSTRACT
 Introduction
 Materials and Methods
Results
 Discussion
 LITERATURE CITED
 
All experimental procedures were approved by the University of Illinois Animal Care and Use Committee. Three studies were conducted using male chicks (New Hampshire male x Columbian female) obtained from the University of Illinois Poultry Farm. Chicks were housed in thermostatically controlled starter batteries with raised-wire flooring in an environmentally controlled room with continuous lighting. From hatch to d 7 post-hatch, chicks were fed a typical corn-soybean meal starter diet that provided 230 g/kg crude protein (CP) and was adequate in all dietary nutrients (11). After overnight food deprivation, the chicks were weighed, wing-banded, and randomized to dietary treatments on d 8 such that mean initial pen weights and weight distributions were similar across treatments.

In each of 3 bioassays, chicks were fed a purified, choline-free basal diet (Table 1) for either 9 d (assays 1 and 2) or 11 d (assay 3). This basal diet was previously shown to contain little, if any, bioavailable choline (12). Supplemental L-Met was included at 1.2 g/kg to satisfy the minimal Met plus cyst(e)ine requirement for young chicks fed this diet (13) and the basal diet contained surfeit folate, vitamin B-12, and vitamin B-6. Experimental diets and tap water were freely available to chicks at all times. We measured body weights of individual chicks and pen food intakes at the termination of each bioassay. Weight gain, food intake, and food efficiency (gain:food) were calculated for each replicate pen of chicks.


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  		TABLE 1 Composition of experimental basal diet1

 
    Assay 1. The objective of this assay was to qualitatively compare choline and betaine when included in a choline-free diet. The basal diet was supplemented with choline and betaine, each at 300 mg/kg, in a bioassay containing a 2 x 2 factorial arrangement of dietary treatments. Experimental diets were fed to 4 replicate pens of 3 chicks during a 9-d feeding period (d 8–17 post-hatch), after which growth performance was evaluated.

    Assay 2. This assay sought to determine whether betaine or Met possessed choline-sparing activity in chicks. A comparison between potential methyl-donating compounds was made by supplementing the choline-free basal diet. Choline was added at 0, 150, and 300 mg/kg to produce a linear response in chick growth performance. The choline requirement of young chicks consuming a purified diet was previously shown to be 600 mg/kg (14). As a positive control, the choline-free basal diet was supplemented with choline at 1000 mg/kg. Additionally, betaine was added to the choline-free basal diet at 260 and 600 mg/kg to assess its ability to supply methyl-equivalents. Finally, L-Met was added to the choline-free basal diet at 1289 mg/kg, a moderate excess for this age chick, to determine whether Met could spare choline in the chick. This assay was 9 d in length (d 8–17 post-hatch) and diets were fed to 4 replicate pens of 3 chicks.

Responses to choline, betaine, and Met were assessed by growth performance, BHMT activity, and plasma total Hcy concentration. After completing the 9-d assay, chicks were bled by cardiac puncture into evacuated tubes containing EDTA. Liver samples were collected and immediately snap-frozen in liquid nitrogen. Equal volumes of plasma from chicks within each replicate pen were pooled and immediately deproteinized with sulfosalicylic acid (15). Plasma free Hcy was determined using an enzyme immunoassay (Axis-Shield Diagnostics); this procedure reduces all forms of Hcy (e.g. homocystine or oxidized Hcy) to allow estimation of the total quantity of free Hcy. Hepatic BHMT activity was assayed using procedures described previously (16). Enzyme activity was expressed as units per milligram of protein after measurement of total protein in crude liver extracts using the Bradford method. In this context, a unit of BHMT activity was defined as nanomoles of product formed per milligram protein per hour.

    Assay 3. The dietary requirement for choline in the absence and presence of 1000 mg/kg betaine was assessed using the choline-free basal diet. Choline was included at 7 graded levels ranging from 0 to 900 mg/kg in each betaine series. Five replicate pens of 3 chicks were fed the experimental diets for an 11-d period (d 8–19 post-hatch) after which growth performance was evaluated.

    Statistical analysis. All data were subjected to ANOVA using the general linear model procedure of SAS (17). Data were analyzed using pen means, with procedures appropriate for a completely randomized design. Data are presented as mean values with pooled SEM. In assays 1 and 2, means separation was conducted using Fisher's protected least significant difference procedure assuming an {alpha} level of 0.05. Responses in growth performance, BHMT activity, and plasma total Hcy were evaluated in assay 2 using orthogonal polynomial single df contrasts. In assay 3, weight gain data from individual pen replicates were fitted to a 1-slope broken-line regression model (18,19) at each supplemental betaine concentration. Weight gain (g/d) was regressed on supplemental choline intake (mg/d) to control for differences in food consumption. This procedure provided quantitative estimates of the minimal supplemental choline requirement of chicks in the absence and presence of 1000 mg/kg betaine.


   Results
TOP
 ABSTRACT
 Introduction
 Materials and Methods
 Results
Discussion
 LITERATURE CITED
 
    Assay 1. Weight gain, food intake, and gain:food increased (P < 0.01) when 300 mg/kg choline was added to the choline-free basal diet (Table 2). However, addition of 300 mg/kg betaine was without effect in the absence of choline and resulted in numerically lower growth responses compared with the unsupplemented basal diet. Interactive effects (P < 0.05) between choline and betaine were evident for each growth performance criterion, resulting in the greatest responses when choline and betaine were included in combination.


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  		TABLE 2 Effect of supplemental choline and betaine on growth of chicks fed a purified diet devoid of bioavailable choline (assay 1)1

 
    Assay 2. Supplementation of the choline-free basal diet with graded levels of choline resulted in linear increases (P < 0.05) in weight gain, food intake, and gain:food (Table 3). Additionally, hepatic BHMT activity decreased linearly (P < 0.05), whereas plasma total Hcy remained unchanged. Addition of 1000 mg/kg choline improved (P < 0.05) weight gain but not gain:food relative to the 300 mg/kg choline addition, suggesting satisfaction of the choline requirement. Addition of either 260 or 600 mg/kg betaine to the choline-free diet did not increase weight gain, food intake, gain:food, or hepatic BHMT activity. However, 600 mg/kg betaine reduced (P < 0.05) plasma total Hcy similar to that of 1000 mg/kg supplemental choline. Addition of 1289 mg/kg L-Met increased (P < 0.05) weight gain only slightly over the unsupplemented diet; there were no effects of supplemental Met on food intake, gain:food, or BHMT activity. However, this modest excess of L-Met elevated (P < 0.05) plasma total Hcy to the highest concentration observed in this chick bioassay.


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  		TABLE 3 Effect of supplemental choline, betaine, or Met for chicks fed a purified diet devoid of bioavailable choline (assay 2)1

 
    Assay 3. Chick weight gain increased (P < 0.05) due to choline supplementation alone, reaching a plateau before the highest supplementation level (Fig. 1). Weight gain data suggested an estimated minimal supplemental choline requirement of 20.8 ± 1.50 mg/d choline in the absence of supplemental betaine. Choline supplementation in the presence of 1000 mg/kg betaine also markedly improved (P < 0.05) weight gain, reaching a plateau similar in magnitude to that observed in the absence of betaine. In the presence of 1000 mg/kg supplemental betaine, the estimated minimal supplemental choline requirement was 10.5 ± 1.03 mg/d choline. The fitted 1-slope broken-line regressions had r2 values of 0.90 and 0.86 in the absence and presence of betaine, respectively.


Figure 1
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  		FIGURE 1  Weight gain of young chicks fed graded levels of supplemental choline in the absence or presence of 1000 mg/kg supplemental betaine in a purified diet devoid of bioavailable choline (assay 3). Values are means ± SEM of 5 replicate pens of 3 chicks during an 11-d feeding period from 8 to 19 d post-hatch. Mean initial weight was 88.0 g. A 1-slope broken-line regression of weight gain (g/d) on supplemental choline intake (mg/d) was fitted to individual pen-replicate values at each betaine level according to procedures described by Robbins et al. (19). Minimal supplemental choline requirements of 20.8 ± 1.50 mg/d (722 mg/kg diet) and 10.5 ± 1.03 mg/d (412 mg/kg diet) were calculated for diets containing 0 and 1000 mg/kg betaine, respectively. The experimental pooled SEM for weight gain was 0.58 g/d.

 

   Discussion
TOP
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
LITERATURE CITED
 
It is well established that avian species require preformed dietary choline due to limited synthetic capacity (3,4). Moreover, biosynthesis of acetylcholine and phosphatidylcholine requires choline per se to sustain life. Based on initial rate kinetics, there appears to be a clear preference for choline to satisfy these 2 functions, whereas choline oxidation (i.e. betaine formation) tends to fluctuate relative to dietary intake (7). Superficially, choline metabolism appears simple; there exists a physiological requirement for choline in animals for metabolic purposes. However, this picture is quickly complicated when considering the biological functions of choline. Priority exists for production of acetylcholine and phosphatidylcholine (8,9).

Another function of choline, donation of labile methyl groups via betaine, is not revealed in growth criteria until requirements for the first 2 functions have been satisfied. In this regard, complexity arises because myriad compounds can supply methyl moieties (e.g. Met, betaine, S-methyl-Met (SMM), and dimethylsulfoniopropionate) and many of these compounds are closely interrelated (i.e. Met and choline metabolism). If uncontrolled, the effects of extraneous methyl donors will confound results obtained with choline. Controversy has surrounded the choline-sparing effect of Met in poultry (6,20–23), but it is clear that limited phosphatidylethanolamine methyltransferase activity precludes efficient choline-sparing by Met.

The purified diet based on soy protein isolate used in our chick bioassays was devoid of bioavailable choline (12) and SMM (24) and contained only small quantities of betaine (25). Results from assay 2 suggest the basal diet contained adequate but not excess Met, because supplementation with 1289 mg/kg Met had little effect on growth but markedly increased plasma total Hcy. Finally, the basal diet used in these bioassays was not deficient in folate or vitamin B-12, thereby reducing the likelihood that remethylation of Hcy by Met synthase would confound the effects of choline and betaine on BHMT activity. Both folate and vitamin B-12, in fact, were present in surfeit levels. Thus, the basal diet used in our chick bioassays was clearly first-limiting in bioavailable choline, as evidenced by marked growth responses to this nutrient in all 3 bioassays.

Our data provide clear evidence that supplemental betaine has no growth-promoting efficacy in the absence of choline. Addition of 260, 300, 600, or even 1000 mg/kg betaine to the choline-free diet afforded no significant improvement in chick growth in any of our bioassays. This is indirect evidence that metabolic prioritization exists for choline, a concept first suggested in 1947 when McKittrick (9) concluded "if growth were limited by lack of essential choline or methionine, the addition of betaine should be without effect." Similar evidence can be inferred from previous work in our laboratory (8,10,16,26). Our data suggest a minimal dietary requirement for preformed choline, not replaceable by betaine, of 150 mg/kg (~3 mg choline/d) or less as quantified in young chicks consuming a soy protein isolate-based purified diet.

Growth responses to supplemental choline in the absence and presence of 1000 mg/kg betaine from assay 3 provide compelling evidence for the choline-sparing effect of betaine. Similar to assays 1 and 2, weight gain in assay 3 was only improved by betaine when supplied in combination with choline. Consistent with our hypothesis, the choline-sparing effect of betaine was not evident until at least 150 mg/kg choline was provided. This concentration of minimal preformed choline is considerably lower than the value of 450 mg/kg suggested by Lowry et al. (8).

The total choline requirements estimated in assay 3 were 20.8 and 10.5 mg/d in the absence and presence of 1000 mg/kg betaine, respectively. When weight gain (g/d) was regressed against supplemental choline concentration (milligram per kilogram diet), total choline requirements of 722 and 412 mg/kg diet were obtained (data not shown). Previous work from our laboratory (8) using a basal diet of similar composition suggested total choline requirements of 625 and 467 mg/kg diet in the absence and presence of 1000 mg/kg betaine.

The quotient of choline requirements estimated in the presence and absence of surfeit betaine provides an estimate of the relative contribution that must be supplied by choline per se (i.e. the portion of the total choline requirement that cannot be replaced by betaine). Results from assay 3 suggest this portion may be as low as 50% (i.e. 10.5/20.8). Alternate methyl donors (e.g. betaine) would theoretically be beneficial in satisfying the remainder of the total choline requirement.

In assay 2, choline reduced hepatic BHMT activity but had little effect on plasma total Hcy. Remethylation of Hcy to Met is catalyzed by both BHMT and the parallel action of folate-vitamin B-12-dependent Met synthase. The degree to which these 2 systems can compensate for each other is unclear. Whereas the literature is fraught with studies reporting differential effects of dietary sulfur amino acids, choline, and betaine on BHMT activity (16,27–29), there is relatively little known of how fluxes through these systems are affected. Recent evidence suggested excess choline or betaine reduced the flux of Hcy through BHMT in chicks regardless of Met adequacy (30,31). Concomitantly, the flux of Hcy through Met synthase was increased, thereby indicating that BHMT may not be responsive to dietary conditions as previously concluded. Whether changes in flux through BHMT and Met synthase occurred under the dietary conditions used in our chick assays is unknown.

Finkelstein et al. (27) reported that betaine supplementation elicited maximal hepatic BHMT activity when rats consumed choline-free, Met- and Cys-adequate diets. Moreover, both betaine and choline have been shown to markedly elevate hepatic BHMT activity when supplied to chicks (16) and pigs (28) in either purified or practical-type diets containing adequate choline, Met, and Cys. As opposed to these previous studies, we observed decreased hepatic BHMT activity due to modest additions of choline and no effect of supplementing even 600 mg/kg betaine to the choline-free basal diet. The discrepancy between studies cannot be explained by Met status, although both deficient and excess Met are known to stimulate BHMT activity (32). The only evident difference in experimental conditions between these previous studies and our own was the dietary ratio of Met to Cys. Thus, our basal diet contained more Met (4.2 g/kg) than Cys (2.5 g/kg) and no bioavailable choline. Although we cannot speculate on the mechanism by which this elevated ratio would affect BHMT activity, we are intrigued that addition of supplemental Cys to a Cys-adequate diet was previously shown to exacerbate the stimulatory effect of betaine on chick BHMT activity (16). Moreover, addition of Cys to a Met-containing diet was previously shown to reduce the activity of hepatic cystathionine ß-synthase and therefore increase Hcy levels (33). Because BHMT activity and plasma Hcy concentrations are integrally linked, a thorough investigation into the potential regulatory role of the Met:Cys ratio seems prudent.

The only methylating compound that has been shown to directly spare choline in chicks fed choline-free diets is SMM (24). Data from our laboratory suggest SMM can donate a methyl group directly to phosphatidylethanolamine, thereby sparing free choline by facilitating choline biosynthesis. Both SMM and dimethylsulfoniopropionate are components of foods and feeds (24,34,35), but our unpublished data suggest dimethylsulfoniopropionate, unlike SMM, cannot spare choline when it is added to a choline-free diet for chicks. Similar to dimethylsulfoniopropionate, we observed no response in growth performance or BHMT activity when chicks consumed choline-free diets with supplemental betaine. Betaine could only spare the nonmethyl donor functions of choline by first inducing Met remethylation (i.e. BHMT). Subsequent methylation of phosphatidylethanolamine by S-adenosyl-Met would ultimately facilitate choline biosynthesis.

Considerable emphasis has been placed on the plasma concentration of Hcy, because this biomarker has been implicated as an independent risk factor for the development of vascular disease in humans (36). Results in our chick model confirm 2 important points regarding Hcy. First, both betaine (600 mg/kg) and choline (1000 mg/kg) reduced plasma total Hcy, lending credence to the beneficial effect of supplemental betaine therapy for the treatment of homocystinuria (37,38). Second, addition of Met at 1289 mg/kg markedly elevated plasma total Hcy, highlighting the fact that transmethylation of Met into Hcy is efficient when all metabolic substrates are present in surfeit concentrations. Consequently, Hcy is effluxed from cells under conditions of even slight Met excess (36). It is interesting that under the dietary conditions in our chick assays, neither 600 mg/kg betaine nor 1289 mg/kg Met influenced hepatic BHMT activity, but their supplementation resulted in opposite effects on plasma total Hcy. Thus, it is evident that, at least in chicks, the regulatory mechanisms of BHMT are quite sensitive to dietary concentrations of Met, choline, and betaine.

In conclusion, we present strong evidence that betaine cannot replace the first 2 functions of choline. Thus, choline per se is necessary for the formation of acetylcholine and phoshphatidylcholine. This conclusion was based on the repeatable observation that betaine was unable to affect chick growth performance in the absence of preformed choline. Through quantification of the total choline requirement in the absence and presence of surfeit betaine, we suggest that choline per se must provide at least 50% of the total choline requirement. The remaining portion of the choline requirement can be replaced by betaine.


   FOOTNOTES
 
1 Author disclosures: R. N. Dilger, T. A. Garrow, and D. H. Baker, no conflicts of interest. Back

5 Abbreviations used: BHMT, betaine-homocysteine methyltransferase; CP, crude protein; Hcy, homocysteine; SMM, S-methyl Met. Back

Manuscript received 28 June 2007. Initial review completed 17 July 2007. Revision accepted 26 July 2007.


   LITERATURE CITED
TOP
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
 LITERATURE CITED
 

1. Nesheim RO, Johnson BC. Effect of a high level of methionine on the dietary choline requirement of the baby pig. J Nutr. 1950;41:149–52.[Free Full Text]

2. Kroening GH, Pond WG. Methionine, choline and threonine interrelationships for growth and lipotropic action in the baby pig and rat. J Anim Sci. 1967;26:352–7.[Abstract/Free Full Text]

3. Baker DH, Sugahara M. Nutritional investigation of the metabolism of glycine and its precursors by chicks fed a crystalline amino acid diet. Poult Sci. 1970;49:756–60.

4. Jukes TH, Oleson JJ, Dornbrush A. Observations on monomethylaminoethanol and dimethylaminoethanol in the diet of chicks. J Nutr. 1945;30:219–23.[Abstract/Free Full Text]

5. Jukes TH. The effect of certain organic compounds and other dietary supplements on perosis. J Nutr. 1941;22:315–26.[Abstract/Free Full Text]

6. Molitoris BA, Baker DH. Choline utilization in the chick as influenced by levels of dietary protein and methionine. J Nutr. 1976;106:412–8.[Abstract/Free Full Text]

7. Garrow TA. Choline. In: Zempleni J, Rucker RB, McCormick DB, Suttie JW, editors. Handbook of vitamins. 4th ed. Boca Raton (FL): CRC Press; 2007. p. 459–87.

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