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Food and Chemical Toxicology: Badreldin H. Ali, Amal Ziada, Gerald Blunden
Food and Chemical Toxicology: Badreldin H. Ali, Amal Ziada, Gerald Blunden
Review
a r t i c l e i n f o a b s t r a c t
Article history: Gum arabic (GA) is a branched-chain, complex polysaccharide, either neutral or slightly acidic, found as a
Received 6 March 2008 mixed calcium, magnesium and potassium salt of a polysaccharidic acid. The backbone is composed of
Accepted 3 July 2008 1,3-linked b-D-galactopyranosyl units. The side chains are composed of two to five 1,3-linked b-D-galac-
topyranosyl units, joined to the main chain by 1,6-linkages. Pharmacologically, GA has been claimed to
act as an anti-oxidant, and to protect against experimental hepatic-, renal- and cardiac toxicities in rats.
Keywords: These reports could not be confirmed by others. GA has been claimed to alleviate the adverse effects of
Gum arabic
chronic renal failure in humans. This could not be corroborated experimentally in rats. Reports on the
Phytochemistry
Pharmacology
effects of GA on lipid metabolism in humans and rats are at variance, but mostly suggest that GA inges-
Toxicity tion can reduce plasma cholesterol concentrations in rats. GA has proabsorptive properties and can be
. used in diarrhoea. It enhances dental remineralization, and has some antimicrobial activity, suggesting
a possible use in dentistry. GA has been shown to have an adverse effect on electrolyte balance and vita-
min D in mice, and to cause hypersensitivity in humans. More studies are needed before the pharmaco-
logical properties of GA can be utilized in therapy.
Ó 2008 Published by Elsevier Ltd.
Contents
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
2. Chemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
3. Pharmacological properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
3.1. GA as an anti-oxidant . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
3.2. Effect of GA on renal function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
3.3. Effect of GA on blood glucose concentration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
3.4. Effect of GA on the gastrointestinal tract. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
3.4.1. Intestinal absorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
3.4.2. Degradation of GA in the intestines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
3.5. Effects of GA on lipid metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
3.6. The effect of GA on tooth mineralization. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
3.7. Effect of GA on hepatic macrophages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
4. Adverse effects and toxicity of GA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
5. Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
* Corresponding author.
E-mail address: [email protected] (B.H. Ali).
1. Introduction galactan (AG), had a very low protein content (0.35%) and a molec-
ular mass of 3.8 105 Da [from gel permeation chromatography
Gum arabic (GA, E-Number 414) is an edible, dried, gummy (GPC) data; 2.79% 105 Da from light scattering]. The second frac-
exudate from the stems and branches of Acacia senegal and A. seyal tion (10.4% of total), an arabinogalactan-protein complex (AGP),
that is rich in non-viscous soluble fiber (Williams and Phillips, contained 11.8% protein and had a molecular mass of 1.45 106
2000). It is defined by the FAO/WHO Joint Expert Committee for Daltons (both methods). The third fraction (1.2% of total gum), re-
Food Additives (JECFA) as ‘a dried exudation obtained from the ferred to as a low molecular weight glycoprotein (GP), had a pro-
stems of A. senegal (L.) Willdenow or closely related species of Aca- tein content of 47.3%, and a molecular mass of 2.5 105 Da (GPC
cia (family Leguminosae)’ (FAO, 1999). data). Ray et al. (1995) fractionated GA by both hydrophobic affin-
In 1982 JECFA classified GA as ‘ADI not specified’ (FAO, 1982). ity chromatography and GPC; their results were in broad agree-
However, as a result of subsequent research, the specifications ment with those of Randall et al. (1989). The major amino acids
for GA have been revised on several occasions (FAO, 1986, 1990, present in the protein of AG and AGP were hydroxyproline, serine
1999; WHO, 1990a,b). and proline, whereas in GP, aspartic acid was the most abundant
GA has wide industrial uses as a stabilizer, thickening agent and (Islam et al., 1997).
emulsifier, mainly in the food industry (e.g. in soft drinks syrup, A wattle blossom model was proposed for describing the struc-
gummy candies and marshmallows), but also in the textile, pottery, ture of the AGP complex. It was postulated that the high molecular
lithography, cosmetics and pharmaceutical industries (Verbeken weight fraction of the gum is composed of large carbohydrate
et al., 2003). It has a complex chemical composition (see below). blocks with a molecular mass of approximately 2.5 105 Da; these
In folk medicine, GA has been reported to be used internally for are attached covalently to a polypeptide chain (Fincher et al., 1983;
the treatment of inflammation of the intestinal mucosa, and exter- Connolly et al., 1987, 1988). An alternative model was suggested
nally to cover inflamed surfaces (Gamal el-din et al., 2003). Despite by Qi et al. (1991), but more recent studies have indicated that
the fact that GA is widely used as a vehicle for drugs in experimen- the molecules of the AGP complex have a globular structure, which
tal physiological and pharmacological experiments, and is assumed supports the wattle blossom model (Verbeken et al., 2003, and ref-
to be an ‘‘inert” substance, some recent reports have claimed that erences quoted therein).
GA possesses anti-oxidant, nephroprotectant and other effects Osman et al. (1993) fractionated GA by hydrophobic interaction
(Rehman et al., 2001; Gamal el-din et al., 2003; Ali et al., 2008). chromatography to yield four fractions, all of which had a similar
Clinically, it has been tried in patients with chronic renal failure, carbohydrate composition, but differed in their content of protein,
and it was claimed that it helps reduce urea and creatinine plasma amino acid composition and molecular mass distribution. All four
concentrations and reduces the need for dialysis from 3 to 2 times fractions reacted with an array of anti-arabinogalactan-protein
per week (Suliman et al., 2000). These findings are not universally monoclonal antibodies via anti-carbohydrate epitopes and were
accepted and their confirmation, validity, reliability and mode of precipitated by Yariv’s reagent, which indicated that all four frac-
action await further studies. tions were AGPs. It was shown that at least one protein was unique
The present article attempts to collate some recent published data to each fraction.
on the chemical, pharmacological and toxicological properties of GA. Enzyme-linked immunosorbent assays (ELISAs) have been
developed to differentiate between GA and the gums of other Aca-
cia species, including A. seyal. Polyclonal antibodies raised against
2. Chemistry GA in rabbits readily differentiated between the various Acacia spe-
cies, indicating significant structural differences between the spe-
The chemical composition of GA is complex and numerous pa- cies (from Islam et al., 1997).
13
pers have been published on this subject (for example, the review C NMR spectroscopy has been shown to be a powerful analyt-
of Islam et al., 1997 and papers cited therein). It is not the intention ical method for the unambiguous identification of GA; samples
of this current review to give a comprehensive report on the chem- adulterated with other gums are readily detected using this tech-
istry of the gum, but to give a summary of the principle findings. nique (Anderson et al., 1991). Al-Assaf et al. (2005) found that anal-
GA is a branched-chain, complex polysaccharide, either neutral ysis of GA using GPC coupled to a multi-angle laser light scattering
or slightly acidic, found as a mixed calcium, magnesium and potas- detector, a refractive index detector and an UV detector set at
sium salt of a polysaccharidic acid (arabic acid). The backbone is 214 nm provided a useful ‘fingerprint’ for the rapid evaluation of
composed of 1,3-linked b-D-galactopyranosyl units. The side chains GA for specific applications. The method was able to assess protein
are composed of two to five 1,3-linked b-D-galactopyranosyl units, content and its distribution in the various gum components.
joined to the main chain by 1,6-linkages. Both the main and the GA is primarily indigestible to both humans and animals. It is
side chains contain units of a-L-arabinofuranosyl, a-L-rhamnopyr- not degraded in the small intestine, but fermented in the large
anosyl, b-D-glucuronopyranosyl and 4-O-methyl-b-D-glucurono- intestine by microorganisms to short-chain fatty acids, particularly
pyranosyl, the last two mostly as end units (Anderson and propionic acid (Phillips, 1998; Kishimoto et al., 2006). Such degra-
Stoddart, 1996; Islam et al., 1997; Verbeken et al., 2003). Idris dation products are absorbed in the human colon and subse-
et al. (1998) reported GA to be comprised of 39–42% galactose, quently utilized energetically in metabolism (Phillips, 1998). In
24–27% arabinose, 12–16% rhamnose, 15–16% glucuronic acid, an experiment using an enrichment culture of pig cecal bacteria,
1.5–2.6% protein, 0.22–0.39% nitrogen, and 12.5–16.0% moisture. Kishimoto et al. (2006) showed that a Prevotella ruminicola-like
The chemical composition of GA can vary with its source, the bacterium was the predominant organism that was most likely
age of the trees from which it was obtained, climatic conditions to be responsible for the fermentation of GA to propionate.
and soil environment (Al-Assaf et al., 2005; Anderson et al.,
1968; Idris et al., 1998; Islam et al., 1997; Karamalla et al., 1998;
Verbeken et al., 2003). GA from A. senegal var. karensis has almost 3. Pharmacological properties
double the weight average molecular weight of A. senegal var.
senegal (Al-Assaf et al., 2005). 3.1. GA as an anti-oxidant
GA is a highly heterogeneous material, but was separated into
three major fractions by hydrophobic affinity chromatography The purported action of GA as an antioxidant has led to the
(Randall et al., 1989). Most of the gum (88.4% of total), an arabino- publication of a series of articles by the same group claiming a
B.H. Ali et al. / Food and Chemical Toxicology 47 (2009) 1–8 3
protective effect of GA against experimental gentamicin and cis- Binding of nitrogen compounds to inert, orally administered
platin nephrotoxicity (Al-Majed et al., 2002, 2003), doxorubicin sorbents, such as either charcoal or oxystarch has been used in
cardiotoxicity (Abd-allah et al., 2002) in rats, and acetaminophen experimental uremia (Fukagawa, 2006; Iwasaki et al., 2006). Mod-
hepatotoxicity (Gamal el-din et al., 2003) in mice. All of these stud- ification of nitrogen compounds by ingesting enzymes derived
ies were based on the assumption that GA has strong anti-oxidant from either soil bacteria or packaged in artificial cells has also been
properties, and a major mechanism for the induction of these tox- attempted (Winchester, 2002). Evidence indicates that strains of
icities is the generation of free radicals (Ali and Al Moundhri, 2006; bacteria can be induced to synthesize enzymes that recycle urea
Hinson et al., 2004). However, Ali et al. (2003) reported that treat- and other nitrogen compounds retained by uremic patients. Verifi-
ment of rats with GA produced only slight palliation of gentamicin cation of the safety, usefulness and reliability of bowel substitution
nephrotoxicity, a result that does not confirm the work of Al-Majed in renal failure will, if proven in controlled clinical trials, accelerate
et al. (2002). development of a practical regimen to extend patients’ longevity
Using a lipid model system, Trommer and Neubert (2005) stud- where no other means are possible (Friedman, 1996; Winchester
ied eight different polysaccharidic compounds (including GA) for et al., 2003).
their antioxidant and lipid peroxidation lowering effects in vitro. The study of Matsumoto et al. (2006) examined the potential
It was found that GA protected against lipid peroxidation in skin role of butyrate in modifying the generation of the pro-fibrotic
in a dose-dependent manner. More recently, however, Cindoruk cytokine transforming growth factor-beta (TGFbeta1) by renal epi-
et al. (2007) reported that GA was ineffective in ameliorating hep- thelial cells. Following 8 weeks of dietary supplementation with
atocelluar damage in cholestasis induced by fenofibrate in rats. 25 g/day of a special type of GA (SUPERGUM), there was a twofold
It has also been reported by Ali (2004) that administration of GA increase in serum butyrate (n = 7, P = 0.03). In vitro work demon-
at concentrations of 2.5%, 5.0% and 10.0% in the drinking water for strated that exposure of renal epithelial cells to elevated concen-
eight consecutive days to rats did not significantly alter either the trations of butyrate suppressed both basal and stimulated TGF-
concentrations of the free radical scavengers, reduced glutathione beta1 synthesis. The action of butyrate was mediated by suppres-
(GSH), ascorbic acid (AA), and superoxide dismutase (SOD), or lipid sion of the extracellular, signal-regulated, kinase/mitogen-acti-
peroxidation. This finding seems to suggest that there is no evi- vated, protein kinase signaling pathway. In addition, butyrate
dence that GA has a strong anti-oxidant action. It is difficult to ex- exposures reduced the response of renal epithelial cells to TGF-
plain the claimed hepato-, nephro- and cardio-palliative and beta1, as assessed by luciferase activity of a TGF-beta-responsive
protective effects of GA reported by Al-Majed et al. (2002, 2003) reporter construct. Attenuation of TGF-beta1 signaling was associ-
and Abd-allah et al. (2002), through an antioxidant mechanism, if ated with reduced 114 phosphorylation of Smad 3 and decreased
GA lacks an appreciable antioxidant action. trafficking of TGF-beta1 receptors into signaling, non-lipid, raft-
associated membrane fractions. These data demonstrated that die-
3.2. Effect of GA on renal function tary supplementation with ‘‘SUPER GUM” (a naturally processed
polysaccharide exudate from A. senegal) increased serum butyrate,
Either end stage renal failure or end stage renal disease requires which, at least in vitro, has beneficial effects on renal pro-fibrotic
renal replacement therapy (RRT) in the form of either dialysis or cytokine generation (Matsumoto et al., 2006).
renal transplantation for survival. However, provision of RRT re- More recently, Nasir (2007), in a thesis studying the effect of GA
quires expert teams, working in specialized units, which makes on renal functions in healthy mice, claimed that it not only in-
therapy of patients with renal failure expensive. Maintenance per- creased fecal weight consistent with the action of dietary fibers,
itoneal dialysis and hemodialysis sustain the lives of approxi- but also showed binding of free water, which resulted in reduction
mately 250,000 uremic patients in developing countries of intestinal fluid absorption and thus of urine volume. This was
(Friedman, 1996). The number of end-stage renal disease patients paralleled by an increase in ADH secretion. GA also bound intesti-
requiring RRT has increased dramatically throughout the world nal Na+, which was again reflected by reduced renal excretion.
during the last decades (Locatelli et al., 2006).The cost of treating These findings are at variance with earlier findings that GA actually
uraemia represents a growing demand on the health care systems enhances water and Na+ absorption in a rat model of chronic-os-
of both rich, developed and poor, developing countries, the last motic diarrhea by improving oral rehydration (Teichberg et al.,
being affected most. The literature is replete with publications on 1999a,b; Wapnir et al., 1997). This difference, according to Nasir
the impact of nutrition on kidney disease (Younes et al., 2006; Lac- (2007), might be related to the fact that she studied the effect of
son et al., 2007). Most dietary attempts to treat chronic renal fail- GA in healthy mice, and that the water-holding capacity of dietary
ure (CRF) and to decrease uremia use a protein restriction regimen fibers may have opposite consequences in intact intestine and dur-
(Fouque et al., 2006; Chaturvedi and Jones, 2007). An alternative ing diarrhea.
dietetic approach has relatively recently been proposed, based on One of the unexplained findings of Nasir (2007) is that GA treat-
fermentable carbohydrate (FC) supplementation of the diet ment was associated with an increased 24 h-creatinine clearance
(Winchester and Salsburgh, 2004). This has been claimed to result in healthy mice. The exact mechanism for this remains unclear,
in a similar urea-lowering effect by increasing urea nitrogen (N) since it represents a remote effect of GA on the kidney, which re-
excretion in stools, with a concomitant decrease in the total N quires one or more humoral factors. It is well known that GA is fer-
excreted in urine of adults (Lukichev et al., 1992; Bliss et al., mented by intestinal bacteria leading to formation of various
1996; Ali et al., 2008) and children (Al Mosawi, 2002, 2004, degradation products, such as short-chain fatty acids (Bliss et al.,
2007). Some of these papers will be discussed below. 1996). In a recent study, serum butyrate concentrations were in-
Based on laboratory data (e.g. Younes et al., 1995), extraction, creased following treatment with GA in healthy subjects (Matsum-
modification, and recycling of nitrogenous wastes by the gastroin- oto et al., 2006) and this may have a role in the claimed salutatory
testinal tract is a potentially low-cost means of substituting for effect on creatinine clearance and GFR. In contrast, in an experi-
missing renal function. Multiple approaches to the bowel as a mental model of chronic renal failure CRF (rat kidney remnant
‘‘substitute kidney” have been attempted. Direct removal of nitro- model), Ali et al. (2004) showed that treatment of rats with GA
gen-containing compounds by an external gut fistula, gastric, ileal, at doses of 3 or 6 g/100 mL in the drinking water for five consecu-
or colonic gavage (dialysis), or induced diarrhea extract water and tive weeks was not effective in either reversing the decrease in
urea, but only minimal amounts of larger molecules, such as creat- body weight or the increases in creatinine and urea observed 2
inine (Friedman, 1996). weeks after the surgical induction of the CRF. These results do
4 B.H. Ali et al. / Food and Chemical Toxicology 47 (2009) 1–8
not support the notion of a beneficial effect of GA in experimental experiments, net water absorption was unaffected (Wapnir
CRF, as was reported in patients in two centers in the USA (Bliss et al., 1996). The higher concentration of GA was also associated
et al., 1996). Whether that lack of effect was related to the severity with expansion of the basolateral intercellular space. Experimen-
of the CRF, inadequate dosage, species difference, or other reasons tal diarrhea was induced in rats by either one week of drinking a
is unknown. cathartic (magnesium citrate-phenolphthalein) solution to pro-
Recently, a report from Sudan assessed the effect of GA on the duce chronic osmotic-secretory effects or by jejunal perfusion of
concentration of certain metabolites in the sera of patients with theophylline to induce jejunal secretion. Addition of GA to the
CRF on a low-protein diet (Ali et al., 2008). GA was given at an oral jejunal ORS-perfusate resulted in roughly a twofold increase in
dose of 50 g/day for 3 months, with or without supplementing the absorption of sodium, potassium and water in the chronic osmo-
diet with ferrous sulfate (200 mg/day) and folic acid (5 mg/day). tic-secretory diarrhea model, and neutralized theophylline in-
Serum creatinine, urea, phosphate and uric acid concentrations duced abolition of net sodium and potassium absorption, in
were reported to be significantly reduced by GA, while the treat- addition to reversing water and glucose malabsorption (Wapnir
ment significantly increased that of serum calcium. No explana- et al., 1997). The observed expansion of the basolateral intercellu-
tions for these results have been offered, and the inclusion of lar spaces between villus absorptive epithelial cells and the lam-
iron and folic acid supplements has not been justified, although ina propria induced by GA perfusion was considered a reflection
it was concluded that GA could alleviate ‘‘adverse effects of CRF”. of the enhanced water and sodium reabsorption. GA added to
an ORS also reduced chloride, and sodium secretion in rats per-
3.3. Effect of GA on blood glucose concentration fused under anesthesia with cholera toxin in the jejunum (Turvill
et al., 2000). The positive effects of the GA on fluids and electro-
Wadood et al. (1989) gave powdered seeds of Acacia arabica or- lyte absorption observed in jejunal perfusion studies were also re-
ally to normal rabbits and rabbits with allaoxan–induced diabetes. ported in rats recovering from chronic osmotic diarrhea induced
It was found that the powder (at doses of 2, 3 and 4 mg/kg) signif- by cathartic agents (Teichberg et al., 1999a,b). Free living rats
icantly reduced the blood glucose concentration of normal, but not drinking the GA-supplemented ORS ad libitum showed accelerated
diabetic rabbits. The authors concluded, albeit without experimen- recovery in comparison to those receiving either water or ORS
tal evidence, that A. arabica initiated the release of insulin from without gum. Recovery parameters included greater enhancement
pancreatic b cells of normal rabbits. Previously, experiments were of weight gain, food and fluid intake, and a lower fecal output in
carried out in vitro and in normal human subjects to evaluate alter- rats whose ORS contained GA. This increase was evident after 4 h
native food-grade viscous polysaccharides as agents for reducing of recovery and persisted for 24 h. The authors ascribed the
postprandial hyperglycemia and to assess the relationship be- weight gain to the increased fluid intake and solid food consump-
tween the in vitro and in vivo performance of the polysaccharides tion. However, no ready explanation for the persistent increased
(Edwards et al., 1987). solid food intake was offered. The relative decrease of fecal output
Mixtures of different types of gum (not including GA) have been noted was ascribed to the increased fluid absorption – a feature
shown to inhibit glucose movement in vitro, and lower postpran- that was also observed with GA in acute jejunal perfusion studies
dial blood glucose and plasma insulin in human subjects when (Wapnir et al., 1996, 1997). The previous data suggest that GA is
incorporated in a drink containing 50 g glucose (Edwards et al., equally effective when consumed orally as when directly intro-
1987; Torsdottir et al., 1989). Infusion of meals containing starch duced post-stomach, as in intestinal perfusion studies (Wapnir
showed that a decrease in the digestion rate of starch in the upper et al., 1996, 1997; Teichberg et al., 1999a,b; Rehman et al.,
small intestine accounted for part of the effect of viscosity on gly- 2000, 2001, 2003; Wingertzahn et al., 2001). Indeed, orally admin-
cemic response, whereas the main effect of gum was apparently to istered GA added to an isotonic electrolyte-glucose-zinc solution
slow gastric emptying (Leclère et al., 1994). resulted in a higher blood concentration of zinc achieved after
15 min and throughout 3 h. There was also a significant time ef-
3.4. Effect of GA on the gastrointestinal tract fect for sodium and water (Ibrahim et al., 2004). Investigating
intestinal transport effects of GA was extended to involve other
3.4.1. Intestinal absorption solutes such as glutamate and non nutrient (pharmacological)
The small intestine is the major site of electrolytes and organic agents. GA containing solutions, also orally administered, resulted
non-electrolytes absorption in the gastrointestinal tract (GIT) in a faster rate of absorption for glutamate under normal physio-
through various mechanisms operating at the cellular and molec- logical conditions, and for the pharmacological agent acetamino-
ular levels (Wapnir and Teichberg, 2002). Simultaneous intestinal phen during intestinal dysfunction induced by theophylline
secretion is a physiological phenomenon also tightly controlled by (Codipilly and Wapnir, 2004). Various mechanism(s) have been
mechanisms. This maintains within the intestinal lumen a state of proposed to account for the proabsorptive effects of GA on intes-
fluidity, dilution, and solubilization indispensable to the normal tinal water and electrolytes under normal conditions and more so
intestinal function of digestion and absorption. The net effects of in conditions of diarrheal illness (Codipilly et al., 2006). GA is a
these mechanisms maintain the normal mammalian small intes- soluble fiber with moderate emulsifying properties (Menzies
tine in an absorptive mode. However, under certain circum- et al., 1996; Phillips, 1998) that may result in greater accessibility
stances, secretion forces exceed absorption and a net secretory of electrolytes and associated water to the microvillous mem-
condition ensues leading to diarrhea and dehydration. Diarrheal brane. This was probably reflected in the increased lumen-to-ser-
disease is a major cause of morbidity and mortality, especially osa water influx noted with GA administration in the chronic
in the pediatric age group (Thapar and Sanderson, 2004). It has osmotic-secretory diarrhea model (Wapnir et al., 1997). However,
been shown that GA improves small intestinal absorption of so- this simple effect of GA on membrane accessibility was not sup-
dium in normal rats (Codipilly and Wapnir, 2004; Wapnir et al., ported by the evidence in theophylline-induced secretory diar-
1996) and of sodium and water in two animal models of diarrheal rhea. In these animals the events were complex in that the net
disease (Wapnir et al., 1997). In normal male juvenile rats, addi- increments in absorption were the algebraic sum of small positive
tion of 5 and 10 g/L of GA increased the rates of sodium removal changes in lumen-to-serosa influx and decreases in serosa-to-
from the intestinal lumen perfused with oral rehydration solu- lumen efflux. This prompted further research for alternative an-
tions (ORS) containing either 60 mM or 90 mM sodium. Although swers. Additional work indicated that GA enhanced absorption
GA tended to facilitate bidirectional fluid movement in these of the solutes transported by diffusion (via transcellular and/or
B.H. Ali et al. / Food and Chemical Toxicology 47 (2009) 1–8 5
transjunctional transport pathways) and does not act via sodium member of the intestinal microbiota of the human large intestine
dependent mechanisms (Wingertzahn et al., 2001). Other evi- (Benno et al., 1989).
dence shows that GA may exert its proabsorptive effects by mod- Short chain fatty acids have considerable effects on intestinal
ulating the levels of the free radical nitric oxide (NO) in the upper and liver metabolism as either fuels or metabolic effectors. Propi-
intestine, either by scavenging NO produced in the enterocyte and onate produced by bacterial fermentation from GA is the major
diffusing into the lumen (Wingertzahn et al., 1998), or by inhibit- SCFA metabolized by the liver (Moundras et al., 1994), particularly
ing inducible NO synthase (Rehman et al., 2004). This antioxidant as a gluconeogenic substrate. It is utilized at a faster rate than ami-
capability of GA was demonstrable both in vivo and in vitro, with no acids, thus reducing amino acids deamination and luminal
the observed scavenging effect being more significant than NO ammonia generation. Bacterial growth within the large intestinal
synthase inhibition. NO alters water and electrolyte transport lumen requires a nitrogen source (Younes et al., 1995) and GA fer-
through activation of guanylate cyclase (Mourad et al., 1999). This mentation provides the energy for bacteria to uptake ammonia as a
upregulates the synthesis of cGMP, a potent activator of intestinal nitrogen source. In addition, proprionate is also known to reduce
secretion. Removal of NO from the intestinal lumen either by ureogenesis from ammonium chloride in hepatocytes (Wyatt
scavenging or by inhibiting synthesis may therefore be partially et al., 1986; Kishimoto et al., 2006). The decrease in luminal ammo-
responsible for the antisecretory effects of GA. Earlier experiments nia concentration may enhance diffusion of urea down its concen-
have indicated that the beneficial proabsorptive effects of GA tration gradient from the blood into the lumen. As such, nitrogen is
might derive from regulation of NO-dependent gating of the trapped for elimination in the faeces.
membrane basolateral potassium channels (Rehman et al.,
2001), and from its capability of enhancing intestinal paracellular 3.5. Effects of GA on lipid metabolism
transport (Rehman et al., 2003). In a recent publication, Wapnir
et al. (2008) extended their investigations on the mechanisms of The effects of GA on lipid metabolism are variable. GA increased
action of GA to the molecular level. Their goal was to determine cholesterol biosynthesis in rats fed a cholesterol-containing diet,
whether GA could be associated with modulation of NF kB expres- but had no effect in rats on a cholesterol-free diet (Kelly and Tsai,
sion in a model of intestinal dysfunction induced by the cathartic 1978). Ross et al. (1983) and Sharma (1985) reported reductions of
agents phenolphthalein and magnesium citrate, both known to in- total serum cholesterol by 6% and 10.4%, respectively when sub-
crease local production of NO (Izzo et al., 1998). They also ques- jects received 25 g/day and 30 g/day of GA for periods of 21 and
tioned whether this would be associated with reduction of the 30 days. The decrease was confined to LDL and VLDL cholesterol
inflammatory response caused by cathartics (evidenced by intesti- only, with no effect on HDL and triglycerides. In another study,
nal mucosa cytokine production and gene expression). NF kB is a Mee and Gee (1997) used a combination of fibers derived from
nuclear transcription factor which upregulates the expression of GA and apples individually known to have potential hypercholes-
inducible NO synthase (Ahn and Aggarwal, 2005), the key control- terolemic properties (Ross et al., 1983; Sharma, 1985; Sicart and
ler of tissue NO concentration. It may also regulate the synthesis Sablé-Amplis 1987) for 6 weeks. Although the levels of fiber sup-
of pro-inflammatory cytokines, which in turn can upregulate plementations used in this study were modest compared to previ-
inducible NOS (Karrasch and Jobin, 2008). Wapnir and colleagues ous studies, there was a significant cholesterol-lowering effect.
(2008) reported that addition of GA to the cathartic solution re- Total cholesterol dropped by 10% and LDL by 14%, with no signifi-
duced NF kB expression towards values associated with control cant change in either HDL or triglyceride concentration. The
animals that received tap water only. Interestingly, this was not authors ascribed the exaggerated outcome to the concerted effects
paralleled by down regulation of pro-inflammatory cytokine of the two fibers. In contrast, consumption of GA at a dose of 15 g/
expression in the small intestinal mucosa. The authors argued that day for 4 weeks by normal (Haskell et al., 1992) or hypercholester-
cathartic-induced intestinal dysfunction does not behave as a typ- olemic subjects (Jensen et al., 1993) had no significant effect on
ical inflammatory phenomenon, such as clinical and experimental plasma lipids. In rats, the results were as contradictory. Topping
sepsis, and therefore these results were not unexpected. et al. (1985) has shown that plasma cholesterol concentrations
were unaffected by feeding GA, but plasma triacylglycerols were
3.4.2. Degradation of GA in the intestines significantly lower than in controls. In another study (Annison
It has been reported that GA is not degraded in the stomach et al., 1995), GA was fed to rats replacing cellulose in purified diets
and small intestine, but undergoes complete fermentation within supplemented with cholesterol and cholic acid. No significant ef-
the cecum of rats (McLeanRoss et al., 1984; Walter et al., 1988; fects of increasing concentrations of GA were found on the concen-
Phillips 1998), and humans (Phillips, 1998). Such fermentation trations of either plasma or liver cholesterol when compared to
promotes bacterial proliferation (May et al., 1994), and the larger levels found in rats that consumed control diet containing cellulose
bacterial mass induces increased production of short chain fatty alone. Plasma triacylglycerol concentrations were, however, higher
acids (SCFAs) linked with enlargement of the cecum (Younes in rats fed GA, whereas liver triacylglycerols were lower.
et al., 1995). Indeed incorporation of GAa into fiber-free diets Various mechanisms have been proposed to explain the hypo-
resulted in increased weight of the cecal wall or increased pro- cholesterolemic effect of GA (Kelley and Tsai, 1978; Moundras
liferation of cecal epithelial cells (Howard et al., 1995). Hypertro- et al., 1994; Annison et al., 1995; Tiss et al., 2001). Some studies
phy of the cecum enlarges the cecal absorptive mucosa and have suggested that the viscosity of fermentable dietary fibers con-
increases cecal blood flow (Tulung et al., 1987). The major SCFAs tribute substantially to the lipid lowering effects in animals and
produced are acetate, propionate and butyrate (Kishimoto et al., humans (Gallaher et al., 1993; Superko et al., 1988; Moundras
2006), with propionate production most stimulated by GA et al., 1994), whereas another suggests that this property does
(Tulung et al., 1987; Annison et al., 1994; May et al., 1994). not relate to plasma lipids (Evans et al., 1992). The mechanism
Kishimoto et al. (2006) showed that a Prevotella ruminicola-like most clearly implicated is related to increased fecal bile acid and
bacterium was the predominant organism that is most likely neutral sterol excretion or a modification of lipid digestion and
responsible for fermentation of GA to propionate (Kishimoto absorption (Eastwood, 1992; Moundras et al., 1994). Dietary fibers
et al., 2006). This specific bacterium was isolated from an enrich- are believed to either bind or sequester bile acids, diminishing
ment culture of pig cecal bacteria, and, therefore extrapolation of their active reabsorption in the ileum and leading to their excre-
such results to the human colon has to await further studies. tion in the feces. This consequently results in promoting diver-
However, it is of relevance that this bacterium is a common sion of cholesterol to bile acid synthesis, in addition to inducing
6 B.H. Ali et al. / Food and Chemical Toxicology 47 (2009) 1–8
increased numbers of lipoprotein receptors in the liver and de- et al., 1995; Mochida et al., 1990). The authors inferred that such
creased plasma cholesterol concentration (Trustwell and Beynen, effects of GA would merit consideration in the therapy for chronic
1992). Furthermore, GA has a high cation-binding capacity, partic- liver disease, as deranged function of Kupffer cells and hepatic
ularly for calcium (Ca2+). Degradation of GA in the cecum releases macrophages occurs in this disease and is involved in its complica-
the sequestered bile acids and the acidic pH generated during the tions, such as endotoxemia.
fermentation process renders them insoluble. The bound calcium is
also released and forms insoluble complexes with bile acids, there-
4. Adverse effects and toxicity of GA
by promoting their excretion (Moundras et al., 1994). Moundras
et al. (1994) investigated the plasma cholesterol-lowering effect
Historically, the first case of an occupational sensitization to GA
of different polysaccharides in rats. Bile acid excretion was found
in a candy factory was reported more than seven decades ago. That
essential in the cholesterol lowering effect of soluble fibers, and
was followed by a number of reports of GA causing contact derma-
this was connected with induction of key enzymes of cholesterol
titis and asthma (e.g. Ilchyshyn and Smith, 1985). In all these re-
metabolism (i.e. HMG CoA reductase and cholesterol 7a-hydroxy-
ports, the offending allergen has not been identified. However, in
lase). In this study, GA was neither as potent in affecting fecal bile
1998, a carbohydrate specific IgE was identified in a chocolate con-
acid excretion and lowering plasma cholesterol concentrations nor
fectioner with cough and dyspnea (Fötisch et al., 1998). More re-
was it as capable of inducing key enzymes of cholesterol metabo-
cently, Sander et al. (2006) found that sensitization to GA
lism when compared to the other polysaccharides (guar gum or b-
carbohydrate structures occurs casually in atopic patients with
cyclodextrin). The same group investigated whether the amount
pollen sensitization without obvious exposure to GA, and that al-
and type of SCFA metabolized in the liver could directly influence
lergy to GA is mediated preferentially by IgE antibodies directed
lipid metabolism and reinforce the effects of bile acid losses in-
to polypeptide chains of GA.
duced by dietary fiber. A negative correlation was found between
Doi et al. (2006) studied the subchronic toxicity of a new type of
portal propionate and plasma cholesterol concentrations. In sup-
GA (SUPER GUM [Acacia (sen) SUPER GUM]), a naturally processed
port, several studies proposed that propionate could limit the
polysaccharide exudate from A. senegal, when given to both sexes
induction of key enzymes of cholesterol metabolism (Chen et al.,
of F344 rats at dietary levels of 0 (control), 1.25%, 2.5%, and 5.0%
1984; Illman et al., 1988, Wright et al., 1990). However, in another
(10 rats/sex/group). During the study, the treatment had no effect
experiment, addition of propionate failed to affect these enzymes
on clinical signs, survival, body weights, food and water consump-
(Levrat et al., 1994). At the level of modifying lipid digestion and
tion, urinalysis, ophthalmology, hematology, and blood biochemis-
absorption, Pasquier et al. (1996), mimicking pH conditions pre-
try, and no gross pathological or histopathological alterations.
vailing in the stomach, evaluated the effects of several soluble fi-
Increased relative cecum (filled) weights, evident in both sexes of
bers, including GA, on dietary fat emulsification and lipolysis
the 5.0% group and females of the 1.25% and 2.5% groups, were
in vitro. The authors proposed that the smaller the emulsion drop-
considered to be a physiological adaptation. It was concluded that,
let size and thereby surface area generated in the presence of vis-
at least, up to a dietary level of 5.0%, SUPER GUM (equivalent to
cous fiber, the lower the extent of lipolysis. GA strongly inhibited
3117 mg/kg body weights/day for males, and 3296 mg/kg body
lipolysis at pH 5.4 after 30 min, but without having any effect on
weights/day for females) caused no adverse effect. This confirms
emulsion droplet size. Inhibition of lipolysis in this study was
earlier reports that documented the safety of GA (Anderson,
attributed to possible strong interaction of the protein moiety of
1986). The safety of GA (5, 10, 20 or 40 g in water for 4 weeks)
GA with the available droplet (lipid/water) interface (where gastric
has recently been confirmed in healthy men (Calame et al., 2008).
lipase acts), blocking it or preventing the release of the non-ester-
GA (10% in the drinking water) for either 3 or 14 days decreased
ified fatty acids generated at the droplet surface.
urinary excretion of inorganic phosphate and increased that of cal-
cium (Ca2+) and magnesium (Mg2+), and also decreased plasma
3.6. The effect of GA on tooth mineralization
concentrations of 1,25-dihydroxy vitamin D in healthy mice (Nasir
et al., 2008). The magnitude of these metabolic disturbances in
Dental caries occur when tooth enamel is lost due to an imbal-
mice with renal insufficiency has not been determined, but is ex-
ance of the demineralization and remineralization phases, and pre-
pected to be more pronounced.
vention can be achieved when the remineralization phase is
enhanced (Aoba, 2004). Several agents have been used for that pur-
pose, including fluoride (Cheng et al., 2007). Recently, it has been 5. Conclusions
shown, using histopathological methods, that GA has the ability
to enhance remineralization (Onishi et al., 2008), probably by sup- GA is a non-digestible food ingredient that has found many
porting other remineralization activities. This supporting role was applications in the food and pharmaceutical industries. The gums
ascribed to the rich content of Ca2+, Mg2+, and K+ salts of polysac- claimed therapeutic usefulness in hepatic and renal failure
charides in GA, and to the effect of the gum on the metabolism of awaits further verification in animal models and humans. No sig-
Ca2+ and possibly phosphate. It is also known that GA contains cya- nificant adverse or toxic actions have been associated with the
nogenetic glycosides and several different types of enzymes (such use of GA.
as oxidases, peroxidases and pectinases) that exhibit antimicrobial
properties against certain organisms such as Prophyromonas gingi- Conflict of interest statement
valis and Prevotella intermedia (Clark et al., 1993).
The authors declare that there are no conflicts of interest.
3.7. Effect of GA on hepatic macrophages
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