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CLAYS AND CLAY MINERALS AS DRUGS

M.T. DROY-LEFAIXa AND F. TATEOb

aBeaufour-IPSEN, F-75016 Paris, France

bIstituto di Ricerca sulle Argille, CNR, I-85050 Tito Scalo (PZ), Italy

(Please note that the terms bentonite and montmorillonite are synonyms.

Montmorillonite is the main constituent of the volcanic ash weathering product, bentonite.)

Clay therapy is based on the ability of clays and clay minerals to adsorb and

retain harmful and toxic substances. The beneficial effects of these materials to

human health, notably in the treatment of gastrointestinal disorders, were recognized.

Indeed, the eating of clay (‘geophagy’) was practiced since antiquity in all

parts of the world. Among the variety of clays and clay minerals that were used by

primitive tribes are bentonite, kaolinite, montmorillonite, smectite (calcium and sodium bentonites), and ‘pascalite’

(a calcium bentonite from Wyoming, USA) (Eaton and Eaton, 1995).

Examination of the diets of certain tribes in the high Andes of South America and

central Africa, and those of Australian aborigines, showed that these people use clay

to avoid getting stomach-ache, dysentery, and food infections. Indeed, the Quetchus

Indians of South America used to dip their potatoes into an aqueous suspension of

clay, immediately before eating, in order to prevent the build-up of acidity in the

stomach. This dietetic procedure is still being followed by some tribes of American

Indians. A similar practice was traditionally carried out on board ships where sailors

used clays not only to adsorb odours and moisture but also to treat dysentery, burns,

boils, sore mouths, and other internal and external disorders.

Although recent research confirmed that clays and clay minerals possess general

curative properties, it is the treatment of disorders that remains the focus of attention.

By adsorbing ‘aggressors’ (infectious factors) of the gastrointestinal mucosa

barrier, these materials can serve as both prophylactic and therapeutic agents.

11.6.1. INTERACTIONS OF CLAY MINERALS WITH

GASTROINTESTINAL MUCUS

At the surface of the gut, a mucus gel adheres to the epithelial cells of the mucosa.

This adherent mucus is dynamic, being continuously secreted by the caliciform cells

and regularly eroded by environmental ‘aggressors’ present in the gut lumen.

The mucus gel is largely composed of glycoprotein polymers, lipids, and proteins,

linked together by covalent bonds. As such, it acts as a physical barrier protecting

the mucosa against penetration by extraneous molecules and mechanical injury.

By maintaining a pH gradient and competing with the epithelial surface for microorganisms,

the mucus gel also acts as a chemical barrier.

Thus, a weakening of the mucus gel barrier may be at the origin of disorders such

as gastritis and colitis (Droy-Lefaix, 1987). Short-term treatment with clay minerals,

such as smectite (calcium and sodium bentonites)s (More´ et al., 1987) and attapulgite (More´ et al., 1992) increases the

thickness of the adherent mucus. This may be ascribed to interactions of mineral

particles with mucus components (Leonard et al., 1994) by which the gastrointestinal

glycoproteins are modified, and their polymerization is enhanced (Droy-Lefaix

et al., 1986). Similarly, aluminium (hydr)oxides (e.g., boehmite) can reduce mucus

degradation (Bouyssou et al., 1990). The beneficial effects of minerals are also associated

with improvements in the rheological properties of the mucus gel, such as

spinability. This reflects the increased extent of polymerization, and the improvement

in quality, of the adherent mucus (Droy-Lefaix et al., 1985). Changes in the

physico-chemical properties of the mucus, induced by the action of clay minerals,

were confirmed by electron paramagnetic resonance and fluorescence spectroscopy.

The results indicate that clay mineral ingestion decreases mucus solubility. At the

same time, the viscosity and hydrophobicity of the mucus increases, enhancing its

adhesion to epithelial cells.

11.6.2. CLAY MINERALS, MUCOSAL BARRIER, AND

GASTROINTESTINAL ‘AGGRESSORS’

By acting directly on the mucus gel, clays and clay minerals exert a stabilizing

effect on the mucosal barrier (Gwozdzinski et al., 1997), providing protection against

different ‘aggressors’ of the gastrointestinal mucosa.

Pepsin, a substance necessary for digestion, is a typical ‘aggressor’. Experiments

with rats showed that if pepsin secretion at the surface of the gastric mucosa is

strongly increased (due to pathological disregulation), the adherent mucus layer is

progressively disrupted. At the same time haemorrhagic mucosal lesions appear, and

significant bleeding occurs in the lumen as well as localized ulceration in an otherwise

intact epithelium. By binding to the mucus components, smectite (calcium and sodium bentonites) can completely

inhibit the damage induced by pepsin (Leonard et al., 1994).

Samson et al. (1995), for example, showed that patients with ulcerative colitis

show a six-fold greater mean total faecal proteinase activity (expressed in mmol

terminal NH2/min/g dry weight of faeces) than the control. smectite (calcium and sodium bentonites) totally inhibits

this enzyme activity. The effects of smectite (calcium and sodium bentonites) on mucus proteolysis are assessed using a

model of mucolytic activity, assayed by the release of degraded colonic mucin

from the adherent mucus gel of freshly prepared pig colonic bags in vitro. Similarly,

trypsin (2 mg/mL) releases three times more soluble mucin per bag than the

control. smectite (calcium and sodium bentonites) (100 mg/mL) inhibits trypsin activity, causing the level of degraded

mucin to fall below the normal value. This is ascribed to the interaction of smectite (calcium and sodium bentonites)

with the adherent mucus layer, and the binding of trypsin to the mineral (Samson

et al., 1995).

Clay minerals can also provide protection against attack by bile acids that cause

gastrointestinal ulceration. In rats, oral administration of sodium glycodeoxycholate

or sodium taurocholate induces severe erosion of the jejunal mucosa. After treatment

with smectite (calcium and sodium bentonites) (which interacts closely with the mucus glycoproteins) the severity of

surface erosion is greatly diminished (Fioramonti et al., 1990), while the rheological

properties of the adherent mucus gel are maintained within normal limits (Droy-

Lefaix et al., 1985).

Because of their strong bioadhesive properties, clay minerals also afford protection

of the colon against damage from reactive oxygen species. Oxygenated free

radicals, released by infiltration of white cells into the colonic mucosa barrier, are

very unstable. Their presence can induce severe erosion of the colonic mucosa,

leading to mucolysis. By maintaining the solution viscosity of the colonic mucin, and

inhibiting the hypersecretion of mucus, smectite (calcium and sodium bentonites) can prevent the onset of mucolysis

(Pearson et al., 1996; Knight et al., 1998).

In many digestive diseases, the intestinal barrier is weakened by the release of proinflammatory

cytokines, induced by abnormal activation of the epithelial cells and

the underlying immune system. These cytokines include a tumour necrosis factor–a

(TNF-a) and an interferon-g factor (INF-g). When intestinal cells (line HT 29-19 A)

are incubated with TNF-a and INF-g, intestinal function (assessed in Ussing chambers

by measuring ionic conductance, apicobasal fluxes of 14C-mannitol, and intact

horseradish peroxidase) is altered, and the tight junction between cells is disrupted.

In the presence of smectite (calcium and sodium bentonites) (100 mg/mL) the values of these parameters are similar to

those of the control (Mahraoui et al., 1997).

The cytoprotective effects of clay minerals can also account for their ability to

prevent damage of the gastrointestinal mucosa caused by such ‘aggressors’ as

ethanol and anti-inflammatory drugs. Ethanol, directly administered into the stomach,

gives rise to severe gastric ulcerations and macroscopic necrosis of the

gastric mucosa. These deleterious effects are accompanied by a decrease in the gastric

transmural potential difference which serves as a criterion of the functional

integrity of the mucosa (Fioramonti et al., 1990). Erosion of the mucus layer leads to

a significant alteration of rheological properties (Droy-Lefaix et al., 1992; Slitine-

Bonet et al., 1994). smectite (calcium and sodium bentonites) treatment for two days can significantly counteract the

harmful effect of ethanol, reducing the irritative index (Fioramonti et al., 1990).

Clay minerals also provide protection against the action of anti-inflammatory

drugs. For example, the oral administration of aspirin (2 g) to pigs, and phenylbutazone

(200 mg/kg) to rats, decreases the gastric potential difference, and induces

severe ulceration due to mucus alteration (Fioramonti et al., 1990; Droy-Lefaix

et al., 1992). The extent of lesion and mucus degradation is significantly reduced

after treatment with smectite (calcium and sodium bentonites). In humans the symptoms of gastropathies, induced by

non-steroid anti-inflammatory drugs, can be successfully treated by ingestion of

smectite (calcium and sodium bentonites) (Peignot et al., 1997).

11.6.3. ADSORPTIVE PROPERTIES OF CLAYS AND CLAY MINERALS

The adsorptive properties of clay minerals provide the basis for the therapeutic

uses of clays.

A. Toxins

Clays can adsorb a variety of toxic substances, such as strychnine (Droy-Lefaix,

1986), mycotoxins (e.g., T2 toxin) (Fioramonti et al., 1987b), aflatoxin (Schell et al.,

1993), enterotoxins (Brouillard and Rateau, 1989), and toxins produced by Vibrio

cholerae, Escherichia coli (Fioramonti et al., 1987b), and Yersinia pseudotuberculosis

(Carnoy et al., 2000).

By doing so, clays can provide active protection against disturbances during

gastrointestinal transit. In mice, for example, gastric emptying and small intestinal

transit are significantly accelerated after oral administration (1 mg/kg for 4 days) of

T2 toxin. However, if the toxin is incubated with smectite (calcium and sodium bentonites) for 24 h beforehand, no

increase in the rate of gastric emptying and small intestinal transit occurs (Fioramonti

et al., 1987a).

In conscious dogs, intraduodenal administration of cholera toxin (200 mg) affects

gastrointestinal transit, and disrupts the migrating motor complexes (MMCs) of the

stomach and jejunum. According to the duration of treatment (at a dose of 100 mg/

kg/day), smectite (calcium and sodium bentonites) can effectively counteract the effects of cholera toxin (Fioramonti

et al., 1987b).

smectite (calcium and sodium bentonites) can also adsorb the enterotoxin of Clostridium difficile (Martirosian

et al., 1998). In rats, this toxin causes intestinal permeability to increase through

hypersecretion of colonic water. Both these conditions can be alleviated by treatment

with 51Cr-EDTA in the presence of smectite (calcium and sodium bentonites) (Fioramonti et al., 1994).

E. coli toxin is an infectious agent causing diarrhoea. Heat-stable toxin (ST) from

E. coli, directly administered to New Zealand rabbits, induces a significant increase

in intestinal permeability (as estimated by Evans Blue) and severe damage to ileal

loops (as revealed by scanning electron microscopy). The presence of smectite (calcium and sodium bentonites) in the

ileal loops has a protective effect (Pons et al., 1997).

Similar results are obtained with the enterotoxin of Bacteroides fragilis administered

to HT/29 C1 cells (human colon adenocarcinoma cell line). Prior incubation

of this toxin with smectite (calcium and sodium bentonites) suppresses its toxic effects (Martirosian et al., 1998).

B. Pesticides

Because of their high adsorptive capacity, clay minerals can also protect the digestive

mucosa against pesticide damage. Diquat, a widely used non-selective desiccant

herbicide, induces erosion of intestinal mucosa and fluid hypersecretion. In rats that

were given diquat, treatment with smectite (calcium and sodium bentonites) (500 mg/kg for 2 weeks) brings about a

normalization of mucus rheological properties and intestinal permeability, as

746 Chapter 11.6: Clays and Clay Minerals as Drugs

indicated by urine analysis using 51Cr-EDTA (Theodorou et al., 1995). Similarly,

montmorillonite and bentonite are good adsorbents, and may be recommended for

the treatment of pesticide poisoning (Meredith and Vale, 1987).

C. Microorganisms

Clay minerals are efficient drugs for treating disorders of the gastrointestinal mucosa,

induced by microorganisms. Kaolinite and montmorillonite are capable of

adsorbing viruses (Lipson and Stotzky, 1984). As such, these minerals can induce

rapid recovery when administered to children suffering from gastroenteritis.

Similarly, the strong adsorptive power of smectite (calcium and sodium bentonites) lies behind its ability to aggregate

bacteria, such as strains of E. coli with the plasmid P, carrying a virulence factor

in the form of an external protein CS 31A (Girardeau, 1987).

In the stomach, Helicobacter pylori is associated with gastritis and gastroduodenal

ulcers. This bacterium is also one of the most important ethiopathogenic factors

causing peptic ulcer. smectite (calcium and sodium bentonites), on HeLa cells infected by H. pylori isolated from

human biopsies, significantly reduces adhesion of the bacteria to the surface of

epithelial cells (Bonneville et al., 1990). This is why smectite (calcium and sodium bentonites) is effective in treating

the symptoms of people with non-ulcer dyspepsia who are infected by H. pylori

(De Korwin et al., 1993).

In the intestine, smectite (calcium and sodium bentonites) is effective against diarrhoea as shown by clinical data for

new-born calves with neonatal gastroenteritis. Faeces analysis reveals the presence of

rotavirus in 41.3% of the animals as well as that of E. coli K99, coronavirus, and

Salmonella. Recovery is observed in 72% of calves after 2.8 and 2.2 days of receiving

250 and 500mg/kg smectite (calcium and sodium bentonites), respectively, and after 4.2 days in calves which do not

receive smectite (calcium and sodium bentonites). After 4 days of treatment, the consistency of the faeces is significantly

better in calves receiving smectite (calcium and sodium bentonites) than in the control animals (Espinasse et al., 1987).

D. Gas

Clay minerals can serve as gas adsorbents in patients with symptoms of flatulence

and abdominal distension. Thus, smectite (calcium and sodium bentonites) can reduce the amount of hydrogen

emitted during colonic fermentation (Frexinos et al., 1986; Arbeille et al., 1991).

E. Alimentary Allergy

Food allergy is also responsible for disturbances in colonic transit, water absorption,

and intestinal permeability. Guinea pigs that were sensitized by b-lactoglobulin from

cow milk show colonic transit acceleration, a colonic hypersecretory response, a

strong increase in intestinal permeability, and a decrease in faecal dry matter. These

effects are not observed in animals that were treated with smectite (calcium and sodium bentonites). Clays can inhibit

anaphylaxia probably by controlling the release of mediators at the origin of the

degranulation of the mast cells (Theodorou et al., 1994).

11.6.4. CLAY MINERALS AND CLINICAL APPLICATIONS

Being good adsorbents and mucostabilizers, clay minerals are efficacious against

several aggressive agents causing severe intestinal disorders. Acute gastroenteritis is a

major cause of morbidity and mortality among children worldwide (Madkour et al.,

1993). By adsorbing viruses, bacteria, and other digestive irritants, clay minerals can

shorten the course of acute diarrhoea, and reduce the occurrence of prolonged diarrhoea.

Furthermore, these minerals do not interfere with the electrolyte balance,

and are well tolerated by patients (Buttron, 1987; DuPont et al., 1990; Bauer and

Hirschbrunn, 1992; Charritat et al., 1992; Dupont et al., 1992; Vivatvakin et al.,

1992; Lexomboon et al., 1994; Karas, 1996; Milocco et al., 1999; Guarino et al.,

2001; Narkeviciute et al., 2002).

Clay minerals also provide protection against diarrhoeas induced by antibiotics

treatments (Benhamou et al., 1995), alleviate chronic diarrhoeas induced by chemotherapy

and radiation (Hornbrink et al., 1995; Ippolite, 1998; Santantonio et al.,

2000), enteral nutrition (Perrotin et al., 1990), and HIV infection (Phanuphak et al.,

1992; Mastroianni et al., 1998).

Clay minerals are promising drugs in the treatment of irritable bowel syndrome

(IBS), a rather frequent disease in adults with a complex pathogenic mechanism.

By enhancing the thickness of the mucus barrier, both colon movement function and

faeces consistency are restored, and the symptoms of IBS are alleviated (Opriu et al.,

1996; Secondulfo et al., 2002). In parallel, clay minerals have a positive effect on

flatulence and abdominal distension (Lukas and Lukas, 2000).

11.6.5. CONCLUSIONS

Clay minerals protect and are efficient against several ‘aggressors’ that cause major

disorders of the gut. These beneficial effects of clay minerals (on the gastrointestinal

mucosa) are associated with two mechanisms of action: (1) adsorption of the ‘aggressors’

or their toxic secretions and (2) modification of the thickness and rheological properties

of the adherent mucus, reinforcing the natural defenses of the gastrointestinal mucosa.