This report describes results from a study in which normal healthy rodents (C57bl/6 mice) were maintained for 15 months on a HFWD with and without a dietary supplement consisting of a mineral-rich extract. The HFWD was formulated to mimic the diet consumed by many individuals in Western countries.20
Previous studies have shown that normal mice maintained on such a diet develop abnormalities in the mucosa of the large intestine, including crypt hyperplasia, colonic polyps, and occasional carcinomas.20,22,23
In addition to containing a high content of saturated fat, the diet is low in a number of nutrients that are thought to protect against carcinogenesis in the gastrointestinal tract. The findings presented here substantiate earlier work demonstrating the consequences of the high fat diet on the colonic mucosa. More importantly, our studies show that supplementation of the HFWD with a mineral-containing extract from the red marine algae, Lithothamnion calcareum (Pallas)
, suppresses the outgrowth of grossly visible raised polyps and reduces microscopically visible mucosal hyperplasia.
How the mineral-rich extract prevents outgrowth of colonic polyps in the HFWD mice is not fully understood. One possibility is a direct inhibitory effect on epithelial cell proliferation. Our recent studies showed that the same mineral-rich extract induced differentiation and reduced proliferation of human colonic epithelial cells in vitro
. The mineral-rich extract was equally effective with cells that were resistant to growth-regulating activity of Ca2+
alone as with cells that were Ca2+
Our past studies have demonstrated the importance of the extracellular calcium-sensing receptor (CaSR) in mediating the growth-regulating effects of Ca2+
in the colon.11,12,15,24,25
Other past studies have shown that many of the multivalent (lanthanide) metal ions present in the algae extract are more effective than Ca2+
itself in upregulating CaSR expression.16,26
Based on these findings, one could hypothesize that the ability of the mineral-rich extract to directly inhibit proliferation of colonic epithelial cells underlies its effectiveness in preventing polyp outgrowth.
Alternatively, suppression of polyp outgrowth may be secondary to the concomitant inhibition of inflammatory events in the gastrointestinal tract. A high-fat diet is known to increase oxidant and inflammatory stress. In a recent study it was demonstrated that a diet rich in dairy products inhibited generation of reactive oxygen species and, concomitantly, suppressed generation of several pro-inflammatory cytokines in mice on a similarly-formulated high-fat diet.27
alone inhibited the inflammatory changes but was less effective. Consistent with these findings, several of the trace elements in the mineral-rich extract (e.g., copper, zinc, selenium, manganese and molybdenum) are key components of anti-oxidant enzymes.28
Supporting an optimal antioxidant barrier may counteract pro-oxidant and pro-inflammatory processes and thereby prevent mutagenic events that lead to a loss of growth control.
A third related possibility is that improved mucosal differentiation in the presence of the mineral-rich extract is directly related to reduced inflammation in mice on the high-fat diet. Epithelial cell differentiation is required for effective barrier formation.29
An adequate level of Ca2+
is required for epithelial differentiation9–12
, and one could imagine that in the high-fat diet (which is also low in Ca2+
relative to the level in normal mouse chow) failure of epithelial differentiation occurs, leading to a “leaky” barrier throughout the gastrointestinal tract. Bacteria, bacterial products, food allergens, and other toxins could then enter the submucosa and provide a constant pro-inflammatory stimulus. By promoting effective differentiation, the mineral-rich extract could counteract this effect, thereby reducing systemic inflammation and the downstream consequences of inflammation.
Mechanisms aside, it is important to ask whether the mineral-rich algae extract could be used routinely in humans as a dietary supplement under conditions needed for effective chemoprevention in the colon. The algae extract is already available as a food supplement [under the name Aquamin® (GRAS 000028)] and is currently used in various products for human consumption in Europe, Asia, Australia, and North America. A recent (small) clinical study in humans has been done and no serious adverse events were observed in any of the treated subjects.18,19
Other (non-serious) adverse events were similar in the treated group and a placebo group. Based on the positive results generated in the present study and the lack of observed detrimental effects, it would appear worthwhile to undertake a long-term comprehensive prospective study in human volunteers. Ultimately, only such a study in humans can determine whether or not the algae extract will have effective chemopreventive activity against colon cancer.