Prebiotics

Prebiotics are defined as non-digestible food ingredients that may beneficially affect the host by selectively stimulating the growth and/or the activity of a limited number of bacteria in the colon. Thus, to be effective, prebiotics must escape digestion in the upper gastrointestinal tract and be used by a limited number of the microorganisms comprising the colonic micro flora. Prebiotics are principally oligosaccharides. They mainly stimulate the growth of bifidobacteria, for which reason they are referred to as bifidogenic factors.*

Difference Between Prebiotics and Probiotics

Prebiotics are a dietary fiber that triggers the growth of bacteria having favorable effects on the intestinal flora. Probiotics, however, are live microorganisms contained in the food we eat. They remain intact throughout the digestive process, and deliver healthy bacteria directly to the large intestine.*

Since probiotics do not stimulate metabolic activity they provide a different set of benefits than prebiotics. Both sets of benefits are valuable for our health wellness, and can act symbiotically to provide numerous health benefits. Both prebiotics and probiotics can be prescribed together.*

Inulin and oligofructose belong to a class of carbohydrates known as fructans. The main sources of inulin and oligofructose that are used in the food industry are chicory and Jerusalem artichoke. Inulin and oligofructose are considered as functional food ingredients since they affect the physiological and biochemical processes in rats and human beings, resulting in better health and reduction in the risk of many diseases. Experimental studies have shown their use as bifidogenic agents. Oligofructose are non-cariogenic, as they are not used by Streptococcus mutans to form acids and insoluble glucans that are the main culprits in dental caries.*

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Prebiotics may have anti-carcinogenic, antimicrobial, hypolipidemic and glucose-modulatory activities. They may also have activity in improving mineral absorption and balance and may have anti-osteoporotic activity.*

Mechanism of action

The possible anti-carcinogenic activity of prebiotics is not well understood. It may be accounted for, in part, by the possible anti-carcinogenic activity of butyrate. Butyrate, along with other short-chain fatty acids, is produced by bacterial fermentation of the various prebiotic oligosaccharides in the colon. Some studies suggest that butyrate may induce growth arrest and cell differentiation and may also up regulate apoptosis, three activities which could be significant for its possible anti-carcinogenic activity.*

The prebiotic oligosaccharides may also aid in increasing the concentrations of calcium and magnesium in the colon. Elevated concentrations of these cations in the colon may help to control the rate of cell turnover. Elevated concentrations of calcium in the colon may help to control the formation of insoluble bile or salts of fatty acids. This might reduce the potential damaging effects of bile or fatty acids on colonocytes. The prebiotics may stimulate the growth of bifidobacteria and lactobacilli in the large intestine. There are in vitro and animal data suggesting that these bacteria can bind to and inactivate some carcinogens, can directly inhibit the growth of some tumors and can inhibit bacteria that may convert pre-carcinogens into carcinogens.*

The possible antimicrobial activity of the prebiotics may be accounted for by their growth-promoting effects on bifidobacteria and lactobacilli. These bacteria can reinforce the barrier function of the intestinal mucosa, helping in the prevention of the attachment of pathogenic bacteria, essentially by crowding them out. These bacteria may also produce antimicrobial substances and stimulate antigen specific and nonspecific immune responses.*

The prebiotics may lower triglyceride levels in some. The mechanism of this possible effect is unclear. Decreased hepatocyte de novo synthesis of triglycerides is one hypothetical possibility. The prebiotics may also lower total cholesterol and LDL-cholesterol levels in some. Again, the mechanism of this possible effect is unclear. Propionate, a product of oligosaccharide fermentation in the colon, may inhibit HMG-CoA reductase, the rate-limiting step in cholesterol synthesis.*

The possible effects of the prebiotics on blood glucose may be accounted for in a few ways. The oligosaccharides may delay gastric emptying and/or shorten small intestinal tract transit time. This may be via the short-chain fatty acids produced from the oligosaccharides in the colon. Short-chain fatty acids may be involved in the so-called "ileocolonic brake," which refers to the inhibition of gastric emptying by nutrients reaching the ileo-colonic junction. Short-chain fatty acids may also stimulate contractions of the ileum and shorten ileal emptying. In addition, propionate may inhibit gluconeogenesis by its metabolic conversion to methylmalonyl-CoA and succinyl-CoA. These metabolites could inhibit pyruvate carboxylase. Propionate may also reduce plasma levels of free fatty acids. High levels of free fatty acids lower glucose utilization and induce insulin resistance.*

Finally, propionate may enhance glycolysis via depletion of citrate in hepatocytes. Citrate is an allosteric inhibitor of phosphofructokinase. In short, the mechanism of the possible effects of prebiotics on glucose tolerance are not well understood.*

The oligosaccharides may bind/sequester such minerals as calcium and magnesium in the small intestine. The short-chain fatty acids formed from the bacterial fermentation of the oligosaccharides may facilitate the colonic absorption of calcium and, possibly, also magnesium ions. This could be beneficial in the prevention of osteoporosis and osteopenia.*

Pharmacokinetics

Following ingestion, the prebiotic oligosaccharides reach the colon with very little of them being digested in the upper gastrointestinal tract. The oligosaccharides are fermented by bifidobacteria, lactobacilli and some other bacteria in the colon to produce the short-chain fatty acids acetate, propionate and butyrate; the gases hydrogen, hydrogen sulfide, carbon dioxide and methane; and lactate, pyruvate, succinate and formate. Acetate, propionate and butyrate that are not metabolized in colonocytes are absorbed from the colon and transported via the portal circulation to the liver. These short-chain fatty acids are extensively metabolized in hepatocytes. Acetate, propionate and butyrate that are not metabolized in hepatocytes are transported by the circulation to various tissues where they undergo further metabolism. Butyrate is an important respiratory fuel for colonocytes.*

Indications and usage

Some prebiotics are used, pharmaceutically, for the treatment of constipation and hepatic encephalopathy. Prebiotics may protect against some intestinal pathogens and may be helpful in some inflammatory bowel disease. They may have some anti-carcinogenic effects and may exert favorable lipid effects in some. They may, in some instances, enhance mineral absorption and might help protect against osteoporosis. There is some preliminary research that certain prebiotics might be of some benefit in diabetes mellitus.*

Research summary

Inulins have suppressed experimentally induced colonic aberrant crypt foci in rats, and lactulose helped protect colonic mucosa against a known colon carcinogen in another study. FOS has also shown experimental anti-carcinogenic effects, significantly reducing incidence of colon tumors, for example, in one animal study.*

A fermented milk product containing FOS lowered LDL-cholesterol levels in male subjects with borderline elevated serum cholesterol levels in a double blind, placebo-controlled study. There is a small study in which inulins reportedly lowered plasma total cholesterol and triglyceride levels significantly in healthy male volunteers. Results have been mixed, however, with respect to prebiotic effects on lipids, and more research is needed.*

Contraindications

Prebiotics are contraindicated in those who are hypersensitive to any component of a prebiotic-containing supplement.*

Some lactulose preparations contain galactose. Therefore, lactulose is contraindicated in those who require a low galactose diet.*

Precautions

Those who develop gastrointestinal symptoms (flatus, bloating, diarrhea) with the use of dietary fiber should exercise some degree of caution in the use of prebiotics. Those receiving whole body radiation or radiation to the gastrointestinal tract should avoid prebiotic supplements.*

Adverse reactions

Doses of prebiotic oligosaccharides up to 10 grams daily are well tolerated. Higher doses may cause gastrointestinal symptoms, such as flatulence, bloating and diarrhea*

Larch arabinogalactan

Larch arabinogalactan is a polysaccharide powder derived from the wood of the larch tree (Larix species) and comprised of approximately 98 percent arabinogalactan. It is composed of galactose and arabinose molecules in a 6:1 ratio, with a small amount of glucuronic acid. Arabinogalactans are long, densely branched polysaccharides of varying molecular weights (10,000-120,000).*

Lower molecular weight polysaccharides typically exhibit an anti-inflammatory, anti-complement, anti-allergy effect, while those of higher weights stimulate natural killer (NK) cell cytotoxicity and reticuloendothelial cells. In the case of larch arabinogalactan, molecular weights of the two major fractions are 16,000 and 100,000, perhaps accounting for its wide range of therapeutic properties.*

A number of chronic diseases are characterized by decreased NK cell activity, including chronic fatigue syndrome, viral hepatitis, HIV/AIDS, 2 and autoimmune diseases such as multiple sclerosis. Stimulation of NK cell activity by larch arabinogalactan has been associated with recovery in certain cases of chronic fatigue syndrome. Viral hepatitis (hepatitis B and C) is also characterized by a decrease in NK cell cytotoxicity and therefore these patients may benefit from its stimulation by larch arabinogalactan.*

In the case of multiple sclerosis, a small 2-year study of patients with the relapsing/remitting type concluded that disease severity was correlated with NK cell functional activity, supporting the hypothesis that NK cells play a role in the immuno-pathogenesis of this disease.*

Research has demonstrated larch and other arabinogalactans to be capable of enhancing the immune response to bacterial infection via stimulation of phagocytosis, competitive binding of bacterial fimbriae, or bacterial opsonization. This was found to be particularly true for infection by gram-negative organisms such as Escherichia coli and Klebsiella species. In addition, D'Adamo reports a decrease in occurrence and severity of otitis media in pediatric patients supplemented prophylactically with larch arabinogalactan*

Fructooligosaccharides (FOS)

Fructooligosaccharides (FOS) refers to a class of non-digestible carbohydrates or sugars that occur naturally in a wide variety of foods throughout the plant kingdom. Since they are non-digestible, they pass through the human digestive virtually unchanged. When the fructooligosaccharides reach the colon, they are used by the good or beneficial bacteria found there (known as bifidobacteria or bifidus) for growth and multiplication. A healthy population of these beneficial bacteria in the digestive tract enhances the digestion and absorption of nutrients, detoxification and elimination processes, and helps boost the immune system.*

Fructooligosaccharides can also help maintain a healthy balance of the "good" bacteria with the "bad" bacteria in the digestive tract. When the "bad" bacteria dominate, a condition known as "dysbiosis" can occur. Dysbiosis can then lead to other problems throughout the body. Fructooligosaccharides may also be of benefit in helping to relieve constipation and other gastrointestinal disorders, including problems related to irritable bowel syndrome, inflammatory bowel disease, and lactose intolerance.*

Direct protection against intestinal infection*

Continuous priming of the intestinal immune system from birth onwards*

Provision of nutrients to the host, including B-vitamins and short chain fatty acids*

Possible influence on reducing risk of colorectal cancer development*

A characteristic of all prebiotics is that they escape digestion in the small intestine and are fermented in the large intestine by the microflora. This produces predominantly lactate, the short chain fatty acids (scFA's) -- acetic, propionic and butyric, and the gases hydrogen, methane and carbon dioxide (Cummings & Macfarlane, 1997). These characteristics of FOS and other prebiotics have caused the National Academy of Sciences to revise its definition of fiber to include these prebiotics materials. Once in the large intestine, the ability of FOS to stimulate populations of Bifidobacteria and to a lesser extent Lactobacilli, while reducing the other components of the microflora, notably Clostridia, E. coli and other Coliforms such as Klebsiella and Enterobacter, have been demonstrated in vitro using chemostat models of the colon (Wang & Gibson, 1993; Davidson et al., 1998; Rycroft et al., 2001).*

Butyrate provides 70% of the energy for the colonic epithelial cells, or colonocytes (Roediger, 1980; Cummings & Macfarlane, 1997). Without this energy source, the colonocytes can atrophy with consequent loss of integrity of the mucosal barrier. This results in the leakage and translocation of bacteria and dietary components in an unregulated way from the gut lumen to the systemic environment. As such, lack of butyrate is probably the most important cause of intestinal permeability.*

Butyrate controls the turnover and differentiation of the colonic epithelial cells and is capable of inducing differentiation in colon carcinoma cell lines. (Smith et at., 1998; Velzquez et al., 1996).*

Butyrate induces apoptosis (programmed cell death) in normal growing colonic cells and reverses resistance to apoptosis in colonic cancer cells (Bornet, 2002).*

Butyrate increases immunogenicity (susceptibility to immune cell policing, e.g. by NK cells) of cancer cells. Indeed, butyrate in combination with interleukin 2 caused complete clearance of induced colon carcinoma in rats (Perrin et al., 1994; Bornet et at., 2002).*

Inulin

Inulins refer to a group of naturally occurring fructose-containing oligosaccharides. Inulins belong to a class of carbohydrates known as fructans. They are derived from the roots of chicory (Cichorium intybus) and Jerusalem artichokes. Inulins are mainly comprised of fructose units and typically have a terminal glucose. The bond between fructose units in inulins is a beta- (2-1) glycosidic linkage. The average degree of polymerization of inulins marketed as nutritional supplements is 10 to 12. Inulins stimulate the growth of Bifidobacterium species in the large intestine.*

In resent research, a trial testing inulin from chicory in the Simulator of the Human Intestinal Microbial Ecosystem (SHIME) resulted in stimulation of intestinal bacteria, namely bifidobacteria. Insulin has also displayed specific benefits to digestive illness, including alleviating diarrhea. Similarly, FOS combined with L. Sporogenes has been shown to significantly reduce duration of antibiotic-induced diarrhea in children. On its own, FOS reduced intestinal inflammation in an animal colitis model by increasing intestinal lactic acid bacteria.*

Many studies have documented the favorable effects of inulin on various aspects of digestive health. In each of these studies, two of the parameters measured are fecal weight and frequency. Inulin consistently increases both fecal weight and frequency.*

Further, in studies involving constipated individuals, inulin has been shown to relieve constipation and promote regularity. (Den Hond et al., 2000) (Kleesen et al., 1997)*

The second component of digestive health is digestive efficiency. A key function of the digestive system is the effective absorption of nutrients. Inulin has been shown to increase the efficiency of the digestive system in several ways. Human clinical studies show that the ingestion of inulin significantly increases the absorption of calcium in the diet by making the digestive system more efficient at absorbing calcium. In addition, animal models show that inulin increases the size and absorptive capacity of the digestive tract. As noted previously, inulin significantly increases the levels of beneficial Bifidobacteria in the digestive tract. In addition to their other contributions, these bacteria are known to produce vitamins and enzymes that may also help contribute to the efficiency of the digestive process.*

L-Glutamine

Glutamine is an amino acid, which is normally found in greater abundance in the body than any other free amino acid. It is crucial for many aspects of healthy body function, including maintenance of optimal antioxidant status, building and maintenance of muscle tissue, maintenance of optimal immune function, and repair and maintenance of intestinal tissue.*

It has been shown that glutamine deficiency may cause many serious problems, including inadequate antioxidant status in the body, wasting, and loss of both intestinal and immune function. Dr. Shabert points to the research showing that during the stress of infection or injury, the demand for glutamine is very high.1 The muscles respond to this demand by releasing their stored glutamine. In fact, the rate of release of glutamine from the muscles is dramatically increased, to levels 3-4 times normal. According to Dr. Shabert, the body does this in order to provide glutamine to the intestinal tract, liver, kidneys, and immune system cells.*

Glutamine is also critical for maintaining the health of the intestinal tract since it is required for the constant rebuilding of intestinal cells. The cells lining the intestine function to absorb nutrients and to block the uptake of pathogens. These cells are regenerated every 3-4 days. The energy, which allows this process to occur, comes from glutamine. If glutamine concentrations are low, the result is intestinal tissue atrophy and decreased absorption, with resulting lack of uptake of nutrients vital to the body's function. Glutamine is also necessary to maintain the barrier function of the intestines, the body's ability to block the uptake of pathogens, improperly digested food particles, and so on. As is readily apparent, glutamine's ability to help repair the intestines is among its most important benefits*

It has been found to help modulate the immune system and protect the mucosal protective layer in the intestine. Studies have demonstrated that glutamine can help improve blood flow in inflamed segments of the colon in patients who have ulcerative colitis, although its benefits did not extend to the most seriously affected portion of the colon (Kruschewski et al., 1998). Glutamine is also able to reduce leakiness of the intestine, which may help to reduce symptoms of inflammatory bowel disease.*

Isomalto-oligosaccharides

Isomalto-oligosaccharides comprise a mixture of alpha-D- (1m6)-linked glucose oligomers, including isomaltose, panose, isomaltotetraose, isomaltopentaose, nigerose, kojibiose, isopanose and higher branched oligo-saccharides. Various enzymatic processes produce isomalto-oligosaccharides. They act to stimulate the growth of Bifidobacterium species and Lactobacillus species in the large intestine. Isomalto-oligosaccharides are marketed in Japan as dietary supplements and in functional foods. They are being developed in the United States for similar uses.*

Study on the regulative effect of isomaltooligosaccharides on human intestinal flora

Gu Q, Yang Y, Jiang G, Chang G. Tianjin Centers for Disease Control and Prevention, Tianjin 300011, China. (PMID: 12731290 [PubMed - indexed for MEDLINE])

OBJECTIVE: In order to study the effect of Isomaltooligosaccharides on Human and mouse intestinal flora in vivo. METHODS: 1. 30 health subjects (15 male, 15 female) were randomly selected from the clinic of Tianjin CDC. They were provide 15 g Isomaltooligosaccharides once a day for 7 days; 2. 40 BABL/c mice were divided into 4 groups, 3 experimental groups and 1 control group. These 3 experimental groups were fed different dose of Isomaltooligosaccharides by gavage for 7 days. Feces of both human and mice were determined before and at the end of the experiment. RESULTS: The results showed that the reproduction of Bifidobacteria and Lactobacillus greatly increased, and the growth of Clostridium perfriengenes was significantly inhibited both in mice and human intestinal tracts. CONCLUSION: Isomaltooligosaccharides could regulate and improve the intestinal flora in both mice and human intestine.*

References

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Flickinger EA, Wolf BW, Garleb KA, et al. Glucose-based oligosaccharides exhibit different in vitro fermentation patterns and affect in vivo apparent nutrient digestibility and microbial populations in dogs. J Nutr. 2000; 130:1267-1273.

Gibson GR. Dietary modulation of the human gut microflora using prebiotics. Br J Nutr. 1998; 80:S209-S212.

Grizard D, Barthomeuf C. Non-digestible oligosaccharides used as prebiotic agents: mode of production and beneficial effects on animal and human health. Reprod Nutr Dev. 1999; 39:563-588.

Macfarlane GT, Cummings JH. Probiotics and prebiotics: can regulating the activities of intestinal bacteria benefit health. West J Med. 1999; 171:187-191.

Murosaki S, Muroyama K, Yamamoto Y, et al. Immunopotentiating activity of nigerooligosaccharides for the T helper 1-like immune response in mice. Biosci Biotechnol Biochem. 1999; 63:373-378.

Ohkusa T, Ozaki Y, Sato C, et al. Long-term ingestion of lactosucrose increases Bifidobacterium sp. in human fecal flora. Digestion. 1995; 56:415-420.

Roberfroid MB. Chicory fructooligosaccharides and the gastrointestinal tract. Nutrition. 2000; 16:677-679.

Roberfroid MB. Health benefits of non-digestible oligosaccharides. Adv Exp Med Bull. 1997; 427:211-219.

Roberfroid MB. Prebiotics and synbiotics: concepts and nutritional properties. Br J Nutr. 1998; 80:S197-S202.

Roberfroid MB. Prebiotics and probiotics: are they functional foods. Am Clin Nutr. 2000; 71 (6 Suppl):1682S-1687S, discussion 1688S-1690S.

Soontornchai S, Sirichakwal P, Puwastien P, et al. Lactilol tolerance in healthy Thai adults. Eur J Nutr. 2000; 38:218-226.

Teramoto F, Rokutan K, Kawakami Y, et al. Effect of 4G- beta-D-galactosylsucrose (lactosucrose) on fecal microflora in patients with chronic inflammatory bowel disease. J Gastren- terol. 1996; 31:33-39.

Wang X-D, Rakshit SK. Biosynthesis of nutraceutical iso-oligosaccharides by multiple forms of transferase produced by Aspergillus foetidus. Nahrung. 2000; 44:207-210.

*These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure, or prevent any disease.