Probiotics: A Closer Look

US Pharm. 2003;33(6):40-44.

Probiotics are dietry supplements that have been used for centuries as natural components in health-enhancing foods. Probiotics contain potentially beneficial bacteria or yeasts. According to the currently adopted definition by the World Health Organization/Food Agricultural Organization, probiotics are "live microorganisms which when administered in adequate amounts provide a health benefit on the host."¹ Lactic acid bacteria are the most common type of bacteria used in the food industry and have been used for many years because they are able to convert sugars (including lactose) and other carbohydrates into lactic acid. This not only provides the characteristic sour taste of fermented dairy foods such as yogurt, but by lowering the pH it may also create less chances for pathogenic organisms to grow, hence providing many health benefits, such as preventing gastrointestinal infections.² The most widely used probiotic bacteria are Lactobacillus and Bifidobacterium.

The rationale for the use of probiotics is that the body contains certain bacteria known as the gut flora . The body's naturally occurring gut flora fall out of balance in a wide range of circumstances, including the use of antibiotics or other drugs, excess alcohol, stress, certain diseases, or exposure to toxic substances. In cases like these, the bacteria that work well with our bodies may decrease in number, allowing harmful competitors to jeopardize our health.³

Probiotics are recommended more frequently by nutritionists and sometimes by physicians after a course of antibiotics or as part of the treatment for gut-related candidiasis. The intake of probiotics has been associated with beneficial effects due to their immunomodulatory activity, such as improved disease resistance and diminished risk of allergies.⁴ Maintenance of a healthy gut flora is, however, dependent on many factors, especially the quality of food intake. A significant proportion of prebiotic foods in the diet has been demonstrated to support a healthy gut flora and may be another means of achieving the desirable health benefits promised by probiotics. Interest in probiotics in general has been growing; Americans' spending on probiotic supplements, for example, has nearly tripled from 1994 to 2007.

History of Probiotics
In the early 20th century, the positive role of certain nonpathogenic bacteria was first noted by Russian scientist and Nobel laureate Eli Metchnikoff. He suggested that it would be possible to modify the gut flora and to replace harmful bacteria by useful bacteria. Metchnikoff believed that proteolytic bacteria produce toxic substances such as phenol, indols,Ü and ammonia in the large bowel from the digestion of proteins. As a result, he proposed that these compounds were responsible for intestinal autointoxication, which, he said, caused the physical changes associated with old age.

In the meantime, researchers discovered that milk fermented with lactic-acid bacteria inhibited the growth of proteolytic bacteria due to the resulting low pH produced by lactose fermentation. Metchnikoff had also observed that some Russians who lived largely on milk fermented by lactic-acid bacteria were exceptionally long-lived. Based on these facts, Metchnikoff proposed that consumption of fermented milk would seed the intestine with harmless lactic-acid bacteria and decrease the intestinal pH, which in turn would suppress the growth of proteolytic bacteria.

Subsequently, Henry Tissier from the Pasteur Institute isolated a bifidobacterium from a breast-fed infant and named it Bacillus bifidus communis (later renamed Bifidobacterium bifidum). Tissier showed that bifidobacteria are predominant in the gut flora of breastfed babies, and he recommended administration of bifidobacteria to infants suffering from diarrhea. The mechanism claimed was that bifidobacteria would displace the proteolytic bacteria that cause the disease.

After Metchnikoff's death in 1916, the center of probiotics activity moved to the United States. It was reasoned that bacteria originating from the gut were more likely to produce the desired effect in the gut, and in 1935 certain strains of Lactobacillus acidophilus were found to be very active when implanted in the human digestive tract. Trials were carried out using this organism, and encouraging results were obtained, especially in the relief of chronic constipation. In the 1970s the dairy industry began to promote fermented milk products containing L acidophilus. In subsequent decades, other Lactobacillus species were introduced, including Lactobacillus rhamnosus , Lactobacillus casei, and Lactobacillus johnsonii, because they are intestinal species with beneficial properties.⁵

Probiotics Versus Prebiotics
Probiotics are not the same thing as prebiotics--nondigestible food ingredients that selectively stimulate the growth and/or activity of beneficial microorganisms already in the colon. When probiotics and prebiotics are mixed,Ü they form a synbiotic.

Probiotics can be used as complementary and alternative medicineÜ (CAM) to prevent and treat certain illnesses and support general wellness. They are available in foods and dietary supplements as capsules, tablets, and powders and in some other forms as well. Examples of foods containing probiotics are yogurt, fermented and unfermented milk, miso, tempeh, and some juices and soy beverages.

Most probiotics are nonpathogenic bacteria similar to those naturally found in people's guts, especially in those of breast-fed infants (who have natural protection against many diseases). Most often, the bacteria come from two previously named species, L acidophilus and B bifidum. Within each species, different strains or varieties are available. Therefore, it is important to remember that the safety and efficacy associated with probiotics are dependent on the strain of the bacteria and can differ widely, even among similar bacteria species. A few common probiotics, such as Saccharomyces boulardii , are yeasts, which are different from bacteria.⁶

Lactobacillus Species
Lactobacillus acidophilus is a bacterium that produces lactic acid, thereby creating an environment unfavorable to the overgrowth of potentially pathogenic fungi and bacteria (including putrefactive bacteria) and favoring establishment of aciduric flora. ⁷

L acidophilus and Lactobacillus bulgaricus have been used for more than 75 years in the treatment of uncomplicated diarrhea, particularly diarrhea caused by modification of the intestinal flora by antibiotics. Lactobacillus preparations may assist in reestablishing the normal physiologic and bacterial flora of the intestinal tract and have also been used in patients with infectious diarrhea, ulcerative colitis, irritable colon, diverticulitis, colostomies with either diarrhea or constipation, functional constipation, mucous or spastic diarrhea, and diarrhea following amebiasis. However, there is currently a lack of substantial evidence from well-designed, controlled studies to support claims of efficacy for Lactobacillus preparations in the treatment of diarrhea.

L acidophilus is administered orally, preferably with milk, fruit juice, or water. The conventional capsules, tablets, and granules may be chewed or swallowed whole, and the granules or contents of Intestinex capsules may be added to or taken with cereal, food, milk, fruit juice, or water. The commercially available enteric-coated capsules should be swallowed whole.

Dosage
Dosage of the commercial preparation containing L acidophilus and sodium carboxymethylcellulose is two capsules two to four times daily. Dosage of the commercial preparations containing L acidophilus and L bulgaricus is two capsules, four tablets, or one packet of granules three or four times daily. Dosage of the commercially available enteric-coated capsules containing L acidophilus and L casei is one capsule daily for the first two weeks of therapy; dosage may then be increased up to a maximum of three capsules daily if necessary.

For self-medication of diarrhea, L acidophilus preparations should generally not be used for more than two days or in the presence of a high fever unless otherwise directed by a physician. They may produce an increase in intestinal flatus at the beginning of therapy, but this usually subsides with continued use. One manufacturer recommends that L acidophilus not be used for treatment of diarrhea in infants and children younger than 3 years unless under the direction and supervision of a physician. Individuals sensitive to milk products should not use the drug.⁸

Commercial preparations should be stored at 2C to 8C. The commercially available Lactinex tablets and granules carry an 18-month expiration date, and the capsules carry a two-year expiration date. No methods of standardization of the cultures used in the commercial preparations have been published.

Bifidobacterium Species
Bifidobacterium include more than 28 species that are a normal component of the bacterial flora of the lower gastrointestinal tract. Their metabolic activity produces a variety of beneficial vitamins as well as an environment that suppresses the growth of pathogenic species. Bifidobacteria of the colon digest sugars to acidic short-chain fatty acids, creating a slightly acidic pH, which suppresses the growth of bacteria, yeasts, and other pathogenic organisms. Bifidobacteria may influence the metabolism of fatty acids, bile acids, cholesterol, and steroid hormones in the intestinal tract. They also produce a number of vitamins, including several B vitamins and vitamin K, which are absorbed into the circulation. In addition, the short-chain fatty acids produced by Bifidobacterium species are a primary source of energy for colonic epithelial cells.⁹

Strain Specificity
Probiotic bacteria exhibit a variety of properties, including immunomodulatory activity, which are unique to a particular strain. Thus, not all species will necessarily have the same therapeutic potential in a particular condition. Recent studies compared the response of symptoms and cytokine ratios in irritable bowel syndrome (IBS) with ingestion of probiotic preparations containing a Lactobacillus or Bifidobacterium strain. Bifidobacterium infantis 35624 was found to be a probiotic that specifically relieves many of the symptoms of IBS. This symptomatic response was associated with normalization of the ratio of an anti-inflammatory to a proinflammatory cytokine, suggesting an immune-modulating role for this particular organism.¹⁰

Health Benefits
Generalization of probiotic effects should not be made,Ü and critical scientific evaluation must be used in directing patients to select the appropriate probiotic. There are several reasons that people are interested in probiotics for health purposes. ¹¹ First, the world is full of microorganisms (including bacteria) and so are people's bodies--in and on the skin, in the gut, and in other orifices. Friendly bacteria are vital to proper development of the immune system, to protection against microorganisms that could cause disease, and to the digestion and absorption of food and nutrients. Each person's mix of bacteria varies. Interactions between a person and the microorganisms in his or her body, and among the microorganisms themselves, can be crucial to the person's overall health and well-being.

Pathogenic microorganisms such as disease-causing bacteria, yeasts, fungi, and parasites can also upset the balance. Researchers are exploring whether probiotics could halt these unfriendly agents in the first place and/or suppress their growth and activity in conditions like infectious diarrhea, IBS, inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), infection with Helicobacter pylori (H pylori, a bacterium that causes most ulcers and many types of chronic stomach inflammation), tooth decay and periodontal disease, vaginal infections, stomach and respiratory infections that children acquire in day-care settings, and skin infections.

Another reason for the interest in probiotics stems from the fact that there are cells in the digestive tract connected with the immune system. It is believed that alteration of the microorganisms in a person's intestinal tract (such as by introducing probiotic bacteria) may affect the immune system's defenses.

Some uses of probiotics for which there is some encouraging evidence are as follows¹²:
• To treat diarrhea (this is the strongest area of evidence, especially for diarrhea from rotavirus)
• To prevent and treat infections of the urinary tract or female genital tract
• To treat IBS
• To shorten the duration of an intestinal infectionÜ caused by the bacterium Clostridium difficile
• To prevent and treat pouchitis (a condition that can follow surgery to remove the colon).

Risks
Much more scientific knowledge is needed about probiotics, including their safety and appropriate use. Effects found from one species or strain of probiotics do not necessarily hold true for others, or even for different preparations of the same species or strength. Probiotics' safety has not been thoroughly studied scientifically, and more information is needed, especially on how safe they are for young children, the elderly, and those with compromised immune systems. Generally, probiotics' side effects tend to be mild and digestive (such as gas or bloating). More serious effects have been seen in some people. The Food and Drug Administration has special labeling requirements for dietary supplements and treats them as foods, not drugs. No CAM therapy should be used in place of conventional medical care or to delay seeking that care.

Key areas for future research include the following:
1) Exploring bacteria at the molecular level to learn how they may interact with the body (such as the gut and its bacteria) to prevent and treat diseases. Advances in technology and medicine are making it possible to study these areas much better than in the past.
2) Determining what happens when probiotic bacteria are treated or are added to foods. Is their ability to survive, grow, and have a therapeutic effect altered?
3) Finding the best ways to administer probiotics for therapeutic purposes, as well as the best doses and schedules.
4) Investigating probiotics' potential to help with the problem of antibiotic-resistant bacteria in the gut and whether they can prevent unfriendly bacteria from getting through the skin or mucous membranes and traveling through the body (e.g., which can happen with burns, shock, trauma, or suppressed immunity). ¹³

Role of Pharmacists and Physicians
In the U.S., consumer pressure will undoubtedly stimulate a lot of interest in probiotics. As a result, pharmacists, nutritionists, and family physicians need to improve their knowledge and be informed about them so they can advise their patients appropriately. Based on the current understanding, positive health effects of probiotics have been reported in the management of diarrhea and inflammatory and allergic diseases in adults and infants.¹⁴ As a result, it is critical to know what strain the product is and what research backs that strain. Physicians and pharmacists should be encouraged to research the strain of bacteria and the product before they recommend them, as a number of probiotic products have been associated with quality concerns, including contamination with strains not included on the label.

REFERENCES
1. Food and Agriculture Organization (FAO) of the United Nations and World Health Organization (WHO). Guidelines for the Evaluation of Probiotics in Food. Report of a Joint FAO/WHO working group on drafting guidelines for the evaluation of probiotics in food. Accessed December 7, 2006.
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8. Lactobacillus. Thomson MICROMEDEX AltMedDex System Web site. Accessed December 7, 2006.
9. Bifidus. Thomson MICROMEDEX AltMedDex System. Web site. Accessed December 7, 2006.
10. Whorwell PJ, Altringer L, Morel J, et al. Efficacy of an encapsulated probiotic Bifidobacterium infantis 35624 in women with irritable bowel syndrome. Am J Gastroenterol. 2006;101:1581-1590.
11. Cabana MD, Shane AL, Chao C, et al. Probiotics in primary care pediatrics. Clin Pediatr. 2006;45:405-410.
12. Hammerman C, Bin-Nun A, Kaplan M. Safety of probiotics: comparison of two popular strains. BMJ. 2006;333:1006-1008.
13. Huebner ES, Surawicz CM. Probiotics in the prevention and treatment of gastrointestinal infections. Gastroenterol Clin North Am. 2006;35:355-365.
14. Salminen SJ, Gueimonde M, Isolauri E. Probiotics that modify disease risk. J Nutr. 2005;135:1294-1298.

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