Probiotics and Prebiotics as Functional Food

Ashima Hooda 1*, Ishan Ghai1, Simran Kochar1

Abstracts: Probiotics and Prebiotics are specialized functional foods with physiologically active components, that reduces the risk of chronic diseases and provide health benefits, beyond basic nutrition. Compared to a Probiotic which introduces exogenous bacteria into the colon, Prebiotics are generally colonic food that enters the colon & serve as a substrate for endogenous colonic bacteria, indirectly providing the host with energy, metabolic substrate and essential micronutrients. Probiotics are administered in the form of bacterias, yeasts and moulds that are clinically useful in Infectious Diarrhea, Bacterial aginosis, Gastroenteritis, Urinary Tract Infections and Immune System Disorders. Microorganisms used as Probiotics are Lactobacillus spp., Streptococcus spp. etc. Prebiotics are available in form of various polyols, disaccharides & non-digestible oligosaccharides. Generally, Probiotics and Prebiotics are well tolerated amongst individuals, in rare cases complications may arise such as Cardiac valvular disease (lactobacillus species only), impaired intestinal epithelial barrier like intestinal inflammation, Central venous catheter in premature infants etc. Therapeutic doses of Probiotic varies with probiotic strain, test subject & delivery form, when it is taken with food. Again, effective dosages of Prebiotics, may differs for different Prebiotics, as these are generally a mixture of different chain length carbohydrates. Some of the established marketed brand of Probiotic are Yogurt Drink , a beverage that contains Lactobacillus acidophilus La -5, Bifidobacterium bifidum BB12 and fruit juice . The product has the combination of cranberries with biocultures, for positive balancing of friendly bacteria in the digestive system. Japans Glico Diary product has Probiotics, with added values in a different way. Its constituents are Bifidobacterium containing yogurt that includes blueberries which are antioxidant polyphenols. INTRODUCTION In recent times, there has been increased awareness amongst consumers, towards improving health standard. Thus we find the health aspect, gaining more and more importance due to the factors like change in socioeconomic factors - higher life expectancy, increasing costs for health care systems, discontent with the traditional medicine and increasing number of allergic persons. The consumers are now not averse to accepting and using the so called functional foods as supplements to their normal diet. They fully recognize the potential role of these products in a balanced diet and in ensuring good health. In broader terms, a Functional food1,11 comprises of: i) Conventional foods containing bioactive substances2 (e.g. Dietary fibers) ii) Foods enriched with bioactive substances (e.g. Probiotics, Antioxidants) iii) Synthesized food ingredients introduced in traditional foods (e.g.: Prebiotics) The term functional foods encompasses some bacterial strains and the products of plant or animal origin that contains physiologically active compounds, beneficial for human health. Its usuage reduces the risk of chronic diseases and are prophylactically2 useful in managing health disorders. This included Probiotics, Prebiotics, Natural Antioxidants, Minerals, Vitamins, Amino Acids, Proteins and Peptides. Thus, a functional food can be defined as food that contains physiologically active components
1PDM

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substances, which selectively stimulate the growth or activity of limited no. of probiotic bacteria in the colon and thereby benefit the host organism 3 . Compared to a Probiotic, which introduces exogenous bacteria into the colon micro biota, Prebiotics, are generally colonic foods that enter the colon, serve as a substrate for endogenous colonic bacteria8 and indirectly provide the host with energy, metabolic substrate and essential micronutrients. Microorganisms Used As Probiotics Criteria Related to Safety, Functional Effects and Technological Properties13,14 for Microorganisms to Achieve a Probiotic Status: The probiotic should not be pathogenic It should have no connection with diarrhoergenic bacteria and no ability to transfer antibiotic resistance genes Must maintain genetic stability Acid and bile stable Resistant to digestive enzymes Adhesion to intestine surface and antagonistic activity against human pathogens

Key Words: Exogeneous Bifidobacterium, Polyphenol

Bacteria,

Oligosaccharides,

College of Pharmacy, Bahadurgarh, Harayana, India. E-mail: *Corresponding author

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PROBIOTICS & PREBIOTICS The term Probiotic is derived from Greek word meaning pro life. The concept of Probiotics was evolved in 20th century from a hypothesis first produced by Nobel Prize winning Russian scientist Elie Metchnikoff 4. He is known as father of immunology. He suggested that long healthy life of Bulgarian peasants resulted from the consumption of fermented milk products 7,16 that contained lactobacillus, which had positive effect on the micro flora of the colon by decreasing toxic microbial activities. The consumption of live bacteria as Lactobacillus bulgaris and S. thermophillus 15,17 in form of yoghurt are useful for GI healing and longetivity12 . Gibson and Roberfroid who exchanged pro for pre which means before or for introduced the term prebiotic. They defined prebiotics as non, low digestible food

that provides health benefits, beyond basic nutrition as it affects one or more functions in the body in a targeted way.3 Thus the clear emergence of Probiotics and Prebiotics as functional foods over the past number of years, is a subject matter of debate and intense research. Clinically, the human gut contains large variety of bacterial genera15 , species and strains, which are either beneficial6 (eg: bifidobacterium, eubacterium and lactobacillus) or detrimental6 (Clostridium, Shigella and Veillonella) to their health. The Prebiotics & Probiotics success lies in their successful selection of beneficial live microorganisms & usuage in formulating functional food. Further, these Probiotics and Prebiotics are inexpensive, safe and are formulated into specialized food supplements or pharmaceuticals that contribute to health benefits.

Lactobacillus,

Biocultures

Criteria Related to Safety, and Technological Properties for Microorganisms to Achieve a Prebiotic Status 15 a) It should be resistant to hydrolysis and digestion and should not be absorbed in the upper part of GI tract. b) It should be a selective substrate, for a number of potentially beneficial bacteria commensal to the colons, which are stimulated, to grow and metabolically activated. c) It should be resistant to fermentation by colonic micro flora and should be able to alter the colonic micro flora, to a healthy composition. Types of Prebiotic Substrates 22,25 Polyols (sugar alcohols) Xylitol Sorbitol Mannitol (stereoisomer of sorbitol) Disaccharides lactose) Lactulose Lactilol (synthetic

derivatives

of

Non-digestible Oligosaccharides Palatinose Isomaltooligosaccharides Galactosyl lactose

Oligosaccharides Raffinose Soya bean oligosaccharides (raffinose + stachyose) Fructo oligosaccharides (FOS) 22 Oligofructose Galacto oligosaccharides [Transgalacto sylated oligosaccharides (TOS)]22

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Table 1: Microorganism involved in Prebiotics & Probiotics BACTERIA Lactobacillus spp. L.acidophillus L.sporogenes L.plantarum L.rhamnosum L.delbrueckii L.fermentum L.lactis L.cellobiosus L.brevis Bifidobacterium spp. B.bifidum B.infantis B.longum B.thermophilum B.animalis YEAST AND MOULDS Aspergillus cerevisiae Aspergillus niger

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28,34

Streptococcus spp. S.lactis S.cremoris S.alivarius S.intermedius

Enterococcus spp E.faecium Leuconostoc spp. Pediococcus spp. Propionibacteriumspp. Bacillus spp. Acanthosis oryzae Saccharomyces boulardii Candida pintolopesii

Table 2: MECHANISM OF ACTION OF PROBIOTICS :30,37 TARGET HEALTH BENEFITS POSTULATED MECHANISM Resistance to enteric pathogens Secretory immune effect Alteration of intestinal conditions (pH, short chain fatty acids, bacteriocins) Up regulation of intestinal mucin production Interfering with pathogen attachment to intestinal epithelial cells Small bowel bacterial infections Influence on activity of overgrown flora Decreasing toxic metabolite production Urogenital infections Adhesion to urinary and vaginal tract cells Colonization resistance Infections caused by Helicobacter Production of inhibitors of H.Pylori (Lactic acid) pylori Promotion of lactose digestion Bacterial lactase hydrolyses lactose Immune system modulation Strengthening of non specific defence against infection . Adjuvant effect in antigen specific immune responses Enhancement of secretary IgA production Hepatic encephalopathy Inhibition of urease producing gut flora Anti -colon cancer effect Mutagen binding Inhibition of carcinogen producing enzymes of colonic microbes Effect on allergic states Prevention of antigen translocation into blood stream Effects on blood lipids, heart Assimilation of cholesterol within bacterial cell disease Increased excretion of bile salts due to deconjugation by bile salt hydrolase Antihypertensive effect Peptidase action on milk protein yields tripeptides which inhibits angiotension converting enzymes Cell wall components act as ACE inhibitors Table 3: Clinical Applications 27,29,31 Clinical applications of probiotics in G.I conditions Diarrheas various origins -antibiotic associated diarrhea - Rota virus diarrhea -Travelers diarrhea -Gastroenteritis -Nosocomial diarrhea -Clostridium difficile diarrhea -HIV/AIDS diarrhea -Enteral feeding associated diarrhea Irritable bowel syndrome Inflammatory bowel disease Reduction of antibiotic

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Table 4 Non gastrointestinal applications of Probiotics 35 Prevention of vaginitis Urogenital infections Enhancement of oral vaccine administration Atopic eczema Cystic fibrosis Dental caries Various cancers Hypercholesterolemia Asthma Juvenile chronic arthritis Aphthous ulcers Halitosis

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Table 5: Various Types of Classified Risk Factors 54 Major risk factor Immunocompromised or debilitated state Premature infant Lacto sucrose

Risks and Adverse Effects Probiotics are generally well tolerated. Most of the clinical studies have found that Probiotics are usually safe and have almost no side effects. The most common side effects are gastrointestinal, flatulence and constipation. There are few reports of bacteremia53 or sepsis occurring in patients. These adverse effects are usually seen in immune-compromised53 or severly debilitated with multiple complications cases. There are few reports of Lactobacillus bacteremia and endocarditis. In all the cases, there were underlying conditions like cancer, diabetes mellitus and recent surgery. There is one report of meningitis caused by bifid bacterium in infant.

Polysaccharides Inulin Resistant starch (starch modifications resistant to host endogenous glycolytic enzymes)26

Safety Proof56 According to the safety point of view Probiotic micro organisms should not be pathogenic, must not have connection with diarrhoeagenic bacteria and no ability to transfer antibiotic resistance genes, as well as be able to maintain genetic stability. Few microbes have been tested in safety and tolerance studies. Tolerance test for species of Lactobacillus rhamnosus, bulgaricas and Bifid bacterium longum have show that these bacteria are tolerated at levels greater than 6g/kg body wt . Lactobacillus rhamosus, Lactobacillus acidophilus, Bifidobacterium lactis were safe at 50 g/kg/d for a mouse. The FDA lists some bacteria in the federal register 21 CFR parts , which includes Lactobacillus acidophilus, Lactobacillus bulgaris, S.thermophilus and lactic acid producing bacteria culture. In Europe, microorganisms with no traditional use in

Marketed Products The effective dose of Probiotics is about 1-3 g/d for infants and 5-15 gm /d for adults. Effective dose differs for different Prebiotics, as Prebiotics are generally mixtures of different chain length carbohydrates. An FAO/WHO working group recommended that the physiological benefit of Probiotic food be substantiated with phase 2, double blind randomized, and placebo controlled trial..Standards for good clinical practices have been described by international committee on harmonosation (ICH). The Yakult Honsha Company is generally credited with introducing the first branded probiotic in Japan well over 70 years ago. The term "probiotic" had not yet been developed, but the "Yakult" lactic acid beverage became the standard for the category. Yakult's probiotic bacteria strain, Lactobacillus casei Shirota, served as the scientific base for the brand. According to a recent Yakult company profile, over 25 million people in 26 countries now consume Yakult every day. Fermented dairy products containing beneficial bacteria have been around for thousands of years. Scientists have investigated that dairy is the preferred delivery vehicle for these probiotic cultures. Instead international marketers are much more progressive when it comes to formulating and marketing probiotic dairy

food production are considered novel food . This regulation theoretically establishes a list of approved Probiotics for novel foods.The international dairy federation (IDF) prepared a list of microorganisms with a documented history of use in food. This list, developed in conjunction with EFFCA, In Canada, according to the Labelling Standard for Intestinal Flora Modifiers for a pharmaceuticalproduct(notforfood) only L.acidophilus .L.rhamnosus ,L.bulgaricus , Lcasie , Lhelveticus , B.bifidum , B.longum and S.thermophilus can be used if claim relating to GI tract restoration is made .

Minor risk factor Cardiac valvular disease (lactobacillus species only) Central venous catheter Impaired intestinal epithelial barrier like intestinal inflammation

products. Packages of new Ocean Spray plus Probiotic Yogurt Drink55 boldly state that beverage contains Lactobacillus acidophilus La -5, Bifidobacterium bifidum BB12 and fruit juice the product is the combination of cranberries with biocultures for a positive balance of friendly bacteria in the digestive system . French firm group Danone recently launched a novel Probiotic in Belgium called Zen. This fermented milk drink contains an extra boast of magnesium with helps in building muscular health. The Japanese are the leaders in the whole health of which the probiotics are an important segment. Japan gave birth to daily dose Probiotic drink Yakult 50 years ago. Since Yakults introduction both the regulated FOSHU market and unregulated market in Japan are growing at a high speed.. Kyodo Milk Industry Co., markets a fermented milk beverage called Lactobaccillus casei & Lactoferrin. Japans Glico Diary products has added value in a different way. The companys new Bifidobacterium containing yogurt includes blueberries which are antioxidant polyphenols. In Europe,Mona GmbH, Austria, markets the Well and Active drink line by the label probiotic milk which is fermented milk and fruit juice. Germanys plus Vertriebs recently added ProBiotischer Drink to its Almsana yougurt brand. In Czech Republic , Valasske Mezirici dairy has rolled out a range of probiotic yoghurt drinks targetted to different age groups. From Wales in U.K , Rachels Organic dairy ltd ., recently launched its product line with a fat free probiotic yoghurt range. Regulatory Requirements 56,57,58 Regulatory approaches to Probiotics and Prebiotics differ amongst different countries worldwide. There is no harmonization of

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standards among European countries. The term `Probiotics remains undefined legally in many countries. Due to these Probiotics and Prebiotics has been diversified into many categories in different parts of the world. U.S food and drug administration (FDA) defined 4 food categories. conventional foods foods for special dietary use medical foods and dietary supplements Probiotics containing foods could be fit into several 4 categories of food described by the FDA. However there is no explicit recognition of any health benefits of Probiotics, Prebiotics or Cultures Added Dairy Foods55 in the United States. Conventional foods containing probiotics bacteria can be sold but the FDA regulates their labeling and marketing strictly. However the level of awareness and acceptance of Probiotics and Prebiotics in Europe is advanced. In Europe the consumers have strong interest in foods claiming health benefits and keen awareness of the relation between diet and health. However a distinction is made between medicinal products and foods for particular nutritional uses (parnut foods). In Europe, the Prebiotics and Probiotics Diary Foods have been key focused as functional food, whereas in the U.S the mineral and vitamin fortification 9 of foods have been the key area of development.Diary products, accounting for 65% of the total European functional foods market are at the forefront of probiotics development . FAO/WHO has defined probiotics as Live microbial organisms which when administered in adequate amounts confer a health benefit on the host. In U.S Probiotics have been regulated under DSHEA(full form) act. In Japan there is no official definition of Probiotics but several Prebiotics and Probiotics have been given status under FOSHU and have been regulated and approved by Japanese health ministry. In 1991 functional foods were given legal status in Japan, where they are described as FOSHU 58, indicating foods for specific health use 2 . A FOSHU is defined as a food expected to have certain health benefits and that has been licensed to bear a label to that effect The regulatory status and claims relating to the health-promoting properties of functional foods were addressed in Europe and the United States in the late 1990s According to Berner and O'Donnell 6, "it is possible to envision functional foods in any of the categories of foods and supplements mentioned above." Interest in functional foods is high in the United States, as reflected by the volume of news reports and conference announcements targeting functional foods and neutraceuticals, which are regarded by many as the current buzzwords in the food industry. In European Union at present there is no regulatory framework for Probiotics, although the novel

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food regulations EU 258/97 could be relevant in some specific cases.EFSA (European food safety authority) in collaboration with SCAN (Scientific Committee on Animal Nutrition)56 has initiated in drafting regulations /guidelines for both human and animal probiotics. Categories which encompass probiotics products including food, novel food natural remedy (Denmark, Sweden and Finland), natural health products, (Canada), dietetic food (Italy), dietary supplement (USA),Biotherapeutic and pharmaceuticals(Probiotic pharm available in Canada, China, Germany, Italy). It is generally agreed in Japan that the market for FOSHU products with gastrointestinal health claims is approaching saturation. Official published data from the Japan Health Food and Nutrition Food Association (JHNFA)58 indicated that 44% of the 583 products approved at that time were focused on gastrointestinal health, primarily probiotics and prebiotics to "help maintain good gastro-intestinal condition. but growth has slowed and their percentage of total FOSHU sales has declined. In an attempt to stimulate sales, interesting new claims are also now being used in approved FOSHU preand probiotic products. These include prebiotic indigestible dextrin dietary fiber to "moderate the absorption of sugar," for example, and fructooligosaccharide to "increase the rate of calcium absorption ... suitable for making strong bones." More recent probiotic claims include Nestle Japan's "LC1" lactic acid bacteria drink claim related to reducing pathogenic bacteria in the gut. There are many non-FOSHU pre- and probiotic products being marketed in Japan with at least implied and/or off-label claims focused on important health issues. These include red cedar pollen allergy, H. pylori bacteria colonization in the stomach, and immune function enhancement. Cancer prevention and suppression is being researched with some encouraging developments, but is necessarily a long-term project. The positive safety and efficacy experience with the probiotic and prebiotic ingredients in Japan is important in helping establish credibility for the new claim developments. MHLW has a stake in allowing such developments to proceed, but is expected to maintain a relatively cautious and conservative approach to new approvals.
1. Salminen S, Bouley C, Boutron-Ruault MC, et al. Functional food science and gastrointestinal physiology and function. Br J Nutr 1998; 80(suppl):S14771. 2. Gibson GR, Roberfroid MB. Dietary modulation of the human colonic microbiota: introducing the concept of prebiotics. J Nutr 1995;125:140112 3. Roberfroid MB, Delzenne N. Dietary fructans. Annu Rev Nutr 1998; 18:11743.[Medline] 4. Roberfroid MB. Prebiotics and synbiotics: concepts and nutritional properties. Br J Nutr 1998;80(suppl):S197202.[Medline]

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