BIFILACINTRODUCTION At the beginning of the last century, the Russian immunologist Elie Metchnikoff argued that life-long intake of yoghurt containing lactic acidproducing microorganisms could explain the differences in length of life between ethnic groups. The idea was that the bacteria in the fermented products competed with microorganisms that are injurious to health1. Today it is known that the normal human microflora is important as a barrier against colonization by exogenous pathogenic microorganisms and potentially pathogenic bacteria already present in small numbers in 2 the microflora . The normal microflora influence several biochemical, physiological and immunological features of the host, particularly the gastrointestinal flora, which consists of the most dense and diverse 3. collection of bacteria Disturbances in the normal microflora can be caused by several things, one 4 being the administration of antimicrobial agents . The normal microflora 5 is also disturbed in infectious conditions of the gastrointestinal tract and also when there is inflammation of the gastrointestinal tract (Ulcerative 6-9 colitis, Crohn's disease, Chronic pouchitis) . Probiotic microorganisms are thought to counteract disturbances and 10 thereby reduce the risk of colonization by pathogenic bacteria . Studies on strains of microorganisms used in probiotic dietary supplements have demonstrated that several strains produce antimicrobial substances such as organic acid, bacteriocins and peptide. In vitro and animal studies have further shown inhibitory effects of probiotic bacteria to be mediated by their interference with the adhesion of gastrointestinal pathogens or with toxins produced by the pathogenic microorganisms. Adjuvant-like effects on intestinal and systemic immunity have also been demonstrated for 11 some strains . A number of clinical trials using various probiotic strains in various gastrointestinal conditions are underway. Some of the completed trials have shown promising results in conditions like infectious diarrhoea, antibiotic associated diarrhoea, irritable bowel syndrome, inflammatory bowel disease (ulcerative colitis, and Crohn's disease). Therapy using prebiotics and probiotics as bacteriotherapy seems to be more realistic now and the future in treatment of many gastrointestinal disorders. helping in the digestion process in the intestine. Viruses.THE NORMAL GASTROINTESTINAL FLORA AND INTESTINAL ECOSYSTEM Normal gastrointestinal flora The condition and function of the gastrointestinal tract is essential to our well being. illness. and also during life within the same individual. it is now known that the normal gut flora plays an important role in maintaining good health by stimulating the immune system. aging.1. Interactions of the typical intestinal bacteria may also contribute to stabilization or destabilization of the gut flora.positive Lactobacilli and Bifidobacteria. This largely depends on the maintenance of proper balance of the intestinal ecosystem. causing gastrointestinal disorders. These live bacteria are known as intestinal or gut flora. such as the gram . lifestyle can upset this balance12. pH. Indeed. Around 85 % of the intestinal microflora in a healthy person should be good 12 bacteria and 15% bad bacteria . aiding the digestion and assimilation of food and protecting the host from invading bacteria and viruses. The intestinal ecosystem The gastrointestinal tract of an adult human is estimated to harbor about 100 trillion viable bacteria. The human intestinal microflora contributes largely in maintaining a normal balance of the intestinal ecosystem.100 billion CFU/gm in the large . They also help in the synthesis of beneficial substances for the host like B complex vitamins and vitamin K. The human intestinal microflora is highly important to the host for several reasons. A state of balance within the microbial population within the GI tract can be called “eubiosis” while an imbalance is termed “dysbiosis”. Many factors. For optimum “gut flora balance”. but these normally form only a minor component of the total resident population of microorganisms in healthy individuals.000 CFU/ml in the stomach to 10 . the beneficial bacteria. as well as by protecting against the overgrowth of already present potentially pathogenic organisms. The density of microorganisms in the gut flora increases dramatically from 10 . race. microflora benefits the host by increasing resistance to colonization by potentially pathogenic microorganisms ingested through food and water. fungi and protozoa can also be present. should predominate. The composition of the gastrointestinal flora differs among individuals. Firstly. Another function important to the host is the high metabolic activity of the intestinal flora. socio economic circumstances. infection geographic location. presenting a barrier to invading organisms. stress. medication (especially antibiotics). such as diet or climate. intestine12 and these belong to as many as 400 different species.107 / ml of fluid) Distal small intestine Lactobacilli + Enterococcus faecalis + Coliforms + 8 Bacteroides (10 bacteria / ml of fluid) Colon Bacteroides + Bifidobacteria (10 bacteria / ml of fluid) Table I Composition of the human gastrointestinal microflora13 11 . bifidobacteria. propionibacteria and clostridia. mainly E. lactobacillus. Proximal small intestine Lactobacilli + Enterococcus faecalis (10 5 .. coli. Among aerobic and anaerobic bacteria enterobacteria. The predominant microflora in the GI tract is as follows. and enterococci predominate. and anaerobic bacteria outnumber aerobic bacteria by a factor of 1000:1. Anaerobic flora is dominated by bacteroides spp. Because vaginal flora and intestinal flora 15 are similar.negative organism dominate because of a more alkaline milieu and the absence of the prebiotic modulatory factors present in breast milk. lactoferrin. Instead enterobacteria and gram . volatile fatty acids. Another factor affecting the intestinal flora of the newborn is delivery mode.positive and gram . The infant tends to acquire the flora swallowed from the vaginal fluid at the time of delivery. The initial colonizing bacteria also vary with the food source of the infant. Bifidobacteria are not predominant17. this transfer is completely absent. their flora may differ from maternal flora. cesarean delivered infants less 16 frequently harbor E. as well as production of lactic acid. which reduces the intestinal pH. Bifidobacteria account for more than 90 % of the total intestinal bacteria. A normal vaginal delivery commonly permits transfer of bacteria from the mother to the infant. infants are exposed to microbes that originate from the mother and the surrounding environment including breast milk or formula14. lysozyme. In bottle . They produce antimicrobial compounds (bacteriocins). During cesarean deliveries. especially Bacteroides. and oligosacharides (prebiotics). than vaginally delivered infants. cause an acid milieu and are the main reasons for its bifidogenic characteristics. Mechanisms by which the normal intestinal flora protects the host against 18 intestinal disease 1. the presence of specific anti . and more often klebsiellae and enterobacteria . In breast fed infants. Thus infants delivered by cesarean section are colonized with more anaerobic bacteria. and lactic acid. therefore. organic acids. The low concentration of protein in human milk. These compounds reduce the number of viable pathogenic organisms in the gastrointestinal tract. The establishment of an intestinal microbial ecology is very variable at the beginning but will become a more stable system similar to the adult microflora by the end of the breastfeeding period.infective proteins such as immunoglobulin A. These infants commonly acquire and are colonized with flora from the hospital's environment and. an infant's flora may closely mimic the intestinal flora of the mother .fed infants. . Production of inhibitory substances Bacteria of the normal gut flora produce a variety of substances that are inhibitory to both gram . but beginning with the birth process. Clostridium perfringens is the anaerobic bacterium most frequently isolated after cesarean deliveries. When colonized.negative bacteria.ESTABLISHMENT OF INTESTINAL MICROFLORA IN THE NEW BORN INFANT Fetuses are sterile in the womb. coli. thereby inhibiting the growth and multiplication of potentially pathogenic organisms.2. 4. Competition for nutrients The gut microflora compete directly with gut pathogenic organisms for the essential nutrients necessary for survival and multiplication. 3. However. Blocking of adhesion sites The gut microflora compete directly with gut pathogenic organisms for epithelial attachment sites in the gastrointestinal tract. . Stimulation of immunity The underlying mechanisms of immune stimulation by the gut microflora are not well understood. local gut immunity enhancement by the gut microflora may be one possible mechanism of inhibiting growth of potentially pathogenic microorganisms. thereby preventing attachment and colonization of the GI tract by the potentially pathogenic organisms. Replenishing the depleted gut microflora. b. L. rhamnosus. . 3. bifidobacteria). Improving the properties of the indigenous microflora. A probiotic by general definition is a “Live microbial feed supplement. Offers increased resistance to establishment of infection by potentially Pathogenic organisms in the intestine. Health benefits offered by probiotics are 1. lactic acid bacteria and include 1. beneficially affect the host by improving the properties of the indigenous microflora12. Bifidobacterium species like Bifidobacterium bifidum.g. L. reuteri. Probiotics are generally mono or mixed cultures of live microorganisms which otherwise form the major component of the gut microflora (e. Lactobacillus species like Lactobacillus acidophilus. bulgaricus. L. when ingested. B. L. The desirable properties of a probiotic dietary supplement are19 1. B. which beneficially affects the host by improving the host's intestinal microbial balance”. which may have occurred due to use of antibiotics. though not exclusively. 6. casei. lactobacilli. L. illness. Probiotic bacteria are generally. salivarius. travel or lifestyle changes. Ingestion of probiotics beneficially affects the host by a. infantis. L. and Vitamin K for the host (man) Be nonpathogenic and nontoxic Contain a large number of viable cells Be capable of surviving (should not be killed by gastric juice and bile acids) and metabolizing in the gut Remain viable during storage and use Be antagonistic to pathogens 3. stress.PROBIOTICS What are Probiotics? The word probiotic is derived from the Greek meaning “for life”. 4. Probiotics. Must be of human origin and be able to inhabit the small and large intestine Exert a beneficial effect on the host by helping in proper digestion and assimilation of nutrients and synthesis nutrients like B complex Vitamins. 2. Saccharomyces boulardii (yeast) Streptococcus thermophilus. 7. 4. 5. longum. plantarum. 2. The lactic acid helps in reducing the pH in the intestine and thereby creates an environment.positive. Lactobacilli are Gram . which gives it stability and the ability to withstand high temperature. which cannot be metabolized by the body and so is not preferable as a nutritional supplement. The WHO has recommended use of lactobacillus species that produce L (+) lactic acid. 9. Prevention of colon cancer. IMPORTANT PROBIOTIC SPECIES Lactobacilli and bifidobacteria are Gram . which will inhibit the growth of potentially pathogenic organisms. Decreased duration of diarrhoea (antibiotic associated. aerotolerant or anaerobic. which is not conducible for growth of pathogenic organisms (pathogenic intestinal organisms prefer an alkaline environment for growth and proliferation). travelers'. Regulation of gut motility (constipation. non . 5. They have the capability of transforming into the spore form. 6. 8. . irritable bowel syndrome). Reduction in serum cholesterol concentration. Increased nutritional value (better digestibility. Reduction in allergy. They have complex nutritional requirements. infective). Use in lactose intolerance (promotion of intestinal lactose digestion). They are essentially lactic acid producing bacteria.positive lactic acid producing bacteria that constitute a major part of the normal intestinal microflora in humans and animals. Reduction in carcinogen /co-carcinogen production. Maintenance of mucosal integrity of the intestine. Lactobacillus sporogenes produces biologically active L (+) lactic acid. potentially pathogenic organisms.1. which is completely metabolized leading to glycogen synthesis. It also produces enzymes required in the digestion of various carbohydrates. these spores geminate in the upper small intestine and produce lactic acid thereby creating an environment. gastric acid and bile acid. acidophilic and are found in habitats rich in carbohydrate containing substrates such as the human intestinal mucosal membrane13. Once consumed by the host. Some other strains of lactobacillus like lactobacillus acidophillus produce L (-) lactic acid. They play an important role in resistance to colonization against exogenous. 2. 4. 3. especially in infant nutritional formula.spore forming rods or coccobacilli. Lactobacillus sporogenes is present predominantly in the small intestine and helps in synthesis of B complex vitamins and Vitamin K. increased absorption of vitamins and minerals). and proteins and also aids in their absorption. They predominantly colonize the upper and lower small intestine. fats. 7. S. It is considered a transient yeast in the human intestines. They constitute a major part of the normal intestinal microflora in humans throughout life. B.positive rods with varying appearance. boulardii is described as a probiotic which has the ability to beneficially affect the delicate balance of the intestinal bacteria. Saccharomyces Boulardii belongs to the yeast species. As it travels to the intestines. being found both in infant and adult feces . . There are some reports in medical literature of infections (septicemia) in immnuocompromised patients after treatment with S. which means that it does not set up residence in the mucosal membrane of the intestinal tract like the lactobacillus and bifidobacteria. They are mainly found in the upper and lower small intestine and produce lactase enzyme. which lower the intestinal pH and thereby inhibiting the growth of pathogenic yeast and bacteria. and also has the capacity to prevent or reduce the effects of harmful pathogenic organisms. They predominantly colonize the large intestine. boulardii. This also encourages a good environment for the intestinal resident bacteria (lactobacillus and bifidobacteria).pathogenic and non . It is non .colonizing. Gram . Their number tends to decrease with age. The mechanism of probiotic action is probably by production of acetic and lactic acid. which is helpful in digestion of lactose. this yeast has the ability to aggressively displace species of pathogenic yeast and bacteria and at the same time it does not harm the normal intestinal flora. non . Most strains are strictly anaerobic.spore forming. Streptococcus Thermophilus are lactic acid producing aerobic gram-positive cocci. a sugar found in milk.Bifidobacteria are nonmotile. longum may be considered as the 13 most common species of bifidobacteria. g. This lactic acid bacteria is found in the region from the upper to lower part of small intestine. Clostridium butyricum TO-A are live gram-positive. prebiotics promote the proliferation of bifidobacteria in the colon. bifidobacteria). and be utilized selectively by a restricted group of microorganisms that have been clearly identified to a health promoting properties (e. a variety of oligosaccharides (especially fructo-oligosaccharides or FOS). They proliferate actively through the symbiotic action with B. lactitol. It is a spore forming bacteria and produces an amylolytic enzyme (amylase) and protease to activate proliferation of streptococcus TO-A. They also serve as source of nutrient for intestinal mucosal cells. It is also . and inulin. To be effective. The short chain fatty acids. They proliferate actively through the symbiotic action with streptococcus faecalis T110. in addition. butyricum TO-A to yield lactic acid with inhibition of growth of harmful bacteria. They proliferate actively through the symbiotic action with streptococcus faecalis T-110 to yield short chain fatty acids such as butyric acid and acetic acid with a resultant decrease in intestinal pH and inhibition of growth of harmful bacteria. anaerobic. aerobic. spore forming bacilli. Clostridium butyricum TO-A (butyric acid bacteria) c. Some of them also help in promoting the proliferation of lactobacilli in the small intestine to a certain extent. stimulating the growth and / or activity of beneficial organisms and suppressing potentially deleterious bacteria. and reach the large bowel. lactobacillus. Bacillius mesentericus TO-A are live gram-positive. Bacillius mesentericus TO-A (amylolytic bacteria) Streptococcus faecalis T-110 are live gram-positive.PREBIOTICS What are prebiotics? Prebiotics are range of non-digestible dietary supplements. non-spore forming cocci. spore forming bacilli. aerobic. help to regularize abnormal bowel movements. mesentericus TOA and C. The short chain fatty acids also help in adjustment of water and electrolyte concentration of the intestinal tract. Streptococcus faecalis T-110 (lactic acid bacteria) b. which modify the balance of the intestinal micro flora. These supplements include lactulose. prebiotics should escape digestion in the upper gut. It is found predominantly in the region from the upper small intestine to the colon. In particular. Three live bacteria that act as prebiotic and probiotic agents The three live bacteria that act as pre and probiotic are a. It is found predominantly in the small intestine. To a lesser extent they also facilitate proliferation of lactobacilli in the intestine (prebiotic effect). They can therefore pass unaffected Through the upper GI tract (stomach and duodenum) and . The growth acceleration of bifidobacteria in the intestine by the three live bacteria is through the production of a growth factor by the bacteria bacillus mesentericus TO-A. The three bacteria normalize the intestinal flora. Salmonella Typhi. help in adjustment of water and electrolyte concentration of the intestinal fluid and also serve as a source of nutrient for the intestinal mucosal cells. on the bowel wall. Additionally. Vibrio parahaemolyticus.responsible for production of a nutrient which helps in increasing the count of bifidobacteria. In vitro studies using bacterial cultures have shown that when the three live bacteria are grown together with potentially pathogenic bacteria like entero toxigenic Escherichia coli. the three live bacteria significantly inhibited the growth of the above mentioned potentially pathogenic organisms. Regulation of abnormal bowel movements is done by the action of short chain fatty acids such as butyric acid and acetic acid. Campylobacter. Clostridium perfringers. butyric acid and acetic acid (by Clostridium butyricum TO-A). thereby increasing their count significantly in the intestine. prevent colonization of the gastrointestinal tract by potentially pathogenic organisms and help regulate abnormal bowel movements. acetic acid and butyric acid. produced by Clostridium butyricum TO-A. Important properties of the three live bacteria The three bacteria proliferate actively throughout the intestinal tract through symbiosis. Prevention of colonization of the gastrointestinal tract by potentially pathogenic organisms is by lowering of intestinal pH by production of lactic acid (by Streptococcus faecalis T-110). Intestinal flora is normalized through its prebiotic action that helps in the proliferation of bifidobacteria and lactobacillus. The three live bacteria have been shown to be resistant to the action of gastric juice and intestinal juice including bile. which is defined as the biological association of two or more species to their mutual benefit. produced by Clostridium butyricum. Yersinia enterocolitica. The three activated bacteria strongly inhibit the growth of potentially pathogenic bacteria in the gastrointestinal tract (probiotic effect). The three bacteria facilitate the proliferation of bifidobacterium. produces Glutamine from NH4 + and glutamic acid in the intestine. What is bacteriotherapy? Bacteriotherapy by general definition is using harmless and beneficial bacteria to displace pathogenic organisms. when a preparation contains both prebiotic and probiotic. . So. This is shown by a reversal of ratio of predominant aerobic : anaerobic bacteria to a predominant anaerobic : aerobic bacterial ratio. when taken orally. The increased count of bifidobacteria. it is known as synbiotic. intake of these three live bacteria can lower the counts of the pathogenic bacteria. In cases of intestinal infection with pathogenic bacteria. Glutamine is the fuel for the intestinal cells and helps in maintaining the integrity of the intestinal mucosal barrier. the colonization by potentially pathogenic microorganisms in the intestine is inhibited. In this manner. It is an alternative and promising way of combating infections. It has been shown that these live bacteria help in normalizing the intestinal flora by promoting the growth of beneficial bacteria and preventing the growth of harmful bacteria. generated in the intestine through the action of the three live bacteria. while simultaneously increasing the count of beneficial bacteria. the anaerobic bacteria signify the beneficial resident bacteria in the intestine.colonize in the lower GI tract (upper and small intestine and colon). Here the aerobic bacteria signify the potentially pathogenic organisms whereas. What is synbiotic? Synbiotic is a combination of prebiotic and probiotic. THE RELATIONSHIP BETWEEN PROBIOTIC AND PREBIOTIC BACTERIA AND POTENTIALLY PATHOGENIC MICROORGANISM (PPMS). . 7.BIFILAC (PREBIOTIC + PROBIOTIC) Preparations Bifilac is available as granules (in sachets) and as capsules. Bifilac is therefore safe to use. Diverticular disease of colon. 9. 3. protozoal). as the ingredients of Bifilac confine themselves only to the lumen of the gastrointestinal tract. Adults one to two capsules three times a day or as directed by the physician. Safety The three live bacteria along with Lactobacillus sporogenes in Bifilac colonize in the intestinal tract and do not enter into systemic circulation. Antibiotic associated diarrhoea. 6. Safety of Bifilac in pregnancy and lactation has not been estabilished. As advised by the physician. Bacillus mesentericus TO-A are the three live bacteria which proliferate together by a process of symbiosis in the gastrointestinal tract and act as a prebiotic and probiotic. Travelers' diarrhoea. 8. Duration of treatment Indications 1. Lactobacillus sporogenes is a probiotic. Bifilac must not be administered to infants less than 3 months of age. bacterial. Lactose intolerance. Infective diarrhoea (viral. 4. Crohn's disease) Irritable bowel syndrome. Clostridium butyricum TO-A. Dosage Children one sachet three times a day or as directed by the physician. Recurrent aphthous ulcers and stomatitis Inflammatory bowel disease (ulcerative colitis. Post operative state. . 5. 2. Each sachet / capsule contains Streptococcus faecalis T-110 30 million Clostridium butyricum TO-A 2 million Bacillus mesentericus TO-A 1 million Lactobacillus sporogenes 50 million Streptococcus faecalis T-110. Has predominant action in large intestine. Does not colonize in the intestinal tract. Possible side effects None Danger of Septicemia when used in immunocompromised patients No action.Superiority of Bifilac over other probiotic preparations available Properties 1. Prebiotic + Probiotic 2. Maintenance of intestinal mucosal integrity Intestinal mucosal integrity is strengthened and maintained by production of butyrates and acetates by the three live bacteria and through glutamine produced by bifidobacteria. It is a noncolonizing yeast. Supplements lactobacilli only which predominantly colonize the small intestine. 5. No action. Natural gut flora Lactobacillus Species Probiotic only Saccharomyces boulardii Probiotic only Bifilac Yes Helps in supplementing & in proliferation of predominant natural gut flora organisms like lactobacilli and bifidobacteria. Does not alter normal bowel flora. Helps in proliferation of both lactobacilli (small intestine) and bifidobacteria (large intestine)& thereby provides beneficial effects to the whole gut. . None Helps in supplementing lactobacilli only. Extent of colonization of beneficial bacteria in GI tract. 3. 4. The three live live bacteria have been shown to inhibit the growth of many potentially pathogenic intestinal organisms independently.6. Correction of abnormal bowel movements regulation of bowel movements. No such nutritional benefit to host. Lactobacilli and bifidobacteria benefit the host by producing B complex vitamins and Vitamin K. Nutritional benefit to host Lactobacilli species to a certain extent produce B complex vitamins and Vitamin K. The acetates and butyrates produced by the three live live bacteria help to normalize abnormal bowel movements. 8. Has some action on inhibiting growth of potentially pathogenic intestinal microorganisms. Both lactobacilli and bifidobacteria have been shown to beneficially affect dietary intolerance or malabsorption states by helping better digestion of food and assimilation of nutrients. . help in better digestion of food a nd assimilation of nutrients. No action on abnormal bowel movements. apart from a similar action by the probiotic bacteria namely lactobacillus & bifidobacteria. Action on potentially pathogenic bacteria in intestine. No action on abnormal bowel movements. Dietary intolerance / Malabsorption states Lactobacilli to a No such role certain extent identified. Lactobacillus species has some action on inhibiting growth of potentially pathogenic intestinal microorganisms. 7. 9. Effect of antimicrobial agents on the ecological balance of human microflora.A. Journal of Pediatrics 138. (1994). 487..) pp. H. 635-9.. M. P. Digestive Diseases and Sciences 45. 2. Metchnikoff. 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