Cap   UD-Care (Cranberry + Probiotics) Brand: UD-Care Generic: Cranberry + Probiotics Class: Medical Food Supplement Route of administration: Oral Dosage form: Capsule Dose: 1 capsule daily Contraindications: Pregnancy: Cat. C Pack Size: 10 tabs. Price: Rs. 650/- Supplement facts: Total Probiotic Blend 5 billion Lactobacillus acidophilus 1.5 billion CFU Lactobacillus rhamnosus 1.5 billion CFU Lactobacillus casei 750 million CFU Lactobacillus fermentum 500 million CFU Bifidobacterium longum 750 million CFU Cranberry 36:1 (Vaccinium macrocar-pon) Powdered fruit extract 200 mg 1. Cranberry Juice Cranberry is produced from the berry fruit of a North American evergreen shrub. Cranberry is acidic and can interfere with unwanted bacteria in the urinary tract. Cranberry is also believed to act as a diuretic ("water pill").Cranberry (as juice or in capsules) has been used in alternative medicine as a possibly effective aid in preventing symptoms such as pain or burning with urination. Cranberry will not treat the bacteria that causes a bladder infection [1]. Infection occurs when bacterial adhesins located on its outer cell wall interact with mucosal glycoproteins and epithelial mucins. This mechanism has been recently exploited to target the adhesive process of H. pylori. Compounds such as polysaccharides are found to interact with the bacterial adhesins before adhesinmucin, thus avoiding the infection process [2]. Because adhesion to epithelial cells is the most essential step of the infectious process for almost all bacterial pathogens, many efforts have been aimed at developing antiadhesin therapy. Sialyllactose (NeuAc[K2-3] Gal[L1-4]Glc), an inhibitor of the sialic acid-specific adhesin of H. pylori, was found to reduce the load of bacteria in monkeys. Cranberry juice has also been found to be useful in treating H. pylori infection via inhibition of sialic acid-specific adhesion of H. pylori to human gastric mucus and to human erythrocytes [3]. Similarly, root extracts of Pelargonium sidoides DC (Geraniaceae), which contain a polysaccharide fraction, EPs 7630, with antiadhesive activity against H. pylori, was found to be useful for treating acute respiratory infections [4]. Glycyrrhzia glabra L. root is a rich source of polysaccharides composed of arabinose, galactose, glucose, and glucuronic acid and is able to interact with the outer membrane surface adhesins of H. pylori, avoiding its adhesion to mucus [4]. 2. PROBIOTICS: 2.1. Introduction The term “probiotic” is derived from the Greek and means “for life”; however, it has had several different meaning over the years. The history of probiotics began with the consumption of fermented foods by Greeks and Romans. Probably the first foods that contained living microorganisms were the fermented milks that are recorded in the Old Testament (Genesis 18:8), which reported that “Abraham owed his longevity to the consumption of sour milk.” The consumption of fermented milks in many different forms has continued until the present day. The beneficial effects of yogurt were found scientifically in the early of the twentieth century. Ilya Ilyich Metchnikoff (1908, 1910), a Nobel Prize winner working at the Pasteur Institute in Paris, France, was the first who proposed the beneficial effect of fermented milk on human health and regarded the microflora of the lower gut as having an adverse effect on the health of the human adult. He put forward the theory that the effect of detrimental microbes in the intestinal tract could be alleviated by the ingestion of beneficial microbes. Metchnikoff also postulated that the longevity of the Bulgar mountain people was attributable to the consumption of the yogurt produced by fermentation with Lactobacillus bulgaricus (previously called the Bulgarian bacillus). It should be emphasized that Metchnikoff was not concerned with sour milk but rather what we now call yogurt; subsequently, when pure cultures became available he advocated the use of milk fermented with a single strain of Lactobacillus. So, probiotics and the phenomenon of probiosis were discovered by Metchnikoff. Probiosis can be defined as the positive effect of consumption of fermented dairy products with cultures of lactic acid bacteria (LAB) on the equilibrium of intestinal microflora. It is presently known that viable LAB implantation in the digestive tract act directly on the composition of the microbial population. Metchnikoff’s work can be regarded as the birth of probiotics, that is, microbes ingested with the aim of promoting good health. The habit was given added support by the publication of the book “The Bacillus of Long Life” in 1911, where the author, Loudon Douglas, reiterated the connection between fermented milk and longevity [6]. The term probiotic, as is used today, was first used in 1974 by Parker, who defined probiotics “as substances and organisms that contribute to intestinal microbial balance.” During this period there grew a realization that the gut microflora was involved in protection of the host against disease. These studies reinforced the view that not all bacteria were having adverse effects on the host and that there was a population of bacteria in the gut necessary for the continuing positive health and wellbeing of the host by improving its intestinal microbial balance [7]. This definition was broadened by [8], who included in the definition the following: “a viable mono- or mixed culture of microorganisms that, applied to animal or man, beneficially affects the host by improving the properties of the indigenous microflora.” This implies that the term probiotic is restricted to products that: (i) contain live microorganisms (such as freeze-dried cells or in a fermented product); and (ii) improve the health status of humans or animals and exert their effects in the mouth or gastrointestinal tract (GIT) (aerosol) or in the urogenital tract (by local application). Probiotics are defined in human nutrition as “live microorganisms that can provide benefits to human health when administered in adequate amounts that confer a beneficial health effect on the host” [9]. There is an increasing amount of evidence indicating health benefits by their consumption [10]. Temporary colonizing of the gut with an appropriate probiotic strain not only promotes the state of eubiosis (favorable balance of the gut flora) but also may have a favorable immunomodulatory effect [11]. The probiotic products can contain one or several species of probiotic bacteria; however, there is still a significant way to go before the association of specific probiotic health benefits with specific strains of bacteria. Probiotics are commonly defined as “viable microorganisms (yeast and LAB) that exhibit a beneficial effect on the health of the host when they are ingested, although its health benefits are strain-specific and not species-specific or genus-specific.” Many physiological responses and health-promoting effects in the consumer attributed to probiotic microorganisms are related, among others, to the GIT, and show the ability to survive through the upper GIT and the capability of surviving and growing in the intestine (acid and bile resistant) in a strain-specific manner safe for human consumption. They produce antimicrobial substances like bacteriocins (nisin and pediocin), can adhere to human intestinal cell lines, and colonize the intestine. Probiotics produce short-chain fatty acids (SCFA) that lower the pH, thus favoring the growth of harmless microorganisms, including low-molecular-weight carboxylic acids with six to eight carbon atoms (i.e., acetate, propionate, butyrate). With this acidic pH, probiotics can easily penetrate the bacterial cell. Probiotics are live microorganisms, generally bacteria but also yeast, that interact with the gut microflora and host when ingested in a sufficient amount. They have a positive effect on the health of an individual beyond the nutritional ones commonly known. These bacteria can help to maintain internal microbial balance and defend against harmful bacteria; three mechanisms of promoting human health has been described: (i) providing endproducts of anaerobic fermentation of carbohydrates such as organic acids that can be absorbed by the host, these end-products being able to influence human mood, energy level, and even cognitive abilities; (ii) successfully competing with pathogens; and (iii) stimulating host immune responses by producing specific polysaccharides [12]. Probiotics for consumption should not cause disease in humans, should be completely nonpathogenic, and should not be able to evolve into pathogenic variants. Probiotics are readily available to consumers and are commonly found as food probiotics (e.g., yogurts, cheeses, milk-based beverages, fermented fish, meats, and vegetables, among others) and as food supplement probiotics (e.g., tablets, capsules, pills, powders, liquid concentrates in vials, and soft gels, among others) [13]. Although probiotics can technically be any type of beneficial microorganism, certain bacteria are more commonly found on the food market. Currently, the most widely used food-grade probiotics in the majority of countries include LAB (LAB), from the genera Lactobacillus, and Bifidobacteria, with some strains of Enterococcus and Saccharomyces species being among the exceptions. LAB are Gram-positive anaerobic aero-tolerant nonspore-forming rods and cocci that are indigenous inhabitants of the human GIT, vagina, and human skin. Lactobacillus acidophilus and Bifidobacterium represent two distinct phyla of bacteria, the Firmicutes and Actinobacteria; even though they are genetically quite distinct, they have many phenotypic similarities (e.g., producers of lactic acid that can easily be added to traditionally fermented foods, such as cheeses, yogurts, and other dairy products). For this reason, Bifidobacteria are often included in the LAB, but because the LAB are a taxonomic group of genetically similar bacteria, the Bifidobacteria cannot be included from a taxonomic point of view. Both are inhabitants of GI flora of humans and animals, with the Lactobacilli believed to be important for small intestine functionality and Bifidobacteria for colon functionality [13]. 2.2. Probiotics and their sources The probiotic bacteria generally belong to the Lactobacillus and Bifidobacterium genera. However, other bacteria and some yeast also have probiotic properties. Common bacteria include the following [14]: ● Lactic acid bacteria (LAB): Genus: Lactobacilli spp.; Species: Lactobacillus acidophilus, L. amylovorus, L. brevis, L. bulgaricus, L. casei, L. cellobiosus, L. crispatus, L. curvatus, L. delbrueckii spp. bulgaris, L. fermentum, L. gallinarum, L. helveticus, L. johnsonii, L. lactis, L. paracasei, L. plantarum, L. reuteri, L. rhamnosus; Genus: Streptococcus spp. Species: Streptococcus salivaris spp. thermophiles; Genus: Lactococcus ssp., Species: L. lactis cremoris; Genus: Leuconostoc, Species: Lc. mesenteroides; and Genus: Pediococcus spp., Species: P. pentosaceus, P. acidilactici. Bifidobacteria: Genus: Bifidobacterium spp., Species: B. adolescentis, B. animalis, B. bifidum, B. breve, B. essensis, B. infantis, B. laterosporum, B. thermophilum, B. longum. ● Propionibacteria: Genus: Propionibacterium spp., Species: P. acidipropionici, P. freudenreichii, P. jensenii, P. thoenii. ● Enterobacteria: Genus: Enterococcus spp., Species: E. fecalis, E. faecium. ● Sporulated bacteria: Genus: Bacillus spp., Species: B. alcolophilus, B. cereus, B. clausii, B. coagulans, B. subtilis. ● Other bacteria: Genus: Escherichia coli, Species: E. coli; Genus: Sporolactobacillus spp. Species: S. inulinus. ● Yeasts: Genus: Saccharomyces spp., Species: S. cerevisae (boulardii); that isolated from litchi fruit in Indonesia have also been accepted and used as probiotics. To be considered as probiotics, the different strains should be normal inhabitants of a healthy intestinal tract, survive the upper digestive tract, be capable of surviving and growing in the intestine (acid and bile resistant), be safe for human consumption, produce antimicrobial substances (i.e., bacteriocins), and have the ability of adherence to human intestinal cell lines and colonization. [15] established the criteria for microorganisms to be included in the probiotic group as follows: (i) surviving on passing through the GIT at low pH and on contact with bile; (ii) adhesion to intestinal epithelial cells; (iii) stabilization of the intestinal microflora; (iv) nonpathogenic; (v) survival in foodstuffs and possibility for production of pharmacopeia lyophilized preparations; (vi) fast multiplication, with either permanent or temporary colonization of the GIT; and (vii) generic specificity of probiotics. 2.3. Mechanism of Action of Probiotics The mechanistic approach to probiotics first established than many GIT dysfunctions are based on disturbances or imbalances of intestinal microflora. The productions of inhibitory substances by probiotics such as organic acids, hydrogen peroxide, and bacteriocins are of much interest. However, the mechanisms whereby Lactobacilli function as anti-infective defenses are still not fully understood [13]. The actions of microorganisms are useful to assist the GIT by breaking down sugars and carbohydrates to promote good digestion, boost the immune system, maintain proper intestinal pH, and successfully compete with pathogens. Among the expectations for probiotics, many strains have been shown to modulate the intestinal microflora and to prevent the duration and symptoms of rotavirus-induced diarrhea; probiotic bacteria also reinforce the intestinal wall by crowding out pathogenic microorganisms, therefore helping to prevent their attachment to the human gut, where they have been shown to be safe. The consumption of probiotics has been shown to influence various aspects of the innate nonspecific immune system like promotion of mucin production, inhibition of pathogenic bacteria, decrease in gut permeability, macrophage activation, and phagocytic capacity, and natural killer (NK) cell activity. Regarding the adaptive immune system, the effects observed are an increase in the production of antibodies (IgA, IgM, and IgG), and also an influence in the arrangement of both branches of the immune system by the production of cytokines and other regulatory elements. Hydrogen peroxide is produced by many species of Lactobacillus because antimicrobial agents are oxygen dependent. Because Lactobacillus does not produce catalase, the hydrogen peroxide produced cannot be degraded and acts as an oxidant by forming free radicals. Bacteriocins are proteinaceous antimicrobial substances that are sometimes associated with lipids and carbohydrates. Bacteriocins have demonstrated inhibitory actions in both Gram-positive and Gram-negative bacteria. Probiotics usually modify the resident microflora. It is known that probiotic bacteria alter the physical environment so that the pathogenic bacteria cannot survive. Probiotic bacteria act in two ways. First, they compete with pathogenic bacteria for food and energy sources. Second, they produce an inhibitory substance that impedes the growth of the pathogen by consuming the nutrients that pathogens need. Probiotics and pathogenic bacteria are in competition; probiotics inhibit the pathogens by adhering to the intestinal epithelial surfaces and blocking the adhesion sites [13]. The second generation of probiotics are genetically modified microorganisms that provide the host with some necessary components (e.g., production of immunomodulators, such as interleukines, or Helicobacter pylori and rotavirus antigens) [16]. Probiotics have several putative mechanisms such as modulation of immune or sensory-motor function, enhancement of mucosal barrier function, and antipathogen effects. The epithelial barrier consists of a thick mucus layer containing immunoglobulins, mainly IgA and antimicrobial components; their dynamic functional role is to regulate permeability between cells. Intestinal mucosal barrier function is formed by a common mucosal immune system that provides communication between the different mucosal surfaces of the body. In the future, a greater understanding of probiotic-specific mechanisms could allow for precise selection of a particular probiotic strain to target a patient’s specific pathogen defect and clinical problem [17]. 2.4. PROBIOTICS USED IN FOOD OR AS MEDICINES Most probiotics are marketed as foodstuffs or medicines. Lactobacillus, Leuconostoc, and Pediococcus species have been used extensively in food processing throughout human history, and ingestion of foods containing live bacteria, dead bacteria, and metabolites of these microorganisms has taken place for a long time [18]. Currently, the most widely used probiotics include Lactobacilli, Bifidobacteria, and some nonpathogenic strains, mostly of human origin, that confer health benefits to the host and enable prevention of or improvement in some diseases when administered in adequate amounts. An important fact is that probiotics must retain their viability during the storage, manufacturing process, and transit through the stomach and small intestine. Prior to being categorized as probiotics, organisms need to follow a process of testing, including strain testing, identification by genotype and phenotype, functionalized characterization and safety assessment testing, and double-blind, placebo-controlled human trials to verify their health benefits; the guidelines for the evaluation of probiotics in food have been proposed [9]. Most probiotic foods contain Lactobacilli and/ or Bifidobacteria. Microorganisms used as probiotics in animals are mainly bacterial strains of members of the heterogeneous group of LAB: Lactobacilli (L. acidophilus, L. casei, L. plantarum, L. reuteri, L. rhamnosus, L. salivarus), Bifidobacteria (B. breve, B. longum, B. lactis), Bacillus (B. subtilis), and Enterocococcus (E. faecium), among others. The yeast Saccharomyces boulardi is also used as a human probiotic, although it is delivered in capsules or powders rather than by food. It is noticed that Bacillus and Lactobacillus differ in many characteristics and that the Bacillus and the yeasts are not usual components of the gut microflora. It has been shown that most Lactobacillus species (L. acidophilus, L. rhamnosus, and L. reuteri) have no pathogenicity or acute oral toxicity in animals [13]. The use of probiotics in medical practice is important. The effects and applications of probiotics in various infectious diseases have been summarized by [19], who categorized into four groups the clinical applications for probiotics by level of evidence of efficacy. The first group includes the application to cases of acute/antibiotic-associated gastroenteritis, for which benefits of probiotics are well proven. The second group includes allergic reactions, specifically atopic dermatitis I, for which there is substantial evidence of efficacy. The third group includes applications that have shown promise (e.g., childhood respiratory infections, dental caries, inflammatory bowel disease, combating nasal pathogens, and the prevention of relapsing Clostridium difficile-induced gastroenteritis). The fourth group covers potential future applications for rheumatoid arthritis, irritable bowel syndrome, cancer, alcohol-induced liver disease, diabetes, and graft-versus-host disease. Lactobacillus probiotics as single species or combination probiotic products have been tested for preventing Clostridium difficile–induced gastroenteritis, a common nosocomial and community-based medical condition that has had increased incidence, morbidity, and mortality in past years. Treatment with antibiotics results in disturbance of the GI flora, which is associated with diarrhea and abdominal discomfort in a variable fraction of patients, depending on the age group and the antibiotic used; approximately 15–30% of patients experience recurrence of symptoms after discontinuation of antibiotics. A treatment period with antibiotics only temporarily changes the composition of the microbiota, causing environmental changes. In most cases the cause of the diarrhea is unknown, but a varying proportion of the cases are caused by Clostridium difficile. The C. difficile toxins may cause anything from mild diarrhea, which can be cured simply by terminating the antibiotic treatment, to the life-threatening disease pseudomembranous colitis [20]. Probiotics may also maintain or restore gut microecology during or after antibiotic treatment; Bifidobacteria or Lactobacilli will decrease the duration and/or severity of acute diarrheal disease in infants and children [21]. 2.5. Toxicities: Studies in humans A number of short-term clinical trials on healthy volunteers attest to the safety of current probiotics. In most studies it is only mentioned that the probiotics did not induce more adverse effects than the placebo or that their tolerance was excellent. In some studies, the presence or absence of GIT disorders has been especially studied, which seems rational because the first and probably only contact between bio-products and the host occur in the GIT [22]. In a few studies, biological parameters were analyzed because it was thought that the probiotics might have an influence on them. References: 1. Guay, D. R. P. (2009). Cranberry and urinary tract infections. Drugs, 69(7), 775–807.https://doi.org/10.2165/00003495-200969070-00002 2. Kusters, J.G., van Vliet, A.H., Kuipers, E.J., 2006. Pathogenesis of Helicobacter pylori infection. Clin. Microbiol. Rev. 19 (3), 449–490. 3. Burger, O., Ofek, I., Tabak, M., et al., 2000. A high molecular mass constituent of cranberry juice inhibits helicobacter pylori adhesion to human gastric mucus. FEMS Immunol. Med. Microbiol. 29 (4), 295–301. 4. Wittschier, N., Faller, G., Hensel, A., 2007. An extract of Pelargonium sidoides (Eps 7630) inhibits in situ adhesion of Helicobacter pylori to human stomach. Phytomedicine: Int. J. Phytother. Phytopharmacol. 14 (4), 285–288. 5. Wittschier, N., Faller, G., Hensel, A., 2009. Aqueous extracts and polysaccharides from liquorice roots (Glycyrrhiza glabra L.) inhibit adhesion of Helicobacter pylori to human gastric mucosa. J. Ethnopharmacol. 125 (2), 218–223. 6. Douglas, L., 1911. The Bacillus of Long Life. G.P. Putnam’s Sons,New York, US. 7. Fuller, R., 1992. History and development of probiotics. In: Fuller, R. (Ed.), Probiotics. The Scientific Basis Chapman and Hall, London, pp. 1–8. 8. Havenaar, R., Ten Brink, B., Huis in’t Veld, J.H.J., 1992. Selection of strains for probiotic use. In: Fuller, R. (Ed.), Probiotics. The Scientific Basis Chapman and Hall, London, pp. 209–224. 9. FAO/WHO, 2002. Joint FAO/WHO Group Report on Drafting Guidelines for the Evaluation of Probiotics in Food, London Ontario, Canada, April 30 and May 1, 2002, pp. 1–11. 10. Sullivan, A., Nord, C.E., 2002. Probiotics in human infections. J. Antimicrob. Chemother 50, 625–627. 11. Hamilton-Miller, J.M.T., 2003. The role of probiotics in the treatment and prevention of Helicobacter pylori infection. Int. J. Antimicrob. Agents 22, 360–366. 12. Saier, M.H., Mansour, N.M., 2005. Probiotics and prebiotics in human. J. Mol. Microbiol. Biotechnol. 10, 22–25. 13. Anadón, A., Martínez-Larrañaga, M.R., Arés, I., et al., 2016. Prebiotics and probiotics: an assessment of their safety and health benefits. In: Watson, R.R., Preedy, V.R. (Eds.), Bioactive Foods in Promoting Health: Probiotics and Prebiotics. Elsevier Inc, Academic Press, Oxford, UK, pp. 1–23. 14. Mercenier, A., Pavan, S., Pot, B., 2003. Probiotics as biotherapeutic agents: present knowledge and future prospects. Curr. Pharm. Des. 9, 175–191. 15. Tomasik, P.J., Tomasik, P., 2003. Probiotics and prebiotics. Cereal Chem. 80, 113–117. 16. Mercenier, A., Pavan, S., Pot, B., 2003. Probiotics as biotherapeutic agents: present knowledge and future prospects. Curr. Pharm. Des. 9, 175–191. 17. Ciorba, M.A., 2012. A gastroenterologist’s guide to probiotics. Clin. Gastroenterol. Hepatol. 10, 960–968. 18. Mäyrä-MäKinen, A., Bigret, M., 1993. Industrial use and production of lactic acid bacteria. In: Salminen, S., von Wright, A. (Eds.), Lactic Acid Bacteria Marcel Dekker, Inc., New York, NY, pp. 65–96. 19. Goldin, B.R., Gorbach, S.L., 2008. Clinical indications for probiotics: an overview. Clin. Infect. Dis. 46 (Suppl. 2), S96–S100. 20. Vanderhoof, J.A., Whitney, D.B., Antonson, D.L., et al., 1999. Lactobacillus GG in the prevention of antibiotic-associated diarrhea in children. J. Pediat. 135, 564–568. 21. Oberhelman, R.A., Gilman, R.H., Sheen, P., et al., 1999. A placebocontrolled trial of Lactobacillus GG to prevent diarrhea in undernourished Peruvian children. J. Paediatrics 134, 15–20. 22. Salminen, S., von Wright, A., 1998. Current probiotic-safety assured? Microb. Ecol. Health Dis. 10, 68–77.

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