Earn 3 CPD Probiotics Points online

Probiotics – Evaluating the benefits

Introduction Interest in probiotics has grown over the past two decades, particularly as a result of recent research investigating the role gut microbiota play in the development of chronic diseases.

Clinical update KEY MESSAGES report by • The clinical use of probiotics has benefited from recent quality randomised clinical trials (RCTs). • Cochrane review supports the beneficial effects of specific probiotic strains in the treatment of antibiotic-associated diarrhoea in children and adults. • Prevention of necrotising enterocolitis (NEC) with probiotics in preterm infants is widely accepted, with input from with supportive evidence from South African studies in HIV-exposed premature infants. Prof Leon M.T. Dicks • Probiotics show potential in the prevention of chronic disorders (obesity, metabolic disorders, Professor of Microbiology non-alcoholic fatty liver disease) Department • A South African probiotic developed at the University of Stellenbosch has passed the key hurdles of Stellenbosch University safety and efficacy studies in both in vitro and in vivo systems. Further clinical studies are warranted. Faculty of Health Sciences

Probiotics are defined as ‘live micro- reflected in the fact that many of today’s organisms that beneficially affect the ‘functional foods’ contain probiotics. host by improving microbial balance’.1 In pharmaceutical medicine, probiotics A recent WHO Food and Agricultural are classified as ‘nutraceuticals’ and offer Organisation definition has redefined this a more concentrated form of the probi- to include the need for adequate levels otic or probiotic combination. of probiotics to be administered. This Initial trials of probiotics suffered from definition states that ‘probiotics are live many shortcomings, similar to those of organisms which, when administered in dietary supplements. In the last decade, adequate amounts, confer health benefits however, a large number of scientific to the host.’ studies have addressed the mechanism of Probiotics have been shown to provide action of probiotic strains. Increasingly, beneficial effects by replenishing natural clinical trials are undertaken to support gastrointestinal flora. In African culture, ‘health claims’ and to provide a better fermented milk is regarded as having understanding of which probiotics are health benefits for the gastrointestinal beneficial and to define their evidence- tract. The popularity of probiotics is based use.

This article was made possible by an unrestricted educational grant from Cipla, which had no control over content.

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Major micro-organisms Table 1. Micro-organisms considered to be considered to be probiotics probiotics Lactobacillus Bifidobacterium Lactic acid are the major species species group of bacteria suitable for use as L. acidophilus B. adolescentis probiotics. They are Gram-positive and L. casei B. animalis catalase-negative, and produce lactic L. crispatus B. bifidum acid as the main end product from the L. gallinarum (Mainly B. breve fermentation of carbohydrates. The most used in animals) important genera are Lactobacillus and L. gasseri B. infantis Bifidobacterium, which are used in food B. lactis (Recently reclassified L. johnsonii products and nutraceuticals. as B. animalis subsp. lactis) is also an important lactic acid bacterium, L. paracasei B. longum which is often used in combination with L. plantarum either Lactobacillus or Bifidobacterium. Table 1 provides a list of species used and L. reuteri cited in clinical research.2 L. rhamnosus

Essential probiotic properties “The most Probiotics need to be able to withstand the probiotic can compete even more the harsh gastric environment to reach successfully with pathogenic bacteria) important probiotic the intestine and adhere to the mucosal 4. Bile salt hydrolase activity genera are and epithelial surfaces. In vitro tests are 5. Resistance to certain antibiotics, so used to determine the following desirable that the probiotic is able to restore the Lactobacillus and properties: microbial balance and prevent antibi- Bifidobacterium” 1. Acid and bile tolerance; essential for otic side-effects oral administration 6. Quantity of viable micro-organisms, 2. Adhesion to mucosal and epithelial although not precisely defined, should surfaces to compete with and exclude reach a minimum total of 108 – 109 pathogenic bacteria from the receptor colony forming units (CFUs). Viability 3. Production of antimicrobial activity should also be maintained under nor- against pathogenic bacteria (so that mal storage conditions.

Mechanisms of action Probiotics have various mechanisms of is considerable evidence that probiotics action. These include the production influence the acquired and innate immune of bacteriocins (antibacterial peptides) response by inducing phagocytosis and and short-chain fatty acids, lowering of IgA secretion, modifying helper T-cell gut pH, stimulation of mucosal barrier response and the release of cytokines in a function and immunomodulation. There strain-specific manner.3

Evaluating the benefits of probiotics in the perinatal period and early childhood Maternal probiotic supplements

A recent double-blind randomised clini- Bifidobacterium BL999, also Lactobacillus cal trial (RCT) of probiotic supplementa- GG.5 A recent Cochrane review6 from the tion during pregnancy (two months prior Department of Clinical Epidemiology to delivery) and breastfeeding found the and Biostatistics, McMaster University, Earn 3 CPD points at supplementation safe and effective in Canada, conducted a meta-analysis of 29 www.denovomedica.com reducing the risk of eczema in infants RCTs and supported this outcome, but Click on ‘Accredited of allergic mothers positive for skin- pointed out that the certainty of the evi- 4 CPD modules’. prick tests. The strains used in this trial dence for various probiotic strains is still were Lactobacillus rhamnosus LPR and low.

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“Probiotic Probiotics of Lactobacillus and to transfer into breast milk.7 Ingestion of supplementation Bifidobacterium species were evaluated viable probiotic bacteria (Bifidobacterium to be safe when administered to healthy and Streptococcus thermophiles) in infant reduces the risk of pregnant women in the last trimester of formula over a six-month period has also eczema in infants at pregnancy. As probiotics are rarely sys- been shown to be well-tolerated, safe and 8 high-risk” temically absorbed, they are not expected conducive to adequate growth. Prevention of antibiotic-associated diarrhoea (AAD) in otherwise healthy children A recent Cochrane review of 23 studies to determine the changes in intestinal using a diverse selection of probiotics (bifi- microbiota composition after antibi- dobacteria, lactobacilli, lactococci, strep- otic treatment in early life.10 These types tococci, Clostridium butyricum, Bacillus of studies will become more frequent as species) has shown a protective effect of gene analysis of microbiota is applied to probiotics in preventing AAD with a num- clinical settings and will provide a further ber-needed-to-treat (NNT) of 10.9 The basis for probiotic intervention. report singled out a benefit of Lactobacillus The long-term safety of probiotics rhamnosus / Saccharomyces boulardii and given as nutraceuticals from birth to noted that probiotics should not be used six years of age (Bifidobacterium and in severely debilitated or immune-compro- Lactococcus) has been assessed in terms of mised children. the development of gut microbiota11 and A large study was recently concluded, found not to result in lasting differences but results are not yet available. It aimed to the composition thereof.

Prevention of Clostridium difficile-associated diarrhoea in children (and adults) “Cochrane review A meta-analysis of 23 randomised tri- nausea, fever, flatulence and taste distur- shows protective als suggests that when probiotics are bance) were also reduced by concomitant effect of probiotics administered with antibiotics, they reduce probiotic administration.12 The probiotic the risk of Clostridium difficile-associ- species most used were Lactobacillus, on antibiotic- ated diarrhoea by 64%. The most com- Bifidobacterium, Saccharomyces and a associated diarrhea” mon side-effects (abdominal cramping, combination of these strains.

Prevention of necrotising enterocolitis (NEC) in preterm infants The American Pediatric Surgical Assoc- probiotic therapy consisting of 1 × iation supports the use of prophylactic 109 colony forming units (CFUs) of probiotics in preterm infants weighing Lactobacillus GG and Bifidobacterium less than 2.5 kg to reduce the incidence infantis in HIV-exposed premature infants of NEC, as well as the use of breast milk showed that this combination safely rather than formula where possible.13 reduced the incidence and severity of A South African study using a daily NEC in these infants at risk of HIV.14

Probiotics in adults Irritable bowel syndrome (IBS)

Several trials and meta-analyses have it may be a post-inflammatory and stress- shown that probiotics (particularly lacto- related condition. Probiotics appear to be and bifidobacteria) reduce abdom- a useful option in terms of both efficacy inal pain and symptom severity in IBS.15 and safety, but until the pathophysiology Earn 3 CPD points at IBS is, however, a heterogeneous func- of the condition is clear, evidence of pro- www.denovomedica.com tional disorder, which is still incompletely biotic benefit will remain elusive. Click on ‘Accredited understood, and evidence is growing that CPD modules’.

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Prevention of chronic disorders (obesity, metabolic disorders, non- alcoholic fatty liver disease) As the understanding of the role of the for probiotics emerges as a therapeutic gut microbiota in the development of tool to reduce the prevalence of these seri- chronic diseases unfolds, a potential role ous chronic conditions. South African probiotics (Enterococcus mundtii ST4SA and Lactobacillus plantarum 423) – safety and efficacy data • Adhesion of Enterococcus mundtii • Lactobacillus plantarum 423, isolated ST4SA and Lactobacillus plantarum 423 from sorghum beer, produces a bacte- compared well to that recorded for the riocin, an antibacterial peptide. probiotic Lactobacillus rhamnosus GG.14 • Adhesion of this probiotic com- • Using an in vitro gastrointestinal bination displaced 81% of cells of model (GIM), Enterococcus mundtii Clostridium sporogenes and 91% of ST4SA and Lactobacillus plantarum cells of Enterococcus faecalis, reducing 423 used in combination survived well their bacterial pathogenic action.18 at conditions that mimic those in the • Using rat models, the probiotic combi- 16 “Probiotics can duodenum and ileum. nation showed no signs of perforating • Using an in vivo system (rats) with a epithelial cells.19 be valuable in fluorescent marker to tag the probiotic, • The strain Lactobacillus plantarum 423 reducing symptoms the Enterococcus mundtii ST4SA and exhibited no virulence factors, while Lactobacillus plantarum 423 combination Enterococcus mundtii ST4SA contains of Irritable Bowel was shown to colonise the caecum and a few non-functional genes. Safety has Syndrome” colon, persisting for at least 24 hours.17 been confirmed. References 1. Fuller R. Probiotics in man and animals. Journal of 5: CD006095. (www.thecochranelibrary.com) Applied Bacteriology 1989; 66(5): 365-378. 13. Dounard CD, Renaud E, St Peter SD, et al. Treatment of 2. Kechagia M, Basoulis D, Konstantopoulou S, et al. necrotizing enterocolitis: An American pediatric surgical Health benefits of probiotics: A review. ISRN Nutrition association outcomes and clinical trials committee 2013. doi.org/10.5402/2013/481651. systematic review. J Pediatr Surg 2012; 47(11): 2111- 3. Fong FL, Shah NP, Kirjavainen P, et al. Mechanism of 2122. action of probiotic bacteria on intestinal and systemic 14. Van Niekerk E, Nel DG, Blaauw R, Vusten GF. Probiotics immunities and antigen-presenting cells. Int Rev reduce necrotizing enterocolitis severity in HIV-exposed Immunol 2015; Nov 25: 1-11. premature infants. J Trop Pediatr 2015; 61(3); 155-164. 4. Rautava S, Kainon E, Salminen S. Maternal probiotic 15. Botes M, Loos B, van Reenen CA, Dicks LMT. Adhesion supplementation during pregnancy and breastfeeding of the probiotic strains Enterococcus mundtii ST4SA reduces the risk of eczema in the infant. J Allergy Clin and Lactobacillus plantarum 423 to Caco-2 cells Immunol 2012; 130(6): 1355-1360. under conditions simulating the intestinal tract, and 5. Foolad N, Brezinski EA, Chase EP. Effect of nutrient in the presence of antibiotics and anti-inflammatory supplementation on atopic dermatitis in children. JAMA medicaments. Arch Microbiol 2008: 190: 573-584. doi: Earn Dermatol 2013; 149(3): 350-355. 10.1007/S00203-008-0408-0. 6. Cuello-Garcia CA, Brozek JL, Fiocchi A, et al. Probiotics 16. Botes M, van Reenen CA, Dicks LMT. Evaluation CPD for the prevention of allergy: a systematic review and of Enterococcus mundtii ST4SA and Lactobacillus meta-analysis of randomised controlled trials. J Allergy plantarum 423 as probiotics by using a gastro-intestinal points Clin Immunol 2015; 136(4): 952-961. model with infant milk formulations as substrate. 7. Elias J, Bozzo P, Einarson A. Are probiotics safe for use International Journal of Food Microbiology 2008: 128: online during pregnancy and lactation? Can Fam Physician 362-370. doi:10.1016/j.ijfoodmico.2008.09.016. 2011; 57(3): 299-301. 8. Saavedra JM, Abi-Hanna A, Moore H. Long-term 17. Van Zyl WF, Deane SM, Dicks LMT. Use of the mCherry consumption of infant formulas containing live probiotic Fluorescent Protein to study intestinal colonization bacteria. Am J Clin Nutr 2004; 79(2): 261-267. by Enterococcus mundtii ST4SA and Lactobacillus Visit 9. Goldberg JZ, Lvtvyn L, Steurich J, et al. Probiotics for the plantarum 423 in mice. Appl Environ Microbiol 2015: www.denovomedica.com prevention of pediatric antibiotic-associated diarrhea. 81(17): 5993-6002. doi: 10.1128/AEM.01247-15. Cochrane Database Syst Rev 2015; 12: CD004827. 18. Ramiah K, van Reenen CA, Dicks LMT. Surface-bound Click on 10. Rutten NBMM, Rijkers GT, Vlieger AM. Intestinal proteins of Lactobacillus plantarum 423 that contribute ‘Accredited CPD modules’. microbiota composition after antibiotic treatment in to adhesion of Caco-2 cells and their role in competitive early life: The INCA study. BMC Pediatr 2015; 15: 204. exclusion and displacement of Clostridium sporogenes Log in or register and start 11. Rutten NB, Gorrisen DM, Eck A, et al. Long term and Enterococcus faecalis. Res Microbiol 2008; 159(6): 470-475. earning CPD points today. development of gut microbiota composition in Atopic children: Impact of Probiotics. PLoSOne 2015; 10(9): 19. Ramiah K, ten Doeschate K, Smith R, Dicks LMT. Safety assessment of Lactobacillus plantarum 423 and Certificates will be e0137681. 12. Goldenberg JZ, Ma SS, Saxton JD, et al. Probiotics for the Enterococcus mundtii ST4SA determined in trials with emailed to you. prevention of Clostridium difficile-associated diarrhea in Wistar rats. Probiotics Antimicrob Proteins 2009; 1(1): adults and children. Cochrane Database Syst Rev 2013; 15-23.

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