Probiotics & prebiotics in disease - relevance for clinical practice

Transcription

1 Probiotics & prebiotics in disease - relevance for clinical practice Ian Rowland Department of Food and Nutritional Sciences University of Reading UK i.rowland@reading.ac.uk

2 What is a probiotic? Probiotics are live microorganisms which when administered in adequate amount confer a health benefit on the host (FAO 2001). Usually comprise lactic acid producing bacteria (LAB): Lactobacillus Bifidobacterium But others (Saccharomyces, B coagulans, Closbutyricum, E coli) also used

3 What do probiotics do?

4 Types of evidence In vitro experiments Animal studies Human studies dietary interventions >500 Randomized, blinded, placebo-controlled trials Meta-analyses : In several health areas, there are sufficient studies to combine them into a meta-analysis Provide more compelling evidence for efficacy 4

5 Potential benefits of probiotics on human health Immune function/ Allergies Gut function Urogenital infections Mental function/stress Oral microbiology Dental caries Heart health Skin microbiology Weight management/ Growth of undernourished children Key Good evidence- many human trials Emerging evidence Poor evidence 1-2 trials

6 Specific lysis % Probiotics and immune function Many studies indicate that probiotics can modulate immune status which has implications for: Upper respiratory tract infections (URTI) Vaccination for influenza Allergies, eczema Critically ill patients L caseishirota& NK cell activity Placebo * Probiotic Before After Immunomodulation may also underlie effects of probiotics on gut infections eg rotavirus diarrhoea

7 Probiotics and respiratory tract infections Adults have an average of 2 4 colds a year and primary school children have an average of 3 8 In the USA, 20 million school days are lost per annum

8 Probiotics reduce risk of URTI episodes RR (95% CI) * study in children, ^ study in marathon runners Overall RR = 0.58 ( 42%) Favours probiotic Favours control Identified 27 clinical trials, 10 used for meta-analysis Hao et al 2011 Cochrane Library 9 Additional findings: Reduced use of antibiotics ( 33%); Reduced risk of 3 or more URTI episodes ( 47%) 8

9 Probiotics and respiratory infections Probiotic Lactplantarum HEAL9 Lactparacasei 8700:2 1 x 10 9 /d Target group Healthy adults (272) aged Study design Double blind, randomized placebo controlled, parallel study, 12 weeks Outcome markers Incidence, duration and severity of respiratory infections Berggren et al (2011) Eur J Nutr 50,

10 Probiotics & Colds Berggren et al EJN 2011 Control Probiotic Duration of episode 8.6d 6.2d (P<0.05) Symptom score (NS) 10

11 Probiotics and AD/eczema Prevalence of atopic dermatitis (AD) has risen over the past decades, especially in western societies. Now 10-20%. 7 trials on prevention & 12 trials on treatment No consistent effects Van de Aa et al Boyle et al 2009 But some studies show certain strains are effective 11

12 Probiotics & critically ill patients Systematic review of 23 RPC trials in critically ill patients Probiotics associated with reductions in : Infectious complications RR 0.82 (95%CI ) Ventilator assoc pneumonia RR 0.75 ( ) ICU mortality (trend) RR 0.80 ( ) No effect on length of stay in ICU or hospital Clinical and statistical heterogeneity noted Petrof et al Crit Care Med 40, 3290, (2012) NB Severe acute pancreatitis study showed probiotics associated with increased mortality (bowel ischaemia) (Besselink et al Lancet ; 2008) 12

13 Probiotics in elective surgery Meta-analysis of 13 RPCTs (n=962) with preoperative probiotics and synbiotics in patients undergoing elective general surgical procedures. Incidence of postoperative sepsis was reduced probiotic group OR= 0.42; 95% CI, ; P =.003 synbiotic group OR = 0.25; 95% CI, ; P =.002. No reduction in the incidence of pneumonia, urinary tract infections, or wound infections in the postoperative phase Synbiotics reduced the length of postoperative antibiotic use (P = 0.03). Kinross et aljparenter Enteral Nutr (2):

14 Probiotics and gut health

15 Probiotics and gut health Antibiotic associated diarrhoea (AAD) Clostridium difficile (C diff) Helicobacter pylori Irritable bowel syndrome (IBS) Acute infectious diarrhoea Necrotizing enterocolitis (NEC) Pouchitis Travelers diarrhoea Meta analysis Lactose maldigestion Constipation Colorectal cancer Colic in infants Inflammatory bowel conditions (UC; CD) 15

16 Probiotics reduce incidence of many gut disorders meta-analysis RR (95% CI) AAD C. difficile H. pylori IBS Infdiarrhoea NEC Pouchitis Trav diarrhoea Total 0.43 ( ) 0.59 ( ) 0.66 ( ) 0.77 ( ) 0.35 ( ) 0.39 ( ) 0.17 ( ) 0.92 ( ) Overall RR = 0.58 ( 42%) Favours probiotic Favours control Ritchie &Romanuk Plos1 7,

17 Probiotics and AAD Diarrhoea is common side effect of broad spectrum antibiotics in older people, hospitals & nursing homes, Frequency 10-60%. Clostridium difficile implicated in 15-25% of AAD AAD is one of the most well studied areas for probiotics, >80 studies, 4 meta-analyses, children, adults, elderly, RR = Largest (Hempel et al 2012) : 25/63 studies showed sig reduction in risk: overall 42%

18 Beausoleilet al (2007) Can. J. Gastroenterol.21: 732 Probiotics and AAD Probiotic Lactobacillus acidophilus CL1285 Lactobacillus casei Bio-K + CL1285 Target group Hospitalised older individuals (89) anticipated to be taking three days of antibiotics Study design Outcome markers 50 x 10 9 in a fermented milk drink, half-dose for two days then once daily or placebo, during antibiotic treatment Incidence of diarrhoea, duration in hospital

19 No. patients/ days duration Probiotics and AAD p<0.05 P= % p< % Placebo Probiotic 16% 16% 2.3% AAD CDiff Mean RR=0.34 RR=0.13 hospitalisation Beausoleilet al (2007) Can. J. Gastroenterol.21: 732

20 Irritable Bowel Syndrome - IBS Common gut complaint - around 20% prevalence May be related to imbalances in gut microbiota - aetiology remains unclear Identified by symptoms (bloating, abdominal pain, diarrhoea, constipation). 2 meta-analyses RR= 0.77

21 IBS Meta-analysis Maupas 1983: S. boulardii Gade 1989: Strep. faecalis Halpern 1996: L. acidophilus Nobaek 2000: L. plantarum Niedzielin 2001: L. plantarum Kim 2003: VSL#3 Kajander 2005: Mixture Simren 2006: L. plantarum Whorwell 2006: B. infantis10 6 Whorwell 2006: B. infantis10 8 Whorwell 2006: B. infantis10 10 Enck 2007: E. coli + Strep. faecalis Marteau 2007: Mix Simren 2007: Mix Overall 0.77 (0.62, 0.94) Favours probiotic Favours placebo McFarland & Dublin (2008) World J. Gastroenterol. 14:

22 Probiotics and IBS Probiotic Target group Study design Outcome markers B. bifidum MIMBb75 IBS patients (122) aged with mild to moderate IBS (Rome III) Randomised, double-blind, placebocontrolled. Daily 1 x 10 9, freeze-dried in capsules. Two week run-in, four week feeding, two week washout. Global symptom assessment on 7-point Likert scale Guglielmetti et al. (2011) Aliment. Pharmacol. Ther. 33:

23 Symptom score Probiotics and IBS Global IBS scores (0-6 scale) 2.5 Placebo 2.0 B. bifidum MIMBb Week Guglielmetti et al. (2011) Aliment. Pharmacol. Ther. 33:

24 Symptom score Probiotics and IBS Pain and discomfort Likert 0-6 scale 2.5 Placebo Week B. bifidum MIMBb75 Guglielmetti et al. (2011) Aliment. Pharmacol. Ther. 33:

25 Probiotics and IBS % B. bifidum MIMBb75 Placebo Adequate relief after treatment Week 6 post treatment, week 8 post washout Week 6 Week 8 Guglielmetti et al. (2011) Aliment. Pharmacol. Ther. 33:

26 Agrawalet al (2009) Aliment. Pharmacol. Ther.29: 104 Probiotics & IBS Probiotic Bifidobacteriumanimalis DN Target group Women with IBS-C (34), age >c40 Study design 1 x 10 10, yoghurt twice daily, placebo, 4 weeks Outcome markers Quality of life and digestive discomfort scores, bloating

27 Agrawalet al (2009) Aliment. Pharmacol. Ther.29: 104 Irritable Bowel Syndrome 4 Placebo Probiotic Score 3 * * ** ** 2 Overall IBS Abdominal pain Flatulence Bloating

28 Agrawalet al (2009) Aliment. Pharmacol. Ther.29: 104 Bloating Abdominal inductance plethysmography cm Placebo Probiotic Hours

29 NEC Necrotizing enterocolitis (NEC) associated with increased morbidity and mortality in preterm infants (<1.5kg). Incidence 7-14% Mortality up to 50% Causes: immature gut/immune system, abnormal microflora 29

30 Probiotics and NEC Cochrane review & meta-analysis: 16 eligible studies on LBW infants (n=2842) in hospitals Enteral probiotics supplementation significantly reduced ä Incidence of severe NEC (stage II-III) RR= 0.35 (95% CI: ) ä MortalityRR =0.40 (95%CI: ). ä Effective strains L acidophilus, LGG, B infantis; B infantis+bbifidum+ Strep thermophilus (Alfaleh et al. Cochrane Database Syst Rev Mar 16;(3):CD005496) 30

31 Prebiotics 31

32 What is a prebiotic? A selectively fermented ingredient that allows specific changes, both in the composition and/or activity in the gastrointestinal microbiota thus conferring benefit on host health Gibson GR, Probert HM, Van Loo J, Rastall RA &Roberfroid MB (2004) Dietary modulation of the human colonic microbiota: updating the concept of prebiotics. Nutr Res Rev17,

33 Non-digestible oligosaccharides (NDO) Low molecular weight carbohydrates DP 2 10 Occur in plants (chicory, asparagus, artichoke, onions, garlic, soy) and human breast milk. Synthesized/extracted for supplements Inulin Fructo-oligosaccharides (FOS) Galacto-oligosaccharides (GOS) Lactulose Soybean oligosaccharides Xylo-oligosaccharides (XOS) Isomalto-oligosaccharides (IMO)

34 Claimed health benefits of prebiotics Immune func Infections/al lergy IBS/IBD Diarrhoea (TD; AAD) Colon cancer Modify colon flora Lipid metabolism Laxation Mineral absorption

35 Claimed health benefits of prebiotics Immune func Infections/al lergy IBS/IBD Diarrhoea (TD;AAD) Colon cancer Modify colon flora Lipid metabolism Laxation Mineral absorption

36 Travellers Diarrhoea Cummings et al AlimPharmTher 15, 1139 (2001) 244 subjects given 10g FOS or placebo 2 wk before visiting high risk destination. TD incidence: Placebo 19%, FOS 12% (P=0.08) Drakoularakou et al, Eur J Clin Nutr (2010) 160 volunteers travelling for at least 2 weeks to high or low risk countries TD incidence : Placebo 39%, GOS 25% (P<0.05) TD duration : Placebo 4.6d, GOS 2.4d (P<0.05)

37 Prebiotics & immune function infant formulas

38 Prebiotics and atopic dermatitis in infants RDBPC trial, 206 infants 11+/-9d old Basic formula: hydrolysed cow s milk whey (hypoallergenic) Placebo: 0.8g/100ml maltodextrin Prebiotic: 0.8g/100ml (90% GOS/10% FOS) Atopic dermatitis and infections monitored for 6-24 months Moro et al Arch Dis Child Arslanoglu et al J. Nutr. 138: , 2008.

39 Effect of prebiotic infant formula on atopic dermatitis Infants at risk of atopic disease given prebiotic formula (0.8% GOS/lcFOS 9:1) or control (0.8% maltodextrin) for 6 mo. Follow up at mo. (Moro et al Arch Dis Child ; Arslanoglu et al J. Nutr. 138: , 2008.

40 Effect prebiotic infant formula on infections at 2 years Infants at risk of atopic disease given prebiotic formula (0.8% GOS/lcFOS 9:1) or control (0.8% maltodextrin) for 6 mo. Data shown for follow up at mo. N=68/66 *P<0.05, **P<0.01, *** P< Arslanogluet al J. Nutr. 138: , 2008.

41 Prebiotics & Ca absorption in adolescents 95 m&f adolescents 9-13y; 8g/d Synergy (FOS/inulin) or maltodextrin for 1 y Placebo (n=48) FOS (n=47) Ca absorption % * (stable isotope) BMC g * BMD g/cm ** (whole body) Sig different from placebo *P<0.05; ** P<0.01 Abrams et al AJCN 82, 471 (2005)

42 Pro- pre-biotics and cancer risk - cell proliferation in biopsies 12 wk intervention in resected polyp patients 1. Placebo Maltodextrin (sachet + capsule) 2. Probiotics LGG (10 10 /d), B lactis BB12 (10 10 /d), plus Prebiotic FOS12g/d) * P<0.05 vs 0 wk (Rafter et al AJCN 85:488 ) 42

43 PREBIOTICS & IRRITABLE BOWEL SYNDROME 43

44 Prebiotics and IBS Prebiotic Target group Study design Outcome markers B. bifidum synthesised GOS (Bimuno) IBS (D/C/A) patients (44) aged with mild to moderate IBS (Rome II) Randomised, double-blind, placebocontrolled. 1.4 g/day or 2.75g/day Bimuno or placebo, 12 week treatment. Global symptom assessment on 7-point Likert scale, subjective global assessment, QOL assessment and microbiological evaluation. Silk et al (2009) Aliment. Pharmacol. Ther.29:

45 Improvement from start of study Prebiotics and IBS * B-GOS (1.37g/day) Placebo * * * Flatulence Bloating Likert scale SGA : significantly different from the start *: significantly different from the start and the placebo Silk et al (2009) Aliment. Pharmacol. Ther.29:

46 Prebiotics and the low FODMAP diet Low FODMAP diet aims to reduce fermentable carbohydrates in the diet to regulate gas production Fermentable carbohydrates identified in several groups: Fermentable Oligosaccharides Disaccharides Monosaccharides And Polyols Fructans Galactooligosaccharides Lactose

47 Prebiotics and the low FODMAP diet Intervention Target group Study design Outcome markers FODMAP diet versus control IBS patients (41) aged with mild to moderate IBS (Rome III) Control diet or fermentable carbohydraterestricted diet for 4 weeks Incidence and severity of symptoms Faecal bacteriology Staudacheret al (2012) J. Nutr.142: 1510

48 Proportion of patients (%) Prebiotics and the low FODMAP diet * * Control diet Low FODMAP diet * * Staudacheret al (2012) J. Nutr.142: 1510

49 Conclusions -Probiotics There is a large number of human trials and a lot of sound science to support biological effects and health benefits of probiotics Probiotics are not effective in all areas of health Best evidence comes from studies on immune function and gut health For some health endpoints, meta-analyses indicate that beneficial effects are common to many probiotics, but in some cases effects are species- and even strain- specific.

50 Conclusions - Prebiotics Fewer human studies than probiotics RCTs indicate beneficial effects on Traveller s diarrhoea & AAD recurrence Ca absorption in adolescents Atopic dermatitis & infections in infants IBS (but not consistent with FODMAP) Microbiota modulation Emerging evidence for reduction in cancer risk