Prebiotic Fibres: An Asian Perspective Professor Bob Rastall Department of Food and Nutritional Sciences The University of Reading What are prebiotics? Professor Bob Rastall Department of Food and Nutritional Sciences The University of Reading Prebiotic definition “A dietary prebiotic is a selectively fermented ingredient that results in specific changes, in the composition and/or activity of the gastrointestinal microbiota, thus conferring benefit(s) upon host health” International Scientific Association for Probiotics and Prebiotics, Nov 2008, London, Ontario IFIS Functional Foods Bulletin 2011; 7, 1–19 Reported prebiotic oligosaccharides Inulin Fructo-oligosaccharides Galacto-oligosaccharides Xylo-oligosaccharides Isomalto-oligosaccharides Lactulose Lactosucrose Group A • • • Good microbiology with state of the art techniques Good human studies Health benefits shown Group B • • • Some good microbiology with state of the art techniques Some or poor human studies Few health benefits shown Group C Soybean oligosaccharides Gentio-oligosaccharides • • • Little or poor microbiology often with questionable techniques No human studies No health benefits shown Group A prebiotics Professor Bob Rastall Department of Food and Nutritional Sciences The University of Reading anti-inflammatory allergy prevention Th2 Th1 impact on obesity? IL-10 IFNg IL-10 Tr TGF-b immunomodulation impact on chronic kidney disease? IL-1b IL-6 suppress IBD inflammation high SCFA scavenging Reduced cancer risk? increased absorption M Cell improved bowel habit faecal bulking reduced gas production prebiotics Bifidobacteria Firmicutes Methanogens reduced procarcinogenic enzymes reduced renal toxin production reduced pH Ca++ Mg++ reduced intestinal infection Butyrate Acetate Propionate selective fermentation defence against pathogens M Cell maintenance of barrier function Zonulin Occludin GLP-2 reduced inflammation ZO1 reduced LPS translocation Leptin GLP-1 PYY immune stimulation increased satiety NK activity phagocytic activity Group A prebiotics: Inulin and oligofructose Professor Bob Rastall Department of Food and Nutritional Sciences The University of Reading Inulin van Loo et al (1995) Crit. Rev. Food Sci. Nutr. 35: 525-552 Plant Edible part Inulin (% fresh wt) Chicory Root 15-20 Jerusalem artichoke Tuber 14-19 Globe artichoke Heart 3-10 Onion Bulb 2-6 Leek Bulb 3-10 Garlic Bulb 9-16 Camas Bulb 12-22 Burdock Root 3.5-4.0 Murnong Root 8-13 Yacon Root 3-19 Salsify Root 4-11 Banana Fruit 0.3-0.7 Rye Cereal 0.5-1.0 Barley Cereal 0.5-1.5 Inulin-derived fructans Inulin [Frub2→1]nFrub2↔1aGlc n = 1 – 50 Inulinase Oligofructose [Frub2→1]nFru [Frub2→1]nFrub2↔1aGlc n = 1-5 Inulin in obese women • • • • 44 obese women (BMI >30) aged 18-65 16g inulin + oligofructose or maltodextrin per day for 3 months Microbiology by qPCR and HITChip Anthropometric measurements, inflammatory status and 1H NMR metabonomics Dewulf et al (2013) Gut 62: 1112-1121 HITChip analysis – phylum level Baseline Placebo 3 Months 3.7% 0.4% 4.2% 34.7% 61.2% Prebiotic 0.6% 58.3% 2.3% 0.2% 67.5% 36.9% Firmicutes Bacteroidetes Actinobacteria Others 3.3% 29.9% 1.9% 37.3% 57.5% Dewulf et al (2013) Gut 62: 1112-1121 HITChip analysis – species level 0.7 8 0.5 6 0.4 4 0.3 0.2 2 Relative contribution (%) Placebo 0.6 0.1 0 0 0.7 8 Prebiotic 0.6 0.5 6 0.4 4 0.3 0.2 2 0.1 0 0 Baseline 3 months Dewulf et al (2013) Gut 62: 1112-1121 9 2 8 7 6 5 4 Baseline 3 mo Baseline 3 mo Change in population Bifidobacterium spp. Log(CPU/g faeces) Bifidogenic response Placebo Prebiotic 1.5 10 Change in population Lactobacillus spp. Log(CPU/g faeces) 0 -1 11 9 8 7 1 Baseline 3 mo Baseline 3 mo 1.0 0.5 0.0 -0.5 Placebo Prebiotic -1.0 Dewulf et al (2013) Gut 62: 1112-1121 Anthropometric measurements Placebo Prebiotic 0.0 Waist/hip ratio Differential values BMI (kg/m2) Differential values 0.0 -0.5 -1.0 -1.5 -1 -2 Prebiotic -0.01 -0.02 -0.03 Placebo Prebiotic 0.04 Fat mass/lean mass ratio Differential values Fat mass (%) Differential values 0 Placebo 0.02 0.00 -0.02 Prebiotic Placebo -0.04 -0.06 Dewulf et al (2013) Gut 62: 1112-1121 Inflammatory status 0.3 0.0 Placebo Prebiotic 0.1 0.0 Prebiotic Placebo Serum LPS (EU/dl) Differential values Plasma CRP (mg/dl) Differential values 0.2 -0.2 -0.4 -0.1 -0.2 -0.6 Dewulf et al (2013) Gut 62: 1112-1121 Sucrose-derived fructans Sucrose Frub1↔1aGlc b-Fructosidase Glc Frub1↔1aGlc Short-chain FOS [Frub2→1]nFrub2↔1aGlc n = 1-3 Group A prebiotics: Galacto-oligosaccharides Professor Bob Rastall Department of Food and Nutritional Sciences The University of Reading Galacto-oligosaccharides Lactose Galb1→4Glc b-Galactosidase Galb1→4Glc Glc GOS Galb1→6Galb1→4Glc Galb1→3Galb1→4Glc Galb1→4Galb1→4Glc Irritable bowel syndrome Log10 cells/g faeces 0.5 Single blinded randomised placebo controlled study 66 D/C/A-IBS patients stratified on 4wk treatment 0.4 0.3 Total Bifidobacteria Bacteroides Clostridia Lactobacilli 0.2 0.1 0 -0.1 -0.2 Placebo 3.6g GOS Significant improvements seen in: • stool consistency • flatulence • bloating • subjective global assessment • composite score of symptoms • anxiety 7.0g GOS Silk et al (2009) Aliment. Pharmacol. Ther. 29: 508-518 Metabolic syndrome Log10 cells/g faeces • 45 overweight adults with ≥3 metabolic syndrome risk factors • 12 week cross over study feeding GOS or placebo 11 10 9 8 * * Baseline GOS Placebo No significant changes in: Atopobium spp Lactobacillus spp Clostridium coccoides/E. rectale E. cylindroides E. hallii Clostridium cluster IX Faecalibacterium prausnitzii beta-proteobacteria Vulevic et al. (2013) J. Nutr. Metabolic syndrome Change from baseline • Changes in C-reactive protein and faecal calprotectin GOS Placebo 15 10 5 0 P<0.0012 -5 -10 P<0.0001 -15 P<0.0001 -20 Wk 6 Wk 12 CRP (mg/l plasma) Wk 6 Wk 12 Calprotectin (mg/g dry weight faeces) Vulevic et al. (2013) J. Nutr. Metabolic syndrome • Changes in plasma triglycerides and cholesterol:HDLcholesterol ratio Change from baseline GOS Placebo 0.6 0.4 0.2 0 -0.2 -0.4 -0.6 -0.8 -1.0 -1.2 †: Difference from placebo P<0.0001 *: Difference between sexes P<0.005 * * *† *† Female Male TG (mM plasma) Female Male Plasma TC/HDL-C Vulevic et al. (2013) J. Nutr. Group B prebiotics Professor Bob Rastall Department of Food and Nutritional Sciences The University of Reading Reduced cancer risk? impact on chronic kidney disease? immune stimulation M Cell reduced procarcinogenic enzyme activities improved bowel habit reduced phenolic toxins faecal bulking prebiotics Acetate Butyrate selective fermentation Propionate reduced pH Ca++ Mg++ increased absorption Group B prebiotics: Xylo-oligosaccharides Professor Bob Rastall Department of Food and Nutritional Sciences The University of Reading Xylo-oligosaccharides Commercial sources • Corn cob xylan – dp 2-3 • Wheat arabinoxylan – dp 2-5 Xylo-oligosaccharides Log10 bacteria/g dry wt • 20 healthy individuals in a randomized, controlled, crossover trial • 10 g arabinoxylans (AXOS) per day for 3 weeks • Faecal bacteriology and physiological parameters 10 9 * * 8 * Before AXOS After AXOS Before placebo After placebo 7 * 6 5 Total Bifidobacterium B. adolescentis Lactobacillus Roseburia Enterobacteria E. rectale group Cloetens et al. (2010) Br. J. Nutr. 103:703-713 Xylo-oligosaccharides • Corn cob XOS (8g/day) • Bifidobacterium animalis subsp. lactis Bi-07 (109 cfu/day) • Synbiotic combination • 41 healthy adults (25-65 yr) for 21 d • Faecal microbiology • Immune function 0.5 0.4 0.3 0.2 0.1 0 -0.1 0.8 0.5 0.3 0 -0.3 Placebo B. lactis Bi-07 XOS 7.5 XOS + B. lactis Bi-07 Placebo B. lactis Bi-07 XOS XOS + B. lactis Bi-07 200 5.0 IgA 95% CI IL-4 95% CI Log B. lactis 95% CI Log Bif164 95% CI Xylo-oligosaccharides 2.5 0 -2.5 0 -200 -400 -5.0 Placebo B. lactis Bi-07 XOS XOS + B. lactis Bi-07 Placebo B. lactis XOS Bi-07 XOS + B. lactis Bi-07 Childs et al. (2014) Br. J. Nutr. doi:10.1017/S0007114513004261 Group B prebiotics: Isomalto-oligosaccharides Professor Bob Rastall Department of Food and Nutritional Sciences The University of Reading Isomalto-oligosaccharides Isomaltose Glca16Glc Panose Glca16Glca14Glc Isomaltotriose Glca16Glca16Glc Isomalto-oligosaccharides 13 constipated volunteers aged 82.5 ± 1.9 years Placebo (4 wk) - 10 g/d IMO (4 wk) - 10 g/d IMO (4 wk) - post (4 wk) Microbiology by FISH but using two qPCR primers as probes 10 Log count/g wet faeces • • • All significantly different from placebo p<0.05 9.5 9 Total Bif164 Laa1* Bac203 LB1* 8.5 8 7.5 Placebo IMO1 IMO2 Post Yen et al (2011) Nutr. 27: 445-450 Isomalto-oligosaccharides Glucose TC mM LDL-C HDL-C TG * significantly different from placebo p<0.05 5 4.5 * 4 * 3.5 Faecal mass (g/wk) 350 300 * 2 * 200 150 2 1 0.5 0.5 0 0 Post Placebo IMO1 IMO2 Defaecations per week * 0 1 IMO2 * 50 1.5 IMO1 * 100 1.5 Placebo * 250 3 2.5 * Wet Dry Placebo IMO1 IMO2 Post Post Yen et al (2011) Nutr. 27: 445-450 Group B prebiotics: Lactulose Professor Bob Rastall Department of Food and Nutritional Sciences The University of Reading Lactulose Lactulose Galb14Frub • Chemically synthesised • Alkali-catalysed isomerisation of lactose Lactulose Log10 per g faeces • 8 healthy adults • 3g lactulose per day for two weeks • Bacteriology by selective media 11 10 9 8 7 6 5 4 * p<0.05 p<0.01 p<0.001 ** * * * * Before 4 days 7 days 14 days Washout Terada et al (1992) Microbial Ecol. Health Dis. 5: 43-50 Lactulose Baseline Placebo Lactulose Log10 cells * 11 10 9 8 7 6 5 4 3 • • • • * * * * * * 12 healthy adults per group 20g lactulose per day for four weeks Glucose+lactose placebo Bacteriology by selective media 70 60 50 40 30 20 10 0 * * * * * * * Phenol Skatol Specific activity 5 50 4 3 2 1 0 * * * * * 40 30 20 * * 10 0 Cresol Indole Ballongue et al (1997) Scand. J. Gastroenterol. Suppl. 222: 41-44 Lactulose • 255 polypectomised adults • 20g lactulose per day for 18 months or no treatment control • Recurrence of adenoma determined % Adenoma free 100 Lactulose 80 60 No treatment 40 20 0 0 200 400 600 800 1000 1200 1400 1600 1800 2000 Time (days) Roncucci et al (1993) Dis. Colon & Rectum. Suppl. 36: 227-234 Lactulose 9.2 p=0.017 9 8.8 8.6 8.4 8.2 8 Before After Urinary p-cresol (mg day-1) Log10 bifidobacteria per g wet weight • 29 healthy adults fed 10g lactulose day-1 for 4 wks • 19 healthy adults fed 10g OF + inulin day-1 for 4 wks • Bacteriology by qPCR 25 p=0.001 20 15 10 5 0 Before After de Preter et al. (2008) Aliment. Pharmacol. Ther. 27: 504-513 Group B prebiotics: Lactosucrose Professor Bob Rastall Department of Food and Nutritional Sciences The University of Reading Lactosucrose Sucrose Frub1↔1aGlc b-Fructosidase Glc Lactose Galb1→4Glc Lactosucrose Galb1→4Glca11bFru Absorption (%) Lactosucrose 60 50 40 30 20 10 0 *p<0.05 * * • 17 healthy young women • 12 g per day • 96 weeks • Mineral balance study Retention (%) 0 -5 * * * -10 -15 -20 -25 -30 Calcium Magnesium Phosphorus Teramoto et al (2006) J. Nutr. Sci. Vitaminol. 52: 337-346 Group C prebiotics Professor Bob Rastall Department of Food and Nutritional Sciences The University of Reading Soybean oligosaccharides Raffinose Gala16Glca12bFru Stachyose Gala16Gala16Glca12bFru Verbascose Gala1 6Gala1 6Gala16Glca12bFru Log10 bacteria/g 11 10.5 10 ** p<0.05 * 9.5 0 hr 5 hr 24 hr 9 8.5 • • 8 Anaerobic faecal batch culture Microbiology by FISH 7.5 7 Total Bif164 Lab158 Bac303 His150 Str493 EC1531 FISH probe Rycroft et al (2001) J. Appl. Mirobiol. 91: 878-887 Gentio-oligosaccharides Gentiobiose Glcb16Glcb Log10 bacteria/g Gentiotriose Glcb16Glcb16Glcb 11.5 11 10.5 10 9.5 9 8.5 8 7.5 7 * * p<0.05 * ** * 0 hr 5 hr 24 hr * • ** • Anaerobic faecal batch culture Microbiology by FISH Total Bif164 Lab158 Bac303 His150 Str493 EC1531 FISH probe Rycroft et al (2001) Lett. Appl. Mirobiol. 32: 156-161 Are bifidobacteria the mechanistic link? Professor Bob Rastall Department of Food and Nutritional Sciences The University of Reading The gut microbiota Oligosaccharides Polysaccharides Mucins Bacteroides Bifidobacterium Lactobacillus CO2 Acetate Clostridium IX Clostridium XIVa E. halli R. hominis H2 Propionate SO4-- Sulfate Reducing Bacteria Lactate Butyrate clostridia peptostreptococci peptococci Succinate Clostridium IV F. prausnitzii Acetogens Proteins & peptides H2S Methanogens Methane p-cresyl sulphate Indoxyl sulphate NH4+ Amines The gut microbiota Oligosaccharides Polysaccharides Mucins Bacteroides Bifidobacterium Lactobacillus CO2 Acetate Clostridium IX Clostridium XIVa E. halli R. hominis H2 Propionate SO4-- Sulfate Reducing Bacteria Lactate Butyrate clostridia peptostreptococci peptococci Succinate Clostridium IV F. prausnitzii Acetogens Proteins & peptides H2S Methanogens Methane p-cresyl sulphate Indoxyl sulphate NH4+ Amines To conclude… • Regulatory authorities do not consider an increase in bifidobacteria a health benefit - need good human studies on Group B & C prebiotics • Need to characterise changes in the microbiome and the metabolome as well as health outcomes • Prebiotics do not act like drugs – they induce changes in a complex ecosystem • There is potential for Group B and C prebiotics given more data Thank you for your attention! 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