Dietary Fiber, Prebiotics, & Probiotics

1. Dietary Fiber, Prebiotics, &Probiotics Martin H. Floch,M.D.MACG,AGAF Yale University AGA Fellow’s Nutrition Course - 2007 Aga fello AGA

2. MICROECOLOGY

4. GUT WALL • Hollow Lumen Organ • Epithelial Lining Varies at Each Organ • Mucous Layer Protective and Nurtures Flora • Permits Selective Absorption • Helps Regulate pH • Integrity Affected by Diet and Flora

5. Definitions • Dietary Fiber = Nonstarch polysaccharides of plant foods poorly digested by human enzymes • Prebiotics = Nonstarch polysaccharide or other substance supplements poorly digested by human enzymes that nurture probiotic organisms • Probiotics = human microorganisms fed as supplements that benefit the host

6. Dietary Fiber • By chemical analysis fiber can be broken into soluble and insoluble components (resistant starch identified by other chemical method) • Soluble components are pectic substances, some hemicelluloses, gums and mucilages and are completely fermented by the bacterial flora • Insoluble components are cellulose, some hemicelluloses, waxes, and lignin primarily in plant cell walls as well as resistant starch are only slightly fermented • Wheat is 90% insoluble and 10% soluble Oats are 50% insoluble and 50% soluble Psyllium 10% insoluble and 90% soluble

7. Dietary Fiber Physiologic Properties 1. Slows transit in small bowel 2. Increases stool bulk 3. Holds on to water 4. Forms gels 5. Binds minerals and organic substances 6. Stimulates bacterial growth 7. Metabolized to SCFA

9. SCFA Production in Colon Starch Bacterial Butyric (22) + Acetic (56) Non-starch Enzymes Propionic(61) Polysaccharides

10. DIETARY FIBER INTAKE • Recommended intake 25-35 gm/day • Actual intake 8 - 50 gm/day 1.Cereal content varies but bran is usually cell wall.Examples- Raisen Bran -8gm. Fiber One, and All Bran -12-14gm. 2.Fruits and vegetables vary and portion can contain 2-5gm fiber [apple 2.8,beans 5,berries 5, potatoe 1.8]- fruits tend to be > soluble and vegetable 50/50 sol/insol 3.Meats, fowl, fish, eggs and pure dairy contain 0 fiber

11. Benefits of Dietary Fiber • Large Literature on Benefits. Some Conflicts But General Consensus Is: • Intake of greater than 25 to 35 gm/day associated with: 1. Prevention of Coronary Heart Disease and Hyperlipidemia Control 2.Decrease Stroke in Males 3.Prevention and Treatment of Diabetes 4.Treatment of Dietary Constipation 5.Prevention and Treatment of Diverticular Disease 6.Inverse Relationship with Colon Cancer Development (AGA consensus)

12. Fiber in Cancer Prevention • Numerous epidemiologic studies • Prospective Decosse study in human familial polyposis of the colon showed that subjects on bran supplementation had less polyp formation • Animal studies show that Lactobacilli degrade carcinogens. • Bifidobacteria with and without prebiotics decrease carcinogen activity and tumor development in numerous animal studies.

13. PREBIOTICS Supplements not digested by human enzymes that stimulate growth of beneficial bacteria • Fructo-oligosaccharides • Inulin • Galacto-,galactosyllactose-,xylo-,isomalto-and soya oligosaccharides • Pyrodextrins (glucose oligosaccharides) • Lactulose • Breast milk oligosaccharides

14. Oligosaccharides • Usual pleasant slight sweet taste • Add texture to foods • Naturally occurs in artichoke, onion,garlic, chicory, leek, and to a lesser degree in cereals • Raffinose and stachynose are major CHO of beans and peas • Commercially produced (FOS)

15. Benefits of Oligosaccharides • Promote the growth of bifido-and lactobacilli • Lower colon pH • Discourage growth of Clostridia • Prevent constipation and diarrhea • Have low glycemic index • Water-soluble and of low viscosity • Do not bind minerals

16. Inulin • Naturally occurs in fruits and vegetables • Longer chain length than FOS • Provides a fat mimicking texture when added to food • Now available in a supplement

17. Clinical use of Prebiotic Inulin • Constipation- 40g/d inulin for 19 days increased bifidobacteria and produced soft stools (Kleeson-AJCN,1997) • IBS- two studies- no significant effect • IBD- two Japan reports in open label decreased symptoms. • Controversial lipid lowering effect • Main positive reports are increase in bifidobacteria in infants by use of FOS

18. Bifidobacteria • At least 4g/day of FOS are needed to increase counts • Effect increases with increased doses • Ferment oligosaccharides to SCFA • Produce B vitamins and some amino acids • Restore flora after antibiotics • Inhibit the growth of pathogenic bacteria

19. Hepatic Encephalopathy • Lactulose as a prebiotic alters the enteric flora and successfully reduces encephalopathy • Lactobacillus acidophilus has also been used and associated with a decrease in urease and amino-acid-oxidase activity

20. Prebiotic Substances Available Commercially In USA FOS (Ross), Guar (Novartis) Lactulose (Solvay and Bartek) Inulin (Fibersourse,P & G) In Japan and Europe many of the other oligosaccharides

21. PROBIOTICS Lactobacillus acidophilus Floch,Gastro Clin NA 2005;34:517 : Huebner Gastro Clin NA 2006 :35;355

23. Elie Metchnikoff • 1845-1916 , Nobel Prize Winner • Phagocytosis and Ageing • “Intoxication from the gut flora” • Putrefactive bacteria produced toxic substances absorbed from the gut affecting the nervous and vascular systems causing ageing • His radical solution for autointoxication was removal of the flora by colectomy • Another approach was to replace putrefactive bacteria with carbohydrate fermenting bacteria

25. PROBIOTICS • Live microbial food supplements which beneficially affect the host animal by improving its intestinal microbial balance. • Usually strains of bacteria (lactobacilli or bifidobacteria) or yeasts (Saccharomyces) • Administered in yogurts or capsules • Survive passage thru the gut

26. PROPERTIES of PROBIOTICS • Human origin • Resist upper GI tract secretions • Adhere to human intestinal cells • Colonize the human intestinal tract • Production of antimicrobial substances • Antagonize carcinogenic/ pathogenic flora • Safe in clinical use at > 1010 • Stimulate immune process • Fermentation

27. Probiotics Used in Human Studies • Analysis of 186 published human studies [1980-2004] • 171 controlled, 79 RDBPC (Montrose- JCG ’05) - 173* used single organism - 82* used multiple organisms - 84% reported significant benefit • Most common used single are L.acidophilus,L.reuteri,L.plantarum,L.GG, B.bacterium, B.brevi, E.coli Nistle etc • Most common multiple are combo of L.acidophilus & Bifidobacterium. • VSL#3 has 8 organisms

28. Dose of Probiotic • Varies greatly with product • Live and active cultureYogurts must contain >108[100 million] • L.rhamnosus GG has 10 billion • VSL#3 has 300 to 450 billion per packet • Common OTC have millions

29. DOSE • In Crohn’s Studies • 12 billion organisms of L.rhamnosus GG did not prevent recurrence post-op in placebo controlled study • 300 billion Saccharomyces were effective in decreasing symptoms and preventing relapse in placebo and mesalamine controlled studies • 300 billion of eight organisms in VSL#3 effective in preventive post-op relapse.

30. Clinical Relevance * • Excellent evidence = A recommendation • Studies mixed = B recommendation • Too little information = C recommendation *Floch. JClinGastro 2005;40:275

31. IMMUNOREGULATION (A/B) • Increase IgA production • Increase anti-rotaviral IgA • Production of gamma intereferon, TNF-alph,IL-1 by mononuclear cells incubated with Lactobacillus. • Adherant Lactobacilli and Bifidobacteria significantly increase phagacytosis. • Lactobacillus GG has been used to treat cow milk allergy and atopic eczema

32. Treating Infection Antibiotic AssociatedDiarrhea (A) • Associated with C.difficile which may cause pseudomembraneous colitis • 3.2-29% of hospitalized patient • Freeze dried lactobacillus not successful • Lactobacillus GG successful in eradicating C.difficile • Saccharomyces boulardii in DBC study reduced recurrence from 22% to 9.5% • BMJ “02 of nine studies revealed probiotics may prevent C.difficile diarrhea • Probiotics used in prevention and as adjuvant therapy in AAD.

33. CHILDHOOD DIARRHEA (A) • Metanalysis revealed length of course of childhood diarrhea reduced one day when probiotic added to treatment • Several species of lactobacilli effective • B.bifidum reduces risk of diarrhea when added to acidified milk or formula TRAVELLER’S DIARRHEA (B) • Incidence reduced from 71 to 43% in tourist study with S.boulardii

34. Genitourinary (C) • Recurrent Candida Vaginitis and Bacterial Vaginosis have been successfully treated by administration of both oral and vaginal Lactobacilli - 11 woman had 36 infections compared to 11 woman who were on yogurt who only had 4 infections. • Recent RDBC study in 185 Nigerian woman with vaginosis – L.rhamnosus + L.reuteri + metronidazole more effective than metronidazole alone – 88% to 40%* *Anukum. Mic and Inf. 2006

35. Probiotics in Pouchitis (A) • Reduced counts of lacto-and bifidobacteria -Gut ‘94 • Gionchetti et al - Gastroenteroogy ‘00 -random trial in 40 patients in remission -6gm/day of VSL#3 for 9 mo. -300 billion org/gm of 8 strains -20/20 controls but only 3/20 treated relapse • Oral probiotic therapy prevented relapse

36. Probiotic Use in IBD (C) • Ten controlled studies • 3 in CUC, 4 in Crohn’s, 3 in pouchitis • Varied organisms , varied doses • CUC-E.coli Nissle effective in all three • Crohn’s-Saccharomyces effective in two and VSL#3 in one. L.GG ineffective in one. • Pouchitis-VSL#3 effective in three • Probiotics effective but in varing response

37. Probiotics in IBS(C) • Nobaek et al- AmJClin Gastro’00 – random trial of 60 patients 400ml of 50million L.plantarium org/ml L.plantarium recovered from feces Decrease in flatulence and pain in treated Symptoms difficult to measure but authors feel strongly their results are significant • Six other controlled studies published from 1985-2004. Three positive results and three negative . 190 pts in six studies – no conclusions can be drawn. Larger controlled studies needed.

38. Lactobacillus and Bifidobacterium in IBS: • Symptom response and cytokine profiles –IL10 and IL-12 dysregulated in IBS • L.salivarius,B.infantis,or placebo in malted milk drink for eight weeks • Probiotics recovered from stool • B.infantis improved symptoms and IL-10 increased with IL-12 decreasing in IBS O’Mahoney-Gastroenterology-3/2005

39. Bifidobactor sp. (bifidum, longum, breve,animalis, infantis,adolescentis) Streptoccus thermophilus Saccharomyces boulardii,cerevisiae Enerococcus faecium Lactobaciilli sp. (casei, acidophilus, bulgaricus, gaseri) L.rhamnosus, GG Lactococcus sp. (lactis,cremaris) Probiotic Organisms in USE

40. CLAIMS FOR PROBIOTICS • Increase resistance to infection • Decrease duration of diarrhea disease • Stimulate immunity, modulate cytokine gene expression, stimulate phagocytosis • Beneficial effect on blood pressure,serum cholesterol, diabetes mellitus,lactose digestion and allergy • Regression of tumors and reduction in carcinogens

41. The Future • Continued research to evaluate present known organisms of the flora • Engineered or alter organisms to create desired immune or therapeutic response (Lactococcus lactis secreting ovalbumin induced specific tolerance - Gastroenterol 2007;133:517)

42. Summary • “Microflora of the large intestine complete digestion through fermentation, protect against pathogenic bacteria and stimulate the immune system. Probiotics and prebiotics(and fiber) in the diet can modify the composition and some metabolic activities of the microflora. Many claims for the potential benefits of prebiotics remain unproved, whereas probiotics appear effective in treatment of childhood diarrhea, post-antibiotic diarrhea, and pouchitis. They affect immune modulation and there are varied but encouraging results in vaginosis, IBS and IBD,”