مکانیسم اثرپروبیوتیک ها و پره بیوتیک ها در درمان و پیشگیری از بیماریها مهدیه حسین زاده متخصص تغذیه و رژیم درمانی عضو هیئت علمی و استاد یار دانشگاه علوم پزشکی شهید صدوقی یزد

Prebiotics Non-digestible food ingredients selectively stimulating the growth and/or activity of one or a limited number of bacteria in the colon improve host health FOS (fructooligosaccharides) Inulin GOS (galacto-oligosaccharides)

Prebiotics food sources Prebiotics are natural food ingredients that are available in a variety of food sources. Bananas, garlic, barley, onion, wheat, chicory root.

Potential Benefits of Prebiotics Improve bowel function Increase stool frequency Increase stool weight Increase production of short-chain fatty acids Promote the growth of the health promoting bacteria Lactobacilli and Bifidobacteria Restore gut flora during or after antibiotic therapy Inulin can reduce insulin concentrations and lowered triglyceride levels

Potential Adverse Effects of Prebiotics GI Disturbances: Constipation Abdominal pain Flatulence Bloating

Probiotics Probiotics – WHO  : ‘Live microorganisms which when administered in adequate amounts confer a health benefit on the host’ Probiotics are non-pathogenic and improve the balance of microorganisms in the colon.

Probiotics (Friendly Bacteria) Normalise Intestine ImmunomodulationMetabolic effects Suppression of PPMs Intestinal mucosal integrity Regulation of bowel movement IBS Strengthens immunity Alleviate food allergy symptoms Conrol of IBD Production of vitamins; improves digestion Lactose tolerance Lowers cholesterol (Bile acid deconjugation &Secretion)

Potential Benefits of Probiotics Treatment of diarrhea (specially diarrhea followed by long term A. biotic administration) Restore the normal balance of microbes in the intestines Treatment of gastroenteritis Alleviate some of the symptoms of irritable bowel syndrome such as: Constipation Diarrhea Abdominal pain Flatulence Bloating Improve immune function Decrease Blood Cholesterol level Decrease allergy and eczema incidence in children H. pylori infection treatment

Potential Benefits of Probiotics (Continued) Improve lactose digestion and tolerance Prevent cancer by: Decreasing fecal concentrations of enzymes and secondary bile salts Reducing absorption of harmful mutagens that may cause colon cancer Increases essential ions bioavailability (Ca, Fe, Cu, P, Zn, Mg) Increases sausage movement Antioxidant syntheses Decreases osteoporosis

Characteristics of Probiotics Categorized as normal human Micro-flora Reach to the intestine in alive and active form Resistant to the gut acid and bile salts Compete with pathogen bacteria in attaching to the epithelia Enable to produce bactericides like Lactic Acid, Bacteriocin, and Hydrogen Peroxides, Acetates, propionate, Succinate and butyrate.

1. Infective diarrhea (viral, bacterial) 2. Antibiotic associated diarrhea 3. Lactose intolerance 4. Recurrent aphthous ulcers and stomatitis 6. Inflammatory IBD (Ulcerative colitis, Crohn’s) 7. Irritable bowel syndrome 5. Travelers’ diarrhea 9. Pouchitis 8. Post operative state 10. Diverticular disease of colon

A breakdown in gut barrier function has been linked with numerous diseases Inflammatory bowel disease Chronic kidney disease Sepsis pancreatitis Celiac disease Type 1 diabetes Food allergies Alcoholic liver disease

MOA of Probiotics

Mechanism of Action Inhibit Potentially Pathogenic Microorganisms (PPMs) Reduction in Intestinal pH ( through production of SCFAs) Production of bacteriocins Competitive blocking of adhesion sites Competition for nutrients

IBD – Inflammatory Bowel Disease Symptom : Diarrhoea / Dysentery / fever / Wt.loss normalize the bowel flora and there by reduces the inflammation Probiotics promotes the antigen specific IgA immune response and shortens the diarrheal phase.

1. Infective diarrhea (viral, bacterial) 2. Antibiotic associated diarrhea 3. Lactose intolerance 4. Recurrent aphthous ulcers and stomatitis 6. Inflammatory IBD (Ulcerative colitis, Crohn’s) 7. Irritable bowel syndrome 5. Travelers’ diarrhea 9. Pouchitis 8. Post operative state 10. Diverticular disease of colon

Probiotics: gut immune system stimulation of gut immune system –Up-regulation of mucin gene –Enhance secretory IgA –Maintain normal macrophage function Competition for essential nutrients Production of antimicrobial factors Provide favorable environment of other beneficial bacteria Production of short-chain fatty acids with anti inflammatory properties

Advantages Produce lactic acid- lowers the pH of intestines and inhibiting bacterial villains such as Clostridium, Salmonella, Shigella, E. coli, etc. Decreases the production of a variety of toxic or carcinogenic metabolites. Aid absorption of minerals, especially calcium, due to increased intestinal acidity. Production of β - D- galactosidase enzymes that break down lactose. Produce vitamins (especially Vitamin B and vitamin K ) Act as barriers to prevent harmful bacteria from colonizing the intestines

Colon cancer – Certain probiotics (Lactobacillus bulcaricus) may help prevent colon cancer by preventing the breakdown of enzymes ( β- glucuronidase) that contribute to the growth of cancer causing agents. Lowering cholesterol - a range of LAB able to break down bile in the gut, thus inhibiting its reabsorption (which enters the blood as cholesterol) Blood pressure reduction - Consumption of milk fermented with various strains of LAB may result in modest reductions in blood pressure, due to the ACE inhibition-like peptides produced during fermentation.

Antibiotic associated diarrhea(AAD)- 1. Results from an imbalance in the colonic microbiota 2.Probiotic treatment can reduce the incidence and severity of AAD 3.Efficacy of probiotic AAD prevention is dependent on the probiotic strain(s) used and on the dosage.

Treat allergy – 1.Degradation/structural modification of enteral antigens. 2.Normalization of the properties of aberrant indigenous microbiota and of gut barrier functions. 3.Regulation of the secretion of inflammatory mediators, and promoting development of the immune system. 4.Prevents food allergy by promoting endogenous barrier mechanisms and alleviating intestinal inflammation. 5.Stimulating immune response and reduction of serum IgE levels. 6.Reduction of Th2 cytokine response.

Prebiotic Mechanisms Mechanisms by which prebiotics modulate the immune system; Increases the amount of lactic acid producing bacteria Increases the amount of Short Chain Fatty Acids (SCFAs) Macrophage Activation Induce Natural Killer cells activation

Mechanism No.1 Bifidobacteria and lactobacillus : naturally occurring bacteria found in our intestine Increase absorption of vitamins and minerals Improve digestion Increase protection against harmful microorganisms such as fungi and viruses Prebiotics Inulin and Oligofructose increase the amount of lactic acid producing bacteria

Mechanism No.1 (continued) Immune cells and epithelia cells respond to this shift in the microflora This leads to the signaling of toll-like receptors that activate the secretion of pro-inflammatory cytokines Probiotics Lactic Acid Bac. Flora Composition Proinflamatory Activities

Mechanism No.2 When prebiotics such as Inulin and Oligofructose are supplemented, it increases the number of SCFAs in the gut. Butyrate, for example, if beneficial for the immune system because it: Suppresses lymphocyte proliferation Inhibits cytokine production of certain lymphocytes Induces T-lymphocyte apoptosis Activates G-protein-coupled receptors

Mechanism No.2 (Continued) Probiotics Ligand Concentration Activates G-protein-coupled receptors found on leukocytes Supplies fuel to immune cells

Mechanism No.3 Certain phagocytes (immune cells) in the gut express lectin * type receptor sites These sites mediate cellular cytotoxic reactions against foreign cells * Lectins are sugar-binding proteins which are highly specific for their sugar moieties. They typically play a role in biological recognition phenomena involving cells and proteins. For example, some viruses use lectins to attach themselves to the cells of the host organism during infection.

Mechanism No.3 (Continued) The immune cells in the gut with lectin type receptors can be stimulated by the undigested prebiotic carbohydrates and therefore increase the activity of proinflammatory reactions.

L APC IgA Tumors Th 0 Th 1 B IL-2 ↑ IFN- γ ↑ Th 2 Antibody mediated response Cell mediated response Viruses TGF-β↓ IL-4 ↓ IL-10 ↓ + IL-2 ↑ IFN-γ ↑ TNF-α ↑ IFN-α ↑ Natural killer cells ↑ Macrophages ↑ Cytotoxic T-lymphocytes ↑ L L L Immune Response M Intestinal Epithelium Microorganisms B IgG ↑ IgM ↑ IgE ↓ Non-adhesive Adhesive M = M cells of intestinal epithelium L = Lymphocytes APC = Antigen presenting cells Th = T-helper cells IL = Interleukines TGF = Tumour growth factor IFN = Interferon TNF = Tumour necrosis factor Ig = Immunoglobulin