Aspirin Resistance 2003 08 13

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1 : Role of Probiotics in Infant Nutrition Dr. Kuntal Biswas MBBS, DPH, DNB (P), PhD, FCCP, FCAM, FMCESA Medical Registrar Medical College & Hospitals, Kolkata. Symbiotic relationship That began and stayed Stable millions of years
2 : Some basic facts about the microbiota 2. Björkstén B, et al 2001. Journal of Allergy and Clinical Immunology, Volume 108, Issue 4, Pages 516-520. 1. Beaugerie L et al 2004. Best Pr & Res Clinical Gastroenterology, Volume 18, Issue 2, Pages 337-352. 3. Ann M O'Hara, The gut flora as a forgotten organ. EMBO reports 7, 688 - 693 (01 Jul 2006) 2
3 : Immune Boost 80% of the body’s immune cells are located in the gastrointestinal tract Having the right bacterial balance is important for optimizing the immune system Increased levels of IgA and phagocytes (immune cells and cells which can engulf and destroy harmful components), the better the immune system fights unwanted components Probiotics are proven to be able to strengthen natural defenses and stimulate the immune system Immune health is the second largest indication area within probiotics after intestinal health Target group: Those who are under consistently high levels of stress and/or those who have a weak or compromised immune system. 3
4 : Importance of Intestinal Microbiota Nutritional benefits to host like vitamin synthesis and break down of complex polysaccharides Plays important role in generation of Immuno -physiological regulation in gut Provides crucial signals in for development of immune system in infancy Formation & maintenance of Gut associated immunologic homeostasis in later life Forms natural defence barrier against harmful microbes in environment 4
5 : Development of microbiota Gut of normal fetus is sterile Neonates exposed to diverse microbial populations; not all colonize gut Specific microbes become established in particular host during different phases of development – microbial succession 5
6 : Development of Micro flora in Neonates Fetal gut sterile Experimental evidence: Bacterial infection of amniotic fluid through placenta Colonization of microbes occurs at birth Birth canal Gut (feces) Skin Birth attendants Breast milk Pediatrics 2006, JPGN 2004 6
7 : Infant microbiota Breast fed infants: bifidobacteria (infantis, longum & brave) forms 60-90% & lactic acid bacilli <1%. Small part by clostridia, bacteroides, enterobacteria & enterococci. ELBW babies: bifidobacteria & lactobacilli are almost absent. Predominant species are Enterococcus fecalis, E.coli, Enterobacter cloacae, Kleb.pneumoniae, Staph.epidermidis & Staph hominis Intestinal microbiota forms basis for Probiotic action 7
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9 : “This one time, answering the parent …” Mom: “Dr.! My baby won’t stop pooping, and its really runny!” “What do I do?” Resident: “That’s too bad, unfortunately your baby probably has a viral gastro and it will just take time for the illness to run its course.” Mom: “But Dr. its everywhere!” “Do you have kids, do you know what I’m going through right now?” Resident: “No, but I have a dog ” Mom: “Well that’s great…has you’re dog ever had diarrhea?” Resident: “No.” Mom: “Well, this is awful and I can’t take it anymore…I can’t keep him in diapers! You have to help me!” Resident: “I wish I could offer you more but just make sure that your baby stays well hydrated and come see me in clinic if if doesn’t get any better… have a good day!” 9
10 : Acute Diarrhea Diarrhea - WHO defines as passage of loose or watery stools; 3 or more per day. Among children in the U.S., diarrhea accounts for more than 1.5 million outpatient visits, 200,000 hospitalizations, and ~300 deaths per year. 10
11 : Current findings Rehydration therapy is the most important intervention for acute diarrhoea. Probiotics produce clear benefits by shortening the duration of the diarrhoea episode and reducing stool frequency. Probiotics appear to be safe. 11 11
12 : Probiotics: definition World Health Organization: “live microorganisms which when administered in adequate amounts confer a health benefit on the host” They: Survive stomach acid and bile Establish residence in the intestines Impart health benefits 12
13 : Probiotic examples Lactobacillus sp. reuteri casei ramnosus Acidophilus Streptococcus sp. Bifidobacterium sp. Infantis (breastmilk) lactis longum breve bifidum Sacharomyces boulardii Enterococcus sp Mixtures Formulations: drops, chewable tablets, lozenges, capsules, straws, bottle caps, sticks 13
14 : Increasing number of dietary supplement Probiotic product launches in 2007 (driven by Europe) 14
15 : Probiotics (functional food) First identified by Russian scientist Metchnikoff Non-digestible food ingredients that stimulate the growth and/or activity of probiotics Typically oligosaccharides: galacto oligosaccharides (GOS), fructo -OS (FOS), xylo -OS (XOS), Inulin Found in: Breast milk, Jerusalem artichoke, chicory root, raw dandelion greens, leeks, onions, garlic, asparagus, whole grains, beans, banana Adding Prebiotics to Probiotics increases production of gut Short-Chain Fatty Acids (SCFA) 15
16 : Probiotics- normal source Colonization at birth with maternal species Specific organisms vary by age in first year Become established by 1 year Diet – maternal milk, fermented milk, pickles, fermented soy (tempeh), etc. “Successful” probiotic treatment leads to temporary colonization 16
17 : Manage lactose intolerance (L acidophilus) Antibiotic-associated diarrhea and infectious diarrhea Decrease constipation Decrease risk of NEC and all cause mortality in premature infants Decrease dental caries Treatment of H pylori infections, UTI Decrease colic Decrease risk of developing eczema Decrease upper respiratory tract infections Primary Pediatric Uses of Probiotics 17
18 : Long term benefits of neonatal Probiotic treatment Reduction in atopic eczema by L.rhamnosus GG supplement antenatally to mothers and for first few months to infants Gut 2002, Lancet 2003 Reduced incidence and severity of Inflammatory Bowel Diseases JPGN..2000 18
19 : Antibiotic-associated Diarrhea Systematic review of 9 placebo-controlled studies (2 in children) using various products: 60% reduction in incidence and duration of antibiotic associated diarrhea compared with placebo (P<0.01) 2002 9/10 pediatric trials (different products) favored probiotics (RR 0.49; 95% CI 0.32 to 0.74). None of the 5 trials monitoring adverse events (n = 647) reported a serious adverse event. Johnston BC. Cochrane Database Syst Rev, 2007 D’Souza et al. BMJ, 2002 Recommend 2-4 weeks of probiotics for all kids who receive an antibiotic prescription. 19
20 : Chemotherapy-associated diarrhea Benefits for pediatric oncology patients with diarrhea (incl C diff). Benchimol EI. J Pediatric Hematology/Oncology, 2004 Breast cancer and colorectal cancer patients receiving chemotherapy had markedly less diarrhea with probiotics El- Atti S.Journal of Parenteral & Enteral Nutrition, 2009; Osterlund P. Br J Cancer, 2007 Radiation induced diarrhea attenuated with probiotics. Delia P.Tumori, 2007; Fuccio L. J Clin Gastroenterol, 2009; Giralt J. Intl J Rad Onc Bio Physics, 2008 20
21 : Mechanism of action Probiotics compete directly or hinder adhesion of pathogens on stereo-specific receptors on GI surface Influence development of intestinal microbiota in infants Modulate intestinal & systemic immune responses 21
22 : Immunological effects of Probiotics Counteract inflammatory response by stabilizing gut microbial environment Stabilize intestinal permeability barrier Enhance degradation of enteral antigens & alter their immunogenicity Improve intestinal immunological barrier, particularly IgA responses Balance between Pro- & Anti-inflammatory cytokine Contribute to TH cell population that maintains a disease free state of gut 22
23 : Probiotics: proposed mechanisms Adherence and subsequent 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 for growth of other beneficial bacteria Production of short-chain fatty acids with anti-inflammatory properties 23
24 : Probiotics – Mechanisms of Action Probiotic strain 24
25 : Probiotic & atopy LGG treatment of pregnant women failed to influence fetal antigen specific immune responses Modulation of fetal immune response by probiotics may not prevent eczema Composition of intestinal micro flora is different in those with atopic eczema Reduced bifidobacteria Increased clostridia 25
26 : Probiotics & NEC Meta-analysis of 9 trials randomizing 1,425 premature infants (<37 weeks or < 2500 gms) to prophylactic probiotics, vs. placebo or TAU; probiotics significantly reduced severe NEC by RR 0.32 and mortality by 0.43 (P<0.05); no impact on nosocomial sepsis or length of TPN. Safety: no observed cases of systemic infection with the probiotic agents. More research needed in ELBW infants. Alfaleh K. Neonatology, 2010 26
27 : Oral Probiotics Prevent NEC in VLBW Preterm Infants The incidence of death or NEC and NEC alone was significantly lower in the study group compared to control Pediatrics. 2008 Oct;122(4):693-700. 27
28 : Probiotics Prevents Sepsis and NEC in Preterm Neonates Prophylaxis with combination of lactoferrin and Lactobacillus rhamnosus showed statistically significant reduction in NEC A reduction in late-onset sepsis was observed In the groups that received lactoferrin alone (RR 0.34, 95% CI 0.17, 0.70) Or in combination with Lactobacillus rhamnosus GG (RR 0.27, 95% CI 0.12) Cochrane Database Syst Rev. 2010 May 12;(5):CD007137 28
29 : Probiotics Supplementation Helps Reduce UTI and NEC Results of a double-blind study showed that preterm infants supplemented with Lactobacillus GG had reduced UTIs and NEC when compared to the control group Biol Neonate. 2002 Aug;82(2):103-8 29
30 : Benefit of Probiotics in Preterm Infants Meta-analysis of probiotics for preventing NEC in preterm neonates confirm significant benefits of probiotic supplements in reducing death and disease in preterm neonates Feeding preterm infants with a formula supplemented with probiotics (or prebiotics) may stimulate gastric emptying and improve maturation of the cutaneous electrogastrography activity mimicking the effect of breast milk Pediatrics. 2010 May;125(5):921-30. J Physiol Pharmacol. 2009 Dec;60 :27-31. J Perinatol. 2009;29 :S2-6. 30
31 : Probiotic Supplementation Increases Body Weight in Preterm Infants In antibiotic-treated infants, probiotic supplementation resulted in a higher body weight compared with placebo (p < 0.001) Fecal IgA was higher in probiotic group compared with the placebo group (p = 0.021) Pediatric Res. 2008 Oct;64(4):418-22. 31
32 : Lack of Probiotics Supplementation on Preterm Infants In a randomized, double-blind, placebo-controlled trial oral supplementation of probiotics (Bifidobacterium longum and Lactobacillus rhamnosus GG) was given to 45 VLBW preterm infants and placebo to 49 infants The primary endpoint was not significantly different between the probiotic (57.8%) and placebo (57.1%) groups (P = 0.95) However, in infants who weighed >1000 g, probiotic supplementation was associated with a shortening in the time to reach full enteral feeding (P = 0.04) Am J Clin Nutr. 2009 Jun;89(6):1828-35 32
33 : Probiotics: colic RCT of L reuteri vs. simethicone for 28 days in 83 breast-fed infants Daily median crying time Day 7 P:159 minutes vs S: 177 minutes Day 28 P: 51 minutes vs S: 145 minutes (P<0.01) Percent responders by 28 days: 95% of Probiotic vs. 7% of simethicone (P<0.01) No adverse effects reported Savino F. Pediatrics, 2007 33
34 : Which organism to use? S boulardii, Lactobacillus, and E faecium have prevented antibiotic-associated diarrhea L GG and L reuterii reduced infectious diarrhea L GG for eczema L reuteri for colic Lactobacillus rhamnosus GG, reuterii- best studied to date Combination products not well studied, but may work as well Typical effective “dose”: 10 billion organisms/d Most require refrigeration Can give in cool food/drink Probiotics: prescribing 34
35 : Case reports of bacteremia, fungemia, endocarditis, meningitis in immunocompromised children on ventilators 2% bloating, gas, diarrhea Increased allergic sensitization? Food is safer than pills! 35 Probiotic safety
36 : “The Shelf-Life Equation” =25OC =0.15 aw =5% Shelf life × = × Water Activity Temperature Oxygen 24 months = x x Rule-of-thumb recommendation: 36
37 : Conclusion Preterm infants have abnormal pattern of bowel colonization and as a result bowel becomes reservoir for antibiotic resistant bacteria Which may contribute to the pathogenesis of neonatal NEC-leading causes of morbidity and mortality in preterm infants Supplementation with probiotics can help achieve desirable flora Probiotics is an effective upcoming weapon for preterms in the germ warfare fought in the NICUs. 37
38 : Conclusion Clinical studies have shown benefits of probiotics in preterm infants with respect to Increased weight Increased Immunoglobulins Prevention of urinary tract infections and bacterial sepsis Decreased NEC However some studies also lacked to show benefit of probiotics supplementation There is need for studies in developing countries 38
39 : Take home points… Good evidence for: Infectious diarrhea, tx Antibx -assoc diarrhea NEC; premature mortality Promising evidence for: Preventiong atopic conditions Constipation In the future we may be using probiotics as we use antibiotics today: with specific strains used for certain clinical situations guided by controlled studies Prescribing Lactobacillus GG best studied to date Combination products not well studied, but may work as well 10 billion organisms/d Keep refrigerated (except Culturelle and BioGaia) Give in cool food/drink 2% risk bloating/gas 39
40 : Start with something so simple as not to seem worth stating & End with something so paradoxical that no one will believe it. Bertrand Russell1872-1970 THANK YOU Together we improve the quality of food and health for people all over the world 40


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