PREBIOTICS & PROBIOTICS

Probiotic -- The concept

The concept of probiotics is a century old Elie Metchnikoff (Pasteur Institute): first to demonstrate that Lactic acid bacillus conferred health benefits and promoted longevity. In 1917, Alfred Nissle isolated non pathogenic Ecoli in the stool of a first world war soldier who did not develop enterocolitis during a shigella outbreak.

Probiotic The concept

Henry Tissier (Pasteur institute) isolated bifido bacter in a breast fed neonate and also demonstrated that bifido bacter would displace proteolytic bacteria that caused diarrhea and recommended its administration for persons with diarrhea. The term probiotic was first introduced by Lilly and Stilwell in 1965 In 1989, Roy Fuller demonstrated that Probiotics should be viable to produce benefit in host.

What is Prebiotic?
Nondigestible substances that provide a beneficial physiological effect for the host by selectively stimulating the favorable growth or activity of a limited number of indigenous beneficial bacteria Commonly known prebiotics are Oligofructose Inulin Galactooligosaccharides Lactulose, Breast milk oligosaccharides (3-6 gm/dl). The prebiotic oligofructose is found naturally in many foods eg wheat, onions, bananas, honey, garlic and chicory roots

What is a Probiotic
An oral supplement or a food product that contains a sufficient number of viable microorganisms which, when administered orally, alter the micro flora of the host and confer a health benefit on the host Most common forms of probiotics are Dairy products , eg yoghurt Probiotic fortified foods Capsules/sachets containing freeze dried bacteria
The most studied probiotic bacteria to date are Lactobacillus rhamnosus GG(LGG), Bifidobacterium lactis, Streptococcus thermophilus

Symbiotic
A combination of prebiotic & probiotic

Functional food
Any modified food , that provides a health benefit beyond that ascribed to any of the specific nutrients it contains Eg : Live culture yoghurt, breast milk

Development of intestinal mucosal defense system

Infants gut is sterile but bacterial colonization occurs rapidly on starting enteral feeds

The ingested human milk containing bacterial components derived from mother are thought to influence the infants developing immune system (bacterial imprinting)
Beyond infancy, composition of fecal flora is less variable & not dependent on diet Human intestine contains more than100,000 billion bacteria Belong to > 100 different species Mainly in the colon Different people have different organisms Exhibhit a symbiotic relationship

contd

Intestine is the body's most important immune function related organ Approximately 60% of body's immune cells are present in intestinal mucosa and is called gut associated lymphoid tissue (GALT) Maturation and development of GALT depends on the development & composition of indigenous micro flora & vice versa This immune system controls immune response against dietary proteins & pathogenic microorganisms Interference with or dysregulation of this early development is thought to cause chronic diseases like atopy & autoimmune diseases

Immunologic benefits of probiotics

Activate local macrophages to increase antigen presentation to B lymphocytes and increase secretary immunoglobulin A

Modulate cytokine profiles Induce hypo responsiveness to food antigens

Nonimmunologic benefits of probiotics

Digest food and compete for nutrients with pathogens Alter local pH to create unfavorable local environment for pathogens

Produce bactericidal substances like lactic & butyric acids & bacteriocins to inhibit pathogens
Scavenge super oxide radicals Stimulate epithelial mucin production Enhance mucosal barrier function Compete for adhesion with pathogens Modify pathogen derived toxins

Release of gut protective metabolites like arginine, glutamine and SCFA

Potential benefits of prebiotics

Sources of energy for the micro flora Resistant to digestive enzymes of the gut but fermentable by colonic micro flora and bifidogenic bacteria Production of SCFA Increase calcium absorption Increase fecal weight Shorten GI transit time Possibly lowers blood lipid levels Bacteriostatic activity by blocking receptors on T cells open for interaction with pathogens Enhance host immunity(IgA production, Cytokine modulation etc)

Safety concerns

The committee on Nutrition of the European Society of Pediatric Gastroenterology, Hepatology & Nutrition states that more studies are required to establish safety & efficacy. To date these products seem to be safe for healthy infants & children

Serious infections including sepsis & meningitis, endocarditis has been reported in neonates, infants, children & adults. Patients at risk are
- Immunocompromised - Preterm neonates - Children with indwelling catheters/medical devices

Safety concerns
Other possible adverse effects are Transfer of antibiotic resistance Lactic acidosis due to D lactate production as a metabolic by product Contamination Flatulence, bloating abdominal pain

Probiotics & Prebiotics in infant formula

Addition of probiotics to infant formula has not been demonstrated to be harmful in healthy term infant, but lacks evidence demonstrating clinical efficacy to recommend their routine use Addition of prebiotics is not unreasonable, but lacks evidence demonstrating clinical efficacy. Cost benefit studies are also necessary to support

Clinical applications

Decreases the number of diarrhea stools and duration of acute infectious diarrhea of viral etiology by 1 day, when started early in course of the disease. Prevents antibiotic associated diarrhea May be of some benefit as an adjuvant to eradicate H.pylori, but more studies are required

Prevention of hepatic encephalopathy

Clinical application - contd

Treatment of ulcerative colitis. Probiotic E.Coli Nissle may be equivalent to mesalazine in maintaining remission. May reduce symptoms of irritable bowel syndrome Reduce symptoms of lactose intolerance May reduces risk of NEC in preterm>1kg Despite encouraging results of some studies, there is insufficient evidence to support routine use of probiotics in prevention or treatment on atopy Decreased risk of colorectal cancer in animal model

Evidence based Indications

Disease
Acute infectious diarrhea

Product
L rhamnosus L reuteri L acidophilis + B infantis S boulardii

Daily Dose
1010 to 1011 cfu BD 1010 to 1011 cfu BD 109 cfu each TDS

200 mg TDS

Evidence based Indications

Disease
Antibiotic associated diarrhea (prevention)

Product
L rhamnosus L acidophilis + B infantis S boulardii

Daily Dose
1010 cfu OD/BD 107 + 106 cfu/gram 250 mg BD

Evidence based Indications

Disease Product Daily Dose
1010 to 1011 cfu BD 109 cfu BD 107+ 108 cfu / gram

Nosocomial L rhamnosus diarrhea L reuteri (prevention) S thermophilus + B lactis B lactis

109 cfu BD

Evidence based Indications

Disease Clostridium difficile diarrhea (Adults) Product L casei with L bulgaricus + S thermophilus S boulardii L acidophilus + B bifidum Daily Dose 1010 cfu BD

2X1010 cfu /day 2X1010 cfu each per day

Evidence based Indications

Disease Adjuvant therapy for H pylori Product L rhamnosus GG L bulgaricus + S thermophilus + L casei S boulardii B clausii Daily Dose 6X109 cfu BD

1010 cfu BD

5X109 cfu per day 2x109 spores TDS

Evidence based Indications

Disease Irritable bowel syndrome (adults) Product B infantis L rhamnosus GG L rhamnosus GG, LC 705, B breve Bb99, propionobacter freudenreichii spp B animalis,B bulgaricus + S thermophilus Daily Dose 108 cfu OD 6X109 cfu BD 1010 cfu OD

10x1010 cfu OD

Evidence based Indications

Disease Ulcerative colitis & pouchitis (maintain remission, prevention) Product Daily Dose

E coli (Nissle 5X1010 bacilli BD 1917) VSL# 3 mixture 4.5X1011 cfu BD (S thermophilus, Lactobacillus, Bifidobacterium)

Evidence based Indications

Disease
Prevention of NEC

Product

Daily Dose

B infantis, S 0.35 X109 cfu each thermophilus, B OD bifidum L acidophilus + 109 cfu BD B infantis

Evidence based Indications

Disease Product Daily Dose

Constipation Lactulose oligofructose Hepatic Lactulose Encephalop athy Lactose Yoghurt, intolerance L bulgaricus+ S thermophilus

20-40 gram OD >20gm/day 45-90gm/day

Pasteurized Yoghurt

Clinical application - contd

Available evidence does not support routine use of probiotics to prevent infectious diarrhea. Probiotics are not recommended for treatment of antibiotic associated diarrhea in children Not recommended for chrons disease, constipation, IBS in children at present.

Should not be used in seriously or chronically ill patients until safety is established

Questions unanswered

Optimal duration of administration

Preferred microbial species

Accurate dose
Long term effect on gut micro flora of children

Regulation

Require pre-market review and approval by regulatory body (excl dietary supplements)

The safety, purity, potency & efficacy of the product must be demonstrated for approval.
The FDAs Center for Food Safety and Applied Nutrition regulates probiotics and prebiotics marketed as dietary supplements or food ingredients. Probiotics marketed for treatment and prevention of diseases are classified biological products & require FDA review & approval FDA has not yet approved any claim for probiotics that relate to reduction of risk of disease Structure-function claims are commonly used for probiotics & these do not require FDA approval

Regulation
No regulatory guidelines for probiotics in food in India ICMR has formed a task force which laid the following guidelines

Identification of genus, species & strains using standard methodology, as effect of probiotics is strain specific In vitro tests to screen the potential, eg, resistance to gastric & bile acids, antimicrobial activity against potential pathogen, ability to reduce pathogen adhesion, bile salt hydrolase activity In vivo safety studies in animal model (may not be necessary for strains with established documented use) In vivo efficacy studies in animal model Evaluation of safety in human use Evaluation of efficacy in human use (may not be needed for probiotics in food) Minimum effective dose should be clearly indicated

Regulation

If a probiotic food has a record of documented long & safe use outside India, the data could be reviewed & decided sufficient to allow marketing However labeling of health benefits will require efficacy studies conducted in Indian subjects Labeling requirements - Genus, species and strain designation - Viable number of organisms of each strain at the end of shelf life - Approved indications for use - Suggested serving - Suggested storage guidelines

References

Prebiotics & probiotics. World Gastroenterology Organization Practice Guideline. May 2008. ICMR-DBT Guidelines for Evaluation of Probiotics in Food.July 2011. Thomas DW, Greer FR. Clinical ReportProbiotics and Prebiotics in Pediatrics. Pediatrics.2010;126:1217-27