ROLE OF PROBIOTICS IN ADULT GASTROENTEROLOGY

Dr Ajay BhallaPrincipal Consultant & HOD GastroenterologyFortis Hospital Noida

PROBIOTICS

“You’ve been fooling around with alternative medicine, haven’t you?”

For life

HISTORY OF PROBIOTICS

Lactic acid bacteria can render a great service in the fight against intestinal putrefaction’

‘Postpone and ameliorate old age’

The Prolongation of Life (1908)

　　　　Elie Metchnikof (1845-1916)

PROBIOTICS: DEFINITIONS

World Health Organization: “live microorganisms which when

administered in adequate amounts confer a health benefit on the host”

A bacterial strain that: Survives the stomach acid and bile Adheres to intestinal lining Grows and establishes temporary residence in

the intestines Imparts health benefitsR Fuller. Probiotics: The Scientific Basis. London: Chapman and Halls. 1992

PROBIOTICS Colonization at birth Similar to maternal species Specific organisms vary by age in first

year but become established by 1 year No. of bacteria in gut 10 times the

total no. of body cells. Composition of each individuals

microbiota is so distinctive…..it could be used as an alternative to fingerprints..!

Composition also influenced by age,socio-economic srroundings & use of antibiotics

THE GUT MICRO BIOTA AND ITS INFLUENCE ON HEALTH

O’Hara A.M. et al. EMBO reports 2006; 7: 688-693.

DISTRIBUTION OF MICROBES IN THE GUT Present in all parts of the intestinal tract Increase from esophagus to colon

acid production bile motility ileocecal valve

Surface-lumen axis: more anaerobes in the outer mucus

Bacteria are not in direct contact with the mucosa – at least, in healthy subjects

Microbes in Intestinal Health and Disease; A.S. Neish Gastroenterology 2009;136:65-80

Increasingly recognized as a risk factor for human disease: Infections, Obesity, Diabetes, NEC, IBS, IBD PNAS March 15, 2011 Suppl.

Dysbiosis in the Gut

Disturbance of the balance of the

intestinal microbiota

Stress

Ageing

Diet

Infection

Medication (Antibiotics)

PROBIOTICS Lactobacillus sp.

reuteri casei ramnosus acidophilus

Streptococcus sp. Bifidobacterium sp.

infantis lactis longum breve bifidum

Sacharomyces boulardii (non-human)

VSL no.3

DESIRABLE CHARACTERISTICS OF A PROBIOTIC STRAIN

Stable and well-described microbe

Non-toxic, non-pathogenic

Able to survive and multiply in desired location

Able to combat pathogens

Efficacious in promoting specific health claim

Scalable production

Easy to distribute

Mechanism of Action

In vitro studies, In vivo animal studies, Human observational/epidemiology studies ,Human experimental studies, Randomized Double Blind Placebo Controlled studies with validated biomarkers

In 2010, there were 1158 articles: in high ranking peer-reviewed journals; increasing DBPCRTs ….

Meta-analyses are usually based on a generic probiotic benefit

Reviews and meta-analyses will include relevant trials with different strains but generic conclusions may not be true for individual strains

Each Probiotic strain to be supported by its own dossier of

scientific evidence…

Scientific Evidence for Probiotics

Benefits and Application

Preventive and therapeutic modality for

gastrointestinal disorders such as Antibiotic

associated & infectious diarrhoea, IBS, IBD,

Management of NAFLD,MHE & Hepatitis

Immune stimulation

Prevention of allergic disorders

Prevention of chronic inflammatory diseases

Prevention of cancers

Reduction of respiratory diseases

INFECTIOUS DIARRHOEA – PROBIOTICS AS A TREATMENT ?

Allen et al (2010) Cochrane Systematic ReviewUsed alongside rehydration therapy, probiotics appear to be safe and have clear beneficial effects in shortening the duration and reducing stool frequency in acute infectious diarrhoea.

Wolvers et al (2010) ReviewModerate to significant benefit of many probiotic strains in management of acute watery diarrhoea (RV infections) in children.

• Moderate improvements in acute infections (~1 day ↓ duration diarrhoea)• Significant improvements in watery diarrhoea and viral gastroenteritis• More evident when intervention started early in course of infection

The use of probiotics for acute infectious diarrhoea in children is an accepted therapy in Europe

Recommended by the European Society for Paediatric Gastroenterology, Hepatology and Nutrition & European Society of Paediatric Infectious Diseases Expert Working Group

Functional Constipation(IBS) – probiotics as a treatment?

Chimielewska et al (2010) Systematic Review

5 RCT’s , N= 377 ( 266 adults , 3 RCT’s and 111 children, 2 RCT’s) Bifidobacterium lactis DN-173 010, Lactobacillus casei Shirota, Escherichia coli Nissle 1917, Lactobacillus casei rhamnosus Lcr 35, Lactobacillus rhamnosus GG

Results Bifidobacterium lactis DN-173 010, Lactobacillus casei Shirota and

Escherichia coli Nissle 1917 are effective in improving defecation frequency and stool consistency in adults.

In children, Lactobacillus casei rhamnosus Lcr 35 shows a beneficial effect.

Lactobacillus rhamnosus GG did not demonstrate any benefit

Probiotics and Constipation

Rationale Some evidence of - Aberrant microbiota - Antibiotic benefit - Link with methane oxidation Up to 66% of the dry weight of stool is bacteria Microbial production of SCFA and metabolism of bile acids help lower gut pH and stimulate motility - Some metabolic products act as neurotransmitters which affects motility.

•Research•Endpoints: symptom questionnaires-pain, bloating, completeness of evacuation, stool consistency defecation frequency, transit time measurements •Hoveyda & Whorwell et al-improvement in 3D with Bifidobacterium infantis 35624(BMC Gastrointestinal-2009)•Evidence is accumulating for some other strains also

CONSTIPATION

Krammer HJ Coloproctology 2011, 33: 109-113

Double blind Randomized Placebo Controlled trial (n=24)

Yakult or placebo daily for period of 4 weeks Significant acceleration of the total colonic transit

time from 95.6 h to 76.5 h (p=0.05) in probiotic group; No statistically significant change in the total colonic transit time (before: 95.8 h, after: 87.1 h, p=0.282) in the placebo group

Probiotics in IBD

Still evolving and contentious..microbiota as cause??

Pouchitis: positive reports (in adults), with a mixture of bacterial strains(VSL3)-85% remission vs 6%(Mimura et al 2004 GUT)Ulcerative Colitis: some positive effects

- maintenance of remission- induction of remission in mild-mod flare ups

Crohn disease:minimal- no benefit

Choice of strain, dosing, and disease activity severity might well account for variable results

Eamonn et al Nutr clin Pract 2012

Conclusion?: more high quality data (RCT’s) are required!

INFLAMMATORY BOWEL DISEASE

An open label preliminary trial conducted on 10 patients with mildly to moderately active Ulcerative Colitis (UC)

Intervention: LcS (8x1010 CFU/day) in addition to conventional therapy daily for 8 weeks

Significantly better clinical activity index score seen after LcS treatment as compared with pre-treatment and control group

LcS effectively treats UC at least in part through the inhibition of interleukin-6 signalling

Mitsuyama K et al J Clin Biochem Nutr 2008, 43 (Suppl.1):78-81

MICROBIOTA & DISEASE

Antibiotic associated diarhhoea:Normal microbiota eliminated by antibiotics helps other disease causing bacteria to proliferate(Cl.diff.)

Necrotizing Enteroclotitis in premature infants Small Intestinal bacterial overgrowth Bacterial translocation from Gut flora in - Critically ill - Surgery or Trauma - CLD with SBP

PROBIOTICS & LIVER DISEASES

NAFLD/OBESITY:Qualitative change in Gut microbiota with more avid extractors of absorbale nutrients…hence more Cal. to host(Iacano et al J Nutr Biochem 2010)

Hepatic Encephalopathy(MHE):As effective as Lactulose in decreasing Blood Ammonia levels (Changing gut pH by SCFA,decreasing Bacterial urease activity & decreasing intestinal permeability to ammonia)-Shukla et al Aliment Pharmacol Ther 2011.

Salmonella induced liver damage prevented by probiotics by decreasing bacterial translocation to liver(Rishi et al FEMS Microbiol Ecol 2009)

SAFETY/CAUTION

Premature neonates or Immunodef. Infants

Short bowel syndrome-Septicemia Severe acute Pancreatitis-Increased

Mortality ??? Etiology

CONCLUSIONS

•Role of Probiotics well established in Infective & antibiotic ass. diarrhoea.•+ve Role of Probiotics in Pouchitis & UC but in Crohn’s??•MicrObesity- a new concept about microbial community participating in development of fat deposition,insulin resisitence & NAFLD•Pre/pro/symbiotics improve MHE significantly(almost as good as lactulose) •Biologic effects of probiotics are likely to be strain specific.

Thank You