Probiotics for Disease Prevention and Amelioration. Neerja Hajela, PhD Yakult Danone India Pvt. Ltd.

Transcription

1 Probiotics for Disease Prevention and Amelioration Neerja Hajela, PhD Yakult Danone India Pvt. Ltd.

2 Microbiology turns inwards Human Metagenome project and Meta Hit project reveals that the gut micro flora has more than 1000 species and 100 trillion organisms. Metabolic activity of the gut flora is like a virtual organ within an organ

3 Gut Microbiota and its Influence on Health O Hara A.M. et al. EMBO reports 2006; 7:

4 Dysbiosis in the Gut Disturbance of the balance of the intestinal microbiota Stress Diet Ageing Infection Medication (Antibiotics) Increasingly recognized as a risk factor for human disease: Infections, Obesity, Diabetes, NEC, IBS, IBD PNAS March 15, 2011 Suppl.

5 Modulation of the Gut Flora Probiotics Live microorganisms which when administered in adequate amounts confer a health benefit on the host FAO/WHO (2001) Prebiotics Prebiotics are non-digestible substances that when consumed provide a beneficial physiological effect on the host by selectively stimulating the favorable growth or activity of a limited number of indigenous bacteria Gibson GR & Roberfroid MB (1995) Synbiotics Probiotic + Prebiotic

6 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

7 Mechanism of Action Preidis et al, 2011

8 Scientific Evidence for Probiotics 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. 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..

9 Number of peer-reviewed article (PubMed Central) >200 >100 >25 >10 L. casei Shirota B. lactis BB-12 L. acidophilus NSFM L. casei CRL 431 L. rhamnosus GG E. coli L. plantarum 299V L. paracasei F19 (LGG) strain Nissle 1917 L. johnsonii LA-1 B. bifidum Yakult S. boulardii VSL#3 L. rhamnosus GR-1 L. acidophilus LA5 B. breve Yakult L. rhamnosus LCR-35 L. acidophilus CERELA L. rhamnosus R0011 B. longum BB536 L. gasseri OLL2716 L. rhamnosus HN001 L. acidophilus NCFB1748 B. lactis HN019 P. freudenreichii ET-3 L. salivarius UCC118 L. casei DN L. rhamnosus Lcr35 B. lactis DN L. rhamnosus LC705 VSL#3 is a composite probiotic containing multiple strains of three viable lyophilized bacteria species: three strains of Bifidobacterium (B. longum, B. infantis and B. brev e); four strains of Lactobacillus (L. acidophilus, L. casei, L. bulgaricus and L. plantarum ); and one strain of Streptococcus (S. salivarius subspecies thermophilus ) March 2012

10 Benefits and Application Preventive and therapeutic modality for gastrointestinal disorders such as diarrhoea, constipation, IBS, IBD Immune stimulation Prevention of allergic disorders Prevention of chronic inflammatory diseases Prevention of cancers Reduction of respiratory diseases

11 Infectious Diarrhoea Probiotics as a Treatment? Allen et al (2010) Cochrane Systematic Review Used alongside rehdration 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) Review Moderate 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 for clinically proven strains Recommended by the European Society for Paediatric Gastroenterology, Hepatology and Nutrition & European Society of Paediatric Infectious Diseases Expert Working Group

12 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. Research Endpoints: symptom questionnaires (pain, bloating, completeness of evacuation, etc); defecation frequency, stool consistency, transit time measurements Evidence is accumulating for some strains, despite placebo effect

13 Proof of evidence in Functional constipation Chimielewska et al (2003) Systematic Review 5 RCT s, N= 377 ( 266 adults - 3 RCT s and 111 children -2 RCT s) Bifidobacterium lactis DN , Lactobacillus casei Shirota, Escherichia coli Nissle 1917, Lactobacillus casei rhamnosus Lcr 35, Lactobacillus rhamnosus GG Results Bifidobacterium lactis DN , 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

14 IBS & Probiotics Research IBS is always difficult to study - Different aetiologies - Range of symptoms - Subjective endpoints - High placebo effects Rationale Patients may have an altered microbiota: - Lower levels of Lactobacilli, Bifidobacteria, Enterobacteria - Higher levels of Clostridia - Abnormal colonic fermentation Probiotics are associated with improvement in global IBS symptoms and less abdominal pain (McFarland & Dublin 2008) Probiotics appear to be efficacious in IBS, but the magnitude of benefit and the most effective species and strain are uncertain (Moayyedi 2010)

15 1. Ulcerative colitis IBD (Haller et al 2010) Strains / Product Result / Conclusion VSL#3 Several studies (one in children) Active UC and in remission (+/- treatment) Maintenance of remission; reduction of activity score E. coli Nissle Maintenance & duration of remission Effects comparable to mesalazine B.breve Yakult, B. bifidum Yakult, L. acidophilus YITO168 LGG Studies in active disease (+ treatment) Improved disease activity score Better than treatment in prolonging remisision L. casei Shirota Significantly better clinical activity scores Enterococcus, Bifidus, Lactobacillus B longum + Synergy Fewer relapse than treatment alone Reduced inflammation in patients with active disease

16 Trials of probiotics (Haller et al 2010) 2. Crohn s disease Strains / Product Result / Conclusion S. boulardii Reduced relapse rate (+ treatment) LGG Three studies: no effect (recurrence/relapse; activity) L. johnsoniii La1 Two studies: no effect on post op recurrence 3. Pouchitis Strains / Product Result / Conclusion VSL#3 Maintenance of remission (3/3) Prevention of disease after poch-anal anastomosis (1) Treatment of active disease (1) LGG No effect

17 Probiotics and Allergy Research strategies Intervention for atopic/allergic disease: eczema and asthma - in pregnant women with family history ( Kim et al 2010: B. bifidum BGN4, B. lactis AD011, L. acidophilus AD031; eczema) - babies and infants with family history (e.g. Kalliomaki et al 2001: LGG; eczema, asthma, rhinitis) Probiotic intervention in adults sufferers, e.g. rhinitis (e.g. Ivory et al 2008: L. casei Shirota; immune endpoints) Clinical outcomes (symptom scores) and/or immune endpoints Considerations Strain Specificity Consistency of results Length of duration; time of intervention

18 Common Infectious Diseases Example trail: siga and colds Gleeson et al (2011) Int J Sport Nutr Exercise Metab 21: Trial with 86 elite athletes at Loughborough University 58 completed 16 weeks intervention with LcS FMD or placebo Probiotic group had approx 50% incidence of URTI cf. placebo Associated with maintenance of salivary IgA (P=0.03) Endpoint Probiotic group Placebo group Proportion of subjects with >_ 1 week URTI symptoms P=0.021 Mean number of URTI episodes 1.2 ± ± 1.2 P<0.01 Proportion of weeks with URTI episodes P<0.001 Proportion of days with GI discomfort symptoms P<0.008 P

19 New & Emerging Research Cancer Gut-brain axis Obesity-related disorders Liver disease Autistic spectrum disorder Designer Probiotics

20 Are Probiotics a feasible intervention for the prevention of disease in India??

21 WHO Health Report 8 out of 10 adult deaths in India are due to Non Communicable Diseases (NCD s) such as Cardio Vascular Disease, Cancers, Diabetes and Chronic Respiratory Disorders India had 51 Mn. diabetics in 2008, estimated to rise to 80 Mn. by Mn. CVD s in 2005, estimated to rise to 64 Mn. by Mn. cancer cases Source: WHO

22 CAUSES OF 1.83 MILLION DEATHS IN INDIAN CHILDREN < 5 YEARS: 2008 Injury Congenital abnormalities Other non-communicable disease (Black et al., Lancet, 2010) Birth asphyxia Preterm birth complications 14% 7% Neonatal sepsis 3% 3% 3% 10% Other infections 15% Infectious diseases 67% Pneumonia 20% Diarrhoea 13% 4% 5% Pertussis Measles Meningitis 2% Tetanus 1% AIDS 0.5% Malaria 0.3%

23 Growing Need Rise in disease burden and an interest in optimal health have resulted in an increased interest in preventive medicine. Antibiotic resistance serious threat to public health, increases medical cost, alternate medicine is being explored Probiotics may be an important intervention in the prevention and management of diseases

24 Clinical Evidence From India Indication Result / Conclusion Reference Treatment of acute water diarrhoea (L rhamnosus GG, L acidophilus) Treatment of acute diarrhoea (Saccharomyces boulardii ), Bifilac ( combination of strains) Treatment of Persistent Diarrhoea (L rhamnosus GG) Diarrhoea Prevention (Bifidobacterium lactis HN019 ) (Lactobacillus casei strain Shirota) Prevention of Necrotizing Enterocolitis (B infantis, B bifidum, B longum, L acidophilus) Treatment of Bacterial Vaginosis (Ecoflora % Metronidazole ) - Misra et al 2009 Basu et al 2007 Khanna et al Riaz et al Narayanappa et al Basu et al Sazawal et al 2004 Sur et al Samanta et al Thulkar et al 2009

25 Infectious diarrhoea Probiotics as Prevention? Sur et al (2010) Epidemiol Infect DBPCRT in an urban slum community in Kolkata, India N=3758 children, one to five years old Yakult, One bottle a day for 12 weeks Assessment for further 12 weeks Results incidence of diarrhoea (0.88 cases/child/year vs 1.029) Equivalent to reduction of diarrhoea risk or protective efficacy of 14% (P<0.01) Range of pathogens detected in feces Reduction of Aeromonas and Cryptosporidium

26 SCHEMATIC DIAGRAM OF PROBIOTIC TRIAL FOR PREVENTION OF ACUTE DIARRHOEA IN CHILDREN Nutritional assessment (height, weight and mid-arm circumference) was done at ❶,❷ and❸ (baseline, after 12weeks, and at the end of follow-up)

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28 OCCURRENCE OF DIARRHOEA & PROTECTIVE EFFICACY OF PROBIOTIC Variable Probiotic (n=1802) Nutrient (n=1783) Protective efficacy of probiotic (95% CI)* Simple analysis Adjusted analysis # Percent Children with diarrhoea Child week of follow-up 35,845 34,039 Incidence of diarrhoea no. of cases /child / year (4-23) 14 (4-23) * p<0.01 for the comparison between probiotic group and nutrient group # Adjusted for variables used to stratify for randomization as well as age Based on time to first episode of diarrhoea Sur et al., Epidemiol Infect 2010

29 Conclusion from the trial Protective efficacy 14% (95% CI: 4%,23%) in the probiotic group. Statistically significant impact on prevention of diarrhoea among children. No significant difference in anthropometric measurements. Etiological agents were almost similar in both groups.

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