Antibiotic Resistance and Probiotics - A Metagenomic Viewpoint

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1 Antibiotic Resistance and Probiotics - A Metagenomic Viewpoint Neerja Hajela, PhD General Manager-Science & Regulatory Affairs Yakult Danone India Pvt. Ltd.

2 Outline of the Presentation Global Epidemiology of Antibiotic Resistance Impact of Antibiotics on the Gut Microbiota Probiotics 1. Restoring the balance of the Gut Microbiota 2. An Alternative Strategy for Reducing the Use of Antibiotics 3. Where do they Stand?

3 Antibiotic Resistance A Global Concern Antibiotic Resistance mechanisms spreading globally - inability to treat common infectious diseases. Organ transplantation, Cancer chemotherapy, diabetes management and major surgery - very high risk. Antibiotic resistance - increases cost of health care. Gains of the Millennium Development Goals at risk Dangers achievement of the Sustainable Development Goals.

4 Examples of Alarming Resistance Rates Drug resistant rates for fluoroquinolones over 30%. E coli bacteremia - Ampicillin resistance as high as 55% S aureus, one of the hazardous bacterial pathogen Vancomycin resistant Salmonella enterica serotype typhimurium resistant to Ampicillin, Chloramphenicol, Streptomycin, Sulphonamides, Tetracycline, Ceftriaxone

5 Source: World Economic Forum Global Epidemiology

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7 Cause to worry!

8 Impact of antibiotics through life span Langdon et al. Genome Medicine (2016) 8:39

9 Mechanism -antibiotic impact on the gut microbiota Depletion of bacterial diversity, taxonomic richness, and evenness Altered gene expression, protein activity and overall metabolism Increased susceptibility to infections Antibiotics Gut Microbiota Establishment of resistant bacteria Accumulation of antibiotic resistances Untreatability of bacterial infections Disruption of Treg/Th balance Deregulated metabolism Francino et al Frontiers Immune Homeostasis in Microbiology Obesity, metabolic syndrome, diabetes

10 Impact of antibiotic administration - bacterial community of the colon Resistant bacteria Susceptible bacteria C. Jernberg et al.(2010) Microbiology.156

11 Suchita P et al. (2014) Plos One.9

12 Short term impact of antibiotics Microbial composition at the phylum level based on 16s rrna gene sequences Suchita P et al. (2014) Plos One.9

13 Short Term Impact of Antibiotics Suchita P et al. (2014) Plos One.9

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15 Long term impact of antibiotics C. Jernberg et al.(2010) Microbiology.156

16 Collateral consequences on the gut microbiota Loss of important taxa and diversity - Reduced colonization resistance to pathogens and disease development. Reduced diversity of Firmicutes and Bacteroidetes- Overgrowth of Eneterobacteriaceae Altered gene expression, protein activity and metabolism-gut microbiota Increase vulnerability for post antibiotic expansion of enteropathogenic strains like Clostridium difficile. Horizontal transfer of resistance genes - evolution of drug resistant pathogens and spread of antibiotic resistance.

17 Live micro-organisms which, when administered in adequate amounts, confer a health benefit on the host

18 Probiotics to restore the antibiotic induced gut dysbiosis Gallo A et al. Modulation of microflora in intestinal diseases.2016

19 Underlying Mechanisms Level 1 Direct Antagonism and exclusion of pathogens Competitive exclusion of pathogens -Colonization Resistance Antibacterial substances - short chain fatty acids, hydrogen peroxide, nitric oxide, bacteriocins, cationic antimicrobial peptides, defensins etc. Down-regulation of virulence factors in pathogens and host receptors Rijkers et al 2010, J Nutr 140:671S-676S; Ewaschul & Madsen 2009, Function Food Rev 2:29-41

20 Underlying Mechanisms Level 2 Level 2 Improving Barrier Function and Immune Modulation Upregulate expression of ZO 1, ZO2, ZO3 and opioid, cannabinoid receptor expression on IEC s Upregulate the expression of MUC 2 and MUC 3 genes - stimulating production of mucus from goblet cells Interaction with epithelial and immune cells through NOD 1 and TLR receptors Stimulate production of Secretory IgA and increases the activity of Natural Killer cells protection from viruses and cancer. Signaling anti inflammatory cytokines like IL- 10 and TGF β and reduce pro- inflammatory cytokines Rijkers et al 2010, J Nutr 140:671S-676S; Ewaschul & Madsen 2009, Function Food Rev 2:29-41

21 Underlying Mechanisms Level 3 Impart an effect on the systemic immune system as well as other cell and organ systems such as liver and brain. Rijkers et al 2010, J Nutr 140:671S-676S; Ewaschul & Madsen 2009, Function Food Rev 2:29-41

22 Adverse Effects of Antibiotics Pathogenesis of Disease Prolonged antibiotic treatment in first days of life Necrotizing Enterocolitis Treatment with antibiotic disrupts host microbiota Antibiotic Associated Diarrhea. Patients receiving antibiotics Increased risk of Clostridium difficile infection Meta-analysis indicate that probiotic administration in preterm infants significantly reduces the incidence of severe Necrotizing Enterocolitis (NEC) and mortality. Swah Sc et al Peer J. 4:24-29 Recent meta analysis shows that administration of probiotics prevents antibiotic associated diarrhea Hempel S et al JAMA.9.307(18): Probiotics prevent Clostridium difficile infetion. Goldenberg JZ et al Cochrane database Syst review

23 Health and clinical targets for different probiotics Sanders et al. Gut. Author manuscript.2015

24 Probiotics for prevention of Diseases Clinical Condition Results / Conclusions References Necrotizing Enterocolitis (NEC) Gastrointestinal Diseases Treatment of Acute Infectious Diarrhoea Prevention and Treatment of Antibiotic-Associated Diarrhoea (AAD) Prevention of Clostridium difficile-associated diarrhea (CDAD) Meta-analysis, 11 RCT s (n=2176 subjects) Probiotic studies using strains of Bifidobacterium, Lactobacillus, Saccharomyces and/or S. thermophilus to prevent NECs showed reduction in the frequency and overall mortality. Meta-analysis, 84 trials (n=10351 patients) Probiotics are generally beneficial in prevention of GI diseases. Cochrane review, 63 studies (n=8014) Shortened duration of diarrhoea and reduced stool frequency. Meta-analysis, 82 RCT s (n=11811) Probiotics associated with reduction in AAD with an RR of The treatment effect equates to an NNT of 13. Review includes 31 RCT s; n=4492 subjects Reduces the risk of developing CDAD by 64% in adults and children. Deshpande G et al, Ritchie ML and Romanuk TN, Allen SJ et al, Hempel S et al, Goldenberg JZ et al, 2013.

25 Continue. Clinical Condition Results / Conclusions References Treatment of Irritable Bowel Syndrome (IBS) Common Infectious Diseases Review includes 19 RCT s; n=1650 patients Probiotics appear to be efficacious in IBS but the magnitude of benefit and the most effective species and strain are uncertain. Meta-analysis, 10 trials (n=3451) Probiotics reduced the number of participants experiencing upper respiratory tract infections (URTI). Moayyedi P et al, Hao Qet al, Nonalcoholic fatty liver disease (NAFLD) Review includes 4 RCT s (134 patients) Probiotic therapies can reduce liver aminotranferases, total-cholesterol, TNF-α and improve insulin resistance in NAFLD patients. Ma YY et al, 2013.

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27 Schematic Diagram Probiotic Group 1894 children 7/12/07 10/13/07 1/5/08 Probiotic drink (65 ml/ day) Follow up 12week 12week 3758 children (1 to 5 years) Double-blind Controlled Trial Nutrient Group 1864 children Determine & Compare incidence, duration, outcome, and pathogens of acute diarrhoea 12week 12week Nutrient (65 ml/ day) Follow up Nutritional assessment (height, weight and mid-arm circumference) will be done at the, and (beginning, after 12weeks, and at the end of follow-up)

28 Isolation of different enteric pathogens in the probiotic and nutrient groups Sur D.2011.Epidemiol. Infect.139.(6)

29 Result / Conclusion a) (0.88 cases / child / year vs 1.029/ cases/ child/ year) incidence of diarrhoea b) Protective efficacy of 14% (P<0.01) in the probiotic group. c) Probiotics are useful in the prevention of diarrhoea in Indian children

30 Evidence-based pediatric indications for probiotics and prebiotics in gastroenterology World Gastroenterology Organisation, 2011

31 Continue..

32 Evidence-based adult indications for probiotics and prebiotics in gastroenterology World

33 Continue.. World Gastroenterology Organisation, 2011

34 Continue.. World Gastroenterology Organisation, 2011

35 How Probiotics can help.. Stabilize the gut microbiota and reduce the risk of Gastrointestinal and extra- intestinal disorders such as IBS, IBD, vaginal infections. Enhance innate and adaptive immune responses which in turn aids in the eradication of pathogenic organisms decreases infection. Reduce the risk of Antibiotic-associated diarrhea and Clostridium difficile diarrhea.

36 Safety of probiotics Probiotics do not contribute to the spread of antibiotic resistance and may even reduce it. Members of Lactobacilli and Lactococcus commonly designated as Generally Regarded as Safe or Qualified Presumption of Safety. Intrinsic resistance minimum potential for horizontal spread. Centre for Disease Control and Prevention actively researching on the subject. Ouwehand et al Annals of Medicine 2016

37 Probiotics To prevent Antibiotic Resistance Clear association of microbiome alterations with a progression from health to disease. Definition of validated biomarkers to be advanced The precise benefit in probiotic-inducted microbiome changes remain to be verified. Probiotic benefits are strain specific elucidate the underlying mechanisms of action of specific probiotics Determine which specific organism is most likely to provide a benefit for a particular condition. A mechanistic based approach coupled with carefully conducted multicenter, randomized, controlled trials potential of probiotics as an alternative management option for various disease condition.

38 The enemy of my enemy is my friend The enemy of my enemy is my friend is an ancient proverb which suggests that two opposing parties can or should work together against a common enemy.