The science behind probiotics Colin Hill, APC Microbiome Institute University College Cork Ireland

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1 The science behind probiotics Colin Hill, APC Microbiome Institute University College Cork Ireland Illustration Charis Tsevis

2 Probiotics live microorganisms that, when administered in adequate amounts, confer a health benefit on the host Commercially available probiotics in many product categories Some supported by excellent clinical evidence, including RCT s Most lack mechanistic insights; metabolic effects, microbiota effects, immunomodulation?

3 A vibrant research area Search term probiotics (PUBMED) 0

4 .. but translation is declining? Search term probiotics + Clinical Trial (PUBMED)

5 The Probiotics Paradigm No probiotic works in any health condition Don t work Regulators All work Consumers Scientists Some work All probiotics work in all health conditions Each probiotic works in only one health condition

6 Probiotics don t work? The term probiotic is a health claim. Stating contains probiotic (or similar) on a product implies that the product contains a substance that may be beneficial for health. For this reason, the term probiotic, when used on a food label, is considered to be a health claim. Any terms that imply probiotic activity are health claims and are not permitted. For example if terms like live or active are used to describe bacteria, these imply a probiotic function and therefore are considered to be health claims. There are no approved health claims for probiotics.

7 One probiotic fits all? Lactobacillus rhamnosus GG Originally selected based on three criteria (biological robustness, adherence to epithelial cells and inhibition of other bacteria) Target Outcome Reference Intestinal permeability in children Significant improvement Sindhu, CID (2014) NAFLD in mice Protective Ritze, PLOS ONE (2014) Vaccine immune responses in children Reduced response Licciardi, Front. Immunol. (2013) Rotavirus infection in gnotobiotic pigs Protective Liu, J. Pad. Gastro. Nutr. (2013) Obsessive-compulsive-like behaviour in mice Attenuated OCD Kantak, Behav. Pharmacol. (2013) Pseudomonas lung infection in mice Improved 7 day survival Khailova, Shock (2013) Rhinovirus infections in infants Lower incidence Luoto, J. Allergy Clin Immun. (2013) Sepsis in mice Reduced mortality Khailova, Anesthesiology (2013) Procarcinogenic fecal enzymes in rats Decreased activity Verma, Nutr. Cancer (2013) Fussing and crying in preterm infants Reduced symptoms Partty, J. Pediatrics (2013)

8 Most work in some conditions? Blend 63 RCTs, with participants Conclusions The evidence suggests that probiotics are associated with a reduction in AAD. More research is needed to determine which probiotics are associated with the greatest efficacy and for which patients receiving which specific antibiotics. Bacillus Bifidobacterium Enterococcus Lactobacillus Saccharomyces

9 Probiotics and CDAD July 2007

10 Prescription probiotics? (Dublin hospital: patient with cellulitis on iv antibiotic therapy) July 2007 Need mechanism of action Actimel TM contains Lactobacillus casei Everybody TM contains Lactobacillus rhamnosus

11 Probiotics and infection Murine listeriosis Screened potential probiotics (human origin) for protection against infection with Listeria monocytogenes Effects were strain specific and dramatic life or death outcomes

12 Probiotic mechanisms Probiotic effect was entirely due to the ability of Lactobacillus salivarius UCC118 to produce a bacteriocin. The bacteriocin is highly active against Listeria monocytogenes. Kills the pathogen within 30 minutes of it s arrival in the gut. Bacteriocin negative strains offer no protection

13 MoA can drive discovery Overlaid with Clostridium difficile a b Isolated >50,000 sporeformers from faecal specimens Bacillus thuringiensis Thuricin CD; a two component bacteriocin, highly active against Clostridium difficile

14 Thuricin CD Thuricin CD is a novel two component sactibiotic, with three sulphur to a- carbon bridges in each peptide

15 Faecal fermentations Thuricin CD equally as effective as frontline antibiotics in killing C. difficile T 0 T 24 But did not cause collateral damage to the microbiota control Van (90uM) Met (90uM) Thurici n (90uM)

16 Mouse Trial (n=10) Rea et al., unpublished. Mice rectally inoculated with Clostridium difficile Thuricin added 60 minutes post-inoculation Mice sacrificed 60 minutes post-treatment Colonic contents (caecum to anus) plated for survivors cfu/colon Effect of Thuricin CD added rectally post inoculation with C. difficile ribotype 027 P < Placebo Thuricin (2.5mg)

17 A magic bullet for C. difficile C. difficile Lb. casei DN Bif. lactis Bb12 Lb. casei Shirota Lb. johnsonii LA1 Lb. rhamnosus GG

18 Probiotics and the brain

19 Probiotic effect on behaviour o Feeding Lactobacillus rhamnosus strain to mice reduced stress behaviour o Reduced levels of corticosterone Stress induced hypothermia Elevated maze Forced swim test

20 Probiotic mechanisms o Lactobacillus rhamnosus JB-1 produces high levels of GABA a neurotransmitter o Increased levels of GABA receptors in the brain of probiotic fed mice o Vagotomised mice no longer responded to probiotics 30 % in centre 75 Moves to centre control probiotic control probiotic

21 Conclusions Some health conditions may respond to almost any safe bacteria Other conditions may require a very specific bacterium (rare mechanism) Some bacteria may have widespread activity, others may have very specific activity Need mechanism of action to select appropriate probiotics AAD IBS CD

22 APC Microbiome Institute