Science and

nature in

balance

Probiotics and IBS

Science

and nature

in balance

My background

• Dr Ashton Harper MBBS, iBSc

(Phys/Pharm), MRCS

• MD from University College London

School of Medicine

• 5 years clinical experience in medical

and surgical disciplines

• Special interest in gastrointestinal

diseases

• Head of Medical Affairs at the UK’s

leading probiotic manufacturer

• Lead for clinical research at Protexin

• Facilitate the understanding & use of

probiotics in clinical medicine

Science

and nature

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Why use probiotics?

Science

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Clinical outcomes - IBS

• 1793 patients were included from 24 clinical trials

• Abdominal pain score RR of responders probiotics vs placebo

= 1.96 (P = 0.01)

• Global symptom score RR of responders probiotics vs placebo

= 2.43 (P = 0.02)

• Adequate improvement of general symptoms in IBS RR

probiotics vs placebo was 2.14 (P = 0.03)

• ‘Probiotics reduce pain and symptom severity scores. The

results demonstrate the beneficial effects of probiotics in IBS

patients in comparison with placebo.’

• 3406 patients – 9 SRs and 35 RCTs

• 29 dose specific probiotic formulations

• 16 single strain RCTs

• 19 multi-strain RCTs

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McKenzie et al 2016 - Results

• 83% of RCTs improved at least 1 outcome measured

• Global symptoms –14 of 29 trials found a ‘statistically significant improvement’

• 65% multi-strain

• 35% single strain

• ‘Clinically meaningful improvement in abdominal pain’ – 8 of 35 trials

• 63% multi-strain trials

• 37% single strain trials

• QoL - 16/35 measured

• Only 2 of 16 found ‘clinically meaningful improvement

• 100% multi-strain

• No reported ‘serious adverse events’

• GI AE in 1 RCT

Supplementation with a multistrain probiotic formulation (Bio-Kult®) in the management of Irritable Bowel Syndrome - a randomized, double-blind, placebo-controlled clinical trial (Completed 2017 - awaiting publication)

• Male and female patients 18-55yrs

• Rome III diagnosis of moderate-severe IBS-D

• Exclusion of non-functional GI disease

• 4 months of intervention

• Monthly follow-up – final at 5 months

• 2 capsules BD = 8 billion CFU/day of multi-strain formula (or cellulose placebo capsules with identical appearance)

2 billion microorganisms per capsule

(1x1010 CFU/gram)

Guaranteed 2 year shelf-life

14 strains of live bacteria

No refrigeration required

Bio-Kult® Advanced

•Bifidobacterium bifidum PXN 23

•Bifidobacterium breve PXN 25

•Bifidobacterium infantis PXN 27

•Bifidobacterium longum PXN 30

•Lactobacillus acidophilus PXN 35

•Lactobacillus delbrueckii ssp. bulgaricus PXN 39

•Lactobacillus casei PXN 37

•Lactobacillus plantarum PXN 47

•Lactobacillus rhamnosus PXN 54

•Lactobacillus helveticus PXN 45

•Lactobacillus salivarius PXN 57

•Bacillus subtilis PXN 21

•Lactococcus lactis ssp. lactis PXN 63

•Streptococcus thermophilus PXN 66

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Outcome measures and sample size

• Primary outcome:

• Abdominal pain (IBS-SSS)

• Secondary outcomes:

• Global symptom severity (IBS-SSS)

• QoL (IBS-QoL)

• 400 patients randomised:

• Minimum clinically important difference = 30% (based on SD from G. Sisson et al 2013) and accounting for attrition the adjusted sample size = 400

NB: mainly small and underpowered studies:

• Only 10/35 had total sample size >100

• Only 3/35 >100 per arm

• Therefore ~75% were pilot studies

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Assessing IBS symptoms

IBS-Severity Scoring System (IBS-SSS):

• 5 questions

• Covers: pain (x2), distension/bloating, bowel habit satisfaction and interference with life.

IBS-Quality of Life (IBS-QoL) questionnaire:

• 34 items, each with a five-point response scale (1. Not at all 2. Slightly 3. Moderately 4. Quite a bit 5. Extremely)

• Cover 8 domains: Dysphoria, Interference with Activity, Body Image, Health Worry, Food Avoidance, Social Reaction, Sexual, Relationships

IBS pain results • IBS pain severity decreased by 69% in the

probiotic arm

NB: IBS pain frequency decreased by >70% (7.7 per 10 days to 2.2 at month 5 vs 3.9 from 8.1 in placebo)

69% 66% 58%

• Internationally agreed symptom outcome measures are lacking!

Establishing clinically meaningful outcomes in IBS

NB: placebo effect is 37.5% in pharmaceutical RCTs in IBS

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Further results

IBS-SSS:

• Significant benefit of probiotic over placebo at all time points

• Reduced by 145 points within 30 days (vs. 117 points in the placebo group)

• Reduced by 223 points by month 5 (vs. 157 points in the placebo group).

Severity (moderate to severe) at end of follow-up:

• <14% probiotic

• 48% placebo

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Conclusions

• Multi-strain probiotics have the most frequent success in IBS management

• Protexin have conducted the largest IBS-D probiotic trial to date

• If you have moderate to severe IBS-D taking Bio-Kult could:

• Improve the severity and frequency of your pain by ~70%

• Decrease distension by 2/3rds

• Cut trips to the loo by >50%

• Significantly boost your QoL

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References

1. Morgan XC, Segata N, Huttenhower C (2013) Biodiversity and functional genomics in the human microbiome. Trends Genet 29(1):51–58.

2. Sender, R., Fuchs, S. & Milo, R. Are we really vastly outnumbered? Revisiting the ratio of bacterial to host cells in humans. Cell 164, 337–340 (2016).

3. Lozupone CA, Stombaugh JI, Gordon JI, Jansson JK, Knight R. Diversity, stability and resilience of the human gut mi- crobiota. Nature 2012; 489: 220-230 [PMID: 22972295 DOI: 10.1038/nature11550]

4. Qin, J. et al. A human gut microbial gene catalogue established by metagenomic sequencing. Nature 464, 59–65 (2010).

5. Clemente JC, Pehrsson EC, Blaser MJ, Sandhu K, Gao Z, Wang B, Magris M, Hidalgo G, Contreras M, Noya-Alarco´ n O´ et al.: The microbiome of uncontacted Amerindians. Sci. Adv. 2015, 1: e1500183.

6. Lacy BE et al. Bowel Disorders. Gastroenterology 2016; 150:1393-1407

7. Matricon J. Review article: associations between immune activation, intestinal permeability and the irritable bowel syndrome. AP&T 2012. 36: 1009–1031

8. Kennedy PJ. Et al. Irritable bowel syndrome: A microbiome-gut-brain axis disorder? World J Gastroenterol 2014 October 21; 20(39): 14105-14125

9. Parkes GC, Rayment NB, Hudspith BN, et al. Distinct microbial populations exist in the mucosa-associated microbiota of sub-groups of irritable bowel syndrome. Neurogastroenterol Motil 2012; 24:31–9.

10. Rigsbee L, Agans R, Shankar V, et al. Quantitative profiling of gut microbiota of children with diarrhea-predominant irritable bowel syndrome. Am J Gastroenterol 2012; 107: 1740–51.

11. Jalanka-Tuovinen J, Salojarvi J, Salonen A, et al. Faecal microbiota composition and host-microbe cross-talk following gastroenteritis and in postinfectious irritable bowel syndrome. Gut 2013; doi: 10.1136/gutjnl-2013-305994 [Epub ahead of print].

12. Straudacher HM. Mechanisms and efficacy of dietary FODMAP restriction in IBS. Nature Reviews Gastroenterology & Hepatology 11, 256–266 (2014)

Science

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References continued

1. Marshall JK, Thabane M, Garg AX, Clark WF, Salvadori M, Collins SM. Incidence and epidemiology of irritable bowel syndrome after a large waterborne outbreak of bacterial dysentery. Gastroenterology 2006; 131: 445-450;

2. Maxwell PR, Rink E, Kumar D, Mendall MA. Antibiotics increase functional abdominal symptoms. Am J Gastroenterol 2002; 97:104-8; PMID:11808932; http://dx.doi.org/10.1111/j.1572- 0241.2002.05428.x

3. Villarreal AA, Aberger FJ, Benrud R, Gundrum JD. Use of broad-spectrum antibiotics and the development of irritable bowel syndrome. WMJ 2012; 111: 17-20 [PMID: 22533211]

4. Aziz I. Small intestinal bacterial overgrowth as a cause for irritable bowel syndrome: guilty or not guilty? Current Opinion in Gastroenterology 2017. 33; 196-202

5. Crouzet L, Gaultier E, Del’Homme C, Cartier C, Delmas E, Dapoigny M, Fioramonti J, Bernalier-Donadille A. The hypersensitivity to colonic distension of IBS patients can be transferred to rats through their fecal microbiota. Neurogas- troenterol Motil 2013; 25: e272-e282 [PMID: 23433203 DOI: 10.1111/nmo.12103]

6. Verdu EF, Bercik P, Verma-Gandhu M, et al. Specific probiotic therapy attenuates antibiotic induced visceral hypersensitivity in mice. Gut 2006;55:182e90.

7. Ibeakanma C, Miranda-Morales M, Richards M, Bautista- Cruz F, Martin N, Hurlbut D, Vanner S. Citrobacter ro- dentium colitis evokes post-infectious hyperexcitability of mouse nociceptive colonic dorsal root ganglion neurons. J Physiol 2009; 587: 3505-3521 [PMID: 19470777 DOI: 10.1113/ jphysiol.2009.169110]

8. O’Mahony SM, Marchesi JR, Scully P, Codling C, Ceolho AM, Quigley EM, Cryan JF, Dinan TG. Early life stress alters behavior, immunity, and microbiota in rats: implications for irritable bowel syndrome and psychiatric illnesses. Biol Psychiatry 2009; 65: 263-267

9. Anitha M, Vijay-Kumar M, Sitaraman SV, Gewirtz AT, Srinivasan S. Gut microbial products regulate murine gas- trointestinal motility via Toll-like receptor 4 signaling. Gas- troenterology 2012; 143: 1006-1016.e4 [PMID: 22732731 DOI: 10.1053/j.gastro.2012.06.034]

10. Bercik P, Denou E, Collins J, Jackson W, Lu J, Jury J, Deng Y, Blennerhassett P, Macri J, McCoy KD, Verdu EF, Col- lins SM. The Intestinal Microbiota Affect Central Levels of Brain-Derived Neurotropic Factor and Behavior in Mice. Gastroenterology 2011; 141: 599-609.e593 [PMID: 21683077 DOI: 10.1053/j.gastro.2011.04.052]