The effect of a liquid multi-strain

probiotic in symptomatic

diverticular disease –a

randomised double-blid controlled

trial

C.L. Kvasnovsky, S. Papagrigoriadis, N.

Donaldson, I. Bjarnason

King's College Hospital, London, UK

Disclosures

• Symprove Research Grant to King’s College Hospital for RCT on treatment of chronic symptoms of diverticular disease

Gut Microbiome: Large & Complex

• 100 trillion bacteria

• 500 -1,000 species

• Weight of 1 kg!

• Great variance: • Only 18 species common in all

individuals

• 75 common species in half of people

Hierarchical organization of taxonomic levels used for

classifying organisms. Adapted from Tyler et al.

• Gut microbes are only 7-9 of 50 known bacterial phyla:

• Firmicutes

• Bacteroides

• Proteobacteria

• Actinobacteria

A role under exploration

• Colonic bacteria responsible for fermentation of 10% of daily nutrition

• Digestion of amino acids and glycans

• Vitamin production

• Fluid reabsorption

• Prevention of pathogen development

• Role in immune function & disease state under exploration

Anti-inflammatory role

• Bacteria ferment dietary fibre into short chain fatty acids SCFA • Butyrate

• SCFA are main energy source for colonic epithelial cells • SCFA: anti-inflammatory action

• Limit lymphocyte proliferation • Inhibit IL-2 and other cytokines • Decreased SCFA exposes to increased inflammation • SCFA improve Glucose regulation

In UC microbiome changes exist with effectiveness of treatment

• IBD patients have decreased SCFA producing bacteria which results in reduced SCFA detectable in patients’ faeces

• Treatment alters microbiome: • Immunosuppressants and infliximab increase enterococcus • 5 ASA reduce Escherichia/ Shigella

• Probiotics improve efficiency of treatment in UC and also in pouchitis after surgery

• Mallon 2007

• Naidoo 2011

• Shen 2014

• Tomasz 2014

Large alterations of microbiome in Irritable Bowel Syndrome

• The variety of forms of IBS presents various types of microbiome

The Microbiome in Diverticular Disease

• Higher levels on mucosa of colon of bifidobacterium in diverticulitis than in IBD or cancer

• Guiemonde 2007

• Comparison of microbiome between acute diverticulitis and controls with PCR and Principle Coordinate Analysis

• Different microbiome patterns in diverticulitis • Proteobacteria and Enterobacteriacae differences could predict the

diagnosis with accuracy 84%

• Daniels 2014

Probiotics

• “Live microorganisms which when administered in adequate amounts confer a health benefit to the host”

• Have shown benefits in several conditions

• Addition of VSL3 increased remission in ulc colitis

Sood 2009

• VSL3 protects from pouchitis

• Gionchetti 2003

• Prevention of antibiotic-associated diarrhoea

• McFarland 1998

Probiotics in Diverticular Disease Lead author,

Year

Study design Probiotic Indication / time since

symptom onset

Cases vs. Controls Outcome

Tursi, 2013 179 DB RCT* mesalazine +/- L.

casei

Maintenance of remission

symptomatic diverticular

disease / Asymptomatic

patients enrolled, unclear

time since last symptom

55 patients on

probiotic only vs. 54

patients on probiotic

+ mesalamine and 50

patients on placebo

Probiotic alone was

equivalent to mesalazine

in terms of recurrence

disease, combination did

best

Tursi, 2006 180 open label RT mesalazine +/- L.

casei

Prevention of recurrence

of symptomatic

diverticular disease /

Unclear

29 patients on

probiotic only vs. 29

patients on probiotic

+ mesalazine

Equivalent to mesalazine

in terms of recurrence

disease, combo did best

Tursi, 2007 181 randomised pilot

study

VSL#3 +/- balsalazide Prevention of recurrence

of diverticulitis / At least

2 weeks after diverticulitis

episode

15 patients on

probiotic alone

10% overall relapse rate,

no difference between

groups

Stollman, 2013 37

DB RCT mesalamine +/- B.

infantis

Remission of symptoms

following acute

diverticulitis / Within 2

weeks of acute

diverticulitis episode

36 patients on

mesalamine and

probiotic vs. 41

patients on probiotic

and 40 patients on

mesalamine only

Addition of probiotic did

not increase efficacy of

mesalamine

Lahner, 2012 32 RCT Fibre +/- L. paracasei Remission of

symptomatic diverticular

disease / Unclear

30 patients on

probiotic plus fibre

vs. 22 patients high

fibre only

Faster improvement of

symptoms compared to

control; less bloating.

Fric, 2003 182 Open-label case

series

E. Coli Nissle 1917

for 5 weeks

Remission of

symptomatic

uncomplicated

diverticular disease /

Unclear

15 patients Prolonged the remission

period and improved the

abdominal syndrome

Annibale, 2011 183

RCT High-fibre diet +/- 1

or 2 sachets

Lactobacillus

paracasei F19, 14

days/month for 6

months

Remission of

symptomatic

uncomplicated

diverticular disease /

Unclear

18 patients on one

sachet probiotic BID

vs. 16 patients on 2

sachets BID vs. high

fibre alone

Probiotic better than

fibre alone in decreasing

abdominal pain and

bloating

Lamiki, 2010 184 Open-label case

series

**SCM-III for 6

months

Remission of

symptomatic

uncomplicated

diverticular disease /

Unclear

46 patients 68% symptom free

following study

Giaccari, 1993 185

Open label case

series

Lactobacillus spp.

5x108 7 days out of

the month, rifaxamin

else, for 12 months

Remission of

symptomatic

uncomplicated

diverticular diasease /

Unclear

79 patients 80% symptom free

following study

Symprove

• The probiotic examined was Symprove (Symprove Ltd, UK)

• Liquid form

• Four strains of bacteria • Lactobacillus rhamnosus

• L. plantarum

• L. acidophilus

• Enterococcus faecium

Which Probiotics Survive the Stomach?

M. Fredua-Agyeman and S. Gaisford Beneficial Microbes, 2015; 6(1): 141-151

Comparative survival of commercial probiotic formulations: tests in biorelevant gastric fluids and real-

time measurements using microcalorimetry

School of Pharmacy, University College London

• 8 commercially available probiotics tested

• 3 only showed to survive gastric acid and be able to subsequently proliferate • ACTIMEL

• SYMPROVE

• VSL#3

M. Fredua-Agyeman and S. Gaisford

146 Beneficial Microbes 6(1)

Table 2. Buffer capacity, osmolality, pH and surface tension of porcine gastric fluid, the simulated gastric fluids and human

gastric fluid.

Simulated fluid pH Buffer capacity (mmol/l/∆pH) Osmolality (mOsm/kg) Surface tension (mN/m)

PGF1 3.381±0.031 12.85±0.684 255.333±0.577 46.075±2.552

SGF2 1.2 1.211±0.022 43.333±0.714 255.667±0.577 74.175±3.562

FaSSGF3 1.6 1.599±0.008 41.7±0.404 138.000±1.000 52.038±2.202

SGF2 3.4 3.363±0.020 1.7±0.424 82.25±1.8930 73.183±0.248

FaSSGF 3.4 3.372±0.036 1.233±0.236 83.50±1.9149 65.383±1.864

Human gastric fluid 1-2.5 4

up to 5 (fed)5

7-18 (fasted)6

14-28 (fed)6

559-217 6 30-31 6

35-45 7

1 Porcine gastric fluid (PGF) was taken from a freely fed animal; volume was the only variable for the fed versus fasted test system.2 Simulated gastric fluid (SGF) made to pH 1.2 or 3.4.3 Fasted state simulated gastric fluid (FaSSGF) made to pH 1.6 to represent the fasted state.4 Evans et al. (1988).5 Fordtran and Walsh (1973).6 Kalantzi et al. (2006).7 Efentakis and Dressman (1998).

0

2

4

6

8

0

2

4

6

8

0 5 10 15 20 25 30

0

2

4

6

8

Via

ble

cells

/log

(cfu

/ml)

Time/min

A

B

C

ActimelAlignBiobalance supportBio-kult

Pro-bio 7SymproveVSL3Yakult

Figure 2. Gastric tolerance of commercial probiotic products

in (A) porcine gastric fluid, (B) simulated gastric fluid and (C)

fasted state simulated gastric fluid at matched pH 3.4.

0

2

4

6

8

0 5 10 15 20 25 30

0

2

4

6

8

Via

ble

cells

/log

(cfu

/ml)

Time/min

A

B

ActimelAlignBiobalance supportBio-kult

Pro-bio 7SymproveVSL3Yakult

Figure 3. Gastric tolerance of commercial probiotic products in

(A ) s im ulated gas tric fluid (p H 1.2 ) an d (B ) fas ted s tate s im ulated

gastric fluid (pH 1.6).

• RCT on 152 pts

• Symprove was associated with a significant reduction of IBS symptoms compared with placebo

• RCT on 160 patients

• Symprove increases mucosal healing

A Randomised controlled trial on a liquid multi-strain probiotic v. placebo in symptomatic

diverticular disease

• AIM: to examine the effect of a probiotic on symptoms of uncomplicated diverticular disease

• MATERIALS: Patients attending the Diverticular Disease Clinic of King’s College Hospital

• Diagnosis put with CT scan, colonoscopy, clinical and laboratory

• At least 3 months of symptoms

• No complications

• METHODS: Randomized double – blind controlled trial

• DURATION: 3 months

• London- Riverside Ethics/ R&D Committee, Clinicaltrials.gov NCT02115867

• Study funded by probiotic manufacturer Symprove Ltd.

• Primary Outcome: reduction in abdominal pain from month 0 to month 3

• Secondary Outcomes: • Symptom scores (diarrhoea, constipation, PR bleeding, mucorrhea, dysuria,

back pain, vaginal discharge, bloating)

• Quality of life measured with SF-8

Table 1: Baseline characteristics of patients with symptomatic diverticular disease enrolling in clinical trial

All Placebo Trial P value N = 143* N = 72 N = 71

Patient characteristics

Age 63

(52-72)

63.5

(54-72.5)

60 (52-72) 0.55

Male 45 (31.5) 20 (44.4) 25 (55.6) 0.34

BMI* 28.5 (24.9-32.2)

29.5 (25.1-32.3)

27.7 (24.6-31.9)

0.8

Ethnicity

White 89 (62.2) 43 (48.3) 46 (51.7) 0.49

Black 42 (29.4) 21 (50.0) 21 (50.0)

Other 12 (8.4) 8 (66.7) 4 (33.3)

ASA

1 41 (28.7) 20 (48.8) 21 (51.2) 0.81

2 82 (57.3) 43 (52.4) 39 (47.5)

3 20 (14.0) 9 (45.0) 11 (55.0)

Previous probiotic use

No previous probiotic 105 (73.4) 55 (52.4) 50 (47.6) 0.42

Probiotic within the last 6 months,

including yogurt

29 (20.3) 15 (51.7) 14 (48.3) 0.87

Pain at trial start

Lower abdominal pain 125 (87.4) 63 (50.4) 62 (49.6) 0.97

No abdominal pain 8 (5.6) 5 (62.5) 3 (37.5) 0.48

Moderate or severe bloating 73 (52.5) 38 (52.1) 35 (48.0) 0.67

Bowel habits at trial start

Normal 3 (2.1) 0 3 (100) 0.44

Bloating only 10 (7.0) 4 (40.0) 6 (60.0)

Constipation 34 (23.8) 18 (52.9) 16 (47.1)

Loose stools 43 (30.1) 23 (53.5) 20 (46.5)

Alternating 53 (37.1) 27 (50.9) 26 (49.1)

Prior history of acute diverticulitis

Prior diverticulitis 91 (63.6) 49 (53.9) 42 (46.2) 0.27

Number prior episodes 1 (0-3) 1 (0-3) 1 (0-2) 0.54

Hospitalised with acute

diverticulitis

85 (59.4) 43 (50.6) 42 (49.4) 0.94

Location of diverticula

Left-sided disease 116 (84.7) 58 (50.0) 58 (50.0) 0.84

Pan disease 23 (16.8) 12 (52.2) 11 (47.8) 0.79

FC** 41.5 (21.5-

112)

47.5 (22-

125)

36.5 (21-

111)

0.23

* Row percents presented with N (%) listed, except ** median (IQR). LLQ- left lower

quadrant

• Age 63 (52-72)

• 31% Males

• BMI 28.5 (24.9 – 32.2)

• 62% Whites, 29% Blacks

• 75% ASA I/ II

• Abdominal Pain 87%

• Bloating 52%

• Normal Bowel Habits 2%

• Constipation 23%

• Loose stools 30%

• Alternating 37%

• Prior Acute Diverticulitis 63%

• 1 episode (0-3)

• Hospitalized 59%

• Left Disease 84%

• Faecal Calprotectin + 41%

Baseline Characteristics

Pain score change was not significantly different at end of study

Other symptoms improved on Symprove at end of study

• Constipation p=0.0000

• Diarrhoea p=0.001

• Mucorrhea p-0.03

• Back pain p=0.01

• No difference in Quality of Life as measured by SF-8

Symprove associated with decrease in faecal calprotectin significantly in males

Table 3: Multivariate linear regression for final faecal

calprotectin result in male patients only

Variable Univariate

parameter

estimate (95%

CI)

P

valu

e

Multivariate

parameter

estimate (95%

CI)

P

value

Log

baseline FC

0.46 (0.08-

0.84)

0.02 0.41 (0.04-

0.78)

0.03

Symprove -0.96 (-1.74- -

0.18)

0.02 -0.76 (-1.5-0) 0.05

Prior

diverticuliti

s

-0.37 (-1.28-

0.54)

0.41 -0.51 (-1.30-

0.28)

0.20

Adverse Events

• More patients on placebo had an episode od acute diverticulitis during the trial (8) v. on Symprove (3) > p=0.12 –non significant

• No difference in time to diverticulitis

• One (placebo) patient was hospitalised

• 25 patients experienced 28 adverse events (15 Symprove, 13 Placebo)

• Nausea, abdo pain, minor PR bleeding, constipation, dyspepsia

• No difference in adverse events (p=0.71)

• Equally resulting in treatment terminations (p=0.06)

Discussion • The 4 strain probiotic Symprove did not reduce abdominal pain in

patients with chronic symptoms of uncomplicated diverticular disease

• Chronic Pain may have established sensory abnormalities

• Symprove was associated with improvement in other abdominal symptoms, constipation, diarrhoea, mucous discharge.

• Symprove was associated with a lower faecal calprotectin in males

• The findings suggest that Symprove may be beneficial in certain groups of patients with uncomplicated DD • Those with persistent inflammation as shown by faecal calprotectin • Those with functional symptoms of constipation, diarrhoea, mucous

discharge

• Data on microbiota of trial patients are under analysis

• A further RCT has been planned at King’s College Hospital to examine the role of Symprove in settlement of inflammation after hospitalised acute diverticulitis.