Clinical trial: the effects of a probiotic mixture on non-steroidal anti-inflammatory drug enteropathy - a randomized, double-blind, cross-over, placebo-controlled study.

Abstract

Non-steroidal anti-inflammatory drugs (NSAIDs) can cause serious gastrointestinal side effects. Faecal calprotectin assay represents a simple and practical method for diagnosis of NSAID enteropathy. Intestinal micro-organisms are necessary for the development of NSAID-induced small bowel lesions and hence it has been suggested that probiotics could protect against NSAID enteropathy.
To evaluate the effect of a probiotic mixture in comparison with placebo on faecal calprotectin concentrations (FCCs) in healthy volunteers receiving indomethacin.
In a double-blind, cross-over trial, 20 healthy volunteers ingested a daily dose of probiotic mixture (VSL#3) or placebo for 21 days. From day 16 to day 19, all subjects were also administered 50 mg/day of indomethacin. FCCs were measured the day before starting probiotic/placebo ingestion (T0), and every day from day 15 to day 21.
During dosing with probiotic, median FCCs were significantly increased only at day 17 with respect to T0 values, whereas during dosing with placebo, they were significantly increased at every day from day 17 to day 21 with respect to T0 values.
Treatment with VSL#3 before and during indomethacin therapy significantly reduces FCCs in healthy subjects with respect to placebo, suggesting that this approach could be useful in decreasing indomethacin-induced intestinal inflammation.

Full text

Page 1

For Peer Review







THE EFFECTS OF A PROBIOTIC MIXTURE ON NSAID
ENTEROPATHY: A RANDOMIZED, DOUBLE-BLIND, CROSS-
OVER, PLACEBO-CONTROLLED STUDY.


Journal: Alimentary Pharmacology & Therapeutics
Manuscript ID: APT-0096-2010.R2
Manuscript Type: Original Scientific Paper
Date Submitted by the
Author:
31-Mar-2010
Complete List of Authors: Montalto, Massimo; Catholic University, Internal Medicine
gallo, antonella; catholic university, internal medicine
curigliano, valentina; catholic university, internal medicine
d'onofrio, ferruccio; catholic university, internal medicine
Santoro, Luca; catholic university, internal medicine
covino, marcello; catholic university, internal medicine
dalvai, sara; catholic university, internal medicine
gasbarrini, antonio; catholic university, internal medicine
gasbarrini, giovanni; catholic university, internal medicine
Keywords:
Small intestine < Organ-based, General practice < Topics, NSAIDs
< Topics, Probiotics/prebiotics < Topics




Alimentary Pharmacology & Therapeutic
Author manuscript, published in "Alimentary Pharmacology & Therapeutics 32, 2 (2010) 209"
peer-00552560, version 1 - 6 Jan 2011
DOI : 10.1111/j.1365-2036.2010.04324.x

Page 2

For Peer Review
Istituto di Medicina Interna

1
Original manuscript to Alimentary Pharmacology and Therapeutics


THE EFFECTS OF A PROBIOTIC MIXTURE ON NSAID ENTEROPATHY: A
RANDOMIZED, DOUBLE-BLIND, CROSS-OVER, PLACEBO-CONTROLLED
STUDY.

Massimo Montalto, M.D., Ph.D., Antonella Gallo, M.D., Valentina Curigliano, M.D.,
Ferruccio D’Onofrio, M.D., Luca Santoro, M.D., Marcello Covino, M.D., Sara Dalvai,
M.D., Antonio Gasbarrini, M.D., Giovanni Gasbarrini, M.D.

Institute of Internal Medicine - Catholic University – Rome – Italy

Running Head: probiotics in NSAID enteropathy.
Keywords: NSAID enteropathy, probiotics, fecal calprotectin

CORRESPONDENCE ADDRESS:
Massimo Montalto
Policlinico “A. Gemelli”
Università Cattolica del Sacro Cuore
Largo A. Gemelli, 8 – 00168 – Roma, Italia
Tel: +39-6 30154334
Fax: +39-6 35502775
e-mail: mmontalto@rm.unicatt.it
Page 1 of 21 Alimentary Pharmacology & Therapeutic
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
peer-00552560, version 1 - 6 Jan 2011

Page 3

For Peer Review
be useful in decreasing indomethacin-induced intestinal inflammation.

2

ABSTRACT
Background. Non-steroidal anti-inflammatory drugs (NSAIDs) can cause serious side
gastrointestinal effects. Fecal calprotectin assay represents a simple and practical method for
diagnosis of NSAID enteropathy. Intestinal microorganisms are necessary for the
development of NSAID-induced small bowel lesions, so it has been suggested that probiotics
could protect against NSAID enteropathy.
Aim. To evaluate the effect of a probiotic mixture in respect to placebo on fecal calprotectin
concentrations (FCCs) in healthy volunteers receiving indomethacin.
Methods. In a double-blind, cross-over trial, 20 healthy volunteers ingested a daily dose of
probiotic mixture (VSL#3) or placebo for 21 days. From day 16 to 19 all subjects were also
administered 50 mg/day of indomethacin. FCCs were measured the day before starting
probiotic/placebo ingestion (T0), and every day within the day 15 and 21.
Results. During dosing with probiotic, median FCCs were significantly increased only at
day 17 in respect to T0 values, while during dosing with placebo they were significantly
increased at every day from day 17 to day 21 in respect to T0 values.
Conclusions. Treatment with VSL#3 before and during indomethacin therapy significantly
reduces FCCs in healthy subjects in respect to placebo, suggesting that this approach could
Page 2 of 21Alimentary Pharmacology & Therapeutic
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
peer-00552560, version 1 - 6 Jan 2011

Page 4

For Peer Review
measurement, as well as the intestinal permeability tests (3). In particular, Tibble et al.

3
INTRODUCTION
Non-steroidal anti-inflammatory drugs (NSAIDs) are largely used in clinical settings for
their anti-inflammatory, analgesic and antipyretic effects. Nevertheless, they can also cause
serious side effects, mainly in the gastrointestinal tract (1). Till now, stomach and duodenum
injuries induced by NSAIDs have been well established and described (2). However, there is
a growing interest in NSAID side effects on small bowel (the so-called “NSAID
enteropathy”), since new endoscopical techniques are now are available for the detection of
small intestinal lesions (2-3).
It has been showed that the pathogenesis of NSAID enteropathy is multifactorial, involving
a combination of biochemical events, represented by inhibition of cyclooxygenase (COX) 1
and 2 and by topical effects of NSAIDs on enterocytes, all responsible for an alteration of
mucosal integrity and the disruption of intercellular junctions (2). This results in an increased
intestinal permeability, allowing mucosal exposure to a variety of luminal aggressors
(bacteria, bile acids, etc.), with consequent inflammatory reactions and macroscopic
alterations (3-4).
Different techniques have been used to detect NSAID enteropathy: the recently introduced
enteroscopy and capsule endoscopy, and other indirect methods, such as the assessment of
intestinal inflammation by the 111Indium labeled leucocyte technique or fecal calprotectin
showed that the assay of fecal calprotectin concentrations (FCCs) represents a simple,
practical and reliable method for the diagnosis of NSAID enteropathy in humans (5).
It has been suggested that intestinal microorganisms are necessary for the development of
NSAID-induced small bowel lesions, since “germ-free” animals were found to be resistant
to indomethacin injuries (3,6). It has also been showed that NSAID ingestion may disrupt
the homeostasis of intestinal flora and may induce the overgrowth of Gram-negative and
Page 3 of 21Alimentary Pharmacology & Therapeutic
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
peer-00552560, version 1 - 6 Jan 2011

Page 5

For Peer Review
protective role of a combination of probiotic bacteria in gastrointestinal disorders, such as

4
anaerobic bacterial species, able to exacerbate the intestinal injury caused by NSAIDs (7-
10).
Probiotics have been defined as “living microbial supplements which beneficially affects the
host animal by improving its microbial balance” (11). It has been showed that the use of
probiotic bacteria may have therapeutic effects in gastrointestinal disorders such as
inflammatory bowel diseases (IBDs) (12-15), irritable bowel syndrome (16), intestinal
infections and antibiotic-induced diarrhea (17-18).
In consideration of these evidences, it has been suggested that modulating the intestinal flora
by probiotics could protect against NSAID-induced enteropathy. Some studies using
different strains of probiotics have been carried out on this topic in animals, but results were
not concordant (19-20). The only study performed in humans, by Gotteland et al., showed
that the regular ingestion of Lactobacillus GG (LGG) may protect the integrity of the gastric
mucosal barrier against indomethacin, but has no effect on the intestinal permeability
alterations induced by the NSAIDs (4).
Moreover, uncertainties still remain regarding the probiotic strain to be chosen, the correct
dosage, as well as the possibility of a different efficacy of a probiotic mixture in respect to a
single strain. Just regarding this latter topic, all the above cited works evaluated the probable
protective effect of only a single strain of probiotic. Conversely, different studies showed a
experimental colitis and Crohn’s disease, whereas a single species of probiotic resulted to be
lower or not effective at all (12,21-23). Therefore, the possibility of a synergistic action
among the individual strains present in a probiotic mixture has been suggested, leading to a
more efficacious protective role on gastrointestinal mucosa (21,24).
The aim of this study is to evaluate the effect of a probiotic mixture in respect to placebo on
FCCs in healthy volunteers receiving indomethacin.
Page 4 of 21Alimentary Pharmacology & Therapeutic
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
peer-00552560, version 1 - 6 Jan 2011