Clinical Nutrition ESPEN xxx (2017) 1e7

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Clinical Nutrition ESPEN

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Original article

Clinical effects of probiotics in cystic brosis patients:

A systematic review
Stephanie Van Biervliet a, Dimitri Declercq a, Shawn Somerset b, *
a
Cystic Fibrosis Centre, University of Ghent, Belgium
b
School of Allied Health, Faculty of Health Sciences, Australian Catholic University, Brisbane, Queensland, Australia

a r t i c l e i n f o s u m m a r y

Article history: Cystic brosis (CF) is characterised by a build-up of thick, intransient mucus linings of the digestive and
Received 26 January 2017 respiratory mucosa, which disrupts digestive system functioning and microbiota composition. In view of
Accepted 27 January 2017 the potential for probiotics to enhance microbiota composition in other contexts, this study investigated
the current evidence for probiotics as an adjunct to usual therapy for CF. Electronic clinical databases
Keywords: were interrogated for human randomised, controlled, intervention trials (1985e2015) testing the effects
Probiotics
of probiotics on clinical endpoints in CF were reviewed. From 191 articles identied in initial searches, six
Inammation
studies met the critical inclusion criteria, and were reviewed in detail. These studies varied in size
Cystic brosis
Systematic review
(n 22 to 61) but were generally small and showed substantial diversity in protocol, specic probiotic
species used and range of clinical outcomes measured. Probiotic administration showed benecial effects
on fecal calprotectin levels, pulmonary exacerbation risk, and quality of life indicators. In one study, such
changes were associated with variations in gut microbiota composition. Despite encouraging preliminary
results, the limited number of small and highly varied studies to date do not justify the addition of
probiotics as an adjunct to current CF treatment protocols. Importantly, very minimal adverse effects of
probiotics have been reported.
2017 European Society for Clinical Nutrition and Metabolism. Published by Elsevier Ltd. All rights
reserved.

1. Introduction The inuence of pancreatic insufciency on inammation is not

Although recent advances in CF treatment protocols have led to
substantial improvements in nutritional status, gut inammation
remains an important issue inuencing growth and clinical status
[1,2]. Since there is a strong relationship between gut inammation
and the systemic inammatory state, the understanding, preven-
tion and treatment of gut inammation has become a promising
new approach to CF management [3]. Gut inammation is often
measured using faecal calprotectin. This leucocyte-derived protein
remains stable in faeces, reects the number of activated leuko-
cytes in the gut and can be measured using commercially available
immunoassays [4]. Calprotectin is, however, degraded by trypsin
[5,6] and therefore correlates best with lower gut inammation [7].
Abbreviations: CF, cystic brosis.
* Corresponding author. School of Allied Health, Faculty of Health Sciences,
Australian Catholic University, Brisbane, Queensland, PO Box 456, Virginia 4014,
Australia.
E-mail address: shawn.somerset@acu.edu.au (S. Somerset).
well studied up to now [6].
The CF gut is characteristically susceptible to bacterial over-
growth due to impaired mucosal barrier function [8e10], disturbed
gut motility, thick mucus layers [11] and frequently used CF treat-
ments such as proton pump inhibitors and antibiotics [12]. Small
intestinal bacterial overgrowth indeed inuences fat absorption,
however, this is not the sole explanation of gut inammation
[13,14].
A dysbiosis characteristic of CF has been described in the liter-
ature, albeit based on only a limited number of small studies [15].
The microbiota is characterised by a tendency for decreased bac-
terial abundance, diversity and species richness. Some studies
indicate a reduction in Firmicutes, Bacteroides, Bidobacterium and
Clostridium cluster XIVa, corresponding to increases in Enterobac-
teriaceae, and Fusobacterium species [16]. Larger and more detailed
studies are needed to conrm these initial observations, and to
specify the location within the gastrointestinal tract where these
variations occur.
Probiotics have been shown to resolve dysbiosis in a range of
clinical contexts clinical effects, however, need further

http://dx.doi.org/10.1016/j.clnesp.2017.01.007
2405-4577/ 2017 European Society for Clinical Nutrition and Metabolism. Published by Elsevier Ltd. All rights reserved.

Please cite this article in press as: Van Biervliet S, et al., Clinical effects of probiotics in cystic brosis patients: A systematic review, Clinical
Nutrition ESPEN (2017), http://dx.doi.org/10.1016/j.clnesp.2017.01.007
2 S. Van Biervliet et al. / Clinical Nutrition ESPEN xxx (2017) 1e7
investigation [17]. In CF, some studies have reported that despite
the paucity of supporting evidence, the use of probiotics is
rational. Del Campo reected that the use of probiotics has been in
practice since the 1980s, despite a lack of appropriate evidence and
specic guidelines. In view of the disrupted digestive functioning in
CF, and an apparent plausibility for a therapeutic role for probiotics
in CF [18], this study sought to ascertain the current level of sup-
porting evidence for probiotics as an adjunct to usual practice.
2. Methods
2.1. Review question
This systematic literature review was conducted on the clinical
effects of probiotic supplementation in patients with cystic brosis.
For the review nutritional status, gastrointestinal inammation,
pulmonary function and exacerbations were considered as primary
outcomes and quality of life, abdominal complaints and faecal
microbiotic composition as secondary outcomes.
2.2. Review method
The review is performed following the guidelines of the centre
for reviews and Dissemination procedures [19].
Study selection: selection criteria are described in Table 1.
2.3. Study identication
Three independent researchers conducted literature searches in
December 2015 using the databases PubMed, Web of Science and
the CCTR using the following MESH terms: probiotics; Micro-
biota; AND cystic brosis' as well as the free text microbiome.
Reference lists of each identied study were reviewed to locate
any further relevant studies. The lists of studies identied by each
of the three independent researchers were compared and differ-
ences resolved to control for selection bias.
To Account for unpublished data, clinical trials registries were
searched for studies using the terms cystic brosis and probiotics.
The registries searched were: EU Clinical Trials register, Clinical
Trials.gov, Netherlands trial register, IRSCTN registry, IRCT registry,
panAfrican Trial registry.
3. Results
This systematic review investigated current evidence support-
ing probiotic supplementation as part of dietary management for
cystic brosis. Reference list audit revealed no further studies.
Initial literature searches yielded 191 articles of which 188 were
written in English, 174 were human studies, 126 were research ar-
ticles and 25 dealt with the gut microbiome (Fig. 1). There were 16
studies describing the microbiome and 3 studies used supplements
without control population, leaving six randomised controlled
intervention studies for the present review [20e25], summarised
in Table 2. Different clinical trial registry sites (EU Clinical Trials
register, Clinical Trials.gov, Nederlands trial register, IRSCTN regis-
try, IRCT registry, panAfrican Trial registry) were searched for
Table 1
Inclusion and exclusion criteria used to select the articles of interest.
Inclusion criteria
Full text available
Written in English
Placebo controlled probiotic intervention study in Cystic brosis patients
Clinical outcome parameters
Please cite this article in press as: Van Biervliet S, et al., Clinical effects of probiotics in cystic brosis patients: A systematic review, Clinical
Nutrition ESPEN (2017), http://dx.doi.org/10.1016/j.clnesp.2017.01.007
174 Arcles
16 arcles
126 Research
describing
arcles
microbiome
25 Gut 3 Uncontrolled
Microbiome probioc trials
6 Randomised
controlled
probioc trials
Fig. 1. Overview of the article selection process.
unpublished studies. Summary of excluded intervention studies as
well as the results of registry search for unpublished studies are
given in Table 3.
Important limitations of this review are due to common general
issues associated with these studies include small sample size,
short follow-up duration, varied probiotic formulations and varia-
tions in outcome indicators used to measure clinical effects. None of
the studies used corrections for multiple analyses. Elevated drop-
out rates in some studies weakened data analysis and conclusions
(Table 1). Across the six studies identied for the present review, a
range of clinical outcomes were explored: Gastrointestinal and
nutritional effects, microbiome changes, pneumological effects and
quality of life effects. However, the way of reporting varied largely
making pooling of data impossible.
Over all the studies included 14/249 patients dropped-out of the
study protocol [20,25]. The reasons were: non fullment of protocol
(n 5), vaginal candida (n 3), pulmonary exacerbation (n 5)
and vomiting (n 1). In the not included studies only Weiss et al.
mention atulence in 3/10 patients which was not important
enough to stop the probiotic [26].
3.1. Gastrointestinal and nutritional effects
Faecal calprotectin, an indicator of gastrointestinal inamma-
tion, decreased in 3 studies (Fallahi (number of included patients
(n 47) (p 0.031)), Bruzzese (n 22) (p < 0.001) and del Campo
(n 39) (p 0.003)) after the probiotics use [20,21,23]. However,
the study by Di Nardo et al. (n 61) showed no signicant change
(ns) (Table 4) [22]. Faecal calprotectin levels at baseline varied
markedly, from 33 (23.5 mg/g) to 184 (146 mg/g). To evaluate the
clinically relevant decrease, the proportion of patients with a
normal calprotectin was extracted from studies (Table 4). Pooled
together, 51/96 (53%) CF patients had an abnormal calprotectin
value (>50 mg/g) at baseline or after placebo [20,21,23]. This
Exclusion criteria
Reviews, opinions, letters
Other languages
Animal or experimental studies
No clinical outcome parameter
 Table 2
Nutrition ESPEN (2017), http://dx.doi.org/10.1016/j.clnesp.2017.01.007
Please cite this article in press as: Van Biervliet S, et al., Clinical effects of probiotics in cystic brosis patients: A systematic review, Clinical
Overview of the retained articles after the literature search. (L. lactobacillus, B. Bidobacterium, S. Streptococcus, E. Eubacterium, F. Faecalibacterium, CFU Colony forming units, NS not signicant p value not
mentioned in the article, FEV1%: forced expiratory volume in 1 s %, BMI body mass index, GIQLI gastrointestinal quality).
Reference Study design & duration
del Campo et al. Randomised Double blind
[20] Placebo
controlled
Cross over (6 months)
Bruzzese et al. Randomised Double blind
[21] Placebo
controlled (1 month)
Di Nardo et al. Randomised Double blind
[22] Placebo
controlled (6 months)
Fallahi Randomised Double blind
et al. [23] Placebo
controlled (1 month)
Jafari SA et al. [24] Randomised Double blind
Placebo
controlled (1 month)
Bruzzese E et al. Randomised Single blind
[25] Placebo controlled
Cross over (6 months)
Patients included Probiotic & dosage Primary and secondary outcome Major inclusion/exclusion criteria
& signicance
N 39 L. reuteri FEV1% no change (p 0.73) Inclusion
(9 drop-out; 23%) 108 CFU BMI no change (p 0.98) CF patients >4 years
Median age: 17.7 yr Weight no change (p 0.95) Exclusion
Range: 8e44 Calprotectin decrease (p 0.003) Terminal stage of disease,
GIQLI improved (p 0.003) Acute pulmonary exacerbation
Microbiotic diversity no sign change Acute exacerbation of lung infection, immune decient
(p-value condition.
not mentioned)
N 22 L. rhamnosis GG Calprotectin decrease (p < 0.05) Inclusion
(0 drop-out) 6  109 CFU Microbiome changed: Bacteroides decrease Clinically stable children with CF
10 placebo (p 0.03) No acute intestinal or extraintestinal diseases
12 probiotic E. rectale, F. prausnitzii no change (ns)
Median age: 7 yr
Range: 2e9
S. Van Biervliet et al. / Clinical Nutrition ESPEN xxx (2017) 1e7
N 61 L. reuteri FEV1% no change (NS) Inclusion
(1 drop-out; 1.6%) 1010 CFU Exacerbations decrease (p < 0.01) FEV1 > 70%;
Median age: 17.5 yr Hospitalisations no change (NS) No inhaled or systemic steroids;
Range: 6e29 Calprotectin no change (NS) No antiinammatory drugs, antileukotrienes, and mast cell
membrane
Stabilizers;
No serious organ involvement.
Exclusion
History of pulmonary exacerbation or upper respiratory
infection
In previous 2 months;
Changes of medications in last
2 months;
History of haemoptysis in last 2 months;
Colonization with Burkholderia cepacia or mycobacteria.
N 47 Mix: L. rhamnosis, Calprotectin decrease (p 0.031) Inclusion
(0 drop-out) L. acidophilus, >4 years of age
23 placebo L. casei, L. bulgaricus, B. breve, CF diagnosis based on two positive sweat tests,
24 probiotic B. infantis, S. thermophilus All had steatorrhea as sign of pancreatic insufciency.
Mean age: 8.6 yr (4.2) 109 CFU Not used any non-steroidal anti-inammatory drug for two
weeks.
Not on antibiotic therapy at time of study.
N 37 Mix: L. rhamnosis, IV treated exacerbation (p 0.96) Inclusion
(0 drop-out) L. acidophilus, Orally treated exacerbation (p < 0.01) Aged 2e12 years,
17 placebo L. casei, L. bulgaricus, B. breve, PEDsQL Parent (p 0.01) Positive sweat test (Cl >60 meq/l) absence of other chronic
20 probiotic B. infantis, S. thermophilus PEDsQL Child (p 0.6) illnesses
Mean age: 5.4 yr (2.7) 2  109 CFU Pancreatic insufciency was common
N 43 L. rhamnosis GG FEV1% increase (p 0.008) Inclusion
(5 drop-out; 11.6%) 6  109 CFU Exacerbations decrease (p 0.02) Children with elevated sweat Cl_concentration,
Mean age: 13.3 yr Hospitalisations decrease (p 0.01) Moderate/severe disease
Range: 5e18 Weight increase if probiotic rst (p 0.01) Chronically infected with Pseudomonas,
BMI no change (NS) All had pancreatic insufciency
All had preventive administration of inhaled antibiotics.
All were enrolled within one month from the last suppressive
therapy
3
4 S. Van Biervliet et al. / Clinical Nutrition ESPEN xxx (2017) 1e7

Table 3
Overview of published and registered studies not included in the review. (NS mentioned as non signicant in the article without the exact p value).

Article Study type Language Clinical data

Intestinal inammation is a frequent feature of cystic brosis and is reduced by probiotic Uncontrolled open English Calprotectin decrease (p < 0.01)
administration. Bruzzese E, Raia V, Gaudiello G, Polito G, Buccigrossi V, Formicola V, (n 10, 1 m)
Guarino A. Aliment Pharmacol Ther. 2004 Oct 1; 20 (7): 813e9. (NCT01956916)
Improvement of intestinal function in cystic brosis patients using probiotics. Uncontrolled open study Spanish Abdominal comfort improved (81%)

n O, Maldonado
Infante Pina D, Redecillas Ferreiro S, Torrent Vernetta A, Segarra Canto (n 20, 1 m) Number of stools decreased (56%)
Smith M, Gartner Tizziano L, Hidalgo Albert E. An Pediatr (Barc). 2008 Dec; 69 (6): Stool fat decreased (p < 0.05)
501e5. Spanish. Stool Sugar decreased (p < 0.05)
Probiotic supplementation affects pulmonary exacerbations in patients with cystic Uncontrolled open study English Exacerbations decreased (p 0.02)
brosis: a pilot study. Weiss B, Bujanover Y, Yahav Y, Vilozni D, Fireman E, Efrati O. (n 10, 6 m) Sputum culture identical (NS)
Pediatr Pulmonol. 2010 Jun; 45 (6):536e40. doi: 10.1002/ppul.21138 (NCT01201434) IL-8 identical (NS)
Pulmonary function identical (NS)

Registry search Study n Study evolution, type

ClinicalTrials.Gov registry NCT00977158 Withdrawn before start

IRCT registry IRCT201205219823N1 Unblinded, uncontrolled
ACTRN12616000797471 Not yet started July 2016
EU Clinical Trials Register EudraCT Nr: 2009- Ongoing since 2009
015875-28
EudraCT Nr: 2009- Ongoing since 2009
011289-27

Table 4
Calprotectin results in the different treatment arms from the different studies. (Co Controlled, IQR interquartile range, NS not signicant P value not mentioned in article,
* Chi-square on clustered data).

Study Group Calprotectin value Number abnormal

calprotectin values

Before After Before After

Fallahi et al. [23] Placebo (n 23) 70.2 182.1 13/23 15/23

Placebo Co (Mean, no SD) Probiotic (n 24) 101.4 56.2 18/24 3/24
(p 0.1) (p 0.031)
Bruzzese et al. [21] Placebo (n 12) 251 (174) 176 (125) 12/19
Placebo Co Probiotic (n 10) 164 (70) 78 (54)
(p < 0.05)
Di Nardo et al. [22] Placebo (n 31) 37.2
Placebo Co Probiotic (n 30) 60.6
(NS)
del Campo et al. [20] After placebo (n 30) 33.8 (23.5) 8/30
Cross-over After probiotic (n 30) 20.3 (19.3) 3/30
(Median and IQR) (p 0.03)
Summary Baseline/Placebo 51/96
Probiotic 6/54 (p 0.0001*)

decreased to 6/54 (11%) after probiotic supplementation
(p 0.0001).
Abdominal complaints, investigated in one study (n 39) [20],
improved signicantly (p 0.003) after probiotic use using a
gastrointestinal quality of life index (GIQLI) [27].
Two studies examined potential effects of probiotics on body
weight or body mass index (BMI), with a paucity of statistically
signicant effects. The cross-over study of Bruzzese et al. (n 43)
showed weight gain in children after probiotic supplementation,
although this gain was only statistically signicant (p 0.03) in the
group receiving probiotics rst [25]. Further, the body weight dif-
ference was only 300 g (0.07 kg/m2) which may not be clinically
signicant since time of day for weighing was not articulated. No
differences in BMI were observed. del Campo et al. (n 39) showed
non-signicant (p 0.95, 0.98) increases in body weight and BMI,
respectively [20].
Although much of the conceptual basis for probiotics use in CF is
based on an apparent dysbiota characteristic of CF, only two studies
actually evaluated the potential effects of probiotic intervention on
microbiota composition [20,21]. del Campo et al. (n 39) found
that probiotic therapy was associated with an overall increase in
bacterial diversity (16S rDNA sequences density 630 3353.6 vs
1221 4653.6), although not statistically signicant [20]. At
baseline, a predominance and potential overgrowth, in g-proteo-
bacteria and an associated decrease in Firmicutes and Bacteroides
was noted. Bruzzese et al. (n 22) described a signicant
(p < 0.001) increase in Bacteroides, and a non signicant increase in
Faecalibacterium prausnitzii and Eubacterium rectal, after probiotic
intake in children [21].
3.2. Pneumological effect
Pulmonary function data are available in two studies. Bruzzese
et al. (n 45) described an improved FEV1% (p 0.008) after
probiotic treatment [25]. Twenty of the 29 children able to perform
pulmonary function tests increased their FEV1% after probiotic
treatment compared with no change during the placebo period. In a
larger study (n 61) of both adults and children, Di Nardo et al.
found a more important decline in FEV1%, though not signicant, in
the placebo group (2.64 (10.3) probiotic, 4.15 (12.8) placebo)
[22]. The authors speculated that inammatory markers in sputum
may be more reliable as an indicator of lung deterioration than
FEV1% in this particular context.
Pulmonary exacerbations declined after probiotic administra-
tion in all studies reporting them [22,24,25] (Table 5). Di Nardo
et al. (n 61) described an important decreased risk of pulmonary

Please cite this article in press as: Van Biervliet S, et al., Clinical effects of probiotics in cystic brosis patients: A systematic review, Clinical
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 S. Van Biervliet et al. / Clinical Nutrition ESPEN xxx (2017) 1e7
Table 5
Data from different studies concerning the exact amount of exacerbations and hospitalisations. (IQR interquartile range, sd standard deviation, Hosp/exa hospitalisations
per exacerbation).
Article
Bruzzese et al. [25] Placebo (median, IQR)
Probiotic (median, IQR)
Di Nardo et al. [22] Placebo
Probiotic
Jafari et al. [24] Mean (sd) Oral treated
Mean (sd) IV treated
exacerbations in the probiotic group (OR 0.06 (CI 0e0.4)), corre-
sponding to a decrease in upper respiratory tract infections (spe-
cically otitis) [22]. However, hospitalisations remained equivalent
in both probiotic and control groups [22]. Bruzzese et al. (n 43)
found a signicant (p 0.03) reduction in respiratory infection
incidence during probiotic treatment, in both pooled and separate
subgroup data [25]. Furthermore, infections were more severe
during the placebo period resulting in an increased hospitalisation
rate [25]. Jafari et al. (n 37) describe a signicant (p 0.0001)
decrease in exacerbation rates in probiotic compared to control
group, as well as decreased oral antibiotic treatment when patients
were compared with themselves in the same months a year prior to
the study (p < 0.01). There was no difference in intravenous anti-
biotic treatment [24].
3.3. Quality of life
Only two studies investigated the impact of probiotics on quality
of life (QoL) indicators, with no clear pattern of effect. Using a
paediatric quality of life inventory, Jafari et al. described differences
(p < 0.01) in total QoL (parental) score between placebo and pro-
biotic groups at 3 months after probiotic cessation [24]. This dif-
ference was not sustained after 6 months, implying that effects may
be linked to the continuation of probiotic supplementation.
Although there were some signicant differences according to
function eld, these were sporadic, inconsistent, and varied be-
tween parent and child reporting, and thus require larger conr-
matory studies to clarify.
del Campo et al. demonstrated a signicant (p 0.003) increase
in QoL associated with probiotic intake and demonstrated a posi-
tive correlation between increased QoL and decreased fecal cal-
protectin levels [20]. A role for probiotics in the prevention of
vulvovaginal candidiasis (a potential mechanism for affecting QoL)
was postulated. However, the reporting of this effect was obser-
vational and requires conrmation in larger, specic studies.
Participant selection is a potential source of bias in each of the
studies, and consequently for the present systematic review.
Table 2 outlines details of the inclusion criteria for each of the
included studies. Having pancreatic insufciency was a common
inclusion characteristic, as was the absence of current courses of
antibiotics. Otherwise the subjects of each of the studies appeared
relatively healthy and without major complications.
4. Discussion
The limitations of the current literature on the clinical effects of
probiotics in cystic brosis are the scarceness of double blind pla-
cebo controlled trials and the varying study protocols as well as
Please cite this article in press as: Van Biervliet S, et al., Clinical effects of probiotics in cystic brosis patients: A systematic review, Clinical
Nutrition ESPEN (2017), http://dx.doi.org/10.1016/j.clnesp.2017.01.007
5
Exacerbation Hospitalisation
2 (4) 32
1 (3) 16
(p 0.02) (p 0.01)
1/30 1 hosp/exa
11/30 1.09 (0.3)
(p < 0.01) (NS)
Before probiotic 2.05 (1.82)
After probiotic 0.7 (1.03)
(p < 0.01)
Before probiotic 0.2 (0.52)
After probiotic 0
(p 0.96)
probiotic strains used. The study durations were also short, varying
from 1 to 6 months, limiting time for major clinical changes to
emerge. Finally, the total of studied patients was 249 but the me-
dian number of included patients per study was only 41 (22e61)
with a drop-out rate of 0.8% (0e23%).
Gastrointestinal problems in cystic brosis are characterised by
pancreatic insufciency and disturbed nutrient absorption [28].
However, other problems such as constipation, distal intestinal
obstruction syndrome [28], intestinal inammation [1,2,29],
abnormal bile acid absorption [30] and bacterial overgrowth
[12e14] can impair the quality of life of CF patients. Patients and
clinicians attempt to alleviate common symptoms such as bloating,
abdominal discomfort and diarrhoea with over-the-counter prod-
ucts such as probiotics. However, there is only limited evidence to
support this therapy in cystic brosis. di Nardo et al. reected on
the rationality of probiotic use as CF patients have a signicant
burden on gut function due to antibiotics and other CF-related
medications [22]. Del Campo et al. reported that probiotics had
been used in their clinical setting since the 1980s [20].
Probiotics are thought to interact with the gastrointestinal im-
mune system, moderating localised inammatory cytokine pro-
duction and gastrointestinal inammation (measured by fecal
calprotectin) [20,21,23]. Fecal calprotectin correlates well with gut
inammation but is susceptible to trypsin degradation [5,6]. In-
testinal inammation has been described in CF [1,2,29], however,
the relation with the level of fecal calprotectin as well as the in-
uence of pancreatic insufciency [6] and pancreatic enzyme
replacement therapy has not yet been reported in CF patients. The
various studies included in this review display a marked variation
in fecal calprotectin at baseline [20e23]. The basis for this variation
is unclear, but factors such as different calprotectin assay methods,
cut-off values as well as the prevalence and extent of pancreatic
insufciency within the study groups could inuence the results.
Calprotectin, being abnormal in half of the studied CF patients at
the start of the study normalised in 90% after probiotic therapy.
Bruzzese et al. described the same decrease in gut inammation in
a previous uncontrolled study monitoring calprotectin as well as
rectal NO measurements [31]. In view of the apparent skewing of
baseline calprotectin levels seen across the reviewed studies, larger
studies are required to discount a possible regression to the mean
effect [32].
Chronic undernutrition with a consequent lower BMI has been
a continuing challenge in CF management [32]. This issue is
particularly critical in children, where failure to thrive has both
short- and long-term consequences critical to survival [33].
Bruzzese et al. demonstrated better growth in children associated
with probiotic intake, a nding which requires conrmation in
larger studies [25].
6 S. Van Biervliet et al. / Clinical Nutrition ESPEN xxx (2017) 1e7
The most favoured mechanism by which gut modications
impact upon pulmonary function is through the relationship be-
tween gut inammation and systemic inammation [3]. Bruzzese
et al. observed a signicant increase in serum IgG during the pla-
cebo period [25]. Di Nardo et al. studied systemic inammation
using plasma TNF alpha, IL-6 and IL-8, but detected no difference
after probiotic treatment [22]. Despite this observation, a decline in
pulmonary exacerbations was observed after probiotic treatment
[22,24,25]. This, however, did not result in an unequivocal
improved pulmonary function nor was there a difference in hos-
pitalisations [22,25]. This apparent contrast might be the result of
the limited study durations.
There was signicant positive effect on the mean quality of life
lasting three months after probiotic cessation [24]. This effect was
attributed to the observed decrease in pulmonary exacerbations.
The evaluation of abdominal complaints using the GIQLI showed a
signicant improvement in gastrointestinal comfort score during
probiotic treatment [20]. Although this test has been used previ-
ously in studies on gastric tumours, transplantation and gallstones
[27], it has not been validated for use in children with CF.
Altered intestinal microbiome in CF, including a reduced bac-
terial variability, has been described in multiple papers
[20,21,34,35]. Bruzzese et al. as well as Del Campo et al. demon-
strated a partial restoration of the intestinal microbiota composi-
tion after probiotic treatment [20,21].
In studies to date, the choice of probiotic strain has been limited
to readily available commercial products, most likely because they
are already in mass consumption and generally regarded as safe.
Although only a small number of clinical trials have been conducted
to date, a majority (4/6) of studies in the present review adopted
Lactobacillus rhamnosis as the probiotic strain, either exclusively or
as part of a cocktail (see Table 2), with some consistency of effect
[21,23e25]. The remaining two studies used Lactobacillus reuteri
[20,22]. All probiotic supplements in the studies reviewed were
puried preparations. The use of probiotics via commercially
available foods remains to be explored.
Finally, it has been shown previously that various bacterial and
yeast strains, not extensively used in commercial food products
(e.g. Bidobacterium animalis, Lactobacillus johnsonii, Bidobacte-
rium lactis and Saccharomyces cerevisiae boulardii) display differing
abilities to affect the immune system [36]. An expansion of the
range of probiotics tested to include these various other species will
provide further insight into the most promising probiotic strains for
clinical applications in CF. A limitation of this review is the limited
access to raw clinical data from each of the studies analysed.
Various limitations in the present review and the studies
included in the analysis are worth noting. The heterogeneity of the
subjects in terms of age, disease severity and treatment history
make generalisability difcult. Further, there is little consistency in
the outcome measures from the various studies, making identi-
cation of general effects challenging. Inconsistency of intervention
in the form of combinations of probiotic strains and the small
number of eligible studies amplify the aforementioned challenges.
A further limitation of this review is the limited access to raw
clinical data from each of the studies analysed.
Despite a recent proliferation in the number of studies related to
the effects of probiotics in the general population, studies specic
to cystic brosis are relatively sparse. Since this scarcity is likely to
continue into the future, a more strategic approach to further
research is necessary. A series of priority areas emerge from the
literature to date. Firstly, a consensus on the microbiota charac-
teristic of cystic brosis is a necessary benchmark for assessing the
impact of probiotic supplementation. Further, an expansion of the
range of probiotics tested to include these various other species will
provide further insight into the most promising probiotic strains for
Please cite this article in press as: Van Biervliet S, et al., Clinical effects of probiotics in cystic brosis patients: A systematic review, Clinical
Nutrition ESPEN (2017), http://dx.doi.org/10.1016/j.clnesp.2017.01.007
clinical applications in CF. Insight into potential prebiotics also
require attention given recent ndings that micronutrient intake is
association with gut microbiota variations in CF [37]. Since the
putative mechanisms for the clinical effects of probiotic supple-
mentation operate via gut inammation, future studies would
benet from an extensive focus on indicators of inammation as
outcome measures. An extension of these measures to assess
immunological crosstalk would be useful, since this is a proposed
mechanism via which changes in the gut can impact clinical effects
in the lung and other organs [38].
5. Conclusion
The limited available evidence suggests a positive effect on in-
testinal inammation, pulmonary exacerbation as well as quality of
life. Only minor potential adverse clinical effects of probiotic usage
were reported comprising bedside vomiting in 1/38 subjects [25]
and mild atulence in 3/10 subjects in another study [26].
Further larger studies on an expanded range of probiotic strains are
needed to conrm these preliminary observations before they can
be recommended as additional treatment in CF patients.
Conict of interest
None.
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