Food and Nutrition Sciences, 2013, 4, 27-39
Published Online November 2013 (http://www.scirp.org/journal/fns)
http://dx.doi.org/10.4236/fns.2013.411A005
Open Access FNS
The Role of Lactic Acid Bacteria in the Pathophysiology
and Treatment of Irritable Bowel Syndrome (IBS)
Julia König, Ignacio Rangel, Robert J. Brummer
School of Health and Medical Sciences, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
Received August 30th, 2013; revised September 30th, 2013; accepted October 7th, 2013
Copyright © 2013 Julia König et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
ABSTRACT
Irritable bowel syndrome (IBS) is a multifactorial chronic disorder characterized by various abdominal complaints and a
worldwide prevalence of 10% - 20%. Although its etiology and pathophysiology are complex and still not completely
understood, aberrations along the microbe-gut-brain axis are known to play a central role. IBS is characterized by inter-
related alterations in intestinal barrier function, gut microbe composition, immune activation, afferent sensory signaling
and brain activity. Pharmaceutical treatment is generally ineffective and, hence, most therapeutic strategies are based on
non-drug approaches. A promising option is the administration of probiotics, in which lactic acid bacteria strains are
considered specifically beneficial. This review aims to provide a concise, although comprehensive, overview of the role
of lactic acid bacteria in the pathophysiology and treatment of IBS.
Keywords: Irritable Bowel Syndrome (IBS); Probiotics; Lactic Acid Bacteria; Gut-Brain Axis
1. Introduction
Irritable bowel syndrome (IBS) has a worldwide preva-
lence of 10% - 20%. It strongly affects the patients’ qual-
ity of life and causes substantial economic costs due to
the need for medical consultation and work absenteeism
[1,2]. Symptoms vary between patients and include ab-
dominal pain or discomfort, constipation and/or diarrhea,
bloating, flatulence, fecal urgency, a sense of incomplete
evacuation and relief of pain or discomfort upon defeca-
tion [3].
IBS is a multifactorial disease, and both etiology and
pathophysiology are complex and still not completely
understood. It is, however, well accepted that a dysregu-
lation of the microbe-gut-brain axis plays a profound role.
Associated pathophysiologic aberrations include visceral
hypersensitivity, abnormal gut motility, and autonomic
nervous system dysfunction [4]. Furthermore, there is a
growing evidence that an aberrant function of the im-
mune system is part of the pathogenesis of IBS. Mild
immune activation has been found both locally in the gut
as well as systemically [5], and mucosal biopsies from
IBS patients are characterized by an increased quantity of
various immune-associated cells, including mast cells
[6-8]. Own preliminary data applying immune finger-
printing of intraepithelial and lamina propria lympho-
cytes isolated from mucosal biopsies, show that patients
suffering from IBS after an episode of infectious gastro-
enteritis (so called post-infectious IBS) display an altered
composition of immune cells compared to healthy con-
trols. In agreement with the hypothesis that an altered
bidirectional gut-brain interaction has a central role in
IBS, psychological and environmental factors like anxi-
ety, depression and significant negative life events are
believed to contribute to IBS symptom development [9].
Pharmaceutical treatment, apart from anti-depressive
drugs like selective serotonin reuptake inhibitors (SSRI),
is generally ineffective and, hence, most therapeutic
strategies are directed at improving gut-brain interaction
by improving life style (diet, physical activity, stress
management, etc.) and the intestinal ecosystem (espe-
cially probiotics, see below) as well as by cognitive be-
havioral therapy in selected cases.
A growing body of evidence points to the presence of
an altered intestinal microbiota composition in IBS [10,
11]. Especially post-infectious IBS seems to be causally
linked to aberrations in the gut ecosystem [12]. IBS
symptoms can be improved by treatments targeting the
intestinal microbial ecosystem, such as antibiotics, pro-
biotics (living organisms which upon ingestion have

The Role of Lactic Acid Bacteria in the Pathophysiology and Treatment of Irritable Bowel Syndrome (IBS) 28
beneficial health effects) and prebiotics (food compounds
that are selectively fermented by desirable intestinal mi-
crobiota) [13-15]. Among the bacterial groups compos-
ing the gut microbiota, lactic acid bacteria have gained
most attention as potentially beneficial microbial strains
in probiotics.
This review aims to provide a concise, although com-
prehensive, overview of the role of lactic acid bacteria in
the pathophysiology and treatment of IBS, based on the
paradigm that aberrant microbe-gut-brain interactions
play a pivotal role in IBS.
2. Aberrant Ecosystem in IBS—Focus on
Lactic Acid Bacteria
Numerous studies have investigated the gut microbiota
composition in IBS and found a deregulated ecosystem
that differs from healthy controls [10]. Here, we will put
special emphasis on aberrations regarding lactic acid
bacterial strains (Table 1).
Already earlier studies using culture-based techniques
described abnormal numbers of Lactobacillus and Bifi-
dobacterium in IBS patients. Balsari et al. detected de-
creased amounts of both species in fecal samples of IBS
patients compared to controls [16], while another study
found lower numbers of fecal Bifid obacterium, without
any differences in Lactobacillus and Enterococcus spp.
[17]. Tana et al. found a higher amount of Lactobacillus
in IBS [18]. A study investigating fecal samples of diar-
rhea-predominant IBS (IBS-D) patients detected a ten-
dency of lower amounts of Lactobacillus spp. using cul-
ture-based methods (p = 0.08) [19]. Additional qPCR
analysis, however, revealed contrary results. In this case,
levels of Lactobacillus spp. were significantly higher in
IBS-D than in controls.
Even though culture-based techniques are suitable for
accurate species identification, results must be inter-
preted with caution and are not representative, as only a
fraction of the bacteria in the intestine is cultivable. Ma-
linen et al. were the first to apply a culture-independent,
specifically designed qPCR assay covering approxi-
mately 300 bacterial species for the analysis of fecal mi-
crobiota in IBS [20]. The assay targeted Bifidobacterium,
Lactobacillus and Enterococcus spp., amongst others.
When dividing the IBS patients according to symptoms,
they found that lower amounts of Lactobacillus spp. were
present in fecal samples of IBS-D compared to constipa-
tion-predominant patients (IBS-C). Furthermore, in com-
bined samples from all IBS subtypes collected at three
time points during a 6-month period, lower amounts of B.
catenulatum were found compared to healthy controls. In
this comparison, no difference could be detected in Lac-
tobacillus and Enterococcus spp. or in strains such as B.
adolescentis, B. bifidum, and B. longum. The same re-
search group was also the first to apply high-throughput
16S rRNA (small subunit ribosomal RNA) gene cloning
and sequencing [21]. Pooled bacterial genomic DNA
samples were separated according to their guanine cyto-
sine content to be able to identify also less abundant spe-
cies. In one of the three selected fractions, Lactobacillus
spp. were absent in all IBS samples, whereas in another
fraction, IBS-D patients had significantly lower amounts
of Bifidobacterium spp. Furthermore, qPCR analysis of
the individual samples combining all subtypes suggested
lower levels of B. catenulatum in IBS (p = 0.09). Ra-
jilic-Stojanovic et al. analyzed the microbial composition
of fecal samples in 62 IBS patients and 46 controls, re-
spectively, using a high-throughput phylogenic microar-
ray (HITChip) that enables the unbiased detection of
over one thousand phylotypes [22]. One of the notable
differences between IBS and control samples was a sig-
nificantly decreased level of Bifidobacterium spp. in IBS
patients (all subtypes combined). Here, the most signifi-
cant differences were ascribed to B. gallicum and B.
pseudo catenulatum. In addition, higher amounts of
Streptococcus intermedius et rel., another species com-
prising lactic acid strains, were detected in patients with
IBS and especially in those with alternating episodes of
diarrhea and constipation (mixed type IBS). Lactobacil-
lus and Enterococcus spp. did not differ significantly
between IBS patients and healthy controls. The authors
correlated IBS symptom scores with the abundance of
specific phylogenetic groups and found a negative asso-
ciation of pain scores with Bifidobacterium spp. and a
positive association with L. gasseri et rel. The associa-
tion of specific bacteria with specific IBS symptoms is a
promising tool to provide insight into factors contributing
to IBS. However, it needs to be taken into account that
identical symptoms are not necessarily related to the
same pathophysiology in IBS. Jeffery et al. applied py-
rosequencing of 16S rRNA to analyze the fecal microbi-
ota in IBS [23]. In this study, the IBS patients clustered
into three different groups based on their microbiota
composition. The so-called “normal-like IBS group” con-
sisting of 15 of the 37 included patients was indistin-
guishable from the healthy controls, whereas the two
other groups clustered very differently from the healthy
controls. In these, an increase in B. adolescentis in IBS
was detected, but the number of other Bifidobacterium
species was unchanged. Applying 16S rRNA high-
throughput sequencing, Carroll et al. detected Entero-
coccus and unspecified Lactobacillaceae species in the
fecal samples of IBS-D patients which were below detec-
tion limit in healthy controls [24]. Own preliminary
HITChip data revealed a higher level of several Lactoba-
cillus strains (L. gasseri et rel., L. plantarum et rel., L.
salivarius et rel.) in fecal samples of IBS patients com-
pared to healthy controls, whereas no differences in bifi-
dobacterium spp. were detected.
Most studies published so far have focused on investi-
Open Access FNS

The Role of Lactic Acid Bacteria in the Pathophysiology and Treatment of Irritable Bowel Syndrome (IBS)
Open Access FNS
29
Table 1. Alterations in the intestinal microbiota in IBS—Focus on lactic acid bacteria.
Reference Subject populations Sample Method Outcome
Balsari et al., 1982 [16] IBS (n = 20), HC (n = 20) Feces Culture Lactobacillus and Bifidobacterium spp.
Si et al., 2004 [17] IBS (n = 25), HC (n = 25) Feces Culture Bifidobacterium spp.
Malinen et al., 2005 [20]
IBS (n = 27), HC (n = 22)
IBS-D (n = 12), IBS-C (n = 9),
IBS-A (n = 6)
Feces qPCR
IBS-D vs. IBS-C: Lactobacillus spp.
IBS vs. HC: B. catenulatum
16S rRNA sequencing
after GC profiling
IBS vs. HC: Lactobacillus spp.
IBS-D vs. IBS-C&HC: Bifidobacterium spp.
Kassinen et al., 2007 [21]
IBS (n = 24), HC (n = 23)
IBS-D (n = 10), IBS-C (n = 8),
IBS-A (n = 6)
Feces
qPCR IBS vs. HC: B. catenulatum (p = 0.09)
FISH (only FS) Bifidobacterium spp. (Feces)
Kerckhoffs et al., 2009
[30] IBS (n = 41), HC (n = 26) Feces, duodenal mucosa qPCR B. catenulatum (Feces + mucosa)
Culture Lactobacillus spp.
Tana et al., 2010 [18] IBS (n = 26), HC (n = 26) Feces qPCR no changes in Bifidobacterium spp.
Culture Lactobacillus spp. (p = 0.08) (Feces)
qPCR Lactobacillus spp. (Feces) Carroll et al., 2010 [19] IBS-D (n = 10), HC (n = 10)
Feces,
sigmoidal
mucosa No alterations in mucosa-associated microbiota
Rajilic-Stojanovic et al.,
2011 [22] IBS (n = 62), HC (n = 42) Feces Phylogenetic microarray (HITChip)
Bifidobacterium spp.
B. gallicum and B. pseudocatenulatum
Streptococcus intermedius et rel.
Jeffery et al., 2012 [23] IBS (n = 37), HC (n = 20) Feces 16S rRNA
pyrosequencing IBS subgroups 1&2: B. adolescentis
Carroll et al., 2012 [24] IBS-D (n = 23), HC (n = 23) Feces 16S rRNA sequencingEnterococcus and Lactobacillaceae spp.
Parkes et al., 2012 [29] IBS (n = 47), HC (n = 26)
IBS-D (n = 27), IBS-C (n = 20)Rectal mucosaFISH IBS-C vs. IBS-D&HC: Bifidobacterium spp.
n—number of randomized subjects. FISH—fluorescent in situ hybridization, HC—healthy controls; HITChip—human intestinal tract chip; IBS-A—alternating
mixed type IBS; IBS-C—constipation-predominant IBS; IBS-D—diarrhea-predominant IBS; qPCR—quantitative PCR.
gating fecal microbiota, and not many results can be
found on mucosa-associated bacteria, even though it is
known that their compositions differ significantly
[25-27]. In general, IBS patients seem to have a higher
number of mucosa-associated bacteria than healthy con-
trols [28,29]. Kerckhoffs et al. examined fecal and duo-
denal mucosa brush samples in IBS patients using qPCR
[30]. They detected significantly lower B. catenulatum
levels in IBS patients (combined and in subtypes), while
no difference could be found in the numbers of B. ado-
lescentis, B. bifidum, and B. longum. These results ap-
plied to both fecal and mucosal samples. The only dif-
ference between the two sample types was a lower per-
centage of B. bifidum of the total bifidobacterial counts
in the fecal samples in both IBS and healthy controls.
The authors further investigated fecal samples using
FISH analysis and detected lower numbers of bifidobac-
teria in IBS compared to healthy controls. An additional
study investigating IBS-D patients and respective healthy
controls did not detect any differences in Lactobacillus
or Bifidobac terium spp. in mucosal samples obtained
from unprepared sigmoidoscopies using both culture-
based and qPCR analyses [19]. Own preliminary HIT-
Chip data also did not reveal any significant differences
in sigmoidal mucosa lactic acid bacteria between IBS
patients and healthy controls. Parkes et al. applied FISH
to investigate the presence of selected bacterial groups in
the mucosa of IBS patients’ rectal biopsies from a pre-
pared bowel [29]. When analyzing all IBS samples as
one group, no differences in the numbers of bifidobacte-
ria and lactobacillus-enterococci were detected. Analysis
of subgroups, however, showed that higher numbers of
bifidobacteria were present in the IBS-C samples com-
pared to IBS-D and control samples. In addition, the ma-
ximum number of stools per day negatively correlated
with the number of mucosa-associated bifidobacteria and
lactobacilli-enterococci.
In conclusion, the presented studies show rather in-
consistent results regarding the role of lactic acid bacteria
as part of a deregulated gut ecosystem. This can partly be
explained by the heterogeneous character of the IBS
pathophysiology, which is characterized by a large in-
ter-individual variation of aberrations along the mi-
crobe-gut-brain axis. Furthermore, classifications of pa-
tients according to symptoms varied between studies, and
often a small number of patients were included. Impor-
tantly, studies applied various different methods and
techniques for sampling and especially for microbiota
analysis, which often are subject to selection biases [11].
In addition, most of the applied analyses only investi-
gated bacteria at the species level instead of performing
deeper analyses that would reveal differences between
strains. Moreover, when analyzing the intestinal micro-
biota, it is always difficult to account for exogenous fac-

The Role of Lactic Acid Bacteria in the Pathophysiology and Treatment of Irritable Bowel Syndrome (IBS) 30
tors, and especially diet has shown to have a strong in-
fluence on the microbiota composition [31].
Further studies analyzing the microbiota composition
of fecal and mucosal biopsies on a strain-specific level
are essential to elucidate the role of lactic acid bacteria in
IBS.
3. Clinical Intervention S t ud i es
Lactic acid bacteria administered as probiotic compounds
promise to be a new therapeutic option for the treatment
of IBS, and numerous studies testing the effect of a wide
selection of different probiotic strains, the majority of
them lactic acid bacteria, have been published [11]. Sev-
eral meta-analyses concluded that probiotics in general
improve IBS symptoms [32-34]. As meta-analyses com-
bining the results of studies using different probiotic
strains carry the risk of masking the success, or failure,
of a specific strain, the authors agreed that it needs to be
further investigated which strains and which doses are
most effective.
Clarke et al. gave a comprehensive overview of the
various intervention trials that specifically investigated
lactic acid bacteria in IBS [35]. Of the 42 evaluated
studies, 34 reported beneficial effects in at least one of the
endpoints or symptoms. However, a lack of standardized
endpoint measurements hampered comparisons within
studies. In addition, the quality of the studies varied wide-
ly and often included small patient numbers. The authors
highlighted the importance of considering strain-specific
effects. While some lactic acid bacteria strains were able
to improve abdominal pain in IBS patients, others pri-
marily affected bloating and flatulence or stool frequency.
Even within one strain, the influence of delivery vehicle
and dose-dependency needs to be considered.
Not all studies distinguished between the various IBS
subtypes such as diarrhea or constipation-predominant
IBS, discounting the fact that most strains are probably
more effective in treating one kind than the other. As
mentioned before, it also needs to be considered that IBS
symptoms not necessarily predict the underlying patho-
physiology. Hence, it would be ideal to administer lactic
acid bacteria that specifically target the respective pa-
thophysiologic mechanism instead of applying a treat-
ment based on symptoms. An additional factor to be ta-
ken into account is that clinical trials are often conducted
in a hospital setting, which may give rise to an inclusion
bias in comparison to subjects suffering from IBS in the
general population. These groups may differ in the pro-
portion of the various pathophysiologic mechanisms con-
tributing to IBS symptoms.
However, even considering these biases, most of the
higher-quality clinical trials reported beneficial effects of
lactic acid bacteria on IBS symptoms. So far, only one
study reported symptom deterioration using L. plantarum
MF1298 [36]. B. infantis 35624 is one of the strains that
demonstrated IBS symptom improvement in more than
one controlled clinical trial with a substantial number of
patients. Administration of this strain significantly re-
duced composite and individual scores for abdominal
pain/discomfort, bloating/distension and bowel move-
ment difficulty during an 8-week treatment, compared to
administration of placebo and of L. salivarius UCC4331.
Furthermore, it was able to normalize aberrant IL-10/IL-
12 ratios in peripheral blood samples of these IBS pa-
tients [37]. In a large, multicenter trial that included 362
female IBS patients in a primary care setting, B. infantis
35624 improved abdominal pain, the composite score,
individual scores for bloating, bowel dysfunction, incom-
plete evacuation, straining, and the passage of gas after a
4-week study period [38].
In addition, the so-called ‘Finnish combination’ con-
sisting of L. rhamnosus GG, L. rhamnosus Lc705,
Propionibacterium freudenreichii ssp. shermanii JS and
B. breve Bb99 or B. animalis ssp. lactis Bb12, respec-
tively, yielded noteworthy positive results. In a 6-month
trial including 103 patients, its administration lead to a
42% reduction in total symptom scores compared to a
6% reduction with placebo administration [39]. In a sec-
ond clinical trial with 86 IBS patients, treatment with this
multispecies probiotic during a 5-month period led to a
37% mean reduction in IBS score compared to a 9% re-
duction in the placebo group [13].
Only few probiotic intervention studies have looked
deeper into the underlying mechanisms and evaluated for
instance the impact of the tested lactic acid bacteria on
the microbiota composition in IBS. Kajander et al. inves-
tigated the effect of the multispecies “Finnish combina-
tion” (see above) on the fecal microbiota composition of
IBS patients using strain- and species-specific qPCR as-
says. They did not detect any changes, apart from an in-
crease in Bifidobacterium spp. in the placebo and a de-
crease in the treatment group [40]. In addition, no differ-
ences in the presence of short-chain fatty acids and bac-
terial enzymes in fecal samples were found. They con-
cluded that other mechanisms apart from an increased
colonization with the administered bacteria must have
been responsible for the beneficial effects on IBS symp-
toms, probably involving a direct interaction with the
intestinal epithelium. Another explanation could be a
more dominant effect of some lactic acid bacteria in the
small bowel rather than in the colon, as some strains have
been shown to provoke a direct metabolic or immu-
nologic effect in the small bowel [41-43]. Furthermore,
the applied techniques were probably not sufficient to
detect all underlying microbial changes. In a subsequent
study, the same group applied a similar qPCR assay with
a broader target of phylotypes to evaluate the effect of
the same probiotic combination on the fecal microbiota
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The Role of Lactic Acid Bacteria in the Pathophysiology and Treatment of Irritable Bowel Syndrome (IBS) 31
in 42 IBS patients. They reported that a phylotype with
94% similarity to Ruminococcus torques was decreased
and Clostridium thermosuccino-genes 85% was in-
creased in the probiotic compared to the placebo group
[44].
Effects of probiotic treatment on the mucosa-adherent
bacteria have not been reported in IBS patients yet.
4. Putative Mechanisms of How L actic Acid
Bacteria Affect the Gut Ecosystem in IBS
Even though lactic acid bacteria seem to be effective in
improving IBS symptomatology, the mechanisms behind
their beneficial effects are still not completely understood.
Here, we will provide an overview of putative mecha-
nisms. It needs to be highlighted that all mechanisms
described below are highly interrelated, and many spe-
cifically cluster around improving intestinal barrier func-
tion.
4.1. Microbe-Microbe Interaction
4.1.1. Compet i ti ve Acti o n
Initially, it was hypothesized that the beneficial effects of
the administered probiotic bacteria were associated with
their ability to adhere and colonize to the intestinal mu-
cosa. By this means, they were thought to act as antago-
nists against pathogenic species by replacing existing
pathogens or by inhibiting their adherence [45]. There is,
however, limited evidence of strains that can actually
adhere to the mucosal tissue, and a persistent coloniza-
tion after the intake has been stopped is very rare. Nev-
ertheless, a competitive action of probiotics, mainly lac-
tic acid bacteria, on pathogens has been demonstrated for
the treatment of Helicobacter pylori infection in humans.
After administration of probiotics, most studies showed a
decrease in H. pylori colonization and consequently im-
provement of H. pylori-induced gastritis [46].
4.1.2. pH-Lowering Effect
An additional antimicrobial mechanism of lactic acid
bacteria is their ability to lower the pH by producing lac-
tic acid during fermentation processes [47,48]. Once this
organic acid has passed the cell membrane of a pathogen,
the acidity of the molecule needs to be overcome by
driving out the excess protons in order to maintain the
intracellular pH. This implies a high requirement of en-
ergy to sustain the activity of the ATPase in charge of the
process, resulting in an inhibitory effect against respec-
tive pathogens [49].
4.1.3. Bacteriocins
Lactic acid bacteria secrete a variety of different antim-
icrobial substances, so-called bacteriocins [50]. Bacterio-
cins produced by L. acidophilus and L. casei inhibited
the growth and viability of Cronobacter sakazakii, a
pathogen that can cause bacteremia, meningitis, and ne-
crotizing enterocolitis in infants [51]. In another study,
substances secreted by a L. plantarum strain showed in-
hibitory effects on the growth, biofilm formation, and
invasion and adhesion ability of Salmonella enterica se-
rovar Enteriditis [52]. Gassericin A, a bacteriocin pro-
duced by L. gasseri, is thought to cause cell death via a
pore-formation mechanism as a result of the dimerization
and location of this bacteriocin on the cell membrane of
gram-positive pathogens [49].
4.2. Effect on Mucus Composition
Mucin is the first barrier protecting the gastrointestinal
mucosa from opportunistic pathogens [53]. There is lim-
ited information about the alterations of the mucus layer
in IBS, however, changes in the expression of genes as-
sociated with the production of mucins in the colon of
IBS patients have been reported [54]. In addition, an
overproduction of mucus has been detected in colonic
biopsies of IBS patients [55]. Lactic acid bacteria are
known to regulate the expression of mucin genes such as
MUC2 and MUC3 [56,57]. Results from animal studies
are, however, mostly contradictory. For instance, sup-
plementation with the multistrain probiotic product
VSL#3, which contains lactic acid bacteria strains, did
not affect the expression levels of MUC1, MUC2, MUC3
and MUC4 in a mouse model of colitis [58] or the ex-
pression of MUC5ac in a rat model of gastric ulcer [59].
On the contrary, administration of VSL#3 to healthy
Wistar rats resulted in the upregulation of MUC2, MUC3
as well as MUC31 gene levels [60]. These examples
strongly indicate that in particular human clinical trials
are mandatory to clearly determine the effect of these
bacteria on mucus layer production, quality and integrity.
4.3. Immunomodulatory Effect
Increased immune activation with signs of low-grade
inflammation is frequently observed in subgroups of IBS
patients, like those with the diarrhea-predominant or
post-infectious subtype [5]. Accordingly, lactic acid bac-
teria are known to exert immunomodulatory effects [61].
For instance, we could show that Lactobacillus planta-
rum WCFS1 affected NFκB pathways correlating with
immune tolerance in healthy subjects [41,42], and acti-
vated TLR2 signaling [62]. Toll-like receptors (TLR) are
members of the family of pattern-recognition receptors
(PRR) and are a fundamental part of the inherent immune
system, where they are in charge of recognizing and dis-
criminating microbial infections. Changes in intestinal
microbiota in IBS are consistent with altered TLR ex-
pression in colonic biopsies as well as TLR-related cyto-
kine responses in peripheral blood of IBS patients [63,
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The Role of Lactic Acid Bacteria in the Pathophysiology and Treatment of Irritable Bowel Syndrome (IBS) 32
64]. Polymorphisms in the TLR9 gene have been associ-
ated with a higher risk of post-infectious IBS [65].
Various lactic acid strains are known to act via the ex-
pression of TLRs [66]. Recent studies demonstrated that
different Lactobacillus species could inhibit the pro-
voked production of cytokines such as IL-8 via TLR9 in
Caco-2 cells and via TLR4 in T24 urothelial cells, re-
spectively [67,68]. In another study it was found that
stimulation of peripheral blood mononuclear cells
(PBMC) from healthy volunteers with L. rhamnosus, L.
casei and a B. breve strain was TLR9 dependent [69]. In
addition, the effect of B. breve on production of proin-
flammatory cytokines was the result of TLR2 signaling
activation, an effect that was not observed when PBMCs
were stimulated with lactobacilli strains. We also dem-
onstrated a strain-specificity of human cellular pathway
modulation within the species L. plantaru m [43].
4.4. Effect on Epithelial Barrier Function
As stated earlier, the intestinal barrier plays a central role
in the pathophysiologic concept of IBS integrating the
intestinal ecosystem, immune activation, mucosal integ-
rity, afferent sensory signaling and brain activity. De-
regulation of immune responses and deterioration of the
intestinal barrier function are associated processes, and
may provoke sustained immune activation, mucosal in-
flammation and increased afferent sensory signaling
leading to abdominal complaints [70]. A disturbed intes-
tinal barrier function coincides with changes in mucosal
integrity and tight junction function. The functional con-
sequence of this can be increased mucosal permeability.
A subset of diarrhea-predominant IBS patients showed
increased intestinal permeability correlating with severity
of symptoms [71]. Acute stress may disturb intestinal
barrier function, and corticotropin releasing factor (CRF)
and post-stress intestinal mast cell activation play a cen-
tral mechanistic role in this. Hence, maintenance of tight
junction function plays an important role in the resilience
of intestinal barrier function.
Several studies have demonstrated protective effects of
lactic acid bacteria on intestinal epithelial cell integrity in
vitro or in experimental animal studies, as shown by im-
proved transepithelial resistance and relocalization of
tight junction proteins, amongst others [72-74]. Evidence
on the potential effect of lactobacilli regarding the regu-
lation of the intestinal barrier function in humans was
provided by a study of Karczewski et al. [62]. The ad-
ministration of L. plantarum WCFS1 via a feeding
catheter led to an upregulation of the epithelial tight junc-
tion proteins ZO-1 (zonula occludens-1) and occludin in
the duodenum. In addition, lactic acid bacteria might
have a protective effect on the mucosal integrity through
the regulation of mucin proteins, or through TLR signal-
ing, as outlined above. Apart from their role in immu-
noregulatory processes, TLRs are involved in epithelial
cell proliferation, IgA production, and maintenance of
tight junctions, all of which are highly relevant for a
well-functioning epithelial barrier [75].
4.5. Effect on Oxidative Stress
Reactive oxygen species (ROS) are mediators of both the
innate and adaptive immune regulatory function and play
a role in the interaction between the intestinal ecosystem,
the immune system and intestinal barrier function. Mast
cell activation in IBS, resulting in release of e.g. hista-
mine and the activation of proteases, may well lead to
increased levels of ROS and thus oxidative stress. Scav-
enging of ROS may protect the intestinal barrier in cases
of increased oxidative stress such as metabolic stress and
mast cell activation.
Although clear evidence of a beneficial effect of lactic
acid bacteria on oxidative stress is lacking in the human
setting, a number of experimental animal studies have
shown anti-oxidative properties. L. rhamnosus GG re-
duced markers of alcohol-induced intestinal and liver
oxidative stress as well as improved parameters of intes-
tinal barrier function in a rat model of alcoholic steato-
hepatitis [76]. L. paracasei F19 significantly reduced the
harmful effects of ischemia/reperfusion in a rat model
associated with reduction of the ischemia/ reperfusion
induced alteration in the intestinal microbiota [77]. A
multistrain mix of lactic acid bacteria was shown to be
able to beneficially affect oxidative networking and ef-
fectively reduce doxorubicin-induced oxidative stress in
rats [78]. These anti-oxidative properties are very strain
specific and not clearly associated with lactic acid pro-
duction. In a mice model of Giardia parasitic infection, L.
rhamnosus GG was not only able to increase levels of
antioxidants in the intestine but also nearly restored nor-
mal mucosal morphology [79].
4.6. Neurogenic Action
An increasing number of studies substantiate a crosstalk
between the gut ecosystem and the central nervous sys-
tem, and it has become evident that even behavior can be
affected by the intestinal microbiota [80,81]. This has
been nicely demonstrated by a study of Bercik et al. in
which the gut microbiota of mice belonging to the timid
and less explorative strain BALB/c was exchanged with
the microbiota of highly explorative NIH Swiss mice.
This resulted in a more explorative behavior of the
BALB/c mice, similar to that of the donor mice [82].
Accordingly, specific lactic acid bacteria administered as
probiotics have been shown to exert neurogenic effects.
B. infantis 35624 reversed behavioral deficits in a rat
maternal separation model and restored noradrenaline
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The Role of Lactic Acid Bacteria in the Pathophysiology and Treatment of Irritable Bowel Syndrome (IBS) 33
levels in the brain [83]. An effect of lactic acid bacteria
on brain function and behavior has also been demon-
strated for B. longum NC3001, which normalized anxi-
ety-like behavior and hippocampal brain derived neuro-
trophic factor (BDNF) levels in a mouse model of
chronic gastrointestinal inflammation [84]. Administra-
tion of L. rhamnosus (JB-1) reduced anxiety and depres-
sion related behavior in mice by modulating GABA re-
ceptor expression in the brain [85]. Only a very limited
number of studies have looked at a neurogenic effect of
lactic acid bacteria in humans. The strains L. helveticus
R0052 and B. longum R0175 showed beneficial effects
on psychological distress and cortisol levels in healthy
human volunteers in addition to an anxiolytic-like effect
in rats [86]. A fermented milk product containing B.
animalis subsp Lactis, S. thermophiles, L. bulgaricus,
and L. lactis subsp Lactis modulated brain activity in
healthy women. Its ingestion reduced task-related brain
responses and altered resting-state networks, thus suc-
cessfully demonstrating an effect on gut-brain commu-
nication in humans [87]. Consuming a milk drink con-
taining L. casei Shirota elevated mood in subjects with
initially poor mood [88]. The same strain led to a de-
crease in anxiety symptoms in patients with chronic fa-
tigue syndrome, however, an association with enhanced
bowel function and/or reduced abdominal complaints
was not assessed [89].
A number of in vitro and animal studies suggest that
the administration of specific lactic acid bacteria might
be beneficial for the treatment of visceral hypersensitiv-
ity and abdominal pain in IBS. L. acidophilus NCFM
modulated the perception of visceral pain in rodents with
a morphine-like effect and induced the expression of
cannabinoid receptors, while L. acidophilus NCFM as
well as L. salivarius Ls-33 induced the expression of
opioid receptors in human HT-29 epithelial cells in vitro
[90]. Also B. infantis 35624 was able to reduce visceral
pain in rats [91].
4.7. Interaction with Metabolic Networking
The intestinal microbiota in healthy adults forms a com-
plex ecosystem that is composed of more than 1000 mi-
crobial species [92,93]. These organisms live in a close
symbiotic relationship with the host as well as each other,
which is based on metabolic interaction and networking.
Modulation of this system by adding for instance lactic
acid bacteria may lead to a chain of interrelated actions
within the metabolic networking. Especially the so-called
crossfeeding results in highly complex interactions.
Crossfeeding denotes the nutritional interdependence
between two or several species, which utilize products
provided by other species for their own metabolism. For
instance, the administration of lactic acid bacteria might
affect the growth of bacteria utilizing lactate as their sub-
strate, such as Anaerostipes caccae and Eubacterium
hallii, which convert lactate into the beneficial short-
chain fatty acid butyrate [94]. Butyrate is an important
energy source for epithelial cells and has protecting ef-
fects on colonic mucosal function including inhibition of
inflammation and carcinogenesis [95-97]. Our own pre-
liminary data showed that IBS patients have a lower
proportion of butyrate-producing microbiota both in fecal
and unprepared mucosal samples compared to healthy
controls. The administration of butyrate via enemas re-
sulted in a substantial decrease of visceral perception in
healthy volunteers [98,99], and could reduce the fre-
quency of abdominal complaints in IBS patients [100].
Consequently, lactic acid bacteria might also contribute
to improvement of IBS symptoms by promoting the
growth of butyrate-producing bacteria. The increased
production of butyrate in turn can affect other bacteria
that utilize butyrate as a substrate. Moreover, butyrate is
not the only short-chain fatty acid produced from lactate,
and other compounds such as propionate also play a role
in this complex metabolic networking.
The metabolic effects of lactic acid bacteria are strain-
specific, as it was demonstrated by the different amounts
of butyrate produced by various B. animalis strains [101].
In addition, a host-specific effect needs to be considered.
Even though all adults share a common microbial core,
each person has its own subject-specific intestinal micro-
biota composition [93], which is also strongly influenced
by the individual diet [31,102]. Hence, it seems plausible
that the gut ecosystem reacts subject-specific to the ad-
ministration of lactic acid bacteria.
5. Future Applications of Lactic Acid
Bacteria in the Treatment of IBS
With regard to a future application of lactic acid bacteria
in the treatment of IBS, it still needs to be investigated if
their efficacy is higher if administered as monospecies or
in a multispecies mixture. As several pathophysiologic
mechanisms are involved in IBS, and in addition, pa-
tients show different aberrations along the microbe-
gut-brain axis, a combination of several lactic acid bacte-
ria could provide a more comprehensive treatment cov-
ering various needs. In a multispecies mixture, one strain
could deliver a beneficial neurogenic effect, while an-
other strain could improve intestinal barrier function. A
multispecies probiotic could also be more effective in the
various segments of the intestine. Furthermore, it was
shown, by applying an in vitro human intestinal mucus
model, that individual strains may strongly enhance each
other’s adherence if combined with other strains, with
some combinations being more effective than others
[103]. However, besides a potential synergistic effect,
lactic acid bacteria could also exert antagonistic effects
against each other if administered in combination.
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The Role of Lactic Acid Bacteria in the Pathophysiology and Treatment of Irritable Bowel Syndrome (IBS) 34
An additional consideration in the case of using lactic
acid bacteria as a treatment for IBS, might be a combined
administration with a specific prebiotic substance. Pre-
biotics are food compounds that are selectively fer-
mented in the intestine by specific desirable bacteria,
mostly bifidobacteria or lactobacilli. They confer favor-
able health effects on the host by stimulating the metabo-
lism and growth of these bacteria [104]. Prebiotics and
probiotics administered in combination are denoted as
synbiotics. The addition of the prebiotic might enhance
the viability and activity of the administered lactic acid
bacteria and also of resident bacteria, resulting in a syn-
ergistic effect. So far, there is only one placebo-con-
trolled trial evaluating the effect of synbiotics on IBS
symptoms. It included 68 IBS patients and reported im-
provement of abdominal pain and bowel habits using a
novel synbiotic known as SCM-III. Its uptake success-
fully increased numbers of lactobacilli, eubacteria and
bifidobacteria [105]. Further beneficial effects have been
described in several open-label studies. Those results,
however, need to be assessed with caution, as the placebo
response in IBS is high [106].
Lactic acid bacteria will probably play a central role in
the probiotic treatment of IBS. One of the clear advan-
tages of probiotics over conventional pharmacological
medication is their favorable adverse effect profile, whi-
ch enables chronic administration and preventive treat-
ment.
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