MINI REVIEW ARTICLE
published: 06 February 2013
Tailoring gut immune responses with lipoteichoic
acid-deficient Lactobacillus acidophilus
Yaíma L. Lightfoot1,2and Mansour Mohamadzadeh1,2*
1Department of Infectious Diseases and Pathology, College of Veterinary Medicine, University of Florida, Gainesville, FL, USA
2Division of Gastroenterology Hepatology & Nutrition, Department of Medicine, College of Medicine, University of Florida, Gainesville, FL, USA
Francesca Granucci, University of
Simone Guglielmetti, Università degli
Studi di Milano, Italy
Kirschning Jürgen Carsten, University
of Duisburg-Essen, Germany
Department of Infectious Diseases
and Pathology, College of Veterinary
Medicine, University of Florida,
2015 Southwest 16th Avenue,
Gainesville, FL 32608, USA.
is lost, homeostatic interactions between gut microbiota, resident immune cells, and
the gut epithelium are key in the maintenance of gastrointestinal health. Gut immune
responses, whether stimulatory or regulatory, are dictated by the activated dendritic cells
(DCs) that first interact with microorganisms and their gene products to then elicitT and B
cell responses. Previously, we have demonstrated that treatment with genetically modified
Lactobacillus acidophilus is sufficient to tilt the immune balance from proinflammatory to
regulatory in experimental models of colitis and colon cancer. Given the significant role
of DCs in efficiently orchestrating intestinal immune responses, characterization of the
signals induced within these cells by the surface layer molecules, such as lipoteichoic
acid (LTA), and proteins of L. acidophilus is critical for future treatment and prevention of
gastrointestinal diseases. Here, we discuss the potential regulatory pathways involved in
the downregulation of pathogenic inflammation in the gut, and explore questions regarding
the immune responses to LTA-deficient L. acidophilus that require future studies.
Keywords: Lactobacillus acidophilus, lipoteichoic acid, S-layer proteins, gut inflammation, dendritic cells, immune
The gastrointestinal tract possesses a highly specialized immuno-
logic system comprised of both innate and adaptive immune
components. These defense systems act in concert to maintain
a state of alertness or physiological inflammation in the gut that
remaining tolerant to the commensal microbiome (Sansonetti,
2004). By virtue of their antigen processing and presenting abili-
responses (Chang etal., 2012). DCs in the lamina propria con-
them to resident T cells. Under steady state conditions, intesti-
nal DCs induce the development of Th1 and Th17 effector T
cells; however, at the same time, a specialized subset of regula-
tory CD103+DCs promote the generation of induced regulatory
T cells (iTregs; Siddiqui and Powrie, 2008) that prevent exacer-
bated Th1 and Th17 effector responses, and thus limit collateral
tissue damage. Tregs express the transcription factor FoxP3 and
suppress proinflammatory immune responses through the pro-
duction of anti-inflammatory cytokines, including interleukin
(IL)-10 and transforming growth factor-beta (TGF-β), and the
surface expression of inhibitory molecules, such as cytotoxic T
lymphocyte antigen 4 (CTLA-4) and lymphocyte activation gene-
3 (LAG-3; Huang etal., 2004; Li etal., 2007; Rubtsov etal., 2008;
Wing etal., 2008; Bos and Rudensky, 2012). Indeed, the trans-
fer of total CD4+CD25+Tregs efficiently mitigated established
colitis in an experimental model of the disease (Mottet etal.,
2003), and a deficiency of this cell population has been found in
patients with ulcerative colitis (Takahashi etal., 2006). Although
subsequent studies have emphasized the importance of iTregs for
of peripheral Tregs by regulatory DCs in the gut seems to be par-
ticularly crucial for microbial coexistence and colonic health. In
support of this notion, colonic Tregs were found to express T cell
receptor (TCR) repertoires that were distinct from those found
on Tregs from other organs and were also specific for antigens
encoded by commensal bacteria (Lathrop etal.,2011).
of the gut microbiota (Round and Mazmanian, 2009; Consor-
tium, 2012; Holmes etal., 2012). Recent elegant studies have
contributed to our understanding of intestinal immune modula-
For instance, monocolonization of germ-free (GF) mice with
the human commensal, Bacteroides fragilis, induced the devel-
2010). Moreover, Clostridium-colonized GF mice demonstrated
a marked increase in the number of CD4+Tregs in the colon
(Atarashi etal.,2011). Interestingly,a significant percentage of the
Tregs were not positive for Helios,a transcription factor expressed
by natural Tregs (Thornton etal., 2010), indicating that these
Tregs were locally derived through regulatory signaling cascades
(Atarashi etal., 2011). In line with these reports, our work has
shown that oral treatment with a novel strain of Lactobacillus aci-
inflammation-induced colitis and colonic polyposis, and restored
intestinal homeostasis in experimental models (Mohamadzadeh
February 2013| Volume 4|Article 25|1
Lightfoot and MohamadzadehImmune regulation by LTA-deficient L. acidophilus
etal., 2011; Khazaie etal., 2012). Nonetheless, despite current
advances in the field, the specific signals delivered by microbes
to innate immune cells, particularly DCs, to foster tolerance
are not completely understood. To this end, this review focuses
on the immunomodulating characteristics of specific cell surface
components of L. acidophilus and discusses potential mecha-
nisms whereby LTA-deficient L. acidophilus is able to promote the
suppression of pathogenic intestinal autoinflammation.
Lactobacillus acidophilus AND ITS SURFACE LAYER
Oral consumption of probiotics has been associated with multi-
ple health benefits, including induction of mucus-secreting cells,
maintenance of intestinal permeability, production of antimicro-
regulation (Gareau etal., 2010). Attesting to the importance of a
are associated with gut dysbiosis or alterations in the intestinal
microbial composition (Nishikawa etal., 2009; De Palma etal.,
cal intestinal balance,lactobacilli have been tested in clinical trials
with favorable outcomes (Ouwehand etal., 2002). These bene-
fits are, in part, due to induced changes in the immune system,
as specific Lactobacillus species are known to stimulate DCs to
produce stimulatory and regulatory cytokines that direct subse-
quent T cell responses (Christensen etal., 2002; Mohamadzadeh
etal., 2005; Konstantinov etal., 2008). The immunomodulatory
effects of lactobacilli are attributed to the interactions between
bacterial cell surface components and pattern recognition recep-
tors (PRRs) expressed on innate cells, such as Toll-like receptors
(TLRs) and C-type lectins (CLRs; Konstantinov etal., 2008;
tionof theseproteinsisimperativefortheachievementof tailored
immune responses. Dissecting the downstream consequences of
host immune cell–microbial interactions is of particular impor-
tance in cases where preexisting inflammation or a propensity
for inflammatory conditions might be exacerbated or promoted,
respectively, by otherwise harmless bacterial constituents.
Lactobacillus acidophilus, one of the most widely consumed
positive bacterium that expresses the highly conserved LTA and
other surface-exposed (S-layer) molecules, such as the proteins
encoded by slpA, slpB, and slpX. S-layers have putative roles in
cell adhesion,cell shape determination,as protective barriers,and
as anchoring sites for accessory proteins, all of which may con-
tribute to bacterial survival and host–microbial cell interactions
within the gastrointestinal tract. Under laboratory growth condi-
(Boot etal., 1996), which is coexpressed with the lesser expressed
protein SlpX (Goh etal., 2009). On the other hand, SlpB, due to a
chromosomal inversion, is only coexpressed with SlpX in a small
fraction of laboratory-grown L. acidophilus (Boot etal., 1996) or
in some mutants devoid of SlpA (Boot etal., 1996; Konstanti-
nov etal., 2008; Goh etal., 2009). While deletion of SlpA leads to
decreased binding ability in vitro (Buck etal., 2005), the absence
of SlpX did not result in morphological changes, reduced adher-
ence to epithelial cells in vitro, or increased sensitivity to cellular
stresses (Goh etal., 2009). Still, a L. acidophilus mutant lacking
SlpX and SlpB is cleared faster in vivo than the wild-type strain
(Zadeh etal., 2012), suggesting that SlpX and SlpB, albeit to a
lesser extent, may also contribute to the gastrointestinal interac-
tions of L. acidophilus. In terms of immunomodulatory effects,
DCs stimulated in vitro with a SlpB-dominant strain (SlpA−)
produced higher levels of the proinflammatory cytokines IL-12
and tumor necrosis factors-alpha (TNF-α) than those challenged
with the parental L. acidophilus strain (SlpA+; Konstantinov etal.,
that could very well account for our recent exciting observations
(Mohamadzadeh etal., 2011; Khazaie etal., 2012). Additionally,
the SlpA−mutant demonstrated reduced binding to DC-specific
ICAM-3-grabbing non-integrin (DC-SIGN), a CLR expressed on
nov etal.,2008),implying that L. acidophilus SlpA does not signal
to DCs via TLR2. Conversely,L. helveticus-derived SlpA,although
regulate inflammation-associated gene expression when tested in
vitro using an epithelial cell line, but promoted proinflammatory
effects in macrophages via TLR2, also in vitro (Taverniti etal.,
2012). The authors ascribed these discrepancies to differences in
SlpA remains to be elucidated and is currently under extensive
scrutiny in our laboratories to decipher its immunoregulatory
effects using a range of experimental animal models.
In contrast, LTA is regarded as the Gram-positive counter-
part of the potent and proinflammatory Gram-negative stimulus,
lipopolysaccharide (LPS; Sriskandan and Cohen, 1999; Su etal.,
2006). LTA is a zwitterionic glycolipid found in the cell wall of
many Gram-positive bacterial strains, including L. acidophilus,
which is believed to facilitate adhesion, colonization, and inva-
sion of host cells (Reichmann and Gründling, 2011). In addition
to the likely role of LTA in Lactobacillus adhesion to mucosal
surfaces, this molecule promotes immune cellular activation via
TLR2 signaling, which then activates downstream proinflamma-
tory cytokine signaling cascades (Schwandner etal., 1999; Chiu
conflicting reports suggested that LTA from certain Lactobacillus
species induces anti-inflammatory cytokine production (IL-10),
and only results in the generation of proinflammatory media-
tors in preexisting inflammatory conditions [i.e., co-culture with
interferon-gamma (IFN-γ); Kaji etal., 2010; Kang etal., 2011].
Taken together, these data contend that the functions of LTA
might differ between bacterial species (beneficial lactobacilli ver-
milieu (steady state versus proinflammatory). However, a caveat
of these studies is that the work was performed in vitro, which
prompts the following question: what is the physiological role of
IMMUNE REGULATION INDUCED BY LTA-DEFICIENT
To clarify the in vivo effects of L. acidophilus-LTA, we recently
developed a L. acidophilus strain lacking the gene encoding
Frontiers in Immunology |Antigen Presenting Cell Biology
February 2013| Volume 4|Article 25|2
Lightfoot and MohamadzadehImmune regulation by LTA-deficient L. acidophilus
FIGURE 1 | Immune regulation established by lipoteichoic acid
(LTA)-deficient Lactobacillus acidophilus. (A) In steady state conditions,
molecules expressed on the cell surface of L. acidophilus activate dendritic
cells (DCs) to promote effectorTh1 andTh17 responses that are held in check
by the accompanying generation of induced regulatoryT cells (iTregs).
However, in preexisting inflammation or susceptible individuals, immune
activation by L. acidophilus-LTA exacerbates inflammatory responses and fails
to promote immune regulation. Oral intake of mutant strains lacking LTA
expression (LTA−L. acidophilus) predominantly results in suppression of
exacerbated immune responses via the induction of regulatory IL-10-secreting
DCs (B), which then promote the conversion of naiveT cells into iTregs. (B)
Confocal microscopy analysis of DCs (CD11c+, green; CD11b+, red) that
produce IL-10 (white) in the colons of healthy control mice after treatment
with LTA-deficient L. acidophilus.
February 2013| Volume 4|Article 25|3
Lightfoot and Mohamadzadeh Immune regulation by LTA-deficient L. acidophilus
phosphoglycerol transferase, an enzyme required for the biosyn-
thesis of LTA. As opposed to treatment with the wild-type strain,
oral inoculation with LTA-deficient L. acidophilus not only pre-
vented chemical and pathogenic T cell-induced colitis, but also
quickly resolved established colitis, as measured by diminished
percent weight loss, lower diarrhea and fecal occult blood scores,
and reduced disease activity index (Mohamadzadeh etal., 2011).
By the same token, LTA-deficient L. acidophilus dramatically
reversed colonic preneoplasia in genetically predisposed animals
(Khazaie etal., 2012). While protection from colitis in our stud-
ies correlated with an increase in IL-10-producing DCs and the
number of iTregs (Mohamadzadeh etal., 2011; Khan etal., 2012),
polyposis reversal coincided with an overall dampening of local
and systemic immunity that was linked with restoration of Treg
function and stability (Khazaie etal., 2012). Importantly, proin-
flammatory Tregs have also been identified in colorectal cancer
(CRC) patients (Blatner etal., 2012), further supporting the clin-
ical applicability of LTA-deficient L. acidophilus for the treatment
of intestinal maladies given its potential ability to prevent the
formation of proinflammatory FoxP3+RORγt+Tregs.
Moreover, in vitro co-culture of DCs with LTA-deficient L.
acidophilus led to a regulatory DC phenotype, as demonstrated
by enhanced IL-10 secretion, low expression of costimulatory
molecules, and concomitant decreases in IL-12 and TNF-α pro-
duction. Alternatively, no beneficial effects could be induced in
IL-10−/−mice in vivo, highlighting the important role of this
anti-inflammatory cytokine in the control of pathogenic intesti-
nal inflammation in our system, similar to previous findings by
others (Asseman etal., 1999; Grangette etal., 2005; Rubtsov etal.,
2008). Activation of mitogen-activated protein kinases (MAPK)
signaling pathways differentially controls features of both innate
production by regulatory DCs has previously been found to be
(ERK1/2) activation, while suppressed IL-12 secretion resulted
from impaired p38 activation (Qian etal., 2006). Indeed, signifi-
tissues of mice orally treated with LTA-deficient L. acidophilus,
whereas the wild-type strain promoted p38 phosphorylation
(Saber etal., 2011). Furthermore, DC stimulation with LTA-
deficient L. acidophilus resulted in only weak TLR2-dependent
cytokine production and did not enhance the expression of this
PRR; these data indicate that LTA is in fact the proinflamma-
tory molecule most strongly associated with TLR2 activation by
L. acidophilus in DCs, and that the in vivo regulatory response
noted after LTA-deficient L. acidophilus treatment is a direct con-
sequence of its absence. Collectively, the favorable effects of
LTA-deficient L. acidophilus may be due to weak TLR2 activation
and downstream signaling,together with the predominant activa-
tion of alternative DC-related PRRs, such as CLRs (Konstantinov
etal., 2008), by different surface-associated molecules, including
SlpA (summarized in Figure 1A).
CONCLUDING REMARKS AND FUTURE DIRECTIONS
Although the exact signaling pathways whereby LTA-deficient
L. acidophilus promotes the generation of regulatory DCs and,
consequently, iTregs, are currently under intensive investigation,
data obtained thus far clearly demonstrate that IL-10-dependent
L. acidophilus. In addition, work by others point to SlpA as
a potential regulatory molecule in L. acidophilus (Konstantinov
etal., 2008). Notably, as seen in the wild-type L. acidophilus
strain, the presence of this S-layer protein alone is not sufficient
to counterbalance the proinflammatory actions of LTA. Addi-
tional studies performed in our laboratories demonstrated that
a mutant strain expressing LTA and SlpA, but not SlpX and
SlpB, was unable to afford any protection against colitis (Zadeh
etal., 2012). In fact, oral treatment with this LTA+SlpA+L.
acidophilus strain led to a higher number of TNF-α-producing
colonic DCs, in addition to sustained IL-12 production by DCs
in the colon, when compared to the LTA-sufficient parental
strain (Zadeh etal., 2012). These findings may be interpreted
to imply that the other S-layer proteins expressed by L. aci-
dophilus NCFM also contribute to the regulation of LTA-induced
inflammation; however, attempted deletion of SlpA in this strain
resulted in slightly lower expression levels of the protein when
compared to the parental strain, which then suggests that even
small perturbations in the amount of SlpA expressed can exacer-
bate LTA-mediated inflammation. Consequently, ongoing studies
aim to investigate the specific contribution of the S-layer com-
ponents (i.e., SlpA) to conserve and support gut homeostasis by
techniques previously described (Goh etal., 2009) and purifying
our protein of interest, SlpA. Thus, the therapeutic value of both
SlpA+SlpB−SlpX−LTA−L. acidophilus and purified SlpA will be
determined in vivo.
In other respects, it is likely that LTA-deficient L. acidophilus
confers additional benefits to the host through mechanisms inde-
pendent of the immunomodulatory effects mentioned above. For
instance, intestinal epithelial cells not only create a protective
barrier against invading pathogens, but also sense and inter-
act with microbes through PRRs to influence subsequent innate
immune responses (Wells etal., 2011). Accordingly, the status of
the mucosal epithelium is central to gastrointestinal health and
accumulating evidence indicates that aberrant epigenetic modifi-
of pathogenic intestinal inflammation, we recently tested the
effects of LTA-deficient L. acidophilus treatment on the epigenetic
landscape of the intestinal mucosa and found that this bacterium
induced the expression of CRC-associated, epigenetically con-
trolled genes that are often downregulated in cancer-promoting
pathogenic conditions (Lightfoot etal., 2012). These important
results create a strong position to precisely define the bacterial
gene products that may dampen detrimental gut inflammation
and protect against inflammatory conditions, including inflam-
cell modulation, but also via direct interactions with the gut
Science Award to the University of Florida (UL1 RR029890).
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February 2013| Volume 4|Article 25|4
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