Role of Lactobacillus Reuteri in Human Health and Diseases: Qinghui Mu, Vincent J. Tavella and Xin M. Luo

REVIEW
published: 19 April 2018

doi: 10.3389/fmicb.2018.00757
Role of Lactobacillus reuteri in

Human Health and Diseases
Qinghui Mu, Vincent J. Tavella and Xin M. Luo*
Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech,
Blacksburg, VA, United States
Lactobacillus reuteri (L. reuteri) is a well-studied probiotic bacterium that can colonize
a large number of mammals. In humans, L. reuteri is found in different body sites,
including the gastrointestinal tract, urinary tract, skin, and breast milk. The abundance
of L. reuteri varies among different individuals. Several beneficial effects of L. reuteri
have been noted. First, L. reuteri can produce antimicrobial molecules, such as organic
acids, ethanol, and reuterin. Due to its antimicrobial activity, L. reuteri is able to
inhibit the colonization of pathogenic microbes and remodel the commensal microbiota
composition in the host. Second, L. reuteri can benefit the host immune system.
For instance, some L. reuteri strains can reduce the production of pro-inflammatory
cytokines while promoting regulatory T cell development and function. Third, bearing
Edited by:
the ability to strengthen the intestinal barrier, the colonization of L. reuteri may decrease
Rustam Aminov, the microbial translocation from the gut lumen to the tissues. Microbial translocation
University of Aberdeen,
across the intestinal epithelium has been hypothesized as an initiator of inflammation.
United Kingdom
Therefore, inflammatory diseases, including those located in the gut as well as in remote
Reviewed by:
Julio Galvez, tissues, may be ameliorated by increasing the colonization of L. reuteri. Notably, the
Universidad de Granada, Spain decrease in the abundance of L. reuteri in humans in the past decades is correlated
Michael Gänzle,
University of Alberta, Canada
with an increase in the incidences of inflammatory diseases over the same period of
Teresa Zotta, time. Direct supplementation or prebiotic modulation of L. reuteri may be an attractive
Consiglio Nazionale Delle Ricerche
preventive and/or therapeutic avenue against inflammatory diseases.
(CNR), Italy
*Correspondence: Keywords: Lactobacillus reuteri, probiotic, microbiota, immune system, inflammatory diseases
Xin M. Luo
xinluo@vt.edu
INTRODUCTION
Specialty section:
This article was submitted to Probiotics are defined as “live microorganisms which, when administered in adequate amounts,
Microbial Immunology, confer a health benefit on the host” by the World Health Organization. While the idea to use
a section of the journal
probiotics for health benefits is not new, the interest has significantly increased in recent years
Frontiers in Microbiology
(Islam, 2016). This may be due, in part, to the increase in antibiotic resistance particularly in the
Received: 29 September 2017 treatment of diseases in the gastrointestinal (GI) system, as well as an increasing desire by the
Accepted: 04 April 2018
public for natural health promotants. Those probiotic microorganisms that have been shown to
Published: 19 April 2018
have beneficial properties include Lactobacillus spp., Bifidobacterium spp., Saccharomyces boulardii,
Citation:
Propionibacterium spp., Streptococcus spp., Bacillus spp., Enterococcus spp., and some specific strains
Mu Q, Tavella VJ and Luo XM (2018)
Role of Lactobacillus reuteri in Human
of Escherichia coli (Kechagia et al., 2013).
Health and Diseases. There are certain criteria that a probiotic must have to be considered efficacious. These
Front. Microbiol. 9:757. include the capacity to survive in the GI tract, a high resistance to gastric acids, the lack
doi: 10.3389/fmicb.2018.00757 of any transferable antibiotic resistance genes, and the capacity to exert clear benefits in the
Frontiers in Microbiology | www.frontiersin.org 1 April 2018 | Volume 9 | Article 757

Mu et al. L. reuteri in Health and Disease
host (Montalban-Arques et al., 2015). Probiotics promote Valeur et al., 2004; Weizman and Alsheikh, 2006; Mangalat et al.,
a healthy body through diverse mechanisms. A widespread 2012; Jones et al., 2012a,c; Hoy-Schulz et al., 2016). The results
generalization describing common mechanisms among studied showed that a dose as high as 2.9 × 109 colony-forming units
probiotic genera includes colonizing resistance, producing (cfu)/day was still well tolerated, safe, and efficacious in humans.
acid, and short chain fatty acid (SCFA), regulating intestinal There have also been numerous articles enumerating the benefits
transit, normalizing perturbed microbiota, increasing enterocyte of L. reuteri as a probiotic. These benefits include promoting
turnover, and competitive exclusion of pathogens (Hill et al., health, reducing infections, improving feed tolerance, enhancing
2014). Though not widely observed, there are a lot of effects the absorption of nutrients, minerals, and vitamins, modulating
among specific probiotic species, some being strain specific. For host immune responses, promoting gut mucosal integrity, and
instance, some probiotic strains can improve host food digestion reducing bacterial translocation (Tubelius et al., 2005; McFall-
by metabolizing bile salt or complementing the functions of Ngai, 2007; Indrio et al., 2008; Spinler et al., 2008; Hou et al.,
missing digestive enzymes (Amara and Shibl, 2015; Shi et al., 2015). In the current review, we will focus on the particular
2016). probiotic, L. reuteri, and discuss its beneficial functions in
Lactobacillus spp. are one of the most widely used probiotics promoting health and preventing infections and diverse diseases.
and can be found in a large variety of food products throughout
the world (Giraffa et al., 2010). The genus Lactobacillus comprises
a large heterogeneous group of Gram-positive, nonsporulating, PROBIOTIC PROPERTIES OF L. reuteri
facultative anaerobic bacteria which include L. acidophilus,
L. rhamnosus, L. bulgaricus, L. casei, and L. reuteri. This genus There are some prerequisites for becoming potential probiotics:
plays a very important role in food fermentation and can also to survive in low pH and enzyme-enriched environments, to
be found in the GI system of humans and animals in variable adhere to epithelium for host-probiotic interaction, competition
amounts depending on the species, age of the host, or location with pathogenic microorganisms, and most importantly, safety.
within the gut (Duar et al., 2017). L. reuteri meets all of these requirements. Here, additional
Animal studies and preclinical results have shown that probiotic properties of L. reuteri are discussed that contribute to
Lactobacilli may help in the prevention and treatment of its diverse beneficial effects on host health and disease prevention
numerous GI tract disorders. Among these disorders are and/or amelioration (Figure 1).
enteric infections, antibiotic-associated diarrhea, necrotizing
enterocolitis in preterm neonates, inflammatory bowel disease, Gut Colonization of L. reuteri
colorectal cancer, and irritable bowel syndrome (Lebeer et al., Built for digestion and absorption, some sites of the GI system
2008). Although the GI tract is the site where Lactobacilli have developed to be harsh for microorganism colonization.
are believed to show the most benefits, probiotic applications Examples of this can be seen in the low pH conditions caused
of some Lactobacillus strains at other sites of the body have by gastric acids and bile salts in upper small intestine. Thus, the
been reported. These include the prevention and treatment of very first step of colonizing the GI tract is to survive in such
urogenital diseases and bacterial vaginosis in women, atopic environments. Multiple L. reuteri stains are resistant to low pH
disease, food hypersensitivity, and the prevention of dental caries and bile salts (Seo et al., 2010; Krumbeck et al., 2016). This
(Lebeer et al., 2008). resistance is believed to be at least partially dependent on its
One species of Lactobacillus, L. reuteri has multiple beneficial ability to form biofilms (Salas-Jara et al., 2016).
effects on host health such as prevention and/or amelioration L. reuteri is capable of attaching to mucin and intestinal
of diverse disorders. L. reuteri was first isolated in 1962. It epithelia, and some strains can adhere to gut epithelial cells in
has been characterized as heterofermentative species that grows a range of vertebrate hosts (Li et al., 2008; Hou et al., 2014, 2015).
in oxygen-limited atmospheres and colonizes the GI tract of A possible mechanism for adherence is the binding of bacterial
humans and animals (Kandler et al., 1980). The fact that it surface molecules to the mucus layer. Mucus-binding proteins
normally colonizes the GI tract may be the reason it confers great (MUBs) and MUB-like proteins, encoded by Lactobacillales-
probiotic properties. This organism can withstand a wide variety specific clusters of orthologous protein coding genes, serve as
of pH environments, employs multiple mechanisms that allow it adherence mediators, or so-called adhesins (Roos and Jonsson,
to successfully inhibit pathogenic microorganisms, and has been 2002; Kleerebezem et al., 2010; Gunning et al., 2016). The
shown to secrete antimicrobial intermediaries (Jacobsen et al., considerable diversity of MUBs among L. reuteri strains and the
1999; Valeur et al., 2004). variation in the abundance of cell-surface MUBs significantly
L. reuteri has been shown to be one of the truly indigenous correlates with their mucus binding ability (Mackenzie et al.,
bacteria of the human GI tract (Sinkiewicz, 2010). It naturally 2010). The strain-specific role of MUBs in recognizing mucus
colonizes a wide range of vertebrates, including pigs, rodents, elements and/or their capability of promoting aggregation can
and chickens. In fact, it has gone through long-term evolution to explain the contribution of MUBs on the adherence of L. reuteri.
diversify into host-adapted lineages (Oh et al., 2010; Walter et al., Factors that mediate the attachment to the surfaces include
2011). This organism is most typically found in the proximal multiple large surface proteins (Walter et al., 2005; Wang
digestive tract of the host (Frese et al., 2013). Several studies have et al., 2008; Frese et al., 2011), MUB A (Jensen et al., 2014),
assessed the safety of this organism in adults, children, infants, glucosyltransferase A (GtfA) and inulosucrase (Inu) (Walter
and even in an HIV-infected population (Wolf et al., 1998; et al., 2008), and D-alanyl ester (Walter et al., 2007).

FIGURE 1 | Probiotic properties of L. reuteri.
As L. reuteri that has colonized to the host GI tract can biofilm formation. However, the contribution of the bfrKRT and
form biofilms, efforts have been made to study the regulation of cemAKR to in vivo biofilm formation remains to be elucidated.
L. reuteri biofilm secretion and its association with the adherence The role of exopolysaccharide (EPS) in assisting colonization was
of bacteria to host GI epithelium. By doing in vitro biofilm assay, also examined with L. reuteri 100-23. The production of EPS was
Water, J. et al. uncovered the contribution of GtfA and Inu in the eliminated due to a mutation of the fructosyl transferase (ftf )
biofilm formation of L. reuteri TMW1.106 (Walter et al., 2008). gene (Sims et al., 2011). After administration to Lactobacillus-free
The in vivo biofilm formation of L. reuteri strains seems to be mice, compared to the wild-type strain, the colonization of the ftf
dependent on the host origin of the strains. In one study, nine mutant in the forestomach and cecum was largely impaired. This
L. reuteri strains isolated from different hosts (human, mouse, rat, indicates EPS production can enhance the colonizing ability of
chicken, and pig) were given to germ-free mice and the biofilms strain 100-23 in the gut. Interestingly, L. reuteri RC-14 has been
were evaluated after 2 days. Interestingly, only rodent strains were demonstrated to be able to penetrate mature E. coli biofilm and
able to form biofilms and adhere to the forestomach epithelium, become part of it (McMillan et al., 2011). Recently, L. reuteri
although the luminal populations were comparable among was delivered as a biofilm on microsphere and such delivery
strains of different origins (Frese et al., 2013). Another study by was found to promote the adherence of L. reuteri to intestinal
the same authors showed that a specialized transport pathway epithelium and enhance its probiotic property (Olson et al., 2016;
(the SecA2-SecY2 system) was unique in the rodent and porcine Navarro et al., 2017).
strains (Frese et al., 2011). By using a rodent strain L. reuteri
100-23, they compared extracellular and cell wall-associated Production of Metabolites With
proteins between the wild-type strain and the secA2 mutant. Health-Promoting Effect
Only one surface protein, L. reuteri 70902, was absent in the The antimicrobial and immunomodulatory effects of L. reuteri
secA2 mutant. In vivo colonization studies showed that the strains are linked to their metabolite production profile. Here, we
absence of L. reuteri 70902 leads to almost completely eliminated discuss a few well-studied metabolites with regard to the probiotic
biofilm formation. This strongly suggests that L. reuteri 70902 potential of L. reuteri.
and the SecA2-SecY2 system are key factors regulating biofilm
production from L. reuteri 100-23 in germ-free mice (Frese et al., Reuterin
2013). Another group investigated the role of two-component Most L. reuteri strains of human and poultry lineage are able
systems bfrKRT and cemAKR in in vitro biofilm formation of to produce and excrete reuterin, a well-known antimicrobial
L. reuteri 100-23 (Su and Ganzle, 2014). They found the deletion compound (Talarico et al., 1988; Talarico and Dobrogosz,
of certain genes in the operons enhanced the adherence and 1989; Cadieux et al., 2008; Jones and Versalovic, 2009;

Mishra et al., 2012; Greifova et al., 2017). Reuterin is a mixture of secreting metabolites that have antiviral components (Ang et al.,
different forms of 3-hydroxypropionaldehyde (3-HPA) (Talarico 2016). Furthermore, some studies suggest that L. reuteri may have
and Dobrogosz, 1989). It is known that L. reuteri can metabolize antifungal properties as well, where L. reuteri antagonizes, stops
glycerol to generate 3-HPA in a coenzyme B12-dependent, the growth of, and eventually kills various species of Candida
glycerol dehydratase-mediated reaction (Talarico and Dobrogosz, (Jorgensen et al., 2017).
1990; Chen and Chen, 2013). The production of 3-HPA has also
been demonstrated in a few other bacterial species (Zhu et al., Histamine
2002; Raynaud et al., 2003; Yang et al., 2007). However, L. reuteri A few strains of L. reuteri are able to convert the amino
is unique in its ability to produce and secrete 3-HPA in a manner acid L-histidine, a dietary component, to the biogenic amine
more than its bioenergetics requirement (Stevens et al., 2011). histamine (Diaz et al., 2016; Greifova et al., 2017). A human
Moreover, the antimicrobial activity of reuterin seems to rely on commensal bacterium, L. reuteri 6475 was used as the model
the spontaneous conversion of 3-HPA to acrolein, a cytotoxic strain for studying histamine in L. reuteri. J. Versalovic’s group
electrophile (Stevens and Maier, 2008; Engels et al., 2016). reported that L. reuteri 6475-derived histamine suppressed
Reuterin can inhibit a wide range of microorganisms, mainly tumor necrosis factor (TNF) production from stimulated
Gram-negative bacteria (Cleusix et al., 2007). Not surprisingly, human monocytes (Thomas et al., 2012). This suppression
most Lactobacillus species are resistant to reuterin, among which was dependent on the activation of histamine H2 receptor,
L. reuteri strains exert the most resistance (Jones and Versalovic, increased intracellular cAMP and protein kinase A, and the
2009; Mishra et al., 2012). In addition to its antimicrobial inhibition of MEK/ERK signaling. The production of histamine
property, reuterin is able to conjugate heterocyclic amines, which and subsequent in vitro TNF-suppressing function are regulated
also seems to be dependent on the formation of acrolein (Engels by a complete chromosomal histidine decarboxylase (hdc) gene
et al., 2016). This suggests acrolein is an essential compound in cluster, which contains hdcA, hdcB, and hdcP (Rossi et al., 2011;
the activity of reuterin. Thomas et al., 2012). The same group of researchers also found
Apart from reuterin, several other antimicrobial substances, that oral administration of hdc+ L. reuteri could effectively
including lactic acid, acetic acid, ethanol, and reutericyclin, have suppress intestinal inflammation in a trinitrobenzene sulfonic
been determined as products of some L. reuteri strains (Ganzle acid (TNBS)-induced mouse colitis model (Gao et al., 2015).
and Vogel, 2003; Burge et al., 2015; Gopi et al., 2015; Yang Y. Moreover, intraperitoneal injection of L. reuteri 6475 culture
et al., 2015; Greifova et al., 2017). With the synthesis of these supernatant to TNBS-treated mice resulted in similar colitis
substances, L. reuteri has been shown to be effective against attenuation. These results strongly indicate the involvement
a variety of GI bacterial infections. These infections include of L. reuteri metabolites, including histamine, in intestinal
Helicobacter pylori, E. coli, Clostridium difficile, and Salmonella immunomodulation (Thomas et al., 2016). Further investigations
(Reid and Burton, 2002; Cherian et al., 2015; Abhisingha et al., showed that a gene called rsiR was necessary for the expression
2017; Genis et al., 2017). One of the more notable illustrations of hdc gene cluster in L. reuteri 6475 (Hemarajata et al.,
of the efficacy of L. reuteri as a probiotic against infections is 2013). Inactivation of rsiR gene led to reduced TNF inhibition
the use of L. reuteri to treat H. pylori. H. pylori infection is in vitro and diminished anti-inflammatory function in vivo.
a major cause of chronic gastritis and peptic ulcers, as well as Additionally, both the in vitro TNF suppression and the in vivo
a risk factor for gastric malignancies (Franceschi et al., 2007; anti-colitis effects appear to be regulated by a gene named folC2
Lesbros-Pantoflickova et al., 2007; Park et al., 2007). The use (Thomas et al., 2016). Inactivation of folC2 gene resulted in
of L. reuteri against H. pylori has been explored in many suppression of the hdc gene cluster and diminished histamine
studies (Table 1). It has been suggested that L. reuteri works by production. Notably, histamine production by L. reuteri is highly
competing with H. pylori and inhibiting its binding to glycolipid strain-dependent, and most studies have been focused on strains
receptors (Mukai et al., 2002). The competition reduces the of human origin (Mishra et al., 2012).
bacterial load of H. pylori and decreases the related symptoms
(Lionetti et al., 2006; Francavilla et al., 2008). Some studies have Vitamins
shown that L. reuteri has the potential to completely eradicate There are 13 essential vitamins for humans due to the inability
H. pylori from the intestine (Ojetti et al., 2012). Importantly, of the human body to synthesize them (Linares et al., 2017).
L. reuteri is advantageous in the treatment of H. pylori as Like many other Lactobacillus spp., several L. reuteri strains are
the supplementation eradicates the pathogen without causing able to produce different types of vitamins, including vitamin
the common side effects associated with antibiotic therapies B12 (cobalamin) and B9 (folate). As mentioned earlier, B12 is
(Francavilla et al., 2014). vital in reuterin production because the reduction of glycerol to
A considerable amount of research has been done to 3-HPA requires a B12-dependent coenzyme. Up to now, at least 4
determine the beneficial effects of L. reuteri against viruses and/or L. reuteri strains with various origins have been found to produce
fungi. There is evidence showing the benefit of L. reuteri against B12 (Taranto et al., 2003; Santos et al., 2008b; Sriramulu et al.,
pneumoviruses, circoviruses, rotaviruses, coxsackieviruses, and 2008; Gu et al., 2015). Among these strains, L. reuteri CRL1098
papillomaviruses (Shornikova et al., 1997a,b; Preidis et al., 2012; and L. reuteri JCM1112 are the most studied (Morita et al., 2008;
Ang et al., 2016; Brenner et al., 2016; Piyathilake et al., 2016; Santos et al., 2008a, 2011). In one study, the administration of
Karaffova et al., 2017). It has been suggested that L. reuteri L. reuteri CRL1098 together with a diet lacking vitamin B12
ameliorates viral infection by regulating the microbiota and was shown to ameliorate pathologies in B12-deficient pregnant

TABLE 1 | Clinical efficacies of L. reuteri against H. pylori.
Strain Treatment Subjects Result Citation
DSM 17648 14 days Adults Decrease in pathogen load in the stomach Holz et al., 2015
DSM 17938 20 days Patients 93% successful eradication of the pathogen Dore et al., 2016
with inhibitor-tetracycline-metronidazole –
L. reuteri therapy
ATCC 55730 10 days Infected children Improvement of GI symptoms Lionetti et al., 2006
– 7 days Patients No improvement of the standard triple therapy Scaccianoce et al., 2008
ATCC 55730 4 weeks Patients Significant decrease of pathogen load and Francavilla et al., 2008
improvement of dyspeptic symptoms
SD2112 4 weeks Patients Decrease of pathogen density and suppression Imase et al., 2007
of urease activity
DSMZ 17648 14 days Patients Decrease in pathogen load Mehling and Busjahn, 2013
DSM 17938, ATCC PTA 6475 During therapy Patients Reduction of antibiotic-associated side effects Francavilla et al., 2014
in eradication therapy
DSM 17938 8 weeks Patients Decrease of urease activity in pantoprazole Dore et al., 2014
therapy
female mice and their offspring (Molina et al., 2009). This clearly composition and metabolic function of the gut, oral, and vaginal
points to the potential application of L. reuteri in treating B12 microbiotas. These effects are largely strain-specific (Yang Y.
deficiency. In addition to B12, folate can also be synthesized by et al., 2015; Garcia Rodenas et al., 2016; Galley et al., 2017; Su
some specific L. reuteri strains, including L. reuteri 6475 and et al., 2017).
L. reuteri JCM1112 (Santos et al., 2008b; Thomas et al., 2016).
Gut Microbiota
Exopolysaccharide (EPS)
Studies have shown the modulatory effects of L. reuteri on
The EPS produced by L. reuteri is important for biofilm
the microbiotas of rodents, piglets, and humans. One study
formation and adherence of L. reuteri to epithelial surfaces (Salas-
assessed oral administration of a human-origin L. reuteri strain
Jara et al., 2016). In addition, EPS synthesized by L. reuteri is
(DSM17938) to scurfy mice, which have gut microbial dysbiosis
able to inhibit E. coli adhesion to porcine epithelial cells in vitro
due to the foxp3 gene mutation. The results indicated that this
(Ksonzekova et al., 2016). More importantly, EPS-mediated
strain of L. reuteri was able to prolong the lifespan of the
blocking of adhesion also suppresses gene expression of pro-
mice and reduce multi-organ inflammation while remodeling
inflammatory cytokines that are induced by E. coli infection,
the gut microbiota (He et al., 2017). Changes of gut microbiota
including IL-1β and IL-6. Further in vivo experiments in piglets
included increases in the phylum Firmicutes and the genera
showed similar results in that EPS originated from L. reuteri
Lactobacillus and Oscilospira. Notably, the disease-ameliorating
prevented piglet diarrhea in bacterial infection by reducing the
effect of L. reuteri was attributed to the remodeled gut microbiota,
adhesion of E. coli (Chen et al., 2014). In addition, EPS of
though the community composition was still distinct from
L. reuteri origin has been reported to suppress the binding of
wild-type littermates. Further investigation showed that inosine
enterotoxigenic E. coli to porcine erythrocytes (Wang et al., 2010).
production was enhanced by the gut microbiota upon L. reuteri
EPS produced by rodent L. reuteri 100-23 was also demonstrated
administration. Through adenosine A2A receptor engagement,
to induce Foxp3+ regulatory T (Treg) cells in the spleen (Sims
inosine can reduce Th1/Th2 cells and their associated cytokines.
et al., 2011). In contrast, an L. reuteri 100-23 strain with the
These results suggested that the L. reuteri – gut microbiota –
ftf mutation that eliminates EPS production from L. reuteri did
inosine – adenosine A2A receptor axis serves as a potential
not induce splenic Treg cells. This suggests that EPS is required
therapeutic method for Treg-deficient disorders. Moreover, oral
for the L. reuteri-mediated induction of Treg cells and indicates
L. reuteri 6475 treatment led to a higher diversity of microbiota
the potential of using wild-type L. reuteri 100-23 to treat Treg
in both jejunum and ileum in an ovariectomy-induced bone loss
deficiency.
mouse model (Britton et al., 2014). Specifically, there were more
abundant Clostridiales but less Bacteriodales. However, whether
L. reuteri-Mediated Modulation of Host or not the changed gut microbiota was directly associated
Microbiota with the prevention of bone loss requires further investigation.
Emerging evidence suggests that the host microbiota and Furthermore, L. reuteri C10-2-1 has been shown to modulate the
immune system interact to maintain tissue homeostasis in diversity of gut microbiota in the ileum of rats (Wang P. et al.,
healthy individuals (Kamada et al., 2013; Bene et al., 2017). Many 2016).
diseases have been associated with perturbation of the microbiota Compared to vaginally delivered infants, Cesarean (C)-section
(Mu et al., 2015), whereas restoration of the microbiota has delivered infants display a higher abundance of Enterobacter but
been demonstrated to prevent or ameliorate several diseases less Bifidobacterium in their gut microbiota (Garcia Rodenas
(Scott et al., 2015). L. reuteri is able to influence the diversity, et al., 2016; Nagpal et al., 2016). In one study, treating C-section

babies with L. reuteri DSM 17938 from 2 weeks to 4 months species richness was not altered (Romani Vestman et al.,
of age modulated the development of gut microbiota toward 2015). The alterations disappeared 4 weeks after the treatments
the community pattern found in vaginally delivered infants were terminated, suggesting the fast turnover of the oral
(Garcia Rodenas et al., 2016). The gut microbiota structure microbiome. In another human study, oral L. reuteri treatment
of vaginally born infants remained unaltered upon L. reuteri reduced the amount of periodontal pathogens in the subgingival
supplementation. In another study, treating infants with the same microbiota, though no clinical impact was seen (Iniesta et al.,
L. reuteri strain resulted in decreased anaerobic Gram-negative 2012).
and increased Gram-positive bacterial counts in gut microbiota,
whereas the abundances of Enterobacteriaceae and Enterococci Vaginal Microbiota
were largely lowered by L. reuteri treatment (Savino et al., 2015b). Lactobacilli dominate the vaginal bacterial community in healthy
The differences in infant age, duration of treatment, route of women (Macklaim et al., 2015). One study showed that only
administration, and dosage may explain the differences in results 14 days of oral L. reuteri RC-14 administration could restore
from the two studies. the normal vaginal flora in postmenopausal women (Petricevic
For human adults, L. reuteri NCIMB 30242 administered et al., 2008). Interestingly, the relative abundance of Lactobacilli
as delayed release capsules for 4 weeks was able to increase is largely decreased in bacterial vaginosis patients (Macklaim
the ratio of Firmicutes to Bacteroidetes in healthy individuals et al., 2015). A total of 4 weeks of oral capsule consumption
(Martoni et al., 2015). This strain of L. reuteri is known to be of two Lactobacilli strains including L. reuteri RC-14 increased
able to activate bile salt hydrolase and its effect in increasing the relative abundance of Lactobacilli. A similar increase of
circulating bile acid has been reported (Jones et al., 2012b). Lactobacilli was seen when L. reuteri RC-14 was administered
The upregulation of circulating bile acid has been proposed vaginally together with a L. rhamnosus strain (Bisanz et al.,
as a reason for the modulated gut microbiota (Jones et al., 2014). However, in pregnant women, 8 weeks of oral L. reuteri
2012b). In type 2 diabetes patients, although 3 months of RC-14 treatment did not efficiently restore the normal vaginal
L. reuteri DSM 17938 supplementation did not significantly microbiota (Gille et al., 2016). This suggests that L. reuteri RC-14
change the gut microbial structure, the disease outcome of may not be able to act alone.
L. reuteri treatment was highly correlated with the baseline
gut microbiota structure of individuals (Mobini et al., 2017). Role of L. reuteri in Immunomodulation
Furthermore, the administration of L. reuteri DSM 17938 in Lactobacillus reuteri is able to increase free secretory IgA
cystic fibrosis (CF) patients rescued gut microbiota dysbiosis (sIgA) levels in rats (Wang P. et al., 2016). However, the
by reducing Proteobacteria while also enhancing the relative upregulation of sIgA was eliminated in vitamin A-deficient rats,
abundance of Firmicutes (del Campo et al., 2014). However, suggesting that L. reuteri functions in a vitamin A-dependent
whether or not the modulated gut microbiota contributed to manner. In pregnant women, the intake of L. reuteri did not
improved GI health in probiotic-treated CF patients needs to be alter the levels of total IgA or sIgA in breast milk (Bottcher
explored further. et al., 2008). When it comes to the effect of L. reuteri in
L. reuteri influences the gut microbial community in piglets inducing salivary IgA, the results are controversial. Increased
in a strain-specific manner. For instance, oral L. reuteri salivary IgA levels were reported in humans’ chewing gum
ZLR003 administration was able to change both the diversity containing L. reuteri (Ericson et al., 2013). However, other
and the composition of the gut microbiota (Zhang et al., studies showed that L. reuteri did not affect IgA concentration
2016). However, treatment with the I5007 strain did not affect in saliva (Garofoli et al., 2014; Jorgensen et al., 2016; Braathen
colonic microbial structure in piglets (Liu H. et al., 2017). et al., 2017). The difference in the strains of L. reuteri used
In another study, fodder fermented with L. reuteri changed in the studies may explain the difference in results. Notably,
the abundances of 6 different bacterial taxa, particularly the an important commonality is that salivary L. reuteri-positive
family Enterobacteriacae, in weanling pigs (Yang Y. et al., 2015). individuals have higher salivary IgA levels. Whether L. reuteri
However, the major alterations including increased Mitsuokella affects IgA levels by directly regulating B cells requires further
and decreased a family under phylum Bacteroidetes could only be investigations.
seen with L. reuteri TMW1.656 rather than L. reuteri LTH5794. Many studies have shown that L. reuteri can induce
TMW1.656 is a reutericyclin-producing strain while LTH5794 anti-inflammatory Treg cells, which likely contributes to the
is not, suggesting the possible contribution of reutericyclin beneficial effects of L. reuteri in a wide range of diseased
in modulating gut microbiota in piglets (Yang Y. et al., and non-diseased conditions (Table 2). The Treg-inducing
2015). property of L. reuteri is largely strain-dependent. However, the
anti-inflammatory effect of L. reuteri does not always rely on the
Oral Microbiota induction of Treg cells. A good example is L. reuteri-mediated
The phyla Firmicutes, Bacteroidetes, Fusobacteria, Proteobacteria, suppression of Th1/Th2 responses in Treg-deficient mice
and Actinobacteria are most abundant in the human oral (He et al., 2017). Certain L. reuteri strains are able to reduce the
microbiome (Romani Vestman et al., 2015). In a randomized production of many pro-inflammatory cytokines. For example,
controlled trial, 12 weeks of daily consumption of two L. reuteri GMNL-263 can reduce serum MCP-1, TNF, and
L. reuteri strains – DSM 17938 and PTA 5289 led to a IL-6 levels in mice fed with high fat diet (Hsieh et al., 2016).
shift in oral microbiota composition, though the bacterial Similar effects were observed in mice treated with heat-killed

TABLE 2 | L. reuteri-mediated induction of Treg cells under various diseased and non-diseased conditions.
Condition Subject Tissue Strain Citation
Western-diet-associated obesity Mouse MLN ATCC PTA 6475 Poutahidis et al., 2013b
Wound healing Mouse Biopsy ATCC PTA 6475 Poutahidis et al., 2013a
Systemic lupus erythematosus Mouse Kidney ATCC PTA 6475 Mu et al., 2017c
Necrotizing enterocolitis Mouse Intestine, MLN DSM 17938 Liu et al., 2013, 2014
Wild-type Mouse MLN, Spleen 100-23 Livingston et al., 2010; Sims et al., 2011
Wild-type Mouse Spleen ATCC 23272 Karimi et al., 2009
Wild-type, IBD, atopic dermatitis Mouse MLN, Colon, Ear – Abediankenari and Ghasemi, 2009
IBD Human Peripheral blood RC-14 Lorea Baroja et al., 2007
IBD, inflammatory bowel disease; MLN, mesenteric lymph node.
GMNL-263. However, in some cases, the immunomodulatory Role of L. reuteri in Reversing the Leaky
effects of L. reuteri appear to rely on its metabolites, as the Gut
culture supernatant of L. reuteri BM36301 could reduce TNF
Physical, biochemical, and immunological barriers comprise
production from human myeloid THP-1 cells (Lee et al., 2016).
the gut barrier function, which is required to block the entry
Interestingly, tryptophan catabolites of L. reuteri have been
of exterior antigens and toxins (Mu et al., 2017a). If any
recognized as ligands for aryl hydrocarbon receptor (AhR).
abnormalities occur in the intestinal barrier, the permeability
Through activating AhR, L. reuteri can promote local IL-22
may increase resulting in a leaky gut. Various probiotics are
production from innate lymphoid cells (ILCs) (Zelante et al.,
known for their abilities to enhance mucosal barrier function,
2013). In addition, the derivatives of tryptophan generated
of which L. reuteri is a well-known example (Mu et al., 2017a).
by L. reuteri can induce the development of regulatory
In DSS-induced colitis, L. reuteri administration could reduce
CD4+ CD8αα+ double-positive intraepithelial lymphocytes in
bacterial translocation from the GI tract to the mesenteric lymph
an AhR-dependent manner (Cervantes-Barragan et al., 2017).
nodes (MLN) (Dicksved et al., 2012). In addition, treatment
Considering that AhR is ubiquitously expressed, L. reuteri and
of lupus-prone mice with a mixture of Lactobacillus species
its metabolites may be able to influence many more types
including L. reuteri led to a higher expression of tight junction
of immune cells beyond ILCs and T cells (Nguyen et al.,
(TJ) proteins in intestinal epithelial cells (Mu et al., 2017c).
2013).
Subsequently, the translocation of pro-inflammatory molecules
such as LPS was significantly suppressed, which correlated with
Neuromodulatory Capability of L. reuteri attenuated disease. In addition to mouse studies, several strains
The intestinal microbiota plays a role in the functions of the of L. reuteri have been shown to possess the ability to modulate
enteric nervous system (ENS) (Yoo and Mazmanian, 2017). TJ protein expression and maintain intestinal barrier integrity
Subjects with microbiota depletion exhibit an abnormal ENS state in pigs (Yang F. et al., 2015; Wang Z. et al., 2016). Moreover,
(Anitha et al., 2012; Brun et al., 2013, 2015; Yoo and Mazmanian, the ability of L. reuteri to decrease intestinal permeability has
2017). Antibiotic treatment reduces the number of neurons in the been seen in humans. In children with atopic dermatitis, where
ENS. This may be related to the decrease in Glial cell line-derived the impairment of intestinal barrier function has been positively
neurotrophic factor (GDNF), which can be restored by TLR2 correlated with disease pathogenesis (De Benedetto et al., 2011),
stimulation (Brun et al., 2013). Moreover, germ-free animals treatment with L. reuteri DSM 12246 (and L. rhamnosus 19070-2)
show defective ENS morphology and excitability, which can significantly reduced the frequency of GI symptoms while
be reversed by microbiota colonization (McVey Neufeld et al., decreasing the lactulose to mannitol ratio (Rosenfeldt et al.,
2013; Collins et al., 2014). L. reuteri, specifically, can prevent 2004), which reflects the reversal of a leaky gut (Camilleri et al.,
visceral pain response mainly by reducing the enteric nerve 2010).
activity during the colorectal distension pressure in mice (Kamiya
et al., 2006; Ma et al., 2009). Interestingly, live, heat-killed,
gamma-irradiated L. reuteri, or even the conditioned media L. reuteri ATTENUATE HUMAN
all had a similar effect (Kamiya et al., 2006). L. reuteri can DISEASES
also produce gamma-aminobutyric acid (GABA), the major
inhibitory neurotransmitter in the central nervous system A growing body of evidences links microbiota and bacterial
(Su et al., 2011; Barrett et al., 2012; Pallin et al., 2016). However, translocation with multiple diseases, including several
the in vivo bioactivity of the produced GABA has not been autoimmune disorders (Mu et al., 2015, 2017a). Due to its
addressed (Yoo and Mazmanian, 2017). Furthermore, L. reuteri strong modulatory effects on host microbiota and immune
can increase the excitability and the number of action potentials responses with almost no safety concerns, L. reuteri is a good
in rat colonic sensory neurons (Kunze et al., 2009). These distinct candidate for disease prevention and/or treatment. Indeed, the
effects of L. reuteri may be due to the difference in target neurons therapeutic potential of various L. reuteri strains has been studied
(Lai et al., 2017). in diverse diseases and the results are promising in many cases.

TABLE 3 | Effects of L. reuteri on early-life diseases.
Target Strain Duration Subjects Result Citation
Early caries lesions DSM 17938, ATCC 3 months Adolescent No significant change in fluorescence Keller et al., 2014
PTA 5289 or lesion area
Caries ATCC 55730 First year life Infants Reduced prevalence of caries and Stensson et al.,
gingivitis score when the kids were 2014
9 years old
FAP DSM 17938 4 weeks FAP children Significant decrease in the frequency Weizman et al.,
and intensity of functional abdominal 2016
pain
FAP DSM 17938 4 weeks FAP children Significant reduction of pain intensity Romano et al.,
2014
Infectious diarrhea DSM 17938 5 days Children Safe and well-tolerated; decreased Dinleyici et al., 2015
duration of diarrhea
Rotavirus diarrhea - Up to 5 days Young children Shortened diarrhea duration and large Shornikova et al.,
decrease in the occurrence of watery 1997a,b
diarrhea
Nosocomial diarrhea DSM 17938 During hospital stay Children No effect on the overall incidence of Wanke and
diarrhea, including that related to Szajewska, 2012
rotavirus infection
Acute diarrhea DSM 12246 (with 5 days Children patients Decreased duration of diarrhea; Rosenfeldt et al.,
19070-2) decreased period of rotavirus 2002a,b
excretion
Acute diarrhea DSM 17938 3 days Children Decrease in diarrhea frequency, Francavilla et al.,
duration, and relapse 2012
Acute diarrhea DSM 17938 5 days Hospitalized Effective decrease of the duration of Dinleyici et al., 2014
children acute diarrhea
Diarrhea ATCC 55730 12 weeks Infants Fewer and shorter diarrhea episodes Weizman et al.,
2005
Diarrhea DSM 17938 6 months Children Reduced incidence of diarrhea Agustina et al.,
2012
Diarrhea DSM 17938 3 months Children Decrease in diarrhea episodes and Gutierrez-Castrellon
duration; Benefits against respiratory et al., 2014
infection
Infant colic DSM 17938 3 weeks Breastfed infants Significant reduction in crying time Mi et al., 2015
Infant colic DSM 17938 3 weeks Breastfed infants Reduction in crying and fussing time Chau et al., 2015
Infant colic DSM 17938 12 weeks Newborns Effective preventive and protective Savino et al., 2015a
action
Infant colic ATCC 55730 28 days Breastfed infants Significantly improvement of colicky Savino et al., 2007
symptoms compared with
simethicone
Infant colic DSM 17938 21 days Breastfed infants Improved symptoms; Increase of Savino et al., 2010
Lactobacilli increase and decrease of
E. coli in the fecal microbiota
Infant colic DSM 17938 21 days Colicky infants No effect on the global microbiota Roos et al., 2013
composition
Infant colic DSM 17938 21 days Breastfed infants Higher rate of responders and Szajewska et al.,
reduced median crying time 2013
Infant colic DSM 17938 1 month Infants No effect on crying time Sung et al., 2014
Infant colic DSM 17938 90 days Infants Significant reduction of the mean Indrio et al., 2014
crying time
Infant growth DSM 17938 98 days Healthy infants Well-tolerated but no improvement on Cekola et al., 2015
growth
Atopic dermatitis DSM 122460 (with 6 weeks AD children Improvement of eczema; more Rosenfeldt et al.,
19070-2) pronounced in allergic patients 2003, 2004
Atopic dermatitis ATCC 55730 8 weeks AD children Positive modulation of cytokine Miniello et al., 2010
pattern in the exhaled breath
condensate
Eczema ATCC 55730 −1 to 12 month old Infants with family No protection of the general Abrahamsson
Allergic history occurrence of eczema; Prevention of et al., 2007
IgE-associated eczema
(Continued)

TABLE 3 | Continued
Target Strain Duration Subjects Result Citation
GI motility - 30 days Newborns Faster gastric emptying Indrio et al., 2009

Respiratory allergy ATCC 55730 −1 to 12 month old Infants No effect on the prevalence of asthma, Abrahamsson
eczema or other allergic diseases later et al., 2013
in life
Feeding intolerance DSM 17938 Until out of NICU Preterm infants Decrease in feeding intolerance and Rojas et al., 2012
duration of hospitalization
Necrotising enterocolitis DSM 17938 Until discharge Preterm infants No effect on NEC rate; Decrease in Oncel et al., 2014
feeding intolerance and duration of
hospital stay
Regurgitation DSM 17938 28 days Infants Prevention of regurgitation during the Garofoli et al., 2014
first month of life
Regurgitation DSM 17938 90 days Infants Significant reduction of the mean Indrio et al., 2014
number of regurgitation
FAP, functional abdominal pain; NICU, neonatal intensive care unit; NEC, necrotising enterocolitis.
Early-Life Disorders Therefore, we treated MRL/lpr mice with a mixture of five

Taking advantage of the safety and tolerance of L. reuteri in strains of Lactobacilli to determine their therapeutic benefit.
infants and young children, a lot of efforts have been made to test As anticipated, increasing Lactobacilli in the gut improved
the potential application of L. reuteri against disorders early in renal function, reduced serum autoantibodies, and prolonged
life (Table 3). In general, the results are promising. L. reuteri has the survival of MRL/lpr mice (Mu et al., 2017c). Interestingly,
been demonstrated beneficial in the prevention and/or treatment L. reuteri and an uncultured Lactobacillus sp. accounted for
of many conditions including diarrhea, functional abdominal > 99% of the observed effects. It suggests a central role
pain, caries, atopic dermatitis, allergy, feeding intolerance, and of L. reuteri in attenuating lupus nephritis. Furthermore, we
regurgitation. Infant colic, for example, has been the major found that MRL/lpr mice had a “leaky” gut during disease
therapeutic target of L. reuteri (Table 3). Infant colic is progression, whereas Lactobacillus treatment enhanced the
characterized by immoderate crying and affects 10–30% infants intestinal barrier function in these mice and subsequently
(Mi et al., 2015). The exact cause and efficient treatment of decreased metabolic endotoxemia (Mu et al., 2017c). At the
this condition have remained elusive. The clinical efficacy of same time, the local and systemic pro- and anti-inflammatory
L. reuteri DSM 17938 has been demonstrated as most of the network was rebalanced by Lactobacillus treatment. Specifically,
clinical trials were successful (Table 3). The failure of some IL-10 production was enhanced while the level of IL-6 was
studies may be explained by the differences in the dosage of decreased systemically. Strikingly, the benefits of Lactobacilli
L. reuteri, the infant age when the studies initiated, or the baseline were only observed in females and castrated males but not in
microbiota structure. It is worth mentioning that L. reuteri is intact males. Coincidently, the relative abundance of Lactobacilli
naturally contained in human breast milk (Soto et al., 2014), in gut microbiota did not decrease as disease progressed in
though inconsistencies exist among individuals. The presence male MRL/lpr mice (Zhang et al., 2014). Consistent with
of L. reuteri in milk may complicate the results of studies that our observations, daily consumption of L. reuteri BM36301
involved breastfeeding. When given during pregnancy, L. reuteri significantly lowered serum TNF level in females but not in
did not show a significant effect on allergy and eczema in infants males (Lee et al., 2016). The high serum level of testosterone
after they were born (Table 3). in males may have led to the difference in the response to
L. reuteri. Together, these results suggest possible interaction
Systemic Lupus Erythematosus between sex hormones and gut microbiota in autoimmune
The SLE is a multi-system autoimmune disease that involves both disease development (Markle et al., 2013; Yurkovetskiy et al.,
genetics and environment as the major disease causative factors 2013). Further investigation of this link is required. In another
(Tsokos, 2011; Edwards et al., 2017). The role of gut microbiota lupus mouse model, NZB/W F1, the administration of two
in SLE development was suggested by recent studies, and L. reuteri strains, together with one L. paracasei strain, was shown
probiotics have been proposed as potential immunoregulators in to be effective in ameliorating lupus hepatitis (Hsu et al., 2017).
SLE (Mu et al., 2015, 2017b; de Oliveira et al., 2017; Edwards Liver abnormalities, manifested as increased liver enzymes, portal
et al., 2017; Esmaeili et al., 2017). We reported a significantly inflammation and histopathological changes, have been observed
decreased level of Lactobacillaceae in lupus-prone MRL/lpr in both lupus mouse models and SLE patients (Hsu et al.,
female mice compared to healthy control mice both before and 2008; Grover et al., 2014). In this study, the oral L. reuteri
after the disease initiated in MRL/lpr mice (Zhang et al., 2014). treatment largely mitigated hepatic apoptosis and inflammation,
Moreover, we found that treatment with retinoic acid improved suggesting a protective function of L. reuteri against lupus-
kidney disease in MRL/lpr mice, and that the improvement of associated liver disease (Hsu et al., 2017). The protection seems
lupus symptoms was associated with restoration of Lactobacilli. to rely on the capability of L. reuteri to increase antioxidant
This suggests a possible beneficial effect of Lactobacilli in lupus. activity and reduce cytokines associated with more severe lupus,

such as IL-6 and TNF (Tzang et al., 2017). Interestingly, within Neurodevelopmental Disorder
these two L. reuteri strains, only GMNL-263 can significantly Exposure to maternal obesity in utero increases the chance
promote the differentiation of Treg cells, again emphasizing of neurodevelopmental disorders, such as autism spectrum
the uneven immunoregulatory abilities of different L. reuteri disorder, in children (Connolly et al., 2016). In a recent mouse
strains. study, maternal HFD (MHFD) was shown to induce social
deficits in the offspring (Buffington et al., 2016). The impaired
Obesity social ability in GF mice was restored by fecal microbiota
The correlation between gut microbiota and obesity is well transplantation from offspring with maternal regular diet (MRD)
documented (Okeke et al., 2014; Harakeh et al., 2016). but not MHFD, suggesting a potential role of microbiota in
The microbiota composition varies between lean and obese this process. Further analysis showed that the abundance of
individuals, and a surprisingly high level of Lactobacillus spp. L. reuteri was reduced more than ninefold in the gut microbiome
has been found in the microbiota of both obese adults and obese of MHFD vs. MRD offspring. The social defects in MHFD
children (Armougom et al., 2009; Bervoets et al., 2013). Among offspring were rescued by direct L. reuteri administration,
different Lactobacillus spp., L. reuteri was specifically described suggesting an effect of L. reuteri in regulating neurodevelopment
to be associated with obesity (Million et al., 2012, 2013a). The in MHFD mice. This regulatory function of L. reuteri was
association was further established when vancomycin-resistant attributed to its capability to increase the level of oxytocin
L. reuteri in gut microbiota was determined as a body weight gain (Poutahidis et al., 2013a; Buffington et al., 2016). The results
predictor during vancomycin treatment (Million et al., 2013b). of these studies suggest a potential application of L. reuteri in
However, in a randomized, double-blind and placebo-controlled the treatment of patients who suffer from neurodevelopmental
clinical trial, the administration of L. reuteri JBD301 for 12 weeks disorders.
significantly reduced body weight in overweight adults (Chung
et al., 2016). Moreover, supplementation of infant formula with Stressor Exposure and Enteric Infection
L. reuteri did not increase weight gain in infants (Braegger The composition of gut microbiota shift when the host is
et al., 2011; Koleva et al., 2015). These conflicting results indicate exposed to stressors (Bailey et al., 2010; Galley et al., 2014).
that L. reuteri may influence the development of obesity in a In C57BL/6 males, social stressors led to an altered intestinal
strain-dependent manner. This hypothesis is partially verified microbiota composition, though there was no significant
in an animal study. In that study, three different strains of change in community diversity (Galley et al., 2014). Further
L. reuteri were used to test their influence on diet-induced analysis showed stressor-induced reductions in the families
obesity (Fåk and Bäckhed, 2012). It was demonstrated that Porphyromonadaceae and Lactobacillaceae, especially in the
only L. reuteri PTA 4659 efficiently reduced the body weight genus Lactobacillus. Among Lactobacillus spp., L. reuteri was
of mice fed with high-fat diet (HFD), whereas L. reuteri specifically measured and a lower abundance of L. reuteri
L6798-treated mice even gained some weight. The changes of was evident in stressor-exposed CD-1 mice but not C57BL/6
adipose and liver weights were consistent with the body weight mice. In fact, the level of L. reuteri in C57BL/6 male
change. mice was below the detection limit with or without stressor
In animal studies, several strains of L. reuteri have been exposure (Galley et al., 2014). It is important to note
reported to negatively regulate the development of obesity that stressor exposure increased the severity of Citrobacter
(Dahiya et al., 2017). In addition to the beneficial effect of rodentium-induced inflammation in the gut (Bailey et al., 2010;
L. reuteri JBD301 to human obese patients mentioned earlier, Mackos et al., 2016). The colonization of C. rodentium was
the favorable role of this strain of L. reuteri against weight promoted by stressor exposure, which subsequently resulted
gain was confirmed in HFD-fed mice (Chung et al., 2016). in more severe colonic pathology and increased production of
In HFD-induced obese mouse models, the beneficial role of inflammatory cytokines and chemokines (Mackos et al., 2016).
L. reuteri GMNL-263 was also noted (Hsieh et al., 2016). Further studies revealed that stressor-induced C. rodentium
Treatment with L. reuteri GMNL-263 reduced the body weight colitis was C-C motif chemokine ligand 2 (CCL2)-dependent.
as well as the percentages of adipose tissue and liver to body Interestingly, administration of L. reuteri ATCC 23272 was
weight. Interestingly, heat-killed GMNL-263 appeared to have a able to reverse stressor-induced C. rodentium infection, which
very similar beneficial function (Hsieh et al., 2016; Liao et al., also relied on CCL2 (Mackos et al., 2013, 2016). However,
2016). L. reuteri 6475 has also been shown to be beneficial L. reuteri was not able to restore the gut microbiome
against obesity in mice (Poutahidis et al., 2013b). The function altered by social stressors. This indicates that the beneficial
of L. reuteri 6475 was suggested to be largely dependent on its effect of L. reuteri on stressor exposure and subsequent
capability to induce Treg cells without changing the gut microbial enteric infection is not microbiota-dependent (Galley et al.,
ecology. Furthermore, the weight loss properties of some reagents 2017).
have been attributed to their abilities to increase L. reuteri in
mice. Polymannuronic acid, for example, was able to increase
the relative abundance of L. reuteri and significantly reduce CONCLUSION
HFD-induced body weight gain (Liu F. et al., 2017). Whether the
increase of L. reuteri is the cause of weight loss requires further There has been a decrease in the abundance of L. reuteri in
investigation. humans in the past few decades likely caused by the modern

lifestyle (Antibiotic use, western diet, improved hygiene). Such it may be advantageous to combine different strains of L. reuteri
decrease coincides with higher incidences of inflammatory to maximize their beneficial effects.
diseases over the same period of time. While evidence is lacking
to establish the correlation, it may be helpful to increase L. reuteri
colonization and/or facilitate its probiotic functions as a new and AUTHOR CONTRIBUTIONS
relatively safe strategy against inflammatory diseases. In addition,
through direct regulation or indirect modulation via the host QM and VT wrote the first draft of the review. XL edited and
microbiota, L. reuteri plays an impressive role in eliminating finalized the manuscript.
infections and attenuating both GI diseases and diseases in
remote tissues. The safety and tolerance of L. reuteri has been
proven by the numerous clinical studies. There are multiple FUNDING
L. reuteri strains with different host origins, and many of the
probiotic functions of L. reuteri are strain-dependent. Therefore, This work was funded by NIH R15AR067418 and R01AR073240.
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and gut microbiota diversity. Mol. Nutr. Food Res. 60, 2020–2030. doi: 10.1002/ be construed as a potential conflict of interest.
mnfr.201501065
Wang, Y., Ganzle, M. G., and Schwab, C. (2010). Exopolysaccharide synthesized Copyright © 2018 Mu, Tavella and Luo. This is an open-access article distributed
by Lactobacillus reuteri decreases the ability of enterotoxigenic Escherichia under the terms of the Creative Commons Attribution License (CC BY). The use,
coli to bind to porcine erythrocytes. Appl. Environ. Microbiol. 76, 4863–4866. distribution or reproduction in other forums is permitted, provided the original
doi: 10.1128/AEM.03137-09 author(s) and the copyright owner are credited and that the original publication
Wang, Z., Wang, L., Chen, Z., Ma, X., Yang, X., Zhang, J., et al. (2016). In vitro in this journal is cited, in accordance with accepted academic practice. No use,
evaluation of swine-derived Lactobacillus reuteri: probiotic properties and distribution or reproduction is permitted which does not comply with these terms.

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published: 19 April 2018

Role of Lactobacillus reuteri in

Frontiers in Microbiology | www.frontiersin.org 1 April 2018 | Volume 9 | Article 757

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FIGURE 1 | Probiotic properties of L. reuteri.

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TABLE 1 | Clinical efficacies of L. reuteri against H. pylori.

Strain Treatment Subjects Result Citation

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Condition Subject Tissue Strain Citation

IBD, inflammatory bowel disease; MLN, mesenteric lymph node.

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TABLE 3 | Effects of L. reuteri on early-life diseases.

Target Strain Duration Subjects Result Citation

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Target Strain Duration Subjects Result Citation

GI motility - 30 days Newborns Faster gastric emptying Indrio et al., 2009

Early-Life Disorders Therefore, we treated MRL/lpr mice with a mixture of five

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