Animal Science Journal (2009) 80, 361–371
doi: 10.1111/j.1740-0929.2009.00645.x
REVIEW ARTICLE
Health-beneficial effects of probiotics: Its mode
of action
asj_645
361..371
Yuji OHASHI1 and Kazunari USHIDA2
1
Department of Food Science and Technology, Nippon Veterinary and Life Science University, Musashino, Tokyo,
and 2Kyoto Prefectural University, Shimogamo, Kyoto, Japan
ABSTRACT
It is now widely recognized that probiotics have health-beneficial effects on humans and animals. Probiotics should survive
in the intestinal tract to exert beneficial effects on the host’s health. To keep a sufficient level of probiotic bacteria in the
gastrointestinal tract, a shorter interval between doses may be required. Although adherence to the intestinal epithelial cell
and mucus is not a universal property of probiotics, high ability to adhere to the intestinal surface might strongly interfere
with infection of pathogenic bacteria and regulate the immune system. The administration of probiotic Lactobacillus
stimulated indigenous Lactobacilli and the production of short-chain fatty acids. This alteration of the intestinal
environment should contribute to maintain the host’s health. The immunomodulatory effects of probiotics are related to
important parts of their beneficial effects. Probiotics may modulate the intestinal immune response through the stimulation
of certain cytokine and IgA secretion in intestinal mucosa. The health-beneficial effects, in particular the
immunomodulation effect, of probiotics depend on the strain used. Differences in indigenous intestinal microflora
significantly alter the magnitude of the effects of a probiotic. Specific probiotic strains suitable for each animal species and
their life stage as well as each individual should be found.
Key words: intestinal microflora, lactic acid bacteria, probiotics, short-chain fatty acid.
INTRODUCTION
Live bacterial supplements are widely used for the
promotion and improvement of health in humans and
animals. Such supplements are defined as probiotics
(Fuller 1989). Probiotics provide beneficial effects on
the host’s health by affecting the intestinal microflora.
Their beneficial effects on human health, such as the
alleviation of lactose intolerance, immunomodulation,
decrease in fecal enzymes and mutagenicity, hypocholesterolemic effect, and reduction of the risk of gastrointestinal disease have been demonstrated in many
studies (Macfarlane & Cummings 1999; Roberfroid
2000; Dunne 2001; Marteau et al. 2001; Isolauri et al.
2004; Ljungh & Wadström 2005; Delcenserie et al.
2008). In the case of humans, lactose intolerance is
one of the typical osmotic diarrheas often manifest in
the subjects with a low intestinal b-galactosidase activity (Heyman 2000). Probiotics have been shown to
© 2009 The Authors
Journal compilation © 2009 Japanese Society of Animal Science
alleviate lactose intolerance by lactase activity derived
from probiotic bacteria (Heyman 2000; Roberfroid
2000). Probiotics are also used to treat other types of
diarrhea, such as traveler’s diarrhea caused by enterotoxigenic Escherichia coli, acute rotavirus diarrhea,
antibiotic-associated diarrhea, and radiotherapyinduced diarrhea (Macfarlane & Cummings 1999;
Heyman 2000; Roberfroid 2000; Dunne 2001;
Marteau et al. 2001). In the animal industry, diarrhea
in weaning animals causes serious economic loss
(Madec et al. 1998; Melin et al. 2000). Probiotics are
now considered to be a potential alternative to antibiotics to prevent or cure diarrhea (Sevin 2004). This
Correspondence: Yuji Ohashi, Laboratory of Food Hygiene,
Department of Food Science and Technology, Nippon Veterinary and Life Science University, Musashino, Tokyo 1808602, Japan. (Email: ohashi@nvlu.ac.jp)
Received 14 August 2008; accepted for publication 10
October 2008.
362 Y. OHASHI and K. USHIDA
Preventive and therapeutic effect
Mucosal immune system
Growth inhibition, Exclusion
Gut disorder
Immunomodulation
Lactobacillus
Bifidobacterium
Adherence inhibition
Growth inhibition
Growth stimulation
Pathogens
Harmful Bacteria
Adherence inhibition
Growth inhibition
Probiotic Lactobacillus
Lactate
Lactate utilizing bacteria
Short-chain fatty acids
Preventive and
therapeutic effect
Decreasing in luminal pH
Stimulation of epithelial cell growth
Stimulation of colonic blood flow
Modification of intestinal motility
Absorption of water and minerals
Increasing in mucus production
etc.
potential of probiotics has been stressed because of the
emergence of antibiotic-resistant microbes (Pithie &
Ellis 1989; Carson & Riley 2003). Indeed, the search
for alternative means beyond antimicrobials has intensified in the EU, where the use of antimicrobials as
animal growth promoters became a political issue and
was finally banned to counteract the emergence of
antibiotic-resistant bacteria (Dibner & Richards 2005;
Heuer et al. 2006).
We have investigated the effects of probiotic Lactobacillus on the intestinal microflora and fermentation
in pigs as a potential model for humans in most cases
because of the similarities between humans and pigs in
diet, anatomy on a microscopic level, and contractile
activity of the intestine (Crowell et al. 1992; Lunney
2007). In this review, we will present the mechanisms
involved in probiotic action, particularly in the pig
intestine (Fig. 1).
ROLE OF INTESTINAL MICROFLORA
Pigs have relatively similar intestinal microflora to
those found in the human intestine, with several
exceptions (Mitsuoka & Kanauchi 1977). In pigs, the
population density and composition of the intestinal
microflora differ significantly by site because the
physico-chemical characteristics, i.e. the pH, redox
potential, viscosity, and the biological characteristics
(i.e. the nutrient supply and concentration of biological active compounds) of the luminal contents differ
© 2009 The Authors
Journal compilation © 2009 Japanese Society of Animal Science
Figure 1 Overview of the
health-beneficial effects of probiotic
Lactobacillus.
according to site (Jensen & Jørgensen 1994). The pig
stomach and the proximal small intestine contain relatively few bacteria due to low pH, digestive enzymes,
and fat transit time of digesta, although the pig
stomach harbors a denser bacterial population (105)
than that in humans (<103). The predominant bacteria
in these portions are acid-tolerant bacteria, such as
Lactobacillus and Enterococcus. The principal regions of
bacterial colonization in pigs are the ileum and the
large intestine (Jensen & Jørgensen 1994). The
numbers of bacteria in the ileum and the large intestine are up to 109~1012/g content (Allison et al. 1979).
The majority of bacteria in the large intestine are obligate anaerobes, since the lumen in the large intestine
is under an anaerobic condition. In pigs, the following
genera are the predominant bacteria: Lactobacillus,
Enterococcus, Ruminococcus, Clostridium, Eubacterium,
Fusobacterium, Bacteroides, Prevotella, Selenomonus, Veillonella, Megasphaera, Peptostreptococcus, Acidaminococcus,
Butyrivibrio, Lachnospira, and Escherichia (Robinson
et al. 1981, 1984; Moore, Moore et al. 1987; Pryde et al.
1999; Leser et al. 2002).
Bacterial colonization in the gastrointestinal tract of
newborn animals starts after birth through vertical and
horizontal transmission (Guarner & Malagelada 2003;
Inoue & Ushida 2003a, 2005). The diversification of
the large intestinal microflora starts at weaning (Inoue
& Ushida 2003a, b). The succession of intestinal bacteria is similar in the intestinal tract of humans and
animals (Mackie et al. 1999). This succession is affected
Animal Science Journal (2009) 80, 361–371
PROBIOTICS AND HOST HEALTH
by many factors, e.g. secretion of digestive enzymes
and mucus, intestinal peristalsis, diet composition, and
antibiotics. Colonized bacteria construct a consortium
defined by a complex microbial ecosystem with competition and symbiosis (Cummings & Macfarlane
1997; Mackie et al. 1999). An established, indigenous
microbial ecosystem is relatively stable (Zoetendal et al.
1998) and is known as normal intestinal bacteria.
Normal intestinal bacteria are believed to be closely
related with host health (Chadwick & Anderson 1995;
Cummings & Macfarlane 1997; Isolauri et al. 2004).
This relationship has been demonstrated in humans
and the experimental rodent model, although much
less attention has been paid to pig indigenous microflora (Leser et al. 2000; Canibe & Jensen 2003). Intestinal microflora have metabolic, immunologic, and
protective functions (Cummings & Macfarlane 1997;
Guarner & Malagelada 2003). The metabolic function
is displayed by the production of short-chain fatty
acids (SCFA) and vitamin K. Intestinal bacteria
ferment undigested food materials and endogenous
substances, such as mucus, to produce SCFA. The
cecum and the proximal colon are the principal sites of
fermentation. The pig has a large cecum and colon,
which generate energy as a form of SCFA that can
fulfill up to 30% of the daily energy requirement
(Stevens & Hume 1995). This underscores the importance of bacterial fermentation in the large intestine
for pig nutrition.
The health-beneficial effects of SCFA, butyrate in
particular, for the host have been reported (Cherbut
et al. 1997; Edwards 1997; Sakata 1997). In pigs, the
stimulation of butyrate production promoted growth
of epithelial cells, leading to an increase in the thickness of the cecal and colonic mucosa (Tsukahara et al.
2003). Once the normal equilibrium of the intestinal
microflora was disrupted, for example by antibiotics,
SCFA production was not maintained, and an abnormal accumulation of succinate and lactate was
observed (Tsukahara & Ushida 2002). Such abnormal
fermentation led to the type of diarrhea defined as
antibiotic-associated diarrhea. However harmful substances, including ammonia, hydrogen sulfide,
phenols, indoles, and amines, are simultaneously generated by protein fermentation (Cummings & Macfarlane 1997; Ushida et al. 2001). Potentially harmful
bacteria found in the pig cecum are C. bifermentans,
C. perfringens, and Fusobacterium varium (Ushida et al.
2001).
The immunogenic function of indigenous microflora
promotes the development and maintenance of the
Animal Science Journal (2009) 80, 361–371
363
host immune system. This has been substantiated in
studies on germ-free or gnotobiotic animals. The colonization of bacteria in the gastrointestinal tract of
germ-free animals leads to an increase in the number
of intraepithelial cells (IELs) and Peyer’s patches
(Umesaki & Setoyama 2000). In addition, the composition of IELs, especially the percentage of the phenotype of TCRabIELs, is altered (Imaoka et al. 1996;
Umesaki & Setoyama 2000). The number of
immunoglobulin-producing cells in the lamina propria
and the concentration of immunoglobulin in serum
increases (Cebra et al. 1998; Butler et al. 2000). The
immunological responses to bacterial colonization on
the gastrointestinal tract in germ-free animals
resemble the process of the inflammatory response.
On the other hand, these mucosal immune responses
are relieved in conventional animals, in which the
most indigenous bacteria are coated with IgA (Kramer
& Cebra 1995; Shroff et al. 1995; van der Waaij et al.
1996). This suggests that the homeostasis of the
immune response is maintained by the interaction
between indigenous bacteria and the mucosal immune
system. Thus, bacterial colonization on the gastrointestinal tract, possibly by some essential bacteria, such as
segmented filamentous bacteria, is important for the
development and homeostasis of the host immune
system (Ohashi et al. 2006). The level of IgA is of
importance, particularly in weaning piglets, which
have a very limited level of intestinal IgA (Ushida et al.
2008).
The barrier effect of intestinal bacteria against the
challenge of pathogens is considered as its protective
function. Many, but not all, intestinal bacteria can
adhere to the outmost mucus layer or to food particles
to form a biofilm on their surface (Guarner & Malagelada 2003). The competition for space to adhere
between indigenous bacteria and exogenous pathogens results in the competitive exclusion of exogenous
pathogens from the intestinal lumen (Gueimonde et al.
2007). Additionally, the competition for nutrients
might be another factor to exclude exogenous
pathogens.
PROBIOTICS
As described above, indigenous intestinal bacteria beneficially affect host health. In general, Lactobacillus and
Bifidobacterium are not pathogenetic and are usually
considered to be health-promoting bacteria (Fuller &
Gibson 1997; Mitsuoka 2000). Therefore, the stimulation of these health-promoting bacteria may improve
© 2009 The Authors
Journal compilation © 2009 Japanese Society of Animal Science
364 Y. OHASHI and K. USHIDA
Table 1 Microorganisms commonly used in probiotics for
livestock animals
Lactobacillus
Bifidobacterium
Enterococcus
Bacillus
Pediococcus
Saccharomycecs
Aspergillus
Escherichia
acidophilus
casei
plantarum
delbruekii subsp. bulgaricus
reuteri
gasseri
fermentum
salivarius
bifidum
lactis
faecium
subtilis
cereus
coagulans
licheniformis
pentosaceus
cerevisiae
boulardii
oryzae
coli
host health. The intake of live bacterial supplements
results in beneficial effects on the health of the host
animal by improving its intestinal microbial equilibrium. This approach is defined as ‘probiotics’ (Fuller
1989). Probiotics need to meet the following criteria
(Fuller 1989): (i) probiotic bacteria must be prepared
in a viable manner and on a large scale; (ii) they
should remain viable and stable during use and under
storage; (iii) they should be able to survive in the
intestinal tract; (iv) the host should gain direct and
indirect beneficial effects from the probiotics
(improved intestinal microflora); (v) their safety
should be evident.
The probiotic bacteria commonly used for livestock
animals are shown in Table 1 (Fuller 1989; Tannock
1995). A popular choice of microbes for probiotics is
Lactobacilli in the case of pigs and poultry because
Lactobacilli predominantly colonize the gastrointestinal
tract in these animals (Tannock 1995).
Probiotics are prepared in various ways: as pelleted
feed, fermented feed, capsules, paste, powder, and
granules. Recently, it has been proposed that inactivated bacteria also have a probiotic effect, particularly
an immunological one, and should be included in the
category of probiotics in a broad sense (Tsukahara et al.
2005).
Although adherence to the intestinal epithelial cells
and mucus is not a universal property of probiotics, this
ability is also considered important for the beneficial
effects of probiotics (Bezkorovainy 2001). Probiotic
© 2009 The Authors
Journal compilation © 2009 Japanese Society of Animal Science
bacteria, which have high ability to adhere to the
intestinal surface, are expected to strongly interfere
with the adhesion of pathogenic bacteria (Fuller 1991).
Furthermore, the adherence of probiotic bacteria is
associated with their immunological effects (Ouwehand et al. 2000; Isolauri et al. 2001; Vaarala 2003).
TRANSIT OF PROBIOTIC BACTERIA
IN THE GASTROINTESTINAL TRACT
OF PIGS
The viability and actual level of probiotic bacteria in the
intestinal tract must be investigated because the effect
of a probiotic depends on its viable count in the gastrointestinal tract (Charteris et al. 1998; Lee et al. 2000).
Therefore, their resistance to gastric acid, bile acid, and
digestive enzymes is important (Dunne 2001). In many
studies, their recovery from feces has usually been
assessed to evaluate the survival of probiotic bacteria
(Bouhnik et al. 1992; Yuki et al. 1999; Fujiwara et al.
2001; Ohashi et al. 2001a; Oozeer et al. 2002) due to the
inaccessibility of the digesta in a particular section of the
intestinal tract. In our research using fistulated pigs
receiving both liquid-associated and solid-associated
transit markers, it was demonstrated that the administered probiotic bacterium, L. casei strain Shirota (LcS),
moved mainly with the liquid component of the digesta
in the gastrointestinal tract (Ohashi et al. 2004). In
general, the digesta are retained in the stomach until
fragmented into pieces that are 0.5 mm in diameter
(Meyer 1980). The bacterial cells are obviously smaller
than this critical size, which makes them too small to be
separated from the liquid component in the stomach or,
probably, during transit in the upper gastrointestinal
tract. The low ability of LcS (Lee et al. 2000) to adhere
to the mucus must be involved in the relationship
between LcS and liquid digesta. Most of the probiotic
strain might show the same transit pattern in the gastrointestinal tract as LcS. However, in the case of other
probiotic strains, such as L. johnsonii La1 (Bernet et al.
1994), which possesses the ability to adhere to the
mucus, it is plausible that the transit pattern may be
different from that of LcS.
In the gastrointestinal tract of pigs administered LcS
once a day for 2 weeks, the number of LcS in the cecum
was not stable (Ohashi et al. 2004). It varied greatly
according to the time after feeding (or LcS dose).
Although LcS was not completely washed out from the
cecum during LcS administration, it was not detected in
the pig feces at 2 weeks after administration (Ohashi
et al. 2001a). No report has demonstrated the coloniza-
Animal Science Journal (2009) 80, 361–371
PROBIOTICS AND HOST HEALTH
tion of administered probiotic bacteria in any animals.
Thus, administered probiotic bacteria should not be
permanently colonized in the host animal. To keep a
stable and high level of probiotic bacteria in the gastrointestinal tract, increasing the frequency of the dose
of probiotics for a given period is the only possible
method. In other words, a shorter interval between
doses may be required. The shorter interval may lead to
an elevation of the mean number of probiotic bacteria
in the cecum, thus reducing the level of fluctuation. In
the case of LcS, four doses every 6 h may be required to
maintain the maximum LcS level in the cecum, considering that the number of LcS reaches its maximum 6 h
after dosing (Ohashi et al. 2004). This should hold true
for other probiotic bacteria.
PROBIOTIC LACTIC ACID BACTERIA
CAN STIMULATE THE GROWTH OF
INDIGENOUS LACTIC ACID BACTERIA
In most cases, the effect of probiotics is explained solely
by the contribution of the administered probiotic bacteria. However, we have demonstrated that the administration of various lactobacilli of different origin, LcS
(human intestine origin), L. delbruekii subsp. bulgaricus
strain 2038 (dairy strain), or L. plantarum strain Lq80
(originated from fermented liquid feed for pigs),
increased the number of indigenous Lactobacilli in pigs
(Ohashi et al. 2001a, 2007; Takahashi et al. 2007). They
increased not only the level of the total lactobacillal
population but also the diversity of the population. In
the case of humans, intake of L. rhamnosus DR20
(Tannock et al. 2000) or L. acidophilus NCFMR® (Sui
et al. 2002) altered the composition of indigenous Lactobacilli and increased the fecal number of Bifidobacterium. On the other hand, fermented milk containing
Bifidobacterium increased the fecal number of Lactobacillus. These results indicated that probiotics stimulate the
indigenous Lactobacillus or Bifidobacterium. Surprisingly,
only few reports are so far available on the growthpromoting substances for Lactobacilli or Bifidobacteria
produced by probiotic bacteria. Kaneko et al. (1994)
and Mori et al. (1997) reported that Propionibacterium
freudenreichii and some other intestinal bacteria produced growth-promoting factors for bifidobacteria, of
which one substance was identified as quinone. In our
experiment using pig microflora, we succeeded in the
isolation of a Lactobacillus strain whose in vitro growth
was stimulated by the aqueous extracted from feces
collected from pigs administered LcS and by the supernatant of an L. delbruekii subsp. bulgaricus strain 2038
Animal Science Journal (2009) 80, 361–371
365
culture medium (Ohashi 2006). The growth-promoting
factors produced by probiotic bacteria may explain the
stimulation of indigenous bacteria by probiotics.
PROBIOTICS ENHANCE SCFA
PRODUCTION
The improvement of intestinal microflora with probiotics involves the stimulation of intestinal fermentation. The health-beneficial effects of SCFA, butyrate in
particular, for the host have been reported (Cherbut
et al. 1997; Edwards 1997; Sakata 1997). The stimulation of SCFA production is one of the essential factors
for the beneficial effects exerted by probiotics. A significant increase in indigenous lactobacilli in the large
intestine of the pig as a result of probiotics belonging to
the genera Lactobacillus has been reported, as described
above. Increases in lactobacilli should stimulate lactate
production. However, lactate does not accumulate in
the large intestine, except in those patients with shortbowel syndrome and dyspeptic diarrhea (Mortensen
& Clausen 1996; Tsukahara & Ushida 2001). Lactate is
normally metabolized to acetate or propionate by
lactate-utilizing bacteria, such as Desulfovibrio spp.,
Clostridium propionicum, Selenomonas spp., Veillonella
spp., Propionibacterium spp., and Anaerovibrio spp., and
to butyrate by Megasphaera elsdenii, some Clostridium
spp., Anaerostipes caccae, and Eubacterium hallii (Holdeman et al. 1974; Mackie & Gilchrist 1979; Kuchta &
Abeles 1985; Gibson 1990; Seeliger et al. 2002; Duncan
et al. 2004; Bourriaud et al. 2005; Belenguer et al.
2006). The increase in fecal SCFA by probiotic Lactobacillus would be due to this mechanism (Ohashi
et al. 2001a; Tsukahara et al. 2006). In fact, the oral
administration of the lactate-utilizing and butyrateproducing bacterium, Megasphaera elsdenii, with L.
plantarum Lq80 to pigs increased butyrate production
in the large intestine (Ushida et al. 2006). The administration of probiotics with lactate-utilizing bacteria,
butyrate-producing bacteria in particular, is a more
effective way to achieve the health-beneficial actions.
PROBIOTICS ALTER COLONIC
MOTILITY THROUGH THE
STIMULATION OF LARGE INTESTINAL
FERMENTATION
Digesta kinetics or intestinal motility is an important
variable that determines intestinal comfort. Diarrhea
and constipation are the two extreme conditions of
© 2009 The Authors
Journal compilation © 2009 Japanese Society of Animal Science
366 Y. OHASHI and K. USHIDA
digesta kinetics or intestinal motility. The effects of
probiotics on colonic motility have not been examined, largely due to technical limitations in the methodology. Indeed, difficulties in measuring colonic
movement under conscious conditions are clear
(Bassotti et al. 1993; Sarna 1993; Christensen 1994). A
strain gauge force transducer (SGFT) is a potent
method for the measurement of intestinal motility
(Pascaud et al. 1978; Sarna 1993; Christensen 1994;
Sethi & Sarna 1995). Using an SGFT, the contractions
of intestinal muscle, especially the circular muscle
layer, can be measured directly. We established a
methodology for the application of SGFTs in the pig
model and investigated the effect of LcS on colonic
motility (Ohashi et al. 2001b). The motility of the terminal colon during the sleeping period was increased
by 2-week administration of LcS. Inversely, the defecation frequency during this period was not
increased. Therefore, colonic motility, which acted not
to promote defecation but to retain the digesta, might
be stimulated by LcS. It was considered that such alteration of the colonic motility by LcS should be related to
the stimulation of large intestinal fermentation, as
shown by a decrease in the fecal pH. SCFA, the main
large-intestinal fermentation product, is an important
luminal chemical stimulus to intestinal motility
(Cherbut et al. 1997; Edwards 1997). Although SCFA
has contractile activity at low concentrations (0.1 to
10 mmol/L) with the enteric cholinergic reflex, the
activation of the colonic contraction by SCFA did not
persist (Sakata 1994; Cherbut et al. 1997). A high concentration (100 mmol/L) of SCFA inhibits colonic contraction (Cherbut et al. 1997; Edwards 1997; Sakata
1997). In the proximal large intestine, SCFA is continuously produced by bacterial fermentation. In
humans, the SCFA concentration of large intestinal
digesta was 90 to 130 mmol/L (Cummings & Macfarlane 1991). The SCFA concentration of cecal digesta
was over 160 mmol/L in pigs (Clemens et al. 1975).
Hence, the large intestinal wall may be exposed to a
high level of SCFA. In this situation, SCFA may inhibit
prospective contractions in the large intestine that
drive the digesta downward. This inhibitory effect of
SCFA on large intestinal motility seems reasonable for
bacteria because intestinal bacteria do not retain their
population against a fast digesta movement. Therefore,
the stimulation of SCFA production in the large intestine with probiotics should alter the large intestinal
motility to hold and mix the digesta. This effect is one
of the explanations for the recovery from diarrhea
when probiotics are consumed.
© 2009 The Authors
Journal compilation © 2009 Japanese Society of Animal Science
RESPONSE TO PROBIOTIC BACTERIA
IS DEPENDENT ON INDIGENOUS
MICROFLORA: HIGH AND LOW
RESPONDER
The effects of probiotics could differ from one individual to another due to the difference of intestinal
microflora (Mackie et al. 1999). Probiotics, in general,
should compete with indigenous bacteria for nutrients
and a niche in the intestine (Fuller & Gibson 1997),
but they may establish a symbiotic relationship with
certain indigenous bacteria (Ohashi et al. 2001a, 2007;
Takahashi et al. 2007). In such a situation, the viability
of probiotic bacteria is strongly affected by the indigenous bacteria, which determine the magnitude of the
probiotic effect. It is likely that the composition of
lactate-utilizing bacteria is an important factor in
demonstrating probiotic effects. Lactate produced by
probiotics is further fermented to acetate, propionate,
or butyrate by indigenous lactate-utilizing bacteria.
The production of butyrate from lactate is preferable
for host animals, as described above. However, it is
often unclear which SCFA is produced by the fermentation of lactate because predominant lactate-utilizing
bacteria colonized in the intestine are different
(Ohashi et al. 2004; Bourriaud et al. 2005).
Thus, the difference in indigenous intestinal microflora significantly influences the magnitude of the
probiotic effects. Therefore, it is quite likely that a
probiotic strain that is effective for a particular
animal species will not be suitable to other host
species. This should also be true for the case in individual differences of intestinal microflora within
the same species. In addition, the composition of the
intestinal microflora changes with life stage. In the
weaning period, the intestinal microflora changes
remarkably in pigs (Inoue et al. 2005). There may be
probiotic strains that are suitable for each specific life
stage of the host.
PROBIOTICS ENHANCE MUCOSAL
IMMUNITY
The immunomodulatory effects of probiotics are
related to important parts of their beneficial effects.
Initially, ingested probiotic bacteria interact with gut
epithelial cells. In studies using cell lines, such as Caco-2
or HT-29, probiotic Lactobacillus stimulated the production of pro- and anti-inflammatory cytokines by these
cell lines in a strain-dependent manner (Delcenserie
et al. 2008). Because intestinal epithelial cells regulate
Animal Science Journal (2009) 80, 361–371
PROBIOTICS AND HOST HEALTH
the intestinal immune response (Lu & Walker 2001;
Hase & Ohno 2006), probiotic Lactobacillus may modulate the intestinal immune response through the stimulation of certain cytokine secretion by epithelial cells
(Lu & Walker 2001; Delcenserie et al. 2008).
Some parts of ingested probiotic Lactobacillus are
likely to be subjected to the transcytosis of the M cells,
which are specialized antigen sampling cells (Galdeano
& Perdión 2004). Antigen-presenting cells, dendritic
cells (DC) and macrophages are located under M cells
to receive antigens. M cells scatter on Peyer’s patches
(PP) and isolated lymphoid follicles (ILF) (Fagarasan &
Honjo 2002; Hamada et al. 2002), in which T cells and
B cells are present. Thus, PP and ILF are the inductive
sites of immunological reaction in intestinal mucosa.
Recently, villous M cells were discovered in the villi
(Jang et al. 2004), which are not associated with lymphoid follicles. Dendritic cells in the lamina propria
directly sample luminal antigens from the lumen
(Rescigno et al. 2001). These DCs stimulate T cells
located nearby. T cells activate B cells to produce IgG
or IgA. Immune activation by probiotic Lactobacillus
has been demonstrated in in vitro studies (Vaarala
2003). Probiotic Lactobacillus induces the production of
IFN-gamma and IL-12 from antigen-presenting cells
through activation of the NF-kB and STAT signaling
pathway. These cytokines inhibit the production of
IL-4 but stimulate the production of IFN-gamma by
helper T cells to alter the Th1/Th2 equilibrium toward
Th1. On the other hand, it has been suggested that
probiotics have anti-inflammatory effects on the host
(Madsen et al. 1999) and relieve inflammatory bowel
disease. In IL-10 deficient mice that develop severe
intestinal
inflammation
spontaneously,
proinflammatory cytokine production was reduced with
probiotics (Madsen et al. 1999; O’Mahony et al. 2001;
McCarthy et al. 2003; Pena et al. 2005). It has also been
suggested that the suppression of T cell proliferation
with probiotics can induce anti-inflammatory effects
on the intestinal tract (Carol et al. 2006). Thus, probiotics appear to influence both the Th1 and Th2
responses. Recently, it was demonstrated that probiotics stimulated the production of IL-10, which was
secreted from many immune cells, including DCs,
monocytes, and regulatory T cells (Delcenserie et al.
2008). Because the increase in IL-10 secretion suppresses the production of both anti- and proinflammatory cytokines, probiotics may exert a
simultaneous immunomodulatory action on both the
Th1 and Th2 response (Niers et al. 2005). Since the
cytokine network is a very complex system, the final
Animal Science Journal (2009) 80, 361–371
367
physiological responses brought by the stimulation or
reduction of certain cytokines are often difficult to
define.
IgA production is one often clearly demonstrated
physiological response. Probiotics stimulate systemic
and mucosal IgA production in humans (Kaila et al.
1992; Link-Amster et al. 1994; Fukushima et al. 1998).
This means that probiotics can enhance the immunologic barrier function of intestinal mucosa by IgA.
These immunomodulative effects are induced by the
cell wall component of probiotics, such as lipoteichoic
acids and peptideglycan, and DNA motifs of probiotic
bacteria through recognition by toll-like receptor 2
and toll-like receptor 9, respectively (Kaisho & Akira
2002; Kitazawa et al. 2008).
Consequently, probiotics enhance not only the
mucosal barrier by stimulating innate immune activity, such as phagocytosis, secretion of b-defencin and
natural killer cell activity, and secretion of IgA, but also
by stimulating the anti-inflammatory effect (Isolauri
et al. 2001; Vaarala 2003; Delcenserie et al. 2008).
Based on these immunomodulation activities, the
availability of probiotics for the treatment of chronic
inflammatory disease of the gut and allergies has been
clinically evaluated (Dunne 2001; Ljungh & Wadström
2005; Delcenserie et al. 2008).
CONCLUSION
Probiotic bacteria, according to their definition, must
be prepared in a viable form. They should be stable
during preparation and storage, and of course, they
should survive in the intestinal tract to have beneficial
effects on the host’s health. To retain a high level of
probiotic bacteria in the gastrointestinal tract, a shorter
interval between doses may be required. Although
adherence to intestinal epithelial cells and mucus is
not a universal property of probiotics, a high ability to
adhere to the intestinal surface might strongly interfere with infection by pathogenic bacteria and regulate
the immune system. The health-beneficial effects, in
particular the immunomodulate effect of probiotics,
depend on the strain.
Some of the health-beneficial effects are directly
provided by the administered probiotics. However,
many of them are apparently mediated by indigenous bacteria through the activation of fermentation and the recovery of the equilibrium of the
microflora in the pathogenic condition or after antibiotic therapy.
© 2009 The Authors
Journal compilation © 2009 Japanese Society of Animal Science
368 Y. OHASHI and K. USHIDA
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