




































_____________________________________________________________________________________________________ 
 
*Corresponding author: E-mail: nwobododave@gmail.com, nwobodo.dc@rnu.edu.ng; 
 
 
 

Asian Journal of Immunology 
 
3(1): 46-60, 2020; Article no.AJI.54889 
 

 
 

 

 

Immunomodulatory Potentials of Probiotics:  
A Review 

 
David Chinemerem Nwobodo1,2* and Malachy Chigozie Ugwu2 

 
1
Department of Microbiology, Renaissance University, Ugbawka, Enugu State, Nigeria. 

2
Department of Pharmaceutical Microbiology and Biotechnology, Faculty of Pharmaceutical Sciences, 

Nnamdi Azikiwe University, Awka, Anambra State, Nigeria. 
 

Authors’ contributions 
 

This work was carried out in collaboration between both authors. Author DCN designed the study, 
searched the literature and wrote the draft versions of the manuscript. Author MCU supervised the 

literature search and edited the lay-out. Both authors read and approved the final manuscript. 
 

Article Information 
 

Editor(s): 
(1) Dr. Darko Nozic, Higher Medical School in Belgrade, University of Belgrade, Serbia. 

Reviewers: 
(1) Alessandro Poggi, IRCCS Ospedale Policlinico, San Martino, Italy. 

(2) Ekaterini Simões Goudouris, Universidade Federal do Rio de Janeiro, Brazil. 
Complete Peer review History: http://www.sdiarticle4.com/review-history/54889 

 
 
 
 

Received 18 December 2019 
Accepted 21 February 2020 

Published 31 March 2020 

 
 

ABSTRACT 
 

In recent years, research has focused on natural mechanisms for the management, treatment, and 
curing of human infections and diseases. One of such natural methods is the application of 
probiotics, which are live microorganisms which when administered in adequate amounts confer a 
health benefit on the host. The beneficial effects associated with probiotics were originally thought 
to be a result of improvements in the intestinal microbial balance, however, there are shred 
evidence that probiotics can also provide benefits by modulating the immune functions. The ability 
of these probiotics, majorly the Lactobacillus and Bifidobacterium species to boost the immune 
system is proposed to be a result of their interactions with the cells of the immune system. They 
have been reported to stimulate various parts of the immune system, through several mechanisms 
enhancing their functions. It has also been established that the effects of probiotic bacteria may 
also result from soluble factors from these microbes that alter epithelial permeability or mediate 
activation, maturation or survival of dendritic cells, B and T-cells. Probiotic bacteria, their cell wall 
components, and other stimulating molecules have been shown to have significant effects on the 
functionality of the immune systems through the activation of multiple immune mechanisms. This 
study is aimed at describing the immunological mechanisms of probiotics and their beneficial 
effects on the host immune system. 

Review Article 



 
 
 
 

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Keywords: Immunomodulatory potentials; probiotics; lactobacillus; human infections; bifidobacterium.  
 

1. INTRODUCTION 
 
The word probiotic is derived from a Greek word 
which means “pro-life” [1]. In 1965, Lilly and 
Stillwell first used the term ‘probiotic’ to describe 
substances secreted by one organism which 
stimulates the growth of another [2]. In 2002, the 
Food and Agricultural Organization of the United 
Nations/World Health Organization proposed that 
probiotics are live microorganisms which when 
administered in adequate amounts confer a 
health benefit on the host [3]. Presently, research 
is focused on natural mechanisms for managing, 
treating and curing human infections and 
diseases as a result of the several side effects 
associated with the use of chemotherapeutic 
agents and synthetic drugs. Probiotics known as 
a group of beneficial microbes are currently 
emerging as one of such natural mechanisms. 
 
Most commonly used probiotic microorganisms 
belong to the genera Lactobacillus and 
Bifidobacteria, however, some strains of 
Escherichia coli, Bacillus species, and the yeast 
Saccharomyces are also used [4-6]. Recently, 
Clostridium butyricum was also approved for 
probiotic use in the European Union [7]. Some of 
the reported probiotic microorganisms include; 
Lactobacillus delbruecki subsp.bulgaricus, L. 
rhamnosus GG, L. plantarum, Bifidobacterium 
bifidum and B. infantis [8,9]. B. adolescentis 
BBMN23 and B. longumBBMN68 [10]. Others 
include Streptococcus thermophilus, Escherichia 
coli, Saccharomyces bourladii [6,11], 
Saccharomyces cereviciae [12], some species of 
Lactococcus and Enterococcus [13].  
 
Reported benefits of probiotics include: 
maintaining the balance of the intestinal flora, 
increasing lactose tolerance and synthesis of B 
complex vitamins, absorption of calcium thus 
maintenance of intestinal homeostasis [1]. 
Others are anti-mutagenic/anticancer activity, 
cholesterol-lowering effect, secretion of anti-
pathogen substances and enhancement of the 
immune system/responses [14-16].   
 

The integrity of any eukaryotic organism depends 
not only on the proper expression of its genes 
but also on its freedom from /and defense 
against invading microorganisms [17].  The 
human body is equipped with defense 
mechanisms which serve to protect against 
harmful agents and invading pathogens. It is 
because of the effectiveness of these defensive 

mechanisms that both man and animals have 
survived for so many years. A good example of 
this is the phagocytosis of bacteria by 
macrophages and other phagocytic cells of the 
immune system. However, the host does not 
depend solely on its immune system to protect it 
from these agents of diseases.  
 
One of the most important characteristics of 
probiotics is the regulation of host immune 
response by manipulating the host immune 
response towards the infectious microbes and 
can be useful in the treatment of infectious 
diseases [18]. Innovative approaches had been 
attempted as an alternative to vaccines as 
immune boosters, and these include the use of 
live biotherapeutic agents (probiotics) such as 
yeasts and bacteria. Probiotics have been used 
successfully to improve the host immune 
response in different health conditions [19].  It is, 
therefore, the aim of this review to explore the 
effect of probiotics on the immune system and 
describe the immunological mechanisms in 
modulating the host immune system.    
 

2. BRIEF HISTORY OF PROBIOTICS 
 

The concept of probiotics evolved in the late 
1800s and early 1900s [20]. Different 
microorganisms have been used for their 
supposed ability to prevent and cure diseases, 
which made Lilly and Stillwell derive the word 
probiotics in 1965 [21]. The original observation 
of the beneficial role played by probiotic bacteria 
was first reported at the beginning of the 20th 
century by Russian Scientist and Nobel laureate 
Elie Metchnikoff. He suggested that it would be 
possible to modify the gut flora and replace 
harmful microbes with useful ones and thus 
proposed that the consumption of yogurt 
containing Lactobacillus would result in a 
decrease in toxin-producing bacteria in the gut 
and an increase in the life span of the host [8,20]. 
Henry Tissier, a French pediatrician in the year 
1900 observed that children with diarrhea had in 
their stool a low number of bacteria characterized 
by a particular Y shaped morphology. These 
were named Bacillus bifiduscommunis and were 
later assigned to the genus Bifidobacterium 
(bifid). The “bifid” bacteria were on the contrary 
abundant in healthy children [22]. In 1906, he 
suggested that these bacteria could be 
administered to patients with diarrhea to help 
restore a healthy gut flora [8,20,22]. Thus the 
works of Metchnikoff and Tissier were the first to 



 
 
 
 

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48 

 

make scientific suggestions about the probiotic 
uses of bacteria. The first reported clinical trials 
were done in the 1930s on the effect of probiotics 
on constipation [3]. 
 
The associated effect of probiotics on the 
immune system came into play in 1984, when 
Baalmear et al. [23] observed that animals with 
complete gut flora have increased phagocytic 
activity compared with germ-free animals. 
Similarly, Perdigon et al. [24] discovered that a 
particular probiotic species Lactobacillus casei 
was active in stimulating phagocytic activity when 
administered to mice. In 1987, Brandtzaeg et al. 
suggested that the effect of lactic acid bacteria 
could be a result of the absorption of the cells or 
their products by macrophages and 
transportation to deeper lying lymphatic follicles 
where they interact with immunocompetent cells 
[25]. In an in vitro experiment carried out in 1989, 
Fuller found that Lactobacillus was successful in 
modulating inflammatory diseases, enhanced 
barrier functions and stimulated immunity [26]. 
Nussler and Thomson in 1992 reported that lactic 
acid bacteria and their products can interact with 
immune cells, leading to the production of 
cytokines that have a manifold effect on immune 
and non-immune cells [27]. To date, several 
types of research relating probiotics to the 
immune system have been carried out with 
several mechanisms being proposed to elucidate 
such immuno-stimulating relationships.    

 
3. SAFETY ASSESSMENT OF PRO-

BIOTICS FOR HUMAN USE 
 
Strains of lactic acid bacteria (LAB) have a long 
history of safe use. Different species of 
Lactobacillus and Enterococcus, has been 
consumed frequently since the consumption of 
fermented milk as food [8]. Probiotic species 
such as Lactobacillus acidophilus have been 
safely used for several years [8]. Nevertheless, 
there is a need for the safety aspects to be 
always considered and possible adverse effects 
should be continuously evaluated [28]. Members 
of the genera Lactococcus, Bifidobacteria, and 
Lactobacilli are most commonly given the 
“generally regarded as safe” (GRAS) status, 
while members of the genera Streptococcus, 
Enterococcus and some other genera of LAB are 
considered opportunistic pathogens [8,9,29]. The 
safety of probiotics has been considered in 
reviews and clinical reports which have recorded 
low cases of human bacteremia [29]. In France, it 
was estimated that the risk of Lactobacillus 
infection is about one case per 10 million people 

over a century of probiotic consumption [8,30]. 
Surveillance studies by Adams and Marteau in 
1995 supported the safety of commercial LAB 
[31]. In 1998, Salminen et al. reported that no 
harmful effects were observed in controlled 
clinical studies with Lactobacilli and 
Bifidobacteria [32]. Further evidence of poor 
opportunistic pathogenicity of probiotics were 
provided in clinical studies where certain 
probiotics was safely administered to 
immunocompromised patients, premature 
infants, elderly and patients with Crohn’s disease 
and there were no recorded side-effects [31]. In a 
recent randomized human study involving the 
elderly, Lefevre et al. reported that the probiotic 
product was safe and well-tolerated [16]. 
Different probiotic formulations have been 
administered to a considerable large number of 
individuals suffering from different conditions, 
under controlled conditions and have been 
proven to be without associated risks [9].  
Considering their widespread use, documented 
correlations between adverse events and 
probiotic consumption are very few [8,31].  
 

3.1 Properties of Probiotic Organisms 
 
To be able to exhibit health benefits, probiotics 
should be able to survive the harsh conditions of 
the stomach and GI tract of humans after 
consumption. Some of the properties of an ideal 
probiotic microorganism include [9,33,34]: 

 
i. Ability to survive the passage through the 

digestive system. 
ii. Ability to adhere to the epithelial cells of 

the mucosa. 
iii. Non-pathogenicity and non-toxicity. 
iv. Tolerance to food additives and stable in 

the food matrix. 
v. Excluding or reducing pathogenic 

adherence. 
vi. Multiply and produce acids, hydrogen 

peroxide and bacteriocins antagonistic to 
pathogen’s growth. 

vii. Maintenance of viability in large numbers. 
 

4. PROBIOTICS AND THE INNATE 
IMMUNE SYSTEM 

 

Consumption of probiotics initiates a host 
response due to the interaction with intestinal 
enterocytes, as intestinal cells are known to 
produce various immunomodulatory molecules 
when stimulated by bacteria [35]. Oral 
introduction of lactobacilli can enhance non-
specific host resistance to microbial pathogens 



 
 
 
 

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49 

 

and thereby facilitate the exclusion of pathogens 
in the gut. Lactobacilli modulate the                   
immune response of the host by its interaction 
with the immune cells and the intestinal 
epithelium [36]. Several strains of live lactic acid 
bacteria have been shown to induce in vitro the 
release of the pro-inflammatory cytokines, tumor 
necrosis factor α, and interleukin 6, reflecting 
stimulation of nonspecific immunity, [37].  Studies 
have shown that the Lactobacillus casei 
DN114001 strain induces mucosal immune 
stimulation, reinforces the non-specific barrier 
and modulates the innate immune response in 
the gut, thereby maintaining the intestinal 
homeostasis [38].  

 
4.1 Effect of Probiotics on Phagocytic 

Cells 
 
It has been discovered that animals with 
complete gut flora have increased phagocytic 
activity compared with germ-free animals [11,39]. 
Presumably, the normal flora prevents invading 
organisms from adhering to host cells by 
covering binding sites, thereby easily exposing 
them to phagocytic cells (neutrophils, monocytes, 
macrophages) [2]. Oral introduction of 
Lactobacillus casei and Lactobacillus bulgaricus 
activates the production of macrophages and 
administration of L. casei and Lactobacillus 
acidophilus activates phagocytosis in mice [40]. 
Similarly, enhanced phagocytosis had been long 
reported in humans by L. acidophilus Lal [41]. 
Phagocytosis is responsible for early activation of 
the inflammatory response before antibody 
production [17]. Phagocytic activity results in the 
further recruitment of immunocompetent cells 
and the generation of an inflammatory response 
[5]. The phagocytic activity of RAW264.7 
macrophages murine model is enhanced after 
inoculation with Bifidobacterium adolescentis 
BBMN23 or B. longum BBMN68 [5]. Immune 
stimulation by these probiotics on the 
macrophages could be attributed to the 
enhanced macrophage activity on the 
components of the immune system. It has been 
observed that there is an increase in the 
phagocytic activity of peritoneal macrophage 
after days of feeding with probiotic cultures 
[2,42].  Ordinarily, at the earlier stage of infection, 
the macrophages are recruited to the infected 
site to engulf the microbes, and when 
macrophages are activated after bacterial 

recognition by toll-like receptors (TLRs), they 
consequently produce high level of pro-
inflammatory cytokines such as IL-1β, TNF-α, IL-
8, IL-6 and chemokines which recruits more 
macrophages and other immune cells e.g. 
neutrophils and basophils [43]. Studies show that 
probiotics mostly belong to Gram-positive 
bacteria, and contain lipoteichoic acids and thick 
peptidoglycan cell wall components (Fig. 1). 
These cellular components can activate 
macrophages to secrete cytokines or important 
mediators which could as well trigger other 
immune components leading to the stimulation of 
the immune system [43,44]. There is also a 
report that oral delivery of L. casei probiotic 
strains to mice could activate mononuclear 
phagocytes for increased phagocytic activity and 
lysozyme production [45]. They express non-
specific esterase, lysosomal hydrolases, and 
ectoenzymes, thereby contributing to non-
specific uptake of invading materials [43,45,46]. 
Human studies have confirmed these effects in 
circulating phagocytes of adult subjects including 
the elderly (Table 1.) Continuous engulfment by 
the phagocytes strengthens the immune cells 
and keeps them at alert [5]. 

 
4.2 Probiotic Effects on Inflammatory 

Response 
 
It has been shown that the administration of 
Lactobacillus plantarumat the dose of 10

10
 

CFU/day significantly increased neutrophils, 
macrophages, and fibroblasts [48], (Table 1). In 
the inflammatory response, the neutrophils are 
the first cells to be lured, followed by the 
macrophages for the engulfment of the infecting 
pathogen. The fibroblast halts and prevents 
further spread of the infection [48]. This has also 
been observed and reported that in vitro, 
Lactobacillus has been used to modulate 
inflammatory diseases, enhance barriers 
functions and stimulate immunity [26]. Some 
probiotic bacteria have been reported to induce a 
pattern of dendritic cell (DC) maturation, 
characterized by the release of small amounts of 
tumor necrotic factor α and IL-12, with increased 
levels of IL-10, and inhibit the generation of pro-
inflammatory TH1 cells [49]. The most patent 
anti-inflammatory effects by a probiotic is 
produced by bifidobacteria, which upregulated IL-
10 production by dendritic cells in a dose- 
dependent manner [45]. 



 
 
 
 

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Fig. 1. Mechanisms of immunomodulatory actions of probiotic bacteria 
Key:  ; Increase/ Enhance,     ; Activate/ Stimulate,     ; Induce,       ; Release 

 
Table 1. Clinical evidences of immune stimulation by probiotics [47,48] 

 

Probiotics Immunological Functions Subjects 

Lactobacillus acidophilus La1, 
L. rahmnosusHN001,  
B. bifidum Bb12,  
B. lactisHN019 

Phagocytic activity of blood 
mononuclear and polymorphonuclear 
cells 

Healthy adults and elderly 
volunteers 

Lactobacillus caseiShirota,  
B. lactisHN019 

The tumoricidal activity of blood  
mononuclear cells 

Healthy adults and elderly 
volunteers; patients with 
colorectal cancer 

Lactobacillus brevis Labre,  
B. lactisHN019 

Production of interferons by 
peripheral blood mononuclear cells 

Healthy adults and elderly 
volunteers 

Lactobacillus plantarum Increased neutrophils, macrophages, 
and fibroblast 

Adult volunteers 

Lactobacillus rhamnosus GG Anti-rotavirus antibody responses         Children with rotavirus       

L. rahmnosusGG                         
 

Antibody responses following               
vaccination 

Adult volunteers  

Bacillus subtilis CU1 Increased the levels of secretory IgA 
in stools and saliva, high serum 
IFN-gamma 

Elderly  during common 
infectious disease 

 
According to a report by Nikolov in 2012, the 
inflammation-suppressing properties of probiotics 
may be able to:  

 
(i) Counteract some of the inflammation-

aggravating bacteria. This will decrease 
the inflammatory response;  

(ii) Improve the barrier effect of the mucosa, 
which will inhibit the translocation of 
inflammation-inducing luminal contents into 
the body;  

(iii) Directly interact with pro-inflammatory 
processes [50]. 

 

4.3 Stimulation of Cytokines by Pro-
biotics 

 
Cytokines are chemical messengers used by 
both innate and adaptive immunity. Research 
has shown that live probiotic strains induce the 
production of protective cytokines that enhance 
epithelial cell regeneration and inhibit epithelial 



 
 
 
 

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51 

 

cell apoptosis [51]. Cytokine-induced apoptosis 
was prevented in intestinal epithelial cells in the 
presence of L. rhamnosus GG [48]. Apoptosis 
which is programmed cell death was prevented 
by L. rhamnosus GG, but the mechanism is not 
yet fully known. The inhibition of apoptosis 
enhances the survival of intestinal cells and 
promotes proliferation during recovery from 
epithelial injury [52]. 

 
Probiotics induce pro-inflammatory cytokine 
release in vitro, such as IL-6 and tumor necrosis 
factors (TNFs) [53]. This is in agreement with 
reports by Huang et al. [54] that Bacillus strains 
could stimulate systemic and intestinal IFN- γ 
production in mice. Zhu et al. [5], who reported 
that L. casei had been shown to induce the 
cytokine IL-6 production, also demonstrated that 
B. adolescentis BBMN23 is a strong stimulator 
for TNF production. IL-6 and TNF are cytokines 
usually secreted by macrophages when activated 
[43]. Stimulation of these pro-inflammatory and 
other cytokines by probiotic may be as a result of 
the immunological responses their presence 
caused in the body. In the mucosa, probiotic 
bacteria induce the secretion of cytokines from 
Intestinal Epithelial Cells (IEC) in a strain-specific 
manner. The strain specificity could be due to 
soluble factors produced by probiotic that might 
modulate cytokine production by peripheral blood 
mononuclear cells (PBMC) [2]. The IECs serve 
as the initial point of contact between the host 
and intestinal microbes and they communicate 
expansively with commensal bacteria and 
probiotics. This interaction influences the 
inflammatory signaling pathway in IECs. The IL-6 
and IL-8 released by the epithelial cells are pro-
inflammatory, so an intense epithelial stimulation 
can favor an inflammatory immune response 
[55]. This cytokine produced by IEC, 
macrophages and T cells, can induce the 
terminal development of B cells in plasmatic 
cells, which express IgA. The cytokines released 
by Th2 cells are involved in the induction of the 
IgA immune response [56].  Findings based on 
the use of cell lines as experimental models 
reported that the quality and dose of probiotic 
preparations could impact the IL-8 production by 
enterocytes [57]. IL-8 appears to be a major 
cytokine produced by enterocytes following an 
encounter with probiotics. The IL-8 cytokine 
primarily functions as a neutrophil chemo-
attractant [35]. The macrophages and other 
immune cells stimulate the production of these 
cytokines when they come in contact with the 
probiotic microorganisms, thereby enhancing the 
immune system for the elimination of any 

available pathogen in the case of infection or 
invasion by pathogens. 
 

5. PROBIOTICS AND THE ADAPTIVE 
IMMUNE CELLS 

 

The majority of the studies concerning probiotic 
effects on lymphocytes function has utilized 
animal models. According to Aattouri et al. [58], 
oral ingestion of lactic acid bacteria such as 
lactobacilli and bifidobacteria strains by rats and 
mice increases lymphocyte proliferation and 
interferon production.  
 

5.1 Stimulation of B-lymphocytes by 
Probiotics 

 

Earlier studies using rat models by Naidu et al., 
[59] reveals that lactic acid bacteria administered 
orally increased the number of antibody-
secreting cells, including those in the intestinal 
mucosa with enhanced B-cells proliferation and 
antibody production (IgA and IgG). This could be 
a result of the cell wall components of these 
bacteria leading to the stimulation of antibodies 
and cytokines for the proliferation of B-cells (Fig. 
1). It has been reported that interactions between 
host cells and bacteria or their structural 
components may lead to modulation of T- or B-
cell-mediated immune responses, either locally 
or systemically [60]. When these B-cells are 
proliferated in response to probiotic, they 
differentiate into plasma cells producing more 
antibodies [17]. Early animal studies showed that 
probiotics were able to enhance systemic 
antibody responses to parenterally delivered 
foreign antigen in mice [47,57]. In a study on rats 
co-colonized with L. plantarum and Escherichia 
coli, Herias et al. [61], reported a higher 
circulating concentration of total IgA and E. coli 
specific IgA and IgM compared with rats which 
were colonized with E. coli alone. If in this study 
rats were colonized with E. coli and it stimulated 
the production of IgA and IgM. Then when it was 
co-colonized with L. plantarum, and an increase 
in circulating IgA was recorded, then it could 
probably be that L. plantarum also trigger the 
production of IgA. Also indicating that synergistic 
use of probiotics may yield an increased immune 
effect. Probiotics have also been reported to 
boost overall SIgA antibody responses [16]. This 
results in a significant enhancement of systemic 
antibody response and thereby triggering 
intestinal immunity and subsequent elimination of 
the evading pathogens. This is because most 
SIgA recognizes and opsonizes bacteria in the 
lumen, thus preventing their access to the lamina 
propria (LP) [60,62]. SIgA is important in the 



 
 
 
 

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52 

 

maintenance of gut microbiota homeostasis and 
the protection of the gastrointestinal and 
respiratory tracts against pathogens, as it is the 
main immunoglobulin class in human external 
secretions [16]. The mechanisms whereby 
probiotics modulate immune responses leading 
to tolerance or SIgA activation appear to be 
highly dependent on the strains [49]. In human 
studies, L. rhamnosus GG and B. breve YIT4046 
were shown to stimulate anti-rotavirus antibodies 
in response to rotavirus diarrhea in children 
(Table 1).   
 

5.2 Stimulation of T-lymphocytes by Pro-
biotics 

 
Research has shown that T-helper lymphocyte 
(CD4

+
) numbers are increased in the gut-

associated lymphoid tissue (GALT) following oral 
delivery of L. casei [11,13]. Providing evidence 
that probiotic stimulation can increase the size of 
the lymphocyte population. In a report, orally 
administered lactic acid bacteria in rats revealed 
increased numbers of T- lymphocytes,                
CD4+ cells and also enhanced lymphocyte 
proliferation [59]. The biological property of 
probiotic bacteria involved in lymphocyte 
proliferation is their capacity to affect immune cell 
redistribution by improving the competence of 
lymphatic endothelial cells to trap T lymphocytes 
[63].  

 

5.3 Stimulation of Natural Killer Cells by 
Probiotics 

 
Oral delivery of L. rhamnosus HN001 or L. casei 
Shirota to mice has been shown to increase ex 
vivo natural killer cell tumoricidal activity [45,47].  
This proposes that the consumption of these 
probiotics enhances the destruction of tumor 
cells by stimulating natural killer (NK) cells, 
thereby reducing tumor risks. In human studies, 
B. lactisHN019 has been demonstrated to up-
regulate peripheral blood NK cells mediated 
cytotoxicity against tumor cells (Table 1). 

 
6. MECHANISMS OF IMMUNE MODULA-

TION BY PROBIOTICS 
 

Studies have demonstrated that specific 
chemical compounds isolated from bacteria can 
induce specific immune responses (Figs. 1, 2 & 
Table 2) and thus provide the scientific basis for 
a molecular description of the immunological 
effects observed after the administration of 
probiotics. Excluding the extracellular bacteria 
products, a major role in immunomodulatory 
activity should be mediated by the structural 
components of the cell, particularly the cell 
envelope. This is the outermost structures that 
the immune cells come into contact with first and 
includes the cell wall or S-layer proteins, 
capsules and pellicle [64]. 
 

 
 

Fig. 2. Molecules or parts of probiotic bacterialcells demonstrated to modulate host immune 
and epithelial cells



 
 
 
 

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53 

 

Findings indicated that both cell wall and 
cytoplasm can be recognized and stimulate the 
immune system [33]. Because of the limitation 
that bacteria cannot pass through the epithelial 
cells, it can be uptaken by microfold cells (m-
cells), and only the antigenic particles or 
products of degradation of the bacteria can make 
contact with the immune cells by pattern 
recognition receptors (PRR) that recognize 
pathogen-associated molecular patterns (PAMP) 
[65]. Therefore, PAMP can explain the different 
production of cytokines induced by bacteria, 
demonstrating the different components of the 
cell wall causing the distinct immune-boosting 
effects. In a study, RAW264.7 macrophages 
were exposed to heat-killed probiotic 
Bifidobacterium spp., L. acidophilus, L. 
bulgaricus, L. casie, L. gasseri, S. thermophilus 
including the cell envelope components and 
cytoplasmic extracts of these bacteria and they 
stimulated macrophages to produce TNF-α, IL-6 
and nitric oxide (NO) [45], suggesting that 
bioactive compounds are potentially located 
everywhere in the bacteria cell. 
 
In the intestinal fluid, probiotics influence the 
production of antimicrobial peptides (AMPs) by 
Paneth cells, the production of mucus by goblets 
cells as well as the level of secretory IgA that is 
under the dependence of a proliferation-inducing 
ligand (APRIL) produced by IEC. Probiotics 
affect the expression level of TLRs on DC as 
wells as immune cells in Peyer’s patches, 
leading to a production of a wide range of 
cytokine regulating the evolvement of the 
immune response. 
 

7. IMMUNOMODULATORY MOLECULES 
OF PROBIOTIC BACTERIA 

 

7.1 Bacterial Cell Wall Components 
 

Cell wall components of L. caseiare anti-
inflammatory [48]. Peptidoglycan (PGN) and 
lipopolysaccharide (LPS) are well known potent 
activators of immune responses (Fig. 2). 
Peptidoglycan (PGN) is the main constituent of 
Gram-positive bacterial cell wall, accounting for 
up to 90% of their weight, whereas it constitutes 
only 15-20% of the cell wall of Gram-negative 
bacteria [69]. Specialized conserved pattern 
recognition receptors (PRR) on the host cell 
membranes, such as Toll-like receptors (TLRs) 
and the nucleotide-binding domain (NOD) 
proteins are the primary sensors of the innate 
immune system and recognize microbe-
associated molecular patterns, including PGN 

and LPS [37,50,69]. In particular, TLR4 is a 
specialized receptor for LPS, whereas both 
NOD1 and NOD2 recognize muramyl peptides 
released by PGN [37]. The different immune 
stimulation by cell wall components is shown in 
Fig. 2 and Table 2. In Gram-positive bacteria cell 
walls, molecules are protruding from the external 
surface of the PGN layer known as teichoic acids 
(TAs). TAs are phosphodiester polymers of 
glycol or ribitol and can be covalently linked to 
either peptidoglycan (wall teichoic acid, WTAs) or 
the cytoplasmic membrane (lipoteichoic acid, 
LTAs). LTAs purified from L. casei YIT 9029 and 
L. fermentumYIT 0159 were demonstrated to 
induce elevated levels of TNF-α in mouse 
RAW264.7 macrophages mediated by TLR2 
(Fig. 2) [45].  
 

7.2 Other Immunomodulatory Molecules 
of Probiotic Bacteria 

 
It has been established that the effects of 
probiotic bacteria may also result from soluble 
factors that alter epithelial permeability or 
mediate activation, maturation or survival of 
dendritic cells [70]. 
 
7.2.1 Surface layer (S-layer) 
 

Probiotics can interact with the host immune 
system through their surface layer, a 
monomolecular crystalline envelope produced by 
the self-assembly of protein or glycoprotein sub-
units on the outer cell surface [45]. S-layers are 
commonly found in prokaryotes and makeup to 
10-15% of the total protein content of a cell [71]. 
S-layer protein A (SLpA) released from L. 
acidophilus NCFM cells has been demonstrated 
to be recognized and bound by dendritic cell-
specific intercellular adhesion molecule-3-
grabbing non-intergrin (DC-SIGN), a C-type 
lectin receptor presents on both macrophages 
and dendritic cells [66]. It was observed that L. 
acidophilus NCFM expressing SLpA was 
captured by DC-SIGN on DC, and thus activated 
the IL-4 producing T-cells. These data were 
confirmed by an experiment performed with 
purified SLpA protein, which ligated to DC-SIGN 
and induced IL-10 expression by DCs in the 
presence of lipopolysaccharide [66]. Nuclear 
Factor kappa-light chain enhancing activated B-
cells (NF-kB), is triggered in the presence of S-
layer by human epithelial colorectal 
adenocarcinoma cell line (Fig. 2). NF-kB is a 
protein complex that is found in almost all animal 
cells, which controls the transcription of DNA. It 
is also involved in cellular responses to stimuli



 
 
 
 

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54 

 

Table 2. Immunomodulatory molecules of probiotic microorganisms 
 

Probiotics  Molecules  Effects  

Lactobacillus casei 
Lactobacillus plantarum 

Peptidoglycan                   General immune stimulation [33,48] 

Lactobacillus casei 
Lactobacillus fermentum 

Lipoteichoic acid Increased levels of TNF-α in mouse 
macrophage cell [45]. 

Bifidobacteriumlongum DNA Increased cytokine IL-10 [45]. 
Lactobacillusacidophilus Surface layer Activation of IL-4 producing T-cells [66]. 
B. bifidumMIMBb75 BOpA protein Induce production of IL-8 by colorectal 

cell line [67,68]. 
Escherichia coliNissle 1917 Flagellin Induce production of IL-8 by colorectal 

cell line [68]. 
S. thermophiles 
L. plantarum 

Cell wall-associated 
polysaccharide (CAPs) 

General immune stimulation [33,48]. 

 
such as bacterial and viral antigen with the 
production of cytokines. NF-KB is the key 
signaling channel in the inflammatory signaling 
pathway [2,45].   
 

7.2.2 BOpA protein and flagellin 
 

BOpA is a cell surface-associated lipoprotein of 
B. bifidum MIMBb75 that mediates adhesion to 
the human Caco-2 intestinal epithelial cells. 
Upon purification from B. bifidumMIMBb75 strain, 
BOpA has been demonstrated to induce the 
production of IL-8 by Caco-2 cells in a dose-
dependent manner [67]. Flagellin, a structural 
protein released from E. coliNissle 1917 strain, 
has been reported to increase the production of 
the pro-inflammatory cytokine IL-8 in Caco-2 
cells [68]. 
 

7.2.3 Genomic DNA 
 

It has been shown that prokaryotic DNA contains 
an unmethylatedCpG motif that can activate 
immune responses in vitro and in vivo [45]. DNA 
mixture isolated from the probiotic mixture VSL#3 
containing 8 lyophilized lactic acid bacteria 
strains generated non-inflammatory responses 
from epithelial and immune cells [37,72]. In an 
earlier study, Lammers et al. [73] reported that 
bacterial DNA extracted from bifidobacterial 
cultures of the commercial product, VSL#3 
influenced cytokine production by peripheral 
blood mononuclear cells (PBMCs), increasing IL-
10. The anti-inflammatory effect of genomic DNA 
from VSL#3 bacteria was also confirmed in an in 
vivo murine study, which demonstrated that 
TLR9 signaling was essential in mediating this 
anti-inflammatory effect [74]. It has been 
suggested that the immunological effect 
observed with bifidobacterial genomic DNA is 
favored by the high guanine-cytosine (GC) 
content of the Bifidobacterium genes (58-61%), 

which explains the availability of different CpG 
motifs in the genomes of these bacteria [73]. 
 
7.2.4 Cytoplasmic extracts 
 
Cytoplasmic extracts from different probiotic 
bacteria have demonstrated to stimulate several 
cytokines involved in immune functions, including 
Nitric Oxide (NO) (Fig. 2) [45]. 

 
It is very important to note that the potential 
bioactivity of specific bacterial components can 
be masked by other cell structures, and the effect 
of a single molecule can be influenced by the 
presence of additional bioactive substances. In 
support of this concept, a study by Kaji et al. [75] 
identified TAs as a key factor for triggering the 
synergism of inducing IL-10 production. They 
demonstrated that TAs alone weakly induced IL-
10 production, but when macrophages sensed 
WTAs or LTAs in the presence of L. caseishirota 
strain, these stimuli cooperatively induced potent 
production of IL-10. 

 
8. THE ROLE OF MICROBIOTA AND 

PROBIOTICS IN REGULATING 
IMMUNE RESPONSES IN CANCER 
PATIENTS 

 
The susceptibility and development of cancer is a 
result of a complex interaction between gene 
regulation and the environment [76,77]. Gut 
microbiota is critical for intestinal immune 
maturation, protecting the host against 
pathogens and damaging inflammatory reactions 
[78], and probiotics (and prebiotics) present more 
common ways to establish and maintain healthy 
microbiomes. Lactic acid bacteria (LAB) species 
constitute members of healthy human gut 
microbiota. Recent studies have reported that 



 
 
 
 

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55 

 

certain LAB strains are capable of inhibiting 
tumor progression [79,80]. Generally, the anti-
tumor mechanisms of LAB appear to be by the 
modulation of the immune response and the 
induction of cellular apoptosis. In two 
independent studies by Konishi et al. [79] and 
Baldwin et al. [81], they reported that two strains 
of L. casei decreased tumor cell proliferation and 
enhance apoptosis in allograft models of 
colorectal cancer. In a more recent study, the 
oral administration of the probiotic strain L. casei 
BL23 reduced the onset of chemically induced 
tumors by the stimulation of IL-12 (Fig. 2) or NK-
cell cytotoxicity (Fig. 1) mechanisms [82]. In the 
same study, they demonstrated the protective 
effects of L. casei BL23 in different mouse 
models of cancer, including colorectal-associated 
cancer (CAC) and the TC-1 allograft model. 
Similarly, the Intratumoral inoculation of 3 mg of 
heat-killed Propionibacterium acnes in 
subcutaneous melanoma promoted local and 
systemic Th1 and Tc1 responses associated with 
in situ granuloma formation and tumor regression 
[83]. P. acnes is recognized by TLR2 on 
monocytes, macrophages, and DCs, leading to 
the activation of IL-12 promotor [84]. According 
to Delia et al. [85] and Touchefeu et al. [86], 
preparations containing B. bifidum, L. 
acidophilus, L. casei, and the VSL#3 formulation 
containing Streptococcus, Lactobacillus, and 
Bifidobacterium spp. have been proven to reduce 
radiation-induced gut toxicity, such as diarrhea. 

 
Reports are suggesting that genetically modified 
probiotic microorganisms may have better 
effects. A L. acidophilus strain harboring a 
deletion in the phosphoglycerol transferase gene 
and unable to synthetize LTA prevented the 
progression of colonic polyps in Apc

Dflox
 mice 

[87]. Elafin-overexpressing L. casei and L. lactis 
reduced colitis in mice and ex vivo in inflamed 
epithelial cells from human colitis [88]. L. gasseri 
genetically modified to overexpress superoxide 
dismutase was reported to decrease colitis in IL-
10-deficient hosts [89]. These findings and 
reports further raise the possibility that probiotics, 
if properly considered could become an adjuvant 
therapy for cancer treatment. 

 
9. SPECIAL OBSERVATION 
 
In a very recent study carried out in 2019, it was 
reported that probiotics can have different effects 
on the immune system in males, compared with 
female piglets [90]. It is important to understand 
that immunity differs considerably with sex. 
Accurate development of the immune system is 

crucial in guaranteeing it responds properly to 
both harmful and harmless stimulation 
throughout life, and this development, even 
during the early days of life, is dependent on sex 
[91]. In the study, the immune cells, antibodies, 
and other immune-related molecules were 
different in males and females in response to 
probiotic supplementation. Female pigs produced 
more of the immunoglobulins IgA and IgM in their 
lymph tissue, while in male pigs, the process 
occurred in the large intestine [90]. This 
proposes that, during infancy, females may have 
greater potential for local immune regulation than 
their male counterparts. This finding implies that 
specific probiotics may be more beneficial for 
girls, whilst others could produce improved 
health outcomes for boys. Given the primary 
differences in immune development between 
males and females, taking sex into account could 
provide a means to progress the effectiveness of 
probiotics for pharmaceutics and other therapies 
that act on the immune system.  
 

10. CONCLUSION AND FUTURE PER-
SPECTIVES  

 
Accumulating researches have shown that 
probiotics have effects on the immune system. 
These effects can be seen in their ability to 
trigger or stimulate the immune cells and 
suppress certain immune processes. Meantime, 
research is still ongoing to completely 
understand the mechanisms involved in immune 
modulation by probiotics. A probiotic-induced 
immune stimulation is a complex interplay of the 
host-microbe interactions. The immune 
responses (innate and adaptive) can be 
modulated by probiotic bacteria in a strain- and 
dose-dependent manner. However, there is 
limited knowledge for in vivo use, safety and 
effect in immunocompromised individuals and 
newborns. Thus, improved knowledge of 
probiotics and its effect on the host immune 
system by various mechanisms will promote 
proper strain selection for a specific prophylactic 
or therapeutic use, ultimately leading to more 
personalized therapy. There is also a need for 
more controlled trials with sufficient numbers of 
volunteers. 

 
CONSENT 
 

It is not applicable. 
 

ETHICAL APPROVAL 
 
It is not applicable. 



 
 
 
 

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56 

 

COMPETING INTERESTS 
 

Authors have declared that no competing 
interests exist. 
 

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