Zendeboodi 2020

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com
ScienceDirect
Probiotic: conceptualization from a new approach

Fatemeh Zendeboodi1, Nasim Khorshidian2,
Amir M Mortazavian3 and Adriano G da Cruz4
According to the proposed definition by FAO/WHO, probiotics Introduction

must be alive and abundant once ingested. However, during According to the Greek language, the term probiotic
recent years, new definitions are added to the probiotic means ‘for life’. For life, meaning each substance or
terminology such as ‘paraprobiotics’ (dead/inactive cells of organism that promote health quality of the host. In
probiotics) and ‘postbiotics’ (healthful metabolites of 2002, the WHO and FAO considered probiotics as ‘live
probiotics), because findings have shown that dead cells (intact microorganisms when administered in adequate
or ruptured) could also show significant health impacts on amounts confer a health benefit on the host’. Several
human. However, mentioned terms are not accurate and beneficial effects have been accepted for probiotic bac-
impressive enough to reflect the intended meanings regarding teria such as: a) enhancing nutritional value of food
all states of probiotic benefits and it seems that a disturbance products, b) controlling and reducing the serum choles-
and confusion in probiotic glossary has been occurred. As a terol, c) improving the immune system, d) preventing
result, a new terminology based on a new efficient approach gut infections and suppressing antibiotic-associated diar-
and conceptualization is needed for a global agreement and rhea, e) reducing lactose intolerance symptoms, f) reduc-
usage. In the present paper, we are honored to propose such tion of colon cancer risk, and g) improving the digestion
terminology to provide mentioned comprehensive approach of gliadin against celiac in gluten containing foods which
and terminology for all aspects of probiotic benefits. We are are dependent on the type of probiotic strain [1,2].
proposing three main classes of probiotic including ‘true Regarding these functionalities, people are interested
probiotic’ (TP) referring to viable and active probiotic cell, in consuming products containing probiotics. Among the
‘pseudo-probiotic’ (PP) referring to viable and inactive cell, in products whose allegations of health have been devel-
the forms of vegetative or spore (PPV or PPS) and ‘ghost oped and advertised in the media during the last years,
probiotic’ (GP) referring to dead/nonviable cell, in the forms of probiotic-containing products stand out [3]. The health
intact or ruptured (GPI or GPR). Each of these classes are effects of these delivery systems have resulted in mar-
classified into two groups based on their site of action/impact: keting efforts aiming to manufacture novel functional
internal (in vivo) or external (in vitro). food products. Different types of delivery systems are
commercialized and have been considered as a source of
Addresses probiotics including food products (e.g., dairy products,
1
Student Research Committee, Department of Food Science and
processed meat, vegetable products, juices, and cereal-
Technology, Faculty of Nutrition Sciences and Food Technology,
National Nutrition and Food Technology Research Institute, Shahid based products), nutritional supplements (liquid, tablet,
Beheshti University of Medical Sciences, Tehran, Iran capsule, and powder) and drugs [4].
2
Food Safety Research Center (Salt), Semnan University of Medical
Sciences, Semnan, Iran The definition of the term probiotic has been changed
3
Food Safety Research Center, Shahid Beheshti University of Medical
Sciences, Tehran, Iran
and broadened over the years. Although, the definition
4
Department of Food, Federal Institute of Science and Technology of developed by WHO and FAO is accepted by the majority
Rio de Janeiro, Rio de Janeiro, RJ, Brazil of researchers, but during recent years, new definitions
are added to the probiotic terminology such as
Corresponding author: Mortazavian, Amir M ([email protected])
‘paraprobiotics’ (dead/inactivated cells of probiotics)
and ‘postbiotics’ (healthful metabolites of probiotics).
Current Opinion in Food Science 2020, 32:103–123 Accordingly, findings have shown that dead cells (intact
This review comes from a themed issue on Food microbiology cells or ruptured cells/cell extracts) as well as the cell
metabolites could render significant health impacts on
Edited Amir M Mortazavian
human [5]. Therefore, mentioned terms are not accurate
and comprehensive enough to reflect the intended mean-
ings pertaining to all beneficial aspects of probiotics and it
https://doi.org/10.1016/j.cofs.2020.03.009
seems that a disturbance in glossary has been occurred. As
a result, a new approach and conceptualization in probi-
2214-7993/ã 2020 Published by Elsevier Ltd.
otic terminology is needed to be developed for global
usage in all texts. This review is aimed to fulfill men-
tioned necessary idea. Table 1 illustrates the current
microorganisms used as probiotics.
www.sciencedirect.com Current Opinion in Food Science 2020, 32:103–123

104 Food microbiology
Table 1 probiotics was not justified. In 2001, Schrezenmeir and de

Microorganisms used as probiotics [6,7]. Vrese [15] considered probiotics as viable microorganisms
that exert health effects independent of the site of action.
Probiotic genus Species
In 2001, the WHO and FAO considered probiotics as ‘live
Lactobacillus L. plantarum, L. paracasei, L. acidophilus, L. microorganisms which when administered in adequate
casei, L. rhamnosus, L. crispatus, L. gasseri,
L. reuteri, L. bulgaricus
amounts confer a health benefit on the host’. Finally, in
Bifidobacterium B. adolescentis, B. animalis, B. bifidum, B. 2014, the International Scientific Association for Probio-
infantis, B. lactis, B. longum, B. catenulatum tics and Prebiotics (ISAPP) modified the latter definition
Propionibacterium P. jensenii, P. freudenreichii slightly and defined probiotics as ‘live microorganisms,
Peptostreptococcus P. productus
that when administered in adequate amounts, confer a
Pediococcus P. acidilactici
Leuconostoc Lc lactis subsp. cremoris, Lc. health benefit on the host’. From that time on, this
mesenteroides definition has been widely used by scientific community
Enterococcus E. faecium and is a criterion for considering drugs, foods, and supple-
Streptococcus S. oralis, S. uberis, S. rattus, S. salivarius, S. ments as probiotic products in most of governmental
sanguis, S. mitis, S. thermophilus
Bacillus B. coagulans, B. subtilis, B. laterosporus
institutions. In this definition, viability is one of the
Bacteroides B. uniformis crucial factor for considering a microorganism and the
Akkermansia A. muciniphila relevant product as ‘probiotic’.
Saccharomyces S. cerevisiae, S. boulardii
Findings during recent years have revealed that dead/
inactivated cells (intact cells or ruptured cells/cell extracts)
History of terms associated to probiotic as well as the cell metabolites could render significant
Probiotic health benefits on human [5]. Therefore, the restriction
The first probiotic definition was rendered in 1908 by of ‘viability’ in all probiotic definitions must be modified.
Metchnikoff, who proposed that consumption of fermen- On the other hand, it is worth to mention that using living
ted milk products prolongs the life (longevity effect) [8]. cells in some especial cases might have an adverse effect on
In 1956, Lilly and Stillwell determined that a microor- the health. For example, it has been determined that
ganism secrets some growth stimulators for another probiotics can modulate the immune system; however,
microorganism [9]. This positive effect may cause the the administration of living probiotic cells to host with
application of the term probiotic for these kinds of micro- weak immune system increased inflammatory responses
organisms. The term probiotic was first used by Parker for [16]. In such cases, incorporation of dead cells could be a
the definition of substances and organisms which cause good substitute. Therefore, the administration of killed or
the microbial balance in the gastrointestinal tract [10]. inactivated probiotics developed a new area in probiotic
The existence of the word substances in this definition field and different scientists tried to propose new terms to
resulted in a broad connotation which included antibio- cover mentioned usages. However, the recommended
tics. Fuller [11] improved Parker’s definition and defined terms are not precise and comprehensive from scientific
probiotic as a live microorganism that positively affects meaning point of view. Also, they are somehow confusing.
the warm-blooded animal health by restoring the natural These words are discussed and criticized in following:
gut microflora. Fuller’s definition emphasized on the
viability of probiotic and assigned the positive effect Paraprobiotic
on animals. In the case of probiotics host, Haveenar After 2004, many researchers started to report functional
and In’t Veld [12] defined these microorganisms as ‘viable properties of dead probiotics. Zhang et al. [17] revealed
microorganisms in the form of mono- or mixed cultures the beneficial effect of heat-killed Lactobacillus rhamnosus
applied to human or animals which positively affect the GG (LGG) cells and demonstrated that killed cells were
host health by improving the gut microflora properties’. more effective than viable cells on downregulation of an
Based on Salminen definition, a probiotic is a viable inflammatory response due to their ability to decrease the
microorganism inoculated in dairy products and improve production of interleukin-8 (IL-8). In 2008, Lopez et al. [
the health and nutrition of the host [13]. Schaafsma [14] 18] demonstrated that the UV-inactivated LGG cells
broadened the definition and according to his definition, were effective in decreasing the production of IL-8 in
probiotics are viable microorganisms that exert health the intestinal epithelium [18]. In 2009, Ostad et al. [19]
effects on the host, if ingested in adequate numbers evaluated the ability of heat-killed lactobacillus spices
and when consumed more than inherent basic nutrition. (Lactobacilus acidophilus, Lactobacillus agilis and Lactoba-
Salminen [13] pointed out that probiotic is microbial cillus casei) in preventing the adhesion of Salmonella typhi
culture of dairy products. Therefore, based on this defi- and Escherichia coli to Caco-2 cells. They determined that
nition, food matrix is a key criterion for considering the heat-killed cells similar to viable cells were able to inhibit
microorganism and the food as probiotic. However, due to pathogenic bacteria adhesion. A study of Rampengan
the presence of viable probiotics in non-dairy products, et al. [20] on children with lactose malabsorption indicated
considering the dairy products solely as the matrix of that using probiotics (viable or killed cells) had an
Current Opinion in Food Science 2020, 32:103–123 www.sciencedirect.com

New concept of probiotics Zendeboodi et al. 105
impressive effect on decreasing lactose intolerance symp- viable state, can produce postbiotics. Postbiotic is also
toms. In 2011, Taverniti and Guglielmetti [21] proposed defined as cell-free supernatants, biogenics, metabolites,
the term ‘paraprobiotic’ to indicate inactivated microbial and metabolic waste of activity of probiotic. In 2013, Tsi-
cells or cell fractions to confer a benefit to the host’s lingiri et al. [22] defined postbiotic as any affects obtaining
health. Taverniti and Guglielmetti [21] proposed the from metabolites of probiotics or any extracted or secreted
term paraprobiotic for inactivated microbial cell fractions molecule that offers health benefits to the host directly or
capable of conferring health to the host. Reasons for the indirectly. These soluble compounds include enzymes, exo
revision of Taverniti and Guglielmetti terminology are and endo polysaccharides, surface proteins, vitamins, organic
described. According to Taverniti and Guglielmetti [21], acids, fatty acids, and peptides [22,23,24]. Aguilar-Toalá
the term paraprobiotic refers to ‘non-viable cells (intact or et al. [23] defined postbiotics as soluble factors (products or
tact) or cellular extract which confer health to the host metabolic byproducts), secreted by live bacteria, or released
when administered in adequate amounts’. Based on this after bacterial lysis. Most of literatures discussed the nature
definition, both tact and intact cells considered as para- of postbiotics and their beneficial effects rather than its
probiotics which is one of the confusing points of this terminology that cannot cover the whole meaning of nature
definition. Additionally, entering the cellular extracts of and effects. The prefix ‘post’ literally means ‘after’ and the
probiotics in to the definition of paraprobiotics as a ‘postbiotic’ means ‘after life’. Therefore, if it was meant after
beneficial factor is another confusing point. the viability of microbial cells (nonviable cells), the meaning
is mixed with paraprobiotic, because both states are beyond
Inherently, while the root of term ‘probiotic’ (for life) the viability. Moreover, it must underline that the functions
comprises any health benefits to the host by microbial mentioned for postbiotic are not just related to the dead cells
cells or any cell-associated derivatives, the term and those health promoting components can be obtained
‘paraprobiotic’ does not literally reflect an informative also from viable cells. As appeared, postbiotic in meaning is
impression. In other words, this paraprobiotic is not self- confusing and ambiguous as well as paraprobiotic. Tsilingiri
expressive to the intended meanings. The prefix ‘para’ and Rescigno [22] have proposed postbiotic for any sub-
means ‘in front’ in Latin meaning (as is a common word in stance (bacteria metabolites, cell extraction, or molecule/s
chemistry literatures besides the words ortho and meta), secreted with probiotic organism) that affect beneficially on
whilst, probiotic is a general meaning for being healthful the host directly or indirectly. According to the functionality
for life; and the in front or apposite meaning of probiotic is described by these two scientists, selection of the term
the word ‘antibiotic’, which is healthless, not healthful. ‘pobiotic’ is not appropriate.
Therefore, the application of the word paraprobiotic in
continuous and align with probiotic is meaningless. In Psycobiotic
relevant literature proposed the term paraprobiotic, the In 2013, Dinan and coworkers defined the term
combination of ‘para’ and ‘probiotic’ is interpreted as ‘psychobiotic’ as probiotics when ingested at adequate
‘beside-for life’, which is not convincible. Furthermore, amounts, exert beneficial effects on mental health through
based on its literal meaning of ‘para’ (beside) in conjunc- an interaction with gut microbiota [25]. Also, Nishida et al.
tion with ‘probiotic’, is might be perceived that parapro- [26], suggested the term ‘parapsychobiotic’ for definition of
biotics would have their activity and efficiency only when paraprobiotics that yield advantageous effects on mental
administered beside probiotics and their activities are health. Also, there are some microbial neuroactive metab-
dependent on the presence of probiotics. Given above, olites which affect psychological processes [27].
the term paraprobioitc is somehow confusing. It should be
mentioned that the words ‘inactivated probiotic’, ‘dead It has been reported that probiotics named as
probiotic’, ‘non-viable probiotic’, and ‘ghost probiotic’ ‘psychobiotic’ regulate the neurotransmitters and pro-
have been also used as synonyms for paraprobiotic. It teins, mood, cognitive functions, memory and learning
is worth to mention that inactivation of probiotic cells process [28]. The proposed mechanisms for the effect of
does not necessarily guarantee their death (being inviable probiotics on mental health include production of neuro-
or nonviable). The cells might be viable, but not active. transmitters (gamma-aminobutyric acid (GABA), seroto-
Also, some cells can be active in a matrix, but inactive in nin, catecholamines, and acetylcholine), modulating
another one. In other words, the microbial cell might be hypothalamicpituitary-adrenal axis (HPA) in stressful
‘viable- but-not-culturable’ (VBNC or vbnc). This narrow conditions and anti-inflammatory activities [29]. On the
point is another unclarity of paraprobiotic term. other hand, a growing body of research demonstrated that
gut microbiota play a substantial role in the brain behavior
Postbiotic and cognitive development. Thus, alteration of gut micro-
While the term ‘paraprobiotic’ have mainly emphasized on biota composition can improve brain-associated diseases
the whole inactivated cells or components of membrane or [29]. In this sense, it can be elucidated that administration
cell wall, ‘postbiotic’ has been defined as the extract of of live probiotics or their inactivated form as well as their
nonviable probiotic, which are soluble with the molecular metabolites can affect the gut microbiota and conse-
weight of 50 100 kDa. Overall, probiotics present in a quently health status of the brain.

Given the above, although emerging the term imparting their health impacts, the probiotic class would
‘psychobiotic’ is based on psychiatric criteria, it cannot be be ‘ghost-ruptured-internal’ (GPR-I). Different classes of
considered as an independent and a new class of probiotics probiotic according to its functionality is presented in Table
since its mechanism of action comprises the ones associated 2 and is tersely presented along with their health benefits
with probiotics, paraprobiotics and postbiotics. Therefore, and the mechanisms of action as following:
using this term is not rationale and is just like a creation of
the terms such as ‘gasteroprobiotic’ or ‘gutbiotic’ which True probiotic
positively influence the gastrointestinal tract but actually According to FAO/WHO definition, one of the criterion for
without being adding new concept to the existing ones. considering a product as a source of probiotic is that contain-
ing viable cells. Also, if a viable organism possesses growth
New conceptualization on meaning of (cell multiplication) and/or metabolite production (utilizes
probiotic substrates and transform them into some biochemical
In order to liberate form ambiguity of probiotic terminology metabolites), it can be considered as a viable and active
mentioned in Section ‘History of terms associated to microorganism [30,31]. The activity of microorganisms is not
probiotic’, we are proposed new terminology to cover all emphasized in FAO/WHO definition for a probiotic, so it is
states of health benefits mentioned in the history of probi- not determined clearly that an organism should carry a
otic-associated literature. The main concept for developing particular activity or not to consider it as a probiotic. Indeed,
this terminology is based on the fact that according to the we proposed the term ‘true probiotic’ as an alternative to the
Greek language, the term ‘probiotic’ means ‘for life’. term ‘probiotic’ for more clarity and better understanding.
Therefore, in terms of healthy or beneficial microorganisms, True probiotic must be viable and active, not only remain
‘probiotic’ can be defined as ‘viable or inviable microbial alive (able to live) or survive. According to FAO/WHO
cell (vegetative or spore; intact or ruptured) that is poten- definition, the activity of these microorganisms should con-
tially healthful to the host’. Corresponding to the definition, fer a beneficial effect in the host. These microorganisms
the probiotic concept can be categorized into three classes: exert health benefits through some biotherapeutic activities
‘true probiotic’ (TP: viable and active cell), ‘pseudo- (bioactivities) including reducing pH of the gut, production
probiotic’ (PP: viable and inactive cell, in the forms of of vitamins and enzymes, production of antimicrobials,
vegetative or spore) (PPV or PPS), and ‘ghost probiotic’ balancing the intestinal microflora and reconstructing them
(GP: dead/nonviable cell, in the forms of intact or ruptured) after diarrheas, reducing serum cholesterol, modulation of
(GPI or GPR). Each of these classes are classified into two immune system, anti-oxidative activity, reduction of food
groups based on their site of action/impact: internal (in vivo) allergen responses, reduction of lactose malabsorption symp-
or external (in vitro). For instance, if a probiotic cell produce toms, enhancing calcium absorption and antibiotic therapy
a healthy metabolite or bioactive compound in a food [32]. When probiotic deliver into body via gastrointestinal
matrix, it should be deemed as ‘true probiotic-external’ tract (GIT), it must first be viable (and even active, in
(TP-E); whilst when this viable and active probiotic is fermented foods) in vitro (externally), and then, be viable
transformed into body for doing its specific function in and active in vivo (internally). Being viable and occasionally
target organ, it would be regarded as ‘true probiotic-internal’ active in food/supplement products, probiotics must be
(TP-I). If the former probiotic become inactive (but viable) tolerant to their environmental conditions, while being alive
in food, the probiotic class is recognized as and active in GIT, they must be resistant to saliva, gastric
‘pseudoprobiotic-vegetative-external’ (PPV-E). As another juice (acid and digestive enzymes), bile salts, and competi-
example, a ruptured probiotic cell in food is ‘ghost probiotic- tive conditions of gut. The key characteristic of true probiotic
ruptured-external’ (GPR-E); but when the cell fragments of is its ability to confer beneficial effects in relevant sites of
this probiotic is consumed in a food or supplement for body. Below, the advantages and mechanisms of action of
Table 2
The classes of ‘probiotic’ according to its functionality
Main class Specification First subclass First abbreviation Second subclass Second abbreviation
True probiotic Viable and active – TP Internal TP-I
External TP-E
Pseudoprobiotic Viable and inactive Pseudoprobiotic-Vegetative PPV Internal PPV-I
External PPV-E
Pseudoprobiotic-Spore PPS Internal PPS-I
External PPS-E
Ghost probiotic Nonviable Ghost probiotic-intact GPI Internal GPI-I
External GPI-I
Ghost probiotic-ruptured GPR Internal GPR-I
External GPR-E

true probiotic under in vitro (external) and in vivo (internal) sodium sulfide (DSS) by preventing activity of myelo-
conditions are discussed tersely: peroxidase and interleukin (IL)-12 [43]. Another reason
for enhancing immune systems by TPs is contributed to
True probiotic-internal/in vivo effects (TP-I) inhibiting pro-inflammatory responses in epithelial
The intestinal tract is the place of major accumulation of cells. These probiotics produce some factors that pre-
microorganisms among human organs. Indeed, applica- vent the activity of proteasomes in the intestine, and
tion of viable and active cells in gastrointestinal disorders hence, inhibit the NF-kB pathway and induce some
is not surprising. Several mechanisms which are specific cycoprotective proteins, subsequently [44]. TPs such as
for each strain have been related to the internal beneficial L. rhamnosus GG may also improve the epithelial cell
effect of these cells including conservation of interaction regeneration; thereby, inhibits apoptosis [45]. In vivo
between the host-microbes and prevention of pathogens, application of L. rhamnosus GG inhibits proapoptotic
regulation of mucosae secretion from the intestine cells, p38/mitogen-activated protein kinase activation by
regulation of barrier function of epithelial cells, secreting interferon, IL-1, or tumor necrosis factor-a (TNFa).
antibacterial substances, and regulation of the immune Protection of apoptosis improves survival of epithelium
system of the host [1,33]. cells and enhances proliferation during restoration,
probably. TPs can also affect dendritic cells (DCs) in
True probiotic (TP) cells secret some substances such as the intestine. DCs are important in early recognition of
bacteriocins, H2O2 and organic acids (butyric, lactic and bacterial infections and in producing IL-10 and TGF-ß
acetic acids) that act as antimicrobial agents [34]. Based that stimulate the production of T-cell and B-cells;
on an in vitro experiment, L. acidophilus secreted some indeed, DCs cause the primary oral immune responses.
compounds including lactacin B and acidolin which inhib- The other ability of TP in modulation of the immune
ited the growth of lactobacilli and enteropathogenic system is the effect of these cells on monocytes and
organisms, respectively. Antimicrobial activity of TPs macrophages. For instance, L. plantarum enhanced IL-
also affect pathogens by lowering pH [34], agglutination 10 production in macrophages of inflamed colon [46].
of pathogens, trapping and metabolizing toxic substances Moreover, TPs may affect lymphocytes (B lymphocytes,
[35] or adjusting mobility of the intestine [36] and pro- natural killer (NK) cells and T-cells) directly or second-
duction of mucus in the gut [37]. arily through alteration in the stimulation induced by
changing in macrophages or DCs [47]. L. rhamnosus GG
Mechanisms of cholesterol reduction by TPs have been increased the IgA, IgG, and IgM production by lym-
proposed by many researchers almost based on in vitro phocytes [48]. L. casei in the presence of dextran
experiments (simulated in vivo conditions) comprising bile improved the activity of the NK cells in mice spleen
deconjugation by bile salt hydrolase (BSH), binding pro- [49]. Finally, in respect of the immune system modula-
biotics to cholesterol and incorporation of it into the mem- tory mechanisms, TP cells influence the redistribution
brane [38,39], precipitation of hydrolyzed bile with choles- of T-cells. The latter mechanism is due to enhancing
terol [40], and conversion of cholesterol into coprostanol ability of T-lymphocyte to trap lymphatic endothelial
[41]. Nevertheless, the most accepted hypothesis is the cells by Saccharomyces boullardii [50].
activity of BSH in reducing serum cholesterol, since metab-
olism of bile salts and cholesterol are related very closely. In addition to inhibiting gastrointestinal problem, TPs
Based on scientific literatures, many lactobacilli (L. plan- possess extra effects such as reduction of food allergen
tarum, L. Johnsonii, L. gasseri and L. acidophilus) and bifido- responses. TPs were applied for the treatment of allergenic
bacteria (B. longum, B. bifidum and B. infantis) carry BSH responses (food allergy, rhinitis, and atopic dermatitis) [51].
genes. These TPs cleave amide bonds by BSH. They may They have the capability of altering the structure of anti-
hydrolyze conjugated bile acids (BAs) to free BAs which are gens, decreasing antigens immunogenicity and reducing
not absorbed in the intestine and exert in feces. Viable and the permeability of the intestine and inhibiting the pro-
active probiotics which carry BSH, enhance the bile salt duction of cytokines (pro-inflammatory), which are
production from serum cholesterol, and can decrease cho- increased in many allergic disorders. These cells regulate
lesterol-associated diseases. the immune system by the production of anti-inflammatory
cytokines or by enhancing some metabolites that inhibit
Administration of TPs modulates the immune system the contiguity of antigens and the intestinal mucosa [52].
by a variety of mechanisms which is an internal effect of
these active cells. They affect the epithelial cells by The intestinal tract is the major accumulation of micro-
interaction with Toll-like receptors (TLR) on epithelial organisms among human organs. Indeed, application of TP
cells. These interactions cause the secretion of cyto- cells in gastrointestinal disorders is not surprising. Several
kines which improve the productivity of epithelial cells mechanisms which are specific for each strain have been
and prevent their apoptosis [42]. Immunomudulatory related to the internal beneficial effect of TP cells including
activity of L. casei largely depends on TLRs. L. casei conservation of interaction between host-microbes and
inhibits the development of colitis induced by dextran prevention of pathogens, regulation of mucous secretion

from the intestine cells, regulation of barrier function of Fermented foods containing beneficial bacteria have
epithelial cells, and secreting antibacterial substances and existed for thousands of years. Various fermented food
regulation of immune system of host [1,33,45]. products and beverages contain TPs as starter culture.
Besides health-promoting properties, they use organic
Fragile bones or osteoporosis is originated from hereditary substrates and generate several metabolites such as
and environmental factors. Osteoporosis is related to the organic acids, esters and carbonyl compounds which
mineral density of bone. Many literature have demon- induce flavor and aroma in fermented products as well
strated the positive effect of TP cells on bone mass. L. as formation of bioactive compounds [74,75]. The ability
paracasei and L. reuteri ingestion reduced the production of of TPs to use different substrates is strain-specific and
inflammatory cytokines (IL-1b and TNFa) and enhanced should be considered in formulation of probiotic fermen-
the production of osteoporo-tegerin (OPG) which carried a ted food products [76]. Some TP strains commercialized
potential protective effect against osteoclastogenesis in as starter cultures include L. acidophilus NCFM, L. rham-
animals. TP cells affect bone growth by the production nosus HN001 (DR20) and B. lactis HN019 (DR10)
of enzymes, vitamins or metabolites, as different vitamins (Danisco, USA), L. acidophilus LA-5 and B. lactis BB-12
such as vitamin D, K, C or folate are involved in metabolism (Chr. Hansen, Denmark), L. casei strain Shirota and B.
of calcium and are required for the formation of bone matrix breve strain Yakult (Yakult, Japan), L. fermentum VRI003
and bone generation. Mechanisms related to the bone (PCC) (Probiomics, Australia), L. rhamnosus R0011 (Insti-
accretion include the release of minerals from complexes, tut Rosell, Canada), Streptococcus oralis KJ3 (Oragenics,
enhancing the calcium intake by enterocytes, and anti- Inc., USA) and Saccharomyces cerevisiae and boulardii)
arthritic impact of TP cells [53]. In addition, TP can (Biocodex USA) [77]. Table 4 presents some TPs used
mitigate metabolic syndrome such as obesity. In this as starter culture in different foods and beverages. TPs
respect, probiotic Akkermansia muciniphila has gained an generate various bioactive compounds in food products
increasing attention in recent years [56]. It was announced such as vitamins, amino acids, organic acids, enzymes,
that generation of short chain fatty acids resulting in short chain fatty acids and bacteriocins which enhance
increase of glucagon-like peptide-1 (GLP-1) and glu- nutritional and safety status of food products. Table 5
cose-dependent insulinotropic polypeptide are responsible summarizes some bioactive compounds produced by
for antiobesity activity of A. muciniphila [57] Table 3 shows different TPs in various food matrices.
Selected in vivo/in vitro health evidences related to probi-
otic along with their mechanisms of action. There are evidences that incorporation of TPs into food
products increases antioxidant activity. Balakrishnan and
The administration of TPs with the aim of psychotherapy Agrawal [118] produced fermented milk with high anti-
is a novel field in applied microbiology. In this function, a oxidant activity (93%) from goat milk containing Pedio-
TP or its metabolite(s) is known as ‘psychobiotic’. TPs coccus pentosaceus. In another study, Cheddar cheese was
have the ability to confer health effects on the host brain. prepared using mixture of L. casei and L. plantarum. It was
The psychotropic mechanism of these cells has not been expressed that during ripening, the scavenging activity of
clearly understood. Apparently, TP cells enhance brain DPPH and hydroxyl radicals reached the maximum at the
health through a) enteric nervous system modulation 16th week, whereas reducing power activity reached at
(increasing the glial cells in gut), b) production of neu- 20th week. They attributed antioxidant activity to hydro-
ropeptides and neurotransmitter (i.e., serotonin, gluca- lysis of proteins and generation of peptides with antioxi-
gon-like peptide (GLP)), c) alteration and mediation in dant properties [70]. Similarly, in a mixed fermentation of
sitruin-1 (SIRT1) pathway that decrease Alzheimer’s blueberry pomace with L. rhamnosus GG and L. plan-
symptoms, and d) inhibiting the secretion of a-synuclein tarum-1, antioxidant activity increased as a result of
from enteroendorcine cells in gut whose accumulation increase in total phenols and flavonoids [119]. Further-
causes dopaminergic neurons formation and weakens the more, it has been reported that phenolic compounds
body in Parkinson’s patients [69,70]. increase survival of TPs in foods and they are capable
of improving metabolism and bioavailability (through
aglyconization process) of phenolic compounds through
True probiotic-external/in vitro effects (TP-E) A-ring and C-ring cleavage, dioxygenase-mediated C-ring
It can be inferred from scientific literature that true pro- cleavage, dehydroxylation and alkene hydrogenation
biotics (TPs) can exert several functionalities in external [120,121]. Accordingly, TPs enhance bioavailability of
matrices, mainly food matrices. Main functions of TPs in minerals (such as calcium, zinc, iron and copper) in food
food products are starter culture in fermented products products via various mechanisms including production of
(starter TP), detoxification of toxicants, flavor enhance- short chain fatty acids resulting in decrease of serum
ment of foods, increasing safety of food products and Parathyroid hormone and increase of mineral absorption
production and/or increasing the bioavailability of bioactive through their solubilization, generation of phytase, and
compounds such as vitamins, minerals and phenolic com- hydrolyze glycoside bonds of estrogenic foods [122]. In
pounds [71,72,73]. this regard, TPs such as L. reuteri, L. casei, L. gasseri, L.

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Table 3
Selected in vivo/in vitro health evidences related to probiotic along with their mechanisms of action
Microorganism strain (s) Site (s) of action Mechanism (s) Mode of assay Reference
True probiotics Lactobacillus plantarum Gastrointestinal tract Adhere to epithelial cells, Enhance In vitro (Cell cultures) & [54]
IL-10 production in colon. in vivo (mice)
Lactobacillus plantarum Brain Increase in dopamine and serotonin In vivo (ELS mice) [46]
concentration in the prefrontal cortex
enhance IL-10 production in colon
Lactobacillus helveticus Blood and brain Enhance IL-10 concentration in plasma, In vivo (Male rats) [55]
Increase the concentration of serotonin and
NE levels and BDNF expression in the hippocampus.
Lactobacillus rhamnosus Gastrointestinal tract Adhere to epithelial cells, Production of lactic acid In vitro (Cell cultures) [18]
Brain Improve the epithelil cell regeneration In vivo (Male mice)
Binding to aflatoxin B1,
Increase CORT concentration of Plasma, Increase GABA
receptors expression in cortical regions, Decrease GABA
receptor expression in amygdala, hippocampus and locus
coeruleus
Lactobacillus salivarius Gastrointestinal tract Secretion of low-molecular-weight In vivo (mice) [58]
bacteriocins
Lactobacillus reuteri Gastrointestinal tract Production of reuterin (3-hydroxypropionaldehyde In vitro [59]
Lactobacillus acidophilus and Gastrointestinal tract Binding to essencial elements for pathogens In vitro and in vivo [60]
Lactobacillus delbrueckii Vagina
Lactobacillus acidophilus Gut Production of lactacin and acidolin In vitro (cell culture) [14]
adherence to cholesterol In vivo (human) &
in virto (cell culture)
Lactobacillus casei Gut Inhibition of bacterial translocation In vitro (cell culture) [21,37,45]
Increase expression of MUC-gen In vivo (mice)

adherence to cholesterol
Current Opinion in Food Science 2020, 32:103–123
Inhibition of cholesterol micelles formation

Interaction with TLR receptors
Preventing activity of myeloperoxidase and interleukin
Improve the activity of NK cells
Lactobacillus bulgaricus Gut Adherence to cholesterol In vitro (cell culture) [31]
Lactobacillus paracasei Bone Reduction of inflammatory cytokines In vivo (Mice) [61]
Enhance osteopro-tegerin production
Bifidobacterium longum Gut Binding to aflatoxin B1 In vitro [19]
Bifidobacterium adolescentis Gut Binding to aflatoxin B1 In vitro [19]
Bifidobacterium animalis Gut Increase the intestine mobility In vivo (Human) [20]
Hydrolyse bile salts
Saccharomyces boullardii Gut Redistribution of T-cells In vitro [37]
plantarum, L. paracasei, L. acidophilus, B. longum and

Reference
Enterococcus faecium have been mentioned as an affective

strains in mineral absorption [53].
[62]
[48]
[49]
[50]
[51]
[28]
[63]
[64]
[65]
[66]
[67]
[68]
[67]
Furthermore, it has been stated that probiotics can extend
shelf-life and safety of food products through secretion of
in vitro (cell culture)
In vivo (Hamster) inhibitory metabolites (bacteriocins, organic acids, carbon

In vivo (Human)
In vivo (Human)
In vivo (Human)
In vivo (Human)
In vivo (Mouse)
Mode of assay
dioxide, ethanol, hydrogen peroxide and diacetyl) and

In vivo (Mice)
In vivo (Mice)
In vivo (Mice)
competition with pathogens [123,124].
In vitro
In vitro
In vitro
True probiotics can detoxify biotransform xenobiotics
and convert these compounds to less toxic metabolites
[125,126]. A great number of studies revealed that TPs
Antiproliferative and apoptosis effects against malignant cancer
can bind these toxicants and suppress their detrimental

Suppress the enhancement of alanine amino transferase and
effects. In this sense, binding and mitigation-ability of TP

Secretion of exopolysaccharides, Chelation of ferrous ions,
Suppressing the growth of H2S producing microorganisms
cells to mycotoxins (aflatoxin, fumonisin, ochratoxin A,

patulin, zearalenone), heavy metals, heterocyclic aro-
matic amines (HAAs) or polycyclic aromatic hydrocarbons
Enhance the concentration of Tregulatory cells
(PAHs), acrylamide, nitrosamine and pesticides residue

Secret vitamin E (a-tocopherol) and vitamin C
Secret vitamin E (a-tocopherol) and vitamin C
have been studied. The exact mechanism for removal of

Improve he barrier function of the intestin
toxins has not been elucidated, but binding of toxins to

Inhibits adherence of pathogenic cells
Improve the apoptotic of cancer cells
Inhibition of linoleic acid peroxidation

Decrease translocation of pathogens
Secret superoxide dismutase (SOD)
cell wall components is the most possible that is depen-

Stimulation of host immune system
dent on type of matrix, type and concentration of toxin

aminotransferase in the serum
and type of probiotic strain as well as its density [126]. It

has been reported that polysaccharides and/or proteins are
adherence to cholesterol
major functional components in binding of toxins [127].

Table 6 represents detoxification-ability of different tox-
Not determined
icants by probiotic strains.

Mechanism (s)
Despite advantageous impacts of true pobiotics in food

products, some deleterious effects such as bloating and
cells
flatulence, translocation and bacteremia and fungemia,

and possible transfer of antibiotic-resistance genes have
been detected for these microorganisms [23]. Probiotics
can decarboxylate free amino acids by decarboxylase and
Site (s) of action
Immune system
generate biogenic amines during fermentation of food

Gut & blood
products. Formation of cadaverine, putrescin, tyramine

Intestine
Intestine
and histamine has been reported in cheese, fermented

Spleen
Breast
Gut &
Liver
Gut
Gut
Gut
Gut
Gut
Gut
milk and meat products by various strains such as E.

faecium, L. reuteri, L. casei, L. rhamnosus, L. paracasei [141].
Consumption of these metabolites are correlated with
Leuconostoc mesenteroides
headaches, low blood pressure, heart palpitations, edema,

vomiting and diarrhea [142]. In the case of probiotic
Saccharomyces boulardii
Microorganism strain (s)
Bifidobacterium longum
Lactobacillus plantarum
Lactobacillus plantarum
Lactobacillus helveticus
Lactobacillus paracasei
Lactobacillus paracasei
Lactobacillus pentosus
Enterococcus faecalis
starter cultures, it usually takes a relatively long time to

Lactobacillus brevis
Bifidobacterium sp.
Lactococcus lactis
reach low pH values (slow acidification) during fermen-

tation process which is not acceptable from industrial
viewpoint due to decrease of output and increase of
microbial contamination [143]. Furthermore, components
produced during metabolism of probiotic cultures may
have negative effects on aroma and taste of the food
product which create off-flavor. For instance, the acetic
Table 3 (Continued )
Ruptured probiotic
acid produced by Bifidobacterium spp. can create a vine-

Ghost probiotic
gary taint in products [144], acetaldehyde produced by L.

acidophilus is reduced to ethanol or L. reuteri produces
other metabolites such as ethanol, acetate and carbon
dioxide instead of lactic acid that induce unpleasant
sensory properties in the product [145].

Table 4
Some true probiotics (TPs) used as starter culture in different fermented foods and beverages
Food type Probiotic strain Reference

Dairy-based
Kefir L. rhamnosus GG [78]
Fermented milk L. casei [79]
Yogurt L. casei [80]
Kefir S. cerevisiae KU200284 [81]
Cereal-based
Maize-based beverage L. paracasei LBC-81 and S. cerevisiae CCMA 0731 and CCMA 0732 [82]
Rice-based fermented beverage L. plantarum L7 [83]
Oat flour and barely malt beverage L. acidophilus NCIMB 8821, [84]
L. plantarum NCIMB 8826
L. reuteri NCIMB 11951
Ogi S. cerevisiae [85]
Fruit and vegetable-based
Coconut milk beverage L. plantarum [86]
Soursop juice P. pentosaceus Lbf2 [87]
Pomegranate juice L. bulgaricus and L. plantarum [88]
Prickly pears juice L. fermentum-ATCC 9338 [89]
Meat products
Dry fermented sausage L. casei [90]
Camel sausage L. lactis [91]
Dry fermented sausage (sucuk) L. rhamnosus [92]
Fermented sausage B. longum KACC 91563 [93]
Fermented fish sausage Lactobacillus spp. [94]
Table 5
Some bioactive compounds produced by true probiotics (TPs)
Type of bioactive compound Type of food Probiotic strain Reference

Exopolysaccharide (EPS) Quinoa-based fermented beverage L. plantarum Q823, L. casei Q11, and L. lactis ARH74 [95]
Fermented milk L. lactis [96]
Pico cheese L. citreum [97]
Low-fat akawi cheese L. plantarum [98]
Low-fat cheddar cheese L. plantarum JLK0142 [99]
Riboflavin Kefir-like cereal-based beverages L. plantarum M5MA1-B2 + kefir starters [100]
Folic acid Rice-based fermented beverage L. fermentum KKL1 [101]
B12 Mature coconut water L. plantarum DW12 [102]
Folate Fermented soy milk S. thermophilus TH-4, L. acidophilus LA-5, L. [103]
rhamnosus LGG, L. fermentum PCC, and L. reuteri RC-
14
Conjugated linoleic acid (CLA) Fermented soy milk L. plantarum P1201 [104]
Dahi L. acidophilus and L. casei [105]
Fermented milk B. animalis subsp. lactis [106]
Fermented milk L. rhamnosus + yogurt culture [107]
gamma-aminobutyric acid (GABA) Grape must beverage L. plantarum DSM19463 [108]
Raspberry juice L. brevis GABA100 [109]
Fermented adzuki bean milk L. rhamnosus GG [110]
Traditional fermented vegetable L. plantarum BC114 [111]
Bioactive peptides Yogurt L. casei [112]
Gouda cheese L. plantarum H4 and L. fermentum H9 [113]
Fermented milk L. casei Shirota and L. rhamnosus GG [114]
Fermented camel sausage L. lactis [91]
Short chain fatty acids (SCFAs) Soft cheese L. brevis C1Lb21, L. plantarum G1Lb5 and L. pentosus [115]
G4Lb7
Goat milk yogurt L. rhamnosus GG [116]
Skim milk L. rhamnosus GG ATCC 53013 [117]

Table 6
Detoxification-ability of different toxicants by probiotic strains
Probiotic strain Type of toxicant Conditions Removal (%) Reference

L. acidophilus Aflatoxin M1 Incubation of contaminated UHT 30.9 and 78.3% in first and [128]
skim milk (50.2 ppt) at 37 C second day, respectively
during three days
Kefir starter (2, 4, 6, 8 and Aflatoxin M1 kefir prepared from milk spiked 81.83 88.17% reduction for [129]
10%) and L. casei (0.1, with 500 pg AFM1 (48 hours Kefir starter and
0.3, 0.5, 0.7 and 0.9%) incubation) 69.19 81.98 reduction for L.
casei
L. acidophilus, Aflatoxin B1 maize grain with 50, 100, 200, The least reduction was [130]
L. brevis, L. casei, L. and 500 ng/g aflatoxin B1 were related to the maize
delbruekii, incubated at 37 C contaminated at 500 ng/g.
L. plantarum The most efficient organism
was L. plantarum
Mixed culture of Fumonisin B1 Maize meal was spiked A 56–67% and a 68–75% [131]
Streptococcus lactis Zearalenone separately with FB1 (0.5, 1.0, 2.0, reduction was observed for
and L. delbrueckii and 3.0 mg/g) FB1 and ZEA in the third and
ZEA (0.25, 0.5, 1.0, and 2.0 mg/g) fourth days, respectively.
and fermented for four days
L. paraplantarum CNRZ Fumonisin B1 Physicochemical and enzymatic Freezing and thawing, [132]
1885 Fumonisin B2 treated bacteria incubated at heating and acid treatment
S. thermophilus RAR1 25 C for 1 hour in corn infusion increased removal ability,
containing FB1 and FB2 (5 mg/ while enzymatic treatments
mL) decreased toxin binding
S. cerevisiae LALVIN Ochratoxin A Heat-treated cells or yeast walls Approximately all of the OTA [133]
Rhone 2056 additive in the OTA- was removed by heat-
contaminated red grape juice treated cell after 5 min while
(10 mg/L) for 2 hours for yeast wall, OTA
adsorption was totally
removed after 15 min
L. plantarum, L. brevis Ochratoxin A Viable and heat-treated cells More than 30% OTA was [134]
L. sanfranciscensis (1 and 5 mg dw/mL) in MRS removed by L. plantarum and
medium and PBS buffer L. sanfranciscensis.
conaining1000 ng/mL OTA at The result of PBS was similar
30 C for 24 hours to MRS medium. dead cells
reduced OTA almost twice
than viable cells
S. cerevisiae RC008 Zearalenone Yeast pellets was suspended in Binding percentage ranged [135]
S. cerevisiae RC009 PBS containing ZEA (1, 5, 10, from 48 to 87% and 41.1–6.7
S. cerevisiae RC012 20 and 50 mg/mL) and incubated at the lowest (1 and 5 mg/mL)
S. cerevisiae RC016 for 1 hour at 37 C. and the highest (20 and 50 m
Moreover, 107 cells were g/mL) ZEA concentrations,
exposed to gastrointestinal respectively. Exposure to
conditions (GIT) and then were GIT conditions significantly
transferred into the PBS increased RC009 and RC016
containing 10 mg/mL ZEA for 1 h ZEA binding ability
at 37 C
L. delbrueckii lactis Patulin 0.4 g of inactivated bacterial There was a reduction (47– [136]
22170, powder in 40 mL apple juice 80%) by all tested bacterial
L. rhamnosus 6133, L. containing 100, strains.
rhamnosus 20975, L. 150 and 200 mg/mL PAT, Maximum PAT removal was
rhamnosus 23139, incubation at 4, 30 and 37 C for occurred at 30 C. L.
L. rhamnosus 6224, L. 24 hours rhamnosus 6224 showed the
helveticus 6024, B. highest reduction (80.4%).
animails 6174, B. bifidum
6071, E. faecium 20420,
E. faecium 21605
L. lactis 6020, L. brevis Deoxynivalenol 108 CFU/mL bacterial cell in The strongest toxin binding [137]
1.12 T-2 toxin MRS broth containing 1 mg/mL ability was related to L.
L. casei 6103, L. of DON or plantarum 102
plantarum 102 T-2 toxin and incubation at 37 C
L. plantarum 8014 for 72 hours

Table 6 (Continued )
Probiotic strain Type of toxicant Conditions Removal (%) Reference
L. rhamnosus GG, L. Pb and Cd 1 g/L lyophilized bacteria in The highest binding was [138]
casei Shirota solution containing 50 and 10 m occurred at a pH close to
L. fermentum ME3, B. g/mL Pb and Cd, respectively, neutral. The most effective
longum 2C incubation at 37 C for 5 240 metal removers were B.
B. longum 46, B. lactis min longum 46, L. fermentum
Bb-2 ME3 and B. lactis Bb12
L. lactis subsp. cremoris,
L. lactis subsp. lactis
L. mesenteroides subsp.
cremoris
L. pseudomesenteroides
S. thermophiles, L.
bulgaricus
L. rhamnosus GG Cd and Pb 1 g/L bacterial biomass in ultra- P. freudenreichii shermanii [139]
L. rhamnosus LC705 pure water containing 50 and JS had the most efficient
P. freudenreichii 0.1 mg/mL Cd or Pb, removal of heavy metals
shermanii JS respectively (69.9%). Combination of
B. breve Bbi99/E8 strains resulted in lower toxin
binding than single strains
L. acidophilus Arsenic Incubation of bacterial cell (1 or Maximum As removal was [140]
2 mg dry wt/mL) in the water obtained at pH 7 within 3
solution (pH = 4 10) containing hours by enhancing bacterial
50 2000 mg/mL As for 4 hours concentration (2 times) As
removal was increased
1.16 1.66 times. By
increasing initial metal
concentration the amount of
free As reduced.
Pseudoprobiotic In addition, it can be used in the management of respira-

Probiotic bacteria may enter a dormancy state when tory infection and Helicobacter pylori [148] Since lactoba-
subjected to stressful (detrimental) environmental factors cilli and bifidobacteria are not resistant to harsh condi-
such as non-optimal temperatures, sharp pH or titrable tions, using Bacillus as spore-forming bacteria can open a
acidity alterations, organic toxins, high dosage of oxygen new way for development of probiotic foods with harsh
(for anaerobics), lack of nutrients, low water activities for conditions to vegetative cells such as low water activities,
example under high osmotic pressure as well as drying acidic pHs and the ones exposed to temperatures higher
conditions, freezing, and white light [63,65,146]. Dormant than 60 C [149]. This stability allows long-term storage of
probiotics, although are viable, but are not active and the probiotic food products without need of refrigeration.
rate of growth and/or metabolites generation is almost Dried date paste was used as a carrier for B. coagulans
stopped. Therefore, we called such probiotic as BC4 spores stored at aerobic and anaerobic conditions and
‘pseudoprobiotic’ (PP). This nomination arises from it was observed that no significant change occurred in
the basic that true or real probiotics must be viable and viability during storage of 45 days as well as after in vitro
active (Section ‘True probiotic’). PP might be nonspore- gastric transit [150]. Soares et al. [149] compared the
former or vegetative cell (PPV) (if survives) or spore- resistance of Bacillus, Bifidobacterium and Lactobacillus
former (PPS). Probiotics in mentioned states can possess strains incorporated into ‘requeijão cremoso’ cheese, pas-
different health advantages. PPVs might comprise two teurized orange juice and bread. The results showed that
advantages: 1) the same functionality as ‘ghost probiotic- Bacillus strains had the highest viability which maintained
intact cell’ (GPI) (Section ‘Ghost probiotic’), and 2) as above 80% at the end of shelf life. In agreement with
true probiotic after activation under optimized conditions these findings, B. coagulans ATCC 31284 and B. subtilis
in external matrices or entrance to the body (potential var. Natto ATCC 15245 were added to sausage formula-
function) (Section ‘True probiotic’). tion and it was figured out that spore count after cooking
process and cold storage was <106 CFU/g [151]. The
Certain species of Bacillus such as B. coagulans, B. subtilis, ability of Bacillus spp. to produce bacteriocins after the
B. clausii and B. licheniformis have been approved as PPS spore vegetation can be considered as natural preserva-
and recently been used in human foods as well as treat- tives in food products. Many of these compounds are
ment of intestinal disorders and urinary problems [147]. active against Gram-negative and Gram-positive food-
Bacillus clausii is used in the prevention of child diarrhea borne pathogens and even fungi that gives them superi-
and strengthening of immune system in allergic children. ority compared to other probiotic species [152].

Ghost probiotic including liver, spleen, and blood in mice by decreasing

Despite various scientific evidence demonstrating the the translocation and adherence of pathogenic cells into
beneficial health effects of true probiotic and to less the intestinal cells [155]. Heat-inactivated Leuconostoc
extent pseudoprobiotic, concerns have been increased mesenteroides cells prevented the spleen infection by
about their application due to some difficulties such as: pathogenic microorganisms through the stimulation of
a) the low viability of TP cells during the storage time the host immune responses (local and systemic) [156].
(and need of refrigeration in many cases) in food or feed GPs such as Lactococcus lactis improved the microbial
products which restricts their shelf life, and b) varied balance of the gastrointestinal tract by suppressing the
colonization pattern and durability in the gut, probable of growth of H2S producing microorganisms in the intestine
attainment of virulence gene from pathogenic organisms of a mouse, although the real mechanism of balancing
(one of the important factors for the functionality of TP action is still not understood. Indeed, it is important to
microbes is their capability to colonize and survive in the determine that inactivated L. lactis cells improve the
severe condition of the gut; in fact, true probiotics require microbial quality of the intestine with adherence to
to be specific strains), 3) probable acquisition of virulence epithelial cells or adhere to pathogens and inhibit the
gene by TP cells. Mentioned concerns have motivated adherence of pathogens to the intestine cells [157].
the researchers to prompt an alternative of ingesting
nonviable probiotic cells which confer beneficial effects Ghost-probiotics can inhibit the dysfunction of the intes-
to the host. It is revealed that the concentration of about tinal barrier. Inactivated intact cells of Saccharomyces
105–1014 nonviable cells per unit doses should be admin- boulardii (109 cells) retained the barrier function of the
istered for conferring the health benefits to food products mice intestine and decreased the pathogenic penetration
and the host. New researches have revealed that afore- into the intestine. These beneficial attributes of inacti-
mentioned cells can be used for the treatment of several vated cells was contributed to structural components of
health defects such as diarrhea, inflammation, liver dys- the yeast, probably the cell wall. The mechanism of
functions, and respiratory problems. In addition, they can action is due to cells structure rather than the metabolites
be used for reducing the serum cholesterol and lactose of the yeast. The mechanism of barrier improvement by
intolerance symptoms as well as regulating the immune mixed inactivated cells is stimulation of pro-inflammatory
system. The nonviable/inviable/inactivated/dead probi- cytokines secretion from epithelial cells [158].
otic cell is called ‘ghost probiotic’ (GP) here. The term
‘ghost’ is adopted form the reason that the ghost is not Colon and gastric cancers can be prevented by inviable
alive in our earth life! Ghost probiotic cell might be in the microbial cells. In a simulated in vivo trial, application of
forms of intact (GPI) or ruptured/tact (GPR). The rup- inactivated intact cells of L. paracasei and L. rhamnosus
tured cells that is produced via cell lysis or decay might be inhibited the proliferative activity and improved the
present as cell lysates, cell fragments or cell extracts. apoptotic of cancer cells [159].
Various procedures are applied for obtaining GP cells GPs can modulate the immune system of the host. It has
including ultraviolet (UV) rays (5 30 min), heat inactiva- been demonstrated that the formation of heat-shocked
tion (5 60 min, 60 121 C), and ionization radiation proteins during inactivation of L. plantarum enhanced the
(10 kGy). The mechanism of inactivation involves protein immunomodulation activity of this cells [160]. Heat-
denaturation, enzyme inactivation, nucleotide damage, inactivated L. casei (109 cells daily intake) improved
DNA rupture, and deformation of cell structure. For obtain- the immune system through an increase in the expression
ing GPI cells, inactivation methods should not destroy the of cytokines and transcription of TLRs [161]. In an in vivo
cell membrane and be able to retain the beneficial proper- experiment, administration of inactivated L. rhamnosus
ties of microorganisms [153]. So, optimizing the condition (109 cells daily intake) increased the leucocytes activity in
of each inactivation method is required for obtaining the the blood. This phenomenon might be due to the sensi-
maximum performance and functionality. For instance, tivity of immune cells to inactivated bacterial compounds
different inactivation conditions (temperature and time (i.e., cell wall) [162].
of heating) had various effects on the protective ability
of L. gasseri. Based on an in vivo experiment, L. gasseri Inviable and intact cells (GPI) can reduce the lactose
decreased a higher level of pathogenic organisms when intolerance symptoms in children. Rampengan et al. [20]
inactivated at 70 C for 30 min compared to those inacti- in an in vivo experiment showed the beneficial effect of
vated at 90 C for 5 min [154]. invible cells in the treatment of lactose intolerance. The
mechanism of treatment of lactose intolerance by the
Ghost probiotic-intact cell-internal/in vivo effects (GPI-I) administration of inviable cells is not yet clearly under-
Similar to true probiotics, heat inactivated probiotic cells stood and defined. Based on an in vivo experiment
can also protect the host against pathogenic microorgan- performed by Shin et al. [163], inviable B. longum cells
isms. L. plantarum (inactivated by a heating process) (108–109 cells daily intake) can decrease the serum cho-
prevented Salmonella enterica infection in several organs lesterol through some probable mechanisms.

GPs have the capability of reducing respiratory diseases acid-treated cells [170]. Also, Karazhiyan et al. [171] found
(asthma, colds, pneumonia, and allergic rhinitis). Con- that in the yogurt contaminated with various levels of
sumption of inviable L. paracasei cells (5 109 cells per AFM1 (100, 500 or 750 pg/mL), the highest adsorption
capsule) reduced the allergic rhinitis disease symptoms. It level of AFM1 to S. cerevisiae was obtained by acid-treated
has been revealed that the most important factor in the yeast (76.46 %) followed by heat-treatments (76.39 %) and
treatment of allergic rhinitis by a beneficial microorganism ultrasound-treatments (75.99 %) and viable yeast (74.2 %).
was the integrity of cells wall and not the viability of the cell. It seems that releasing monomers from polysaccharides,
In this respect, the beneficial effect of inviable cells was the decomposing the glycosidic linkages in monomers, protein
immune-regulatory effect of them [68]. Administration of denaturation and Maillard reaction as a consequence of acid
heat-inactivated Enterococcus faecalis FK-23 cells, modu- and heating conditions change cell wall structure and
lated the immune responses in hamsters suffer from allergic provide new binding sites [172]. Adsorption mechanism
rhinitis. This inactivated organism enhanced the concen- of L. plantarum 1.0665, L. plantarum ATCC 8014, L. plan-
tration of T-regulatory cells in the spleen. The T-cells tarum 806, L. casei ATCC 393, and L. acidophilus KLDS
weakened the Th1 and Th2 responses and inhibited the 1.0307 was investigated by [173]. It was observed that heat-
secretion of IgE and eosinophils activity [164]. Inactivated inactivated bacteria had more binding-ability compared to
L. pentosus cells (109–1010 cells/capsule) decreased the untreated ones because of change in the structure of cell
occurrence of the common cold in elderly adults through wall and providing more binding sites. The heat-inacti-
modulating the immune system and enhanced their resis- vated L. plantarum ATCC 8014 showed the highest adsorp-
tance to infection. The mechanism of the immunological tion capacity as a result of possessing the highest-specific
effect of this cell is not still determined [165]. surface and specific volume.
It has been demonstrated that the heat-inactivated cells Recently, incorporation of PPVs into edible films and coat-
(1.4 109) of L. brevis is an important agent in the improve- ings has gained an increasing attention. In these types of
ment of alcohol-induced liver diseases (in vivo). When the bioactive food packaging, the coating is eaten within the
liver is damaged, some enzymes including alanine amino food and therefore, the PPVs ingested can confer their
transferase and aminotransferase migrate to the serum. The health benefits [174]. The materials used for preparation
inactivated L. brevis cells suppress the increase of the of edible films and coatings include hydrocolloids, lipids
mentioned enzyme in the blood and triglycerides and and composites. Various probiotics such as L. rhamnosus
cholesterol in the liver. In fact, L. brevis cells inhibit the GG, L. plantarum, Lactobacillus pentosus, L. reuteri, L. aci-
overproduction of the mRNA belonging to tumor necrosis dophilus, L. casei and B. lactis BB-12 [175] have been used for
factor a, decrease the expression of sterol regulatory ele- this reason. In a study carried out by Ma et al. [176], probiotic
ment binding protein 1 and 2 and enhance the production of edible films composed of sodium alginate/sodium carboxy-
heat-shocked protein in the intestine [166]. methylcellulose showed the highest viability of Lactococcus
lactis and inhibited the growth of St. aureus for seven days.
Ghost probiotic-intact cell-external/in vitro effects (GPI-E) According to Sánchez-González et al. [177], cellulose-based
Emerging evidence indicates that probiotics in inactivated films containing L. plantarum inhibited the growth of
form exert helpful external functionalities (e.g., in food Listeria innocua during the first 8 days of storage at 5 C.
matrices). Detoxification-ability of toxicants is one of these
characteristics explored by few authors. It has been pointed Ghost probiotic-ruptured cells (GPR)
out that this action is a physical phenomenon involving Scientific data have demonstrated that cell free metabo-
bacterial cell wall and there is no need to living bacteria. lites of probiotics produced by live cells or excreted from
Piotrowska [134] stated that ochratoxin A removal-ability of ruptured bacteria have therapeutic effects on the host
probiotics is strain-specific and thermally killed cells [22,178]. Only the latter is regarded as GP.
showed higher ability. Yousefi et al. [167] figured out that
the cell viability was not required for the binding-ability of Several procedures are applied for obtaining bioactive
probiotics to polycyclic aromatic hydrocarbons (PAHs) and metabolite or cell extracts including rupturing the live
even acid-treated, heat-treated and ultrasonic-treated bac- organism using several processes (e.g., heating, sonication
terial cells showed more binding ability. Similarly, binding- individually or in combination) [163,179,180], stimulation
ability of probiotics to mycotoxins has been attributed to of live bacteria to secret the special metabolites [181],
non-covalent interactions such as dipole-dipole interac- extraction of soluble factors from in-viable probiotics
tions or van der Waals forces between cell wall and the [182], enzymatic hydrolysis [67]. These bioactive factors
toxin [168]. In this sense, bacterial cell wall plays a sub- are soluble components such as enzymes, polysaccharides,
stantial role and the main components responsible are teichonoic acids, short-chain fatty acids, proteins of cell
polysaccharides, peptidoglycan layer and teichoic acids surface, vitamins, organic acids, or glycerol derivatives
[169]. In consistent with these findings, binding capacity [22,66]. As these bioactives can confer the biological effect
of viable, heat- and acid-treated S. cerevisiae to AFB1 on the host in the absence of viable cells, thus, the viability
showed that the highest binding-ability was related to and activity of cells is not a crucial factor in this respect. In

addition, concerns associated with the administration of strains of L. plantarum showed anti-proliferative and
viable cells have been described as a health risk factor for apoptosis effects against malignant cancer cells [187].
premature infants due to dysfunction of the immune sys-
tem and patients with intestinal epithelial barrier dysfunc- It has been stated that the antioxidant activity of cell free
tion and immunosuppressing. Hence, the administration of extract is higher than whole cell culture. The antioxidant
metabolites secreted by viable cells or ruptured cells activity is attributed to the enzymatic and non-enzymatic
extracts may represent a safer alternative to prevent risk antioxidants. Some bacterial strains carry the ability of
associated with viable cells, which became a distinguished destruction of hydrogen peroxidase. Glutathione peroxi-
therapy for treating several diseases. Furthermore, these dase and glutathione reductase are two major enzymes
bioactives own some attributes that include distinct chem- that act as antioxidants in cells that scavenge reactive
ical structure and long shelf life (when administered in food oxygen species (ROS). In the respect of bioactives, the
products or nutritional supplements retain their capability most probable mechanism for justifying the antioxidant-
up to five years). Based on some in vitro and in vivo ability is the scavenging attributes of these compounds
experiments, probiotics cellular extracts or metabolites [179,188,189]. Lactobacillus and Bifidobacterium secret
possess several therapeutic activities such as a reduction some vitamins such as vitamin E (a-tocopherol) and
in blood pressure, antioxidant, antimicrobial, immunomod- vitamin C that play an important role in the antioxidant
ulatory, hypocholesterolemic, anti-obesogenic, and anti- activities. Also, mentioned microorganisms are capable of
cancer activity. Based on the majority of research studies, secreting superoxide dismutase (SOD) which is the
several bioactives obtained from Lactobacillus, Bifidobacter- innate cellular defense against the antioxidants and inhi-
ium, Streptococcus, and Faecalibacterium strains [22,66]. bits generation of toxic substances [190]. Additionally,
exopolysaccharides secreted by B. animalis and L. helve-
ticus exert antioxidant activity due to the presence of
Ghost probiotic-ruptured cells-internal/in vivo effects uronic acid in the polysaccharide structure [67,189,191].
(GPR-Ifao)
Despite aforementioned beneficial effects of bioactives It is worth to mention that traditional yogurt bacteria
(Section ‘Ghost probiotic-ruptured cells (GPR)’), the (Streptococcus thermophiles and Lactobacillus delbruechii ssp.
mechanisms of actions are not yet elucidated. However, bulgaricus) are not normally a good TP, because their cells
the therapeutic effects of bioactives is similar to viable is ruptured and killed via transferring through the GI,
cells, but the mechanisms of action might be different. especially by exposing to bile salts. However, they are a
Bioactive derived from GPs carry the anti-hypertensive good GPI in alleviation of lactose intolerance symptoms
capacity that can reduce the blood pressure. The exact when transform into small intestine; because by rupturing
mechanism of this capability has not been discovered; their cells at that site, the endocellular ß-galactosidase
however, blood pressure reduction could be as a result of enzymes are released and the entering lactose is digested
gut microbiota alteration, enhancing barrier function of in sensitive patients [192]. That is why fermented milks
the gut, reduction of inflammation responses, and modu- such as yogurt, in opposite to liquid milk, does not exhibit
lation activity of renal sympathetic nerve [183]. lactose intolerance disorder.
The hypocholesterolemic effect of bioactives belongs to

the activation of the receptor that reduces triglycerides Ghost probiotic-uptured cells-external/in vitro effects
through b-oxidation of fatty acids. Also, bioactives have (GPR-E)
the capability of production of protein 1 that stimulate the Probiotic metabolites impart their beneficial effects
lipolysis in adipocytes to improve protein kinase in mus- through modulation of the physiological and metabolic
cle tissue and liver leading to an increase of the metabo- parameters in the host. These low molecular weight com-
lism of lipids. However, the mechanism of hypocholes- pounds include short chain fatty acids, bacteriocins, pro-
terolemic by viable cells is different so that viable cell teins and amino acids, polysaccharides, peptidoglycans,
reduces the serum cholesterol by adsorption of choles- other cell surface molecules, nucleic acids, nucleotides,
terol in to the cell membrane or inhibiting reabsorption of plasmalogens, vitamins, antioxidants, and quorum sensing
bile acids [184,185]. signals [193]. According to Shenderov [194], these sub-
stances can be used in development of food supplements,
Anticancer activity of derived bioactives contributed to functional foods, drugs for chronic diseases, sport and anti-
the presence of macromolecules including nucleotides, aging foods. In addition to numerous health benefits men-
polysaccharides and protein with the molecular weight of tioned for these metabolites [23,195,196], there are some
>100 kDa and 50 100 kDa. Tan et al. [186] in an in vitro external effects that would be promising in designing and
experiment declared that L. plantarum I-UL4 produce development of high-quality and safe food products.
proteinaceous bioactive metabolites that prevented
breast cancer in human and improved the host health. Antibiofilm potential of metabolites produced by probio-
In another in vivo study, metabolites secreted from six tics have been reported in several studies. Biofilm

formation by pathogenic bacteria plays a pivotal role in for starter culture in fermented products [208]. The
development of infection. It is community of microorgan- presence of cell wall components of ruptured cells of L.
isms adhering together on a surface surrounded by extra- acidophilus such as peptidoglycans, teichoic acids, surface
cellular polymers which creates a barrier against antimi- proteins, and anionic and neutral polysaccharides as well
crobial agents. Zamani et al. [197] investigated antibiofilm as S-layers which can be consumed by yogurt starters
potential of L. plantarum cell-free supernatant (CFS) during fermentation has been reported [209].
isolated from Siahmazgi cheese against multidrug resis-
tance Pseudomonas aeruginosa, S. aureus and E. coli. Results Conclusion
showed that biofilm formation was suppressed by CFS as These existing definitions about probiotics emphasize on
a consequence of the presence of exopolysaccharides in the point that the probiotic must be alive and preferably,
CFS and quorum sensing inhibition. Similarly, Khiralla active. However, in the recent years, findings show that
et al. [198] studied antibiofilm effect of L. pentosus, L. inactivated, nonviable and even ruptured cells of probi-
plantarum and L. pentosus HG against Bacillus cereus and P. otic have beneficial effects on host on one hand, and some
aeruginosa. It was declared that 20 mL CFS prevented concerns about safety problems of live microbial cells on
biofilm formation by pathogenic bacteria. The mecha- the other hand, have caused incorporation of some new
nism of action was attributed to quorum sensing preven- terms to probiotic terminology such as paraprobiotics and
tion via secretion of organic acids, bacteriocins and pro- postbiotics. These terms focused on the healthful effects
biotic-derived metabolites. Moradi et al. [199] evaluated of inactive and nonviable probiotic cells in different
anti-listerial effect of metabolic byproduct of three pro- forms, are confusing and ambiguous due to several rea-
biotic strains (L. acidophilus LA-5, L. casei 431 and L. sons. We proposed new terminology to cover all healthful
salivarius) in vitro and in ground meat and whole milk and impacts of live probiotic cells and their derivatives in all
found that L. salivarius CFS was the most effective strain possible forms; including ‘true probiotic’ (= TP: viable
in this context and antibacterial effect was associated with and active microbial cells), ‘pseudoprobiotic’ (= PP: via-
pyrrolo [1,2-a] pyrazine-1,4-dione besides different ble but inactive cell in the forms of vegetative or spore),
organic acids. and ‘ghost probiotic’ (= GP: nonviable cell in the forms of
intact or ruptured). Mentioned types or states of probiotic
Ma et al. [200] prepared films composed of alginate- (comprising all probiotic area) along with their health
collagen or carboxymethylcellulose-collagen containing impacts and mechanisms of action, were tersely discussed
cell-free supernatant of L. lactis ATCC 11454 and eval- in present review. According to our new definition,
uated their antimicrobial properties against S. aureus ‘probiotic’ can be defined as ‘viable or inviable microbial
ATCC 6538 and E. coli ATCC 25922. The results cell (vegetative or spore; intact or ruptured) that is poten-
showed that 12 mg/mL CFS inhibited the pathogenic tially healthful to the host’. We hope this novel rendered
bacteria and can be considered as natural antimicrobial conceptualization provides a promising approach for all
packaging. Similar results have been obtained in other scientists and researchers to come to a global agreement
studies considering the application of cell-free superna- regarding a clear and efficient terminology comprising all
tant of probiotics against pathogenic bacteria [201–204]. states of probiotic area, while avoiding further distur-
Antimicrobial activity of probiotic metabolites arises bance and confusion in probiotic glossary.
from the presence of enzymes, bacteriocins, small mole-
cules and organic acids that demonstrate bacteriostatic Conflict of interest
and bactericidal effect against gram-negative and gram- The authors declare no conflict of interest.
positive microorganisms [205]. Consequently, they can
be applied as natural antimicrobials in food products. Acknowledgement
The support for this study provided by Shahid Beheshti University of
Exopolysaccharides (EPSs) have been described as Medical Sciences is gratefully acknowledged.
antioxidant agent in in vitro and in vivo models. EPSs
derived from B. animalis RH inhibited lipid peroxida- References and recommended reading
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Available online at www.sciencedirect.

Probiotic: conceptualization from a new approach

According to the proposed definition by FAO/WHO, probiotics Introduction

www.sciencedirect.com Current Opinion in Food Science 2020, 32:103–123

Table 1 probiotics was not justified. In 2001, Schrezenmeir and de

Current Opinion in Food Science 2020, 32:103–123 www.sciencedirect.com

www.sciencedirect.com Current Opinion in Food Science 2020, 32:103–123

The classes of ‘probiotic’ according to its functionality

Current Opinion in Food Science 2020, 32:103–123 www.sciencedirect.com

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Current Opinion in Food Science 2020, 32:103–123 www.sciencedirect.com

New concept of probiotics Zendeboodi et al. 109

Inhibition of cholesterol micelles formation

plantarum, L. paracasei, L. acidophilus, B. longum and

Enterococcus faecium have been mentioned as an affective

In vivo (Hamster) inhibitory metabolites (bacteriocins, organic acids, carbon

dioxide, ethanol, hydrogen peroxide and diacetyl) and

competition with pathogens [123,124].

can bind these toxicants and suppress their detrimental

effects. In this sense, binding and mitigation-ability of TP

cells to mycotoxins (aflatoxin, fumonisin, ochratoxin A,

(PAHs), acrylamide, nitrosamine and pesticides residue

have been studied. The exact mechanism for removal of

toxins has not been elucidated, but binding of toxins to

Inhibition of linoleic acid peroxidation

Secret superoxide dismutase (SOD)

cell wall components is the most possible that is depen-

dent on type of matrix, type and concentration of toxin

and type of probiotic strain as well as its density [126]. It

major functional components in binding of toxins [127].

icants by probiotic strains.

Despite advantageous impacts of true pobiotics in food

flatulence, translocation and bacteremia and fungemia,

generate biogenic amines during fermentation of food

products. Formation of cadaverine, putrescin, tyramine

and histamine has been reported in cheese, fermented

milk and meat products by various strains such as E.

headaches, low blood pressure, heart palpitations, edema,

starter cultures, it usually takes a relatively long time to

reach low pH values (slow acidification) during fermen-

acid produced by Bifidobacterium spp. can create a vine-

gary taint in products [144], acetaldehyde produced by L.

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Food type Probiotic strain Reference

Some bioactive compounds produced by true probiotics (TPs)

Type of bioactive compound Type of food Probiotic strain Reference

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Detoxification-ability of different toxicants by probiotic strains

Probiotic strain Type of toxicant Conditions Removal (%) Reference

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Pseudoprobiotic In addition, it can be used in the management of respira-

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Ghost probiotic including liver, spleen, and blood in mice by decreasing

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www.sciencedirect.com Current Opinion in Food Science 2020, 32:103–123

The hypocholesterolemic effect of bioactives belongs to

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www.sciencedirect.com Current Opinion in Food Science 2020, 32:103–123

Current Opinion in Food Science 2020, 32:103–123 www.sciencedirect.com

competition with pathogens [123,124].

and type of probiotic strain as well as its density [126]. It

major functional components in binding of toxins [127].