Contents lists available at ScienceDirect [616168]

Contents lists available at ScienceDirect
Trends in Food Science & Technology
journal homepage: www.elsevier.com/locate/tifs
Review
Postbiotics: An evolving term within the functional foods field
J.E. Aguilar-Toaláa, R. Garcia-Varelab, H.S. Garciac, V. Mata-Harod, A.F. González-Córdovaa,
B. Vallejo-Cordobaa,∗∗,1, A. Hernández-Mendozaa,∗,1
aLaboratorio de Química y Biotecnología de Productos Lácteos, Centro de Investigación en Alimentación y Desarrollo A.C., carretera a la Victoria KM 0.6, Hermosillo,
Sonora, 83304, Mexico
bCentro de Investigación y Asistencia en Tecnología y Diseño del Estado de Jalisco (CIATEJ), Unidad Noreste. Autopista Monterrey-Aeropuerto, Km 10. Parque PIIT. Vía
de Innovación 404, Apodaca, NL, 66629, Mexico
cUnidad de Investigación y Desarrollo de Alimentos, Instituto Tecnológico de Veracruz, M.A. de Quevedo 2779, Col. Formando Hogar, Veracruz, Veracruz, 91897, Mexico
dLaboratorio de Microbiología e Inmunología, Centro de Investigación en Alimentación y Desarrollo A.C., carretera a la Victoria KM 0.6, Hermosillo, Sonora, 83304,
Mexico
ARTICLE INFO
Keywords:
Bacteria-derived factorsCell lysatesFunctional foods
Health bene fitsABSTRACT
Background: It has been recognized that a number of mechanisms mediating the health bene fits of bene ficial
bacterial cells do require viability. However, new terms such as paraprobiotic or postbiotic have emerged to
denote that non-viable microbial cells, microbial fractions, or cell lysates might also o ffer physiological bene fits
to the host by providing additional bioactivity.Scope and approach: This review provides an overview of the postbiotic concept, evidence of their health
benefitsand possible signaling pathways involved in their protective eff ects, as well as perspectives for appli-
cations in foods and pharmaceuticals.Keyfindings and conclusions: Postbiotics refers to soluble factors (products or metabolic byproducts), secreted by
live bacteria, or released after bacterial lysis, such as enzymes, peptides, teichoic acids, peptidoglycan-derivedmuropeptides, polysaccharides, cell surface proteins, and organic acids. These postbiotics have drawn attentionbecause of their clear chemical structure, safety dose parameters, long shelf life and the content of various
signaling molecules which may have anti-in flammatory, immunomodulatory, anti-obesogenic, antihypertensive,
hypocholesterolemic, anti-proliferative, and antioxidant activities. These properties suggest that postbiotics may
contribute, to the improvement of host health by improving speci fic physiological functions, even though the
exact mechanisms have not been entirely elucidated.
1. Introduction
Several studies have provided plausible evidence of several me-
chanisms underlying the health-promoting e ffects of desirable gut
bacterial cells; these include modi fication of the gut microbiota, com-
petitive adherence to mucosa and epithelium, improvement of epithe-
lial lining barrier function and modulation of the immune system
(Bermudez-Brito, Plaza-Díaz, Muñoz-Quezada, Gómez-Llorente, & Gil,
2012 ;Vyas & Ranganathan, 2012 ). It is important to note that such
mechanisms are clearly dependent on the viability status of bacteria
(Sanders, 2009 ). However, recent evidence suggests that bacterial via-
bility is not necessary to attain the health-promoting e ffects, as not all
mechanisms nor clinical bene fits are directly related to viable bacteria.
Research performed by Lee, Zang, Choi, Shin, and Ji (2002) reportedsignificant immunoregulatory abilities of four di fferent Bifidobacterium
bifidum BGN4 fractions (i.e., whole-cell, cell free extracts, puri fied cell
wall and culture supernatant), where each fraction showed di fferent
patterns of immune reactions. Besides, fractions and extracts from Bi-
fidobacterium andLactobacillus spp., containing high levels of microbial
carbohydrates, have shown profound in vitro tumor-suppressing activ-
ities ( Choi et al., 2006; Raman, Ambalam, & Doble, 2016 ). Therefore,
new terms such as paraprobiotic and postbiotic have emerged whichimply that bacterial viability is not an essential requirement for health
benefits, providing a potential opportunity in the field of functional
foods.
Paraprobiotics, also known as “non-viable probiotics ”,“inactivated
probiotics ”or“ghost probiotics ”, refer to inactivated (non-viable) mi-
crobial cells, which, when administered in su fficient amounts, confer
https://doi.org/10.1016/j.tifs.2018.03.009
Received 10 June 2017; Received in revised form 21 February 2018; Accepted 7 March 2018∗Corresponding author.
∗∗Corresponding author.
1These authors have contributed equally to the direction of this work.E-mail addresses: vallejo@ciad.mx (B. Vallejo-Cordoba), ahernandez@ciad.mx (A. Hernández-Mendoza).Trends in Food Science & Technology 75 (2018) 105–114
Available online 09 March 2018
0924-2244/ © 2018 Elsevier Ltd. All rights reserved.
T

benefits to consumers ( Taverniti & Guglielmetti, 2011 ;Tsilingiri &
Rescigno, 2013 ). Despite of proven health bene fits of probiotics, non-
viable microbial cells may have safety advantages over probiotics by
reducing the risk of microbial translocation, infection or enhanced in-
flammatory responses, shown for some probiotics in consumers with
imbalanced or compromised immune systems ( Taverniti &
Guglielmetti, 2011 ). Bacterial cell inactivation may be achieved by
physical (mechanical disruption, heat treatment, γ- or UV irradiation,
high hydrostatic pressure, freeze-drying, sonication) or chemical (aciddeactivation) methods which may alter microbial cell structures or their
physiological functions; hence, bacteria become incapable of growing
and therefore retain the bene ficial health e ffects their viable form
provides ( de Almada, Almada, Martinez, & Sant'Ana, 2016 ).
On the other hand, the term postbiotics, also known as either me-
tabiotics, biogenics, or simply metabolites/CFS (cell-free supernatants);refers to soluble factors (products or metabolic byproducts) secreted by
live bacteria or released after bacterial lysis. These byproducts o ffer
physiological bene fits to the host by providing additional bioactivity
(Cicenia et al., 2014; Konstantinov, Kuipers, & Peppelenbosch, 2013;
Tsilingiri & Rescigno, 2013 ). Such soluble factors have been collected
from several bacteria strains; examples include short chain fatty acids
(SCFAs), enzymes, peptides, teichoic acids, peptidoglycan-derived
muropeptides, endo- and exo-polysaccharides, cell surface proteins,
vitamins, plasmalogens, and organic acids ( Konstantinov et al., 2013;
Oberg et al., 2011 ;Tsilingiri & Rescigno, 2013 ).
Despite the fact that the mechanisms implicated in the health ben-
eficial effects of postbiotics are not fully elucidated, scienti fic data have
provided evidence that postbiotics possess di fferent functional proper-
ties including, but not limited to, antimicrobial, antioxidant, and im-munomodulatory. These properties can positively a ffect the microbiota
homeostasis and/or the host metabolic and signaling pathways, thusaffecting speci fic physiological, immunological, neuro-hormone biolo-
gical, regulatory and metabolic reactions ( Sharma & Shukla, 2016;Shenderov, 2013).
Currently there is a vast available literature addressing funda-
mentals, therapeutic and technological aspects of viable “good ”bac-
teria. Most of this literature has focused on whole cells (alive or heat-killed cells) or its membrane/cell wall components ( Sánchez, Ruiz,
Guemonde, Ruas-Madiedo, & Margolles, 2012 ;Reid, 2016 ;Chua, Kwok,
Aggarwal, Sun, & Chang, 2017; Huang et al., 2017 ), and little attention
has
been paid for the intracellular soluble fraction (so called post-
biotics). Although the importance of postbiotics has relatively beenoverlooked, scienti fic evidence of their bene ficial health e ffects is pro-
gressively increasing ( Compare et al., 2017 ;Haileselassie et al., 2016;
Kareem, Ling, Chwen, Foong, & Asmara, 2014 ;Lee et al., 2004;
Nakamura et al., 2016 ;Tiptiri-Kourpeti et al., 2016 ), even though their
precise composition and underlying mechanisms are still under in-
vestigation. To the best of our knowledge, there are only a few reports
summarizing findings on postbiotics, mainly focusing on those from
different Lactobacillus species ( Cicenia et al., 2014 ;Konstantinov et al.,
2013 ;Patel & Denning, 2013 ;Shenderov, 2013 ;Tsilingiri & Rescigno,
2013 ). Hence, this review contributes with new and novel information
regarding other bacterial species and yeast reported as a source of
postbiotics, in vitro bioactive properties, in vivo health e ffects and po-
tential mechanisms involved in di fferent bioactivities. Additionally,
promising analytical tools useful for the detection, identi fication and
quanti fication of postbiotics, as well as current trends in food and
pharmaceutical applications, will be addressed.
2. Classes of postbiotics and their characteristics
Gut bacteria depend fully on their host to provide the necessary
nutrients that may promote microbiota growth. However, bacteria
produce small molecular weight metabolites during their lifecycle;
these compounds play a key role in regulating self-growth, develop-
ment, reproduction, encourage the growth of other bene ficial organism,
Fig. 1. Some postbiotics and their potential local and systemic positive e ffects in the host.J.E. Aguilar-Toalá et al. Trends in Food Science & Technology 75 (2018) 105–114
106

Table 1
In vitro and in vivo studies of postbiotics, their bioactivity and/or e ffects.
Bacteria Components Type of study Bioactivity or e ffect Method or tool used for
identification or isolation of
postbioticRef.
Bifidobacterium sp.,L. acidophilus, L. casei, L. delbrueckii
subsp. bulgaricus, L. gasseri, L. helveticus, L. reuteri,
S. thermophilesCell wall components and
cytoplasmic extractRAW 264.7 macrophage cell line Immunomodulation N.I. Tejada-Simon and Pestka(1999)
Faecalibacterium prausnitzii A2-165 (DSM 17677) Cytosolic fraction Caco-2 cells Immunomodulation N.I. Sokol et al. (2008)
L. plantarum K8 (KCTC10887BP) Lipoteichoic acids Human monocyte THP-1 cells Immunomodulation MALDI-TOF
Mass spectrometryKim et al. (2011)
B. bifidum BGN4, Cell free extracts, puri fied cell
wall and supernatantRAW 264.7 cells Immunomodulation N.I. Lee et al. (2002)
L. johnsonni La1, L. acidophilus La10 Lipoteichoic acids Human HT29 cell line Immunomodulation Octyl-Sepharose
®CL-4B column Vidal et al. (2002)
L. casei YIT 9029, L. fermentum YIT 0159 Lipoteichoic acids RAW 264.7 macrophages Immunomodulation Macro-prepHigh Q and Octyl-
Sepharose®CL-4B columnMatsuguchi et al. (2003)
L. paracasei B21060 Cell-free supernatants Dendritic cells from human peripheral blood
monocytesImmunomodulation N.I. Mileti, Matteoli, Iliev, and
Rescigno (2009)
L. paracasei B21060 Cell-free supernatants Human mucosa explant of colon Anti-in flammatory N.I. Tsilingiri et al. (2012)
Bacillus coagulans Cell wall components Human polymorphonuclear cells Immunomodulation and anti-
inflammatory e ffectN.I. Jensen, Benson, Carter,and Endres (2010)
L. rhamnosus GG Cell-free supernatants Human colonic smooth muscle cells Anti-in flammatory N.I. Cicenia et al. (2016)
L. acidophilus (ATCC 43121, ATCC 4356, 606), L. brevis
ATCC 8287, L. casei (YIT 9029, ATCC 393), L.
rhamnosus GGIntracellular content HeLa, MCF7, U-87, Hep G2, U2OS, PANC-1,
HT-29, WiDr, DLD-1 and CX-1 cellsAntiproliferative N.I. Choi et al. (2006)
L. casei ATCC 393 Sonicated-cell suspension Murine CT26 and human HT29 colon cancer
cells lineAntiproliferative N.I. Tiptiri-Kourpeti et al.(2016)
Strep. salivarius ssp. thermophilus ATCC 19258 and L.
delbrueckii spp. bulgaricus ATCC 11842Intracellular content In vitro Antioxidant N.I. Ou et al. (2006)
L. acidophilus KCTC 3111 , L. jonsonnii KCTC 3141 ,L .
acidophilus KCTC 3151 , L. brevis KCTC 3498Intracellular content In vitro Antioxidant N.I. Kim et al. (2006)
L. casei ssp. casei SY13 and L. delbrueckii ssp. bulgaricus
LJJIntracellular content In vitro Antioxidant N.I. Zhang et al. (2011)
7Bifidobacterium, 11Lactobacillus, 6Lactococcus, and 10
Strep. thermophilus strainsIntracellular content In vitro Antioxidant N.I. Amaretti et al. (2013)
B. longum SPM1207 Sonicated-cell suspension High-cholesterol rat model Hypocholesterolemic N.I. Shin
et al. (2010)
L. casei YIT9018 Polysaccharide-glycopeptide
complexesSpontaneously hypertensive rats and renal
hypertensive rats modelsAntihypertensive HPLC
and
1H NMRSawada et al. (1990)
L. amylovorus CP1563 Fragmented cells Obese mouse model Antiobesogenic N.I. Nakamura et al. (2016)
L. fermentum BGHV110 Cell lysate suspension Human hepatoma HepG2 cells Hepatoprotective N.I. Dinić et al. (2017)
Enterococcus lactis IITRHR1 and Lactobacillus acidophilus
MTCC447Intracellular content Cultured rat hepatocytes Hepatoprotective N.I. Sharma et al. (2011)
L. plantarum RG11, RG14, RI11, UL4, TL1 and RS5 Cell-free supernatants In vitro Antimicrobial N.I. Kareem et al. (2014)
N.I: Not identi fied; MALDI-TOF: Matrix-assisted laser desorption/ionization time-of- flight; HPLC: High performance liquid chromatography;1H NMR: Proton nuclear magnetic resonance spectroscopy.J.E. Aguilar-Toalá et al. Trends in Food Science & Technology 75 (2018) 105–114
107

cell to cell communication and protection against stress factors
(Hibbing, Fugua, Parsek, & Peterson, 2010; Netzker et al., 2015 ;Zhang
et al., 2010 ). Some of these soluble metabolites may be secreted by live
bacteria, or released after bacteria lysis, into the host environment,
offering additional physiological bene fits (Fig. 1) by modifying cellular
processes and metabolic pathways in the host. Although bene ficial at-
tributes of one speci fic bacteria (or a cocktail of bacteria) may di ffer
from one another, it is theoretically possible, using bioengineeringprocedures, to design recombinant probiotics capable to exert a variety
of bene ficial properties by expressing biologically copies of such
bioactive metabolites ( Chua et al., 2017; Singh, Mal, & Marotta, 2017 ).
In general, the postbiotics can be di fferentiated either by their ele-
mental composition, i.e., lipids ( e.g.butyrate, propionate, dimethyl
acetyl-derived plasmalogen), proteins (e.g. lactocepin, p40 molecule),
carbohydrates (e.g. galactose-rich polysaccharides, and teichoic acids),
vitamins/co-factors (e.g., B-group vitamins), organic acids (e.g., pro-
pionic and 3-phenyllactic acid) and complexes molecules such as pep-
tidoglycan-derived muropeptides, lipoteichoic acids ( Konstantinov
et al., 2013 ;Tsilingiri & Rescigno, 2013 ), or by their physiological
functions (See Table 1 ) which include immunomodulation, anti-in-
flammatory, hypocholesterolemic, anti-obesogenic, anti-hypertensive,
anti-proliferative, and antioxidant e ffects ( Nakamura et al., 2016;
Sawada et al., 1990; Shin et al., 2010 ).
In general, postbiotics possess several attractive properties such as
clear chemical structures, safety dose parameters, and longer shelf life(up to 5 years, when used as ingredient for foods and beverages or as
nutritional supplements) that are greatly sought out ( Shigwedha,
Sichel, Jia, & Zhang, 2014 ;Tomar, Anand, Sharma, Sangwan, &
Mandal, 2015 ). In addition, research performed by Shenderov (2013)
revealed that postbiotics have favorable absorption, metabolism, dis-tribution, and excretion abilities, which could indicate a high capacity
to signal di fferent organs and tissues in the host thus eliciting several
biological responses. Moreover, it has been demonstrated that post-
biotics can mimic the health e ffects of probiotics while avoiding the
necessary administration of live microorganisms, which may not alwaysbe harmless as previously proved by Tsilingiri et al. (2012) who found,
on a ex vivo assay, that some probiotics can induce a local in flammatory
response that resembles the response induced by Salmonella . Further-
more, theoretical concern associated with live probiotic bacteria ad-ministration (e.g., bloating and flatulence, probiotic-related transloca-
tion and bacteremia and fungemia, and possible transfer of antibiotic
resistance gene) have been described in case reports, clinical trials and
experimental
models, in patients with major (e.g., immunosuppression,
premature infants) and minor (e.g., impairment of the intestinal epi-thelial barrier, concurrent administration with broad-spectrum anti-
biotics to which the probiotic is resistant) risk factors for adverse events
(Doron & Snydman, 2015 ;Williams, 2010 ). Hence, the use of post-
biotics may represent a valid and safer alternative to avoids risk linkedto live probiotic bacteria, which confer to postbiotics certain practical
applicability and functionality to become a prominent strategy for
treating many diseases ( Haileselassie et al., 2016 ;Tsilingiri & Rescigno,
2013 ;Vieira, Fukumori, & Ferreira, 2016 ).
3. Methods used to obtain and identify postbiotics
In general, postbiotics have been obtained by using cell disruption
techniques, which include heat ( Lee et al., 2002 ;Tejada-Simon &
Pestka, 1999), and enzymatic treatments ( Li et al., 2012), solvent ex-
traction ( Kim et al., 2011 ), as well as sonication ( Amaretti et al., 2013;
Choi et al., 2006; Kim et al., 2006 ;Matsuguchi et al., 2003 ;Ou, Ko, &
Lin, 2006 ;Sharma, Singh, & Kakkar, 2011 ;Shin et al., 2010 ;Sokol
et al., 2008; Tiptiri-Kourpeti et al., 2016 ;Zhang et al., 2011).
Besides, additional extraction and clean-up steps such as cen-
trifugation, dialysis, freeze-dried and column puri fication have been
used to assist obtaining procedures ( Matsuguchi et al., 2003 ;Sawada
et al., 1990; Vidal, Donnet-Hugues, & Granato, 2002). For instance,Octyl-Sepharose
®CL-4B column was used for isolation of lipoteichoic
acid (LTA) from L. johnsonii La1 and L. acidophilus La10 ( Vidal et al.,
2002 ), and a combination of Macro-prep High Q and Octyl-Sepharose®
CL-4B column for isolation of LTA from L. casei YIT 9029 and L. fer-
mentum YIT 0159 ( Matsuguchi et al., 2003 ). On the other hand, dialysis
against distilled water in a molecular porous membrane tube for 1 d
was used to assist the extraction of polysaccharide-glycopeptide com-
plex obtained from L. casei YIT9018 ( Sawada et al., 1990 ); as well as
centrifugation in the extraction of intracellular content from variousBifidobacterium spp., Lactobacillus spp., Lactococcus spp., and Strepto-
coccus spp. strains ( Amaretti et al., 2013 ;Ou et al., 2006; Zhang et al.,
2011 ).
On the other hand, di fferent analytical approaches have been pro-
posed for postbiotic identi fication. The selection of instrumental tech-
nique depends on the analytical goals and the type of characterization(qualitative and/or quantitative) pursued. Accordingly, matrix-assisted
laser desorption/ionization time-of- flight (MALDI-TOF) mass spectro-
metry has been employed to identify LTA produced by L. plantarum K8
(KCTC10887BP) ( Kim et al., 2011); and HPLC and proton nuclear
magnetic resonance spectroscopy (
1H NMR) were used to identify and
characterize polysaccharide-glycopeptide complexes of Lactobacillus
casei YIT9018 ( Sawada et al., 1990 ).
Additionally, chromatography coupled with tandem mass spectro-
metry and Fourier transform ion cyclotron resonance mass spectro-metry with direct infusion, have been used to identify and characterize
metabolites (e.g. fatty acids, glycerolipids, purines, sphingolipids, oli-
gosaccharides) in biological samples ( Antunes et al., 2011 ;Kok et al.,
2013 ). However, techniques with high e fficiency and resolution, low
use of solvent and high sensitivity and accuracy such as Ultra Perfor-
mance Liquid Chromatography (UPLC) are greatly preferred ( Dong &
Guillarme, 2013). Recent studies show that UPLC will be indicated dueto superior separation and identi fication capacity of postbiotics; this
technique was used in the pro file identi fication of compounds (e.g.
glutathione reductase, amino acid transport protein) present in in-tracellular content of L. plantarum (Wang et al., 2016) and the in-
tracellular protein pro file (e.g. thioredoxin, phosphoglycerate kinase,
cysteine synthase) in L. mucosea LM1 ( Pajarillo, Kim, Lee, Valeriano, &
Kang, 2015 ). Similarly, Carbon-13 and
1H NMR, infrared, and electro-
spray ionization mass spectrometry techniques have been used to
characterize antifungal metabolites (e.g. phenol) produced by L. brevis
P68 ( Arasu et al., 2015). Moreover, changes in the protein pro file of
intracellular content of L. plantarum 423, when exposed to acid condi-
tions (pH 2.5), was determined by gel-free nanoLC-MS/MS proteomicsapproach ( Heunis, Deane, Smit, & Dicks, 2014). Similarly, the protein
profile of L. plantarum, after bile salt stress, was identi fied using two-
dimensional electrophoresis (2-DE) and liquid chromatography-mass
spectrometry analysis ( Hamon et al., 2011).
Despite that all these techniques could be used to detect, identify
and quantify postbiotics, more research about extraction protocols and
analytical tools are necessary to allow discovery and characterization of
novel postbiotics, but also to understand the mechanisms of action and
the signaling pathway modulation. However, further research is re-
quired to optimize media and culture conditions as well as the analy-
tical methods ( Anvari, Khayati, & Rostami, 2014 ). Once laboratory
scale optimization is achieved, it must be scaled-up and optimized toensure maximum postbiotic yield. It is important to note that clinical
trials are necessary to defi ne adequate dose and optimal administration
frequency ( Patel & Denning, 2013 ). Nevertheless, preclinical studies
should be performed prior to initiation of the clinical trial for better
selection of the postbiotic candidate. Similar to preclinical testing of the
microbial strains, the details of preclinical activities can vary according
to the type of postbiotic and the expected mechanism of action
(Sorokulova, 2008 ).J.E. Aguilar-Toalá et al. Trends in Food Science & Technology 75 (2018) 105–114
108

4. Postbiotic bioactivity and/or e ffects
In recent years, a considerable number of studies using in vitro (e.g.,
diverse cell lines) and in vivo (e.g.,obese and hypertensive rats) models
have been used to assess the potential bioactivity and/or health e ffects
of various postbiotics, including intracellular metabolites and cell wall
components, either as isolated structures or mixtures, such as extracts
or suspensions ( Robles-Vera et al., 2017 ). A summary is depicted in
Table 1.
In the majority of cases, postbiotics are derived from Lactobacillus
andBifidobacterium strains; however, Streptococcus andFaecalibacterium
species have also been reported as a source of postbiotics ( Konstantinov
et al., 2013 ;Tsilingiri & Rescigno, 2013). It has been proven that sup-
plementation with postbiotics reduces blood pressure which confers the
antihypertensive capacity to these compounds. The mechanism of this
protective e ffect on the endothelial function has not been elucidated;
however, this could be due to changes in the gut microbiota and itsmetabolic by-products; the restoration of the gut barrier function; and
the effects on endotoxemia, in flammation, and renal sympathetic nerve
activity ( Robles-Vera et al., 2017 ).
Studies show that the intestinal microbiota also impacts a wide
range of functions in the gastrointestinal tract including the develop-ment of the immune system, defense against pathogens, and in-
flammation ( Klemashevich et al., 2014 ). With the recent development
of the postbiotic concept, growing data, mainly obtained by the analysisof Lactobacilli strains, support the evidence that these bene ficial effects
may depend on secreted-derived factors ( Compare et al., 2017).
Immunomodulation is in fluenced by retinoic acid-driven mucosal-
like dendritic cells and their subsequent e ffects on regulatory T-cells in
vitro using L. reuteri 17938, by producing the anti-in flammatory cyto-
kine IL-10 ( Haileselassie et al., 2016). In related research, Sokol et al.
(2008) reported increased IL-8 levels in Caco-2 cells when exposed to
intracellular extracts and the supernatant fraction of F. prausnitzii . Ad-
ditionally, the data suggested that administration of cell-free super-natant, in a TNBS-induced colitis mice model, exerted an anti-in-
flammatory e ffect by increasing IL-10 and reducing IL-12, which
suggested that secreted metabolites induced this protective e ffect. The
study also revealed that the anti-in flammatory
effect was attributed to a
butyrate-independent pathway. Moreover, the proposed mechanismwas via NF- кB activation blockade; however, the active molecules in-
volved in this protective e ffect were not determined. Additional evi-
dence has indicated that the culture supernatant from Lactobacillus
paracasei B21060 can protect healthy tissue against the infl ammatory
properties of invasive Salmonella in a human mucosa explant of colon
(Tsilingiri et al., 2012 ), and that culture supernatant from Lactobacillus
casei DG can mitigate the in flammatory response in ileac and colonic
mucosa cultures obtained from post-infectious bowel syndrome patients(Compare et al., 2017).
On the other hand, Cicenia et al. (2016) reported that supernatants
from Lactobacillus rhamnosus GG collected at di fferent stages of growth
(middle and late exponential, stationary, and overnight) were able toprotect human colonic smooth muscle cells (HSMCs) against lipopoly-
saccharide (LPS)-induced myogenic damage. Maximal protective e ffect
was observed with supernatants of the late stationary phase, whichreverted 84.1% of LPS-induced cell shortening, and inhibited 85.5% of
acetylcholine-induced contraction and 92.7% LPS-induced IL-6 secre-
tion.
Postbiotics have also been described as pathogenic bacteria in-
hibitors against pathogens such as Listeria monocytogenes L-MS,
Salmonella enterica S-1000, Escherichia coli E−30 and vancomycin-re-
sistant Enterococci when using cell-free supernatants culture obtained
from L. plantarum RG11, RG14, RI11, UL4, TL1 and RS5 strains ( Kareem
et al., 2014 ). Furthermore, antioxidant activity in in vitro and in vivo
models exposed to speci fic exopolysaccharides (EPS) have been re-
ported. Xu, Shang, and Li (2011) observed that EPS from Bifido-
bacterium animalis RH displayed in vitro inhibition of lipid peroxidationand radical scavenging activity (hydroxyl and superoxide radicals).Moreover, Li et al. (2014) described that both crude culture extract and
purifi ed EPS, from Lactobacillus helveticus MB2-1, exhibited strong
scavenging capacity of three kinds of free radicals and chelating capa-
city to ferrous ion.
Among speci fic examples of intracellular bacterial enzymes found to
have bene ficial health e ffects
( e.g.antioxidant) include glutathione
peroxidase (GPx), superoxide dismutase (SOD), nicotinamide adeninedinucleotide (NADH)-oxidase and NADH-peroxidase ( Kim et al., 2006;
Li et al., 2012). On the other hand, some cell wall components havebeen associated to in vitro immunomodulatory properties including li-
poteichoic acids (LTA), and S-layer proteins ( Konstantinov et al., 2013).
Additionally, several postbiotics exhibit multiple bioactivities and can
simultaneously trigger multiple physiological pathways. For example,
some cell wall components, such as LTA, have been reported to exhibit
a variety of bioactivities including antitumor, antioxidant and im-
munomodulatory capacities ( Lebeer, Claes, & Vanderleyden, 2012; Yi,
Fu, Li, Gao, & Zhang, 2009 ). Besides, microbial membrane sterol-like
compounds have received special attention including plasmalogens,
known as endogenous antioxidants, which confer resistance to H
2O2-
induced oxidative stress in several Bifidobacterium strains ( Oberg, Ward,
Steele, & Broadbent, 2012; Oberg et al., 2011 ).
According to other works, SCFAs produced by gut microbiota act as
signaling molecules improving regulation of lipid metabolism, glucose
homeostasis and insulin sensitivity, through the activation of receptors
such as G protein-coupled receptors (GPRs), thus contributing in the
regulation of energy balance while maintaining metabolic homoeostasis
(Canfora, Jocken, & Blaak, 2015 ;Kimura et al., 2013). Speci fic SCFAs
(e.g. butyrate, acetate and propionate) have also proven to contributeto plasma cholesterol homeostasis in rodents and humans ( den Besten
et al., 2013 ).
The hepatoprotective role of postbiotics has also been described. In
this sense, cell lysate suspension from Lactobacillus fermentum BGHV110
reduced acetaminophen-induced hepatotoxicity in HepG2 cells by ac-tivating the autophagy in HepG2 cells through PINK1 signaling
pathway ( Dini ćet al., 2017). In a related work, Sharma et al. (2011)
reported the hepatoprotective e ffect of intracellular content from En-
terococcus lactis IITRHR1 and Lactobacillus acidophilus MTCC447 against
acetaminophen-induced hepatotoxicity in a cultured rat hepatocytesmodel. Additionally, the authors found that postbiotics have the po-
tential to restore the glutathione levels and to reduce levels of oxidative
stress biomarkers.
Additionally, postbiotics may also be produced by yeast metabolic
activity. Canocini et al. (2011) reported that culture supernatants, ob-
tained from Saccharomyces boulardii , improved wound healing capacity
and epithelial cells migration via the activation of α2β1 integrin col-
lagen receptors using in vitro models. Moreover, the authors observed
that daily oral administration of such culture supernatant to mice for 7
days improved enterocyte migration along the crypt-villus axis in small
intestinal tissues, as examined by immunostaining. The data suggested
that these supernatants could improve the repair process of intestinal
epithelium after damage (intestinal restitution) and possess potential
therapeutic applications in a wide variety of gastrointestinal disorders.
Bioactive properties discovered in postbiotics suggest that these
compounds may contribute in the improvement of host health by pro-
viding better speci fic physiological e ffects, through the combined e ffect
of postbiotics, other biological metabolites and the live microorganism.This synergy may result in more e ffective protective qualities ( Thanh,
Loh, Foo, Bejo, & Azhar, 2010 ).
4.1. Potential mechanism involved in postbiotic bioactivity
Despite the previously stated health bene ficial effects of postbiotics,
the mechanisms of action are not fully understood.
The protective e ffect of postbiotics could be caused by compounds
that mimic the bene ficial and therapeutic e ffects
of probiotics, evenJ.E. Aguilar-Toalá et al. Trends in Food Science & Technology 75 (2018) 105–114
109

though the mechanisms of action may vary. For instance, hypocholes-
terolemic mechanisms of probiotic bacteria, include the inhibition on
intestinal cholesterol adsorption and/or the suppression of bile acid re-
absorption ( Ogawa, Kadooka, Kato, Shirouchi, & Sato, 2014 ). On the
other hand, postbiotics have been reported to activate peroxisomeproliferator-activated receptor which causes fatty acid β-oxidation to
reduce triglycerides ( Nakamura et al., 2016). Also, postbiotics were
found to activate nucleotide-binding oligomerization domain-con-
taining protein 1 that induce cell-autonomous lipolysis in adipocytes
(Chi et al., 2014 ), to decrease the enzyme activity of hepatic 3-hydroxy-
3-methylglutaryl-CoA synthase (HMGCS) and 3-hydroxy-3-methylglu-taryl-CoA reductase (HMGCR), and to increase the AMP-activated
protein kinase in liver and muscle tissue ( den Besten et al., 2013 ), thus
promoting lipid metabolism and dyslipidemia control.
Furthermore, it has been found that muramyl dipeptide-based
postbiotics may reduce adipose in flammation and glucose intolerance
via a nucleotide-binding oligomerization domain-containing protein 2
and though the activation of transcription factor IRF4 in obese mice
(Cavallari et al., 2017 ). Moreover, this postbiotic reduced hepatic in-
sulin resistance in obesity and low-level endotoxemia.
Postbiotics have also proven an antiproliferative speci fic activity
against colon cancer cells; most likely related to the activation of pro-apoptotic cell death pathways through regulation of immune responses
(Tiptiri-Kourpeti et al., 2016). It has been reported that postbiotics
obtained from Lactobacillus strains might decrease metalloproteinase-9
activity inhibiting colon cancer invasion ( Escamilla, Lane, & Maitin,
2012 ). To elucidate the active compound responsible for this e ffect, the
postbiotic (cell-free supernatant) was fractionated based on molecular
weight ranges; it was found that the active inhibitory fraction corre-
sponded to the > 100 kDa and 50– 100 kDa compounds, suggesting that
the inhibitory compound may be a macromolecule such as a protein,nucleic acids, or polysaccharides.
Some studies ( Kullisaar et al., 2002 ;Lin & Chang, 2000 ;Saide &
Gilliland, 2005 ) determined that cell-free extracts from lactic acid
bacteria may exhibit signi ficantly higher antioxidant capacity than
whole cell cultures; suggesting that the antioxidant capacity could beattributed to both enzymatic and non-enzymatic intracellular anti-
oxidants. Furthermore, Bifidobacterium infantis ,Bb. breve ,Bb. ado-
lescentis , and Bb. longum are capable of degrading hydrogen peroxide by
producing NADH peroxidase ( Shimamura et al., 1992 ). It has been re-
ported that glutathione peroxidase and glutathione reductase are twoimportant antioxidant enzymes that protect cells from oxidative da-
mage by scavenging reactive oxygen species (ROS). However, the an-
tioxidant capacity and antioxidant enzyme activity could not be posi-
tively correlated for all strains, which indicates that other compounds
may be involved in the antioxidant e ffect ( Kim et al., 2006 ). In this
sense, it has been proposed that the antioxidant capacity of the in-tracellular fraction of di fferent strains of Lactobacillus positively corre-
lates
with the cellular content of reduced glutathione, an important
non-enzymatic antioxidant that plays an essential role in maintaining
intracellular redox state ( Yoon & Byun, 2004). The antioxidant activity
of such non-enzymatic postbiotic could be caused by its ROS and re-active nitrogen species scavenging properties ( Amaretti et al., 2013;
Zhang et al., 2011 ).
Additionally, exopolysaccharides have antioxidant activity ( Pan &
Mei, 2010 ;Xu et al., 2011). Some studies suggest that this activity is
attributed to elevated contents of uronic acid. Some authors ( Li et al.,
2014 ;Liu et al., 2011 ;Xu et al., 2011 ) proposed that uronic acid plays
an important role in the antioxidant properties of polysaccharides from
B. animalis RH and L. helveticus MB2-1. Similarly, Li et al. (2014) re-
ported a polysaccharide from L. helveticus MB2-1, with a greater pro-
portion of negatively charged uronic acid that produced a higher che-
lating capacity ferrous ion. Ferrous ions are involved in the formation of
free radicals by the Fenton and Haber-Weiss reactions, which generate
reactive hydroxyl radicals. In a related research, a direct relationship
between uronic acid content and the radical scavenging capacity of teapolysaccharide was reported ( Chen, Zhang, & Xie, 2004 ;Chen, Zhang,
Qu, & Xie, 2008 ).
It has been suggested that the immunomodulatory and anti-in-
flammatory capacities of postbiotics are mediated by the inhibition and
induction of the immune systems in various animal models. It has been
found that postbiotics regulate the production of the cytokine response
and Th1 pathway inhibition ( Jensen et al., 2010 ;Sokol et al., 2008).
The antimicrobial activity of postbiotics may be attributed to the pre-sence of several known and unknown antimicrobial compounds, usually
including but not limited to bacteriocins, enzymes, small molecules,
and organic acids, which exhibit bacteriostatic or bactericidal proper-
ties against both gram-positive and gram-negative microorganisms
(Kareem et al., 2014).
All these properties suggest that postbiotics may contribute to the
improvement of the host's health status by providing better and speci fic
physiological e ffects, although the exact mechanisms remain to be
elucidated.
5. Food and pharmaceutical potential applications of postbiotics
The increased knowledge of functional foods has led to the devel-
opment of a new generation of health products, including those con-
taining probiotics. However, one issue related to the application of
probiotics is the occurrence of antibiotic resistance genes in some
probiotics strains, as they have the potential to pass the antibiotic re-
sistance genes to pathogenic bacteria through horizontal gene transfer
(Imperial & Ibana, 2016). Another main concern associated with the
probiotic product formulations (i.e., pharmaceutical and commercial
food-based products) is maintaining bacteria viability during product
manufacturing and storage, since the viability of probiotics organism in
a delivery system (i.e., pharmaceutical formulations and commercial
food-based products) could be a ffected by di fferent variables, including
interactions with other microbial species present, final acidity of the
product, water activity, temperature, availability of nutrients, growth
promoters and inhibitors, inoculation level, fermentation time, dis-
solved oxygen, and formulation process procedures such as freeze
drying, spray drying or freeze concentration ( Shah, 2016 ). Further-
more, discrepancies between stated and actual probiotic levels incommercial
products for both human and veterinary use have pre-
viously been reported ( Weese & Martin, 2011). Hence, this lack of
probiotic stability may compromise the expected health bene fits pro-
vided by probiotic products.
In contrast, postbiotics are supposed to be more stable than the
living bacteria they are derived from ( Venema, 2013). Phister,
O'Sullivan, and McKay (2004) reported that peptides with antimicrobial
properties, namely bacilysin and chlorotetaine, produced by Bacillus sp.
strain CS93 are water soluble and active over a wide pH range, which
could allow their application in a wide variety of food products. Fur-
thermore, the use of selected phytase-producing lactic acid bacteria as
starters for breadmaking have been reported as good alternatives for
preparing whole wheat bread with low phytate content ( Palacios,
Haros, Sanz, & Rosell, 2008). However, previous studies have shownthat an advanced hydrolysis of phytate is achieved by increasing the
fermentation time and/or decreasing the pH during whole wheat dough
fermentation; conditions that not only may a ffect the sensory attributes
of the final products, but also could in fluence the synthesis of phytate-
degrading enzymes by microorganisms ( Haros, Bielecka, Honke, &
Sanz, 2008 ). With the use of purifi ed phytate-degrading enzymes, these
compounds would not be a serious issue. Another major advantage of
postbiotics is their favorable safety pro file, as there is no need for the
uptake of billions of living microbes ( Shigwedha et al., 2014 ). Ad-
ditionally, postbiotics can be applied in a controlled and standardizedway, whereas, in the case of the application of living bacteria, the level
of the active structure in the intestine is dependent on the number and
metabolic activity of the respective strain ( Gabriele, 2016 ). Thus, se-
lected soluble factors from speci fic bacteria may become a class ofJ.E. Aguilar-Toalá et al. Trends in Food Science & Technology 75 (2018) 105–114
110

bacterial biological strategy for treating many diseases; however, a big
challenge is translating scienti fic knowledge into commercial applica-
tions and thus bridging science and industry.
Currently, cell-free preparations obtained from the metabolic pro-
ducts of di fferent bene ficial bacteria have been introduced with po-
tential pharmaceutical applications in the prevention or treatment of
diseases ( Klein et al., 2013). For instance, Colibiogen®(Laves-Arznei-
mittel GmbH, Schötz, Switzerland) a commercially protein-free filtrate
derived from cultures of Escherichia coli (strain Laves 1931), containing
amino acids, peptides, polysaccharides and fatty acids, has been shownto be e ffective in inhibiting in vitro both antibiotic resistant and sensi-
tive Salmonella isolates ( Zihler et al., 2009), in the amelioration of
murine colitis ( Konrad et al., 2003 ), and to signi ficantly reduce skin
lesions in patients with polymorphous light eruptions ( Przybilla,
Heppeler, & Ruzicka, 1989 ). Hylak
®Forte (Ratiopharm/Merckle GmbH,
Germany), a bacteria-free liquid containing metabolic products ( e.g.
SCFA, lactic acid an other non-identi fied metabolites) from E. coli DSM
4087, Streptococcus faecalis DSM 4086, L. acidophilus DSM 414, and L.
helveticus DS 4183, has proved to be e ffective in the management of
salmonellosis in infants ( Rudkowski & Bromirska, 1991) and in the
treatment of intestinal dysbacteriosis of patients with chronic gastritis
(Omarov, Omarova, Omarova, & Sarsenova, 2014 ). Besides, has shown
to signi ficantly reduce the incidence and the severity of the radiation-
induced diarrhea in radio-oncology patients ( Timko, 2010 ). CytoFlora®
(BioRay Inc., Laguna Hills, CA, USA), is a preparation of micronized cellwall lysates of L. rhamnosus, B. bi fidum, L. acidophilus, B. infantis, B.
longum, S. thermophilus, L. plantarum, L. salivarius, L. reuteri, L. casei, L.bulgaricus, L. acidophilus DDS-1 and Lactobacillus sporogenes , that has
been used to correct intestinal dysbiosis, promote a balanced immuneresponse, and improve symptoms in autistic children ( Ray, Sherlock,
Wilken, & Woods, 2010). Another commercial product is Del-ImmuneV
®(Pure Research Products, LLC, Boulder, CO, USA), a US Food and
Drug Administration-registered formulation containing muramyl pep-
tides, amino acids and DNA fragments of L. rhamnosus V (DV strain),
has shown to signi ficantly reduce the severity of gastrointestinal dis-
tress in children with Autism Spectrum Disorder when administrated as
blend of Del-Immune V®plus probiotics ( West, Roberts, Sichel, & Sichel,
2013 ).
It has also been reported that probiotic cell lysates may contain
hyaluronic acid, sphingomyelinase, lipotechoic acid, exopolysacchar-ides, peptidoglycan, lactic acid, acetic acid and/or diacetyl, which
provide broad biologic activity that can be harnessed to provide skin
benefits such as improving atopic eczema, atopic dermatitis, healing of
burn and scars, skin-rejuvenating properties, improving skin innateimmunity and protecting against photodamage ( Kober & Bowe, 2015;
Lew & Liong, 2013). According to this, many studies and patents havebeen published on the use of probiotics extracts to development of
personal care products including oral, underarm (deodorants and an-
tiperspirants) and skin products ( Callewaert, Lambert, & van de Wiele,
2017 ;Coronado-Robles, 2016 ;Holz et al., 2017; Huang & Tang, 2015;
O'neill & McBain, 2015; Ouwehand, Lahtinen, & Tiihonen, 2016).
Although several foods are naturally abundant in postbiotics (e.g.,
yogurt, kefi r, pickled vegetables and kombucha) or their precursors
(Chaluvadi, Hotchkiss, & Yam, 2016), some postbiotics have been in-
tentionally applied to certain foods rather than considering its in situ
production by the producer strain. For instance, cell-free supernatantfrom L. pantarum YML007 has been explored as biopreservative on
soybeans grains ( Rather et al., 2013 ). EPS containing rare sugars have
been investigated for new applications in food industry due to their role
in the physicochemical (viscosifying, stabilizing, or water-binding ca-
pacities) and sensorial (palatability) characteristics in the final food
products; however, with the exception of dextran, EPS from lactic acidbacteria have not yet been commercially exploited as food additives
because of their low yields ( Torino, de Valdez & Mozzi, 2015). Nisin, a
lantibiotic produced by speci ficLactococcus lactis subsp . Lactis strains, is
the only bacteriocin approved for use as a food preservative. Examplesof food products with Nisin include canned soups, ice for storing fresh
fish, baby foods, baked goods, mayonnaise and dairy products, espe-
cially cheeses ( Chen & Hoover, 2003 ). With the above in mind, the use
of foods as postbiotics delivery system seems to constitute a field with
several opportunities, but also with big challenges.
Improving animal health is another promising field of application,
since it has been reported that postbiotics may infl uence growth per-
formance of hens, broilers and piglets ( Choe, Loh, Foo, Hair-Bejo, &
Awis, 2012 ;Kareem, Loh, Foo, Akit, & Samsudin, 2016a ;Loh, Choe,
Foo, Sazili, & Bejo, 2014 ;Loh, Thu, Ling, & Bejo, 2013; Thu, Loh, Foo,
Yaakub, & Bejo, 2011 ). In this sense, a recent research performed by
Kareem et al. (2016a) determined that broilers fed with postbiotics
produced by L. plantarum developed signi ficantly
higher final body
weight and total weight gain than broilers fed with a basal diet without
postbiotics. Also, postbiotics were found to increase signi ficantly duo-
denal and ileal villus height. Moreover, the combination of postbioticand inulin may enhance growth performance, improve the final count
of bene ficial bacteria and reduce the presence of Enterobacteria and E.
colipopulations (Kareem, Loh, Foo, Asmara, & Akit, 2016b ). In a similar
study, Loh et al. (2014) found a signi ficantly daily higher egg produc-
tion of hens when treated with a postbiotic supplement.
Some reports proposed that the administration of postbiotics from L.
plantarum exerted a positive e ffect on growth performance and protein
digestibility, as well as reduced diarrhea incidence. Given the collecteddata, authors suggested that postbiotics altered the mucosal archi-
tecture in terms of longer villi and enhanced animal growth perfor-
mance. Also, the use of postbiotics modi fied the intestinal microbiota,
improved the population of protective bacteria ( e.g., Lactobacillus and
Bifidobacterium ) and enhanced the health status of test animals. In ad-
dition, postbiotics could contain antimicrobial substances produced byLactobacillus strains, which may provide nutrients and enhance phy-
siological activities in the animal gut, resulting in absorption im-provement and decreased intestinal pathogenic bacteria. Postbioticscan be considered potential contributors as feed additives to achieve
higher productivity and better animal health ( Loh et al., 2014 ).
Postbiotics may be useful as microbial-free food supplements, fer-
mented functional foods, and prophylactic drugs, as complementary
treatment for several diseases ( Chaluvadi et al., 2016 ). Postbiotics re-
search represents an opportunity not only to understand their me-chanisms of action in detail but also to develop new therapeutic stra-
tegies for health improvement ( Klemashevich et al., 2014 ;Shenderov,
2013 ).
On the other hand, the advent of modern techniques for genetic
manipulation has created opportunities for the development of novelbioengineered probiotic strains capable to produce metabolites targeted
to the prevention and treatment of several diseases ( Paton, Morona, &
Paton, 2012 ;Sola-Oladokun, Culligan, & Sleator, 2017 ). For instance,
genetically modi fied lactic acid bacteria has been used for intestinal
delivery of antimicrobial peptides ( Amalaradjou & Bhunia, 2013 ), an-
giotensin-converting enzyme inhibitory peptides ( Yang et al., 2015),
cancer-suppressing peptide KiSS1 ( Zhang et al., 2016), fusion protein of
HSP65 with tandem repeats of P277 ( Ma et al., 2014) and glutamic acid
decarboxylase and IL-10 cytokine ( Huibregtse et al., 2012 ;Robert et al.,
2014 ), thus providing promising strategies for the treatment of enteric
infections, hypertension, colon carcinoma and intestinal infl ammatory
and autoimmune diseases such as Type 1 diabetes mellitus. Despite of
promising
biomedical application of recombinant probiotic metabo-
lites, important safety and regulatory aspects still need to be addressedin depth.
6. Conclusions
Postbiotics comprise metabolites and/or cell-wall components, se-
creted by live bacteria or released after bacterial lysis, with demon-
strated bene ficial activities in the host. Postbiotics may induce anti-
inflammatory, immunomodulatory, anti-obesogenic, anti-hypertensive,J.E. Aguilar-Toalá et al. Trends in Food Science & Technology 75 (2018) 105–114
111

hypocholesterolemic, anti-proliferative, and antioxidant activities.
These properties suggest that postbiotics may contribute to the im-
provement of host health by providing speci fic physiological e ffects,
even though the exact mechanisms have not been fully elucidated.Additional e fforts are necessary to allow discovery and characterization
of new postbiotics; which may contribute to the understanding of thesignaling pathway modulation. Novel research will allow the genera-
tion of detailed information to insure stability during the manu-
facturing processes of postbiotic products and their e fficacy. Special
attention should be paid in the development of uniform and stringentlydefined culture procedures in order to eliminate possible variability of
postbiotics production, since uncontrolled environmental factors canwell change metabolism and undergo unexpected transient variability.
Beside, well-designed randomized placebo-controlled human/clinical
intervention trials along with metabolomics studies must be conducted
looking to support health claims of postbiotics supplementation.
Acknowledgement
The authors wish to thank the National Council for Science and
Technology (CONACYT) of Mexico for the graduate scholarship for
Aguilar-Toalá and for the research grant CB-2014-01 (230338).
References
de Almada, C. N., Almada, C. N., Martinez, R. C. R., & Sant´Ana, A. S. (2016).
Paraprobiotics: Evidences on their ability to modify biological responses, inactivation
methods and perspectives on their application in foods. Trends in Food Science &
Technology, 58 ,9 6–114.
Amalaradjou, M. A., & Bhunia, A. K. (2013). Bioengineered probiotics, a strategic ap-
proach to control enteric infections. Bioengineered, 4 (6), 379 –387.
Amaretti, A., di Nunzio, M., Pompei, A., Raimondi, S., Rossi, M., & Bordoni, A. (2013).
Antioxidant properties of potentially probiotic bacteria: In vitro andin vivo activities.
Applied Microbiology and Biotechnology, 97 (2), 809 –817.
Antunes, L. C. M., Han, J., Ferreira, R. B., Loli ć, P., Borchers, C. H., & Finlay, B. B. (2011).
Effect of antibiotic treatment on the intestinal metabolome. Antimicrobial Agents and
Chemotherapy, 55 (4), 1494 –1503 .
Anvari, M., Khayati, G., & Rostami, S. (2014). Optimisation of medium composition for
probiotic biomass production using response surface methodology. Journal of Dairy
Research, 81 (1), 59 –64.
Arasu, M. V., Al-Dhabi, N. A., Rejiniemon, T. S., Lee, K. D., Huxley, V. A. J., Kim, D. H.,
et al. (2015). Identi fication and characterization of Lactobacillus brevis P68 with an-
tifungal, antioxidant and probiotic functional properties. Indian Journal of
Microbiology, 55 ,1 9–28.
Bermudez-Brito, M., Plaza-Díaz, J., Muñoz-Quezada, S., Gómez-Llorente, C., & Gil, A.
(2012). Probiotic mechanisms of action. Annals of Nutrition and Metabolism, 61 (2),
160–174.
den Besten, G., van Eunenm, K., Groen, A. K., Venema, K., Reijngoud, D.-J., & Bakker, B.
M. (2013). The role of short-chain fatty acids in the interplay between diet, gut mi-
crobiota, and host energy metabolism. Journal of Lipid Research, 54 , 2325 –2340 .
Callewaert, C., Lambert, J., & van de Wiele, T. (2017). Towards a bacterial treatment form
armpit malodour. Experimental Dermatology, 26 (5), 388 –391.
Canfora, E. E., Jocken, J. W., & Blaak, E. E. (2015). Short-chain fatty acids in control of
body weight and insulin sensitivity. Nature Reviews Endocrinology, 11 , 577 –591.
Canocini, A., Siret, C., Oellegrino, E., Pontier-Bres, R., Pouyet, L., Montero, M. P., et al.
(2011). Saccharomyces boulardii improves intestinal cell restitution through activation
of the α2β1 integrin collagen receptor. PLoS One, 6 (3), e18427. https://doi.org/10.
1371/journal.pone.0018427 .
Cavallari,
J. F., Fullerton, M. D., Duggan, B., Foley, K. P., Denou, E., Smith, B. K., &
Schetzer, J. D. (2017). Muramyl dipeptide-based postbiotics mitigate obesity-induced
insulin resistance via IRF4. Cell Metabolism, 25 ,1–12.https://doi.org/10.1016/j.
cmet.2017.03.021 .
Chaluvadi, S., Hotchkiss, A. T., & Yam, K. L. (2016). Gut microbiota: Impact of probiotics,
prebiotics, synbiotics, pharmabiotics, a postbiotics on human health. In R. R. Watson,
& V. R. Preedy (Eds.). Probiotics, prebiotics and synbiotics. Bioactive foods in health
promotion (pp. 515 –523). London: Elsevier .
Chen, H., & Hoover, D. G. (2003). Bacteriocins and their food applications. Comprehensive
Reviews in Food Science and Food Safety, 2 ,8 2–100.
Chen, H., Zhang, M., Qu, Z., & Xie, B. (2008). Antioxidant activities of di fferent fractions
of polysaccharide conjugates from green tea ( Camelia Sinensis ).Food Chemistry,
106(2), 559 –563.
Chen, H., Zhang, M., & Xie, B. (2004). Quanti fication of uronic acids in tea polysaccharide
conjugates and their antioxidant properties. Journal of Agricultural and Food
Chemistry, 52 (11), 3333 –3336 .
Chi, E., Dao, D., Lau, T. C., Henriksbo, B. D., Cavallari, J. F., & Scjhertzer, J. D. (2014).
Bacterial peptidoglycan stimulates adipocyte lipolysis via NOD1. PLoS One, 9 ,
e97675. https://doi.org/10.1371/journal.pone.0097675 .
Choe, D. W., Loh, T. C., Foo, H. L., Hair-Bejo, M., & Awis, Q. S. (2012). Egg production,faecal pH and microbial population, small intestine morphology, and plasma and yolkcholesterol in laying hens given liquid metabolites produced by Lactobacillus plan-
tarum strains. British Poultry Science, 53 (1), 106 –115.
Choi, S. S., Kim, Y., Han, K. S., You, S., Oh, S., & Kim, S. H. (2006). E ffects of Lactobacillus
strains on cancer cell proliferation and oxidative stress in vitro .Letters in Applied
Microbiology, 42 (5), 452 –458.
Chua, K. J., Kwok, W. C., Aggarwal, N., Sun, T., & Chang, M. W. (2017). Designer pro-
biotics for the prevention and treatment of human diseases. Current Opinion in
Chemical Biology, 40 ,8–16.
Cicenia, A., Santangelo, F., Gambardella, L., Pallotta, L., Iebba, V., Scirocco, A., … Severi,
C. (2016). Protective role of postbiotic mediators secreted by Lactobacillus rhamnosus
GG versus lipopolysaccharide-induced damage in human colonic smooth muscle
cells. Journal of Clinical Gastroenterology, 50 , 140 –144.
Cicenia, A., Scirocco, A., Carabotti, M., Pallotta, L., Marignani, M., & Severi, C. (2014).
Postbiotic activities of Lactobacilli-derived factors. Journal of Clinical
Gastroenterology, 48 ,1
8–22.
Compare, D., Rocco, A., Coccoli, P., Angrisani, D., Sgamato, C., Iovine, B., et al. (2017).
Lactobacillus casei DG and its postbiotic reduce the in flammatory mucosal response:
Anex vivo organ culture model of post-infectious irritable bowel syndrome. BMC
Gastroenterology, 17 (53)https://doi.org/10.1186/s12876-017-0605-x .
Coronado-Robles, M. (2016). Probiotics –promising cosmetic ingredient or marketing
tool? H&PC Today – Household and Personal Care Today, 11 (4), 10 –12.
Dinić , M., Luki ć, J., Djoki ć, J., Milenkovi ć, M., Strahini ć, I., & Goli ć, N. (2017).
Lactobacillus fermentum postbiotic-induced autophagy as potential approach for
treatment of acetaminophen hepatotoxicity. Frontiers in Microbiology, 8 (594)https://
doi.org/10.3389/fmicb.2017.00594 .
Dong, M. W., & Guillarme, D. (2013). Newer developments in HPLC impacting pharma-
ceutical anaysis: Brief review. American Pharmaceutical Review, 16 (4), 36 –43.
Doron, S., & Snydman, D. R. (2015). Risk and safety of probiotics. Clinical Infectious
Diseases, 69 (2), 129 –134.
Escamilla, J., Lane, M. A., & Maitin, V. (2012). Cell-free supernatants from probiotic
Lactobacillus casei andLactobacillus rhamnosus GG decrease colon cancer cell invasion
in vitro .Nutrition and Cancer, 64 (6), 871 –878.
Gabriele, H. (2016). Requirements for a successful future of probiotics. In P. Foerst, & C.
Santivarangkna (Eds.). Advances in probiotic technology (pp. 139 –145). New York:
Taylor & Francis-CRC Press .
Haileselassie, Y., Navis, M., Vu, N., Qazi, K. R., Rethi, B., & Sverremark-Ekstrom, E.
(2016). Postbiotic modulation of retinoic acid imprinted mucosal-like dendritic cellsby probiotic Lactobacillus reuteri 17938 in vitro .Frontiers in Immunology, 7 ,1–11.
Hamon, E., Horvatovich, P., Izquierdo, E., Bringel, F., Marchioni, E., Aoudé-Werner, D., &
Ennehar, S. (2011). Comparative proteomic analysis of Lactobacillus plantarum for the
identification of key proteins in bile tolerance. BMC Microbiology, 11 (63)https://doi.
org/10.1186/1471-2180-11-63 .
Haros,
M., Bielecka, M., Honke, J., & Sanz, Y. (2008). Phytate-degrading activity in lactic
acid bacteria. Polish Journal of Food and Nutrition Sciences, 58 ,3 3–40.
Heunis, T., Deane, S., Smit, S., & Dicks, L. M. T. (2014). Proteomic profi ling of the acid
stress response in Lactobacillus plantarum 423. Journal of Proteome Research, 13 ,
4028 –4039 .
Hibbing, M. E., Fugua, C., Parsek, M. R., & Peterson, S. B. (2010). Bacterial competition:
Surviving and thriving in the microbial jungle. Nature Reviews Microbiology, 8 ,1 5–25.
Holz, C., Benning, J., Schaudt, M., Heilmann, A., Schultchen, J., & Goelling, D. (2017).
Novel bioactive from Lactobacillus brevis DSM17250 to stimulate the growth of
Staphylococcus epidermidis : A pilot study. Beneficial Microbes, 8 , 121 –131.
Huang, M. C. J., & Tang, J. (2015). Probiotics in personal care products. Microbiology
Discovery, 3 (5)https://doi.org/10.7243/2052-6180-3-5 .
Huang, S., Vignolles, M. L., Chen, X. D., Loir, Y., Schuck, P., & Jeantet, R. (2017). Spray
dried of probiotics and other food-grade bacteria: A review. Trends in Food Science &
Technology, 63 ,1–17.
Huibregtse, I. L., Zaat, S. A., Kapsenberg, M. L., Sartori da Silva, M. A., Peppelenbosch, M.
P., & van Deventer (2012). Genetically modi fiedLactococcus lactis for delivery of
human interleukin-10 to dendritic cells. Gastroenterology Research and Practice,
2012 (639291) https://doi.org/10.1155/2012/639291 .
Imperial, I. C. V. J., & Ibana, J. A. (2016). Addressing the antibiotic resistance problem
with probiotics: Reducing the risk of its double-edged sword e ffect.Frontiers in
Microbiology, 7 (1983) https://doi.org/10.3389/fmicb.2016.01983 .
Jensen, G. S., Benson, K. F., Carter, S. G., & Endres, J. R. (2010). GanedenBC30TM cell
wall and metabolites: Anti-in flammatory and immune modulating e ffects in vitro .
BMC Immunology, 11 ,1–15.
Kareem, K. Y., Ling, F. H., Chwen, L. T., Foong, O. M., & Asmara, S. A. (2014). Inhibitory
activity of postbiotic produced by strains of Lactobacillus plantarum using recon-
stituted media supplemented with inulin. Gut Pathogens, 6 (23)https://doi.org/10.
1186/1757-4749-6-23 .
Kareem,
K. Y., Loh, T. C., Foo, H. L., Akit, H., & Samsudin, A. A. (2016a). E ffects of dietary
postbiotic and inulin on growth performance, IGF1 and GHR mRNA expression,faecal microbiota and volatile fatty acids in broilers. BMC Veterinary Research, 12 ,
1–10.
Kareem, K. Y., Loh, T. C., Foo, H. L., Asmara, S. A., & Akit, H. (2016b). In fluence of
postbiotic RG14 and inulin combination on cecal microbiota, organic acid con-
centration, and citokine expression in broiler chickens. Poultry Science, 96 , 966 –975.
Kim, H. S., Chae, H. S., Jeong, S. G., Ham, J. S., Im, S. K., & Ahn, C. (2006). In vitro
antioxidative properties of lactobacilli. Asian-Australasian Journal of Animal Sciences,
19, 262 –265.
Kim, H. G., Lee, S. Y., Kim, N. R., Lee, H. Y., Ko, M. Y., & Jung, B. J. (2011). Lactobacillus
plantarum lipoteichoic acid down-regulated Shigella flexneri peptidoglycan-induced
inflammation. Molecular Immunology, 48 (4), 382 –391.
Kimura, I., Ozawa, K., Inoue, D., Imamura, T., Kimura, K., & Maeda, T. (2013). The gutJ.E. Aguilar-Toalá et al.
Trends in Food Science & Technology 75 (2018) 105–114
112

microbiota suppresses insulin-mediated fat accumulation via the short-chain fatty
acid receptor GPR43. Nature Communications, 4 (1829) https://doi.org/10.1038/
ncomms2852 .
Klein, G., Schanstra, J. P., Ho ffmann, J., Mischak, H., Siwy, J., & Zimmerman, K. (2013).
Proteomics as a quality control tool of pharmaceutical probiotic bacterial lysateproducts. PLoS One, 8 (6), e66682. https://doi.org/10.1371/journal.pone.0066682 .
Klemashevich, C., Wu, C., Howsmon, D., Alaniz, R. C., Lee, K., & Jayaraman, A. (2014).
Rational identi fication of diet-derived postbiotics for improving intestinal microbiota
function. Current Opinion in Biotechnology, 26 ,8 5–90.
Kober, M. M., & Bowe, W. P. (2015). The e ffect of probiotics on immune regulation, acne,
and photoaging. International Journal of Women´s Dermatology, 1 ,8 5–89.
Kok, M. G., Ruijken, M. M., Swann, J. R., Wilson, I. D., Somsen, G. W., & de Jong, G. J.
(2013). Anionic metabolic profi ling of urine from antibiotic-treated rats by capillary
electrophoresis-mass spectrometry. Analytical and Bioanalytical Chemistry, 405 (8),
2585 –2594 .
Konrad, A., Mahler, M., Flogerzi, B., Kalousek, M. B., Lange, J., & Varga, L. (2003).
Amelioration of murine colitits by feeding a solution of lysed Escherichia coli .
Scandinavian Journal of Gastroenterology, 38 (2), 172 –179.
Konstantinov, S. R., Kuipers, E. J., & Peppelenbosch, M. P. (2013). Functional genomic
analyses of the gut microbiota for CRC screening. Nature Reviews Gastroenterology &
Hepatology, 10 , 741 –745.
Kullisaar, T., Zilmer, M., Mikelsaar, M., Vihalemm, T., Annuk, H., & Kairene, C. (2002).
Two antioxidative lactobacilli strains as promising probiotics. International Journal of
Food Microbiology, 72 (3), 215 –224.
Lebeer, S., Claes, I. J., & Vanderleyden, J. (2012). Anti-in flammatory potential of pro-
biotics: Lipoteichoic acid makes a di fference. Trends in Microbiology, 20 ,5–10.
Lee, J. W., Shin, J. G., Kim, E. H., Kang, H. E., Yim, I. B., Kim, J. Y., et al. (2004).
Immunomodulatory and antitumor e ffectin vivo by the cytoplasmatic fraction of
Lactobacillus casei and Bifidobacterium longum .Journal of Veterinary Science, 5 (1),
41–48.
Lee, M. J., Zang, Z., Choi, E. Y., Shin, H. K., & Ji, G. E. (2002). Cytoskeleton re-
organization and cytokine production of macrophages by Bi fidobacterial
cells and
cell-free extracts. Journal of Microbiology and Biotechnology, 12 (3), 398 –405.
Lew, L.-C., & Liong, M.-T. (2013). Bioactives from probiotics for dermal health: Functions
and bene fits.Journal of Applied Microbiology, 114 , 1241 –1253 .
Li, W., Ji, J., Chen, X., Jiang, M., Rui, X., & Dong, M. (2014). Structural elucidation and
antioxidant activities of exopolysaccharides from Lactobacillus helveticus MB2-1.
Carbohydrate Polymers, 102 , 351 –359.
Lin, M. Y., & Chang, F. J. (2000). Antioxidative e ffect of intestinal bacteria Bifidobacterium
longum ATCC 15708 and Lactobacillus acidophilus ATCC 4356. Digestive Diseases and
Sciences, 45 (8), 1617 –1622 .
Liu, C. F., Tseng, K. C., Chiang, S. S., Lee, B. H., Hsu, W. H., & Pan, T. M. (2011).
Immunomodulatory and antioxidant potential of Lactobacillus exopolysaccharides.
Journal of the Science of Food and Agriculture, 91 (2), 2284 –2291 .
Li, S., Zhao, Y., Zhang, L., Zhang, X., Huang, L., Li, D., et al. (2012). Antioxidant activity
ofLactobacillus plantarum strains isolated from traditional Chinese fermented foods.
Food Chemistry, 135 , 1914 –1919 .
Loh, T. C., Choe, D. W., Foo, H. L., Sazili, A. Q., & Bejo, M. H. (2014). E ffects of feeding
different postbiotic metabolite combinations produced by Lactobacillus plantarum
strains on egg quality and production performance, faecal parameters and plasma
cholesterol in laying hens. BMC Veterinary Research, 10 ,1–9.
Loh, T. C., Thu, T. V., Ling, F. H., & Bejo, M. H. (2013). E ffects of di fferent levels of
metabolite combination produced by Lactobacillus plantarum on growth performance,
diarrhoea, gut environment and digestibility of postweaning piglets. Journal of
Applied Animal Research, 41 (2), 200 –207.
Ma, Y., Liu, J., Hou, J., Dong, Y., Lu, Y., Jin, L., et al. (2014). Oral administration of
recombinant Lactococcus lactis expressing hsp65 and tandemly repeated p277 reduces
the incidence of type I diabetes in non-obese diabetic mice. PLoS One, 9 (8), e105701.
https://doi.org/10.1371/journal.pone.0105701 .
Matsuguchi, T., Takagi, A., Matsuzaki, T., Nagaoka, M., Ishikawa, K., Yokokura, T., &
Yoshikai, Y. (2003). Lipoteichoic acids from Lactobacillus strains elicit strong tumor
necrosis factor alpha-inducing activities in macrophages through Toll-like receptor 2.Clinical and Diagnostic Laboratory Immunology, 10 (2), 259 –266.
Mileti, E., Matteoli, G., Iliev, I. D., & Rescigno, M. (2009). Comparison of the im-
munomodulatory properties of three probiotic strains of lactobacilli using complexculture systems: Prediction for in vivo efficacy. PLoS One, 4 (9), e7056. https://doi.
org/10.1371/journal.pone.0007056 .
Nakamura, F., Ishida, Y., Sawada, D., Ashida, N., Sugawara, T., Sakai, M., & Fujiwara, S.
(2016). Fragmented lactic acid bacteria cells activate peroxisome proliferator-acti-vated receptors and ameliorate dyslipidemia in obese mice. Journal of Agricultural and
Food Chemistry, 64 , 2549 –2559 .
Netzker, T., Fischer, J., Weber, J., Mattern, D. J., Köning, C. C., Valiante, V., et al. (2015).
Microbial communication leading to the activation of silent fungal secondary meta-
bolite gene clusters. Frontiers in Microbiology, 6 (299)https://doi.org/10.3389/fmicb.
2015.00299 .
Oberg, T. S., Steele, J. L., Ingham, S. C., Smeianov, V. V., Brinczinski, E. P., & Abdalla, A.
(2011). Intrisic and inducible resistance to hydrogen peroxide in Bifidobacterium
species. Journal of Industrial Microbiology and Biotechnology, 38 , 1947 –1953 .
Oberg, T. S., Ward, R. E., Steele, J. L., & Broadbent, J. R. (2012). Identi fication of plas-
malogens in the cytoplasmic membrane of Bifidobacterium animalis subsp. lactis.
Applied Environmental Microbiology, 78 , 880 –884.
Ogawa, A., Kadooka, Y., Kato, K., Shirouchi, B., & Sato, M. (2014). Lactobacillus gasseri
SBT2055 reduces postprandial and fasting serum non-esteri fied fatty acid levels in
Japanese hypertriacylglycerolemic subjects. Lipids in Health and Disease, 13 (36)
https://doi.org/10.1186/1476-511X-13-36 .
Omarov, T. R., Omarova, L. A., Omarova, V. A., & Sarsenova, S. V. (2014). The chronicgastritis, the dysbacteriosis and the use of Hylak forte at the treatment. Wiadomosci
Lekarskie, 67 , 365 –367.
Ou, C. C., Ko, J. L., & Lin, M. Y. (2006). Antioxidative e ffects of intracellular extracts of
yogurt bacteria on lipid peroxidation and intestine 407 cells. Journal of Food and Drug
Analysis, 14 (3), 304 –310.
Ouwehand, A. C., Lahtinen, S., & Tiihonen, K. (2016). The potential of probiotics and
prebiotics for skin health. In M. A. Farage, K. W. Miller, & H. I. Maibach (Eds.).
Texbook of aging skin (pp. 1299 –1311). Berlin Heidelberg: Springer-Verlag .
O´neill, C., & McBain, A. (May 26, 2015). Anti-bacterial lysate of probiotic bacteria. Patent
WO2015181534 A1, Filed and issued Dec 3, 2015 .
Pajarillo, E. A., Kim, S. H., Lee, J. Y., Valeriano, V. D., & Kang, D. K. (2015). Quantitative
proteogenomics and the reconstruction of the metabolic pathway in Lactobacillus
mucosae LM1. Korean
Journal of Food Science, 35 (5), 692 –702.
Palacios, M. C., Haros, M., Sanz, Y., & Rosell, M. (2008). Selection of lactic acid bacteria
with high phytate degrading activity for application in whole wheat breadmaking.
LWT-Food Science and Technology, 41 ,8 2–92.
Pan, D., & Mei, X. (2010). Antioxidant activity of an exopolysaccharide puri fied from
Lactococcus lactis subsp. lactis 12.Carbohydrate Polymers, 80 , 908 –914.
Patel, R. M., & Denning, P. W. (2013). Therapeutic use of prebiotics, probiotics, and
postbiotics to prevent necrotizing enterocolitis: What is the current evidence? Clinics
in Perinatology, 40 (1), 11 –25.
Paton, A. W., Morona, R., & Paton, J. C. (2012). Bioengineered microbes in disease
therapy. Trends in Molecular Medicine, 18 (7), 417 –425.
Phister, T. G., O´Sullivan, D. J., & McKay, L. L. (2004). Identi fication of bacilysin,
chlorotetaine, and iturin a produced by Bacillus sp. strain CS93 isolated from Pozol, a
Mexican fermented maize dough. Applied and Environmental Microbiology, 70 ,
631–634.
Przybilla, B., Heppeler, M., & Ruzicka, T. (1989). Preventive e ffect of an E. coli -filtrate
(Colibiogen®) in polymorphous light eruption. British Journal of Dermatology, 121 ,
229–233.
Raman, M., Ambalam, P., & Doble, M. (2016). Probiotics and colorectal cancer. In M.
Raman, P. Ambalam, & M. Doble (Eds.). Probiotics and bioactive carbohydrates in colon
cancer management (pp. 15 –34). India: Springer .
Rather, I. A., Seo, B. J., Kumar, V. J. R., Choi, U. H., Lim, J. H., & Park, Y. H. (2013).
Isolation and characterization of a proteinaceous antifungal compound from
Lactobacillus plantarum YML007 and its application as a food preservative. Letters in
Applied Microbiology, 57 ,6 9–76.
Ray, S., Sherlock, A., Wilken, T., & Woods, T. (2010). Cell wall lysed probiotic tincture
decreases immune response to pathogenic enteric bacteria and improves symptoms in
autistic and immune compromised children. Explore, 19 ,1–5.
Reid, G. (2016). Probiotics: De finition, scope and mechanisms of action. Best Practice &
Research Clinical Gastroenterology, 30 ,1 7–25.
Robert, S., Gysemans, C., Takiishi, T., Korf, H., Spagnuolo, I., Sebastiani, G., et al. (2014).
Oral delivery of glutamic acid decarboxylase (GAD)-65 and IL10 by Lactococcus lactis
reverses diabetes in recent-onset NOD mice. Diabetes, 63 , 2876 –2887 .
Robles-Vera, I., Toral, M., Romero, M., Jiménez, R., Sánchez, M., & Pérez-Vizcaíno, F.
(2017). Antihypertensive e ffects of probiotics. Current Hypertension Reports, 19 (26)
https://doi.org/10.1007/s11906-017-0723-4 .
Rudkowski, Z., & Bromirska, J. (1991). Shortening of the period of fecal excretion of
salmonella in infants under treatment with hylak forte. Paediatrie und Paedologie,
26(2), 111 –114.
Saide, J. A., & Gilliland, S. E. (2005). Antioxidative activity of Lactobacilli measured by
oxygen radical absorbance capacity. Journal of Dairy Science, 88 (4), 1352 –1357 .
Sánchez, B., Ruiz, L., Gueimonde, M., Ruas-Madiedo, P., & Margolles, A. (2012). Toward
improving technological and functional properties of probiotic in foods. Trends in
Food Science & Technology, 26 ,5 6–63.
Sanders, M. E. (2009). How do we know when something called “probiotic” is really a
probiotic? a guideline for consumers and health care professionals. Functional Food
Reviews, 1 (1), 3 –12.
Sawada, H., Furushiro, M., Hirai, K., Motoike, M., Watanabe, T., & Yokokura, T. (1990).
Purifi cation and characterization of an antihypertensive compound from Lactobacillus
casei.Agricultural & Biological Chemistry, 54 (12), 3211 –3219 .
Shah, N. P. (2016). Novel dairy probiotic prodcuts. In P. Foerst, & C. Santivarangkna
(Eds.). Advances in probiotic technology (pp. 338 –355). New York: Taylor & Francis-
CRC Press .
Sharma, M., & Shukla, G. (2016). Metabiotics: One step ahead of probiotics; an insight
into mechanisms involved in anticancerous e ffect in colorectal cancer. Frontiers in
Microbiology, 7 , 1940. http://dx.doi.org/10.3389/fmicb.2016.01940 .
Sharma, S., Singh, R. L., & Kakkar, P. (2011). Modulation of Bax/Bcl-2 and caspases by
probiotics during acetaminophen induced apoptosis in primary hepatocytes. Food and
Chemical Toxicology, 49 , 770 –779.
Shenderov, B. A. (2013). Metabiotics: Novel idea or natural development of probiotic
conception. Microbial Ecology in Health and Disease, 24 ,1–8.
Shigwedha, N., Sichel, L., Jia, L., & Zhang, L. (2014). Probiotical cell fragments (PCFs) as
“novel nutraceutical ingredients ”.Journal of Biosciences and Medicines, 2 ,4 3–55.
Shimamura, S., Abe, F., Ishibashi, N., Miyakawa, H., Yaeshima, T., & Araya, T. (1992).
Relationship between oxygen sensitivity and oxygen metabolism of Bifidobacterium
species. Journal of Dairy Science, 75 , 3296 –3306 .
Shin, H. S., Park, S. Y., Lee, D. K., Kim, S. A., An, H. M., Kim, J. R., et al. (2010).
Hypocholesterolemic e ffect of sonication-killed Bifidobacterium longum isolated from
healthy adult Koreans in high cholesterol fed rats. Archives of Pharmacal Research,
33(9), 1425 –1431 .
Singh, B., Mal, G., & Marotta, F. (2017). Designer probiotics: Paving the way to living
therapeutics. Trends in Biotechnology, 35 , 679 –682.
Sokol, H., Pigneur, B., Watterlot, L., Lakhdari, O., Bermúdez-Humarán, L. G., Gratadoux,
J. J., et al. (2008). Faecalibacterium prausnitzii is an anti-in flammatory commensalJ.E. Aguilar-Toalá et al. Trends in Food Science & Technology 75 (2018) 105–114
113

bacterium identi fied by gut microbiota analysis of Crohn disease patients. Proceedings
of the National Academy of Sciences, 105 (43), 16731– 16736 .
Sola-Oladokun, B., Culligan, E. P., & Sleator, R. D. (2017). Engineered probiotics:
Applications and biological containment. Annual Review of Food Science and
Technology, 8 , 353 –370.
Sorokulova, I. (2008). Preclinical testing in the development of probiotics: A regulatory
perspective with Bacillus strains as an example. Clinical Infectious Diseases, 46 ,9 2–95.
Taverniti, V., & Guglielmetti, S. (2011). The immunomodulatory properties of probiotic
microorganisms beyond their viability (ghost probiotics: Proposal of paraprobiotic
concept). Genes & Nutrition, 6 , 261 –274.
Tejada-Simon, M. V., & Pestka, J. J. (1999). Proinfl ammatory cytokine and nitric oxide
induction in murine macrophages by cell wall and cytoplasmic extracts of lactic acidbacteria. Journal of Food Protection, 62 (12), 1435 –1444 .
Thanh, N. T., Loh, T. C., Foo, H. L., Bejo, M. H., & Azhar, K. (2010). Inhibitory activity of
metabolites produced by strains of Lactobacillus plantarum isolated from Malaysian
fermented food. International Journal of Probiotics and Prebiotics, 5 ,3 7–44.
Thu, T. V., Loh, T. C., Foo, H. L., Yaakub, H., & Bejo, M. H. (2011). E ffects of liquid
metabolite combinations produced by Lactobacillus plantarum on growth perfor-
mance, faeces characteristics, intestinal morphology and diarrhoea incidence inpostweaning piglets. Tropical Animal Health and Production, 43 ,6 9–75.
Timko, J. (2010). Probiotics as prevention of radiation-induced diarrhea. Journal of
Radiotherapy in Practice, 9 (4), 201 –208.
Tiptiri-Kourpeti, A., Spyridopoulou, K., Santarmaki, V., Aindelis, G., Tompoulidou, E.,
Lamprianidou, E. E., et al. (2016). Lactobacillus casei exerts anti-proliferative e ffects
accompanied by apoptotic cell death and up-regulation of TRAIL in colon carcinoma
cells. PLoS One, 11 (2), e0147960 https://doi.org/10.1371/journal.pone.0147960 .
Tomar, S. K., Anand, S., Sharma, P., Sangwan, V., & Mandal, S. (2015). Role of probiotic,
prebiotics, synbiotics and postbiotics in inhibition of pathogens. In A. Méndez-Vilas
(Ed.). The battle against microbial Pathogens: Basic science, technological advances and
educational programs (pp. 717 –732). Formatex Research Center .
Torino, M. I., de Valdez, G. F., & Mozzi, F. (2015). Biopolymers from lactic acid bacteria.
Novel applications in foods and beverages. Frontiers in Microbiology, 6 (834) https://
doi.org/10.3389/fmicb.2015.00834 .
Tsilingiri, K., Barbosa, T., Penna, G., Caprioli, F., Sonzogni, A., & Viale, G. (2012).
Probiotic and postbiotic activity in health and disease: Comparison on a novel po-larised ex-vivo organ
culture model. Gut, 61 , 1007 –1015 .
Tsilingiri, K., & Rescigno, M. (2013). Postbiotics: What else? Beneficial Microbes, 4 (1),
101–107.
Venema, K. (2013). Foreword. Beneficial Microbes, 4 (1), 1 –2.
Vidal, K., Donnet-Hugues, A., & Granato, D. (2002). Lipoteichoic acids from Lactobacillus
johnsonii strain La1 and Lactobacillus acidophilus strain La10 antagonize the respon-
siveness of human intestinal epithelial HT29 cells to lipopolysaccharide and gram-
negative bacteria. Infection and Immunity, 70 (4), 2057 –2064 .Vieira, A. T., Fukumori, C., & Ferreira, C. M. (2016). New insights into therapeutic
strategies for gut microbiota modulation in in flammatory diseases. Clinical and
Translational Immunology, 5 , e86. https://doi.org/10.1038/cti.2016.38 .
Vyas, U., & Ranganathan, N. (2012). Probiotics, prebiotics, and synbiotics: Gut and be-
yond. Gastroenterology Research and Practice, 2012 ,1–16.https://doi.org/10.1155/
2012/872716 .
Wang, J., Hiu, W., Jin, R., Ren, C., Zhang, H., & Zhang, W. (2016). Proteomic analysis of
an engineered isolate of Lactobacillus plantarum with enhanced ra ffinose metabolic
capacity. Scienti fic Reports, 6 ,1–12.
Weese, J. S., & Martin, H. (2011). Assessment of commercial probiotic bacterial contents
and label accuracy. Canadian Veterinary Journal, 52 ,4 3–46.
West, R., Roberts, E., Sichel, L. S., & Sichel, J. (2013). Improvements in gastrointestinal
symptoms among children with autism spectrum disorder receiving the Delpro®
Probiotic and immunomodulator formulation. Journal of Probiotics and Health, 1 (102)
https://doi.org/10.4172/jph.1000102 .
Williams, N. T. (2010). Probiotics. Adverse e ffects and safety. American Journal of Health-
System Pharmacy, 66 (6), 449 –458.
Xu, R., Shang, N., & Li, P. (2011). In vitro and in vivo antioxidant activity of exopoly-
saccharide fractions from Bifidobacterium animalis RH. Anaerobe, 17 (5), 226 –231.
Yang, G., Jiang, Y., Yang, W., Du, F., Yao, Y., & Shi, C. (2015). E ffective treatment of
hypertension by recombinant Lactobacillus plantarum expressing angiotensin con-
verting enzyme inhibitory peptide. Microbial Cell Factories, 14 (202) https://doi.org/
10.1186/s12934-015-0394-2 .
Yi, Z. J., Fu, Y. R., Li, M., Gao, K. S., & Zhang, X. G. (2009). E ffect of LTA isolated from
bifidobacteria on D-galactose-induced aging. Experimental Gerontology, 44 (12),
760–765.
Yoon, Y. H., & Byun, J. R. (2004). Occurrence of glutathione sulphydryl (GSH) and an-
tioxidant activities in probiotic Lactobacillus spp. Asian-Australasian Journal of Animal
Sciences, 17 (11), 1582 –1585 .
Zhang, J., Du, G. C., Zhang, Y., Liao, X. Y., Wang, M., & Li, Y. (2010). Glutathione protects
Lactobacillus sanfranciscensis against freeze-thawing, freeze-drying, and cold treat-
ment. Applied and Environmental Microbiology, 76 , 2989 –2996 .
Zhang, S., Liu, L., Su, Y., Li, H., Sun, Q., & Liang, X. (2011). Antioxidative activity of lactic
acid bacteria in yogurt. African Journal of Microbiology Research, 5 , 5194 –5201 .
Zhang, B., Li, A., Zou, F., Yu, R., Zeng, Z., & Ma, H. (2016). Recombinant Lactococcus lactis
NZ9000 secretes a bioactive kisspeptin that inhibits proliferation and migration of
human colon carcinoma HT-29 cells. Microbial Cell Factories, 15 (102) https://doi.org/
10.1186/s12934-016-0506-7 .
Zihler, A., Le Blay, G., de Wouters, T., Lacroix, C., Braegger, C. P., Lehner, A., et al.
(2009). In vitro inhibition activity of di fferent bacteriocin-producing Escherichia coli
against Salmonella strains isolated from clinical cases. Letters in Applied Microbiology,
49,3 1–38.J.E.
Aguilar-Toalá et al. Trends in Food Science & Technology 75 (2018) 105–114
114