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Molecular Biology, Genetics and Biotechnology
Probiotic (symbiotic) bacterial languages
Research Group “Probiotic & Functional Foods”, Moscow Research Institute of Epidemiology and Microbiology after G.N. Gabrichevsky,
Admiral Makarov Street 10, 125212 Moscow, Russia
a r t i c l e i n f o
Received 20 December 2010
Received in revised form
2 May 2011
Accepted 4 May 2011
Available online 23 May 2011
Microbe structural components
Genomic and epigenomic control
microbe/host cross talk
a b s t r a c t
Symbiotic gut microorganisms release of various soluble low molecular weight (LMW)molecules of
different chemical nature (surface and exogenous proteins, nucleases, serpins, sirtuines, other enzymes,
lectins, peptides, amines, bacteriocines, fatty and amino acids, lactones, furanons, miRNA, NO, etc). These
LMW molecules are able to sense environment, interact with corresponding cell surface, membrane,
cytoplasm and nucleic acid receptors, to reply quickly and coordinately by induction of special sets of
genes, to support stability of host genome and microbiome, to modulate epigenomic regulation of gene
phenotypic expression, to ensure the information exchange in numerous bacterial and bacteria-host
systems playing an important role in the control for many genetic and physiological functions,
biochemical and behaviour reactions, in supporting host health in general. Various symbiotic (probiotic)
strains produce different spectrum of such LMW molecules. There is chemical and functional similarity
between LMW molecules synthesized by host eukaryotic cells, indigenous and probiotic microorganisms
and some micronutrients. It means many LMW compounds of different origin may be the universal
regulators contributing to the transmission of information, quorum sensing effects, metagenome stability
and epigenomic control for cell growth and development as well as phenotypic expression of different
genes. Knowledge accumulated concerning molecular languages of symbiotic microorganisms allows us
to better understand the mode of action of known probiotics and to design in principle novel probiotics
(metabiotics) with increased health effectiveness. Now we are only at the beginning of a new era of
molecular personal biotherapy and nutrition. Soon we can successfully manipulate both the host and its
microbiota through interfering in their cross talk, stability and epigenomic regulation of expression of
genes using various types of eukaryotic, prokaryotic and nutrition origin LMW molecules are capable to
modulate genetic, metabolic and physiological activities.
? 2011 Elsevier Ltd. All rights reserved.
Microbes rule the world. We have to listen to the microbial
language and when we have learned more, we shall be able
more and more to interact in harmony with the microbes.
Tore Midtvedt, 2008
Human being is a “superorganism” consisting of a consortium of
vast number of representatives of Viruses, Eukarya, Bacteria and
Archaea [1e3]. The interrelations between these biological systems
must be regulated by different means to control for composition
and quantity of corresponding cells, to prevent competition
between prokaryotic and eukaryotic cells for harbor, similar
nutrient resources, to exchange metabolites, signal molecules,
genetic information and so on. Host-microbial interactions repre-
sent the main factor exerting a decisive impact in the growth,
development and the health of human being. The host-microbial
interplays are determined by host genome and microbiome,
epigenetic systems participating in gene expression and post-
translated modification of gene products, intercellular signaling
(cell-to cell communication) networks between bacteria, eukary-
otes as well as bacteria and host cells, host physiological status,
illness, constituents of the diet, medication, and so on . Unfor-
tunately the equilibrium between symbiotic host eukaryotic and
prokaryotic cells has been often disturbed by various endogenous
and exogenous stress factors and agents (antibiotics and antiseptic
agents, anti-cancer, anti-histamine, antidepressant, and other
medicines, technological nutrient additives, heavy metal salts,
some industrial pollutants, pesticides, radiation, other chemical,
physical, biological stress agents and their combinations) [5,6]. At
the beginning the different hurt agents as rule produce disturbance
in the host-microbial ecology that quite often resulting in
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E-mail address: email@example.com.
Contents lists available at ScienceDirect
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Anaerobe 17 (2011) 490e495
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metagenome, epigenetic and host-bacteria cross talk disorders and
as a consequence the number of various diseases [4,5,12]. To
prevent and restore these disorders for the last 30 years several
approaches have been worked out: various functional (including
personal) foods, medicines, gene-engineering tools and so on
[6,8,9]. To avert and rehabilitate microecological disorders the
generation of specific approaches have been worked out and
introduced in practical medicine under the form of probiotics
[6,7,10], including autoprobiotics [6,11,12], prebiotics and synbiotics
[6,7,13]. The present minireview will focus on new information
emerging about some molecular mechanisms behind probiotic-
conferrered health effects.
2. Factors and conditions influencing to health effects of
Numerous reviews [6,7,13,14,38] have summarized the health
effects of probiotics. Probiotics can confer benefits on the host
through colonization or non colonization of the digestive tract, via
local and/or systemic effects that may be direct and/or indirect,
specific and/or nonspecific. Now there are known plenty factors
and conditions able to determine the beneficial effects of probiotics
to the host (origin of probiotic strains); the type of probiotic
organism (species, strain, genomic structure, place of isolation); the
host genotype; condition of probiotic bacteria (live, dead, cell
fragments, metabolites, signaling molecules); route, frequency of
delivery and dosage of probiotics; viability of the probiotic prepa-
ration; health status of the consumer; condition of gut indigenous
microbiota; physico-chemical conditions in the gut; combination of
all above mentioned factors) [6e8,10,16,17]. Besides probiotic
health-promoting effects depends on strain adaptation and pro-
biotic potentials .
Probiotic bacteria have been shown to modulate various phys-
iological functions, biochemical and behavior reactions, immune
and hormonal responses [5,10,12]. New “omic” technologies will be
very helpful to better characterize and understand the effects of
probiotics on the gastrointestinal microbiota, host metabolism,
physiology and gene expression . However, in spite of the long
probiotic use, the signaling pathways engaged by probiotics are still
only vaguely understood. It is often difficult to understand that
a few grams of daily consumption of probiotic microorganisms can
have a significant influence to the physiological functions and
metabolic reactions on human health in general when the colon of
adult healthy individual contains about 2 kg of bacteria .
Besides the information has been accumulated many effects
obtained from viable probiotic bacteria may be also received from
using population of dead cells . Investigations of the last 10e20
years have showed that gut microorganisms can break down
complex food nutrients and endogenous substances. About 50% of
intestinal microorganisms are dead microbes that also are digested
by intestinal and microbe enzymes. As a result of breaking and
metabolization of different exogenic and endogenous substrates
hundred (thousands) biological active low molecular weight
(LMW) functional ingredients are formed [21e23,27]. It well
known that normal intestinal mucosa allows the passage of
different microorganisms, their fragments, colloidal particles,
plastic microspheres, dietary starch granules and other compounds
in the size range of bacteria across the epithelium. Such small
molecules including microbial origin could be found in the body
fluids and different organs and tissues (e.g. blood, urine, synovial
fluid) in humans within minutes after introduction into gastroin-
testinal tract [24,25]. Using the modern methods of chromatog-
raphy and mass-spectrometry many of these LMW molecules may
be determined in the biological samples rather quickly and easy.
According to the last data  peak area of microbial marker on
selective chromatogram is proportional to biomass of specified
microbe. At the end of last century Russian scientists  offered
concept of small molecules (mol. weight up to 500 amu) microbes
originated (SMOM) homeostasis. According to this concept SMOM
are always present in biological liquids of healthy and ill people
microflora relationships; they can activate, inhibit various host
cell’s activity or stay indifferent; in healthy organism the main
source of SMOM is host normal symbiotic microbiota; broken
homeostasis of SMOM serves as the basis for development of
3. Probiotic (symbiotic) microorganism signaling molecules
On the base of mentioned above information it is possible to
suggest that the translocation of probiotic bacteria and their frag-
ments and metabolites as well as microbial metabolic substances of
epithelia tissue, mucus gel and nutrients origin appeared as
sequences of microbial degradation and metabolism fromintestinal
lumen into different organs and systems may be considered as
a normal condition.
During last decade we have begun better to understand
molecular languages used by symbiotic (probiotic) microorganisms
inphysiology, biochemistryand host/microbe cells communication.
Probiotic bacteria seemed as well as symbiotic gut bacteria in the
intestinal tract can synthesize, release, detect and respond to
numerous LMW bio-active substances of different chemical struc-
ture that being penetrated into intestinal tract or in the corre-
sponding tissues and cells may stimulate or in general modify
practically any physiological or metabolic parameter in human
body acting on local and system levels in the host resulting in
beneficial effects. Material carriers of LMW bio-active regulators of
symbiotic interactions in prokaryotic and eukaryotic cells could be
metabolites and structure components of host and microbial cells
including their signaling molecules that have, possibly, similar
targets. The list of these known and potential bio-active molecules
namedin scientific literature LMW signaling molecules, bio-actives,
autoinducers, chemokinins, modulins or effector molecules is
rather broad and has tendency to increase (Table 1).
Known and potential symbiotic (probiotic) microbial LMW bio-actives families
participating in regulation of bacteria and host cells life and host-bacteria rela-
? Lacton-like autoinducers
? Peptide pheromones and other bio-active peptides
? Type AI-2 protein autoinducers, including furanones
? Damage-associated molecular patterns (stress proteins, uric acid
microcrystals, galuronine, ATP, etc)
? SCFA and other organic acids
? Various enzymes (participants and modificators of metabolic reactions,
epigenomic regulation, QS- communication, DNA and RNA reparation,
post-translated modification of NA, proteins, etc)
? Different simple molecules (CH4, H2S, NO, CO, H2O2, etc)
? Amino acids (glutamate, b e alanine, GABA and others)
? Nucleic acids, miRNA, nucleotides, nucleosides
? Vitamins (biotin, folic acid, etc)
? Amines (histamine, serotonin, etc), polyamines
(spermine, spermidine, etc)
? Hormon-similar substances (e.g. estrogen)
? Polysaccharides, oligosaccharides, peptidoglycans,
lipoteichoic acid, glycopeptides, lipopolysaccharides, etc
? Antimicrobial compounds (antibiotics, bacteriocins,
defensin-like peptides, etc)
? Pigments and so on
B.A. Shenderov / Anaerobe 17 (2011) 490e495
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4. Targets and some effects of probiotic (symbiotic)
microorganism signaling molecules
According to their functions, mode of action or targets, the
symbiotic (probiotic) microbial LMW bio-actives conditionally
could be divided at least into several groups (Tables 2e4).
The synthesis, release of these bio-active LMW molecules as
well as their effects are tightly regulated. For example, Gram-
negative species for communication of bacteria with each other
use small diffusible molecules, typically modified amino acids, to
regulate a variety of responses in a density dependent manner.
Gram-positive bacteria seem to favour oligopeptide signals,
synthesized as inactive precursors. Post-translation modifications
such as proteolytic cleavage and/or glycosylation convert the
precursor into the active receptor ligand. After that proteolytically
activated and secreted signal molecules are recognized by specific
receptors at the bacteria and/or cell surface . Bacteria-host cells
cross talk is mainly based on the exchange of signal molecules in
both directions [29e33].
These metabolic and/or signaling molecules can trigger cascade
of events connected with stability and expression of several
hundred and thousands structural and regulatory genes, bacter-
iaebacteria, bacteria-host cell communication and metabolic
processes. It means that positive effects to animal and human
health of probiotics are connected not only with live but also killed
(heat, radiation and so on) probiotic bacteria as well as with
numerous signaling LMW of microbe origin. The mechanisms may
vary from one probiotic to another (for the same benefit via
different means) and the mechanism may be a combination of
events, thus making this a very difficult and complex area. The
variety of biological processes are under direct and non direct
control of these LMW molecules (stability, replication, post-
translation modification and phenotypic expression of genes
(genetic and epigenetic regulation), intra- and inter communica-
tionprokaryotic and eukaryotic host cells (quorum sensing), energy
and plastic metabolism, microbial and host cell apoptosis, stress
responses, physiological functions, biochemical and behavior
reactions (biofilm formation, transfer of plasmids, genetic compe-
tence and sporulation, synthesis of enzymes, bacteriocins, surface
proteins and polysaccharides, and so on).
Probiotic microorganisms can eliminate or suppress undesirable
microorganisms (competitive exclusion) through production or
stimulation of such anti-microbial LMW substances as SCFA, other
organic acids, bacteriocines-like substances, hydrogen peroxide,
nitrogen oxide, etc. Besides many LMW compounds of probiotic
(symbiotic) bacteria can participate in the competition for binding
sites, essential nutrients and other growth factors, for similar
metabolic pathways of intestinal pathogens or opportunistic
pathogens; probiotic LMW molecules can neutralize or suppress
the harmful toxins and metabolites in pathogen microbes including
their Quorum sensing signal molecules [6,8,13,15,34e38].
Beneficial effects to indigenous host intestinal microbiota may
be connected with ability of probiotic microorganisms produce
various LMW nutrients, antioxidants, growth factors, different
signaling molecules, including QS-signals, receptors for adhesion
and co-adhesion, stress proteins, enzymes common with indige-
nous microflora that improve intestinal mucus surface colonization
and cooperation in the metabolic reactions of host indigenous
microbes optimizing the composition, variability, and temporal
stability of the host core indigenous microbiota first of all dominant
operational taxonomic units (Firmicutes, Bacteroides, Proteobacteria,
Actinobacteria and Archea) [6,8,15,37e41].
Positive interactions with intestinal epithelium and modifica-
tion of local immune responses may be associated with probiotic
(symbiotic) microorganisms production of such LMW bio-actives as
SCFA, NO, glutamate, b e alanine, GABA, biotin, surface proteins,
peptides, nucleic acids, polysaccharides, oligosaccharides, pepti-
doglycans, lipoteichoic acid, glycopeptides, flagellin and their
complexes, lipopolysaccharides, lectins and others that are able to
promote growth, regeneration and apoptosis of intestinal and local
immune cells, modulate motoric, fermentative activities and
structure of the intestinal mucosa, Toll- and other receptor struc-
ture, improve bacteria/intestine and immune cells cross talk,
delivery of regulatory signals to the intestinal and immune cells
epitheliaand instruction of mucosal immune responses, induce and
stimulate activity of defensins and of defensin-like anti-microbial
peptides, modulate of gut vasculature, activate receptors in the
enteric nervous system resulting in pain relief, prevent and repair
the intestine mucosa damages and gut permeability and so on
Heath positive effects towhole host organism may be associated
cells and metabolic pathways outside intestinal tract (systemic
effects) via numerous LMW hormone and neurotransmitters - like
signaling molecules of microbial origin (H2S, NO, CO, GABA, vita-
mins, polyamines, hormones, enzymes, miRNA, other metabolites
modify water-salt, energy, lipid, choline, amino acid metabolism,
nervous system (peripheral, central, including behavior reactions),
Some characteristics of symbiotic (probiotic) bacteria LMW bio-actives.
? They may be
freely diffusible, membrane permeable molecules
needing to be intercepted by specific receptors at the cell surface
? According to effects they may be divided into:
Pure signaling molecules
Molecules possessing simultaneously specific structural,
metabolic or another activity and signaling activity
Such LMW signaling molecules are able to switch on or switch of
corresponding genes via interaction with specific DNA receptors using
different kinases and/or other systems.
Targets and some effects of probiotic (symbiotic) LMW bio-active molecules.
- Metagenome stability and expression of structural and regulatory
microbe and host cell genes
- Epigenetic control of gene expression and post-translation
modification of gene products
- Bacteria/bacteria and microbe/host cross talk (Quorum Sensing
including toxinantitoxin systems controlling programmed apoptosis
and cell death)
- Metabolic and behavior reactions
- “Superorganism” growth, development and health of in general
Effects of probiotic LMW bio-actives are manefesting on the different host levels.
1. Molecular (gene replication and expression, transcription, translation
of genetic information)
2. Cell (surface, membrane, protein and energy biosynthesis in the
mitochondria and ribosomes, post-translated effects)
3. Inside of cell gyaloplasme (place of nucleus, organoids
and inclusion bodies localization)
4. Intercell matrix (place of capillarifs, nervous synapses localization,
metabolic reactions, cellecell information exchange and so on)
5. Tissues, organs, physiological systems
6. Host in the whole
B.A. Shenderov / Anaerobe 17 (2011) 490e495
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metabolic interactions, including epigenomic control of expression
genes, other metabolic reactions and physiological functions in
organs and tissues located out of digestive tract. Some LMW
microbial substances after penetration to body liquids can reach
immune organs outside digestive tract and modulate systemic
innate and acquired immune responses,neutralize intestinal toxic
cells and tissues located outside gut [4,7,15,21,27,34,45e47].
That is why the LMW bio-active substances of different chemical
structure and origin consider to be “words” in original information
language of all living beings including symbiotic (probiotic)
microorganisms. Different probiotic strains can form various set of
bio-active LMW molecules. It means that all probiotics are not
equally effective and there are the multitude mechanisms whereby
probiotics can produce positive effects to human being health.
These mechanisms vary fromone probiotic toanother(for the same
benefit via different means) and the mechanism may be a combi-
nation of some events. Probiotic bacteria, symbiotic bacteria and
their host cells can effect to each other not only via “mechanical”
cross talk between the eukaryotic and prokaryotic cells. Their
interactions may also include biochemical, molecular, biophysical
interplays. Functional effects of probiotic interventions cannot be
fully assessed without probing the biochemistry of the host at
multiple compartmental levels.
In comparing experiments (with and without probiotics) in
different experimental animal models microbiological profiling,
metabolic profiling in intestinal lumen, liver tissues, plasma, urine,
fecal extracts, and other organs and tissues are investigated by
various analytic methods for the detection of response to probiotics
. For example, it was shown that during passages trough
intestinal tract some silent genes of probiotic bacteria may be
induced by host cell signals [31,48,49,50]. So in these conditions the
induction of 72 probiotic L.plantarum WSFS1 genes was observed: 9
genes responsible for sugar transport and production of different
sacharidases, other nine genes- for synthesis of amino acids,
nucleotides, cofactors and vitamins, 4 genes- for out cell proteins
controlling resistance to specific host factors, 46 genes for
production of non identified proteins . There are data which
have shown that probiotics (Lactobacillus GG) being inside intes-
tinal tract can express additionally over 400 new genes involved in
immune response and inflammation, cell growth and differentia-
tion, apoptosis, cell to cell signaling, cell adhesion resulting inwider
impact on the host’s gene expression than thought before the era of
macroarray technologies . It means that probiotic cells inside
the gastrointestinal tract may be involved in the interaction with
host specific factors (e.g. participation in the degradation and
production of different nutrients by different metabolic pathways
in small intestine and colon) .
It should be postulated that the mixture of probiotic bacteria
LMW compounds is responsible for their health-promoting effects,
rather than any one single component . The complexity
of“probiotic signaling” increases tremendously by the feeding of
different foods and by the presence of the intestinal microflora. The
enormous potential of these constant additional participants can
modulate the functionality of probiotic bacteria, their components
and metabolites (both positively and negatively). As a consequence
probiotic functionality and bioavailability may be altered or coin-
cidentally lost. Different types of analytical techniques should be
employed to monitor changes of probiotic effector molecules in the
digestive tract in the presence of food components and other
microorganisms and key intestinal and microbe enzymes involve in
these processes. The knowledge of these complex interactions and
compounds and nutrient ingredients involved may open new page
in the creation of new types of probiotics.
and hostcells LMW
There are no doubts in the nearest future quantity measurement
of probiotic (symbiotic) microbe origin LWM signaling molecules
with specific functional or metabolic activity in various human
biological samples may permit to disclose connection between
microbial ecology disorders and certain pathological condition and
evaluate effectiveness biotherapy. In Table 5 we offer, (as example),
some concrete approaches of use of probiotics and their microbial
LWM as well as separate micronutrients for alterations of Quorum
sensing regulation in prokaryotic and eukaryotic cells. Novel
scientific and applied investigations in the probiotic fields can
permit to work out and introduce principally new types of bio-
logical drugs, additives and functional foods (metabiotics) prepared
on the base of chemically purified substances of probiotic (symbi-
otic) microbe origin or their artificial analogs.
Using AHL biosensors based on the expression of green fluores-
cent protein were able to isolate a QS locus from a metagenome
the possibility to isolate QS loci from yet uncultured, and even
genes are often physically linked to the QS loci, this approached
might be useful also to identify genes that direct the synthesis of
novel bio-active compounds with pharmaceutical potential .
of bio-actives on the base of LMW chemical molecules of microbial
origin has already received development in Russia. During the last
decade next commercial metabiotics on the base of microbial cell
and signaling molecules have already been produced in Russia:
Saccharomyces autolysates (Nagipol), B. subtilis peptidoglycans
(Bactistatin), Corynebacteria cell wall substances (Codivak), Lactic
acid bacteria SCFA (Solcarmon; Frodo) and amino acids (Acilact-S),
bacteriocin preparations (nisin, staphylococcin, tomicid), escher-
ichia, lactobacilli and bifidobacteria Quorum sensing autoregulators
with low molecular masses (Aktoflor C, Poliflor, Microstim). Meta-
biotics as modifiers of physiological functions, biochemical and
behavior reactions have some advantages because they might have
exact chemical structure; they might be well dosed, they would be
very safe and have a long shelf-life.
In this review current knowledge of LMW bio-active molecules
contributing to the health-promoting actions of probiotic micro-
organisms are summarized. Symbiotic (probiotic) microorganisms
release of various soluble LMW molecules of different chemical
nature that are responsible for their pharmabiotic action in the host
resulting in beneficial effects. Their important characteristics may
Modulation of Quorum sensing regulation as target for selection of novel probiotics
and LMW- metabiotics.
? Protein synthesis inhibitors (e.g. antibiotics-inhibitors of protein
synthesis on ribosome level)
? Antagonists of ReceptoreLigand Interactions (e.g. fatty acids
trans-isomers, L eisomers of carbohydrates, lectins)
? Inhibitors of Acyl-HL Signaling (e.g. halogenated furanones;
extracts of different plants)
? Histidine kinase inhibitors
? Enzymes degrading QS-autoinducers (e.g. microbial acylases,
lactonases, specific proteases similar bifidobacteria serpins)
? Synthetic analogs of different autoinducers e imitators of signaling
? Micronutrients of microbial, plant and animal origin interfering in QS
regulation (e.g. lactones, lectins, polyphenols, ecdisteroids, etc)
B.A. Shenderov / Anaerobe 17 (2011) 490e495
Author's personal copy
be presented as both categories: adaptation and probiotic effects.
Thanks to LMW signaling molecules probiotic microorganisms are
capable to sense environment factors, interact with corresponding
cell surface, membrane, cytoplasm and nucleic acid receptors, to
reply quickly and coordinately by induction of special sets of genes,
to support stability of host genome and microbiome, to modulate
epigenomic regulation of gene phenotypic expression, to ensure
the information exchange in numerous bacterial and bacteria-host
systems playing an important role in the control for many genetic
and physiological functions, biochemical and behaviour reactions,
in cell growth and host development, in supporting host health in
general. Various symbiotic (probiotic) strains produce different
spectrum of such LMW molecules. This knowledge will help to
determine the optimal frequency, dose and mode of administration
for known and potential probiotic strains. There is chemical and
functional similarity between LMW bio-active metabolic and
signaling molecules synthesized by host eukaryotic cells (including
mammalian), indigenous and probiotic microorganisms and some
micronutrients. It means that low molecular weight bio-active
molecules are the global (universal) regulators of intra- and inter-
population communication of bacteria, eukaryotic cells and
bacteria with their host cells. Knowledge potential accumulated
concerning molecular languages of probiotic (symbiotic) microor-
ganisms allows researchers to better understand the mode of
action of known probiotics and to design in principle novel pro-
biotics (metabiotics) with increased health effectiveness. Detali-
zation of mode action and the determination of the content of the
known and novel representatives of modulin families remain to be
done. Soon we can successfully manipulate both the host and its
microbiota through interfering in their cross talk, stability and
epigenomic regulation of expression of genes using various types of
eukaryotic, prokaryotic and nutrition origin LMW molecules
capable to modulate human being genetic, metabolic and physio-
The author has declared that he has no interests which might be
perceived as posing a conflict or bias.
I sincerely appreciate the help from professor Tore Midtvedt
who first offered me an idea to prepare the review concerning
signaling molecules of probiotic bacteria and participated in its
design and discussion.
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