Citation
D. Peshev, W. Van den Ende
Fructans: prebiotics and immunomodulators
Journal of Functional Foods
Archived version
Author manuscript: the content of this pre-print version is
identical to the content of the published paper, but without the
final typesetting by the publisher
Published version
insert link to the published version of your paper
http://www.sciencedirect.com/science/article/pii/S175646461
4001376
Journal homepage
insert link to the journal homepage of your paper
http://www.journals.elsevier.com/journal-of-functional-foods/
Author contact
your email wim.vandenende@bio.kuleuven.be
your phone number + 32 (0)16321952
IR
Klik hier als u tekst wilt invoeren.
(article begins on next page)
Abstract
Fructans are natural fructose polymers derived from sucrose that are
produced by some plants and microorganisms. They are best known because
of their prebiotic and health improving properties in functional foods. In
plants, fructans are since long associated with stress responses. Although the
immunomodulatory properties of fructans on animal cells were known since
longer, their true mode of action has only recently been unraveled. It was
found that inulin-type fructans act as signals in animals, stimulating immune
cell activity through Toll Like Receptor (TLR)° mediated signaling. This review
summarizes recent progress in the area with focus on possible fructan
signaling and downstream signaling events in cells. Intriguingly, synergistic
effects with phenolic compounds are often observed. A picture is emerging
that fructans and their fermentation products (short chain fatty acids and
hydrogen gas) lead to a more reduced cellular status and a modulation of the
immune system, aiming at disease prevention. Moreover, evidence is
accumulating that fructans may alleviate inflammatory symptoms in diseased
subjects. Taken together with their well-characterized prebiotic and
antioxidant properties, this further adds to the full recognition of different
types of fructans as valuable functional food ingredients.
1. Introduction
There is increasing interest in functional foods, especially in Western societies.
Functional foods provide physiological or metabolic benefits by boosting the
immune system and counteracting diseases and degenerative disorders (Watzl
et al., 2005; Delgado et al., 2010). The health-beneficial properties of
functional foods are provided by ingredients that are naturally present in or
added to food or feed (Grajek et al., 2005). There are three main groups of
ingredients: probiotics (microorganisms), prebiotics (compounds as fibers) and
antioxidants (Saad et al., 2013), which all have become increasingly popular in
functional food markets.
Among the best known prebiotics are the fructans, fructose-derived oligo- and
polysaccharides accumulating in about 15% of flowering plants (Hendry, 1993),
including the economically important Poaceae and Asteraceae families. In
contrast to starch, plant-derived fructans are water-soluble compounds
directly derived from sucrose. Based on their structure, different types can be
distinguished: inulin (β2→1 linkage), levan (β2→6 linkage) and graminan
(β2→1 linkage and β2→6 linkages) types. Additionally, neo-inulin and neo-
levan type fructans with an internal glucose residue can be found (Di
Bartolomeo et al., 2013). Fructans are associated with stress responses in
plants (Van den Ende and El-Esawe, 2013 and references therein). Synergistic
effects and radical reactions between fructans and phenolic compounds may
occur in plant vacuoles (Peshev et al., 2013). Anthocyanins are an example of
such phenolic compounds acting as powerful antioxidants contributing to
stress tolerance in plants (Pourcel et al., 2013; Zhu et al., 2013; Nakabayashi et
al., 2014).
The regular intake of prebiotic fructans such as the fructose-based
oligosaccharides (FOS) and polysaccharides (e.g. inulin) sustain health and
overall well-being by (i) improving blood parameters, (ii) enhancing resistance
against intestinal as well as extra-intestinal pathogens, (iii) modulating immune
responses, and, finally, by (iv) decreasing allergies (Vos et al., 2007; Delgado et
al., 2010). While FOS and inulin are thought to exert their beneficial activities
mainly in the proximal part of the colon, there is a great interest in finding
different prebiotics or mixtures that exert their biological activity in the distal
colon where many chronic diseases originate. Branched fructans (e.g. cereal
graminans) and arabinogalactans may be beneficial in this respect (Allsopp et
al., 2013; Terpend et al., 2013; Yang et al., 2013). Usually, the effects of these
compounds are attributed to indirect mechanisms via their positive influence
on intestinal microflora (Gibson et al., 2004; Guarner, 2005; Roberfroid, 2007).
However, it has recently been suggested that such prebiotic oligosaccharides
may also contribute through more direct mechanisms, such as redox status
improve, scavenging of reactive oxygen species (ROS) (Van den Ende et al.,
2011) and priming of the immune system (Xu et al., 2006; Vogt et al., 2013a;
Tsai et al., 2013). Only recently, the underlying mechanisms have been
unraveled explaining the immunomodulatory properties of inulin-type fructans
in the human body (Vogt et al., 2013b and references therein).
2. Fructans: prebiotics, antioxidants and immunomodulators
Prebiotics are defined as “selectively fermented ingredients that allow specific
changes, both in the composition and/or activity in the gastrointestinal
microflora that confers benefits upon host well-being and health” (Roberfroid,
2007). Fructans are the most widely used prebiotics, among others (Al-Sheraji
et al., 2013 and references therein). Table 1 summarizes some of the main
fructan sources in human diets (we refer to Jovanovic-Malinovska et al., 2014
for a more extensive list). Inulin-type fructans are commonly commercially
produced from chicory roots (Cichorium intybus L) or Jerusalem artichoke
tubers (Helianthus tuberosus) (Paseephol & Sherkat, 2009). There is growing
interest in utilizing other sources of fructans, such as agave fructans and cereal
fructans (Di Bartolomeo et al., 2013 and references therein). The first clinical
tests with agave fructans are very promising (Holscher et al., 2014).
Additionally, fructan accumulating plants such as onion, garlic, globe artichoke
and
asparagus
are
extensively
used
in
medicine
with
reported
immunomodulatory and antiviral properties (Lattanzio et al., 2009; Lee et al.,
2012; Pandino et al., 2011; Thakur et al., 2012a; Chen et al., 2013). Fructans
are also found in other foods such as wheat, rye, oat, barley, leek, Belgian
endives, lettuce and salsify (Van den Ende and Van Laere, 2007; Di Bartolomeo
et al., 2013). Interestingly, cereals are the major fructan source in American
diets
(Andersson
et
al.,
2013).
Alongside
fructans,
cereal
arabinoxylooligosaccharides (AXOS) likely contribute to prebiotic effects after
consuming cereal products. Wheat bran derived AXOS stimulated the
bifidobacterial population in the same order as FOS. However, higher SCFA
production was observed with AXOS in comparison with FOS (Gullón et al.,
2014).
Prebiotic fructans are not digested (Van den Ende et al., 2011), although, due
to acid sensitivity, they may be subjected to minor hydrolysis in the stomach
(Di Bartolomeo et al., 2013). The inability of the human digestive system to
hydrolyze fructans is due to our lack of proper hydrolytic enzymes able to
tackle β linkages. However, the microflora in the colon is able to degrade these
bindings. When fructans reach the colon, they are more or less intact and
become a substrate for bacterial enzymes belonging to glycoside hydrolase
family GH32 (Van den Ende et al., 2011). The fermentation of fructans (such as
inulin and FOS) and lowered pH changes the colonic environment. This
stimulates the growth of beneficial bacteria such as bifidobacteria and
lactobacilli (Moro et al., 2002; Tarini & Wolever, 2010) (Table 2). In the
process, an increased production of short chain fatty acids (SCFAs: acetate,
propionate, and butyrate), lactic acid, hydrogen (H2) and carbon dioxide gasses
are observed. Inulin and FOS consumption also leads to an improved mineral
uptake in the gut (Scholz-Ahrens et al., 2007; van den Heuvel et al., 2010) and
a reduction in blood serum triacylglycerol levels (Brighenti, 2007). A
connection between inulin/FOS intake and reduced risk of colon cancer has
been suggested (Sauer et al., 2007; Verma & Shukla, 2013; Allsopp et al., 2013)
(Table 2). The modulation of the immune system by inulin-type fructans with
varying DPs (Lomax & Calder, 2009; Van den Ende, 2013) has now been
substantiated by hard data on their mode of action (Vogt et al., 2013b; see
below). Immunomodulatory effects have been suggested for many other
plant-derived polysaccharides (Li et al., 2014).
Next to their prebiotic effects through indirect mechanisms involving microbes
and the formation of SCFAs, fructans have been hypothesized to exert more
direct effects. In plant research, fructans and other sugars are now recognized
as antioxidants being able to scavenge ROS (Chen et al., 2009; HernandezMarin and Martínez, 2012; Peshev et al., 2013; Peshev & Van den Ende, 2013;
Keunen et al., 2013). However, similar processes might occur in foods and at
the gut interphase in humans (Van den Ende et al., 2011) (Table 2). According
to this view, prebiotic fructans may prevent or treat diseases by reducing ROS
levels (Fig. 1). A connection between oxidative stress and an array of gut
diseases is well established (Van den Ende et al., 2011; Bhattacharyya et al.,
2014). Moreover, it has been reported that soluble gut oligosaccharides mimic
the sugar chains on the glycoproteins and glycolipids present on gut epithelial
cells, thereby preventing the adhesion of pathogenic microorganisms (Dai et
al., 2000) (Table 2). Recently, it was proposed that FOS and inulins exert direct
antimicrobial effects (Ortega-González et al., 2014).
3. Immunomodulatory oligo- and polysaccharides acting as signals. The
role of Toll-like receptors.
Plants only rely on innate immunity responses for their defense (Bolouri
Moghaddam & Van den Ende 2013; Pastor et al., 2013), while higher
vertebrates have a complex immune system comprised of innate and adaptive
immunity that has been extensively reviewed elsewhere (Dempsey et al.,
2003). Briefly, innate and adaptive immunity are tightly interlinked and
capable of either preventing or limiting infections, in addition to eliminating
tumor cells. Innate immunity mechanisms are evolutionarily older and include
an ancestral set of defense responses that are found in most multicellular
organisms. Specialized immune cells such as macrophages (and their
precursors, the monocytes), dendritic cells (DC), lymphocytes and neutrophils
are key players in vertebrate innate immunity. These cells contain Pathogen
Recognition Receptors (PRRs) for general recognition of molecular patterns in
microorganisms, the so-called Pathogen-Associated Molecular Patterns
(PAMPs). Along with the capability of macrophages and monocytes to kill
microorganisms by phagocytosis, Natural Killer cells (NK) cells are able to
destroy viruses and tumor cells.
The best characterized PRRs include the Toll-Like Receptors (TLRs), especially
TLR2 and TLR4, which are crucial proteins interlinking native and adaptive
immunity (Akira & Takeda 2004). When these TLRs recognize for instance
lipopolysaccharides (LPS) or other PAMPS, a TLR-associated signaling cascade
leads to the activation of NF-κB and/or other transcription factors (Fig. 1),
increasing the secretion of cytokines and activating genes that play a role in
adaptive immune responses. Natural plant compounds such as oligo- or
polysaccharides and phenolic compounds may mimic PAMPs and bind as
ligands on the TLR receptors, also resulting in immunomodulatory effects (Fig.
1). Therefore, TLRs are emerging as important pharmacological targets for
plant-derived compounds in infectious and inflammatory diseases (Liu et al.,
2011).
It is accepted that β-glucans can act as signals and immunomodulators (Brown
et al., 2002; Ma & Underhill, 2013 and references therein). Similar roles have
been proposed for many other types of (plant-derived) oligo- and
polysaccharides. Along with the antiviral and immunomodulatory properties of
inulins and other fructans (Lee et al., 2011, 2012), they have now been
demonstrated to act as true signaling compounds (Vogt et al., 2013b).
Previously, Roller et al. (2004) predicted that prebiotics can directly influence
the activity of immune cells, independent of their effects on the microbiota.
Several breakthrough papers recently appeared in this area, providing deep
mechanistic insights into the mode of action of plant-derived polysaccharides.
First, it was shown that the maltoheptaose oligosaccharide derived from
wheatgrass activates monocytes through TLR2 signaling (Tsai et al., 2013).
Second, Vogt et al. (2013b) demonstrated that different DP classes of inulintype fructans modulate the activity of human peripheral blood mononuclear
(HPBM) cells, regulated by TLR2, and to a lesser extent by TLR4, 5, 7 and 8 (Fig.
1). Lower DP inulin-type fructans increased the ratio of interleukin 10 (IL10) to
IL12 in HPBM cells, inducing a more anti-inflammatory balance (Vogt et al.,
2013b). TLR4 specificity was earlier reported for levan-type fructans (Xu et al.,
2006). In rat monocytes, prebiotic oligosaccharides directly modulate
proinflammatory cytokine production through activation of TLR4 (CapitánCañadas et al., 2013). Recently, TLR4 was reported to be the main form
involved in immunostimulation with inulin acetate as a novel adjuvant
(Tummula & Kumar, 2013).
Early in their evolution, eukaryotic cells developed a sophisticated energysensing protein kinase complex to monitor metabolic status and maintain
energy homeostasis during both normal growth and development and in stress
conditions (Ramon et al., 2013). AMP-activated kinase (AMPK) fulfills this role
in animals (Viollet et al., 2006). SNF1 (sucrose non-fermenting 1) kinase and
plant SnRK1 (SNF1-related kinase 1) are the counterparts in yeast and plants,
respectively (Ramon et al., 2013). Many hepatic disorders find their origin in
abnormally low AMPK activities in the liver, and developing strategies to
increase these AMPK activities is a major goal in health research (Viollet et al.,
2006). AMPK inhibits nuclear factor kappa-light-chain-enhancer of activated B
cell (NF-κB) signaling (Salminen et al., 2011)(Fig. 1). Another important
signaling cascade in animals is the PI3K (phosphatidylinositol 3-kinase) /AKT
(Protein Kinase B) /mTOR (mammalian target of rapamycin) pathway (Martelli
et al., 2011). It is becoming clear that AMPK lies at the crossroads of
metabolically driven macrophage inflammation and exerts control over
mitochondrial metabolism, and therefore is vital for dictating the
inflammatory status of macrophages (Steinberg and Schertzner, 2014).
It should be noted that macrophages and monocytes are not the only immune
cells that are influenced by fructans, since NK cell activity increases with
fructans have also been reported (Thakur et al., 2012a). In addition to
(poly)saccharides, phenolic compounds are also known as agonists or
antagonists in TLR-mediated signaling (Fig. 1). For instance, malvidin, a red
wine polyphenol, is able to attenuate LPS/TLR4 mediated signaling in
RAW264.7 cells (a murine macrophage line) (Bognar et al., 2013). Therefore,
plant extracts, typically containing variable mixtures of (poly)saccharides and
phenolic compounds, may exert variable effects on downstream NF-κBmediated and/or other signaling pathways(Fig. 1).
Clearly, TLR receptors are more specific for bacterial LPS, but plant-derived
polysaccharides seem to be able to mimic these bacterial ligands to a certain
extent. Caution is warranted when attempting to predict the outcome of such
plant polysaccharide/TLR interactions. Therefore, fructan DP (Vogt et al.,
2013b), linkage type, branching, dose and presence of additional groups (e.g.
acetate, see above) might influence the interactions between these ligands
and the different TLRs, possibly determining the exact outcome of the TLR
signaling process. The minimal DP required for biological activity was
investigated on fructans isolated from Polygonatum cyrtonema that were
hydrolyzed and fractionated. DP 4 and 5 were the shortest chains that retained
activity against herpes simplex virus type 2 (HSV-2) in Vero cell culture (Fen et
al., 2004). Further investigation is needed to determine whether the mode of
action of other immunomodulatory plant-derived (poly)saccharides such as
arabinoxylans and arabinogalactans (Chlubnová et al., 2011; Francois et al.,
2012; Park et al., 2012; Cholujova et al., 2013) also involve TLR-mediated
signaling mechanisms. This seems to be the case for β-1,4-mannobiose which
stimulates innate immune responses and induces TLR4-dependent activation
of mouse macrophages. By contrast, it reduces the severity of inflammation
during endotoxemia in mice (Kovacs-Nolan et al., 2013). Therefore, the effects
of oligosaccharide applications may depend on the cell type and the condition
(diseased or not) of the study objects.
Fructans are also recognized key compounds in major east medical traditions
such as Chinese medicinal herbs, Indian ayurvedic herbs (Thakur et al., 2012b)
and Chikuyo-Sekko-To (a traditional Japanese herbal (Kampo) medicine; Lee et
al., 2011). Chikuyo-Sekko-To is a mixture of herbs that are used to counteract
infections. A highly branched fructan has been recently purified from ChikuyoSekko-To, showing anti-herpes simplex virus type 2 (HSV-2) effects both in vitro
and in vivo. The in vivo anti-HSV-2 effect was evaluated and confirmed using
the murine HSV-2 genital infection model. Fructan antiviral properties have
also been tested in vitro on RAW264.7 cells (a murine macrophage line). The
fructan stimulated production of a viral replication inhibitor, NO, and other
immunostimulatory factors (e.g. IL-1β, IL-6, IL-10, IFN-γ and TNF-α). Also inulin
stimulates NO production in IFN-γ primed RAW264.7 cells (Koo et al., 2003).
Similarly, fructans isolated from Welsh onion (Allium fistulosum L.) stimulated
NO production in RAW 264.7 cells (Lee et al., 2012) and enhanced the
production of antibodies against influenza A virus and demonstrated an
inhibitory effect on virus replication in vivo. However, this fructan fraction
lacked anti-influenza A viral activity in vitro.
4. A role for fructans and SCFAs as signals?
Besides their effects on immune cells, fructans and/or SCFAs might be sensed
by other cells in the human or animal body as well. In the colon, a vast amount
of prebiotic fructans present in diets are fermented to SCFAs and gases (e.g.
H2, Fig. 1) by probiotic bacteria such as bifidobacteria and lactobacilli. Most
studies so far have focused on inulins and FOS-type prebiotics. Theoretically,
intact inulins or FOS present in the ileum or in the proximal part of the colon
could (i) be sensed by PRRs in the gut epithelial membranes (Fig. 1) and (ii) be
subject to absorption in epithelial cells by endocytotic mechanisms (Fig. 1).
The very low default TLR2 expression in human gut epithelial cells seems to
argue against the above-mentioned inulin/FOS signaling mechanisms in nondiseased subjects (Melmed et al., 2003). However, TLR2-unresponsive colon
cells might be indirectly stimulated through TLR1 and TLR4 (Mukherjee et al.,
2013) and TLR2/4 expression in these cells is upregulated in diseased subjects
(Frolova et al., 2008). Alternatively or additionally, other types of PRRs in
human gut epitheleal cells may be involved in sensing prebiotics. In rat
intestinal epithelial cells, different nondigestible oligosaccharides exert
nonprebiotic effects by enhancing the immune response via activation of TLR4
with involvement of NF-κB signaling (Ortega-González et al., 2013). Overall,
TLR expression and functioning might greatly differ between organ and tissue
types, cell types and species (Willcocks et al., 2013).
As discussed before, a limited absorption of inulin/FOS in epithelial cells
cannot be excluded (Van den Ende et al., 2011; Di Bartolomeo et al., 2013).
However, fructans may have difficulties to enter the blood stream since the
low pH in the lysosomes may lead to (partial) hydrolysis, since fructans are
acid-sensitive. Despite these limitations, there is some evidence for absorption
(Fig. 1) of higher DP inulin and lower DP galacto-oligosaccharides from the gut
(Eiwegger et al., 2010; Van den Ende et al., 2011 and references therein).
Further research is required to verify their presence in portal blood in order to
substantiate the possibility that these prebiotics may act as true systemic
signals. Similarly, not all phenolic compounds are believed to be able to cross
the gut epithelial plasma membrane (Scheepens et al., 2010; VelderrainRodriguez et al., 2014) (Fig. 1). The health promoting properties of
anthocyanin-type phenolic compounds, for instance those derived from
blueberries, are well documented (Norberto et al., 2013). Anthocyanins seem
to be able to enter gut epithelial cells (Faria et al., 2009). Moreover,
Phuwamongkolwiwat et al. (2013) suggested that FOS stimulates the uptake of
phenolic compounds. Additionally, non-absorbable phenolic compounds might
be sensed by receptors in the gut epithelial membranes (Fig. 1).
The most general line of thinking in the literature explains the effects of inulintype prebiotics via an indirect mechanism through the formation of SCFAs (Fig.
1), with particular focus on butyrate as a signaling agent (Peng et al., 2009).
The hypothesis proposed by Hu et al. (2010) states that prebiotic-derived
SCFAs are readily taken up in gut epithelial cells (Fig. 1) and may be partly
transported into the liver (Bindels et al., 2012; Endo et al., 2013). Both SCFAs
and H2 gas may contribute to altered redox balances differentially influencing
signaling events (Nishimura et al., 2013) (Fig. 1), potentially counteracting
oxidative stresses and the development of ROS-related diseases (Nishimura et
al., 2013). Regardless of the exact underlying mechanisms, it is clear that
inclusion of fructans in diets can lead to better antioxidant and lipid
parameters in the blood and in different organs (Brighenti et al., 2007; Kazak
et al., 2011), which may be important to prevent or counteract diseases (Van
den Ende et al., 2011 and references therein).
Peng et al. (2009) described that butyrate enhances the intestinal barrier by
facilitating tight junction assembly via activation of AMPK signaling in Caco-2
cell monolayers, a well-known in vitro model for the intestinal epithelium. The
absorption of propionate in the portal blood and entrance in the liver was
recently demonstrated (Bindels et al., 2012). Certain phenolic compounds
might reach the liver via the same route. For instance, a specific green tea
phenolic compound binds to the 67 kDa Laminin Receptor in a human
hepatoma cell line (Fujimura et al., 2012). Can inulin, SCFAs and phenolic
compounds induce AMPK signaling as well (Fig. 1)? Elamin et al. (2013)
demonstrated that SCFAs stimulate AMPK activation in Caco-2 cell
monolayers. In their in vitro studies, Yun et al. (2009) showed that inulin can
increase the uptake of glucose (Fig. 1) in HepG2 hepatoma cells and in C2C12
myotubes. This was also associated with AMPK and AKT signaling. However, it
remains to be demonstrated that inulin (and/or inulin degradation products)
can effectively reach the liver in vivo. The phenolic compounds tangeritin and
chicoric acid are recognized AMPK stimulators (Kim et al., 2012; Schlernitzauer
et al., 2013) (Fig. 1). Recently, Endo et al. (2013) demonstrated that probiotic
application of Clostridium butyricum, a butyrate producer, enhanced butyrate
concentrations in the gut. These authors propose that the butyrate signaling
pathway relies on AMPK activation (Fig. 1) and subsequent regulation of AKT
phosphorylation through the modification of SIRT1, PI3K, and mTORC1/2,
resulting in the stimulation of liver AMPK and PI3K/AKT/mTOR signaling,
counteracting the progression of nonalcoholic fatty liver disease in rats.
In humans, prebiotics and probiotics alleviate the symptoms of chronic
inflammation in patients with ulcerative colitis (Furrie et al., 2004). Opposite to
Benjamin et al. (2011), it was suggested that inclusion of oligofructose
enriched inulin, a mixture of low and higher DP fructans from chicory,
alleviates the symptoms of Crohn disease (CD, Joossens et al., 2012). Recently,
De Preter et al. (2013) showed that CD patients have significantly lower
butyrate levels in their guts as compared to healthy subjects. Moreover, it was
possible to increase butyrate levels again to normal by oligofructose enriched
inulin inclusion in the diets of CD patients. Taken all together, as predicted by
Hu et al. (2010), these observations suggest that microbiota–derived butyrate
may act as local and systemic signals in humans, contributing to disease
prevention and overall health, and alleviating symptoms in diseased subjects.
In wild-type mice with colitis, inclusion of 150 mM Na acetate in the drinking
water alleviated the disease index, while this treatment had no effect on mice
lacking G protein-coupled receptor 43 (GPR43 -/- mice). It was concluded
SCFA–GPR43 interactions modulate colitis by regulating inflammatory cytokine
production in mononuclear cells (Masui et al., 2013). GPR43 -/- GPR41 -/- mice
showed reduced inflammatory responses and had a slower immune response
against Citrobacter rodentium infection, clearing the bacteria more slowly
than wild-type mice (Kim et al., 2013). Interestingly, mice fed with a high fat
diet increased body fat associated with strongly increased GPR43 expression in
subcutaneous adipose tissues. Additionnal supplementation of inulin to the
high fat diet diet counteracted GPR43 expression and adipogenesis (Dewulf et
al., 2011).
Wang et al. (2012) used a fructan containing preparation from Ophiopogon
japonicus, exerting hypoglycemic effects in a mouse model and described the
involvement of the PI3K/AKT signaling pathway. The metabolic syndrome is
promoted by fructose-enriched diets in rats and is associated with increased
levels of oxidative stress and lowered AMPK activities (Viollet et al., 2006;
Rault-Nania et al., 2008) (Fig. 1). Inulin-type fructans are able to counteract
fructose-induced hypertension, probably by activating AMPK signaling and
suppressing inflammatory processes via downregulation of NF-κB signaling
(Fig. 1) (Rault-Nania et al., 2008; Salminen et al., 2011; Nassar et al., 2013).
Similar mechanisms might be involved to explain the health promoting
properties of phenolic compounds
(Huang & Lin 2012; Shahidi &
Chandrasekara, 2013). Indeed, AMPK signaling was also reported to be
involved in such processes (Zang et al., 2006; Wu et al., 2013).
5. Conclusions and perspectives
The recent finding that inulin-type fructans bind as ligands to TLR2 and TLR4
provides a mechanistic explanation for their immunomodulatory properties.
Evidence is accumulating that other fructan-types have prebiotic, antioxidant
and immunomodulatory properties as well. Fructans and their fermentation
products (SCFAs, H2) may act as signaling compounds and/or cellular redox
regulators, differentially affecting different cell types by influencing AMPK
and/or NF-κB signaling pathways. The immunomodulatory effects of fructans
and their fermentation products may counteract the development of various
diseases, but this requires further research. Moreover, evidence is
accumulating that fructans may also alleviate inflammatory symptoms in
diseased subjects. Taken together with their well-characterized prebiotic and
antioxidant properties, this further contributes to the full recognition of
fructans as valuable functional food ingredients.
References
Akira, S. & Takeda, K. (2004). Toll-like receptor signalling. Nature Reviews
Immunology, 4, 499-511.
Allsopp, P., Possemiers, S., Campbell, D., Oyarzábal, I.S., Gill, C. & Rowland, I.
(2013). An exploratory study into the putative prebiotic activity of fructans
isolated from Agave angustifolia and the associated anticancer activity.
Anaerobe, 22, 38-44.
Al-Sheraji S.H., Ismail A., Manap, M.Y., Mustafa, S., Yusof R.K. & Hassan, F.A.
(2013). Prebiotics as functional foods: A review. Journal of Functional Foods, 5,
1542-1553.
Andersson, A.A.M., Andersson, R., Piironen, V., Lampi, A.-M., Nyström, L.,
Boros, D., Fraś, A., Gebruers, K., Courtin, C.M., Delcour J.A., Rakszegi, M., Bedo,
Z., Ward, J.L., Shewry, P.R., & Åman, P. (2013). Contents of dietary fibre
components and their relation to associated bioactive components in whole
grain wheat samples from the HEALTHGRAIN diversity screen. Food Chemistry,
136, 1243-1248.
Arrizon, J., Morel, S., Gschaedler, A. & Monsan, P. (2010). Comparison of the
water-soluble carbohydrate composition and fructan structures of Agave
tequilana plants of different ages. Food Chemistry, 122, 123-130.
Benjamin, J.L., Hedin, C.R., Koutsoumpas, A., Ng, S.C., McCarthy, N.E., Kamm,
M.A., Hart, A.L., Sanderson, J.D., Knight, S.C., Forbes, A., Stagg, A.J., Whelan, K.
& Lindsay, J.O. (2011). Randomised, double-blind, placebo-controlled trial of
fructo-oligosaccharides in active Crohn. Gut, 60, 923-929.
Bhattacharyya, A., Chattopadhyay, R., Mitra, S., & Crowe, S.E. (2014). Oxidative
stress: an essential factor in the pathogenesis of gastrointestinal mucosal
diseases. Physiological Reviews, 94, 329-354.Bindels, L.B., Porporato, P.,
Dewulf, E.M., Verrax, J., Neyrinck, A.M., Martin, J.C., Scott, K.P., Buc Calderon,
P., Feron, O., Muccioli, G.G., Sonveaux, P., Cani, P.D. & Delzenne, N.M. (2012).
Gut microbiota-derived propionate reduces cancer cell proliferation in the
liver. British Journal of Cancer, 107, 1337-1344.
Bognar, E., Sarszegi, Z., Szabo, A., Debreceni, B., Kalman, N., Tucsek, Z.,
Sumegi, B. & Gallyas, F. (2013). Antioxidant and anti-inflammatory effects in
RAW264.7 macrophages of malvidin, a major red wine polyphenol. PloS One,
8(6).
Bolouri Moghaddam, M.R. & Van den Ende, W. (2013). Sweet immunity in the
plant circadian regulatory network. Journal of Experimental Botany, 64, 14391449.
Brighenti, F. (2007). Dietary fructans and serum triacylglycerols: A metaanalysis of randomized controlled trials. Journal of Nutrition, 137, 2552S2556S.
Brown, G.D., Taylor, P.R., Reid, D.M., Willment, J.A., Williams, D.L., Martinez
Pomares, L. & Gordon, S. (2002). Dectin-1 is a major beta-glucan receptor on
macrophages. Journal of Experimental Medicine, 196, 407-412.
Capitán-Cañadas, F., Ortega-González, M., Guadix, E., Zarzuelo, A., Suárez, M.
D., de Medina, F. S. and Martínez-Augustin, O. (2013). Prebiotic
oligosaccharides directly modulate proinflammatory cytokine production in
monocytes via activation of TLR4. Molecular Nutrition & Food Research.
doi: 10.1002/mnfr.201300497
Chen, S.K., Tsai, M.L., Huang, J.R. & Chen, R.H. (2009). In vitro antioxidant
activities of low-molecular-weight polysaccharides with various functional
groups. Journal of Agricultural and Food Chemistry, 57, 2699-2704.
Chen, J., Cheong, K.L., Song, Z., Shi, Y. & Huang, X. (2013). Structure and
protective effect on UVB-induced keratinocyte damage of fructan from white
garlic. Carbohydrate Polymers, 92, 200-205.
Cholujova, D., Jakubikova, J., Czako, B., Martisova, M., Hunakova, L., Duraj, J.,
Mistrik, M. & Sedlak, J. (2013). MGN-3 arabinoxylan rice bran modulates
innate immunity in multiple myeloma patients. Cancer Immunology,
Immunotherapy, 62, 437-445.
Chlubnová, I., Sylla, B., Nugier Chauvin, C., Daniellou, R., Legentil, L., Kralová, B.
&
Ferriáres,
V.
(2011).
Natural
glycans
and
glycoconjugates
as
immunomodulating agents. Natural Product Reports, 28, 937-952.
Dai, D.W., Nanthkumar, N.N., Newburg, D.S. & Walker, W.A. (2000). Role of
oligosaccharides and glycoconjugates in intestinal host defense. Journal of
Pediatric and Gastroenterology Nutrition, 30, S23-S33.
Delgado, G.T.C., Tamashiro, W. & Pastore, G.M. (2010). Immunomodulatory
effects of fructans. Food Research International, 43, 1231-1236.
Dempsey, P.W., Cheng, G. & Vaidya, S.A. (2003). The art of war: Innate and
adaptive immune responses. Cellular and Molecular Life Sciences, 60, 26042621.
De Preter, V., Joossens, M., Ballet, V., Shkedy, Z., Rutgeerts, P., Vermeire, S. &
Verbeke, K. (2013). Metabolic profiling of the impact of oligofructose-enriched
inulin in Crohn’s disease patients: a double-blinded randomized controlled
trial. Clinical and Translational Gastroenterology, 4, e30.
Dewulf, E.M., Cani, P.D., Neyrinck, A.M., Possemiers, S., Van Holle, A.,
Muccioli, G., Deldicque, L., Bindels, L.B., Pachikian, B.D., Sohet, F.M., Mignolet,
E., Francaux, M., Larondelle, Y. & Delzenne, N.M. (2011). Inulin-type fructans
with prebiotic properties counteract GPR43 overexpression and PPARgammarelated adipogenesis in the white adipose tissue of high-fat diet-fed mice.
Journal of Nutritional Biochemistry, 22, 712-722.
Di Bartolomeo, F., Startek, J. & Van den Ende, W. (2013). Prebiotics to fight
diseases: reality or fiction? Phytotherapy Research, 27, 1453-1473.
Eiwegger, T., Stahl, B., Haidl, P., Schmitt, J., Boehm, G., Dehlink, E., Urbanek, R.
& Szepfalusi, Z. (2010). Prebiotic oligosaccharides: in vitro evidence for
gastrointestinal epithelial transfer and immunomodulatory properties.
Pediatric Allergy and Immunology, 21, 1179-1188.
Elamin, E.E., Masclee, A.A., Dekker, J., Pieters, H-J. & Jonkers, D.M. (2013).
Short-chain fatty acids activate AMP-activated protein kinase and ameliorate
ethanol-induced intestinal barrier dysfunction in Caco-2 cell monolayers.
Journal of Nutrition, 143, 1872-1881. Endo, H., Niioka, M., Kobayashi, N.,
Tanaka, M. & Watanabe, T. (2013). Butyrate-producing probiotics reduce
nonalcoholic fatty liver disease progression in rats: new insight into the
probiotics for the gut-liver axis. Plos One, 8(5).
Faria, A., Pestana, D., Azevedo, J., Martel, F., de Freitas, V., Azevedo, I.,
Mateus, N. & Calhau, C. (2009). Absorption of anthocyanins through intestinal
epithelial cells - Putative involvement of GLUT2. Molecular Nutrition & Food
Research, 53, 1430-1437.
Fen, L., Liu, Y.H., Meng, Y.W., Min, Y. & He, K.Z. (2004). Structure of
polysaccharide from Polygonatum cyrtonema Hua and the antiherpetic activity
of its hydrolyzed fragments. Antiviral Research, 63, 183-189.Francois, I.E.,
Lescroart, O., Veraverbeke, W.S., Marzorati, M., Possemiers, S., Evenepoel, P.,
Hamer, H., Houben, E., Windey, K., Welling, G.W., Delcour, J.A., Courtin, C.M.,
Verbeke, K. & Broekaert, W.F. (2012). Effects of a wheat bran extract
containing
arabinoxylan
oligosaccharides
on
gastrointestinal
health
parameters in healthy adult human volunteers: a double-blind, randomised,
placebo-controlled, cross-over trial. British Journal of Nutrition, 108, 22292242.
Frolova, L., Drastich, P., Rossmann, P., Klimesova, K., Tlaskalova-Hogenova, H.
(2008).
Expression of Toll-like receptor 2 (TLR2), TLR4, and CD14 in biopsy samples
of patients with inflammatory bowel diseases: upregulated expression of TLR2
in terminal ileum of patients with ulcerative colitis. Journal of Histochemistry
and
Cytochemistry
56, 267–274.
Fujimura, Y., Sumida, M., Sugihara, K., Tsukamoto, S. & Yamada, K. (2012).
Green tea polyphenol EGCG sensing motif on the 67-kDa Laminin Receptor.
Plos One, 7(5).
Furrie, E., Macfarlane, S., Kennedy, A., Cummings, J.H., Walsh, S.V., O'Neil, D.A.
& Macfarlane, G.T. (2005). Synbiotic therapy (Bifidobacterium longum/Synergy
1) initiates resolution of inflammation in patients with active ulcerative colitis:
a randomised controlled pilot trial. Gut, 54, 242–249
Gibson, G.R. & Roberfroid, M.B. (1995). Dietary modulation of the human
colonic microbiota: introducing the concept of prebiotics. Journal of Nutrition,
125, 1401-1412.
Gibson, G.R., Probert, H.M., Van Loo, J., Rastall, R.A. & Roberfroid, M.B. (2004).
Dietary modulation of the human colonic microbiota: updating the concept of
prebiotics. Nutrition Research Reviews, 17, 259-275.
Guarner, F. (2005). Inulin and oligofructose: impact on intestinal diseases and
disorders. British Journal of Nutrition, 93, S61-S65.
Gullón, B., Gullon, P., Tavaria, F., Pintado, M. & Gomes, A.M. (2014). Structural
features
and
assessment
of
prebiotic
activity
of
refined
arabinoxylooligosaccharides from wheat bran. Journal of Functional Foods, 6,
438-449.
Grajek, W., Olejnik, A. & Sip, A. (2005). Probiotics, prebiotics and antioxidants
as functional foods. Acta Biochimica Polonica, 52, 665-671.
Hendry, G.A.F. (1993). Evolutionary origins and natural functions of fructans –
a climatological, biogeographic and mechanistic appraisal. New Phytologist,
123, 3-14.
Hernandez-Marin, E. & Martínez, A. (2012). Carbohydrates and their free
radical scavenging capability: a theoretical study. The Journal of Physical
Chemistry B, 116, 9668–9675.
Hidaka, H., Tashiro, Y. & Eida, T. (1991). Proliferation of bifidobacteria by
oligosaccharides and their useful effect on human health. Bifidobactaria
Microflora, 10, 65–79.
Holscher, H.D., Doligale, J.L., Bauer L.L., Gourineni, V., Pelkman C.L., Fahey
G.C., & Swanson K.S. (2014). Gastrointestinal tolerance and utilization of agave
inulin by healthy adults. Food & Function. DOI: 10.1039/C3FO60666J.
Hu, G., Chen, G., Xu, H., Ge, R. & Lin, J. (2010). Activation of the AMP activated
protein kinase by short-chain fatty acids is the main mechanism underlying the
beneficial effect of a high fiber diet on the metabolic syndrome. Medical
Hypothesis, 74, 123-126.
Huang, H. & Lin, J. (2012). Pu-erh tea, green tea, and black tea suppress
hyperlipidemia, hyperleptinemia and fatty acid synthase through activating
AMPK in rats fed a high-fructose diet. Food & Function, 3, 170-177.
Joossens, M., De Preter, V., Ballet, V., Verbeke, K., Rutgeerts, P. & Vermeire, S.
(2012). Effect of oligofructose-enriched inulin (OF-IN) on bacterial composition
and disease activity of patients with Crohn. Gut, 61, 958-958.
Jovanovic-Malinovska, R., Slobodanka, K., & Eleonora Winkelhausen, E. (2014).
Oligosaccharide profile in fruits and vegetables as sources of prebiotics and
functional foods. International Journal of Food Properties, 17, 949-965.
Kazak, H., Toksoy, Öner, E., Barbosa, E.M., Dekker, R.F.H. & Khaper, N. (2011).
Biological significance of levan and glucan type exopolysaccharides in
pancreatic cells. Poster presented at the International Heart Conference,
Winnipeg.
Keunen, E., Peshev, D., Vangronsveld, J., Van den Ende, W. & Cuypers, A.
(2013). Plant sugars are crucial players in the oxidative challenge during abiotic
stress. Extending the traditional concept. Plant, Cell & Environment, 36, 12421255.
Kim, M.S., Hur, H.J., Kwon, D.Y. & Hwang, J. (2012). Tangeretin stimulates
glucose uptake via regulation of AMPK signaling pathways in C2C12 myotubes
and improves glucose tolerance in high-fat diet-induced obese mice. Molecular
and Cellular Endocrinology, 358, 127-34.
Kim, M.H., Kang, S.G., Park, J.H., Yanagisawa, M. & Kim, C.H. (2013). Shortchain fatty acids activate GPR41 and GPR43 on intestinal epithelial cells to
promote inflammatory responses in mice. Gastroenterology, 145, 396-406.
Kleessen, B., Sykura, B., Zunft, H.J. & Blaut, M. (1997). Effects of inulin and
lactose on faecal microflora, microbial activity and bowel habit in elderly
constipated persons. American Journal of Clinical Nutrition, 65, 1397–1402.
Koo, H.N., Hong, S.H., Seo, H.G., Yoo, T.S., Lee, K.N., Kim, N.S., Kim, C.H. & Kim,
H.M. (2003). Inulin stimulates NO synthesis via activation of PKC-alpha and
protein tyrosine kinase, resulting in the activation of NF-kappa B by IFNgamma-primed RAW 264.7 cells. Journal of Nutritional Biochemistry, 14, 598605.
Kovacs-Nolan, J., Kanatani, H., Nakamura, A., Ibuki, M. & Mine, Y. (2013). β1,4-mannobiose stimulates innate immune responses and induces TLR4dependent activation of mouse macrophages but reduces severity of
inflammation during endotoxemia in mice. Journal of Nutrition, 143, 384-391.
Lattanzio, V., Kroon, P.A., Linsalata, V., Cardinali, A. (2009). Globe artichoke: A
functional food and source of nutraceutical ingredients. Journal of Functional
Foods, 1, 131-144.
Lee, J.B., Fukai, T., Hayashi, K. & Hayashi, T. (2011). Characterization of fructan
from Chikuyo-Sekko-To, a Kampo prescription, and its antiherpetic activity in
vitro and in vivo. Carbohydrate Polymers, 85, 408-412.
Lee, J.B., Miyake, S., Umetsu, R., Hayashi, K., Chijimatsu, T. & Hayashi, T.
(2012). Anti-influenza A virus effects of fructan from Welsh onion (Allium
fistulosum L.). Food Chemistry, 134, 2164-2168.
Li, J., Nie, S., Xie, M. & Li, C. (2014). Isolation and partial characterization of a
neutral polysaccharide from Mosla chinensis Maxim. cv. Jiangxiangru and its
antioxidant and immunomodulatory activities. Journal of Functional Foods, 6,
410-418.Liu, X., Zheng, J. & Zhou, H. (2011). TLRs as pharmacological targets
for plant-derived compounds in infectious and inflammatory diseases.
International Immunopharmacology, 11, 1451-1456.
Lomax, A.R. & Calder, P.C. (2009). Prebiotics, immune function, infection and
inflammation: a review of the evidence. British Journal of Nutrition, 101, 633658.
Ma, J. & Underhill, D.M. (2013). β-Glucan signaling connects phagocytosis to
autophagy. Glycobiology, 23, 1047-1051.
Martelli, A.M., Evangelisti, C., Follo, M.Y., Ramazzotti, G., Fini, M., Giardino, R.,
Manzoli,
L.,
McCubrey,
J.A.
&
Cocco,
L.
(2011).
Targeting
the
phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin signaling
network in cancer stem cells. Current Medicinal Chemistry, 18, 2715-2726.
Masui, R., Sasaki, M., Funaki, Y., Ogasawara, N., Mizuno, M., Iida, A., Izawa, S.,
Kondo, Y., Ito, Y., Tamura, Y., Yanamoto, K., Noda, H., Tanabe, A., Okaniwa, N.,
Yamaguchi, Y., Iwamoto, T., & Kasugai, K. (2013). G protein-coupled receptor
43
moderates
gut
inflammation
through
cytokine
regulation
from
mononuclear cells. Inflammatory bowel diseases, 9, 2848-2856.
MacGregor, A.W. & Fincher, G.W. (1993). Carbohydrates of the barley grain,
pp 73-130. In A.W. MacGregor and R.S. Bhatty (eds). Barley chemistry and
technology, AACC, St Paul, MN.
Melmed, G., Thomas, L.S., Lee, N., Tesfay, S.Y., Lukasek, K., Michelsen, K.S.,
Zhou, Y., Hu, B., Arditi, M. & Abreu, M.T. (2003). Human intestinal epithelial
cells are broadly unresponsive to Toll-like receptor 2-dependent bacterial
ligands: implications for host-microbial interactions in the gut. Journal of
Immunology, 17, 1406-1415.
Moro, G., Minoli, I., Mosca, M., Fanaro, S., Jelinek, J., Stahl, B. & Boehm, G.
(2002).
Dosage-related
bifidogenic
effects
of
galacto-
and
fructooligosaccharides in formula-fed term infants. Journal of Pediatric and
Gastroenterology Nutrition, 34, 291-295.
Moshfegh, A.J., Friday, J.E., Goldman, J.P. & Ahuja, J.K.C. (1999). Presence of
inulin and oligofructose in the diets of americans. Journal of Nutrition, 129,
1407-1411. Mukherjee, S., Biswas, R. & Biswas, T. (2013). Alternative TLRs are
stimulated by bacterial ligand to induce TLR2-unresponsive colon cell
response. Cellular Signaling, 25, 1678-1688.
Nakabayashi, R., Yonekura Sakakibara, K., Urano, K., Suzuki, M. & Yamada, Y.
(2014). Enhancement of oxidative and drought tolerance in Arabidopsis by
overaccumulation of antioxidant flavonoids. Plant Journal, 77, 367-379.
Nassar, S.E., Ismail, G.M., El Damarawi, M.A. & El-Din, A.A. (2013). Effect of
inulin on metabolic changes produced by fructose rich diet. Life Science
Journal, 10(2).
Nishimura, N., Tanabe, H., Adachi, M., Yamamoto, T. & Fukushima, M. (2013).
Colonic hydrogen generated from fructan diffuses into the abdominal cavity
and reduces adipose mRNA abundance of cytokines in rats. The Journal of
Nutrition, 143, 1943-1949.
Norberto, S., Silva, S., Meireles, M., Faria, A., Pintado, M. & Calhau, C. (2013).
Blueberry anthocyanins in health promotion: A metabolic overview. Journal of
Functional Foods, 5, 1518-1528. Ortega-González, M., Ocón, B., Romero-Calvo,
I., Anzola, A., Guadix, E., Zarzuelo, A., Suárez, M. D., Sánchez de Medina, F. &
Martínez-Augustin,
O.
(2014).
Nondigestible
oligosaccharides
exert
nonprebiotic effects on intestinal epithelial cells enhancing the immune
response via activation of TLR4-NFκB. Molecular Nutrition and Food Research.
58, 384–393.
Ortega-González, M., Molina Santiago, C., Lopez Posadas R., Pacheco, D.
(2014).
Fructooligosacharides
reduce
Pseudomonas
aeruginosa
PAO1
pathogenicity through distinct mechanisms. PLoS ONE 9(1).
Pandino, G., Lombardo, S., Mauromicale, G. & Williamson, G. (2011). Profile of
polyphenols and phenolic acids in bracts and receptacles of globe artichoke
(Cynara cardunculus var. scolymus) germplasm. Journal of Food Composition
and Analysis, 24, 148-153.
Park, D.K., Hayashi, T. & Park, H. (2012). Arabinogalactan-type polysaccharides
(APS) from Cordyceps militaris grown on germinated soybeans (GSC) induces
innate immune activity of THP-1 monocytes through promoting their
macrophage differentiation and macrophage activity. Food Science and
Biotechnology, 21, 1501-1506.
Paseephol, T., Sherkat, F. (2009). Probiotic stability of yoghurts containing
Jerusalem artichoke inulins during refrigerated storage. Journal of Functional
Foods, 1, 311-318.
Pastor, V., Luna, E., Ton, J., Cerezo, M., García-Agustín, P. & Flors, V. (2013).
Fine tuning of reactive oxygen species homeostasis regulates primed immune
responses in Arabidopsis. Molecular Plant-Microbe Interactions, 26, 13341344.
Peng, L., Li, Z., Green, R.S., Holzman, I.R. & Lin, J. (2009). Butyrate enhances
the intestinal barrier by facilitating tight junction assembly via activation of
AMP-activated protein kinase in Caco-2 cell monolayers. Journal of Nutrition,
139, 1619-1625.
Peshev, D. & Van den Ende, W. (2013). Sugars as antioxidants in plants. In:
Tuteja N, Gill SS, eds. Crop Improvement under Adverse Conditions. New York,
USA: Springer Science + Business Media.
Peshev, D., Vergauwen, R., Moglia, A., Hideg, E. & Van den Ende, W. (2013).
Towards understanding vacuolar antioxidant mechanisms: a role for
fructans? Journal of Experimental Botany, 64, 1025-1038.
Phuwamongkolwiwat, P.,
Suzuki, T.,
Hira, T.
& Hara,
H. (2013).
Fructooligosaccharide augments benefits of quercetin-3-O- b -glucoside on
insulin sensitivity and plasma total cholesterol with promotion of flavonoid
absorption in sucrose-fed rats. European Journal of Nutrition, 53, 457-468.
Pourcel, L., Irani, N.G., Koo, A.J.K., Bohorquez-Restrepo, A., Howe, G.A. &
Grotewold, E. (2013). A chemical complementation approach reveals genes
and interactions of flavonoids with other pathways. Plant Journal, 74, 383–
397.
Ramon, M., Ruelens, P., Li, Y., Sheen, J., Geuten, K. & Rolland, F. (2013). The
hybrid four-CBS-domain KINβγ subunit functions as the canonical γ subunit of
the plant energy sensor SnRK1. Plant Journal, 75, 11-25.
Rault-Nania, M.H., Demougeot, C., Gueux, E., Berthelot, A., Dzimira, S.,
Rayssiguier, Y., Rock, E. & Mazur, A. (2008). Inulin supplementation prevents
high fructose diet-induced hypertension in rats. Clinical Nutrition, 27, 276-282.
Roberfroid, M. (2007). Prebiotics: The concept revisited. Journal of Nutrition,
137, 830S-837S.
Roller, M., Rechkemmer, G. & Watzl, B. (2004). Prebiotic inulin enriched with
oligofructose in combination with the probiotics Lactobacillus rhamnosus and
Bifidobacterium lactis modulates intestinal immune functions in rats. Journal
of Nutrition, 134, 153-156.
Rumessen, J.J., Bode, S., Hamberg, O. & Gudman-Hoyer, E. (1990). Fructans of
jerusalem artichokes: intestinal transport, absorption, fermentation and
influence. American Journal of Clinical Nutrition, 52, 675–781.
Saad, N., Delattre, C., Urdaci, M., Schmitter, J.M. & Bressollier, P. (2013). An
overview of the last advances in probiotic and prebiotic field. Food Science &
Technology, 50, 1-16.
Salminen, A., Hyttinen, J.M. & Kaarniranta, K. (2011). AMP-activated protein
kinase inhibits NF-κB signaling and inflammation: impact on healthspan and
lifespan. Journal of Molecular Medicine, 89, 667-676.
Sauer, J., Richter, K.K. & Pool-Zobel, B.L. (2007). Physiological concentrations
of butyrate favorably modulate genes of oxidative and metabolic stress in
primary human colon cells. Journal of Nutritional Biochemistry, 18, 736-745.
Scheepens, A., Tan, K. & Paxton, J.W. (2010). Improving the oral bioavailability
of beneficial polyphenols through designed synergies. Genes & Nutrition, 5,
75-87.
Schlernitzauer, A., Oiry, C., Casas, F., Chabi, B. & Cros, G. (2013). Chicoric acid
is an anti-oxidant molecule stimulating AMP Kinase, PGC-1alpha expression
and mitochondrial activity in a model of skeletal muscular cells. Fundamental
& Clinical Pharmacology, 27, 42-42.
Scholz-Ahrens, K.E., Ade, P., Marten, B., Weber, P., Timm, W., Asil, Y., Gluer,
C.C. & Schrezenmeir, J. (2007). Prebiotics, probiotics, and synbiotics affect
mineral absorption, bone mineral content, and bone structure. Journal of
Nutrition, 137, 838S-846S.
Shahidi, F. & Chandrasekara, A. (2013). Millet grain phenolics and their role in
disease risk reduction and health promotion: A review. Journal of Functional
Foods, 5, 570-581.
Steinberg, G.R. & Schertzer, J.D. (2014). AMPK promotes macrophage fatty
acid oxidative metabolism to mitigate inflammation: implications for diabetes
and
cardiovascular
disease.
Immunology
and
Cell
Biology
doi:10.1038/icb.2014.11
Tarini, J. & Wolever, T.M.S. (2010). The fermentable fibre inulin increases
postprandial serum short-chain fatty acids and reduces free-fatty acids and
ghrelin in healthy subjects. Applied Physiology, Nutrition and Metabolism, 35,
9-16.
Tsai, C., Lin, C., Tsai, H., Chen, C., Li, W., Yu, H., Ke, Y., Hsieh, W., Chang, C., Wu,
C., Chen, S. & Wong, C. (2013). The immunologically active oligosaccharides
isolated from wheatgrass modulate monocytes via Toll-like receptor-2
signaling. Journal of Biological Chemistry, 288, 17689-17697.
Terpend, K., Possemiers, S., Daguet, D. & Marzorati, M. (2013).
Arabinogalactan and fructo-oligosaccharides have a different fermentation
profile in the Simulator of the Human Intestinal Microbial Ecosystem (SHIME®).
Environmental Microbiology Reports, 5, 595-603.
Thakur, M., Connellan, P., Deseo, M.A., Morris, C., Praznik, W., Loeppert, R. &
Dixit, V.K. (2012a). Characterization and in vitro immunomodulatory screening
of fructo-oligosaccharides of Asparagus racemosus Willd. International Journal
of Biological Macromolecules, 50, 77-81.
Thakur, M., Weng, A., Fuchs, H., Sharma, V., Bhargava, C.S., Chauhan, N.S.,
Dixit, V.K. & Bhargava, S. (2012b). Rasayana properties of Ayurvedic herbs: Are
polysaccharides a major contributor. Carbohydrate Polymers, 87, 3-15.
Tummula, H. & Kumar, S. (2013). Inulin and inulin acetate formulations
WO 2013110050 A1.
Van den Ende, W., Peshev, D. & De Gara, L. (2011). Disease prevention by
natural antioxidants and prebiotics acting as ROS scavengers in the
gastrointestinal tract. Trends in Food Science & Technology, 22, 689-697.
Van den Ende, W. & Van Laere, A. (2007). Fructans in dicotyledonous plants:
Occurrence and metabolism. In: Recent Advances in Fructooligosaccharides
Research. ISBN: 81-308-0146-9. pp 1-14 Editors: Shiomi N, Benkeblia N,
Onodera S.
Van den Ende, W. (2013). Multifunctional fructans and raffinose family
oligosaccharides. Frontiers in Plant Science, 4, 247.
Van den Ende, W. & El-Esawe, S. (2013). Sucrose signaling pathways leading to
fructan and anthocyanin accumulation: A dual function in abiotic and biotic
stress responses?. Environmental and Experimental Botany, (epub ahead of
print), art.nr. http://dx.doi.org/10.1016/j.envexpbot.2013.09.017.van den
Heuvel, E.G.H.M., Muys, T., Van Dokkum, W. & Schaafsma, G. (1999).
Oligofructose stimulates calcium absorption in adolescents. American Journal
of Clinical Nutrition, 69, 544–548.
Velderrain-Rodriguez, G.R., Palafox Carlos, H., Wall Medrano, A. & AyalaZavala, J.F. (2014). Phenolic compounds: their journey after intake. Food &
Function, 5, 189-197.
Verma A, Shukla G. (2013). Administration of prebiotic inulin suppresses 1,2
dimethylhydrazine dihydrochloride induced procarcinogenic biomarkers fecal
enzymes and preneoplastic lesions in early colon carcinogenesis in Sprague
Dawley rats. Journal of Functional Foods, 5, 991-996.
Vogt, L., Meyer, D., Pullens, G., Faas, M., Smelt, M., Venema, K., Ramasamy, U.,
Schols, H.A. & de Vos, P. (2013a). Immunological properties of inulin-type
fructans.
Critical
Reviews
in
Food
Science
and
Nutrition.
DOI:10.1080/10408398.2012.656772
Vogt, L., Ramasamy, U., Meyer, D., Pullens, G., Venema, K., Faas, M.M., Schols,
H.A. & de Vos, P. (2013b). Immune modulation by different types of beta 2 ->
1-fructans is toll-like receptor ependent. Plos One, 8(7).
Vos, A.P., van Esch, B.C., Stahl, B., M'Rabet, L., Folkerts, G., Nijkamp, F.P. &
Garssen, J. (2007). Dietary supplementation with specific oligosaccharide
mixtures decreases parameters of allergic asthma in mice. International
Immunopharmacology, 7, 1582-1587.
Viollet, B., Foretz, M., Guigas, B., Horman, S., Dentin, R., Bertrand, L. & Hue, L.
(2006). Activation of AMP-activated protein kinase in the liver: a new strategy
for the management of metabolic hepatic disorders. Journal of Physiology,
574, 41–53.
Wang, L.Y., Wang, Y., Xu, D.S., Ruan, K.F., Feng, Y. & Wang, S. (2012). MDG-1, a
polysaccharide from Ophiopogon japonicus exerts hypoglycemic effects
through the PI3K/Akt pathway in a diabetic KKAy mouse model. Journal of
Ethnopharmacology, 143, 347–354
Watzl, B., Girrbach, S. & Roller, M. (2005). Inulin, oligofructose and
immunomodulation. British Journal of Nutrition, 93, S49-S55.
Willcocks S., Offord V., Seyfert, H.M., Coffey, T-J. & Welling, D. (2013). Speciesspecific PAMP recognition by TLR2 and evidence for species-restricted
interaction with Dectin-1. Journal of Leukocyte Biology, 94, 449-458.
Wu, C-H., Chen, S-C., Ou, T-T., Chyau C-C., Chang Y-C. & Wang C.J. (2013).
Mulberry leaf polyphenol extracts reduced hepatic lipid accumulation
involving regulation of adenosine monophosphate activated protein kinase
and lipogenic enzymes. Journal of Functional Foods, 5, 1620-1632.Xu, Q.,
Yajima, T., Li, W., Saito, K., Ohshima, Y. & Yoshikai, Y. (2006). Levan (beta-2, 6fructan), a major fraction of fermented soybean mucilage, displays
immunostimulating properties via Toll-like receptor 4 signalling: induction of
interleukin-12 production and suppression of T-helper type 2 response and
immunoglobulin E production. Clinical & Experimental Allergy, 36, 94-101.
Yamashita, K., Kawai, K. & Itakura, K. (1984). Effect of fructooligosaccharides
on blood glucose and serum lipids in diabetic subjects. Nutrition Research, 4,
961–966.
Yang, L-C., Lu, T-J. & Lin, W-C. (2013). The prebiotic arabinogalactan of
Anoectochilus formosanus prevents ovariectomy-induced osteoporosis in
mice. Journal of Functional Foods, 5, 1642-1653. Yun, H., Lee, J.H., Park, C.E.,
Kim, M.J., Min, B-I., Bae, H., Choe, W., Kang, I., Kim, S-S. &, Ha, J. (2009). Inulin
increases glucose transport in C2C12 myotubes and HepG2 cells via activation
of AMP-activated protein kinase and phosphatidylinositol 3-kinase pathways.
Journal of Medicinal Food, 12, 1023–1028.
Zang, M., Xu, S., Maitland Toolan, K.A., Zuccollo, A., Hou, X., Jiang, B.,
Wierzbicki, M., Verbeuren, T.J. & Cohen, R.A. (2006). Polyphenols stimulate
AMP-activated protein kinase, lower lipids, and inhibit accelerated
atherosclerosis in diabetic LDL receptor-deficient mice. Diabetes 55, 21802191.
Zhu, J.J., Li, Y.R. & Liao, J.X. (2013). Involvement of anthocyanins in the
resistance to chilling-induced oxidative stress in Saccharum officinarum L.
leaves. Plant Physiology and Biochemistry, 73, 427-433.
Acknowledgement
Darin Peshev and Wim Van den Ende are supported by grants from FWO
Vlaanderen. The authors thank Dr. Su Ma, Drs. Sarah Taylor and Dr. Leonie
Vogt for help and constructive discussions.
Figure legend
Figure 1 Simplified model depicting immunomodulatory activities of fructans,
phenolic compounds, SCFAs and H2.
Dietary fructans are fermented to SCFAs and gases (e.g. H2) in the gut. Dietary
fructans (and other carbohydrates) may stimulate cells through binding mainly
TLR2 and TLR4. Dietary phenolic compounds may mediate agonistic and
antagonistic effects through PRR (TLR) signaling. This leads to the stimulation
of NF-κB and/or other transcription factors, leading to differential
immunomodulation, depending on the particular cell type. Dietary fructans,
phenolics, SCFAs and H2 may counteract ROS, before and/or after their
absorption from the gut. Dietary fructans may stimulate the uptake of both Glc
and phenolics. SCFAs are readily absorbed and may lead to AMPK stimulation,
counteracting inflammation (e.g. Crohn disease), via direct effects or through
repression of NF-κB signaling. In the liver, similar processes may counteract
the adverse effects of excess dietary Fru (e.g. non-alcoholic fatty liver). AMPK:
AMP-activated kinase; Glc: glucose; Fru: fructose; NF-κB: nuclear factor kappalight-chain-enhancer of activated B cells; PRR: Pathogen Recognition Receptor;
ROS: reactive oxygen species; SCFA: short chain fatty acids; TF: transcription
factor; TLR: Toll-Like Receptor.
Tables
Table 1. Total fructan and FOS (small inulin-type fructan contents) contents in selected foods.
Data are taken from Moshfegh et al., 1999 with the exception of data for Agave tequilana
(Arrizon et al., 2010). Barley (MacGregor & Fincher, 1993) and wheat (Andersson et al., 2013)
are expressed in g/ 100g DW. FW: fresh weight. DW: dry weight.
Name
Binomial name
Fructan
FOS
content (g /
content (g
100 g FW)
/100 g FW)
Use
Food. Main source
Jerusalem
Helianthus
artichoke
tuberosus L.
16-20
12-15
for industrial
production of
fructans (inulin,
Chicory root
Agave
Garlic
Cichorium
intybus L
Agave tequilana
Allium sativum
L.
35.7-47.6
19.6-26.2
FOS and agave
fructan)
2.8-12.4
-
9-6
3.6-6.4
Food and
alternative
Onion
Allium cepa L.
Globe
Cynara
artichoke
scolymus L.
Asparagus
Asparagus
officinalis L.
1.1-7.5
1.1-7.5
2.0-6.8
0.2-0.7
2.0-3.0
2.0-3.0
3-10
2.4-8
medicine
Allium
Leek
ampeloprasum
Food. Cereals for
L.
Barley
Hordeum
grain*
vulgare L.
example are the
0.4-0.8
-
main source of
fructans
Banana
Musa sp
Wheat
Triticum
grain*
aestivum L.
0.3-0.7
0.3-0.7
in the american
diet
0.84-1.85
-
Table 2. Effects of FOS and inulin in the human body.
(Suggested) effect
Reference
Selective stimulation of benefical bacteria Gibson & Roberfroid, 1995; Tarini &
(e.g. Lactobacilli and Bifidobacteria)
Wolever, 2010
Relieve of constipation
Hidaka et al., 1991; Kleessen et al., 1997
Yamashita et al., 1984; Rumessen et al.,
Lowering of blood glucose levels
1990
van den Heuvel et al., 1999; Scholz-
Improved mineral uptake
Ahrens et al., 2007;
Reduction in blood serum triacylglycerol levels Brighenti, 2007
Reduction of colon pH
Tarini & Wolever, 2010
Increased production of short chain fatty acids
(SCFAs)
Tarini & Wolever, 2010
Reduced risk of colon cancer
Sauer et al., 2007; Allsopp et al., 2013
Stimulation of the immune system
Lomax & Calder, 2009; Vogt et al., 2013
Prevention
of
adhesion
of
pathogenic
microorganisms
Prevention or treatment of diseases by
reducing ROS levels
Growth
inhibition
microorganisms
of
pathogenic
Dai et al., 2000
Van den Ende et al., 2011
Ortega-González et al., 2014