Edited by: Lidia Santarpia, University of Naples Federico II, Italy
Reviewed by: Fátima Martel, University of Porto, Portugal; Dario Coletti, Sapienza University of Rome, Italy
This article was submitted to Clinical Nutrition, a section of the journal Frontiers in Nutrition
†These authors have contributed equally to this work
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
The hypothesis that links the increase in the intake of plant-source foods to a decrease in colorectal cancer (CRC) risk has almost 50 years. Nowadays, systematic reviews and meta-analysis of case-control and cohort studies confirmed the association between dietary patterns and CRC risk, in which the non-digestible carbohydrates (NDC) from plant-source foods are known to play beneficial effects. However, the mechanisms behind the physicochemical properties and biological effects induced by NDC on the decrease of CRC development and progression remain not fully understood. NDC from plant-source foods consist mainly of complex carbohydrates from plant cell wall including pectin and hemicellulose, which vary among foods in structure and in composition, therefore in both physicochemical properties and biological effects. In the present review, we highlighted the mechanisms and described the recent findings showing how these complex NDC from plant-source foods are related to a decrease in CRC risk through induction of both physicochemical effects in the gastrointestinal tract, fermentation-related effects, and direct effects resulting from the interaction between NDC and cellular components including toll-like receptors and galectin-3. Studies support that the definition of the structure-function relationship—especially regarding the fermentation-related effects of NDC, as well as the direct effects of these complex carbohydrates in cells—is crucial for understanding the possible NDC anticancer effects. The dietary recommendations for the intake of NDC are usually quantitative, describing a defined amount of intake per day. However, as NDC from plant-source foods can exert effects that vary widely according to the NDC structure, the dietary recommendations for the intake of NDC plant-source foods are expected to change from a quantitative to a qualitative perspective in the next few years, as occurred for lipid recommendations. Thus, further studies are necessary to define whether specific and well-characterized NDC from plant-source foods induce beneficial effects related to a decrease in CRC risk, thereby improving nutritional recommendations of healthy individuals and CRC patients.
Cancer is one of the leading cause of death globally. Around one-third of cancer-related death are mostly connected to behavioral and dietary habits including tobacco and alcohol use, lack of physical activity, high body mass index, and low intake of fruits and vegetables (
Recently, a prospective longitudinal study revealed that a dietary pattern characterized by the high intake of plant-source foods is associated to a delayed CRC risk up to 10 years (
Although NDC are resistant to digestion by human enzymes, these carbohydrates are not a static collection of food components that pass through the gastrointestinal tract without inducing biological effects. Instead, NDC modulate nutrient absorption through binding to organic molecules that induce indirect biological effects acting as substrate for colonic fermentation by the gut microbiota (
As the chemical structure strongly influences the physicochemical properties and the biological effects of NDC from plant-source foods, it is necessary to define the main structural patterns of biologically active NDC in CRC models. NDC are comprised mainly by polysaccharides from plant cell wall, such as cellulose, hemicellulose and pectin (
General structure of plant cell wall-derived non-digestible carbohydrates (NDC). Cell-wall derived NDC from plant-source foods include cellulose, hemicelluloses and pectin. Glc, Glucose; Man, Mannose; Gal, Galactose; Xyl, Xylose; Ara, Arabinose; GalA, galacturonic acid; Api, Apiose; Rha, Rhamnose; AceA, Aceric acid; Fuc, Fucose; Ac, Acetylated; Me, Methylated.
Similar to hemicellulose, pectin consists of linear and ramified homo- and heteropolysaccharides; however, pectin contains relatively high amount of acidic monomers compared to hemicellulose including mainly galacturonic acid (GalA). The major fraction of pectin usually consists of linear α-(
As mentioned above, even though NDC is generally considered as a dietary fiber, the diversity of NDC structure from plant-source foods results in different physicochemical properties, fermentation patterns, and biological effects, thereby making the evaluation of the structure-function relationship challenging. Thus, there is an increasing number of studies exploring which specific structural patterns of NDC induce beneficial biological effects in CRC models (
Studies have shown the association between the intake of specific food components and cancer, such as an inverse correlation between the intake of NDC from plant-source foods and CRC development and progression (
There are three main mechanisms in which NDC act against CRC development and progression. The consumption of NDC can induce (A) physicochemical effects in the gastrointestinal tract, (B) fermentation-related effects, and (C) direct effects resulting from the interaction between NDC and cells, such as intestinal epithelial cells (IEC), immune system cells, and CRC cells (
Physicochemical and biological effects of non-digestible carbohydrates (NDC) after the intake.
The physicochemical effects of NDC in the gastrointestinal tract are related to the interaction of these carbohydrates with other components through gel-forming properties, water holding capacity, and the ability of binding to other organic compounds (
Both gel-forming properties and water holding capacity result in increased stool bulk, thereby providing satiety (
The abovementioned physicochemical effects of NDC are dependent on both their macrostructure (e.g., molecular weight, degree of crystallinity, and particle size) and microstructure (e.g., presence of functional groups). In terms of macrostructure, studies suggest that β-glucans from cereals should have a molecular weight above 100 kDa to increase the viscosity of the digestive effluents and to induce a positive effect on post-prandial response (
Recent studies that applied distinct processing methods (e.g., micronization, milling, and enzymatic degradation) in NDC from plant-source foods also support the relationship between changes in both the degree of crystallinity and particle size with changes in the physicochemical effects (
In addition to the enzymatic- and physical-induced changes in the microstructure of NDC, studies are also exploring whether the introduction/removal of functional groups influences the physicochemical effects of specific NDC from plant-source foods. The phosphorylation of NDC from soybean does not appear to change its bile acid binding capacity. However, the water holding capacity of the phosphorylated NDC are 1.5-fold higher compared to the native NDC (
Therefore, processing methods that affect the macrostructure or the microstructure of NDC can be applied to control the physicochemical effects of these dietary components. The knowledge and control in NDC characteristics may in turn be useful for the selection and production of NDC from plant-source foods with desired physicochemical properties that are related to a decreased CRC risk.
The chemical structures of NDC are crucial for colonic fermentation because not all NDC are fermented, and because different metabolites resulting from the fermentation of distinct NDC act on a broad range of downstream signaling pathways in non-cancer cells and in CRC cells (
Some bacteria from the human gut microbiota possess a large repertoire of enzymes that hydrolyse glycosidic linkages from complex carbohydrates to use the hydrolysates and some metabolites as energy sources (
SCFA produced after fermentation of NDC could help to maintain the lumen pH at lower levels, thereby inhibiting pathogens growth and favoring the establishment of a healthy gut microbiota. SCFA, especially butyrate, also stimulate IEC growth by functioning as the primary source of energy for these cells while being metabolized by β-oxidation in the mitochondria. Several mechanisms for SCFA uptake across the apical membrane of IEC had been proposed including transport by monocarboxylate transporter (e.g., MCT1 and SMCT1), counter-transport with bicarbonate, and passive diffusion (
Effects of butyrate in normal cells and colorectal cancer cells (CRC). The butyrate produced during fermentation of non-digestible polysaccharides induces distinct effects in normal cell and CRC cells, as the latter rely on glucose—instead of butyrate—as their primary energy source. Increased glycolysis results in increased intracellular levels of lactate and decreased clearance/utilization of butyrate, whose increased intracellular levels inhibit histone deacetylases (HDAC) and induce death of CRC cells. As normal cells usually use butyrate as the main energy source, relatively low levels of butyrate is accumulated. The figure was modified from Smart Servier Medical Art (
In addition to the induction of IL-18 by IEC, which is also crucial for intestinal immune homeostasis since IL-18 helps maintaining the balance between T helper 17 cells (Th17) and regulatory T cells (Treg) (
Thus, despite CRC cells can use SCFA as energy source for proliferation (
Despite the mechanisms through which the fermentation-induced SCFA production relates to a decrease in CRC risk appear to be well-known, recent studies have also been conducted to explore how specific NDC affect gut microbiota composition. As bacterial strains have distinct prebiotic properties, changes in the microbiota composition induced by these dietary components may influence SCFA production, thereby influencing CRC risk. A previous study strongly supports this hypothesis by showing changes in the microbiota composition of children from Europe and rural Africa during the transition between breast milk feeding and the introduction of solid diet (
Thus, although studies are successfully proving insights into the relationship between the structure and prebiotic function of purified NDC from plant-source foods, the preference of a specific bacterial strain in utilize an NDC from a food matrix appears to be more complex, as the fermentation rate of a single NDC is affected when others NDC and other dietary components (e.g., polyphenols) are present (
NDC share structural features to lipopolysaccharides and other structural carbohydrate-containing molecules at the surface of bacteria (
The abovementioned hypothesis has been confirmed through
PRR existing in IEC and immune system cells regulates epithelial proliferation and intestinal permeability, and maintains gut homeostasis through recognition of harmful organisms and endogenous metabolites (
The PRR include RNA helicases (RLR), Nucleotide binding oligomerization domain (NOD)-like receptors (NLR), C-type lectin receptors (CLR), and Toll-like receptors (TLR), which recognize distinct evolutionarily conserved pathogen-associated molecular patterns (PAMP) of microorganisms—such as the carbohydrate-containing molecules at the surface of microorganisms—as well as endogenous damaged-associated molecular patterns (DAMP) (
Pattern-recognition receptors (PRR) that recognizes non-digestible carbohydrates (NDC) from plant-source foods.
NOD2 | Inulin | Chicory root | Activation in HEK cells, NF-κB release | ( |
NLRP3 | HG, RG-II and HC | Chayote | Inhibition of NLRP3 priming in macrophage-like cells | ( |
Dectin-1 | Mixed linkage β-glucan | Barley | Activation in immune cells, NF-κB release, IL-6 and IL-8 release | ( |
Dectin-1 | Arabinoxylan | Wheat | Inhibition in HEK cells | ( |
TLR2 | Inulin | Chicory | Activation in THP-1 cells, NF-κB release | ( |
TLR2 | RS2 | Maize | Activation in HEK cells, NF-κB release | ( |
TLR2 | Maltooligosaccharides | Wheatgrass | Activation in immune cells | ( |
TLR2 and 4 | FOS | Rice | Induction of dendritic cell maturation in mice | ( |
TLR2 and 4 | HG (varying degree of ME) | Lemon | Activation in T84 cells, maintenance of intestinal epithelial barrier integrity | ( |
TLR2 and 5 | RS3 | Maize | Activation in HEK cells, NF-κB release | ( |
TLR4 | Galactan | Apple | Inhibition of LPS-induced activation in a colitis model | ( |
TLR4 | HG (varying degree of ME) | Citrus | Inhibition of LPS-induced activation in a colitis model | ( |
TLR4 | HG (branched) | Citrus | Inhibition in immune cells | ( |
TLR4 | Levan | Soybean | Cytokine release in mice | ( |
TLR4-8 | Inulin | Chicory | Activation in THP-1 cells, NF-κB release | ( |
TLR1\TLR2 | HG (low degree of ME) | Lemon | Inhibition of intestinal inflammation | ( |
Dectin-1\TLR2 | Galactomannan | Guar gum | Inhibition of IEC |
( |
Dectin-1\TLR2 | Galactomannan | Guar gum | Inhibition of IEC in a colitis model | ( |
All NLR have C-terminal leucine-rich repeat motifs (LRR) for ligand sensing, except NLRP10 (
Among the more than 20 NLR that have been identified in human cells (
Despite the relevance of NLR in CRC risk, few studies have focused on exploring the effects of NDC from plant-source foods in the regulation of NLR because they are cytosolic receptors. Phagocytes including macrophages can internalize NDC (
Furthermore, NDC from chayote fruit, which consists mainly of pectic homogalacturonan and highly branched RG-II, as well as hemicellulosic material including glucomannan, xyloglucan, and glucurono(arabino)xylan, inhibits NLRP3 inflammasome activation in human THP-1 macrophage-like cells. The effects of this NDC on NLRP3 inflammasome can be considered an indirect effect of the interaction between the NDC and other PRR that are essential to induce priming signals required for NLRP3 inflammasome activation (
Unlike NLR that are cytosolic proteins, the main CLR (Dectin-1, Dectin-2, Mannose receptor, and macrophage inducible Ca2+-dependent lectin—Mincle) are trans-membrane PRR widely expressed in myeloid cells. Glycosylated structures are the natural ligands of CLR, which contain conserved carbohydrate-recognition domains (CRD). Thus, it is easy to think that some food-derived carbohydrates interact with CLR. In this regard, studies had explored the interaction between NDC from foods and CLR, especially Dectin-1. However, the effects were investigated mainly using fungal-source foods (
Activation of CLR can induce anti-inflammatory effects, as observed by the activation of the heterodimer Dectin-1\TLR2, which increases suppressor of cytokine signaling (SOCS)-1 expression, thereby resulting in anti-inflammatory effects (
Among all CLR, Dectin-1 seems to have a major impact in innate immune responses against cancer and are present in CRC cells (
Phagocytes can extrude their dendrites across the intestinal epithelium into the gastrointestinal lumen and diet-derived β-glucan could interact with them through Dectin-1. Upon activation of Dectin-1, β-glucan induces mainly the Spleen tyrosine kinase (Syk)-dependent pathway, which triggers adaptive immune response in T cells and B cells that results in the inhibition of both tumor growth and metastasis (
In this context, a barley-derived β-glucan that consists of linear and mixed β-(
TLR are the most studied class of PRR because of both the variety of PAMP and DAMP that interact with these germline-encoded PRR and also because of the biological outcomes that TLR-induction/inhibition could cause in human health (
Among all TLR, TLR2 and TLR4 have been the most studied ones concerning the interaction with NDC from plant-food sources (
In the context of CRC, several studies had explored the role of TLR on cancer development, progression, and invasion, as reviewed by Li et al. (
TLR4 is considered the most important inflammatory inducer amongst all TLR, thereby playing a key role in immune response against intestinal pathogens. However, excessive activation of TLR4 may enhance not only immune response but also gives rise to cancer progression through disruption of intestinal immune homeostasis (
Despite the abovementioned evidences show that inhibition of TLR4-dependent signaling pathways may reduce CRC risk, some NDC from plant-source foods including citrus pectin and ginseng polysaccharides have potential anticancer effects that seems to be related to TLR4-mediated activation (
Apart from the biological relevance of TLR2 and TLR4, TLR3 activation with polyinosinic:polycytidylic acid induced apoptosis of in CRC cells (
Molecules from plant-source foods including polyphenols (
In addition to the TLR-mediated effects of NDC from apple and citrus, it was found that inulin from chicory roots with distinct chain-lengths interacted not only with TLR4, but also with TLR5, TLR6, TLR7, and TLR8 in a MyD88-dependent pathway, and had no effects on cytosolic TLR3 and TLR9 (
In addition to the direct effects of NDC from plant-food sources through PRR-dependent mechanisms in IEC, immune system cells and CRC cells, NDC can also directly interact with cellular components in a PRR-independent pathway. The main PRR-independent effect seems to be related with the interaction between NDC from plant-source foods and the galectin-3 (Gal-3).
Gal-3 is a protein of the lectin family that has a CRD with strong affinity for β-galactosides. Notably, it has been consistently shown in the past two decades a strong association between increased levels of Gal-3 and several types of cancer including CRC (
Gal-3 is present intracellularly—at the cytoplasm or within the nucleus—attached to cell surface, or in the extracellular media as a dimer or as a pentamer (
Among NDC from plant-food sources and Gal-3 inhibition, the modified citrus pectin (MCP) is the most studied one (
Modified sugar beet pectin, papaya pectin, and ginseng pectin have structures composed of neutral (
As NDC are essentially polyhydroxy molecules, which are often esterified, it is possible that the NDC from plant-source foods interacts with other cellular components. The studies that had shown anticancer effects of NDC through interaction with Gal-3 support further studies aiming the investigation of the interaction between NDC and other signaling mediators related to the decreased CRC risk.
The complexity of biological effects resulting from the intake of NDC from plant-source foods and their relationship with decreased CRC risk can be divided into physicochemical effects, fermentation-related effects, and PRR-dependent and PRR-independent direct effects. However, in biological systems, these complex NDC effects occur at the same time in an intricate—and poorly understood—relationship. Although the evaluation of a specific biological effect does not fully answer whether a single NDP from a plant-source food relates to a decreased CRC risk, it can provide further insights to elucidate the structure-function relationship between NDC and their effects in CRC development and progression. Therefore, as recent studies are demonstrating that intrinsic properties of NDC from plant-source foods, as well as individual characteristics among cells and individuals, strongly influence the beneficial effects of NDC on the reduction of CRC risk (
Features that influence the effects of non-digestible carbohydrates (NDC) from plant-source foods in colorectal cancer (CRC). Some of the intrinsic properties of NDC, as well as individual characteristics among cells and individuals, that influence the physicochemical, fermentation-related and direct effects of NDC from plant-source foods on the reduction of CRC risk.
VC-A, SP, and GF wrote the manuscript. JF critical review of the manuscript. SP and VC-A illustrations. VC-A, GF, SP, and JF revised and approved the manuscript.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
aceric acid
acetylated
Apiose
Arabinose
Carbohydrate recognition domain
C-type lectin receptors
Colorectal cancer
damaged-associated molecular patterns
fucose
galactose
galacturonic acid
Galectin-3
Glucose
heat shock proteins
hystone deacetylases
homogalacturonan
intestinal ephitelial cells
lipopolysaccharide
C-terminal leucine-rich repeat motif
mannose
mitogen-activated protein kinase
methylated
modified citrus pectin
non-digestible carbohydrates
nucleotide binding oligomerization domain (NOD)-like receptors
pathogen-associated molecular patterns
pattern recognition receptors
receptor-interacting serine/threonine-protein kinase
rhamnogalacturonan
rhamnose
short-chain fatty acids
toll-like receptors
xylose.