Pectins and TheHealth Effects: Comparison
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Please note this is a comparison between Version 1 by João Paulo Fabi and Version 6 by Jessie Wu.

Pectin, a plant-derived polysaccharide, possesses immense technological and biological application value. Several variables influence pectin’s physicochemical aspects, resulting in different fermentations, interactions with receptors, and other functional properties. Some of those variables are molecular weight, degree of methylation and blockiness, and monosaccharide composition. Cancer cell cytotoxicity, important fermentation-related byproducts, immunomodulation, and technological application were found in cell culture, animal models, and preclinical and clinical assessments. 

  • pectin
  • functional properties
  • fermentation
  • human health
  • dietary fiber

1. InIn Vitro Vitro Exploration of Pectin Biological Effects

1.1. Cytotoxicity Effects of Native and Modified Pectins on Cancer Cells

It is already known that pectins are plant-derived bioactive food polysaccharides with potential cytotoxic properties [1]. Several in vitro studies regarding those properties have been published over the years. Different origins were used for the extraction of pectins, such as papayas [2], sweet potatoes [3], apples [4], citrus [5], olives [6], and sugar beet [7]. Those studies have targeted various cancer models, such as breast cancer, pancreatic cancer, urinary bladder cancer, prostate cancer, and colon cancer [1].
Metastasis inhibition and cancer cell DNA damage are some of the studied effects of this polysaccharide [8]. However, studies show that pectins' biological effects are directly linked to their chemical structure. For example, pectins extracted from sugar beets without any modification did not show a significant decrease in the viability of colon cancer cells; however, alkali treatment increased this effect [7]. The authors suggested that this effect is because the alkali treatment changed the chemical composition of pectins, increasing the ratio of RG-I to HG content and decreasing the degree of esterification.
The ripening of fruits is a natural cause for changing pectins’ structure. This phenomenon has been studied in climacteric fruits such as papaya (Carica papaya), where this specific ripening provides noticeable changes in its pulp structure [9]. The papaya pulp’s cell wall comprises large cells with the cellulose and xyloglucan framework involved in a pectin matrix. As the ripening proceeds, the pulp softens by the action of specific enzymes, including endo-polygalacturonases and exo-galactosidases, which degrade the cell wall’s pectin, depolymerize the pectic polysaccharides, and enhance the soluble sugar content in those fruits, in a high metabolic state. HG and RG-I fragments obtained by the action of enzymes on ripening have been explored for inducing cancer cell detachment, which could mean potential cytotoxic activity [2].
However, different post-harvest ripening points of papaya’s pectin demonstrated distinct results in a study with two different human colon cancer cell lines, HCT116 and HT29, and a prostate cancer cell line, PC3 [2]. The sample extracted from the intermediate ripening phase (3 days after harvest—3DAH) decreased cell viability and induced necroptosis in these three cancer cell lines. This intermediate ripening point presented smaller pectin chains with reduced molecular weight (102 ± 5 kDa), which has been suggested as one plausible pivotal factor for a higher modulation of cancer cell survival. Another structural difference between the samples is that this 3DAH period yielded smaller HG chains, smaller RG-I side groups, and AGII associated with RG-I. These results demonstrated that the enzymes of natural ripening acted in different proportions on cell wall pectin over time and alongside many others, opening the discussion about exogenous modifications to standardize the structure and molecular weight of interest.
Low molecular weight citrus pectin (LCP) was used to reduce the proliferation of two human cancer cell lines, AGS gastric cancer and SW-480 colorectal cancer [10]. LCP contains abundant galactans, believed to antagonize galectin-3 (GAL-3), a pro-metastatic protein that has a critical role in the cancer cell profile. LCP treatment reduced cell viability and decreased GAL-3 levels in both cancer cell lines in vitro [10]. However, many others have contested the ability of pectins and other high-weight polymers to inhibit Gal-3 [11].
When pectin with a variable molecular size is tested, different effects can be observed. Two different human colon cancer cell lines, HCT116 and HT29, and a prostate cancer cell line, PC3, were treated with modified citrus pectin (MCP) produced by thermal treatment and fractionated in different molecular sizes, generating different fragments: MCP30 (higher than 30 kDa), MCP30/10 (between 30 and 10 kDa), MCP10/3 (between 10 and 3 kDa), and MCP3 (smaller than 3 kDa) [5]. MCP30/10 had more esterified HG, while type I arabinogalactans (AGI) were more abundant in MCP10/3 than MCP and MCP30. Both MCP30/10 and MCP10/3 had lower amounts of rhamnogalacturonans (RG-I). The smaller molecular size MCP3 had less esterified HG and the lowest amounts of AGI and RG-I. Enriching AGI and more esterified HG oligomers in MCP fraction structures showed enhanced cytotoxic effects. All MCP fractions exhibited reduced cell viability in all cell lines, but there is a distinct effect on cell death in different cancer cell lines because this researchtudy resulted in divergent effects on proliferation, migration, and aggregation on each cancer cell line with each MCP fraction treatment, showing that these effects are structure-, size-, and cell line-dependent [5].

1.2. Gut Microbiota Affects Pectin Fermentation

Although not digested by the human gastrointestinal tract, pectin is entirely fermented by the gut microbiota, serving as a healthy substrate for gut microorganisms [12]. Several in vitro gut models have been used to study the impact of pectin on gut microbiota, and exciting data presented in some studies demonstrate that the chemical structure of pectins directly affects their fermentation degree based on their complex molecular structure [12]. Five structural characteristics were identified as the most important in the interaction between gut bacteria and pectins: the amidated groups, the DM, the distribution of HG and RG fractions, the composition of neutral sugars, and the degree of branching [13]. Nevertheless, it is important to realize that different microorganisms exhibit specific preferences for defined substrates [12].
The DM will influence the location at which the gut microbiota ferments the pectin. Depending on the initial population, it may have a moderate effect on gut microbiota [13]. Some studies illustrate that low-methoxy (LM) pectin fermented faster than high-methoxy (HM) pectin [14][15][16], while other authors also showed that HM pectin fermentation produced more SCFA (short-chain fatty acid) than LM pectin [13]. Lower DM pectins are entirely fermented in the upper part of the gastrointestinal tract, while higher DM is fermented to a much higher degree in more distal regions [17]. Another study demonstrated that DM has not influenced the pectin fermentation process by the gut microbiota [17]. However, the fermentation of LM and HM pectins is influenced by initial gut bacteria species that affect fermentation kinetics [12], for example, F. prausnitzii, which prefers HM as a substrate compared with LM pectins.
In an in vitro model, Lactobacilli, Bacteroides, and Prevotella populations increased in the gut due to pectin interaction and metabolism [18]. Bacterial strains, such as Prevotella copri, Bacteroides spp., Bifidobacterium, Coprococcus, Ruminococcus, Dorea, Blautia, Oscillospira, Sutterella, Faecalibacterium prausnitzii, and Christensenellaceae oscillated depending on the type of pectin, corroborating the fact that the biological effects of pectins are chemical-structure dependent.
Therefore, microbial preference over a pectic substrate and metabolite production capability according to the pectin structure can generate higher diversity and environmental health stimuli in the intestinal microbiota through both indirect modulations of immune and epithelial cells, mucin production, lower barrier disruption, and others [13]. Five structural characteristics were identified as the most important in interacting with pectins: the amide groups, the DM of HG regions, the distribution of HG and RG fractions, the composition of neutral sugars, and the degree of branching [13].

1.3. Pectin Beneficial Immunomodulation

Pectin has been shown to interact with cells of the immune barrier in the small intestine [18], mainly through interaction with pattern recognition receptors (PRR) [19]. PRRs can be divided into toll-like receptors (TLR) and nucleotide-binding oligomerization domain (NOD)-like receptors (NLR). TLRs are an important family of receptors and the core structure of the innate immune response, which means that they are the first defense mechanism activated upon damage or pathogen invasion, allowing the response of the adaptive immune system to initiate an antigen-specific response [20][21].
Pectin action is dependent on its chemical structure, which was demonstrated by Prado et al. (2020) [19] in a study with papaya pectin at different ripening stages interacting with different TLRs (toll-like receptors) and NOD1 and 2 (nucleotide-binding oligomerization domains). The ripening process changes the structure of papaya’s pectin, resulting in pectins with a higher DM and smaller galactan chains on ripe fruits [19]. The results supported the initial idea of structure-dependent properties of pectin in immunity since all the TLR and NOD receptors were activated by ripe papaya pectin, while only TLR2, 4, and 5 were activated by unripe papaya pectin, whereas TLR3 and 9 were inhibited.
Another study correlated pectin oligosaccharides (POS), a degraded form of polysaccharides present in pectin, with oxidative and inflammation-activated pathways, such as NF-κB, ATP-activated protein kinase (AMPK), and nuclear factor erythroid-2-related factor-2 (Nrf2) [22]. POS affects antioxidant and anti-inflammatory pathways in different ways because of the intrinsic diversity of its structure, which can be standardized with chemical modification. Despite that, POS can potentially control inflammatory and oxidative stress [22].
Pectin has been shown to interact with the cells of the immune barrier in the small intestine [18]. Pectins have a direct interaction with the cells of the gastrointestinal immune barrier, which is composed of multiple layers, containing a mucus layer, a layer of epithelial cells and intraepithelial lymphocytes, and the lamina propria, which is the homing site of innate immune cells [18]. Pectins can affect these layers at different levels. Low DM pectins can strengthen the mucus layer by influencing goblet cells, and very high DM pectins can have mucoadhesive effects, forming hydrogen bonds with mucins. In the epithelial layer, pectins can maintain a strong junction structure and protect the integrity against barrier-disrupting agents. In the lamina propria, pectins can be transported by the microfold cells and interact directly with the immune cells, thus influencing their responses. However, there are controversial results about the interaction between different chemical structures of pectin and innate immune cells, demonstrating that pectin can enhance or inhibit the response of immune cells [18][23][24]. The main findings regarding pectin in vitro effects are detailed below in Table 12.
Table 12.
Summary of in vitro effects from pectin poly- and oligosaccharides from varied sources.
Pectin/Fragment Used In Vitro Model Main Results Found Authors
Size-fractioned oligo- and polysaccharides from MCP HCT116, HT29, and PC3 cell lines MCP30/10 and 10/3 stimulated cytotoxicity through necroptosis and necrosis on the HCT116 cell line; smaller fragments significantly reduced homotypic aggregation and cell migration [5]
Papaya pectin from different ripening points HCT116, HT29, and PC3 cell line Pectins extracted from the third day after harvesting inhibited cancer cell aggregation, migration, and further reduced viability while enhancing cytotoxicity; they also increased pAkt, pErk1/2, p21, and caspase-3 protein expression [2]
Ultrasound-fragmented Sweet Potato pectin with high GalA content and low DM Oxygen radical absorbance capacity and Ferric reducing antioxidant power assay (ORAC and FRAP) The most fragmented pectin performed better in both antioxidant assays, starting in lower doses, compared to the other pectins [3]
Enzymatically extracted apple pectin HCT116 and Caco-2 cell culture Pectins were able to synergize with Irinotecan increasing colorectal cancer cell cytotoxicity through apoptosis induction compared to drug-only controls; ROS levels increased; reduced IL-6 and COX-2 in LPS-induced HCT116 cells; pectins also reduced E. coli adherence to colorectal cancer cells [4]
Acid and heat-treated pectic extracts from olives Caco-2 and THP-1 cell culture Higher doses (3.33 and 10 mg/mL) were able to cease cell proliferation entirely up to seven days; pectin extracts successfully induced caspase-3 activity, compared to MCP and control [6]
Varied potato pectins, citrus polygalacturonic acid, larch AG HT29, DLD1, HCT116, LoVo; and Caco-2 cell culture Potato RGI was the most effective in reducing cell proliferation in a dose-response manner; authors detected ICAM-1 downregulation, and the proposed reduction of proliferation was due to cell detachment [7]
Low-molecular-weight citrus pectin AGS and SW-480 cell culture LCP lowered cell viability, proliferation, and cell cycle progression; the pectin had comparable values of Cyclin B1 and Bcl-xL downregulation to 5-FU [10]
Papaya pectin from different ripening points HEK-TLR reporter cell lines The ripe-fruits pectins activated TLR3, 5, and 9; all pectin samples activated TLR2 and 4; only unripe-fruit pectins inhibited TLR3 and TLR9 [19]
Modified sugar beet pectin fragments HT29 and DLD1 cell culture Pectin stimulated apoptosis and detachment of HT29 cells; the galactan fragment was most efficient in lowering cell proliferation [25]
Acid and neutral fractions of papaya pectins from different ripening points HCT116 and HT29 cell culture, recombinant human Gal-3 hemagglutination The acid fraction from four days after harvest was able to inhibit Gal-3 hemagglutination from the second-lowest dose onward; cell viability was reduced mostly by full water-soluble fractions or acid fractions [26]
Oligosaccharides from jaboticaba, plum, and papaya flours HCT116 cell culture and recombinant human Gal-3 hemagglutination Only jaboticaba oligosaccharides were able to inhibit Gal-3 hemagglutination and colorectal cancer cell viability [27]
Lemon pectins with varying DMs HEK-TLR reporter cell lines Low-DM pectins inhibited TLR2 activity way more than higher-DM ones; specific TLR2-TLR1 heterodimer inhibition was observed [28]
Lemon pectins with varying DMs Human pancreatic islets and MIN6 cells Low-DM pectins showed protective effects on human islets against streptozotocin and IL1b + IFN-y + TNF-a inflammatory stress through a Gal-3 binding-dependent way [29]
High-temperature sunflower pectin and polygalacturonic acid CT26 colorectal cancer cell line Pectins were able to upregulate JNK, ERK, and p38 phosphorylation while down-regulating Akt time-dependently; dose-dependent stimulation of apoptosis was also observed in vitro [30]

2. InIn Vivo Vivo Exploration of Pectin Biological Effects

While in vitro studies provide valuable insights into the cellular and molecular mechanisms underlying the effects of pectin in a controlled laboratory environment, in vivo studies provide a more accurate representation of the safety and efficacy of a substance or treatment on a complex, dynamic living organism. They also provide insights into the mechanisms of action and potential side effects, accounting for the complex interactions between the pectin, gut microbiota, and the host’s immune system, as well as the administration route and bioavailability [31]. In vivo studies can help validate the findings of in vitro studies and provide information about the physiological relevance of the effects observed in vitro. Studies have demonstrated the beneficial effects of native and modified pectin on various health outcomes and different organs (Figure 1), including anti-cancer activity, weight management, lipid metabolism, and glucose control.
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Figure 1.
Schematic depiction of variable pectin molecules and their respective region of higher biological activity.
The most studied dietary fiber is modified citrus pectin (MCP), a type of pectin that has been chemically altered to decrease molecular complexity while increasing its solubility and bioavailability, as already discussed [5]. Cui et al. [32] showed a neuroprotective effect of MCP on ischemic stroke in mice by inhibiting the protein galectin-3. The exact mechanism was observed in a mouse model of myocardial fibrosis, although modified rhubarb pectin (EMRP) was found to be the most potent galectin-3 inhibitor when compared to MCP. Screening analysis revealed that EMRP was abundant in galacturonic acid with the RG-I segment and relatively rich in galactose, which may lead to the observed higher affinity for galectin-3 [33]. Gal-3 binding is thought to occur through the carbohydrate recognition domain (CRD) in the protein and can involve the N-terminal tail or a two-step interaction process. Pectins with diverse molecular structures can interact with Gal-3, including RG-I polysaccharides with long galactan side chains and unesterified pectins with non-substituted GalA segments [34]. The physicochemical changes from CP to MCP due to β-elimination increase pectin solubility and enrich “pharmacophores” found in the RG-I domain of pectin, which are galactans rich in terminal β-galactosides [35]. These galactans can be recognized by the CRD of Gal-3, the target of MCP in vivo models. The molecular mass plays a crucial role in MCP pharmacokinetics, affecting blood concentration, absorption, and excretion [35].
Another well-known benefit effect of MCP is its cytotoxicity, such as in breast cancer [36], prostate carcinoma metastasis [37], and gastric cancer [10], even though it is not an attribute exclusively of citrus pectin. In vivo studies have shown inhibition of tumor growth using heat- or chemically-modified pectins of sunflower [30], apple [38], artichoke [39], and lemon [28][40]. Sabater et al. [39] tested samples of modified pectin of artichoke without galactose and arabinose, interestingly observing that the absence of galactose decreased the anti-inflammatory effect, while the absence of arabinose did not change its anti-inflammatory properties. The inhibition of carcinogenesis happens through several mechanisms, including inflammatory suppression, inhibition of tumor survival signaling and induction of apoptosis, cell cycle regulation, suppression of inflammation, and reduction of tumor cell adhesion to endothelial cells, critical steps in metastasis [8]. Down-regulation of Gal-3 is also related to reducing tumor growth and increasing the sensitivity of tumor cells to chemotherapy drugs due to the protein’s involvement in apoptosis-resistance and drug-resistance pathways [35].
A study by Ren et al. [41] found that low molecular weight pectin from ginseng roots had a more significant effect on weight loss and enhanced glucose and lipid metabolism in type 2 diabetic rats by inhibiting the expression of downstream lipid synthesis genes, mainly due to the action of RG-I fractions. Supplementing pectin on diets presented good results on cholesterol-lowering properties in hamsters, with a significant reduction in serum cholesterol levels compared to the control group. 5% DE pectin was able to downregulate genes related to lipid synthesis and upregulate genes related to lipid degradation [42]. Another study showed that pectin supplementation reduced cholesterol levels in hypercholesterolemic rabbits [43]. The increase in viscosity caused by pectins, due to their structural and chemical composition, is thought to reduce the diffusion and, consequently, the intestinal absorption of available carbohydrates [44]. In addition, pectin interacts with amyloglucosidase, avoiding the hydrolysis of starch into glucose [45].
Studies with lipopolysaccharide-challenged piglets showed that pectin supplementation improved gut health by alleviating morphological damage and restoring goblet cell numbers in the cecum. It also improved gut microbiota, increased beneficial bacteria, and improved the gut barrier and immunity by regulating cytokine expression through attenuating its receptor signaling [46][47]. Flies fed with low molecular weight pectin-enriched diets had a longer lifespan due to several mechanisms related to the pectin effect, such as decreasing reactive oxygen species (ROS), modulating gut microbiota and homeostasis, and regulating the expression of genes related to autophagy [48]. The action of pectin on gut microbiota was also observed as a booster factor in enhancing the efficacy of immunotherapy for colorectal cancer (CRC), as the fermentation product SCFA butyrate assisted T cell infiltration in tumors of mice [49]. Another application of pectin is demonstrated by Yuan et al. [50], whose goal was to build a nanotube system to carry a drug against Salmonella to the intestine. Low-methoxy pectin was incorporated as a protective film to ensure the nanotube would pass through the gastric acid unharmed and reach the intestine in a nondegraded form. In vivo assays revealed that not only was the pectic film effective as a protection film, but it also played a role by attenuating enteritis caused by Salmonella and modulating homeostasis and the microbiota balance.
These studies have typically used animal models, such as rats or mice, to evaluate the effects of native and modified pectin. They provide valuable information about treatments' molecular and physiological systems and how these potential therapies may affect the disease process. Clinical trials, on the other hand, are important because they are the only way to test the safety and efficacy of a given therapy in humans. They provide real-world data on how a given therapy influences the health and well-being of individuals and can help determine the best way to use a given therapy in the clinic. Therefore, the complementarity of these two methods is essential for advancing our understanding of the biology of a disease and the development of safe and effective therapies using plant-derived compounds.

3. Clinical Research and Technological Applications

3. Clinical research and technological applications

There is great interest in the impact of plant-derived dietary fiber on health and disease [51]. As mentioned, beneficial effects could be direct and/or indirect, such as the stimulation of the gastrointestinal immune barrier and the benefits of protecting against cardiovascular diseases [18]. For example, the study by Kumar and Chauhan [52] demonstrated that the formation of a lipase–pectin complex results in lipase inhibition. As a weak acid, pectin resists dissociation in the gastric environment and binds covalently to the active sites of pancreatic lipase. The hypothesis is that the single-bond CO2H groups protonate histidine, and the single-bond OH group of the serine-histidine-aspartic/glutamic acid triad of lipase is what stops the mechanisms to which lipase action is subservient [53][54].

Four studies from the same research group can be cited that used commercially modified pectin (MCP) to investigate the potential for eliminating heavy metals through urine. This specific MCP has been characterized in an earlier in vitro study by one of the same authors as having a smaller size than 15 kDa, under 5% DE, and a content of approximately 10% RG-II. According to the authors of the study, modification is believed to enable preferential transport of short-chain galactans and AG from the small intestinal epithelium into the circulation
Four studies from the same research group can be cited that used commercially modified pectin (MCP) to investigate the potential for eliminating heavy metals through urine. This specific MCP has been characterized in an earlier in vitro study by one of the same authors as having a smaller size than 15 kDa, under 5% DE, and a content of approximately 10% RG-II. According to the authors of the study, modification is believed to enable preferential transport of short-chain galactans and AG from the small intestinal epithelium into the circulation [55][56][57][58].
Two studies investigated the use of pectins as a pharmacological vehicle in nasal sprays for the management of breakthrough cancer pain (BTPC). In the short-term study with Fentanyl Pectin Nasal Spray (FPNS), gel formation was the technological target for pectin inclusion. This formation occurs due to the interaction of the low-methoxyl (LM) pectin with calcium ions present in the mucosal fluid, allowing locally acting drugs to reside for longer at the application site. The treatment was efficacious, safe, and well tolerated for the treatment of BTPC, showing a vehicle application for this polysaccharide [59][60][61]. Also, regarding cancer application, considering that pectin has the property to form gels and that in vitro studies with cancer cells can utilize hydrogels in the cell culture, new technology can be tested on in vitro tumor models containing spheroid cell cultures [62].

4. Final Thoughts

Pectins and other types of dietary fiber provide diverse health benefits and reasonable assistance in treating different diseases and maintaining a healthier gastrointestinal environment. Data from human studies are more limited, and the revealed effects are relatively modest [51]. This only highlights the need to expand and further explore the activity and application of those polysaccharides in the human diet and, in the future, pharmacological approaches. The present resviearchw fulfills its purpose by covering a literature gap by thoroughly evaluating pectin at all levels of clinical research. Most of all, it opens space for increasing focus in technological research on pectin applications as molecules of interest regarding effects and stabilizing and carrying properties.

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