Exosome biomarker for oral cancers.
\r\n\tSynthetic zeolites can be formed from different raw materials and among these many wastes represent some interesting sources due to their chemical and mineralogical composition. Today, a large number of different types of waste resulting from many human activities are produced in the world (e.g. industrial, municipal, agricultural waste) and most of them are deposed of in landfills thus determining a great environmental problem.
\r\n\r\n\tThis book intends to provide the reader with a comprehensive overview of the current state-of-the-art on the possibility to transform the different types of waste materials into useful products, zeolites, through conventional processes and innovative methods. The aim is to demonstrate that waste can be a problem or a resource depending on how it is managed.
",isbn:"978-1-80356-426-5",printIsbn:"978-1-80356-425-8",pdfIsbn:"978-1-80356-427-2",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,isSalesforceBook:!1,isNomenclature:!1,hash:"3ed0dfd842de9cd1143212415903e6ad",bookSignature:"Dr. Claudia Belviso",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11561.jpg",keywords:"Structure, Properties, Natural Material, Synthetic Product, Type, Composition, Production, Disposal, Hydrothermal Method, Pre-fusion Process, Sonication, Multiple Steps",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"February 25th 2022",dateEndSecondStepPublish:"March 25th 2022",dateEndThirdStepPublish:"May 24th 2022",dateEndFourthStepPublish:"August 12th 2022",dateEndFifthStepPublish:"October 11th 2022",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"5 months",secondStepPassed:!0,areRegistrationsClosed:!0,currentStepOfPublishingProcess:4,editedByType:null,kuFlag:!1,biosketch:"Since 2002, Dr. Claudia Belviso has been carrying out research activity in the field of mineralogy and geochemistry aimed at environmental protection. She is responsible for the research activity on zeolite synthesis from waste materials and natural sources which has allowed her to be the inventor of an International Patent, publish numerous scientific articles in peer-reviewed journals, and carry out scientific research in national and international projects.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"61457",title:"Dr.",name:"Claudia",middleName:null,surname:"Belviso",slug:"claudia-belviso",fullName:"Claudia Belviso",profilePictureURL:"https://mts.intechopen.com/storage/users/61457/images/system/61457.jpg",biography:"Claudia Belviso is a researcher at the Institute of Methodologies of Environmental Analysis (IMAA) of CNR. After graduating in Geological Sciences and qualifying as a professional geologist, she earned a Ph.D. in Earth Sciences. Since 2002 has been carrying out her research activity in the field of mineralogy and geochemistry aimed at environmental protection. She is responsible for the research activity on zeolite synthesis from waste materials and natural sources as well as their application to solving environmental problems and as new raw material. These research activities have allowed her to be the inventor of an International Patent, publish numerous scientific articles in peer-reviewed journals, participate in national and international conferences, take part in the organization of international congresses, and carry out scientific research in national and international projects.",institutionString:"National Research Council",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"National Research Council",institutionURL:null,country:{name:"Italy"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"8",title:"Chemistry",slug:"chemistry"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"453622",firstName:"Tea",lastName:"Jurcic",middleName:null,title:"Ms.",imageUrl:"//cdnintech.com/web/frontend/www/assets/author.svg",email:"tea@intechopen.com",biography:null}},relatedBooks:[{type:"book",id:"5306",title:"Zeolites",subtitle:"Useful Minerals",isOpenForSubmission:!1,hash:"eec7f864baf093058440c0f56072a7cf",slug:"zeolites-useful-minerals",bookSignature:"Claudia Belviso",coverURL:"https://cdn.intechopen.com/books/images_new/5306.jpg",editedByType:"Edited by",editors:[{id:"61457",title:"Dr.",name:"Claudia",surname:"Belviso",slug:"claudia-belviso",fullName:"Claudia Belviso"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1591",title:"Infrared Spectroscopy",subtitle:"Materials Science, Engineering and Technology",isOpenForSubmission:!1,hash:"99b4b7b71a8caeb693ed762b40b017f4",slug:"infrared-spectroscopy-materials-science-engineering-and-technology",bookSignature:"Theophile Theophanides",coverURL:"https://cdn.intechopen.com/books/images_new/1591.jpg",editedByType:"Edited by",editors:[{id:"37194",title:"Dr.",name:"Theophile",surname:"Theophanides",slug:"theophile-theophanides",fullName:"Theophile Theophanides"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3161",title:"Frontiers in Guided Wave Optics and Optoelectronics",subtitle:null,isOpenForSubmission:!1,hash:"deb44e9c99f82bbce1083abea743146c",slug:"frontiers-in-guided-wave-optics-and-optoelectronics",bookSignature:"Bishnu Pal",coverURL:"https://cdn.intechopen.com/books/images_new/3161.jpg",editedByType:"Edited by",editors:[{id:"4782",title:"Prof.",name:"Bishnu",surname:"Pal",slug:"bishnu-pal",fullName:"Bishnu Pal"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"371",title:"Abiotic Stress in Plants",subtitle:"Mechanisms and Adaptations",isOpenForSubmission:!1,hash:"588466f487e307619849d72389178a74",slug:"abiotic-stress-in-plants-mechanisms-and-adaptations",bookSignature:"Arun Shanker and B. 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The completion of the human genome project [2, 3, 4], has expanded the trajectory for precision diagnostic and therapeutic potential thereof across many biomedical fields [5, 6]. The clinical lexicon in the post-genomic era is now burgeoning with various personalized application of genomics (and phenomics) to improving the cancer management pipelines [1, 6, 7, 8, 9].
Orthogonal (but complementary) multimodal approaches to conventional histopathology [10, 11], such as liquid biopsies technologies have emerged as useful tools for clinical oncology [11, 12, 13], early tumor diagnosis and biomonitoring [14, 15, 16, 17], as well as therapeutic decision making and delivery [18]. Nano-scaled multivesicular exosomes have emerged as important components of the tumor circulome that has significantly improved the cancer diagnostic field [11, 14]. Furthermore, salivary exosomes have been applied to improve the diagnosis of various cancers [19, 20, 21, 22, 23, 24, 25, 26], including oral cancers [25, 26]. The focus of this chapter is to review the applications and prospects of salivary exosomes in oral cancer detection (Figure 1).
Overview of origin and theranostic value of exosomes in oral cancer.
Human saliva is a multifunctional biological fluid, which facilitates digestion, swallowing, tasting, tissue lubrication and protection against infectious organisms. It is comprised largely of water (99%) and other biochemical substances such as proteins, nucleic acids, mucins, immunoglobulins, a variety of electrolytes and lipids [27, 28]. Whole saliva production is derived from all the salivary glands including the gingival crevicular fluid [29]. Saliva, which has been used for diagnostic purposes for over 2000 years, plays a key role in the maintenance of general and particularly oral health homeostasis [30]. The health of individuals has been determined by salivary changes such as amount produced, smell, ropiness and gustatory sensation [31, 32].
Components of the salivary glands are responsible for production, modification, transportation and secretion of saliva into the oral cavity (via acinar cells, various ductal system cells, and myoepithelial cells) [33]. The close proximity of a network of highly permeable blood capillaries to the saliva producing acinar cells facilitates the free exchange of blood-derived molecules into the acinar cells [34], which enter the salivary tissues either via transcellular (passive and active transport) or paracellular (extracellular ultrafiltration) routes [35, 36]. This transfer potentially influences the molecular constituency of oral fluids. Diffusion is the most common transport mechanism of molecules from blood into the saliva and this process is driven/influenced by the size and the electric charge of the molecules [37]. Active transport involves the transcellular transportation of blood into saliva via secretory acinar cells of the salivary glands. Ultra-filtration is the major mode by which molecules are transported into saliva via the paracellular route, whereby small sized blood molecules filter into saliva through the spaces between ductal and acinar cells [37]. Salivary acini secrete saliva into collecting ducts, where sodium reabsorption, and bicarbonate and potassium are secretion takes place, thus altering the composition of the saliva [38, 39]. Even though blood molecules transported through ultra-filtration into saliva are usually in low concentration in comparison to their levels in blood, this mode of transport enables blood molecules such as DNA, RNA, proteins, metabolites and exosomes into saliva through the salivary gland. This confers the possibility for oral fluids to harbor molecular information indicative of an individual’s current state of health. This information may be reflected by changes in the concentrations of these molecules or mutation in the genetic constitution of the molecules which are also present in saliva - serving as potential salivary biomarkers for diagnosis, prognosis and monitoring of therapeutic responses [40].
Many body fluids have been explored as alternative sources for biomarkers in molecular diagnosis of cancers, genetic, immunological and other systemic diseases [41, 42, 43, 44, 45]. However, blood, urine and saliva are the most used media for discovery of biomarkers [46]. Saliva is a rich source of proteins and its DNA, RNA, and protein content is analogous to that of blood with significant commonality in hormones, antibodies and other molecules. Most of the resident salivary protein constituents are synthesized within the salivary glands, with the rest transported from blood or lymph into saliva and used as biomarkers for disease diagnosis and screening purposes [47].
Saliva has the advantages over blood in that it is a readily available specimen which can be collected by non-invasive techniques and is recommended as the diagnostic medium in vulnerable populations such as children. The retrieval of multiple salivary samples from the same individual is possible with minimal discomfort and saliva is safer to work with when compared with blood samples. For example, there are some factors in saliva which help to inhibit HIV infectivity thereby limiting the rate of HIV transmission through the oral cavity [48]. Saliva sample processing is more economical and does not clot making it easier to store and ship with less manipulation. However, the low level of protein detection in saliva is sensitive to the method of saliva collection and specimen contamination. Normal high-abundance salivary constituents such as amylase and proline rich proteins (during stimulated salivary collection methods especially), may dilute the presence of low-level proteins, which may be more important biomarkers.
Salivary biomarkers are miniscule and measured in (picograms), detection of which can only be achieved by techniques which are both sensitive and specific enough to discriminate between them [49]. Technological advances in diagnostic detection methods (next generation sequencing, mass spectrometry, genome wide association studies and other screening techniques) have paralleled the demand for improved diagnostic test accuracy of salivary genomic and proteomic biomarkers, thereby conferring distinct advantages for saliva in the diagnosis and monitoring of diseases such as oral cancer and precancer.
Salivary exosomes, which are nano-sized salivary biomarkers equipped with all the molecular cargo from the parent cells, have become increasingly detectable due to their stability in the circulation and bodily fluids. They have been extensively explored as diagnostic tools for local and systemic diseases [50].
Fusion of nano-sized (30–100 nm in diameter) multivesicular bodies (MVB) [51] derived from the endocytic pathway with plasma membrane was discovered over 30 years ago [52]. Johnstone et al., detected the release of small vesicles into extracellular spaces by reticulocyte MVB’s and observed that their enzymatic activity mirrored that of the cell culture from which they were shed [52]. These bodies (exosomes), originally believed to be involved in waste disposal, due to their resistance to degradation by lysozymes, is now more understood to subserve vital biological functions when released as extracellular vesicles [53]. These functions are influenced/determined by their target cell with which they interact and include cellular communication and homeostasis, immune control (they contain IgA), RNA processing and transport of drugs [53, 54, 55].
Exosomal release (after formation of intraluminal vesicles), can be compared to the reversal of the endocytosis process, permits their evaluation in the extracellular body fluid environments [56]. The exocytotic release of exosomes into the extracellular domain, reveals that they naturally contain key molecular components derived from the parent cell relating to membrane transport, lipid metabolism and extracellular matrix formation [21, 57]. In addition, cytoplasmic nucleic acid contents such as mRNA and microRNA have been found in exosomes [21, 58, 59]. Considering the important contents as highlighted here, exosomes have been identified to play crucial roles in cell-to-cell communication [21]. All exosomes regardless of their origin possess both shared conserved and cell-specific proteins. Emerging knowledge has associated exosomes with the development of physiological and pathological perturbations [60, 61]. For instance, cancer exosomes have been found to be capable of a range of tumor-promoting activities, such as immunomodulation, development of pre-metastatic niches, as well as dysregulation of angiogenesis [62, 63, 64]. Furthermore, cancer exosomes are vital indicators of potentially malignant events in the tumor microenvironment and may exhibit pheno-genomic perturbation biomarkers of cancer [65, 66].
Due to exosomal release into the extracellular compartment, they are abundantly found in most body fluids such as cerebrospinal fluids, blood, breast milk, plasma, urine, serum, saliva, amniotic fluid, semen and ascetic fluid [21, 52, 53, 54, 55]. Exosomes are highly suitable substrates for biomarker signature discovery. Because of the content-protective packaging of their rich cargo (by lipid membranes) from extracellular lytic enzymes, and significantly lower complexity of its contents in comparison to whole tissue analysis [53].
Analyzing exosomal shuttle RNA (esRNA) in maternal blood, has been proposed as a potential surrogate prenatal diagnostic tool, to avoid risky invasive procedures such as chorionic villus sampling and amniocentesis [54]. This could potentially lower the risk of surgical injuries and miscarriages. Even though, cell free fetal DNA (cffDNA) has been previously used for the prenatal diagnostic purposes, the low content of fetal cffDNA has reduced the accuracy of this method [54, 56]. Information about cancer risk and genetic disease predisposition can be potentially gleaned from exosomal esRNA content analysis.
The use of novel liquid biopsy-based cancer diagnostic tools has significantly improved the precision and efficacy of individualized medicine, particularly in resource-limited settings [11]. Exosomes are capable of providing robust molecular tumor information about cells of origin, are retrievable from easily accessible body fluids; and hence are highly useful for early detection and follow-up of cancer [55].
Exosomes have been successfully isolated from saliva [19, 20, 21, 22, 23, 24, 25]; and the presence of lipids, proteins and nucleic acids in exosomes, makes salivary exosomes attractive substrates for omics analysis (a.k.a Salivaomics) [57, 58, 59, 60]. It has become emergent, that salivary constituents (e.g. mRNAs, proteins, miRNAs, microbes and metabolites such as lipids) may be detected in exosomes and be used as biomarkers for diseases (both local and distal) [54]. Structural, proteomics and transcriptomics analysis of salivary exosomes has been successfully carried out [61, 62, 63, 64, 65]; and salivary exosomes are fast becoming key tools in cancer biomarker theranostics. Exosomes have been revealed as valuable indicators of the micro-environments and perpetrators of cancer intercellular communication [25].
The mean diameter and protein content are used as the basis upon which exosomes isolated from saliva are structurally subdivided into two types (I and II which are ca. 85 nm and 40 nm in diameter, respectively) [20]. Since epithelial barriers between blood vessels and salivary gland structures can be crossed by exosomes [66, 67], they have become important tools for essential transport of key signatures between blood and saliva (which is believed to be an ultrafiltrate of blood) [67, 68, 69]. Important molecular information may be exchanged via transudation, ultrafiltration or selective transport based on their size or presence of transporter molecules [67].
Of all the head and neck cancers, oral squamous cell carcinoma is the most prevalent, often diagnosed in advanced stage and is associated with a low survival and poor prognosis. Early detection of oral cancer is a key goal in epidemiological cancer control and successful management thereof. Using salivary exosomes for identification of oral cancer biomarkers is potentially a highly sensitive, cost-effective and non-invasive point-of-care technique for detecting oral cancer that may be subclinical or missed by routine histological diagnostic approaches [70]. Evaluation of these vesicles shed by cancer cells via multivesicular bodies (MVB’s) into saliva is a viable approach for biomarker detection in oral cancer (Figure 2). Salivary exosomes have played key roles in diagnosis of systemic diseases [51] and have been key player in the molecular characterization of cancer [24]. Due to its reduced complexity as compared to other body fluids, exosomes are reliable tools for early diagnosis of oral cancer and its use as a diagnostic tool may significantly improve cancer survival rates [24].
Pathways for escape of exosomes into saliva. Oral squamous carcinoma cells (OSCC) may release exosomes into saliva, either by fusion of the multivesicular body (MVB) with the plasma membrane (MF) or by plasma membrane rupture (MR) and direct release through endosomal membrane.
Due to its nano-scaled structure, human salivary exosomes have been identified as potential carriers for non-invasive delivery of cancer biomarkers [22]. For example, electrochemical sensing methods, such as electric field-induced release and measurement (EFIRM) approach, has been used to improve the field of salivary liquid biopsy [23]. Not least, salivary exosomes have been used to enhance the detection of human papilloma virus (HPV) positive oropharyngeal cancers [26].
The critical role of tumor-derived exosome in cancer in largely due to the presence of tumor-specific signatures within its functional cargos, which includes proteins, miRNA and mRNA (Table 1).
Biomarker | Type | Sample | Methods | References |
A2M, HPA, MUC5B, LGALS3BP, IGHA1, PIP, PKM1/M2, GAPDH | Protein | saliva | Mass spectrometry analysis and proteomics data analysis | Winck et al. [71] |
miRNA-21 | miRNA | OSCC cell line | miRNA sequencing | Li et al. [72] |
miR-1246 | miRNA | OSCC cell line | MicroRNA microarray | Sakha et al. [73] |
miR-200c-3p | miRNA | OSCC cell line | integrated microarray | Kawakubo-Yasukochi et al. [74] |
miR-34a-5p | miRNA | OSCC cell line | miRNA sequencing | Li et al. [75] |
PF4V1, CXCL7, F13A1, and ApoA1 | protein | serum | RT-PCR | Li et al. [76] |
miR-101-3p | miRNA | OSCC cell line | Microarray analysis | Xie et al. [77] |
miR‑382‑5p | miRNA | OSCC cell line | RT-PCR | Sun et al. [78] |
miR-24-3p | miRNA | saliva | RT-PCR | He et al. [79] |
miR-21-5p | miRNA | OSCC cell line | RT-PCR | Chen et al. [80] |
miR-155 | miRNA | OSCC cell line | RT-PCR. | Kirave et al. [81] |
Exosome biomarker for oral cancers.
The significant physiological interaction and overlap of the blood and salivary proteome (ca. 20–30%) makes exosomal protein biomarkers attractive and many cancer-related exosomal proteins have been identified from oral cancer [23, 82, 83]. Potential proteomic biomarkers of oral cancer such as CFB, CD59, A1BG, M2b, CAT, MRP14, PFN, M2BP, ADA, S100, CFL1, IGHG, TF, IL-1B and IL-8S have been identified from whole saliva [84, 85, 86, 87, 88]. However, protein biomarkers such as MUC5B, A2M, LGALS3BP, HPa, GAPDH, IGHA1, PIP and PKM1/M2 have been specifically identified to be exosomal protein biomarkers of oral cancer with a classification accuracy of 90% [80, 89]. Zlotogorski-Hurvitz et al. (2016), identified CD9/−81 downregulation and CD 63 upregulation in exosomes as early diagnostic protein biomarkers of oral cancer [90]. Furthermore, salivary exosomes isolated from HPV-positive oropharyngeal cancer cell lines has been found to underexpress cyclin D1 and p53 and overexpress p16, T-cell inhibitory protein PTPN11 and E6/E7 proteins [91].
Via their interaction with mRNA, micro RNA’s (miRNA) are involved in a number of physiological and disease processes (when there is aberrant expression). MiRNAs are small non-coding RNAs that mediate destabilization and/or translational repression of target messenger RNA (mRNA) molecules thereby reducing final protein output. Exosomes are a rich source of miRNA’s, provides a vehicle for cell to cell transporting to alter cellular functions as well as offer protection in the extracellular environment. Exosomal miRNAs have been investigated as candidate screening tools (miR-24-3p) [92], in chemoresistance (miR-21) [81], regulating tumor progression (miR-34-5p) [93] and miR-342–3p and miR-1246 [93] and miR-382-5p [78].
In oral cancer, the intercellular transfer of molecules (such as miRNA’s) by cancer associated fibroblast influences the tumor microenvironment. miR-21 represents one of the most abundant miRs transported within EV cargos secreted by oral cancer cells and is a well-established oncogenic miR whose major targets include the tumor suppressors. Its exosomal hideout contributes towards chemoresistance due to the camouflage provided by its vehicle during intercellular transfer of the oncogenic miR. It is thus also an important chemotherapeutic precision target in cancers [81]. Li et al. [94], in a study of 108 patients with OSCC, observed that tumor exosomal miR 21 was upregulated in hypoxic cancer cells as well as internalized by normoxic cells. Exosomal miR-34-5p transfer between CAF’s and neighboring OSCC cells played an important role in regulating tumor progression. Sakha et al. [73], demonstrated that effect that intercellular transfer of exosomal oncogenic miRNA’s (miR-342–3p and miR-1246) could be delivered were evaluated for their role in could have on cancer development and progression by influencing cell motility and invasiveness [73]. Exosomal miR-382-5p in cancer-associated fibroblast (CAF) mediated OSSC migration and invasion by evaluation of tissue samples from 47 patients who had OSSC tumor resection. The results showed that CAF’s transfer miR-382-5p associated with migration and invasion [78]. The expression of exosomal miR-24-3p was found to be higher in salivary exosomes from OSCC patients compared to healthy controls. The AUC for miR-24-3p was 0.738 and could significantly distinguish OSCC patients from normal individuals with 64.4% sensitivity and 80% specificity in 49 patients with OSSC.
The functional cargos which include mRNA has been considered as potential biomarker in the diagnosis and monitoring and treatment of cancer. Valadi et al. first described the presence of mRNAs in exosomes in 2007 [95]. Subsequently, studies have shown the transfer of bioactive mRNAs (tumor suppressor genes or oncogenes) from a malignant cell to a normal cell led to a change in the phenotype and malignant transformation of the normal cell [95, 96, 97].
Few studies have identified mRNA in saliva of oral cancer patients. Li et al. identified potential mRNA biomarker which include IL8, SAT, DUSP, IL1B, OAZ1, H3F3A and S100P, in saliva from oral cancer patients [98]. The study showed that the combination of these biomarkers was highly sensitive and specific in differentiating between OSSC and healthy [98]. An in vitro study showed that oral squamous cell carcinoma cell line (PCI-13, UMSCC47) triggered significant increase expression level of IGFBP-3 mRNA and VEGF mRNA in recipient cells [99].
Even though exosomes have been widely employed to investigate head and neck squamous cell carcinomas [100, 101, 102, 103], unraveling the biologic mechanisms and application of salivary tumor -derived exosomes is still an evolving science [67]. This emergent field of saliva-exosomics warrants further investigation.
Salivary exosomes provide viable, consistent and stable sources of cancer biomarkers. The scope of its utility as well as understanding the molecular mechanisms which underpins it, requires further investigation. Future studies refining the methodology for extracellular vesicle isolation and cleansing presents the greatest challenge that is needed to overcome the restrictions to exploring the full scope of salivary exosomes in systemic diseases including oral cancer.
H.A.A thanks the South African Medical Research Council (SAMRC) for a mid-career scientist and Self-initiated research grant; and the South African National Research Foundation (NRF) for Research Development Grant (RDG) for rated researchers. The authors thank the University Research committee (URC) of the University of Cape Town for funding this book chapter.
The authors declare no conflict of interest.
The primary function of the intestinal tract is to digest food components and absorb nutrients and water from the lumen to the systemic circulation. The intestine is also a physical barrier that is in contact with the environment. As a result, the intestinal epithelium is constantly exposed to potentially pathogenic microorganisms, toxins, and harmful components of the diet. When there are disturbances in the barrier function and mucosal immune homeostasis, the influx of intestine luminal content triggers barrier dysfunction and an exaggerated mucosal immune response [1]. Ultimately, chronic exposition to these detrimental environmental stimuli may lead to the development of local and systemic inflammatory conditions [2, 3] that contribute to barrier dysfunction.
Natural products have been recognized as a source of therapeutic agents for many years [4]. Some plant-derived phenolic compounds show promising anti-inflammatory effects and have been associated with the prevention of certain chronic diseases [5]. Proanthocyanidins (PACs), also known as condensed tannins, are oligo- and polymeric end products of the flavonoid biosynthesis pathway in plants [6]. There has been extensive laboratory research into the effects of both pure PAC molecules and PAC-rich extracts on overall health. These phytochemicals show a wide range of physiological activities [7], including anti-inflammatory and barrier-protective effects in the intestine [8, 9, 10], which may be interesting in the context of diet-induced obesity and inflammatory bowel disease (IBD).
We have reported previously that grape-seed PACs and other flavonoids have beneficial effects on inflammation [11, 12, 13] and protect the intestine against alterations associated with diet-induced obesity in rats [8, 9, 14, 15]. In addition, research conducted during the last decade with cell culture and animal models has made significant progress in determining the underlying mechanism of the health-promoting properties of PACs in the gastrointestinal tract and peripheral tissues.
The intestinal epithelium is a single cell-layer responsible for separating underlying mucosal tissues from the environment and is the largest exposed surface area in the body [16]. As there is a prolific commensal microbial community in the intestinal lumen (intestinal microbiota), epithelial integrity plays a pivotal role in maintaining overall health [16, 17]. The intestinal epithelium is integrated by several cell types with specialized functions. The enterocytes are responsible for the absorptive function and constitute the most abundant epithelial cell lineage. The goblet cells are implicated in the synthesis of secretory mucin glycoproteins that form the mucus layer [18]. Other cellular types integrating the epithelium, microfold (M) [19], Paneth and enteroendocrine cells are specialized in antigen sampling and presentation to dendritic cells, synthesis of antimicrobial peptides, and secretion of hormones, respectively.
The first strategy the host tissue has to maintain its homeostatic relationship with the intestinal microbiota is to minimize the physical interaction with microorganisms, thus limiting microbial translocation and physiological inflammation [20, 21]. The thick mucus layer secreted by goblet cells represents a primary defense line against environmental insults [18]. In addition, the enterocytes are joined together forming an intricately and well-regulated barrier sustained by intercellular junctions linked to the cell cytoskeleton, such as tight junctions (TJs), desmosomes, and adherent junctions. TJs partially seal the paracellular space and prevent passive transport of large molecules, including microbial components and other potentially harmful agents [1, 22].
The paracellular and transcellular pathways are the two major pathways mediating transmembrane transfer of intestinal bacterial substances. Both mechanisms may be involved in intestinal mucosal barrier damage and bacterial translocation. The paracellular pathway is integrated by tight junctions (TJs), consisting of zonulin/zonula occludens (ZO)-1, occludin, claudins, junction adhesion molecules (JAMs), and actin-myosin cytoskeletal proteins. Previous studies have shown that inflammatory cytokines and bacterial antigens can affect the expression level and assembly of these elements, thereby exerting an influence on TJ functions [23]. Immune cells, including neutrophils, dendritic cells, and monocytes, have also been directly implicated in inducing disturbances in TJ barrier function. It has been postulated that pro-inflammatory cytokine-induced opening of the intestinal TJ barrier is an important mechanism contributing to the TJ barrier defects present in various inflammatory conditions of the gut [24]. Previous studies [25, 26, 27, 28] have shown that myosin light chain kinase (MLCK) plays a central role in the regulation of intestinal TJ permeability. The activation of MLCK catalyzes the phosphorylation of myosin light chain (MLC), inducing contraction of the peri-junctional actin-myosin filaments and the opening of the TJ barrier. In contrast, inhibition of MLCK activation prevents this effect [27]. It has been suggested that the cytokine-mediated barrier dysfunction could be mediated by an increase in Nuclear Factor (NF)-kB, which, in turn, activates MLCK gene and protein expression [29] (Figure 1).
Protective properties of PACs in the intestinal barrier function. (A) Chronic exposition to detrimental environmental stimuli may lead to dysbiosis, breakdown of the intestinal barrier, influx of bacterial endotoxins and mucosal inflammation. (B) PACs ameliorate loss of barrier function blocking the activation of MLCK mediated by NF-κB and MAPK signaling. See text for details.
Once intestinal bacteria and endotoxins enter the portal vein and/or lymphatic system, they can reach other tissues and organs, leading to a cascade response modulated by inflammatory mediators. This situation can induce a systemic inflammatory response, which further damages the function of the intestinal barrier [30]. The endotoxin-signaling pathway includes the binding of LPS to LPS-binding protein (LBP) and its subsequent transfer to the CD14 receptor. LBP-bound LPS initiates inflammation via TLRs associated with membrane-anchored CD14 [31]. TLRs are a family of pattern-recognition receptors that play a key role in the innate immune system. Among all, the TLR4 is expressed at high levels in the intestinal tract, and given that LPS is its specific ligand, TLR4 could be considered the first barrier for recognition of bacterial presence in the gastrointestinal tract. NF-kB is the final effector transcription factor of the TLR4 signaling pathway. It promotes the development of many intestinal diseases and also plays a pivotal role in the translation and transcription of inflammatory mediators [30].
In mammals, the NF-kB family comprises five proteins, including p65 (RelA), RelB, c-Rel, p105/p50 (NF-kB1), and p100/p52 (NF-kB2), which associate with each other to form transcriptionally distinct homo- and heterodimeric complexes; the p65:p50 heterodimer is the most abundant and the most relevant for inflammation [32]. In resting cells, the p65:p50 NF-kB heterodimer is sequestered in the cytoplasm by binding to its inhibitory protein, IkappaB (IkB). In response to an inflammatory stimulus, such as LPS, the classical NF-kB activation pathway leads to the activation of the IkB kinase (IkkB), a member of the IKK complex, triggering IkB-a phosphorylation (pIkB-a). Then, pIkB-a is recognized by the ubiquitin ligase machinery, resulting in its polyubiquitination and subsequent proteasomal degradation. After pIkB-a degradation, the p65:p50 heterodimers are able to translocate to the nucleus, where they bind to the kB motif found in the promoter or enhancer regions of numerous pro-inflammatory genes to induce their expression [33].
NF-kB target genes include cytokines (e.g., tumor necrosis factor (TNF)-α and interleukins), adhesion molecules, acute phase proteins, and inducible enzymes (inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX2)), among others [11]. All of these genes contain verified NF-kB binding sites in their sequences, providing strong experimental evidence for their direct control by NF-kB [34]. Among all of these genes, the expression of iNOS and COX2 has been widely studied in relation to intestinal inflammation. In this regard, sustained high nitric oxide (NO) production by iNOS plays a role in the pathology of chronic inflammatory bowel disease [35, 36]. During the last decade, it has become increasingly clear that NO overproduction by iNOS is deleterious to intestinal function [37], thus contributing significantly to gastrointestinal immunopathology. Cyclooxygenases are enzymes that are responsible for the metabolism of arachidonic acid, converting it into prostaglandins. These products influence a wide variety of biological processes, ranging from homeostasis to inflammation [38]. There are two cyclooxygenase isoforms: the constitutive COX1 isoform and the inducible COX2 isoform [38, 39]. As a result of COX2 induction, prostaglandin E2 levels increase at the site of inflammation and can also be detected systemically.
Multiple environmental factors have been identified as potential triggers of intestinal inflammatory conditions, including Western dietary habits [40]. It has been described that saturated fats play a direct role in inflammatory signaling. Saturated fatty acids (SFA) such as lauric (C12:0) and palmitic (C16:0) directly induce NF-κB activation, acting as non-microbial TLR2 and TLR4 agonists in macrophages [41]. Data suggest that activation of TLRs by SFA is mediated by TLR dimerization and recruitment into lipid rafts [42]. We have reported mild intestinal inflammation and increased permeability in rats feeding on a cafeteria diet consisting of high-saturated fat/high-refined sugar food products [43]. This enhanced permeability has been shown to favor bacterial LPS and other potentially pro-inflammatory molecules entering the systemic circulation, which is known as metabolic endotoxemia [15].
Taken together, these data suggest that HF diet-induced changes in the intestinal microbiota could be responsible for metabolic endotoxemia and for the onset of the corresponding diseases. The causative link between changes in intestinal bacteria populations, endotoxemia, and metabolic disease needs further assessment [44], but the mechanisms likely include altered epithelial permeability, translocation of bacterial products, and upregulation of pro-inflammatory cytokines and hormones produced by gut endocrine cells, mechanisms which might be modulated by PACs.
PACs consist of flavan-3-ol subunits with a degree of polymerization (DP) equal to or greater than 2, mainly linked by (4 → 8) or (4 → 6) carbon-carbon bonds (B-type PACs) [45]. In some botanical sources an additional (2 → 7) ether-linkage also occurs (A-type PACs) [46] (Figure 2). Depending on the type of monomers, PACs can be classified into procyanidins, prodelphinidins, and propelargonidins. The most abundant group, procyanidins, consists exclusively of (+)- catechin and (−)- epicatechin monomers [47]. Prodelphinidins and propelargonidins are composed of (−)- gallocatechin/(−)- epigallocatechin and (+)- afzelechin/(−)- epiafzelechin monomers, respectively [45], and have a more limited distribution
Chemical structures of PACs. Flavan-3-ol monomers differ based on the hydroxylation pattern and their cis- or trans-configuration. Dimers A1/A2 and B1/B2 are shown as example of A- and B-type PACs, respectively.
Dietary assessment studies have shown that PACs, especially procyanidins are among the most abundant polyphenols in the human diet [6], as they are present in a variety of botanical sources and plant food products such as tea, fruits, nuts, cacao products, legumes, and cereal grains [1, 2]. However, PAC intake varies widely between geographical regions and cultures and is greatly dependent on eating habits, lifestyle behaviors, and socioeconomic status [48]. The daily PAC (dimers to polymers) intakes in adult populations from Korea, the U.S., Mexico, and EU were estimated as 71 [49], 73 [48], 103 [50], and 123–180 mg [51, 52], respectively, but intakes up to 230 mg d−1 have been reported in some regions of Spain and Norway [53].
Flavan-3-ols are remarkably stable during gastric transit in humans [54]. Monomers such as (+)- catechin and (−)- epicatechin are readily absorbed in the upper sections of the small intestine [55, 56], recognized as xenobiotics and then subjected to an extensive phase II metabolism that generates glucuronidated, sulfated, and methylated conjugates [57]. Flavan-3-ol monomers and their conjugated metabolites reach peak plasma concentration 1–4 h after flavan-3-ol-rich food consumption [58, 59, 60]. Studies conducted in cultivated epithelial monolayers [61, 62, 63], rats [64, 65], and humans [60, 66] indicate that PAC absorption is conversely more limited and is highly dependent on DP, and that the permeation of larger oligomers (DP > 5) and polymers is negligible. No PAC transporter has been identified in the enterocyte membrane in the small intestine. Thus, dimers to tetramers are passively transported across the intestinal epithelium essentially by paracellular diffusion. Although transcellular passive diffusion is not likely to occur due to the hydrophilic nature of PACs conferred by the multiple hydroxyl groups, uptake might be possible by endocytic mechanisms [62].
In humans, a study assessed the contribution of the ingested cocoa flavan-3-ols and procyanidins to the systemic pool, and found that the plasma (−)- epicatechin came from the orally administered cocoa (−)- epicatechin and not from their oligomers or polymers [67]. This is in agreement with the evidence obtained with rats that suggests that PACs from different sources do not depolymerize to monomers after ingestion [68, 69]. Stalmach et al. [56] conducted a study with ileostomized patients who were administered green tea, and found 70% of the ingested flavan-3-ol in the ileal fluid after 24 h. Altogether, these findings suggest that substantial amounts of ingested flavan-3-ol monomers and PACs remain unabsorbed in the small intestine and reach the colon. There, they are efficiently transformed by the colonic microbiota into low molecular weight phenolic compounds that can be absorbed by colonocytes [57].
In vitro fermentation of purified procyanidin dimers with human fecal microbiota has shown to produce mainly 2-(3′,4′-dihydroxyphenyl) acetic acid and 5-(3′,4′-dihydroxyphenyl)-γ-valerolactone [70]. In agreement with this, a randomized cross-over study in healthy humans found that a great portion of the ingested (−)- epicatechin and procyanidin B1 was metabolized by the colonic microbiota to produce phenyl-γ-valerolactones as the major microbial metabolites [60]. In this study, microbial degradation of larger procyanidins was substantially lower, possibly to the inhibition of digesting enzymes or to the antibacterial properties exhibited by these compounds. Other human studies analyzing the bioavailability of flavan-3-ols, reported high levels of phenyl-γ-valerolactones in the circulation and urinary excretion after ingestion of a red grape pomace drink [71] and apple juice [72]. In the colonocytes and hepatocytes, these microbial products undergo further metabolism by phase II enzymes to produce conjugated derivatives. Margalef et al. [73] analyzed the tissue distribution of metabolites derived from a grape-seed proanthocyanidin extract (GSPE) 2 h after ingestion by rats. These authors detected a few microbial metabolites (methyl conjugated phenols) at low concentrations in the colon tissue, while most phase II metabolites (glucuronidated and methyl-glucuronidated forms) were found in the kidneys and liver. In humans, the major contributors to the excretion of phenyl-γ-valerolactones after ingestion of a red grape pomace drink, are sulfated and glucuronidated conjugates of 5-(3′,4′-dihydroxyphenyl)-γ-valerolactone [71].
During the last decade, the beneficial properties of PACs for intestinal function have been reported in several studies performed with cell-culture models and experimental animals (Tables 1 and 2). This experimental data indicate that PACs contribute to maintaining the intestinal barrier and improving mucosal inflammation induced by environmental insults. However, there are few studies on the effect of PACs on human intestinal health, although epidemiological studies connect PAC-rich food consumption with a lower risk of colorectal cancer [88].
In vitro models of inflammation have been fundamental in the comprehension of cellular mechanisms driving physiological effects of bioactive molecules. Studies on intestinal dysfunction have employed human colon carcinoma cell lines, being Caco-2 the most well-established and widely used model of the human intestine barrier ([89] and Table 1). Mucus producer [79], macrophages [90], and B cell lines [91] have been employed in co-culture systems to explore the interaction between cell populations. Although there is a strong trend in the industry toward replacing animal experiments with human cell-culture based models [92, 93], there are no in vitro models of the human intestine that replicate the complex interplay between cell types and the regulation of the barrier function by the mucosal innate and adaptive immunity. Therefore, most physiologically relevant data on intestinal dysfunction comes from the animal model. Most in vivo studies testing the effect of PAC supplementation on intestinal health have been performed in diet-induced obesity models and chemical-induced colitis models. The first resemble intestinal alterations seen in humans with metabolic syndrome [43]. The latter closely mimic histopathological features of human colitis and are frequently used to study the pathophysiology of IBD and the effectiveness of novel therapeutic drugs [94]. Notably, PAC-rich grape-seed extracts (GSPE) are among the most studied botanical extracts, mainly by in vivo approaches in rodents (Table 2).
The data available on the interaction between PACs and permeability and inflammation markers in cell models of intestinal dysfunction are summarized in Table 1. Caco-2-based models have shown to be responsive to pro-inflammatory stimulation, producing a wide range of inflammatory mediators and increasing the paracellular permeability. Pro-inflammatory agents such as LPS, phorbol 12-myristate 13-acetate (PMA), and cytokines (TNF-α and IL-1β) have been used in multiple studies testing the effect of PAC molecules and PAC-rich botanical extracts on Caco-2 cells [10, 74, 77, 78]. Stimulated-Caco-2 cell monolayers incubated with PACs generally show a reduction in gene expression and secretion of TNFα, IL-6, and IL-8 [10, 74, 75, 77], which is often linked to the downregulation of NF-κB signaling at different levels [10, 76, 77]. An increased expression of antioxidant enzymes, such as glutathione peroxidase (GPx), superoxidase dismutase (SOD), and hemeoxygenase 1 (HO-1), has also been reported [10].
When permeable support systems such as transwell or Ussing chamber (UCh) are used, alterations in barrier integrity and paracellular permeability of epithelial cell monolayers are evaluated by transepithelial electrical resistance (TEER), an electrophysiological parameter that measures ion conductance across the monolayer, and by the transepithelial transport of molecular markers such as Lucifer yellow (LY) and fluorescently labeled dextrans (FD) [95, 96]. Some in vitro studies have associated PACs with increased TEER and decreased transport of permeability markers in the context of barrier dysfunction [77, 78, 80]. The expression levels of TJ proteins (claudins, occludins, and ZOs) often correlate, but not always [79], with intestinal permeability and are also considered markers of epithelial integrity. Bitzer et al. [78] found that the dextran sodium sulfate (DSS)-induced loss of barrier function in Caco-2 cells was significantly inhibited by polymeric PACs of cocoa but not by oligomers. Moreover, a higher barrier-protective activity was determined in PACs with DP ≥ 7, which were able to reduce the detrimental effect of DSS in a dose-dependent fashion [78]. Effectiveness of procyanidin B2 ameliorating dextran sodium sulfate (DSS)-induced permeability alterations was examined using a Caco-2/HT29-MTX co-culture model [79]. Although procyanidin B2-incubated cells showed increased levels of the TJ proteins claudin-7, occludin, and ZO-1, these changes did not reduce TEER loss. Altogether, these results suggest that the ability of PACs to strengthen the intestinal barrier integrity depends on the degree of polymerization (DP).
The cafeteria (CAF) diet is a self-selected high-saturated fat/high-refined sugar diet that stimulates hyperphagia and a rapid weight gain in experimental animals [97, 98]. In this feeding regime, highly palatable and energy dense foods commercially available, such as muffins, biscuits, bacon, sausages, and sugared milk, are offered
Chemical agents administered orally to induce colitis in rodents include trinitrobenzene sulfonic acid (TNBS) and DSS. These agents erode the colonic mucosal lining and produce the loss of the intestinal barrier function and colonic inflammation. In these models, the severity of outcomes depends on the dose of the chemical agent and the frequency of administration. Li et al. [102] found that intragastric administration of GSPE in rats at pharmacological doses (100–400 mg kg−1 d−1) prior to TNBS-induced recurrent colitis, reduced weight loss, and attenuated macro- and microscopic tissue damage scores in the colon. This protective effect was accompanied by a reduction in oxidative stress (malondialdehyde; MDA), inflammation (IL-1β), and neutrophil infiltration (MPO activity) in colonic tissues. Remarkably, the beneficial effects of low to high doses of GSPE were comparable to those of sulfasalazine (200 mg kg−1 d−1), a potent inhibitor of NF-κB. Subsequent studies carried out by these authors with the same model, confirmed the role of the GSPE down-regulating NF-κB response [83, 84]. A preventive effect of procyanidin B2 was also evidenced in a mouse model of DSS-induced colitis [85]. Administration of procyanidin B2 (10–40 mg kg−1 d−1) attenuated the severity of tissue damage in the colon and reduced the levels of matrix metalloproteinase-9 (MMP-9), a marker of macrophage infiltration. In addition, inhibition of the NF-κB signaling and of NLRP3 inflammasome activation was observed, with a concomitant reduction in the gene expression of pro-inflammatory cytokines. Overall, the benefits of procyanidin B2 administration, especially at the highest dosage (40 mg kg−1), were comparable to those of mesalazine (200 mg kg−1), a COX inhibitor. The authors suggest that these effects were largely due to the reduction in activated macrophages infiltrating colonic tissues, probably driven by ROS clearance.
The IL-10 deficient mouse is a classic knockout model that develops spontaneous colitis under pathogen-free conditions. Some authors have explored the influence of GSPE in this model, supplementing colitic animals with 0.1–1 g 100 g−1 of dry feed weight for 12–16 days [86, 87]. These studies evidenced a reduction of multiple inflammatory markers in the jejunum and colon, such as TNF-α, IL-1β, IL-6, and IFN-γ gene expressions, as well as MPO activity. This anti-inflammatory effect was associated with the inhibition of the NF-κB signaling. Interestingly, GSPE supplementation also increased the density of goblet cells in the jejunum of treated animals, suggesting that there is an alternative mechanism by which inflammation is attenuated.
Cardoso et al. [13] recently tested both dietary (75 mg kg−1) and pharmacological doses of GSPE (375 mg kg−1) in a rat model of mild intestinal dysfunction induced by intraperitoneal injection of LPS. GSPE was administered daily by oral gavage for 15 days prior to LPS-induced intestinal dysfunction. LPS enhanced intestinal permeability and induced both oxidative stress and inflammation. GSPE-treated animals reduced OVA permeation to the circulation, MPO activity and COX-2 in the small intestine tissues, and reactive oxygen species (ROS) levels in the colon. Furthermore, a gene expression analysis with a low-density microarray technique revealed that unlike the dietary dose of GSPE, the pharmacological dose had a striking effect on the LPS-gene expression profile, showing a strong modulation of multiple genes associated with chemokines and ILs, including upregulation of the anti-inflammatory cytokine IL-13.
Although the use of animal models is the predominate approximation at preclinical stages for testing novel therapies in intestinal permeability, there is a strong trend in the industry towards replacing animal experiments with human cell-culture based models [92, 93]. Nevertheless, advantages related to the usefulness of in vitro models for screening of bioactives and exploring action mechanisms, are offset by limitations regarding the mimicking of the in vivo situation and translation to the human [103]. Thus, some human ex vivo models have been proposed to test immunomodulatory properties of drug candidates in intestinal explants from IBD patients [104, 105]. Intestinal function can also be studied with UCh-based protocols. The UCh system consists of two halves with an opening between them, where mucosal tissue is adapted, thus isolating the apical and basolateral sides of the tissue. This technique has been applied for studying drug absorption [106] and secretion of enterohormones [107] in human endoscopic biopsies. An advantage of UCh models over explant-based models is that UCh models make it possible to measure the electrophysiological parameters, including TEER [106]. All these set-ups permit analyzing the cytokine profiling of intestinal explants or biopsies retaining their in situ conditioning in a polarized fashion [105, 108]. We have employed the UCh to determine TEER and cytokine release (TNF-α) in intestinal tissues from cafeteria diet-induced obese rats treated with GSPE [8, 15]. It could also be useful for testing the effect of bioactives on dysfunctional human intestine. A feature of ex vivo models is that screening of drug effects does not compromise the patients by exposing them to unknown outcomes.
Translation of doses of PAC-rich extracts used in rodent models of intestinal dysfunction to human equivalent doses (HED) indicates that pharmacological doses (up to 5 g d−1 for a 60 kg person) could be required to achieve beneficial effects in clinical trials [14, 15]. Thus, the first uncertainty involved in assessing the use of PACs as therapy agents in humans, is safety. Grape seed and skin proanthocyanidin-rich extracts have been subjected to toxicological tests in rats to determine their safety for use in functional foods [109, 110, 111]. In these studies, the median lethal dose (LD50) was found to be greater than 5000 mg kg−1 bw (HED of ≈50 g) when administered once by oral gavage, and 1400–2000 mg kg−1 d−1 (HED of ≈14–20 g d−1) was found to be the no-observed-adverse-effect level (NOAEL) for systemic toxicity in sub-chronic administration. A recent study evaluated the safety and tolerability of GSPE intake (up to 2.5 g d−1) in a small number of healthy adults for a 4-week period and found a good tolerability without adverse effects on hematological or biochemical parameters [47].
To date, there are few clinical studies that evaluate the influence of PACs on intestinal inflammatory conditions. A clinical study revealed that the postprandial increase of plasma LPS associated with the intake of a high-fat meal was significantly reduced in obese subjects who consumed 1 g of GSPE [112]. As translocation of LPS to the circulation is considered an indicator of intestinal permeability and a critical factor in the appearance of systemic low-grade inflammation in patients with metabolic syndrome [113], reduction of postprandial endotoxemia could be particularly interesting from a therapeutic perspective. Large double-blind clinical studies need to be conducted to provide more information on PAC clinical efficacy in intestinal dysfunction so that these phytochemicals can be used therapeutically to improve intestinal health in obese and IBD individuals.
PACs were often considered to be nutritionally undesirable due to their ability to form complexes with macronutrients and reduce the activity of virtually any enzyme implicated in digestion [114, 115]. Nevertheless, based on the anti-cancerous, anti-mutagenic, and anti-microbial activities these phytochemicals elicited in laboratory experiments, a role in the modulation of the metabolism and immune system was suggested [115]. The ability of PACs to form cross-links with biomolecules can be attributed to the hydroxyl groups and aromatic rings in their structure that can establish hydrogen bonds and hydrophobic interactions [116]. PACs have a significant affinity for proline-rich proteins and peptides [117]. In general, binding to proteins seems to increase with the DP as larger PAC molecules have more potential binding sites for the associations with proline residues [117]. The interaction results in effects determined by the biological function of the target protein. Thus, PACs not only alter enzymatic activity, but they may also prevent ligand-receptor interactions and the binding of transcription factors to their specific sites in DNA. In addition, some PAC molecules can be adsorbed non-specifically onto biomembrane surfaces [118], affecting their physical characteristics, such as fluidity and density, and potentially altering membrane-dependent processes, including protein receptor activity [119]. Altogether, these effects lead ultimately to the alteration of cell signaling pathways and the modulation of gene expression.
The precise mechanisms underlying the improvement in intestine paracellular permeability due to PACs in inflammation are not yet completely elucidated; however, it is known that they lead ultimately to the upregulation (e.g., ZO-1 and claudin-1 [8, 13]) or downregulation (e.g., claudin-2 [86]) of TJ protein expression. Loss of TJ integrity in the pro-inflammatory state is mediated by the NF-κB signaling pathway and by the activation of protein kinases MAPKs, PI3Ks, AMPK, and MLCK [120]. MLCK is particularly crucial in actomyosin-based cytoskeletal functions and multiple studies highlight its important role in intestinal TJ remodeling [121, 122]. PACs reduce the production of pro-inflammatory mediators (e.g., TNF-α) and reactive oxygen species (i.e., iNOS activity) associated with enhancing intestinal permeability by antagonizing the NF-κB signaling pathway. In addition, PACs are potent inhibitors of kinases including MLCK [120, 123]. Contreras et al. [124] also suggested that there is an upstream novel mechanism associated with flavan-3-ols that leads to the prevention of TNF-α-induced intestinal permeability. In this study, TNF-α-stimulated Caco-2 monolayers incubated with (−)- epicatechin showed a reduction of NOX activity, an enzyme that also facilitates activation of TNF-α signaling. This effect was directly associated with the inhibition of ERK1/2 MAPK activity of IκB phosphorylation and of MLCK activation.
Delehanty et al. [125] demonstrated that naturally occurring A- and B-type cranberry PACs were able to bind the lipid A moiety of LPS, exhibiting an affinity similar to that of polymyxin B, a potent LPS-binding molecule. In this study, PACs efficiently blocked endocytosis of bacterial LPS in a dose-dependent manner in HEK 293 (human embryonic kidney cells) that expressed receptors TLR4/MD-2 and CD14, thus preventing the induction of the NF-κB signaling pathway without any interaction with cellular components. However, other authors reported that PACs isolated from cocoa beans did not abrogate the binding of LPS to TLR4 in cultivated human dendritic cells [126]. PAC-LPS binding has been linked to the reduction of the post prandial increase in blood LPS associated with the ingestion of a high-fat meal in obese subjects ingesting an oral dose of GSPE [112].
Diet plays an important role in the composition of intestine microbiota, promoting or inhibiting growth of microorganisms [127]. Alterations in the composition and metabolism of the intestinal microbiota (dysbiosis) have also been associated with the consumption of high-saturated fat diets in rodents and humans [128, 129]. In fact, metagenomic analysis of the intestinal microbiome in Western populations has shown a reduction not only of microbial diversity, but also of functional potential [130]. Dysbiosis is linked to obesity-associated intestinal inflammation, although the “egg or hen” question related to the cause-effect relationship is not answered yet [131]. High-fat intake in rodents often decreases overall diversity of microbiota and the abundance of Bacteroidetes, and increases the relative abundance of Firmicutes [132, 133]. Several human studies have described similar associations [134, 135], but the importance of the ratio Firmicutes to Bacteroidetes remains controversial [136, 137], and some authors state that the experimental results are not sufficiently consistent [138]. Interestingly, the existence of a colitogenic microbiota was demonstrated in T-bet−/− × RAG2−/− deficient mice whose spontaneous ulcerative colitis was horizontally transmissible to wild-type individuals when co-housed [139]. Although mechanisms by which dysbiosis trigger intestinal dysfunction are not fully understood, it is known that they involve the loss of immune tolerance due to local immune homeostasis disruption and continuous abnormal activation of TLRs [140].
Several authors have suggested that both dietary PACs, which are the substrates of intestinal bacteria, and the metabolites produced during PACs degradation in the colon may modulate and induce oscillations in the composition of the microbiota populations by means of prebiotic and antimicrobial effects against gut pathogenic microorganisms [141, 142, 143, 144]. Dietary PACs, specifically longer polymers, reach the distal intestine nearly intact, where they become fermentable substrates for the commensal microbiota [145]. PACs have been associated with prebiotic properties, boosting the composition of several kinds of probiotics such as
A recent study by Casanova-Marti et al. [150] found that oral administration of GSPE in Wistar rats for 8 days resulted in profound changes in the cecal microbiota composition, reducing diversity indices and the ratio of
Cueva et al. [146] found that in vitro fermentation of grape-seed monomers and PACs in human feces resulted in a reduced abundance of
Finally, phenolic acids and phenyl-γ-valerolactones resulting from the colonic fermentation of PACs also exhibit a significant bioactivity in cell models and experimental animals [154]. They therefore may partially account for the beneficial anti-inflammatory effects reported in intestinal and peripheral tissues in vivo. Further research is needed to clarify the importance of these microbial products in health-promoting properties associated with the intake of PACs.
The health-promoting properties of PACs in the intestine are attributed not only to the antioxidant activity inherent to phenolic compounds, but also to the capacity of these phytochemicals to interact with multiple biomolecules, including proteins, biomembrane lipids, and endotoxins. Bioactivity of PACs is highly structure-dependent and enriched botanical extracts composed by a large variety of molecular structures exert a wide range of unrelated physiological effects. In this way, PAC-rich extracts can modulate kinase activity, several signal transduction pathways implicated in the inflammatory response and the remodeling of TJs. Flavan-3-ol monomers and short PAC oligomers are absorbed by enterocytes and immune cells and exert a direct action on kinases and transcription factors. Bioactivity of larger oligomers and polymeric PACs do not require direct intestinal absorption and are able to bind protein receptors on the enterocyte and immune cell surfaces as well as luminal bacterial endotoxins, thus inhibiting pro-inflammatory signaling and improving barrier integrity. Due to the negligible absorption of large PAC molecules in the small intestine, phenyl-γ-valerolactones and phenolic acids produced by the microbiota metabolism in the colon are thought to play an important role in these health-promoting effects, and thus need to be further researched.
The barrier-protective properties of PACs are emerging as a potential adjunctive support to current therapies for managing obesity related intestinal dysfunction and IBD. However, there have been no large, well-designed clinical trials establishing the efficacy of these phytochemicals in chronic conditions. At preclinical stages, the use of animal models is the predominant approach for testing novel therapies for intestinal dysfunction, although several strategies for replacing animal experiments have been proposed. As there are still no studies on the impact of PACs on human intestinal health, ex vivo models of the human intestine could be a more physiologically reliable alternative to human cell lines and an alternative to animal experimentation in preclinical development.
C. González-Quilen has received financial support through a FI-AGAUR grant from the Generalitat de Catalunya. M. Pinent and X. Terra are Serra-Húnter fellows at the Universitat Rovira i Virgili, Tarragona, Spain.
The authors declare no conflict of interest.
This work was funded by the Spanish Ministerio de Economía y Competitividad (Grant: AGL2017-83477-R).
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