Understanding the Gastrointestinal Protective Effects of Polyphenols using Foodomics-Based Approaches

Plant polyphenols are rich sources of natural anti-oxidants and prebiotics. After ingestion, most polyphenols are absorbed in the intestine and interact with the gut microbiota and modulated metabolites produced by bacterial fermentation, such as short-chain fatty acids (SCFAs). Dietary polyphenols immunomodulatory role by regulating intestinal microorganisms, inhibiting the etiology and pathogenesis of various diseases including colon cancer, colorectal cancer, inflammatory bowel disease (IBD) and colitis. Foodomics is a novel high-throughput analysis approach widely applied in food and nutrition studies, incorporating genomics, transcriptomics, proteomics, metabolomics, and integrating multi-omics technologies. In this review, we present an overview of foodomics technologies for identifying active polyphenol components from natural foods, as well as a summary of the gastrointestinal protective effects of polyphenols based on foodomics approaches. Furthermore, we critically assess the limitations in applying foodomics technologies to investigate the protective effect of polyphenols on the gastrointestinal (GI) system. Finally, we outline future directions of foodomics techniques to investigate GI protective effects of polyphenols. Foodomics based on the combination of several analytical platforms and data processing for genomics, transcriptomics, proteomics and metabolomics studies, provides abundant data and a more comprehensive understanding of the interactions between polyphenols and the GI tract at the molecular level. This contribution provides a basis for further exploring the protective mechanisms of polyphenols on the GI system.


INTRODUCTION
Polyphenols are a subclass of phytochemicals, abundantly found in natural products. They are plantbased secondary metabolites that normally contain at least one or more hydroxyl group-linked benzene rings. The chemical structure of polyphenols varies from simple molecules to highly polymerized compounds, including flavonoids, phenolic acids, proanthocyanidins and resveratrol (1). Polyphenols have multiple health benefits owing to their anti-inflammatory (2), anti-oxidant (3), anti-cancer (4), anti-bacterial (5), and anti-diabetic properties (6), inhibition of obesity, and prevention of cardiovascular (7) and cerebrovascular diseases (8). Thus, current scientific research on polyphenols has aroused great interest and significantly attracted the attention of researchers.
The beneficial effects of dietary polyphenols on health depend on their absorption and bioavailability in the body (9). The gastrointestinal (GI) tract is an indispensable digestive organ whose function is crucial to the host's health, as it regulates the absorption and utilization of nutrients by the body (10). Maintaining good health requires a fully functioning digestive system. A damaged GI system, obstructs GI function, which affects the absorption and utilization of nutrients and thereby threatens host health (11). Gut microbiota are a microbial community inhabiting the GI tract, constituting multiple species that are densely distributed, at approximately 10 14 microbial cells (12). Gut microbiota are critical to gut health and fulfill multiple tasks in the host (13). They are affected by various internal and external factors, including diet, genetics, and external environmental factors (14).
Most polyphenols found in the natural food matrix are mostly bound and unbound, with the majority of them in the form of bound polyphenols (15), and these polyphenol compounds are considered xenobiotics because of their complex chemical structure, making them difficult to absorb after ingestion (16,17). Consequently, portions of polyphenols are stored in the large intestine, where they are fermented by the gut microbiota, raising the concentration of short-chain fatty acids (SCFAs) to selectively modulate gut microbiota that can be used by the host (18). Metabolites produced by the catabolism of polyphenols in the intestine may be more bioavailable to gut microbiota and hosts (19). Numerous studies demonstrated that polyphenols maintain gut health by interacting with the gut microbiota (20).
Polyphenols and gut microbiota have interactive effects (21). On the one hand, polyphenols retained in the colon are absorbed and metabolized by gut microbiota and biotransformed into their metabolites, significantly improving bioavailability (22). On the other hand, polyphenols act as a metabolic prebiotics (23), and studies indicate that dietary polyphenols may affect gut microbiota through dual positive effects to benefit GI health, namely, the inhibition of pathogenic microbiota and enrichment of beneficial microbiota (17). When the number of beneficial microbiota in the gut is greater than the number of harmful microbiota, the GI tract's role and health can be preserved. Therefore, polyphenols ingested at specific concentrations may help maintain GI health by modulating the gut microbiota composition (24). Numerous studies showed that plant polyphenols can alleviate inflammatory bowel disease (IBD) and achieve anti-inflammatory effects by interacting with gut microbiota (19). However, our understanding of the mechanisms by which dietary polyphenols modulate gut microbiota composition and the beneficial effects of polyphenols on the GI tract is severely limited.
The comprehensive discipline of foodomics was first defined in 2009 by Cifuentes (25) as the study and analysis of the fields of food and nutrition using advanced omics technologies (such as genomics, proteomics, metabolomics, and transcriptomics), to promote consumer trust and health. Integrating these techniques enable researchers to establish links between diet and health. Recent decades have witnessed rapid growth of various applications of foodomics technologies for investigating the beneficial activities of polyphenols on gut health (26). The aim of this review is to further elucidate the growing number of contributions that use the foodomics approach to assess relevant aspects related to the protective effects of polyphenols on GI health, such as: 1) identifying polyphenols and their metabolites after ingestion using GC-MS-and LC-MS/MS-based metabolomics approaches; 2) using genomic/transcriptomic approaches to determine gene expression/transcription and the interactions between genes and polyphenols; 3) exploring protein expression patterns in response to polyphenols in the GI; 4) combining several omics approaches to determine network changes that exist at the cell, tissue, or whole organism level. An overview of integrated foodomics approaches for better understanding the interactions between polyphenols, gut microbiota, and host health is presented in Figure 1.

POLYPHENOLS IN THE DIET ARE BENEFICIAL TO GI HEALTH
Dietary polyphenols have been linked to a number of health benefits in the GI tract. Upon reaching the GI tract, part of the dietary polyphenols is absorbed by the intestinal barrier and extensively metabolized in tissues, however, the non-absorbed polyphenols from the small intestine are retained in the colon (27). Most dietary polyphenols are retained in the GI tract as xenobiotics and interact with the microbial community in the intestine during digestion. The variations in polyphenol intake available for absorption and metabolism in the GI tract are dependent on their structures. Polyphenols retained in the GI tract are usually catabolized by gut microbiota (28), and the composition of gut microbiota may also result in differences in the metabolism and bioavailability of polyphenols and their metabolites (29). Polyphenols are metabolized via glucosidase, esterase, dehydroxylation, decarboxylation and demethylation activities by gut microbiota to various derivatives (21), all of which further improve the bioavailability of polyphenols and enhance the benefits to GI health.
Polyphenols play an immunomodulatory role by regulating intestinal microorganisms. The gastrointestinal tract contains a large number of macrophages and neutrophils, which play an immunomodulatory role in the immune system through recognition, uptake, and destruction of intestinal microorganisms (30). The immune system interacts with intestinal microorganisms to maintain the health of the gastrointestinal tract, and polyphenols improve the cellular immune response by regulating these intestinal microorganisms and immune factors, which together maintain a healthy balance in the gastrointestinal tract (31). Indeed, multiple studies have addressed the protective effects of polyphenols on the GI tract (17), dietary polyphenols play a prominent role in altering the gut microbiota, improving barrier function, and inhibiting the etiology and pathogenesis of various diseases, including colon cancer, colorectal cancer (32), IBD, and colitis (33). Polyphenols regulate gut microbiota by anti-microbial activity with bacteriostatic or bactericidal actions and serve as are potential prebiotics enhancing the growth of beneficial microbiota. In vitro and in vivo studies indicate that cocoa polyphenols supplements stimulate the population of beneficial bacteria, including Lactobacillus (34), Bifidobacterium (35), Prevotella, Faecalibacterium prausnitzii (36), Blautia (37), Bacteroides uniformis (38), and Lactobacillus reuteri (39). In turn, cocoa polyphenols supplements inhibited the growth of Escherichia coli (E. coli) enterohemorrhagic O157: H7, Salmonella typhimurium, Listeria monocytogenes (34), Bacteroides, Clostridium, Staphylococcus (40), Lactobacillus-Enterococcus group (37), and Clostridium histolyticum (36). Polyphenols from diverse grapes (mostly phenolic acids, flavonols, favan-3-ols, anthocyanins and hydroxybenzoates) (41) (45).
Colon cancer is one of the world's most prevalent tumor (46). The inhibition of colon cancer and colorectal cancer may be achieved by polyphenols and their metabolites owing to the inhibition of cancer cell proliferation (47), promoting cancer cell death (48), and regulating intestinal microbes. For instance, the potential of the date palm extract (Phoenix dactylifera L.), date polyphenol-rich extract and their metabolites SCFAs in Caco-2 cells was investigated, and both significantly increased the growth of bifidobacteria in human fecal batch cultures to enhance colon health and inhibit colon cancer cell growth (49). Berries are rich in polyphenols, and their inhibitory effects on colorectal cancer progression have been assessed by multiple in vitro studies (50). Cranberries polyphenols inhibit colorectal cancer mainly by regulating relevant gene expression, altering cellular signaling pathways, scavenging free radicals in cells, inhibiting cancer cell proliferation and promoting apoptosis (51). Using extracted and purified polyphenols from P. koraiensis pinecone (PPP), anti-proliferative activities against colon cancer cells were studied (52). The authors tested different ethanol concentrations (20%, 40% and 60%) in the PPP extract and found the highest phenolic content (57.25 ± 1.83%) in PPP-40 extract that showed the greatest inhibitory effect against LOVO cells. Apoptosis in LOVO cells caused by PPP-40 was mainly mediated through the activation of intrinsic and extrinsic caspase and mitochondria dysfunction (52).
IBD is a global disease characterized by a group of chronic and recurring inflammatory conditions in the GI tract (53). Several in vivo or in vitro experiments reported that different pathogenesis pathways have been linked to dietary polyphenols which had beneficial effects on the suppression and reduction of IBD symptoms (54). The natural polyphenol resveratrol identified in various plant species, has shown curative effects on IBD via the inhibition of NF-kB activation, decreased PGE 2 and PGD 2 levels, inhibition of neutrophil infiltration, as well as reducing COX-2 expression (55). Green tea polyphenols (GTPs) are rich in (-) epicatechin gallate (ECG), (-) epigallocatechin gallate (EGCG), (-) epicatechin (EC) and (-) epigallocatechin (EGC), all of which have a beneficial impact on attenuating IBD. The mechanism of GTP action includes promoted growth of Bacteroidetes microbiota, with increased SCFA production and down-regulating the inflammation-relating pathways (56).

APPLICATION OF FOODOMICS AND INTEGRATION OF OMICS TOOLS IN FOOD SCIENCES
Foodomics technologies have advanced rapidly in recent years, which is primarily reflected in existing technologies used in food FIGURE 1 | Foodomics helps us understand the interplay between polyphenols, gut microbiota, and host health. Foodomics applies multiple high-throughput omics technologies to provide novel insights into gene transcription, protein expression, and dietary polyphenols metabolism that interact with gut microbiota and host health.
science, making foodomics methodological research more flexible, as shown in Figure 2. Omics technologies mainly include genomics, transcriptomics, proteomics, and metabolomics (57), all of which apply multiple highthroughput omics technologies to investigate related issues in food science. Each omics technology have its own set of research goals, instruments, extraction & separation technologies and data analysis tools. Foodomics helps in the analysis of the biological activities of foods and their potent compounds in order to gain new insights into important molecular mechanisms as well as the exploration and development of novel biomarkers. Foodomics also promotes human health by providing optimal tools to identify information on how dietary nutrition interacts with gene transcription, protein expression, and the metabolism (58). Understanding of foodomics technology is important for researchers to better understand the interactions between polyphenols and gut microbiota.

Genomics
Genomics refers to the sequencing, assembly and analysis of the structure and function of genomic genes within an organism. The primary goal of genomics is to comprehend the various components of biology and to obtain the maximum amount of genetic sequence knowledge as possible about biological components through experiments and calculations. Among the tools used in genomics, the most powerful and versatile ones are high-density arrays of oligonucleotides or complementary DNAs (cDNAs). DNA arrays are a collection of related DNA spots that represent single genes attached to a solid surface by covalent or electrostatic binding with suitable chemical matrices (59). Another powerful tool for studying the structure and function of the genome is the next-generation sequencing (NGS) technologies. Compared to DNA arrays, NGS technology is capable of processing millions of sequencing reactions simultaneously without requiring a sequence library (often referred to as massively parallel sequencing) (60). NGS enhances the speed of acquisition of DNA sequence information and reduces the sequencing costs (61). Single-molecule sequencing (also called third-generation sequencing systems) is likewise an attractive tool for studying genomics. Single-molecule sequencing, unlike NGS, encounters relatively simple orientation errors, and the sequencing samples are single DNA molecules that cannot be cloned or amplified during the preparation process (62). Single-molecule sequencing allows high-density single molecules expand asynchronously, thereby allowing highly flexible chemical kinetics (63).
Genomics provides opportunities for developing genetically modified crops and livestock with various advantages, including high growth performance, increased yield, disease/pest resistance, and improved nutrient levels in food materials. Genomics techniques enable the determination of the gene compositions of a single plant or farm animal. Based on the constructed "graphic genotype", plant breeders can find inheritable chromosome sections and accelerate the selection of marker traits, which may reduce the field labor required. Genomic techniques identify beneficial alleles in the genes that govern food properties and select more nutritious and safer crops FIGURE 2 | Foodomics-application in food sciences. Research priorities and findings in food science are described intuitively in the form of visual data and graphs using foodomics technology.
for better and healthier food (64). Moreover, efforts have been made in using genomics to assess the microorganisms in foods and manage food microbiological issues (65).

Transcriptomics
The transcriptome is the entire set of RNA transcripts produced by the genome, and it serves as a vital link between gene phenotype and DNA coding information (66). Transcriptomics is the study of all RNA information of a single cell or a group of cells, and it is a paramount tool for understanding the functional elements of the genome and revealing the molecular composition of cells (67). Transcription can be precisely measured through transcriptomics, allowing us to understand the extent and complexity of transcriptomes more comprehensively. Gene expression microarrays and large RNA sequencing (RNA-Seq) are the key methods for analyzing thousands of transcriptomics efficiently and quickly). Gene expression microarray technology was introduced in the 1990s and has since been widely used (68), allowing high-throughput research to advance. In recent years, gene expression microarray technology has been widely applied in the research of emerging diseases, production of new medicines, and the mechanism of food reaction.
The application of microarrays in gene expression are classified into two types according to their nature: microarrays on solid flat or microchip substrates and microarrays on cubic or particle substrates (69). Nevertheless, all samples are first tested to obtain the corresponding signal information, and the signals are subsequently processed with the processing method depending on the platform used. After processing, the relative expression level of each transcript from samples under different experimental conditions is calculated and analyzed to classify differentially expressing genes (70). However, there are several shortcomings in gene microarray analysis because it is based on known sequences, and it is thus impossible to characterize unknown RNA sequences. Consequently, a comprehensive and precise characterization of the transcriptome is impossible (66). RNA-seq however, can supplement this (71) allowing for qualitative and quantitative analysis of any kind of RNA, including microRNAs, messenger RNAs (mRNAs), small interfering RNAs (siRNAs), and long noncoding RNAs. RNAseq technology can be used for genome-wide high-throughput transcriptomics since it sequences the entire transcriptome (72).
Currently, transcriptomics technologies are widely applied in food crop production. Transcriptomic-based fingerprinting can be used to detect hazardous food constituents or contaminants, including dioxins, xenoestrogens, organochlorine pesticides, mycotoxins phytoestrogens, Maillard reaction products, and estrogen-like chemicals, allowing more effective control of food quality and safety (73). It also assist in elucidating the molecular mechanisms of metabolic transformations and functionalities in food fermentations (66), and demonstrate the effects of dietary nutrients from foods. Moreover, transcriptomics is used to study the alterations of host gene expression due to various dietary interventions. DNA microarray analysis of rats with on an energy restriction diet of 5-30% revealed 72 genes that underwent restriction level-dependent changes (74).

Proteomics
Proteomics is a complement to genomics and transcriptomics that offers precise biological knowledge for foodomics. The later refers to the use of proteomic techniques to analyze proteins in specific biological food systems on a wide scale. In addition to studying chemical structure and functional proteins, proteomics also investigate proteins alteration effects, quantitative analysis of protein abundance, protein interactions, and their intracellular mechanism exploration (75). Proteomics is dedicated to the qualitative and quantitative analysis of proteins expressed in biological systems at specific times and conditions (76). The procedures of proteomics includes the extraction and separation of proteins, protein digestion into peptides, mass spectrometric (MS) analysis, and then qualitative and quantitative analysis of proteins (77). In generally, there are two methods for protein isolation and separation in proteomics, namely two-dimensional electrophoresis (2-DE); or multi-dimensional liquid chromatography. The 2-DE method of protein isolation and separation is based on the isoelectric point (pI) and molecular mass separation of proteins by 2-DE on polyacrylamide gels, followed by image analysis to classify all discernible spots in the image to provide a reference for subsequent research (78).
The 2-DE process for extracting and separating proteins, on the other hand, has a lot of weaknesses. For example, the performance of the extraction and separation of high-molecular or low-molecular-weight proteins is poor and time-consuming (79). Therefore, multi-dimensional liquid chromatography has been developed, where protein extraction and separation is performed by LC coupled to tandem MS (LC-MS/MS). Currently, the tools used for proteomic analysis to characterize protein samples are MS (80), mainly including matrix-assisted laser desorption/ionization time of flight (MALDI-TOF) and electrospray ion trap (ESI-IT) MS. Both techniques first ionize proteins and then analyze them by MS (81). Proteomics research can be categorized as "bottom-up" or "top-down". In the "bottom-up" approach, purified protein or complex protein mixtures are first enzymatically digested from the corresponding protein into peptides, and then analyzed using MS (82). The "top-down" approach retains most unstable proteins that were destroyed in the "bottom-up" approach, and performs MS analysis on intact proteins without cleavage (83). Therefore, the "top-down" approach is more stable and reliable than the "bottom-up" approach.
These powerful proteomics methodologies had a major impact on the field of food science. Proteomics was applied in the quality control of various food of biological or transgenic origin using different high-performance separation techniques, combined with high-resolution MS (84). Using 2-DE, the proteomic map of Alfalfa (Medicago sativa) was established for the first time, and the protein pattern changes in different processes were studied (85). Proteomics was applied in animal production and health to separate and identify all proteins present in a given tissue or fluid, offering more specific methods for assessing meat maturation, characterizing the proteome changes of post-catch fish muscle, and establishing various production animals proteome maps (86). It is also adopted to identify microbial food contaminants and their toxins (87).

Metabolomics
The emergence and application of metabolomics is another milestone for foodomics studies. Metabolomics technology focuses on the qualitative and quantitative research of small molecule metabolites (<1,000-1,500 Da), to compare the differences among samples (88). One of the main objectives of metabolomics research is to identify biomarkers, which are molecules that have a direct impact on an organism's metabolism or metabolic pathways. In general, metabolomics workflows include the following steps: extraction of target metabolites based on research goals; analytical instrument selection and sample preparation; sample on-board testing; collecting data; and using analytical tools for analysis and detection (89). Bioinformatics and chemometrics are analytical tools mainly used for metabolomics data (90).
There are two basic approaches targeted metabolomics and non-targeted metabolomics. Non-targeted metabolomics includes metabolic profiles and metabolic fingerprints (91), while targeted metabolomics is mainly used to analyze key metabolites on specific metabolic pathways, which can be used to investigate the key metabolic alterations caused by specific gene or protein changes. The scope of non-targeted metabolomics is relatively wide, with metabolic fingerprinting focused on comparing changes in metabolite patterns due to changes in internal or external factors (92). Metabolic profiling is focused on studying the differences in related metabolite levels and the effects of corresponding metabolic pathways, which have been applied for the identification of biomarkers in food and for the development of functional food.
The most frequently used data acquisition platforms in metabolomics are nuclear magnetic resonance (NMR), liquid chromatography-MS (LC-MS), gas chromatography-MS (GC-MS), and capillary electrophoresis-MS (CE-MS) (93). Among them, the application of NMR technology was most common in early metabolomics studies. NMR is a powerful analytical technique, for quantifying metabolites and analyzing structural details. It needs small sample size and requires no complex sample preparation procedures such as sample separation or derivatization. However, NMR analysis technology has the limitation of relatively low sensitivity of metabolite detecting (94). MS-based metabolomics technologies have some advantages, and they are mainly used to identify unknown compounds and for quantitative analysis of metabolites (95). The significant advantages of MS analysis technology requiring a small sample volume, high sensitivity, and fast separation speed (96).
LC-MS is the most widely used among MS technologies. It can be applied in the majority of metabolic profiling studies and is a powerful technology that can quantify metabolites and accurately identify the structural information of metabolites. GC-MS technology focuses primarily on the analysis of volatile, non-polar and thermally stable compounds with high separation efficiency and excellent reproducibility, allowing it to analyze complex metabolic mixtures, and it is still extremely useful with the introduction of capillary gas chromatography (97). The appearance and application of CE-MS technology is a further supplement and improvement to LC-MS and GC-MS. CE-MS likewise requires minimal sample volume, and simple sample processing, high separation efficiency, while it exhibits excellent reproducibility and high sensitivity, and can be used to analyze highly polar or charged compounds (92). All these different omics techniques each have their own advantages, and combining several metabolomics analysis technologies will yield complementary analysis results.
Metabolomics technologies have been widely applied in food science. The usage of NMR-based metabolomics in functional food studies aided in the evaluation and characterization of active ingredients as well as the effects of various biomarkers in corresponding diseases (98). Metabolomic-based approaches combining non-targeted and targeted technologies can be applied in food quality testing, detecting chemical contaminants, evaluating food authenticity and assessing food quality (99). MS-based metabolomics were used for food traceability, which accurately determines the basic composition and origin of foods during various processes of manufacturing. Metabolomics may also be used to monitor changes in the metabolomic profiles and identify specific compounds as markers of food degradation (100). It is also used in nutritional epidemiology to identify biomarkers of dietary intake. The earliest biomarker identified using metabolomics after meat intake was trimethylamine N-oxide (TMAO); 1-methylhistidineas was later confirmed as a biomarker of meat consumption (101).

Integrating Approaches in Foodomics Studies
Foodomics can be used not only for data collection by omic techniques, but also to integrate multiple omic techniques for getting more comprehensive and systematic experimental data (102). Foodomics technologies include chemometrics, epigenomics, bioinformatics and integration approaches. Chemometrics employs mathematical, statistical, and other formal logic-based methods to plan or select optimal measurement procedures and experiments, as well as to analyze chemical data to provide the most important chemical details (103). Chemometrics technology is a subset of metabolomics that involves building a model to define and validate target samples. The methods of identification and classification used in chemometrics technology mainly include unsupervised principal component analysis (PCA), supervised discriminant analysis (DA), hierarchical cluster analysis (HCA), and soft independent modeling of class analog (SIMCA) (104).
The term "epigenetic" simply means "in addition to genetic sequence changes". The term has evolved to refer to any mechanism that alters gene activity without altering the DNA sequence, resulting in changes that can be passed on to daughter cells (although experiments show that some epigenetic changes can be reversed (105). Epigenetics analysis is a fascinating research area of foodomics that involves analyzing changes in epigenetic status across the entire genome (106). Whole genome research is mainly used to investigate changes in chromosome structure, as chromosome structure can affect gene expression and thus the epigenetic status of the corresponding location (107).
Bioinformatics is a technology for reprocessing and analyzing data obtained from various omics technologies. Bioinformatics utilizes a variety of tools to conduct in-depth exploration of data, and to ultimately identify biological significance through functional annotation, genetic and protein data cluster analysis. Biomarkers can be identified and molecular mechanisms can be explained based on bioinformatics, biostatistics and pathway analysis results (108). Integrating multi-omics approaches is necessary due to the unpredictability of the human body and its potential interactions with food. Using multi-omics platform enables researchers to obtain a comprehensive understanding on dietary food components and biological actions in the body.

USING FOODOMICS TO CLARIFY GI PROTECTIVE MECHANISMS OF POLYPHENOLS
A reliable approach is to integrate foodomics to clarify the GI protective effects of polyphenols with high-throughput molecular technologies that drive it. For genomics, transcriptomics, proteomics and metabolomics studies, foodomics is based on a combination of several analytical platforms and data processing. These omics technologies allow the identification of bioactive compounds of polyphenols and determination of changes induced by polyphenols at the molecular level.

Identification of Plant Derived Bioactive Polyphenols Using Foodomics
Due to the high complexity of plant polyphenols, the analysis of polyphenols from plant extracts or biological samples has numerous known difficulties in various analytical procedures. Qualitative and quantitative analysis and data processing are two specific bottlenecks of polyphenolics analysis. Foodomics has introduced novel concepts and advanced technologies for identifying bioactive compounds (109). As a result, advanced foodomics technologies were used to improve the analytical methods of polyphenol compounds. We summarized typical examples of using foodomics approaches to analyze the plant derived polyphenols active compounds in fruits (  1-4).
For the application of foodomics technology in understanding the GI protective effects of polyphenols, we provides an overview of recent studies, on polyphenols or polyphenol-rich foods, the foodomics technology applied (genomics in

Gene-Based Genomics and Transcriptomics to Investigate GI Protective Mechanisms of Polyphenols
Foodomics technologies accurately analyze polyphenol compounds in both qualitative and quantitative aspects. Moreover, gene-based genomics and transcriptomics can be used to study the interaction between polyphenols and the GI tract. Owing to continuous optimization of gene-level research technology, gene expression microarray technology has developed as a crucial analytical technology in the transcriptomics field to investigate the interactions between genes following intake of bioactive constituents from food (159). Alberto et al. applied gene expression microarray technology to investigate the effect of polyphenols from enriched extract of rosemary on two colon adenocarcinoma cell lines. Differences in the G2/M arrest inhibition were found in the two colon adenocarcinoma cell lines after treatment with an enriched extract of rosemary. Rosemary polyphenols induced a low degree of apoptosis in colon adenocarcinoma cell lines and the results also indicated multiple other signaling mechanisms that may lead to apoptosis of colon cancer cells (160). Dolara et al. (141) used transcriptomics to investigate 5,707 expressed genes to further determine the molecular effects of wine polyphenols on colonic mucosa in F344 rats. Wine polyphenols may protect the colonic mucosa by improving intestinal function and having anti-colonic cancer activities by reducing oxidative damage, modulating the colonic microbiota and down-regulating the expression of genes involved in metabolism, transport, signal transduction and intercellular signaling. Wang et al. (161) evaluated the interaction of green tea polyphenols (GTPs) and gut microbiota through transcriptomics. In that study, Female Sprague-Dawley (SD) rats were treated with GTP for 6 months. 16S ribosomal RNA (rRNA) amplicon sequencing (16S-seq) and Shotgun metagenomic community sequencing (SMC-seq) were then used to determine the effect of GTP on the intestine microbiota and the possible connection between improvements in and the beneficial effects of GTP. The SD rats that were treated with GTP over long time periods exhibited a dose-dependent modification of Bacteroides and genes related to energy metabolism, which proved to be beneficial for weight control and maintenance. Yang et al. (162) studied the inhibitory effect of combined polyphenols on colitis-related carcinogenesis (CRC) in mice by the 16S rRNA gene sequence. The data show that the gut microbiota plays a key role in the treatment of CRC, bound polyphenol of the inner shell treated altering the diversity and overall structure of the microbiota in tumor-bearing mice, and also exerts a regulatory effect on 17 signaling pathways involved in related genes.

Protein-Based Proteomics to Investigate GI Protective Mechanisms of Polyphenols
Proteomics is employed to further the understanding of the relationship between the GI tract and polyphenols at the protein level. It assesses the functional protein changes of probiotics in the gastrointestinal transit, metabolic processes using different protein identification approaches by studying the beneficial effects of probiotics on the gastrointestinal tract and the mechanism of action (163). Proteomics is mainly based on MS technology, and it focuses on obtaining functional information about the interaction of polyphenols with the GI tract and related pathway by assessing protein expression changes. Valdeś et al.

Metabolomics Based on Microbial/Colonic Metabolic Metabolites to Investigate GI Protective Mechanisms of Polyphenols
Several researchers have highlighted metabolomics as an important future direction of foodomics, owing to its ability to characterize related biological functions and phenotypes (167). combined CE, RP/UPLC, and HILIC/UPLC, both coupled to TOF-MS for metabolomics analysis. Their findings revealed that dietary polyphenol treatment altered 22 closely related metabolites in HT-29 cells, which has the potential to for inhibit colon cancer.

Multiple Omics Platforms for Understanding the Protective Effects of Polyphenols Against GI Disorders
With the technological development of foodomics, food science studies based on data generated from sequencing approaches and combining two or more technologies ("multi-omics") are considered as more reliable, which also allows for integrating system-level approaches. The multi-omics approach has a more comprehensive and systematic analysis capability, which is more conducive for in-depth investigation of complex issues in food science. Dietary polyphenol interventions for GI disorders involve multiple molecular and biochemical mechanisms during the process of biotransformation and absorption. Integrated multi-omics analysis is necessary to obtain comprehensive omics-data to identify the genes, proteins and metabolites involved in metabolic regulation, and further construct metabolic pathways to comprehensively analyze the mechanism of polyphenols for gastrointestinal protection, and further elucidate the complex network of interactions between the dietary polyphenol, GI tract, and host (156). Mayta-Apaza et al. confirmed that polyphenol-rich tart cherries regulate intestinal health by increasing the quantity of beneficial microbiota in the human colon. To determine how gut microbiota were influenced by polyphenol metabolites from polyphenol-rich tart cherries in the human colon, they authors conducted bacterial fermentation assays on polyphenol-rich tart cherry concentrate juices and pure polyphenols (and apricots) in vitro and assessed the results based on 16S rRNA gene sequence and metabolomics. In vitro, gut microbiota metabolized polyphenols into 4-hydroxyphenylpropionic acids and tart cherries modulate the increase of Bacteroides. In vivo data showed decreased Bifidobacterium, Bacteroides, and increased levels of Collinsella, Lachnospiraceae, Ruminococcus in individuals with high    (173). To examine the metabolites present in the gut microbiota-dependent mitochondrial tricarboxylic acid (TCA) cycle and urea cycle of GTPs, 16S rRNA gene sequencing and hydrophilic interaction liquid chromatography (HILIC)-heated electrospray ionization (HESI)-tandem liquid chromatogram mass spectrometry (LC-MS) were used (174). They found that GTPs enhanced the energy conversion and maintained gut health by increasing the mitochondrial TCA cycle and intestinal microbiota urea cycle in rats.

CONCLUSIONS AND FUTURE PERSPECTIVES
Polyphenols are particularly complex and ubiquitous components of our daily foods sourced from plants, vegetables and fruits. It has shown potential for prevention and treatment of  GI disorders, and the interactions between polyphenols and gut microbiota have gained significant attention due to their relevance to bioavailability and host health. Latest advancement of innovations in foodomics have significantly accelerated our understanding of food science and allowed a more comprehensive understanding at the molecular level of the interactions between polyphenols and the GI tract. However, while awareness of the polyphenol-GI tract relationship is growing, there is still a long way to go. There are evident shortcomings and limitations of the interactions between polyphenols and the GI tract. The majority of polyphenols in the natural food matrix are in the form of bound polyphenols that cannot be directly metabolized. As xenobiotics in the GI tract, polyphenols must be metabolized and transformed by the gut microbiota in the colon before they   can function for the hosts. Numerous studies we reviewed which based on in vitro experiments, used polyphenol extracts from natural foods or single polyphenol compounds to directly affect intestinal cells using foodomics approaches, and the results obtained may be different from the actual state in vivo.
In fact, the digestion process of polyphenols in the colon is highly complex, and gut microbiota play a very important role in the metabolism of polyphenols. Most of the digestion and metabolism of polyphenols is done through gut microbiota. Meanwhile, polyphenols also play a beneficial role in regulating the composition of gut microbiota, even if the results of in vitro experiments to explain the protective effect of polyphenols on the GI tract or the metabolism of polyphenols in the GI tract are not sufficient. Animal experiments or simulated GI experiments will reduce the variability in experimental results for further understanding of the GI protective effects of polyphenols. Integrating foodomics to elucidate the GI protective effects of polyphenols also has several limitations. Notably, polyphenols are a generic term for a class of compounds, and the polyphenols in different natural foods vary significantly. Not all polyphenols in natural foods have common beneficial biological activities, and natural foods may exert their biological activities through one or more polyphenol compounds. Thus further research on the biological activities of polyphenol monomers in natural foods is required to explore and understand the bioactive compounds in natural foods. For instance, foodomics technologies result in massive amounts of data, which require extensive bioinformatics analysis. The comparison with other studies is challenging, due to the lack of information at the molecular level of all cellular processes, which indicates that there are gaps in showing effectiveness. Coincidentally with the applications and continuous development of high throughput technologies, there is a demand to develop more comprehensive tools to shorten the data processing time. Despite current studies using combined analysis methods, there is a lack of comprehensive data at the molecular level. In the future, studies at multiple molecular levels of genes, proteins, and metabolites are required to comprehensively understand the GI protective effects of polyphenols.