The intestinal epithelium is the first line of defense in the digestive tract against pathogens entering the body, and maintains the intestinal homeostasis. Intestinal homeostasis in flies is regulated by evolutionarily conserved molecular pathways, such as JAK/STAT, Nrf2/Keap1, TLR4/NF-κB, Wnt/Wg and Notch signling pathways. An imbalance among these types of pathways in epithelium could result in IBD.

The Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway is a transport hub that transduces cues from extracellular cytokines into transcriptional changes in the nucleus, which participates in many cellular processes, such as cell growth, differentiation and migration of immune cells (O'Shea et al., 2013). The inappropriate activation or delection of JAK/STAT pathway is associated with inflammatory and autoimmune diseases, including IBD, Parkinson’s disease (PD) and psoriasis (Xin et al., 2020). Inhibition of this pathway can suppress multiple cytokine pathways in the treatment of IBD. JAK is a key intracellular signaling mediator in IBD, which transduces signals from cytokine receptors on the cell surface to the nucleues, and its dysregulation leads to the pathological process of IBD (Dudek et al., 2021). Presently, several JAK inhibitors are used to treat IBD patients (Wang L. et al., 2021). Tofacitinib as a JAK inhibitor is clinically used for UC patients, and various other inhibitors such as filgotinib, TD-1473 and upadacitinib are currently being investigated in preclinical and clinical trials (Salas et al., 2020; Harris and Cummings, 2021). In addition, STAT is the final effector of JAK-STAT signaling pathway (Moon et al., 2021). Some STAT inhibitors have also been studied in treating IBD, although no clinical trials have been conducted in patients with IBD (Kasembeli et al., 2018) Various plant-derived natural compounds such as curcumin, ellagic acid and paeonol have been proved to alleviate IBD by affecting the JAK-STAT pathway in IBD animal models (Marin et al., 2013; Yang et al., 2013; Moon et al., 2021). Thus, therapeutic intervention of the JAK-STAT pathway can efficiently regulate the complex inflammation driven by diverse inflammatory cytokines in IBD.

The JAK/STAT pathway in flies has the same essential signaling components as in mammals (Herrera and Bach, 2019). When enterocytes (ECs) in fly midgut are subjected to stress signaling mediated by apoptosis, chemical injury, or pathogen infection, pro-inflammatory ligands (Upd, Upd2, Upd3) are rapidly produced and released. These ligands activate one receptor Domeless (Dome), leading to the activation of one JAK and one STAT transcription factor, termed Hopscotch (Hop) and Stat 92E, respectively. The pathway activity is downregulated by Socs36E in a negative-feedback loop. Socs36E is a suppressor of cytokine signaling protein. Core components of the JAK-STAT pathway in flies are homologous to interleukin 6 (IL-6), the JAK2 and STAT5 in mammals (Myllymaki and Ramet, 2014). The JAK/STAT pathway plays an important role in fly midgut homeostasis and tissue regeneration following various challenges, such as bacterial infection, directed cell ablation or stress signaling (Buchon et al., 2009). Under normal conditions, JAK/STAT pathway facilitates the rapid proliferation and differentiation of ISCs to drive epithelial regeneration (Jiang et al., 2009). The over-activation of JAK/STAT pathway causes excessive proliferation of ISCs and abnormal differentiation of EC cells, which disrupts the balance of intestinal homeostasis, and promotes the deterioration of intestinal epithelium (Herrera and Bach, 2019).

Nuclear factor-erythroid-derived 2-related factor 2 (Nrf2), a member of the basic-region leucine zipper (bZIP) transcription factor, is one of the most important regulators of the cell defense system against oxidative stress and inflammatory damage (Mou et al., 2020). Nrf2 regulates the transcription of more than 200 genes, including antioxidant proteases and inflammatory regulators, by binding antioxidant response elements (AREs) in the promoter region (Raghunath et al., 2018). The activity of Nrf2 is negatively mediated by Kelch-like ECH-associated protein 1 (Keap1) that is a protein rich in cysteine (Sekhar et al., 2010). Various studies have shown that activation of the Keap1-Nrf2-ARE signaling pathway can provide protection against various stress and inflammation-related diseases, including IBD (Cuadrado et al., 2018; Piotrowska et al., 2021). Previous studies found that DSS-induced Nrf2 knockout mice had higher expression of colonic inflammatory markers and cytokines, and more severe colonic injury compared to control colitis mice (Cheung et al., 2014). Administration of Nrf2 activator dimethyl fumarate (DMF) alleviated DSS-induced experimental colitis in mice (Li et al., 2020). The activator of Nrf2, 5-aminosalicylic acid, has been used clinically in the treatment of IBD (Kang et al., 2017; El-Baz et al., 2020). Meanwhile, various plant-derived natural compounds have been demonstrated to alleviate IBD by affecting the Keap1-Nrf2-ARE pathway in animal model systems of IBD, such as luteoline (Li et al., 2016), curcumin (Lin et al., 2019) and Flos puerariae extract (Yang et al., 2022) Therefore, the Nrf2 activator is considered as a potential drug for the treatment of IBD.

Nrf2 is highly homologous to CncC in Drosophila (Loboda et al., 2016). There are three isoforms of Cnc: CncA, CncB and CncC, of which CncC plays an important role in the oxidative stress process in flies (Pomatto et al., 2017). The mechanism of the oxidative stress response in flies is similar to that in mammals. Under non-stress conditions, CncC activity is restricted by dKeap1 (Sykiotis and Bohmann, 2008). When flies are under oxidative stress and intestinal damage, electrophile and ROS interrupt the interaction between CncC and Keap1. CncC forms a heterodimer with Maf-S in the nucleus, binds to the ARE and activates transcription of the target gene (Misra et al., 2013). Nrf2 can promote intestinal homeostasis by specifically controlling the proliferation activity of ISCs. Loss of Nrf2 in ISCs led to accumulation of ROS and accelerated degeneration of the intestinal epithelium (Hochmuth et al., 2011).

TLR4/NF-κB is an important inflammatory signaling transduction pathway, which closely participates in cell differentiation and proliferation, apoptosis, and pro-inflammatory response (Yu et al., 2022). Toll-like receptors (TLRs) play an important role in recognizing invading microbial pathogens and leading to innate immune response for the host defense, and also involved in the pathogenesis of IBD (Frantz et al., 2018; Lu et al., 2018). As one class of TLRs, TLR4 is the first characterized TLR in the mammalian, and mainly regulates the intestinal inflammation. The expression of TLR4 significantly increases in the intestinal epithelium of patients with active UC (Toiyama et al., 2006). Nuclear factor kappa B (NF-κB) is the final transcription factor of the TLR4 pathway. Upon activation, NF-κB dimers translocate to the nucleus, and promotes the transcription and translation of inflammatory mediators, which results in the development of intestinal diseases in mammals (Chen et al., 2018). Many components of natural products such as apigenin, luteolin and hesperidin have been proven to ameliorate intestinal inflammation by inhibiting the TLR4 receptor activation and blocking the nuclear translocation of NF-κB in mammals (Guazelli et al., 2021; Zuo et al., 2021; Begum et al., 2022; Zhang et al., 2022). Thus, downregulation of the TLR4/NF-κB pathway is a potential therapeutic strategy against IBD.

Toll signaling pathway is first identified in Drosophila (Lye and Chtarbanova, 2018). The first identification of TLRs in 1988 and then subsequent recognition of its one homolog called TLR4 in humans in 1997 (Hashimoto et al., 1988; Medzhitov et al., 1997). Activation of Toll in flies results in the formation of a signaling complex containing the adaptor proteins MyD88, Tube and the kinase Pelle via a homotypic TIR interaction (Tauszig-Delamasure et al., 2002). This complex indirectly promotes the NF-κB-like transcription factors Dif and Dorsal to the nucleus, leading to the expression of cytokines and antimicrobial peptides (AMPs) (Lamiable et al., 2016; He et al., 2022). Intestinal epithelial cells have the evolutionarily conserved TLR pathway in flies and mammals (Ferguson and Foley, 2022). Toll signaling in flies plays a role in the maintance of gut homeostasis via regulating the balance between microbe-induced epithelial cell damage and stem cell repair (Buchon et al., 2009).

Wnt signaling pathway is an important pathway for the maintenance of stem cells, which controls cell proliferation, impacts the cell cycle and regulates the self-renewal of some tissues in mammals (Nusse and Clevers, 2017; Liu et al., 2022). Wnt signaling pathway regulates the stem cell proliferation, differentiation and migration in the intestinal epithelium, and participates in the pathogenesis of IBD (Flanagan et al., 2018). Decreased the Paneth cell alpha-defensin is one of the factors in IBD pathogenesis (Khoramjoo et al., 2022). Diminished the Wnt pathway transcription factor (Tcf-4) expression could weaken enteric antimicrobial defense by reducing the Paneth cell alpha-defensin (Pu et al., 2021; Khoramjoo et al., 2022). In addition, studies have shown that in Tcf-4 knockout mice, reduced level of Paneth cell alpha-defensin in intestine permitted bacteria to invade the epithelium and result in colitis (Wehkamp et al., 2007). Inhibition of Wnt signaling pathway could disrupt the intestinal-stem-cell homeostasis, consequently leading to intestinal diseases in mammals (Kuhnert et al., 2004; Perochon et al., 2018). Various natural molecules, such as Astragaloside IV and procyanidin, have been reported to promote mucosal healing and alleviate colitis symptoms by activating the Wnt pathway in mice (Pu et al., 2021). Thus, it is worthwhile to increase the window of opportunities for IBD treatment by activating Wnt pathway.

Fly and mammalian guts not only have similar morphology, but also share the same Wnt signaling pathway. The Drosophila genome encodes seven Wnt genes including Wingless (Wg), Wnt2, Wnt4, Wnt5, Wnt6, Wnt10, and WntD (Tian et al., 2018). Only Wg and Wnt4 are expressed in the fly midgut (Perochon et al., 2018). Wnt pathway plays an important role in the self-renewal of the fly gut. When flies are exposed to damage from chemical toxins, bacterial infection and mechanical stress, the expression level of Wg protein increases in EBs of the midgut epithelium, leading to compensatory ISC proliferation and differentiation to re-establish homeostasis (Jiang et al., 2016; Liu et al., 2017). Meanwhile, the inhibition of Wnt signaling in the intestinal epithelium abolishes gut regeneration (Jiang et al., 2016; Liu et al., 2017).

Notch signaling is a highly conserved cell-cell communication pathway. It regulates the development and differentiation of cells, tissue function, organs formation, and maintains the homeostasis of the body through interactions between adjacent cells (Artavanis-Tsakonas et al., 1999; Herbert and Stainier, 2011). Notch signaling pathway is critically linked to the pathogenesis of several diseases such as IBD, cancer, and autoimmune diseases (Okamoto et al., 2009). In the intestine, Notch pathway regulates the secretory of intestinal cells such as Paneth cells and goblet cells. Increased Notch pathway leads to a deficiency of Paneth cells, and ultimately induces a collapse of the intestinal barrier in patients with IBD (Gersemann et al., 2011). Activated γ-secretase promotes the generation of Notch intracellular domain (NICD) (Kumar et al., 2016). Aberrant expression of NICD leads to decrease in the quantity of goblet cells in patients with UC (Zheng et al., 2011). Consequently, studies have shown that the γ-secretase inhibitor dibenzoazepine alleviates IBD by suppressing the Notch pathway (Shinoda et al., 2010). L. acidophilus could regenerate goblet cells by inhibiting Notch transcriptional program factors to alleviate Salmonella-induced-colitis in mice (Wu et al., 2018). Thus, inhibiting Notch pathway is considered to be an effective strategy in the treatment of IBD.

The Notch gene is first named in flies in the 1910s (Stubbs et al., 1990). Most essential components of the Notch signaling pathway are conserved between flies and humans (Yang et al., 2022). Notch pathway participates in regulating the self-renewal and differentiation of ISCs. In adult Drosophila intestines, the Notch ligand Delta is specifically expressed in ISCs (Ohlstein and Spradling, 2007). Upon division of the ISC, Delta promotes the expression of Notch target genes by activating the Notch receptor in its sister cell (Fre et al., 2011). Notch pathway is closely associated with gut homeostasis. Under normal conditions, Notch pathway promotes ISCs to replenish the loss of EE and EC to maintain intestinal homeostasis (Fre et al., 2011). Ingestion of chemicals or pathogenic bacteria could disrupt stem cell differentiation and midgut homeostasis by activating Notch pathway in the Drosophila intestine (Kux and Pitsouli, 2014).

The gastrointestinal (GI) tract is a first layer of defense against the various microbes. The fly GI tract is the tissue of digestion and absorption, and shares many properties with the mammalian counterparts, including the stomach, small intestine, and colon (Figure 2) (Liu et al., 2017). Fly midgut has emerged as an attractive system to investigate the intestinal inflammatory disease due to not only the cell lineage of this tissue is simple and well-defined, but also it shows similarites to the mammalian intestine (Jiang and Edgar, 2012). The flies intestine is composed of three main regions: foregut, midgut and hindgut (Lemaitre and Miguel-Aliaga, 2013). The foregut encompasses pharynx, oesophagus and crop, which is an organ involved in food storage. The midgut extends from the cardia to the junction with the hindgut, while the Malpighian tubules connect to the gut. The hindgut fulfills the excretory functions of the fly gastrointestinal system, which is similar with the mammal large intestine (Miguel-Aliaga et al., 2018). The copper cell region (CCR) is located approximately in the middle of the midgut and is acidic similar to the mammalian stomach (Strand and Micchelli, 2013). The posterior midgut is the most metabolically active and immune responsive region of the fly gut and is similar with the mammal small intestine, where the hindgut corresponds to the mammal colon (Micchelli and Perrimon, 2006; Capo et al., 2019).

The epithelium of the fly midgut and mammal gut contains uniform ISCs that undergo division and asymmetric cell fate decision (Liu et al., 2017). The adult Drosophila gut is composed of an epithelial monolayer consisting of 4 cell types: intestinal stem cells (ISCs), absorptive enterocytes (ECs), enteroblasts (EBs) and secretory enteroendocrine (EE) cells (Medina et al., 2022). Each ISC divides symmetrically into two ISCs or asymmetrically into an renewed ISC and EB. EBs differentiate into diploid EEs or polyploid ECs (Chen et al., 2018). Similarly, ISCs self-renew and differentiate into the transit amplifying cells in mammals, and then proliferate and differentiate into secretory cells and ECs, and dedicate Paneth cell progenitors (Liu et al., 2017). ISCs are characterized by expression of high levels of cytoplasmic Delta-rich vesicles, triggering Notch signaling in neighboring EBs (Ohlstein and Spradling, 2007). Su(H)Gbe-lacZ as a transcriptional reporter of Notch signaling is used as EB cell marker (Micchelli and Perrimon, 2006). The enhancer trap fly snail family gene escargot (esg) targets both ISC and EB (Micchelli and Perrimon, 2006). Brush border Myosin (MyolA) marks the ECs and Prospero (Pros) marks the EEs (Jiang et al., 2009). Chemicals such as dextran sulfate sodium (DSS) and sodium dodecyl sulfate (SDS), or bacterial infection can damage the midgut, and also stimulate ISC proliferation (Amcheslavsky et al., 2009). Compared to mammalian stem cells, the flies possess a much simpler lineage in intestinal epithelium. However, the cellular functions and molecular principles that dictate ISC proliferation and differentiation are well conserved from flies to mammals (Medina et al., 2022). For example, JAK-STAT pathway (Xu et al., 2011), Wg/Wnt pathway (Liu et al., 2017), Hippo pathway (Ren et al., 2010) and EGFR pathway (Jiang et al., 2011). All these pathways have been implicated in human IBD. Thus, investating the role of ISC proliferation in flies will help us to find the way for human IBD mechanism.

Many preclinical models of IBD are currently estabolished to investigate the pathogenesis and therapy. In rodents, DSS, SDS and 2,4,6-trinitrobenzene sulfonic acid (TNBS) have been frequently employed (Yu et al., 2022; Zhang et al., 2022). Because of the high conservation with mammals, flies are also used to induce intestinal inflammation model via feeding DSS or SDS (Figure 3) (Lee et al., 2021; Wei et al., 2022; Yang et al., 2022). Briefly, newly ecolosed (3–5 day old) female or male flies were maintained on control diet or natural products diet for 7 days. Then flies was transferred into the empty vial containg 1% agar to starve for 2 h, flies were moved into vials containing filter papers soaked with 5% sucrose solution with or without DSS (3% or 4%) or SDS (0.5% or 0.6%), respectively. Filter papers were replaced every 2 days. For survival studies, adult flies were fed with DSS or SDS until all flies died, and number of dead flies was recorded twice per day. For intestinal morphology analysis, flies treated with DSS or SDS for 72 h were dissected in the cold PBS and immediately observed under a microscope. After flies were fed with DSS or SDS for 60 h, the intestine integrity and gastrointestinal acid-base homeostasis were investigated. Smurf assay was widely used to detect the intestine integrity, in which flies were fed with food containing a blue dye (2.5% w/v) for 12 h, fly was remarked as a Smurf when the dye coloration could be observed outside the digestive tract. The bromophenol blue assay was used to measure gastrointestinal acid-base homeostasis, in which flies were fed with 2% Brmophenol blue sodium (Sigma, B5525) for 12 h, images were captured after dissection. For observation of midgut epithelial cells, flies were fed with DSS or SDS for 72 h, then the nucleus and microvilli of midgut epithelial cells were observed by using transmission electron microscope. For dead intestinal cells detection, the dissected guts of flies fed with DSS or SDS for 72 h were stained with 7-amino-actinomycin D (7-AAD) for 30 min. The imaged were observed under confocal microscope. For reactive oxygen species assay, flies were exposed to SDS or DSS for 48 h, the intestines were dissected in cold PBS, incubated in 5 μM H2DCFDA or 5 μM dihydroethidium (DHE) for 10 min in dark environment, then washed in PBST, and immediately observed under a confocal microscope. For detecting proliferation and differentiation of ISCs, the guts of esg-GAl4; UAS-GFP flies or Dl-GAl4; UAS-GFP flies were dissected, and observed under a confocal microscope. The number of progenitor cells or ISCs was performed by counting the number of GFP positive cells per unit area.

Some of the less common agents such as bleomycin, P. aeruginosa, Erwinia carotovora 15 (Ecc15), and paraquat could also lead to gut injury in Drosophila (Amcheslavsky et al., 2009; Apidianakis et al., 2009; Lei et al., 2022). For example, bleomycin leaded to enterocyte-specific damage and cell loss in gut of flies, which in turn caused ISC to divide faster and facilitated enteroblast differentiation into new enterocytes (Amcheslavsky et al., 2009). Oral administration of P. aeruginosa and Ecc15 strains could increase the number of intestinal progenitors and induced apoptosis of mature cells to establish an intestinal injury model (Apidianakis et al., 2009; Lei et al., 2022). Overall, the current methods used to estabolish the IBD model in flies are easy and simple to operate. It is beneficial for researchers exploring the occurrence and development mechanism of IBD in human and screening the potential drugs from nature products.

Natural molecules have exhibited efficiency in protecting intestinal injury and improving symptoms in flies. For example, Acanthopanax senticosus polysaccharides (ASPS) supplementation could improve the disrupted intestinal homeostasis in flies under SDS stimulation, in which reduced the intestinal epithelial cell death, decreased ROS accumulation and antimicrobial peptide (AMP) expression (Zhang et al., 2020). Administration of ASPS also reduced the excessive ISCs proliferation and differentiation mainly by epidermal growth factor receptor (EGFR), JNK and Notch signaling pathway when flies were exposed to DSS (Lei et al., 2022). Consistently, ASPS supplementation in mice could also ameliorate LPS-induced intestinal injury, including decreased intestinal morphological deterioration, elevated the mucosal barrier and enhanced intestinal tight junction proteins expression, which mainly through inhibiting TLR4/NF-κB signaling pathway (Yasueda et al., 2020). Safranal as one of the main components of saffron significantly alleviated the DSS or Ecc15 induced intestinal epithelial cell death and excessive proliferation of ISCs to protect intestinal integrity in flies (Lei et al., 2022). This protective process was regulated through inhibition of the JAK/STAT signaling, EGFR signaling, and JNK signaling pathways in flies (Huang et al., 2022). The protective function of safranal were also reported in vitro and mice (Lertnimitphun et al., 2019), in which safranal supplementation decreased NO production, COX-2 and iNOS in LPS-stimulated RAW264.7 cells, and also alleviated severity of inflammation and crypt damage in the DSS-induced colitis mice. These studies elucidate that safranal may be a candidate for IBD therapy. Agar oligosaccharides (AOS) are marine prebiotics with significant anti-inflammatory effects (Ma et al., 2019). AOS supplementation alleviated the injuries of microvilli and mitochondria of gut, ameliorated the intestinal inflammation by modulating the microbiota and the gene expression of AMPs, mTOR and AMPK pathways that related with immune and cell autophagy in SDS-induced inflammatory model of flies (Ma et al., 2021). Ursolic acid (UA) is an anti-inflammatory natural triterpenoid widely distributed in various vegetables and fruits (Checker et al., 2012). UA could remarkably prevent intestine injury in SDS-stimuated flies by inhibiting ISCs hyperproliferation, decreasing excessive activation of JNK/JAK/STAT signaling pathway (Wei et al., 2022). Meanwhile, UA was found to alleviate the DSS-induced intestinal damage by reducing the upregulation of NF-κB in mice (Liu et al., 2016; Ma et al., 2021). Caffeic acid (CA) is a widespread natural phenolic small molecule, which also inhibited the dysregulation of ISCs, ameliorated the gut hyperplasia defect, and reduced aging induced mortality in flies (Sheng et al., 2021). CA could significantly attenuate the DSS-induced murine UC mainly via ameliorating the disease severity, loss of eptithelium and crypts, mucosal ulcerations, and secretion of inflammatory cytokines (Xiang et al., 2021). Polysaccharide from Premna microphylla turcz (PPMT) have anti-inflammatory functions in vitro (Li et al., 2021). In SDS-induced inflammatory flies, PPMT significantly prolonged the lifespan, reduced the rupture of microvilli and restored the nuclear structure in the midgut, and improved gene expression levels of immune-related AMP pathway, mTOR pathway and Imd pathway (Ma et al., 2021).

Some herbal extractions have also been validated to have great protective function in fly model of IBD. For example, bilberry anthocyanins extracts (BANCs) have a wide range of biological activities and can be used to prevent or treat inflammation-related diseases (Farzaei et al., 2015). In DSS-induced inflammatory flies, BANCs remarkably enhanced the survival rate, restored the intestinal morphology and integrity, which mainly by modulating Nrf2 signaling pathway (Zhang et al., 2022). Consistently, BANCs could reduce intestinal inflammation in acute and chronic DSS-colitis with decreased histological scores and cytokine secretion in DSS-induced Balb/c mice (Piberger et al., 2011). Our previous studies found that Flos Puerariae extract (FPE) ameliorated the intestinal inflammation via modulating intestinal integrity and various signaling pathways in SDS-inflamed flies, in which FPE enhanced the survival rate, maintained intestinal morphological integrity, reduced the ISCs proliferation, and also rescued the altered expression levels of gene and protein in JAK-STAT signaling, Nrf2/Keap1 signaling and Wnt signaling pathways in the gut (Yang et al., 2022). Larvae of the Allomyrina dichotoma (ADL) as a high nutritional food are widely used to treat gut-related disease in China and Korea. In DSS-fed flies, oral administration of ADL extract remarkably increased the survival rate, reduced intestinal cell apoptosis and gut permeability. Meanwhile, ADL extract supplementation promoted the E-cadherin gene expression and restored the original membrane localization of DSS-disrupted E-cadherin contiguous with the armadillo (Lee et al., 2021). Rhodiola crenulata is widely used in phytotherapy in Asian countries and Eastern European (Chen et al., 2020). R crenulata extracts supplementation could prevent inflammatory diseases of the intestine in flies, in which protected against shorten intestinal length and epithelial cell death, decreased ROS levels, and increased the expression of antimicrobial peptide genes under bacterial and SDS stimulation (Zhu et al., 2014). Furthermore, the protective function of R crenulata extracts were also reported in mice. Ingestion of R crenulata extracts alleviated damage of inflammation, maintained intestinal barrier function, inhibited cell apoptosis and regulated gut microbiome in DSS-induced colitis mice (Wang et al., 2021). Extracts of Crocus sativus L. supplementation protected against SDS-induced intestinal damage in flies mainly via decreasing epithelial cell death and ROS levels in the gut (Liu et al., 2016). However, because of multiple compounds in these herbal extractions, the active ingredients and mechanisms have not been determined clearly, which need to be further explored in various animal model of IBD in future.

As mentioned above, the pharmacological function of many natural molecules and herbal extractions in treating IBD is conserved in Drosophila and rodents. Thus, Drosophila can be used as an excellent model for screening natural products for treating IBD that can be subsequently validated in a mammal system (Table 1).