Saponins regulate intestinal inflammation in colon cancer and IBD

Pharmacological Research 144 (2019) 66–72

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Review

Saponins regulate intestinal inflammation in colon cancer and IBD a,1

Jianyi Dong , Wei Liang ⁎ Dapeng Chena, a b c

a,1

, Tianxiao Wang

a,1

a

, Jingru Sui , Jingyu Wang

b,⁎⁎⁎

, Zhaobin Deng

c,⁎⁎

T

,

Dalian Medical University, Dalian 116044, China laboratory Animal Center, Dalian Medical University, China Dalian University Affiliated Xinhua Hospital, China

A R T I C LE I N FO

A B S T R A C T

Keywords: Colon cancer Digestive diseases IBD Intestinal inflammation Saponins

The saponins are natural surface-active glycosides which are the principal components of many popular herbal medicinal plants such as ginseng, astragalus, and bupleurum. Recent studies have suggested that saponins can exert strong anti-inflammatory effects and induce immune homeostasis in many diseases. Intestinal-inflammation-related digestive diseases include inflammatory bowel disease (IBD), irritable bowel syndrome, intestinal ischemia-reperfusion injury, necrotizing enterocolitis and radiation proctitis, as well as intestinal inflammation caused by nonsteroidal anti-inflammatory drugs. The pathogenesis of these diseases is poorly understood, and the patients with these diseases suffer from mental stress and physical pain, while their families (and society) experience heavy economic losses. Results from animal experiments suggest that saponins can suppress intestinal inflammation, promote intestinal barrier repair, maintain the diversity of the intestinal flora, and decrease the incidence rate of colon-inflammation-related colon cancer. In this review, we discuss new findings regarding the effects of saponins on intestinal inflammation and digestive diseases with intestinal inflammation. In addition, we provide a summary of the underlying mechanism for saponins-induced treatment on intestinal-inflammationrelated disease.

1. Introduction Saponins, a class of plant-derived secondary metabolite, are glycosides of triterpene sapogenins or steroidal sapogenins. Based on their aglycone, saponins are divided into two main types: triterpenoid saponins (30 carbon atoms, 30-C), which occur mainly in the plant class Magnoliopsida, and steroidal saponins (27 carbon atoms (27-C) with a 6-ring spirostane or a 5-ring furostane skeleton), which are almost exclusively present in the plant class Liliopsida [1]. The triterpenoid saponins are mainly found in many plants including the Araliaceae, Fabaceae, Polygalaceae, and Campanulaceae families, whereas the steroidal saponins mainly exist in the Liliaceae, Scrophulariaceae, and Dioscoreaceae. The main sources and structures of saponins are shown in Fig. 1. In recent years, saponins have been widely used as natural products for clinical drug development due to their various pharmacological activities, such as immunomodulatory [2], anti-oxidative [3], antiapoptotic [4], anti-diabetic [5], neuroprotective [6], and anti-cancer

[7] effects. Moreover, saponins are attracting a high level of interest because of their obvious anti-inflammatory activities, including the inhibition of neutrophil infiltration [8], the reduction of inflammatory mediators [9] and the reversal of inflammatory hyperplasia [10]. Based on the effects of saponins on the inflammatory response, numerous experiments have been performed and have found that saponins have potential in the regulation of intestinal inflammation. Intestinal inflammation occurs with many gastrointestinal diseases, such as inflammatory bowel diseases (IBD) [11], irritable bowel syndrome (IBS) [12], intestinal ischemia-reperfusion injury [13], and other intestinal-inflammation-related digestive diseases. The pathogenesis of these diseases remains poorly understood, but they are all characterized by repetitive and chronic inflammatory changes in the gut. Inflammatory reactions result in the production of numerous cytokine and inflammatory mediators, causing tissue and intestinal epithelial cell damage, which decreases the intestinal barrier function and promotes the mass reproduction of pathogenic bacteria, breaking the balance of the intestinal flora [14,15]. In addition, excessive inflammatory

⁎

Corresponding author at: Dalian Medical University, Liaoning province, Dalian city, Lvshun south road west section number 9, 116044, China. Corresponding author at: Dalian University Affiliated Xinhua Hospital, Dalian, China. ⁎⁎⁎ Corresponding author at: laboratory Animal Center, Dalian Medical University, Dalian, China. E-mail addresses: [email protected] (J. Wang), [email protected] (Z. Deng), [email protected] (D. Chen). 1 These authors contributed equally to this work. ⁎⁎

https://doi.org/10.1016/j.phrs.2019.04.010 Received 7 December 2018; Received in revised form 4 April 2019; Accepted 4 April 2019 Available online 05 April 2019 1043-6618/ © 2019 Elsevier Ltd. All rights reserved.

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Fig. 1. The sources and structures of saponins, and their functions in regulation of intestinal inflammation.

goblet cell depletion, and severe transmural inflammation [23]. The use of ginsenosides, makino saponins [24], lancemaside A [25], kalopanaxsaponin A [26], soyasaponin I [27], notoginsenoside R1 [28], and soyasaponin Ab [29] could significantly improve the above pathological conditions. Ginsenoside treatment dramatically ameliorated body weight loss, colon shortening, diarrhea, and bloody diarrhea [30]. Monomers in ginsenosides such as ginsenoside Rd, ginsenoside Re, ginsenoside Rg1, ginsenoside Rh1, ocotillol-type ginsenoside, and ginsenoside Rh2 also had therapeutic effects on the colitis models. Oral administration of ginsenoside Rd dose-dependently alleviates colon inflammatory symptoms, which is dependent on NLR family, pyrin domain-containing 3 (NLRP3) inflammasome inhibition [31]. Ginsenoside Re reversed the reduction of intestinal barrier function in IBD [32]. The oral administration of ginsenoside Rg1, ginsenoside Rh1, and ocotillol-type ginsenosides could inhibit colon shortening, which are associated with a restored Th17/Treg imbalance [33]. Ginsenoside Rh2 significantly alleviates local inflammation, and the therapeutic effects can be attenuated by a specific transforming growth factor β receptor I inhibitor SB431542. In addition, astragaloside IV promoted mucosalhealing processes in colitis by its ability to regulate energy metabolism properties [34].

hyperplasia also induces intestinal cancer [16]. Therefore, reducing intestinal inflammation is very important and can become an effective method of treatment for intestinal-inflammation-related digestive diseases [17]. The functions of saponins in regulation of intestinal inflammation are shown in Fig. 1. This review summarizes the regulatory effects of saponins on intestinal inflammation and the mechanisms involved, which will hopefully serve as a reference for the further development of saponins as agents for the treatment of intestinal-inflammation-related digestive diseases. 2. Effects of saponins on IBD IBD is a chronic non-specific inflammatory condition in the digestive tract and it can be divided into ulcerative colitis (UC) and Crohn’s disease (CD). The etiology of IBD is still under studied, recent results showed that genetic, immunologic, and environmental factors are related to IBD development [18,19]. It is estimated that more than 3.7 million people worldwide are affected by IBD, and the prevalence and incidence increase rapidly [20]. In China, according to recent statistics, the prevalence of UC is 11.6/100,000, while that of CD is 1.4/100,000 [21]. Patients with IBD will suffer from repeated abdominal pain, diarrhea, bloody stools, and even various extra-intestinal manifestations such as blurred vision, joint pain, and rash [22]. The disease can be improved by treatment, but most patients have recurrent episodes or remain uncured, which seriously affects the quality of their life and aggravates their psychological burden. In the colitis model induced by 2-, 4-, 6-trinitrobenzenesulfonic acid (TNBS) or dextran sulfate sodium (DSS), the inflamed colonic sites showed thickening of the bowel wall, dilation, hyperemia, edema, mucosal erosions, necrosis, ulcers, adhesion to surrounding tissues,

3. Effects of saponins on IBS IBS is a common gastrointestinal disorder characterized by discomfort, chronic abdominal pain, and altered bowel habits [12]. Worldwide prevalence of IBS is 10%–15% [35]. IBS and IBD patients have some similar clinical manifestations and laboratory test results (e.g. increased serum chromogranin A), which suggest that IBS and IBD may have a common pathogenesis [36]. Underlying mechanisms that 67

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active cell mitosis with significant cell atypia, which indicates tumorigenesis [58]. Trillium tschonoskii steroidal saponins and Paris saponin VII (also from Trillium tschonoskii) effectively protected the mouse model against the incidence of bloody stool, anal prolapse, and tumorigenesis [59,60]. DMH/DSS-induced mice treated with polyphyllin Ⅵ had a mucosal layer with varying degrees of lymphocytic infiltration, and the submucosa occurs to varying degrees, which may suggest that polyphyllin Ⅵ can effectively inhibit the transformation of intestinal inflammation into cancer [61]. In addition, in a xenograft tumor murine model established by the subcutaneous inoculation of 5 × 106 colorectal cancer cells (SW-620) into nude mice, Paris saponin VII decreased the xenograft tumor size remarkably and triggered the apoptosis of tumor cells [60]. in vitro, the effects of saponins were evaluated in human colorectal cancer cells usually using HT-29, SW480, and SW-620 cells. Trillium tschonoskii steroidal saponins can induce the apoptosis of HT-29 cells through both the activation of mitochondrial-mediated apoptotic pathway and inhibition of mitogen-activated protein kinases (MAPKs) [59]. Paris saponin VII induced cell apoptosis, together with cell cycle arrest in the G1 phase, and triggered apoptosis in a caspase-3-dependent manner in HT-29 and SW-620 cells [60]. Rhizoma paridis total saponins inhibited the interleukin-6/Janus kinase-signal transducer and activator of transcription (IL-6/JAK-STAT3) protein signaling pathway to promote the apoptosis of SW480 cells [62].

could lead to IBS include genetic factors (most notably, an identified mutation in SCN5A) [37], low-grade mucosal inflammation [38], postinfectious changes [39], chronic infections and disturbances of the intestinal microbiota [40], immune activation and altered intestinal permeability [41]. A subset of patients with IBS have visceral hypersensitivity, which may have use as a clinical marker of IBS [42]. 5-Hydroxytryptamine (5-HT) system imbalance are closely related to the occurrence of the functional gastrointestinal disease [43,44]. Clinical studies have shown a significant increase in plasma 5-HT concentrations in patients with IBD or IBS [45,46]. Ginsenosides can maintain the 5-HT system balance to regulate the motor and sensory functions of the gastrointestinal tract [47,48]. The increase in 5-HT system activity is reversed by ginsenosides in a rat IBS model [47]. However, reduced 5-HT system activity in a rat model of X-ray irradiation-induced acute pica can be also reversed by ginsenosides [48]. Although the ginsenosides used in the two studies are not the same one, the main active ingredients have been confirmed to be saponins. These results suggest a dual role of ginsenosides on modulation of 5-HT system activity, and the related mechanisms need further study. To our knowledge, as ginsenosides include multiple kinds of saponins, the detail mechanisms underlying ginsenosides induced regulation of 5-HT system activity may be well studied based on metabolomics and proteomics technology. Astragaloside II contributes to epithelial barrier repair following IBS as astragaloside II could promote scratch-wound closure, cell proliferation, and arginine uptake, and could induce the arginine transporters cationic amino acid transporter 1 and cationic amino acid transporter 2 in differentiated human intestinal Caco-2 cells [49]. In addition, lilium saponins and timosaponin, singly or in combination, can exert therapeutic effects towards IBS by reducing the number of colorectal mast cells and the serum concentration of the calcitonin gene-related peptide and the vasoactive intestinal peptide [50].

6. Effects of saponins on other intestinal-inflammation-related digestive diseases In addition to the above diseases, many other digestive diseases are also accompanied by intestinal inflammation, such as nonsteroidal antiinflammatory drug-induced intestinal inflammation [63], necrotizing enterocolitis [64], and radiation proctitis following cancer radiotherapy [65]. In these diseases, mild intestinal inflammation causes intestinal mucosal damage, while severe inflammation can result in intestinal necrosis. Nonsteroidal anti-inflammatory drugs can induce intestinal mucosal damage manifested by inflammatory cell infiltration, intestinal villus degeneration, necrosis, and shedding. This damage can be prevented by ginsenosides via the endoplasmic reticulum stress pathway [66]. Necrotizing enterocolitis is a devastating intestinal inflammatory disease. Astragaloside IV ameliorated necrotizing enterocolitis by suppressing inflammation and attenuating oxidative stress via the vitamin D3-upregulated protein 1/nuclear factor-kappa B (NF-κB) signaling pathway [67]. Radiation proctitis is a common complication of the radiotherapy of pelvic tumors [68]. Clinical studies have found that an injection of aescine in patients after pelvic tumor radiotherapy could alleviate the clinical symptoms of radiation proctitis by anti-exudation and enhancement of venous tension, such as reducing edema of the rectal mucosa and anal sphincter, and relieving tenesmus [69].

4. Effects of saponins on intestinal ischemia-reperfusion injury Intestinal ischemia-reperfusion injury caused by microcirculatory flow disorders is a common pathological and physiological process following severe trauma, burns, or shock, which can cause severe inflammatory damage in the intestine [13]. In the ischemic stage, the intestine is injured as a result mainly of hypoxemia; the resumption of blood flow further increases vascular permeability and damage to vascular endothelial cells [51]. The above process promotes adhesion and activation of inflammatory cells, producing a large amount of reactive oxidative species and inflammatory mediators, which can cause an excessive inflammatory response and oxidative stress to damaged intestine [52,53]. In an intestinal ischemia-reperfusion model established by superior mesenteric artery clipping/reperfusion, pre-operative treatment with Panax notoginseng saponins [54] or post-operative treatment with Panax notoginseng saponins [55] could alleviate intestinal damage39,40. Notoginsenoside R1 can reduce intestinal ischemia-reperfusion-induced intestinal inflammatory response [56]. Ginsenoside Rg1 exerted its therapeutic effects on intestinal ischemiareperfusion injury through the Wnt/β-catenin signaling pathway and provided a novel treatment modality for intestinal ischemia-reperfusion injury [57].

7. Mechanism of the saponin-induced regulation of intestinal inflammation Saponins exert many regulatory effects on intestinal inflammation, and the underlying mechanisms involve multiple signaling pathways such as NF-κB, MAPKs, and STAT3. Here we briefly summarize the potential mechanisms. The functions and potential mechanisms of different saponins on intestinal inflammation related diseases are shown in Table 1.

5. Effects of saponins on colitis-associated colorectal cancer Recurrent and chronic intestinal inflammation is necessary for colitis-associated colorectal cancer (CACRC) development, and studies have shown that up to 25% of colorectal tumors may be caused by chronic intestinal inflammation [16]. Both in-vivo and in-vitro experiments have demonstrated that saponins have an effect on CACRC. in vivo, 1,2-dimethylhydrazine (DMH)/DSS-induced mice are the commonly used CACRC animal model. In the colon of DMH/DSS-induced mice, inflammatory signs such as edema first occur, followed by

7.1. Saponin-induced anti-inflammatory activity Inflammation is a self-protective response against injury by modulating pro-inflammatory and anti-inflammatory components [70]. Imbalances between pro- and anti-inflammatory components are among the key causes of intestinal inflammation like IBD [17]. The NFκB was identified as an important regulator of this balance [71]. Its 68

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Table 1 Functions and mechanisms of saponins on intestinal inflammation related diseases. Application

Mechanism

Saponins

Anti-inflammatory

Inhibition of NF-κB activation

astragaloside IV; echinocystic acid; ginsenoside compound K; ginsenoside R1; ginsenoside Re; ginsenoside Rg1; ginsenoside Rf; gynostemma pentaphyllum saponins; kalopanaxsaponin A; lancemaside A; notoginseng saponins; soyasaponin I; timosaponin AIII ginsenoside Rd; ginsenoside Rf; kalopanaxsaponin A; timosaponin AIII ginsenoside Re; kalopanaxsaponin A; lancemaside A; soyasaponin Ab

Regulate intestinal flora Repair intestinal epithelial

Anti-inflammation-associated colon cancer Immunomodulatory Regulate energy metabolism

Inhibition of MAPK phosphorylation Inhibition of IRAK-1 phosphorylation or interaction between LPS and TLR4 Increase NLRP12 Inhibition of STAT3 activation Inhibition of NLRP3 inflammasome Reduce harmful bacteria and increase probiotics Increase tight junction protein Increase ATP and ATP synthase β Promote epithelial cell proliferation Reduce GRP78 Reduce mucosal cell apoptosis Inhibition of IL-6/JAK-STAT3 Inhibition of MAPKs Increase Ras Restore the balance of Th17/Treg cells Increase SGLT1

ginsenoside gynostemma ginsenoside gynostemma

Rg1 pentaphyllum saponins Rd pentaphyllum saponins; notoginseng saponins; ginsenosides;

ginsenoside Re; saponins from Panax japonicus astragaloside IV astragaloside II ginsenosides gynostemma pentaphyllum saponins Rhizoma paridis total saponins trillium tschonoskii steroidal saponins Paris saponin VII timosaponin AIII; majonoside R2 ginsenoside compound K

macrophages, and the phosphorylation of IRAK-1 [74]. Kalopanaxsaponin A inhibited LPS-induced IRAK-1 phosphorylation but did not affect IRAK-4 expression [26]. Soyasaponin Ab did not affect TLR4 expression or LPS-induced NF-κB activation in TLR4 peritoneal macrophages treated with small interfering RNAs, which indicates that soyasaponin Ab may ameliorate colitis by inhibiting the binding of LPS to TLR4 on macrophages [29].

activation was significantly induced in IBD and promoted the expression of various pro-inflammatory genes, such as tumor necrosis factor-α (TNF-α), IL-6, and Interferon γ, leading to colonic tissue damage [72]. Saponins achieved anti-inflammatory activity by inhibiting NF-κB activation. Such saponins include ginsenoside Rf [32], gynostemma saponins [24], ginsenoside compound K [30], lancemaside A [25], kalopanaxsaponin A [26], timosaponin AIII [73], soyasaponin I [27], echinocystic acid [74], and ginsenoside Re [32]. Some saponins regulated NF-κB upstream factors to control intestinal inflammation. For example, ginsenoside Rg1 induced NLRP12 up-regulation and notoginsenoside R1 activated the pregnane X receptor to relieve intestinal inflammation [28,75]. STAT3, as with to NF-κB, can be phosphorylated to form a dimer, and, once activated, was transferred into the nucleus where it upregulated various genes, such as those encoding pro-inflammatory enzymes and mediators, after stimulation by cytokines, such as IL-6 and TNF-α [76]. The anti-inflammatory effects of the Gynostemma pentaphyllum saponins were achieved by suppressing STAT3 activation [24]. The MAPKs, known to activate NF-κB, comprise three groups: extracellular signal-regulated kinase (ERK), c-Jun NH2-terminal kinase (JNK), and p38 MAPKs, which can be phosphorylated and which can then up-regulate the expression of inducible nitric oxide synthase and cyclooxygenase-2 to promote intestinal inflammation [77]. MAPKs is another important target for the anti-inflammatory effects of saponins. While lipopolysaccharide (LPS)-induced peritoneal macrophages activated MAPKs, kalopanaxsaponin A inhibited this activation [26]. Of the MAPKs, p-ERK was the one most potently inhibited. In TNF-α-induced intestinal epithelial cells and mouse peritoneal macrophages RAW264.7, it was observed that ginsenoside Rf inhibited the phosphorylation of MAPKs [78]. Other studies of in-vivo models of IBD showed that ginsenoside Rd and timosaponin AIII could inhibit the MAPK pathway by depressing JNK and p38 activation, thus, contributing to the remission of IBD [39,79]. Toll-like receptor 4 (TLR4), which is linked to the activation of transcription factor NF-κB via IL-1 receptor-associated kinases (IRAKs), serves as the main mediator of LPS signaling in IBD [80]. Therefore, saponins could alleviate intestinal inflammation by inhibiting the interaction between LPS and TLR4 or the TLR4-IRAK-NF-κB pathway. Ginsenoside Re inhibited IRAK-1 phosphorylation, as well as IRAK-1 and IRAK-4 degradation in LPS-stimulated peritoneal macrophages to ameliorate inflammation [78]. Echinocystic acid, a metabolite of lancemaside A, inhibited the binding of LPS to TLR4 on peritoneal

7.2. Saponins and intestinal microbiota The Human Microbiome Project indicated that the imbalance of intestinal microflora and its metabolites played an important role in the pathogenesis of IBD [14]. More than 95% of the gut microbiota in healthy humans and mice consists of three types of bacteria (Firmicutes, Bacteroidetes, and actinomycetes), of which the proportion of Bacteroidetes is greater than 84% and that of Firmicutes is less than 4% [81]. Compared with healthy people, the intestinal flora of IBD patients changes in diversity and quantity. For instance, they have a higher percentage of Firmicutes and a lower percentage of Bacteroidetes [81]. Saponins have been reported to regulate intestinal flora diversity, reducing harmful bacteria and increasing beneficial bacteria [82]. Notoginseng saponins and Gynostemma pentaphyllum saponins have the ability to shift the Bacteroidetes/Firmicutes ratio [83]. Gynostemma pentaphyllum saponins can decrease sulfate-reducing bacteria, finally lead to the reduction of intestinal epithelial damage caused by hydrogen sulfide [82]. Saponins can increase intestinal beneficial bacteria such as Lactobacillus and Bifidobacterium to relieve intestinal inflammation [83]. Treatment with Gynostemma pentaphyllum saponins, notoginseng saponins, and ginsenosides effectively increased Lactobacillus and Bifidobacterium in the gut, which had been reported to ameliorate dysbiosis and mediate protective effects in patients with Crohn's disease [83,84]. Gynostemma pentaphyllum saponins enhanced the effects of a butyrate-producing bacterium, Faecalibacterium prausnitzii, with butyrate exhibiting a wide range of health effects from anti-inflammatory properties to the enhancement of the intestinal barrier function [83]. 7.3. Saponins and intestinal epithelial repair An intestinal epithelial barrier dysfunction causes bacteria to infiltrate the intestinal mucosa and submucosa such as when an ulcer occurs [85]. This bacterial translocation stimulates inflammatory cells 69

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jejunal loops [104]. The above in-vitro studies suggest that saponins may have the potential to destroy intestinal barrier function, but oral administration of saponins is unlikely to impair the barrier function in mammals. The specific mechanism needs further research.

and induces the inflammatory response while releasing pro-inflammatory chemokines and protein kinases. Epithelial cells, as well as tight junction complexes between epithelial cells, support the intestinal epithelial barrier and the complexes are formed by transmembrane and intracellular proteins such as occludin, zonula occludens (ZO-1), and claudin-1 [86]. In the treatment of TNBS-induced colitis with Baizhuchuanqi capsules containing Astragalus mongholicus saponin, the treatment group had a smaller ulcer surface and regenerated surrounding mucosal epithelium, which indicated that Astragalus mongholicus saponin had the effect of inducing the differentiation or migration of intestinal epithelial cells [87]. Fermented wild ginseng contains more active ginsenosides than non-fermented wild ginseng, and fermented wild ginseng can alleviated the expression and distribution of ZO-1 in DSS-induced mice colitis model [88]. Ginsenoside Re increased the expression of ZO-1, occludin, and claudin-1 to repair intestinal epithelial in IBD [32]. Astragaloside II contributed to epithelial barrier repair by promoting L-arginine uptake in Caco-2 cells, which promoted colonic epithelial wound repair by enhancing cell proliferation and collagen deposition [49,89]. Saponins from Panax japonicus modulated the damage to the intestinal epithelial tight junction by increasing the production of claudin-1 and occludin in aging rats [90]. Astragaloside IV could alleviate the destruction of epithelial F-actin and connexin produced by TNBS, and increased the concentration of adenosine triphosphate (ATP) and ATP synthase subunit β in colon tissue [34].

9. Conclusion In summary, saponins inhibit excessive inflammation by interaction with a plurality of inflammation pathways, such as NF-κB, MAPKs, and TLR4 pathways, which is beneficial for the inhibition of intestinal inflammation. Saponins can also maintain the diversity of intestinal flora and intestinal epithelial integrity. Saponins prevent gastrointestinal lesions from worsening into cancer through triggering apoptotic pathways. This review may provide some scientific information for the future application of saponins in the treatment of intestinal inflammation related digestive diseases. Conflict of interest The authors have declared no conflict of interest. Acknowledgments This work was supported by National Natural Science Foundation of China (Grant No. 81600440), Basic Research Projects of Liaoning Province Universities (Grant No. LQ2017042), and Dalian High Level Talent Support Program (No. 2017RQ017).

7.4. Other mechanisms involved in the effect of saponins against intestinal inflammation

References

Other mechanisms such as oxidative stress [91,92], endoplasmic reticulum stress [93], an imbalance in Th1/Th2 and Th17/Treg cell ratio [94,95], as well as activation of the inflammasome NLRP3 activation [96], also play roles in IBD. Ginsenosides could reduce intestinal inflammatory cell infiltration induced by nonsteroidal anti-inflammatory drugs by reducing the concentrations of endoplasmic reticulum stress protein glucose transporter 78 in intestinal mucosal epithelial cells through the endoplasmic reticulum stress pathway [66]. Ginsenoside Rd acted against TNBS-induced recurrent colitis by inhibiting neutrophil infiltration and promoting the antioxidant capacity of the damaged colonic tissue [97]; Ginsenoside Rd also inhibits the activation of the NLRP3 inflammasome in DSS-induced IBD, resulting in decreased caspase-1 production and decreased IL-1β secretion. And invitro experiments confirmed that ginsenoside Rd significantly inhibited NLRP3 inflammasome activation, which was mainly dependent on the mitochondrial translocation of p62 and mitophagy [31]. Both majonoside R2 and timosaponin AIII ameliorated colitis in mice by restoring the balance of Th17/Treg cells [73,98]. A new theory says that energy metabolism disorders are related to IBD [99]. The Na+/glucose cotransporter 1 also plays a crucial role in glucose uptake in intestinal epithelial cells, which has shown central effects in ameliorating intestinal inflammation. Ginsenoside compound K up-regulated Na +/glucose cotransporter 1 expression through EGFR-CREB signaling activation, which could contribute to reducing intestinal inflammation [100].

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8. Harmful effects of saponins on the intestine A few studies have shown that certain saponins have harmful effects on the intestine. Atlantic salmon fed experimental diets containing soyasaponins displayed severe enteritis [101]. Further studies demonstrates soyasaponins, in combination with one or several unidentified components present in legumes, induces an inflammatory reaction in the intestine, and soyasaponins aggravated enteritis by increasing intestinal permeability, but it did not induce the intestinal inflammation itself [102]. Soyasaponins increase leakage of glycinin into the mucosal cells of rabbit jejunum when the cells were incubated in glycinin [103]. Gypsophila saponin enhanced β-lactoglobulin transfer into isolated rat 70

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