Dihydromyricetin Attenuates Colitis in Mice induced by DSS via Improving Intestinal Barrier Function

doi:10.21203/rs.3.rs-1565495/v1

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Dihydromyricetin Attenuates Colitis in Mice induced by DSS via Improving Intestinal Barrier Function

https://doi.org/10.21203/rs.3.rs-1565495/v1

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The destruction of intestinal barrier plays an important role in the pathogenesis of UC. The anti-inflammatory, anti-oxidation, anti-apoptosis and anti-bacterial effects of DHM have been concerned. However, the effect of DHM on Intestinal Barrier Function remains unclear. In this study, we found that DHM protected intestinal barrier from DSS through suppressing inflammatory cell infiltration and restoring the expression of Tight junction proteins (TJs) occluding and ZO-1. Meanwhile, DHM reduced cell apoptosis in the gut by influencing the expression of Bcl-2 and Caspase3. FITC-dextran leakage and gut microbiota viability experiments were used to tested the protective effect of DHM on intestinal barrier intact. Therefore, DHM may have great therapeutic potential as a new drug for UC.

Ulcerative Colitis

Dihydromyricetin

Tight junction proteins

Intestinal Barrier

Ulcerative Colitis (UC), one of the two forms of inflammatory bowel disease (IBD)[1], is an idiopathic, chronic inflammatory disorder of the colonic mucosa, which starts in the rectum and generally extends proximally in a continuous manner through part of, or the entire, colon [2]. UC is that the comprehensive results from the host genome, exposome, gut microbiome and mucosal immune system[3, 4]. In this study, colitis was induced with dextran sulfate sodium (DSS) in mice, the most severe murine colitis, which most closely resembles human UC[5], is very popular in IBD research due to its rapidity, simplicity, reproducibility and controllability[6]. Impaired gut barrier function is considered to be a major contributor to disease pathology, and then triggering the immune response and tissue destruction[7].

The epithelium is a key component of strongest physical intestinal barrier in gut, which is a monolayer mainly composed of 4 types of intestinal epithelial cells (IECs): absorptive enterocytes, mucus-producing goblet cells, antimicrobial peptide (AMP)-producing Paneth cells, and hormone-producing enteroendocrine cells[8, 9]. Epithelial cells are connected with the apical junctional complex, consisting of adherens junctions, Tight junction proteins (TJs), and desmosomes[10]. TJs can regulate substances translocation, such as ions, solutes, and water across the epithelium [11]. Consequently, the injury of epithelium and TJs, is considered to be a major pathogenesis of UC, as it allows luminal bacteria and other injury factors access to the gut tissues [7](Fig. 1A).

The aim of treatments in UC is inducing and maintaining the patient in remission, returning to normal activities, and improving quality of life, minishing the adverse effects of treatment, rather than modifying or reversing the underlying pathogenic mechanism[12, 13]. These drugs mainly include corticosteroids, aminosalicylates, and immunosuppressive agents [14]. But these drugs have low patient compliance and efficacy due to their severe adverse reactions. Therefore, we need to look for new drugs that are more secure, fewer side effects and can be tolerated by patients for a long time.

Dihydromyricetin (DHM) is a kind of flavonoid that was extracted from Ampelopsis grossedentata, Hovenia dulcis and Cedrus deodara [15](Fig. 1B). In recent years, the anti-inflammatory, anti-oxidation, anti-apoptosis and anti-bacterial effects of DHM have been concerned[15–19]. Therefore, we hypothesized that DHM may attenuates colitis in mice induced by DSS via improving intestinal barrier through reducing inflammation, attenuating intestinal epithelial cells apoptosis and restoring TJs expression.

DHM Attenuates Colonic Inflammation of DSS-induced Colitis in Mice.Previous studies have shown that DHM could inhibit inflammatory response[16, 18, 20], the protective effects of DHM in DSS-induced colitis were examined in this study.

H&E staining was used to examine the effect of DHM and SASP on inflamed colon tissues. The results showed that both of DHM and SASP can decrease the severity of inflammation, depth of inflammatory involvement, and crypt damage (Figure 2A and 2C). An increase in DAI score was observed on day 6 in all DSS-treated groups, indicating that can be used for building ideal model for the study of colitis. The DAI

score of the SASP-treated or DHM-treated groups was significantly lower than the DSS group from the 11th day, suggesting that DHM alleviated the clinical symptoms (Fig. 2C). The colon length, a marker of intestinal inflammation, was significantly reduced by DSS treatment but was apparently improved by DHM or SASP (Fig. 2D).

DHM Protects the Epithelial Cells from Apoptosis in DSS-induced Colitis in Mice.

The intestinal tissue negative control showed no or few TUNEL staining. Extensive numbers of TUNEL positive cells were seen in the tissue sections treated with DSS group. The percentage of positively stained epithelial cells increased significantly when compared to that in the control group, different concentration of DHM treatment significantly attenuated the rate of apoptosis induced by DSS. Similarly, SASP prevented the increase of TUNEL-positive cells induced by DSS (Fig. 3A).

In this study, Western blot analysis was used to detect the expression of apoptosis-associated proteins in the epithelial cells of intestine. The results demonstrated that DHM lowers the level of caspase-3 protein and upregulates the expression level of Bcl-2 protein. However, no significant differences in the expression of BAX were identified (Figure 3B, 3C, 3D).

DHM Protects of the Epithelial Barrier Via Regulating the Expression Levels of Tight Junction Proteins.

The membrane proteins, occludings, together with claudins has been identified as the major constituent of Tight Junction Proteins (TJs) strand. Zonula occludens protein-1 (ZO-1), has been identified as constituting the plaque structures of TJs[22], binding directly to TJs strand. ZO-1 can independently determine whether and where claudins are polymerized[23]. However, knowledge of the function of ZO-1 is limited. To Investigate whether DHM protect the integrity of Epithelial barrier from DSS-induced colitis, ZO-1 and Occludin of TJs were assessed by Western blotting and IHC. Western blot and IHC analyses confirmed that ZO-1(Fig. 4A, 4B) and Occludin (Fig. 4c, 4D) protein levels are downregulated in DSS colitis mice as compared to untreated control. And that down-regulation of the expression of these proteins was notably increased by treatment with DHM or SASP compared to the DSS group.

Evaluation of Intestinal Permeability with FITC-dextran and Bacterial Activity.

The permeability of 4KDa FITC-Dextran was used to assesses the ability of the epithelium to regulate movement of macromolecules across the epithelial sheet, where lower permeability represents a stronger epithelial barrier. LPS is a unique, glucosamine-based phospholipid that makes up the outer monolayer of the outer membrane of most gram-negative bacteria and closely associated with many inflammatory diseases[21].The intestinal epithelial cells exposed to LPS led to FITC-dextran leakage compared with control group, and additional stimulation with DHM alleviated the changes (Fig. 5B). The density of serum FITC-dextran from DSS-induced colitis in mice was higher than that in control mice. However, DHM or SASP significantly inhibited the increase of FITC-dextran in serum (Fig. 5A).

Increased gut leakiness can result in bacterial translocation from the gut to the blood. To test this, we analyzed the blood from these mice as a sign of bacterial translocation. The results showed that bacterial activity in DSS-induced colitis is far higher than control. DHM, but not SASP, had significant antimicrobial activities against gut microbiota (Fig. 5C).

Intestinal barrier defects have been associated with a series of human diseases, such as IBD, IBS and systemic diseases. TJs maintain the function of intestinal barrier through regulating permeability of ions, nutrients, and water[8, 24]. Previous studies have shown that DHM maintained the barrier function by restoring the protein expression of occludin, claudin-1 and ZO-1[25]. Claudins and occludins are composed of TJ strands. Other TJ proteins such as cingulin, ZO-1, ZO-2 and ZO-3 are framework forming proteins connecting transmembrane proteins with the actin cytoskeleton[26, 27]. ZO proteins appear to exert a basic and redundant role in establishing and maintaining intercellular adhesion and communication[28]. Occludin, an integral part of TJ strands, limits paracellular permeability[29]. Occludin may play important role in signal transduction pathways which involved in epithelial transport and/or tissue growth and differentiation[30, 31]. Occludin was also reported to regulate TJs and/or TJ assembly and disassembly of the apical junctional complex, as well as lumen formation in 3D-culture[31]. However, the functional role of occludin is still far from being clear. In this study, we examined that DHM restoring the TJs protein expression of occludin, and ZO-1 in DSS-induced colitis.

Previous study showed that DHM inhibited apoptosis through reducing the expression of Bax and Caspase-3 and restored the expression of Bcl-2[25]. Bcl-2 is a key regulator of apoptosis that inhibits apoptotic and necrotic cell death induced by a series of stimulation[32]. Caspase-3 is a crucial apoptotic protease in the final common pathway of the apoptotic cell death. Bax promotes programmed cell death by the intrinsic pathway with a series of changes including conformational switching, trafficking, and aggregation status changes. However, Bax might mediate caspase-independent death [32, 33]. This study showed that DHM significantly inhibited the expression of caspase-3, up-regulated the expression of Bcl-2, but it was no statistical significance in the expression of Bax.

The gut barrier homeostasis is dependent on the symbiotic relationship between the gut microbiota and host. Members of the gut microbiota influence host metabolic and immune status by modulating nutrient metabolism, xenobiotic and drug metabolism, and production of antimicrobial metabolites that limit numbers of competing microbes for the same niche[34]. However, in the setting of gut barrier dysfunction, the intestinal bacteria translocate to the portal and systemic circulation, and in consequence, the severity of liver and systemic inflammatory response[35]. DHM is widely perceived as contributing to alter the richness and diversity of the gut microbiota and modulate the gut microbiota composition[19]. This study observed DHM can restore the diversity change of gut microbiota in DSS-induced colitis. There were, it's almost the result of DHM maintains the integrity of the intestinal mucosal barrier and reduces the diversity of the gut microbiota.

In conclusion, our study suggests that DSS can cause inflammatory cell infiltration and barrier dysfunction. DHM attenuated intestinal barrier damage through suppressing inflammatory cell infiltration and cell apoptosis, regulating the expression of TJs, restoring the protein expression of occluding and ZO-1. FITC-dextran leakage and gut microbiota viability experiments were used to tested the protective effect of DHM on intestinal barrier intact. There may indicate DHM have therapeutic potential in the treatment of UC.

Mice

Female C57BL/6 mice were used for experiments between the ages of 6 and 8 weeks obtained from the Lanzhou veterinary research institute, Chinese academy of agricultural sciences, Lanzhou, China. Standard mouse chow pellets and water were supplied ad libitum. This study was approved by the Ethics Committee of Lanzhou University Second Hospital and conformed to the Chinese National Institute of Health Guide for the Care and Use of Laboratory Animals (NO. 2017-008).

Induction of colitis and treatment

Colitis was induced in C57BL/6 mice drank with 2% DSS (molecular mass, 36,000–50,000Da) dissolved in drinking water (days1-7)[36]. The mice were randomly divided into four groups, the normal control group (control group) received distilled water for 14 days; the saline control group (DSS group) received 2% DSS for 7 days and saline given orally by gavage from day 8 then continued for an additional 7 days. DHM treatment group (DHM group,) received 2% DSS for 7 days and 40mg/kg or 20mg/kg per day of DHM orally by gavage from day 8 then continued for an additional 7 days. Salazosulfapyridine treatment group (SASP group,) received 2% DSS for 7 days and 40mg/kg per day of SASP orally by gavage from day 8 then continued for an additional 7 days.

Disease Activity Index (DAI)

The DAI scores were calculated according to loss of body weight, stool consistency and gross bleeding, and exhibited as the mean value from the following three parameters: (a) body weight loss: 0 = none; 1 = 1–5%; 2 = 5–10%; 3 = 10–15%; 4 = over 15%; (b) stool consistency: 0 = normal; 2 = loose stools; 4 = diarrhea; (c) gross bleeding: 0 = normal; 2 = hemoccult; 4 = gross bleeding [37].

H༆E Staining and Histological Score

Mice were anesthetized using 10% chloral hydrate and killed by cervical dislocation. Histological examination was performed on samples of the distal colon from each mouse. The samples were fixed in 4% formaldehyde overnight at 4°C. Paraffin sections (4µm) were stained with hematoxylin and eosin (H&E). All histological evaluations were performed according to the histological score calculation method previously described by Morohoshi et al.[38]; the histological score was estimated by the combined of inflammatory cell infiltration and tissue damage. The infiltration scoring was as follows: 0, no infiltration; 1, presence of occasional inflammatory cells in the lamina propria; 2, increased numbers of inflammatory cells in the lamina propria; and 3, confluent inflammatory cells extending into the submucosa. The tissue damage scoring was as follows: 0, no mucosal damage; 1, discrete lymphoepithelial lesions; 2, surface mucosal erosion or focal ulceration; and 3, extensive mucosal damage and extension into deeper structures of the bowel wall. The mean score in each section was calculated.

Western Blotting

Proteins were extracted from colon tissues using RIPA lysis buffer supplemented with proteinase and phosphatase inhibitors (Solarbio, China) as previously described [39]. Protein concentration was assessed using Pierce BCA protein assay (Nanjing JianCheng Bioengineering Institute, China). A 12% tris-glycine gel was used, and the proteins were transferred to a polyvinylidene difluoride (PVDF) membrane after constant pressure electrophoresis (Millipore Corp., Billerica, MA, USA). The membrane was incubated overnight (4°C) with antibodies specific for Caspase3 (dilution of 1:1,000), Bax (dilution of 1:1,000), Bcl-2 (dilution of 1:1,000), Occludin (dilution of 1:10,00), ZO-1 (dilution of 1:10,00), and β-actin (dilution of 1:10,00). Goat horseradish peroxidase linked to an anti-rabbit IgG secondary antibody was added at a dilution of 1:3,000 and incubated for 1 hours at room temperature. All of the antibodies, except Caspase3 was purchased from Cell Signaling Technology (CST, USA), were purchased from Proteintech (China).

Immunohistochemistry staining

Sections of colon tissues were deparaffinized in xylene and hydrated in a series of graded alcohol. After dewaxing and rehydration, the antigen retrieval was done by microwave for 15 minutes. Sections were immersed in 3% hydrogen peroxide in methanol for 20 minutes at room temperature to abolish endogenous peroxidase activities and then they were blocked with normal goat serum at 37°C for 15 minutes. Slides were incubated with polyclonal antibody of ZO-1 (diluted to 1:200, Proteintech, China), Occludin (diluted to 1:500, Proteintech, China), Claudin-2 (diluted to 1:25, Proteintech, China) at 37°C for 60 minutes. After PBS washing, the slides were incubated with a biotinylated horse peroxidase-conjugated secondary antibody and 0.1%DAB substrate, using the standard streptavidin-biotinbased method. The positive cells were observed and evaluated by two independent observers. A cytoplasmic or nuclear brown granule was marked as a positive expression. Finally, the images were gained with a fluorescence microscope.

TUNEL staining

Formalin-fixed, paraffin-embedded sections were stained for apoptotic cells by the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) method with an insitu cell death detection kit according to the manufacturer’s instructions (Solarbio, China). Finally, cells were observed and photographed under fluorescence microscope. The number of cells stained with TUNEL (apoptotic) were counted and then compared with control group.

Bacterial activity

Mice were sacrificed with 10% chloral hydrate at 14th days and the portal blood was collected. Bacterial activity was tested using Microbial Viability Assay Kit-WST (DOJINDO, Japan ) according to the manufacturer’s protocol.

Intestinal Mucosa Permeability

Intestinal permeability was assessed using a FITC-dextran tracer (4kDa, 60mg/Kg body weight, Sigma, USA) as described previously^[6]. Mice were gavaged with 0.4ml of FITC-dextran at 4 h before being euthanized. Blood samples were collected at the time of sacrifice and allowed to clot for 30 min. Then samples were centrifuged for 90 s at 6,000 g. FITC-dextran concentration was determined using fluorescence microplate reader at an excitation wavelength of 485 nm and emission wavelength of 528 nm^[40].

Cell Culture and Evaluation of Barrier Integrity

The rat intestinal epithelial cell line IEC6 was purchased from CHI SCIENTIFIC (Shanghai, China). The IEC6 cells was cultured in Dulbecco’s modifified Eagle’s medium (DMEM; Gibco by life technologyes, Grand, USA) combined with 10% (v/v) foetal bovine serum (EXcell Bio) and 1% (v/v) penicillin/streptomycin ( BasalMedia, China ) in a 37°C humidifified incubator containing 5% CO2. HTS Transwell-24 well permeable support system with a 3-µm pore size (Corning; Cat No. 3396) was used to assess IEC6 permeability induced by LPS. IEC6 cells were seeded on insert membranes treated with 300µg/ml LPS only or with 1mM DHM for 72h at 37°C. Following treatment, Transwell inserts were gently rinsed with warm PBS and then placed in a 24-well plate containing 800µL of complete culture medium per well. Next, 400µL complete culture medium contain 10ul of 10 mg/mL fluorescein isothiocyanate (FITC)-dextran (molecular weight 4000; Sigma; Cat No. 46944) was added to the upper chamber and allowed to incubate at 37°C for 60 min. Finally, the intensity of the dye in the lower chamber was spectrophotometrically assessed in a clear bottom black-walled microplate at 485 nm excitation and 528 nm emission^[41].

Author Contributions: Experimental operation, XiaoJuan Wang and ZhengXu Jin, methodology, DeKui Zhang and XiaoJuan Wang, software, Yi Li and XiaoJuan Wang, formal analysis, XiaoLi Li and XiaoJuan Wang, resources, BinXiong and XiaoJuan Wang, writing—original draft preparation, XueNi Ma and XiaoJuan Wang, writing—review and editing, DeKui Zhang and XiaoJuan Wang, supervision, DeKui Zhang and Yi Li. All authors have read and agreed to the published version of the manuscript.

Institutional Review Board Statement: The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Ethics Committee of Lanzhou University Second Hospital and conformed to the Chinese National Institute of Health Guide for the Care and Use of Laboratory Animals (NO. 2019-105).

Ethics Approval:

All applicable international, national, and institutional guidelines for the care and use of animals were followed in this study.

Consent for Publication:

All authors agree to publish.

Availability of Data and Material:

All data and material included in the present study are available.

Conflict of Interest:

The authors declare that there is no conflict of interest.

Funding:

Not Applicable.

Author Contributions:

Experimental operation, XiaoJuan Wang and ZhengXu Jin, methodology, DeKui Zhang and XiaoJuan Wang, software, Yi Li and XiaoJuan Wang, formal analysis, XiaoLi Li and XiaoJuan Wang, resources, BinXiong and XiaoJuan Wang, writing—original draft preparation, XueNi Ma and XiaoJuan Wang, writing—review and editing, DeKui Zhang and XiaoJuan Wang, supervision, DeKui Zhang and Yi Li. All authors have read and agreed to the published version of the manuscript.

Acknowledge:

The authors thank the technical and scientific advice of TiYun Han (Second Clinical Medical College of Lanzhou University).

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No competing interests reported.

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Dihydromyricetin Attenuates Colitis in Mice induced by DSS via Improving Intestinal Barrier Function

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