楊靖亞，楊蘭珠，郭若暉，李 靜，武萬強(qiáng)

天然產(chǎn)物治療炎癥性腸病的研究進(jìn)展

楊靖亞，楊蘭珠，郭若暉，李 靜，武萬強(qiáng)

(上海海洋大學(xué)食品學(xué)院，上海 201306)

炎癥性腸病是一組慢性胃腸道炎癥性疾病，臨床表現(xiàn)為腹脹、腹瀉、腹痛，有時(shí)甚至出現(xiàn)血便。目前用于治療炎癥性腸病的藥物有氨基水楊酸、糖皮質(zhì)激素和免疫抑制劑等。這些藥物可以減輕或延緩炎癥性腸病的發(fā)生和發(fā)展，但在長期使用后，一些患者可能會(huì)出現(xiàn)某種程度的毒副作用。近年來研究發(fā)現(xiàn)許多天然產(chǎn)物具有明顯的抗炎作用，它們可以降低炎癥性腸病的復(fù)發(fā)率，提高治療安全性。系統(tǒng)綜述了來自幾種植物、動(dòng)物和微生物天然產(chǎn)物的抗炎活性。

天然產(chǎn)物；補(bǔ)充或替代藥物；炎癥性腸??；克羅恩??；潰瘍性結(jié)腸炎

根據(jù)炎癥部位和臨床癥狀的不同，炎癥性腸病(inflammatory bowel disease, IBD)可分為潰瘍性結(jié)腸炎(ulcerative colitis, UC)和克羅恩病(Crohn’s disease, CD)。研究表明用于治療IBD的傳統(tǒng)藥物在某些患者體內(nèi)產(chǎn)生副作用[1]。天然產(chǎn)物富含多種活性成分并且療效溫和，因此可作為傳統(tǒng)藥物的替代品。針對(duì)主要對(duì)幾種具有代表性的天然產(chǎn)物及其抗炎作用進(jìn)行綜述，以期為今后IBD的臨床治療提供參考。

1 植物天然產(chǎn)物

1.1 黃芩

研究發(fā)現(xiàn)黃芩中含有100多種黃酮類化合物，其中根部特有的4’-脫氧黃酮類化合物(4’-deoxyflavones)具有重要的藥理活性，如黃芩苷、黃芩素、漢黃芩苷和漢黃芩素等[2]。黃芩作為一種藥用植物，在抗腫瘤、抗菌、抗氧化、抗炎和神經(jīng)保護(hù)等方面均發(fā)揮重要的作用[3]。Zhu等[4]在活體實(shí)驗(yàn)中發(fā)現(xiàn)黃芩苷對(duì)葡聚糖硫酸鈉(dextran sulfate sodium, DSS)誘導(dǎo)的小鼠結(jié)腸炎有保護(hù)作用，黃芩苷治療組的疾病活動(dòng)指數(shù)(disease activity index, DAI)評(píng)分顯著低于DSS模型組(< 0.001)。此外，黃芩苷(50 μmol·L-1)能抑制脂多糖誘導(dǎo)的M1巨噬細(xì)胞極化，促進(jìn)M2巨噬細(xì)胞極化，降低腫瘤壞死因子-α(TNF-α)、白細(xì)胞介素-23(IL-23)和干擾素調(diào)節(jié)因子5(IRF5)的表達(dá)，增加IL-10、精氨酸酶-1(Arg-1)和IRF4的表達(dá)。在DSS誘導(dǎo)前后連續(xù)7 d內(nèi)給小鼠灌胃黃芩素(10 mg·kg-1或25 mg·kg-1)，可抑制環(huán)氧合酶-2(COX-2)、誘導(dǎo)型一氧化氮合酶(iNOS)和細(xì)胞周期蛋白D1的表達(dá)，并且黃芩素能通過抑制轉(zhuǎn)錄因子核因子κB (NF-κB)的磷酸化和轉(zhuǎn)錄激活物(STAT3)與DNA結(jié)合來抑制STAT信號(hào)轉(zhuǎn)導(dǎo)和NF-κB信號(hào)通路[5]。值得注意的是，黃芩素與黃芩苷聯(lián)合使用效果優(yōu)于單獨(dú)使用，且黃芩苷對(duì)腸道的保護(hù)作用強(qiáng)于黃芩素[6]。這些研究結(jié)果提示黃芩可能是治療IBD的有效藥物。然而，研究發(fā)現(xiàn)雌性小鼠使用大劑量漢黃芩素會(huì)導(dǎo)致胎兒染色體嚴(yán)重畸變，并且孕鼠體重顯著增加[7]。因此，黃芩在IBD患者中的應(yīng)用范圍和局限性有待進(jìn)一步研究。

1.2 白芍

白芍含有200多種化學(xué)成分，包括單萜苷、黃酮、單寧、三萜類、甾體類和丹皮酚[8]。其中，單萜苷主要包括芍藥苷、芍藥內(nèi)酯苷、羥基芍藥苷、苯甲酰芍藥苷和苯甲酰羥基芍藥苷，統(tǒng)稱為白芍總苷[9]。現(xiàn)代藥理學(xué)研究表明這些化學(xué)成分具有廣泛的藥理活性，包括抗炎、抗氧化、抗癌和治療自身免疫性疾病[10]。其抗炎活性在已發(fā)表的白芍藥理學(xué)研究中受到廣泛關(guān)注。

最近，Li等[11]發(fā)現(xiàn)芍藥苷(paeoniflorin, PF)在DSS誘導(dǎo)的小鼠結(jié)腸炎模型中不僅能通過抑制NF-κB信號(hào)通路抑制促炎細(xì)胞因子的產(chǎn)生，還能抑制嗜酸性粒細(xì)胞浸潤。PF治療組(DSS+PF, 20 mg·kg-1)和陽性對(duì)照組(DSS+柳氮磺胺吡啶, 20 mg·kg-1)小鼠體重下降和結(jié)腸長度縮短均明顯小于模型組(DSS誘導(dǎo))。模型組小鼠結(jié)腸長度為(4.56 ± 0.63) cm，PF組和陽性對(duì)照組小鼠結(jié)腸長度分別為(6.40 ± 0.57) cm和(6.22 ± 0.44) cm。這些結(jié)果表明PF治療能顯著改善UC小鼠的炎癥癥狀。同樣，Cao等[12]研究發(fā)現(xiàn)白芍總苷能夠通過抑制Lyn/Snail信號(hào)通路來恢復(fù)結(jié)腸炎小鼠的腸道屏障功能。具體表現(xiàn)為血清和結(jié)腸組織中促炎細(xì)胞因子水平顯著下降、腸通透性降低、腸上皮細(xì)胞緊密連接蛋白和粘附連接蛋白表達(dá)恢復(fù)。此外，Zong等[13]證明丹皮酚對(duì)2, 4, 6-三硝基苯磺酸(2, 4, 6-Trinitrobenzene sulfonic acid, TNBS)誘導(dǎo)的小鼠潰瘍性結(jié)腸炎有抑制作用，且療效呈劑量依賴關(guān)系。模型組小鼠體重減輕、結(jié)腸縮短、粘膜損傷，固有層和平滑肌大量中性粒細(xì)胞浸潤；丹皮酚治療組小鼠結(jié)腸上皮逐漸恢復(fù)，炎性細(xì)胞浸潤減少。作者認(rèn)為丹皮酚能夠通過調(diào)節(jié)Treg/Th17細(xì)胞平衡，抑制促炎細(xì)胞因子表達(dá)和增加抗炎細(xì)胞因子的表達(dá)來抑制結(jié)腸炎。盡管上述這些體內(nèi)實(shí)驗(yàn)結(jié)果說明白芍在結(jié)腸炎中具有治療效果，但它是否對(duì)人類具有治療益處仍有待研究。

表1 其他具有代表性的植物天然產(chǎn)物在IBD中的作用機(jī)制

1.3 雷公藤

雷公藤具有良好的免疫調(diào)節(jié)作用，多年來一直被用于治療自身免疫性疾病，如類風(fēng)濕性關(guān)節(jié)炎和系統(tǒng)性紅斑狼瘡[14-15]。此外，它還具有很強(qiáng)的抗炎、抗腫瘤、神經(jīng)保護(hù)作用和胰島素抵抗特性[16-17]。研究表明雷公藤總苷可通過下調(diào)腸黏膜促炎細(xì)胞因子IL-6、TNF-α、IFN-γ和IL-17A的表達(dá)，調(diào)節(jié)Th17/Treg細(xì)胞平衡，從而減輕TNBS誘導(dǎo)的大鼠結(jié)腸炎[18]。Th17細(xì)胞分泌多種促炎細(xì)胞因子，如IL-17、IL-21和IL-22[19]；相反，Treg細(xì)胞釋放抗炎細(xì)胞因子，如IL-10和TGF-β[20]。因此，調(diào)節(jié)Treg和Th17細(xì)胞的比例直接影響促炎和抗炎細(xì)胞因子的水平，從而控制炎癥反應(yīng)。Yu 等[21]研究表明雷公藤甲素可抑制IL-10?/?小鼠結(jié)腸和CD患者體外培養(yǎng)細(xì)胞mRNA的表達(dá)。MyD88是炎癥通路的一個(gè)中心節(jié)點(diǎn)，它通過同型蛋白相互作用將IL-1受體(IL-1R)或Toll樣受體(TLR)家族成員與IL-1R相關(guān)激酶(IRAK)家族成員連接起來[22]。炎癥反應(yīng)與TLR4/MyD88/NF-κB信號(hào)通路密切相關(guān)[23]，因此，雷公藤甲素可能通過抑制TLRs/NF-κB信號(hào)通路來改善結(jié)腸炎。雖然這些研究表明雷公藤有助于改善腸道炎癥，但有研究表明雷公藤總苷對(duì)肝、腎、心、脾等器官有毒性作用[24]。因此，如何安全使用雷公藤是今后亟待解決的問題。

1.4 其他植物

其他植物活性成分也有可能減輕腸道炎癥。表1簡要說明了其他植物天然產(chǎn)物發(fā)揮抗炎作用的機(jī)制。

2 動(dòng)物天然產(chǎn)物

2.1 蜂膠

蜂膠含有多種化學(xué)成分，如酚酸、黃酮、酯類、二萜、倍半萜、木質(zhì)素、芳香醛和氨基酸等[33]。然而，不同產(chǎn)地的蜂膠在成分上可能存在較大差異。中國蜂膠主要成分是咖啡酸苯乙酯，而巴西綠蜂膠含有豐富的蒿素C (artepillin C)[34]。在過去的幾十年里，蜂膠的藥理作用在抗菌、抗炎等領(lǐng)域引起了人們的廣泛關(guān)注[35]。

20世紀(jì)70年代，Dan?等[36]首次證明了蜂膠對(duì)UC有治療效果。自此各種驗(yàn)證蜂膠對(duì)治療IBD是否有效的模型被建立。一項(xiàng)研究表明，與對(duì)照組(3%DSS)相比，0.3%蜂膠可顯著降低結(jié)腸炎大鼠結(jié)腸DAI評(píng)分(< 0.001或< 0.01)，增加結(jié)腸長度(< 0.05)，改善結(jié)腸組織損傷[37]。這項(xiàng)研究顯示蜂膠雖然不能改變大鼠消化道中短鏈脂肪酸(SCFAs)的含量，但能改善腸道微生物區(qū)系，特別是顯著增加變形桿菌()和酸桿菌門()的數(shù)量。Mariano等[38]報(bào)道稱巴西綠蜂膠水醇提取物(300 mg·kg-1)可顯著減輕DSS誘導(dǎo)的小鼠結(jié)腸粘膜損傷，提高超氧化物歧化酶(superoxide dismutase, SOD)和谷胱甘肽(glutathione, GSH)的水平，但對(duì)MPO活性無明顯影響。同樣，Wang等[34]發(fā)現(xiàn)中國蜂膠和巴西蜂膠均能顯著降低結(jié)腸炎小鼠體內(nèi)丙二醛的水平，提高小鼠的總抗氧化能力(total antioxidant capacity, T-AOC)，減少擬桿菌屬()的數(shù)量以及IL-1β、IL-6和單核細(xì)胞趨化蛋白的表達(dá)，但只有巴西蜂膠能誘導(dǎo)TGF-β的表達(dá)，且只有中國蜂膠能增加腸道菌群的多樣性和豐富度?？傊@些結(jié)果表明蜂膠具有抗炎和抗氧化的特性，可以作為一種潛在的新型療法來改善結(jié)腸炎。

2.2 魚油和磷蝦油

魚油和磷蝦油中富含包括二十二碳六烯酸(docosahexaenoic acid, DHA)和二十碳五烯酸(eicosapentaenoic acid, EPA)在內(nèi)的-3多不飽和脂肪酸(-3 polyunsaturated fatty acids,-3 PUFAs)[39-40]。此外磷蝦油還含有豐富的蝦青素，這是一種天然的抗氧化劑[41]。因此，魚油和磷蝦油可通過它們的抗炎和抗氧化特性來治療炎癥。

在DSS誘導(dǎo)的實(shí)驗(yàn)性結(jié)腸炎模型中，Sharma等[42]發(fā)現(xiàn)魚油(含有180 mg EPA和120 mg DHA)可以減輕小鼠的炎癥癥狀，包括腹瀉、體重減輕和結(jié)腸縮短。與對(duì)照組相比，魚油可下調(diào)TNF-α和COX-2的表達(dá)，維持腸道完整性。一項(xiàng)研究發(fā)現(xiàn)磷蝦油能恢復(fù)豬鞭毛蟲()引起的腸道微生物失調(diào)，顯著提高厚壁菌門和擬桿菌門的比例(, F/B)。低F/B值與腸道菌群失調(diào)密切相關(guān)，F(xiàn)/B值恢復(fù)正常被認(rèn)為是腸道菌群失衡恢復(fù)的關(guān)鍵指標(biāo)[43]。在Sakai等[44]的研究中，蝦青素顯著抑制DSS誘導(dǎo)的結(jié)腸炎小鼠腸粘膜中促炎細(xì)胞因子mRNA的表達(dá)，抑制MAPKs和NF-κB信號(hào)通路的活化。雖然體內(nèi)和體外研究已經(jīng)證明-3 PUFAs在實(shí)驗(yàn)性IBD模型中具有潛在的抗炎活性，但從臨床研究中獲得的數(shù)據(jù)并不是那么明確。Ajabnoor等[40]系統(tǒng)地研究了-3、-6和總多不飽和脂肪酸對(duì)IBD和炎癥標(biāo)志物的長期影響。83項(xiàng)隨機(jī)對(duì)照試驗(yàn)(41 751名參與者)的結(jié)果表明-6和總多不飽和脂肪酸對(duì)IBD的影響有限，而-3 PUFAs對(duì)IBD產(chǎn)生的影響也是相互矛盾的。因此-3 PUFAs是否對(duì)腸道炎癥有效仍有待研究。

3 微生物天然產(chǎn)物

3.1 蕈菌

根據(jù)蕈菌的用途可分為食用菌和藥用菌，如蘑菇、木耳、靈芝、桑黃等[45]。多糖是蕈菌的主要活性成分，主要是指與植物多糖不同的β-D-葡聚糖[46]。Hao等[47]研究表明金針菇多糖可以通過調(diào)節(jié)腸道菌群和代謝過程改善C57BL/6小鼠的腸道健康。16S rRNA基因序列分析顯示金針菇多糖可提高腸道中F/B值。研究表明靈芝多糖能夠改善DSS誘導(dǎo)的小鼠結(jié)腸炎，增加SCFAs的生成和結(jié)腸長度，顯著抑制抗炎細(xì)胞因子TNF-α、IL-1β、IL-6和IL-17A的分泌，影響Th17細(xì)胞、B細(xì)胞、NK細(xì)胞和NKT細(xì)胞的數(shù)量，減少小腸和盲腸中等病原菌的數(shù)量[48-49]。此外，在脂多糖誘導(dǎo)的炎性細(xì)胞模型中，桑黃多糖顯著降低促炎細(xì)胞因子的表達(dá)，抑制MAPK信號(hào)通路和NF-κB的轉(zhuǎn)位[50]?？傊?，這些研究表明蘑菇多糖可以被認(rèn)為是促進(jìn)腸道健康的有效成分。

3.2 益生菌

最常見的益生菌包括乳酸桿菌、雙歧桿菌、唾液鏈球菌、大腸桿菌Nissle 1917和布拉氏酵母菌[51]。最近研究發(fā)現(xiàn)clusters IV、、、、和與益生菌具有相似的功效，這些菌株被描述為新一代益生菌[52]。腸道菌群失衡是腸道炎癥的典型癥狀之一，而益生菌在一定程度上能夠調(diào)節(jié)腸道菌群紊亂。Javed等[53]觀察到嬰兒雙歧桿菌(, BI)可能對(duì)TNBS誘導(dǎo)的小鼠結(jié)腸炎具有保護(hù)作用。與對(duì)照組相比，在BI喂養(yǎng)的小鼠體內(nèi)觀察到肌層、粘膜下層和固有層中的炎性細(xì)胞浸潤以及杯狀細(xì)胞損傷減少。一些研究發(fā)現(xiàn)布拉酵母菌()可顯著降低大鼠體內(nèi)促炎細(xì)胞因子IL-1β的數(shù)量，改善負(fù)責(zé)維持上皮完整性和屏障功能的蛋白質(zhì)表達(dá)水平[54]。開菲爾是一種含有多種益生菌的發(fā)酵乳制品，其中乳酸桿菌是開菲爾中的優(yōu)勢菌群[55]。一項(xiàng)研究發(fā)現(xiàn)開菲爾中含有6種不同的乳酸桿菌，定期使用開菲爾可以對(duì)CD患者的生化指標(biāo)產(chǎn)生積極的影響[55]。在一項(xiàng)包括UC和CD患者在內(nèi)的短期、雙盲、隨機(jī)和安慰劑對(duì)照臨床試驗(yàn)中，益生菌已被證明能有效地減輕UC患者的腸道炎癥，而對(duì)CD患者無效[56]。因此，還需要進(jìn)一步的研究來確定益生菌對(duì)腸道炎癥的療效。

4 總結(jié)與展望

近年來，隨著傳統(tǒng)藥物不良反應(yīng)的逐漸顯現(xiàn)，迫切需要新的更安全的方法來治療IBD?，F(xiàn)有的研究表明，天然產(chǎn)物在預(yù)防和治療IBD方面發(fā)揮著至關(guān)重要的作用。本文揭示了幾種具有代表性的天然產(chǎn)物治療IBD的潛在藥用價(jià)值。我們發(fā)現(xiàn)這些天然產(chǎn)物治療IBD的作用機(jī)制與修復(fù)腸道屏障、調(diào)節(jié)腸道菌群及其代謝產(chǎn)物或調(diào)節(jié)免疫應(yīng)答有關(guān)，并且在各種體內(nèi)和體外研究中均顯示出良好的效果。

目前對(duì)天然產(chǎn)物治療腸道炎癥的研究主要集中在藥用植物和藥食兩用植物上，這與植物資源分布廣、種類多、可再生等特點(diǎn)有關(guān)。此外，大部分植物的藥理作用均在典籍中有記載，因此更具有研究價(jià)值和理論依據(jù)。然而，目前對(duì)非植物來源的天然產(chǎn)物治療腸道炎癥的研究還不夠深入，研究種類不夠豐富，只有少數(shù)幾種，如蜂膠、魚油、益生菌等，并且療效不夠顯著。因此，還需要進(jìn)一步的研究來證明其他來源的天然產(chǎn)物治療IBD的有效性。

盡管研究表明天然產(chǎn)物在治療IBD方面有很大的潛力，但大部分實(shí)驗(yàn)都是在體外和小鼠模型上研究同一化合物在不同劑量下的治療效果。目前還沒有明確的臨床試驗(yàn)來闡明它們治療IBD的可行性，因此我們還需要更多的數(shù)據(jù)來確定它們的安全性和最佳劑量。此外，未來應(yīng)更加關(guān)注新的未經(jīng)測試的天然產(chǎn)物，從而為IBD的臨床藥物治療提供更好的指導(dǎo)，并為其他炎癥性疾病提供新的治療策略。

[1] CROUWEL F, BUITER H J C, DE BOER N K. Gut microbiota-driven drug metabolism in inflammatory bowel disease[J]. J Crohns Colitis, 2020, 15(2): 307-315.

[2] SHEN J, LI P, LIU S S, et al. Traditional uses, ten-years research progress on phytochemistry and pharmacology, and clinical studies of the genus[J]. J Ethnopharmacol, 2021, 265: 113198.

[3] WANG Z L, WANG S, KUANG Y, et al. A comprehensive review on phytochemistry, pharmacology, and flavonoid biosynthesis of[J]. Pharm Biol, 2018, 56(1): 465-484.

[4] ZHU W, JIN Z S, YU J B, et al. Baicalin ameliorates experimental inflammatory bowel disease through polarization of macrophages to an M2 phenotype[J]. Int Immunopharmacol, 2016, 35:119-126.

[5] ZHONG X C, SURH Y J, DO S G, et al. Baicalein inhibits dextran sulfate sodium-induced mouse colitis[J]. J Cancer Prev, 2019, 24(2): 129-138.

[6] LIANG S, DENG X, LEI L, et al. The comparative study of the therapeutic effects and mechanism of baicalin, baicalein, and their combination on ulcerative colitis rat[J]. Front Pharmacol, 2019,10:1466.

[7] ZHAO L, CHEN Z, ZHAO Q, et al. Developmental toxicity and genotoxicity studies of wogonin[J]. Regul Toxicol Pharmacol, 2011, 60(2): 212-217.

[8] TONG N N, ZHOU X Y, PENG L P, et al. A comprehensive study of three species ofstem and leaf phytochemicals, and their antioxidant activities[J]. J Ethnopharmacol, 2021, 273: 113985.

[9] TAN Y Q, CHEN H W, LI J, et al. Efficacy, chemical constituents, and pharmacological actions ofrubra andalba[J]. Front Pharmacol, 2020,11: 1054.

[10] LI P, SHEN J, WANG Z Q, et al. Genus: a comprehensive review on traditional uses, phytochemistry, pharmacological activities, clinical application, and toxicology[J]. J Ethnopharmacol, 2021, 269:113708.

[11] LI J J, REN S Y, LI M, et al. Paeoniflorin protects against dextran sulfate sodium (DSS)-induced colitis in mice through inhibition of inflammation and eosinophil infiltration[J]. Int Immunopharmacol, 2021, 97: 107667.

[12] CAO X Y, NI J H, WANG X, et al. Total glucosides of paeony restores intestinal barrier function through inhibiting Lyn/Snail signaling pathway in colitis mice[J]. Phytomedicine, 2021, 87: 153590.

[13] ZONG S Y, PU Y Q, XU B L, et al. Study on the physicochemical properties and anti-inflammatory effects of paeonol in rats with TNBS-induced ulcerative colitis[J]. Int Immunopharmacol, 2017, 42:32-38.

[14] LUO D, ZUO Z Y, ZHAO H Y, et al. Immunoregulatory effects ofHook F and its extracts in clinical practice[J]. Front Med, 2019,13(5): 556-563.

[15] SONG X Q, ZHANG Y, DAI E Q. Therapeutic targets of thunder God vine (hook) in rheumatoid arthritis (Review)[J]. Mol Med Rep, 2020, 21(6): 2303-2310.

[16] LV H W, JIANG L P, ZHU M D, et al. The genus: a phytochemistry and pharmacological review[J]. Fitoterapia, 2019, 137:104190.

[17] GAO J, ZHANG Y F, LIU X H, et al. Triptolide: pharmacological spectrum, biosynthesis, chemical synthesis and derivatives[J]. Theranostics, 2021, 11(15): 7199-7221.

[18] ZHANG C, JU J Y, WU X H, et al.polyglycoside ameliorated TNBS-induced colitis in rats via regulating Th17/treg balance in intestinal mucosa[J]. J Inflamm Res, 2021,14: 1243-1255.

[19] ZHANG Y Z, LI Y Y. Inflammatory bowel disease: pathogenesis[J]. World J Gastroenterol, 2014, 20(1):91-99.

[20] MA L L, LING Y, FANG M Y, et al. The cytokines (IFN-γ, IL-2, IL-4, IL-10, IL-17) and Treg cytokine (TGF-β1) levels in adults with immune thrombocytopenia[J]. Pharmazie, 2014, 69(9): 694-697.

[21] YU C, SHAN T, FENG A W, et al. Triptolide ameliorates Crohn's colitis is associated with inhibition of TLRs/NF- κB signaling pathway[J]. Fitoterapia, 2011, 82(4): 709-715.

[22] DEGUINE J, BARTON G M. MyD88: a central player in innate immune signaling[J]. F1000Prime Rep, 2014, 6: 97.

[23] XIAO Z, KONG B, YANG H J, et al. Key player in cardiac hypertrophy, emphasizing the role of toll-like receptor 4[J]. Front Cardiovasc Med, 2020, 7: 579036.

[24] XI C, PENG S J, WU Z P, et al. Toxicity of triptolide and the molecular mechanisms involved[J]. Biomed Pharmacother, 2017, 90: 531-541.

[25] LI H B, CHEN X H, LIU J Y, et al. Ethanol extract ofalleviated dextran sulfate sodium-induced colitis: restoration on mucosa barrier and gut microbiota homeostasis[J]. J Ethnopharmacol, 2021, 267:113445.

[26] DE VLVARES GOULART R, BARBALHO S M, LIMA V M, et al. Effects of the use of curcumin on ulcerative colitis and Crohn's disease: a systematic review[J]. J Med Food, 2021, 24(7): 675-685.

[27] GAO Z F, YU C C, LIANG H Y, et al. Andrographolide derivative CX-10 ameliorates dextran sulphate sodium-induced ulcerative colitis in mice: involvement of NF-κB and MAPK signalling pathways[J]. Int Immunopharmacol, 2018, 57: 82-90.

[28] KIM S E, KAWAGUCHI K, HAYASHI H, et al. Remission effects of dietary soybean isoflavones on DSS-induced murine colitis and an LPS-activated macrophage cell line[J]. Nutrients, 2019, 11(8): 1746.

[29] LIU C, WANG J N, YANG Y, et al. Ginsenoside rd ameliorates colitis by inducing p62-driven mitophagy-mediated NLRP3 inflammasome inactivation in mice[J]. Biochem Pharmacol, 2018,155: 366-379.

[30] LI L, WAN G W, HAN B, et al. Echinacoside alleviated LPS-induced cell apoptosis and inflammation in rat intestine epithelial cells by inhibiting the mTOR/STAT3 pathway[J]. Biomed Pharmacother, 2018, 104: 622-628.

[31] QU C, YUAN Z W, YU X T, et al. Patchouli alcohol ameliorates dextran sodium sulfate-induced experimental colitis and suppresses tryptophan catabolism[J]. Pharmacol Res, 2017,121:70-82.

[32] JIA Y Q, YUAN Z W, ZHANG X S, et al. Total alkaloids ofL. ameliorated murine colitis by regulating bile acid metabolism and gut microbiota[J]. J Ethnopharmacol, 2020, 255: 112775.

[33] BRAAKHUIS A. Evidence on the health benefits of supplemental[J]. Nutrients, 2019, 11(11): 2705.

[34] WANG K, JIN X L, LI Q Q, et al.from different geographic origins decreases intestinal inflammation andspp. populations in a model of DSS-induced colitis[J]. Mol Nutr Food Res, 2018, 62(17): e1800080.

[35] SANTOS L M, FONSECA M S, SOKOLONSKI A R, et al.: types, composition, biological activities, and veterinary product patent prospecting[J]. J Sci Food Agric, 2020, 100(4): 1369-1382.

[36] DAN? P, M?LLER E H, JARNUM S. Effect of the natural producton ulcerative colitis and Crohn's disease[J]. Ugeskr Laeger,1979,141(28):1888-1890.

[37] WANG K, JIN X L, YOU M M, et al. Dietaryamelioratesdextran sulfate sodium-induced colitis and modulates the gut microbiota in rats fed a western diet[J]. Nutrients, 2017, 9(8): 875.

[38] MARIANO L N B, ARRUDA C, SOMENSI L B, et al. Brazilian greenhydroalcoholic extract reduces colon damages caused by dextran sulfate sodium-induced colitis in mice[J]. Inflammopharmacol, 2018, 26(5): 1283-1292.

[39] MARTON L T, GOULART R A, CARVALHO A, et al.fatty acids and inflammatory bowel diseases: an overview[J]. Int J Mol Sci, 2019, 20(19): 4851.

[40] AJABNOOR S M, THORPE G, ABDELHAMID A, et al. Long-term effects of increasing omega-3, omega-6 and total polyunsaturated fats on inflammatory bowel disease and markers of inflammation: a systematic review and meta-analysis of randomized controlled trials[J]. Eur J Nutr, 2021, 60(5): 2293-2316.

[41] LIU F, SMITH A D, SOLANO-AGUILAR G, et al. Mechanistic insights into the attenuation of intestinal inflammation and modulation of the gut microbiome by krill oil usingandmodels[J]. Microbiome, 2020, 8(1): 83.

[42] SHARMA M, KAUR R, KAUSHIK K, et al. Redox modulatory protective effects of ω-3 fatty acids rich fish oil against experimental colitis[J]. Toxicol Mech Methods, 2019, 29(4): 244-254.

[43] LEE W T, TUNG Y T, WU C C, et al. Camellia oil (Abel.) modifies the composition of gut microbiota and alleviates acetic acid-induced colitis in rats[J]. J Agric Food Chem, 2018, 66(28): 7384-7392.

[44] SAKAI S, NISHIDA A, OHNO M, et al. Astaxanthin, a xanthophyll carotenoid, prevents development of dextran sulphate sodium-induced murine colitis[J]. J Clin Biochem Nutr, 2019, 64(1): 66-72.

[45] GONG P, WANG S Y, LIU M, et al. Extraction methods, chemical characterizations and biological activities of mushroom polysaccharides: a mini-review[J]. Carbohydr Res, 2020, 494:108037.

[46] SCHWARTZ B, HADAR Y. Possible mechanisms of action of mushroom-derived glucans on inflammatory bowel disease and associated cancer[J]. Ann Transl Med, 2014, 2(2):19.

[47] HAO Y T, WANG X D, YUAN S J, et al.polysaccharide improves C57BL/6 mice gut health through regulation of intestine microbial metabolic activity[J]. Int J Biol Macromol, 2021, 167: 1308-1318.

[48] WEI B, ZHANG R, ZHAI J B, et al. Suppression of Th17 cell response in the alleviation of dextran sulfate sodium-induced colitis bypolysaccharides[J]. J Immunol Res, 2018, 2018: 2906494.

[49] XIE J, LIU Y, CHEN B, et al.polysaccharide improves rat DSS-induced colitis by altering cecal microbiota and gene expression of colonic epithelial cells[J]. Food Nutr Res, 2019, 63: 1559.

[50] HU T, LIN Q L, GUO T, et al. Polysaccharide isolated frommycelia exerts anti-inflammatory effects via MAPK and PPAR signaling pathways[J]. Carbohydr Polym, 2018, 200: 487-497.

[51] SARTOR R B. Probiotic therapy of intestinal inflammation and infections[J]. Curr Opin Gastroenterol, 2005, 21(1): 44-50.

[52] BASSO P J, C?MARA N O S, SALES-CAMPOS H. Microbial-based therapies in the treatment of inflammatory bowel disease-an overview of human studies[J]. Front Pharmacol, 2019, 9: 1571.

[53] JAVED N H, ALSAHLY M B, KHUBCHANDANI J. Oral feeding of probioticinfantis: colonic morphological changes in rat model of TNBS-induced colitis[J]. Scientifica, 2016, 2016: 9572596.

[54] RODRíGUEZ-NOGALES A, ALGIERI F, GARRIDO- MESA J, et al. Intestinal anti-inflammatory effect of the probioticin DSS-induced colitis in mice: impact on microRNAs expression and gut microbiota composition[J]. J Nutr Biochem, 2018, 61: 129-139.

[55] YILMAZ I, DOLAR M E, OZPINAR H, et al. Effect of administering kefir on the changes in fecal microbiota and symptoms of inflammatory bowel disease: a randomized controlled trial[J]. Turk J Gastroenterol, 2019, 30(3): 242-253.

[56] BJARNASON I, SISSION G, HAYEE B. A randomised, double-blind, placebo-controlled trial of a multi-strain probiotic in patients with asymptomatic ulcerative colitis and Crohn's disease[J]. Inflammopharmacol, 2019, 27(3): 465-473.

Advances of natural product for the treatment of inflammatory bowel disease

YANG Jingya, YANG Lanzhu, GUO Ruohui, LI Jing, WU Wanqiang

(College of Food Science and Technology, Shanghai Ocean University, Shanghai 201306)

Inflammatory bowel disease is a group of chronic gastrointestinal inflammatory disease, and its clinical manifestations are bloating, diarrhea, abdominal pain, and even occasionally bloody stools. Currently, many drugs are available for the treatment of inflammatory bowel disease, such as aminosalicylates, corticosteroids and immunosuppressants. These drugs can reduce or alleviate the occurrence and development of inflammatory bowel disease, but certain toxic side effects may develop in some patients after long-term use. In recent years, studies have found that many natural products have obvious anti-inflammatory effects, which can reduce the recurrence rate of inflammatory bowel disease and improve the safety of treatment. This article systematically summarized the anti-inflammatory properties of several natural products derived from plants, animals and microorganisms.

natural products; complementary or alternative medicine; inflammatory bowel disease; Crohn’s disease; ulcerative colitis

R282.7; R93

A

1672-352X (2022)05-0855-06

10.13610/j.cnki.1672-352x.20221111.010

2022-11-14 10:13:06

[URL] https://kns.cnki.net/kcms/detail/34.1162.S.20221111.1112.020.html

2022-01-13

國家自然科學(xué)基金青年項(xiàng)目（82103844）資助。

楊靖亞, 副教授。E-mail：jyyang@shou.edu.cn 楊蘭珠，碩士。E-mail：yanglanzhuy@163.com