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(上海海洋大學(xué)食品學(xué)院,上海 201306)

多糖、腸道微生物與免疫之間的相互影響

鄔軍文,張敏,姚昀,周雪非,劉克海*

(上海海洋大學(xué)食品學(xué)院,上海 201306)

多糖具有免疫活性,也可調(diào)節(jié)腸道微生物菌群,而腸道微生物對宿主的多糖代謝與免疫功能起到重要作用,同時(shí)機(jī)體免疫又對腸道微生物產(chǎn)生影響。本文綜述了多糖、腸道微生物與免疫之間相互影響的相關(guān)研究進(jìn)展,為探究多糖、腸道微生物、免疫三者之間的內(nèi)在關(guān)系及作用機(jī)理提供了參考。

多糖,腸道微生物,免疫,相互影響

多糖存在于動植物體內(nèi)和微生物中,由10個(gè)以上單糖通過糖苷鍵聚合而成[1]。研究表明多糖具有多種生物活性,如抗腫瘤、抗氧化、抗炎、免疫調(diào)節(jié)和免疫刺激[2-4]。其中,多糖在免疫中發(fā)揮重要作用,枸杞多糖激活巨噬細(xì)胞RAW264.7吞噬作用,促進(jìn)NO產(chǎn)生[5]。同時(shí),多糖作為益生元,可選擇性地刺激腸道有益微生物的生長和代謝,改善腸道微生物平衡從而有利于人體健康。

腸道微生物被稱為編碼分解膳食纖維、氨基酸、藥物和產(chǎn)生甲烷、維生素基因的“超級有機(jī)體”[6-8],其編碼基因估計(jì)是人體基因數(shù)目的150倍[9]。大量實(shí)驗(yàn)證實(shí),腸道微生物與宿主的代謝[10]、營養(yǎng)吸收、產(chǎn)生[11-13]以及免疫系統(tǒng)的發(fā)展、調(diào)節(jié)[14]密切相關(guān)。研究發(fā)現(xiàn),腸道微生物中的糖苷酶對代謝不能被消化吸收多糖所必需[15]。此外,人出生時(shí)胃腸道是無菌的,免疫系統(tǒng)幾乎沒有發(fā)育,但很快隨著種類繁多的細(xì)菌定植,免疫系統(tǒng)開始正常發(fā)育并逐步成熟[16]。因此,腸道微生物與多糖代謝,免疫密不可分。

免疫是機(jī)體免疫系統(tǒng)識別自身與異己物質(zhì),并通過免疫應(yīng)答排除抗原性異物,以維持機(jī)體生理平衡。免疫系統(tǒng)由免疫器官、組織、細(xì)胞、免疫效應(yīng)分子及有關(guān)基因等組成,具有抗御病原體的侵害、排除異物及癌細(xì)胞等致病因子、保護(hù)機(jī)體的作用。研究表明免疫系統(tǒng)在維持宿主-腸道微生物體內(nèi)平衡起到重要作用,同時(shí),腸道微生物也塑造機(jī)體免疫系統(tǒng)[17]。本文對多糖、腸道微生物與免疫之間的相互影響研究進(jìn)展進(jìn)行了綜述。

1 多糖對免疫的影響

1.1多糖對免疫器官的影響

多糖促進(jìn)動物胸腺、脾臟等免疫器官生長發(fā)育。Li等[18]研究發(fā)現(xiàn)靈芝多糖能夠提高環(huán)磷酰胺(CTX)介導(dǎo)免疫抑制小鼠胸腺、脾臟指數(shù),同時(shí)促進(jìn)T、B細(xì)胞存活,增加TNF-α、IL-2水平。Ma等[19]評價(jià)灰樹花多糖GFP-A免疫活性,發(fā)現(xiàn)一定濃度GFP-A治療后,CTX介導(dǎo)免疫低下小鼠的胸腺、脾臟指數(shù)提高,而且,其脾細(xì)胞中的TNF-α、IL-1β、IL-2和IL-6 mRNA水平也提高。

1.2多糖對巨噬細(xì)胞的影響

巨噬細(xì)胞是強(qiáng)大的吞噬細(xì)胞,幾乎存在于身體所有組織,在先天和適應(yīng)性免疫反應(yīng)中發(fā)揮關(guān)鍵作用[20]。身體受到病理性或損傷刺激時(shí),巨噬細(xì)胞分泌NO、ROS、TNF-α、IL-1β、IL-6等生物活性分子和細(xì)胞因子防御病原體入侵[21-22]。從青錢柳葉子提取的多糖CP經(jīng)乙?；揎椇蟮玫降亩嗵茿c-CP顯著促進(jìn)巨噬細(xì)胞增殖,其作用明顯強(qiáng)于未修飾的多糖CP;但是,與CP組相比,Ac-CP沒有顯著增強(qiáng)巨噬細(xì)胞產(chǎn)生NO活性;此外,在Ac-CP刺激下,巨噬細(xì)胞RAW264.7吞噬活性增強(qiáng),細(xì)胞因子TNF-α、IL-1β和IL-6水平升高[23]。ESPs-CP是從海洋棕藻分離純化的一種硫酸多糖,研究表明,ESPs-CP增強(qiáng)巨噬細(xì)胞RAW 264.7 TNF-α、TGF-β、IL-6、IL-1β和IL-10 mRNA表達(dá)[24]。Liu等[25]研究發(fā)現(xiàn)一種蘑菇多糖蛋白混合物激活鼠巨噬細(xì)胞RAW264.7,顯著增加NO產(chǎn)生,促進(jìn)IL-6、TNF-α等細(xì)胞因子分泌。研究還發(fā)現(xiàn)桔梗多糖增殖雞腹膜巨噬細(xì)胞,提高吞噬率,促進(jìn)NO產(chǎn)生和TNF-α、IL-1β和IL-6分泌,以及刺激該細(xì)胞的CD80、CD86表達(dá)[26]。而且,尚慶輝等[27]報(bào)道了植物多糖通過增大巨噬細(xì)胞體積、促進(jìn)巨噬細(xì)胞吞噬作用、調(diào)節(jié)巨噬細(xì)胞細(xì)胞因子分泌量和巨噬細(xì)胞酶活性發(fā)揮免疫作用。

1.3多糖對免疫細(xì)胞的影響

1.3.1 多糖對自然殺傷細(xì)胞的影響 自然殺傷細(xì)胞是先天免疫系統(tǒng)中的關(guān)鍵細(xì)胞,能夠直接殺滅腫瘤細(xì)胞和病原體感染的細(xì)胞[28-29]。Surayot等[30]研究發(fā)現(xiàn)刺松藻多糖SP-F2顯著增殖NK細(xì)胞,增加NK細(xì)胞對HeLa細(xì)胞的細(xì)胞毒性;另外,SP-F2處理后,NK細(xì)胞活化增強(qiáng),可能是由于NKp30的表達(dá)增強(qiáng),IFN-γ的分泌,裂解蛋白、穿孔素和粒酶B的釋放。來自植物和真菌的5種多糖通過增強(qiáng)IFN-γ和穿孔素分泌,增加NKp30表達(dá),顯著促進(jìn)NK細(xì)胞細(xì)胞毒性[31]。

1.3.2 多糖對淋巴細(xì)胞的影響 另外,淋巴細(xì)胞是機(jī)體主要的免疫細(xì)胞,其中T淋巴細(xì)胞主要參與細(xì)胞免疫應(yīng)答,B淋巴細(xì)胞主要參與體液免疫應(yīng)答。蔡琨等[32]采用環(huán)磷酰胺建立免疫低下小鼠模型,并連續(xù)灌胃仙茅多糖(COP)10 d,給藥劑量分別是400、200、100 mg/(kg·d)。結(jié)果表明,與正常小鼠相比,模型小鼠外周血CD4+T亞群數(shù)量、CD4+T/CD8+T比值下降顯著,COP處理后CD4+T亞群數(shù)量、CD4+T/CD8+T比值恢復(fù),200 mg/(kg·d)效果最佳。錢葉等[33]研究發(fā)現(xiàn),松乳菇多糖LDG-A劑量依賴性促進(jìn)T、B細(xì)胞增殖,同時(shí)LDG-A減少T、B細(xì)胞在G0/G1期細(xì)胞百分比,促進(jìn)細(xì)胞進(jìn)入G2/M期,促進(jìn)B細(xì)胞分泌抗體IgM、IgD 和IgE。

1.3.3 多糖對樹突狀細(xì)胞的影響 樹突狀細(xì)胞(DC)作為CD4+T細(xì)胞的專職抗原呈遞細(xì)胞,它們在誘導(dǎo)和調(diào)節(jié)有效免疫應(yīng)答抑制腫瘤細(xì)胞發(fā)揮重要作用,被認(rèn)為是癌癥免疫治療靶點(diǎn)[34]。Zhong等[35]研究低分子量牡蠣多糖對小鼠骨髓樹突狀細(xì)胞影響,結(jié)果表明,該多糖增加其表面MHC-II、CD40和CD86的表達(dá),并誘導(dǎo)TNF-α和IL-12分泌。Minato等[36]研究發(fā)現(xiàn)榆黃蘑多糖PCPS誘導(dǎo)DC細(xì)胞表面成熟標(biāo)志物CD80、CD86和HLA-DR表達(dá)的上調(diào),刺激DC細(xì)胞分泌促炎細(xì)胞因子TNF、IL-1β、IL-6、IL-12和抗炎細(xì)胞因子L-10,并增加趨化因子CCL2、CCL3、CCL8、CXCL9、CXCL10和LTA mRNA水平。

1.4多糖對補(bǔ)體系統(tǒng)的影響

補(bǔ)體系統(tǒng)是由超過30種蛋白質(zhì)組成,在自我防御和炎癥中發(fā)揮重要作用,并且包括經(jīng)典、替代、和凝集素三種激活途徑[37]。Zou等[38]研究發(fā)現(xiàn)五種純化的欖仁樹多糖都呈現(xiàn)出補(bǔ)體結(jié)合活性,但多糖之間活性顯示差異,可能是由于多糖單糖組成、糖苷鍵連接類型及相對分子量不同導(dǎo)致。另外,來自于接骨木果實(shí)和接骨木花的兩種果膠多糖都呈現(xiàn)補(bǔ)體結(jié)合活性[39-40]。研究表明當(dāng)歸多糖、茯苓多糖、圓錐繡球多糖、酸棗仁多糖等均可激活補(bǔ)體系統(tǒng)[41]。

2 多糖與腸道微生物的相互影響

2.1腸道微生物參與多糖代謝

由于人類基因組不能編碼足夠的碳水化合物活性酶,僅編碼少量消化寡糖和多糖的酶,而宏基因組研究發(fā)現(xiàn)腸道菌群呈現(xiàn)碳水化合物活性酶的多樣性,因此腸道菌群在代謝未消化多糖中起到關(guān)鍵作用[9,42]。擬桿菌門富含多條代謝碳水化合物的途徑,而厚壁菌門編碼相對更少降解多糖的酶[9]。Larsbrink等[43]研究報(bào)道腸道菌群按照PUL模式代謝木聚糖?？傊?腸道微生物將多糖降解為短鏈脂肪酸,主要是乙酸、丙酸和丁酸等,它們在維持上皮屏障功能,調(diào)節(jié)上皮增殖,調(diào)節(jié)免疫應(yīng)答和預(yù)防結(jié)腸直腸癌癥起著重要作用[44-46]。研究發(fā)現(xiàn)河蜆多糖CSPF-N不能完全被胃-腸道消化液降解,而能被腸道微生物降解成乙酸、丙酸和丁酸等[47];乙酸是合成膽固醇的重要底物,進(jìn)入肝臟參與脂代謝,也作為肌肉、心臟、大腦的主要能源[48-49]。丙酸可作為宿主細(xì)胞能源,還能抑制膽固醇合成,調(diào)節(jié)血糖和胰島素水平[50]。丁酸能被腸道上皮細(xì)胞吸收利用,還能調(diào)節(jié)上皮細(xì)胞和淋巴細(xì)胞生長及凋亡,調(diào)控腸道炎癥反應(yīng)和氧化應(yīng)激[51]。另一方面,代謝產(chǎn)生大量酸導(dǎo)致pH降低,低pH抑制腸道部分病原體生長,也可以改變結(jié)腸細(xì)胞代謝吸收[52]。

2.2多糖調(diào)節(jié)腸道微生物菌群

益生菌是定居于腸道內(nèi)對宿主有益的微生物[53]。多糖促進(jìn)人腸道內(nèi)益生菌增殖,提高腸道微生物多樣性[54-55]。張浩琪等[56]研究發(fā)現(xiàn)大蒜多糖顯著增殖健康雌性昆明小鼠腸道內(nèi)雙歧桿菌,而腸桿菌數(shù)量顯著下降,類桿菌數(shù)量變化不大。張圣方等[57]研究發(fā)現(xiàn)泰山蛹蟲草多糖極顯著增殖免疫環(huán)磷酰胺免疫抑制模型小鼠腸道雙歧桿菌、乳酸桿菌,而大腸桿菌、腸球菌數(shù)量均下降。香菇多糖L2降低成年小鼠盲腸和結(jié)腸部位菌群的豐富度、多樣性和均勻性,增加小鼠糞便菌群的豐富度,但降低糞便菌群的多樣性[58]。兩種筍多糖WBP-1、WBP-2顯著促進(jìn)青春雙岐桿菌和兩歧雙岐桿菌增殖[59]。Fatma Bouaziz等[60]從杏仁膠中提取多糖AGP和半纖維素AGH,通過青春雙歧桿菌,嗜酸乳桿菌體外發(fā)酵評估其益生元特性,結(jié)果表明,AGP和AGH都呈現(xiàn)良好益生元性質(zhì)。同時(shí),河蜆多糖CSPF-N改變腸道微生物結(jié)構(gòu),微生物結(jié)構(gòu)主要由厚壁菌門、變形菌門、放線菌門和擬菌門組成[47]。

3 腸道微生物與免疫的相互影響

3.1腸道微生物對免疫的影響

3.1.1 促進(jìn)腸內(nèi)外免疫功能的形成 腸道微生物菌群是免疫發(fā)育正常所需要,能夠促進(jìn)淋巴細(xì)胞發(fā)展和免疫功能形成,影響T細(xì)胞亞群組成[17]。研究表明無菌動物免疫系統(tǒng)發(fā)育不成熟,表現(xiàn)為淋巴濾泡不發(fā)育,分泌IgA能力下降,血漿、CD8+細(xì)胞數(shù)目減少等免疫缺陷[61]。無菌小鼠定植普通小鼠或人糞便菌群后,發(fā)展低下的免疫系統(tǒng)3周內(nèi)可以恢復(fù)正常[62]。Grnlund等[63]研究發(fā)現(xiàn)半歲以下健康新生兒腸道內(nèi)脆弱類桿菌和雙歧桿菌定植時(shí)間越早,外周血中IgA分泌細(xì)胞的含量就能更早被檢測到,且隨著腸內(nèi)脆弱類桿菌和雙歧桿菌數(shù)量增加,外周血中IgA分泌細(xì)胞數(shù)量也逐漸增加。吳娟娟等[64]建立“無菌雞”模型,結(jié)果發(fā)現(xiàn)飼喂乳酸菌或盲腸內(nèi)容物的仔雞空腸長度、脾臟指數(shù)高于無菌飼糧組,另外,它們十二指腸、空腸和回腸隱窩深度降低、絨毛高度/隱窩深度也增大,而盲腸長度和體積更低。該研究表明,腸道菌群促進(jìn)仔雞腸道發(fā)育,盲腸體積變小;同時(shí)促進(jìn)脾臟發(fā)育,提高免疫。

3.1.2 調(diào)節(jié)免疫系統(tǒng)免疫功能 人體腸道內(nèi)有益菌中雙歧桿菌數(shù)量最多,在維持腸道微生態(tài)平衡、刺激機(jī)體特異性和非特異性免疫發(fā)揮重要作用。雙歧桿菌刺激免疫細(xì)胞分泌IL-1、IL-6,促進(jìn)B淋巴細(xì)胞分化成熟與T淋巴細(xì)胞增殖,增強(qiáng)NK細(xì)胞殺傷能力[65]。范金波等[66]對健康SPF級BALB/c小鼠灌胃雙歧桿菌并測定各項(xiàng)免疫指標(biāo),結(jié)果表明雙歧桿菌能增強(qiáng)小鼠DTH反應(yīng),提高巨噬細(xì)胞吞噬活性,自然殺傷細(xì)胞活性,血清溶血素水平及小鼠脾淋巴細(xì)胞增殖率。同時(shí),一些雙歧桿菌屬的菌株呈現(xiàn)抗炎性質(zhì)[67-69],增加腸道IgA分泌[70],誘導(dǎo)樹突狀細(xì)胞成熟[71]。

另外,其它正常菌群也能調(diào)節(jié)機(jī)體免疫功能,如嗜酸乳桿菌誘導(dǎo)人類外周血單核細(xì)胞分泌TNF-α、IL-6和IL-10[72],促進(jìn)小鼠、人樹突細(xì)胞活化與成熟[73-74],誘導(dǎo)抗原刺激的T細(xì)胞凋亡[75]。徐基利等[76]研究也發(fā)現(xiàn)乳酸菌能提高肉仔雞血清IgG、IgA含量及外周血T淋巴細(xì)胞增殖反應(yīng)。

3.1.3 屏障作用 人體的非特異性免疫是機(jī)體免疫系統(tǒng)識別和排除各種異物的第一道屏障,越來越多研究表明腸道菌群在天然免疫中發(fā)揮重要作用[77]。與宿主相關(guān)微生物菌群干擾外來微生物的定居和建立,這種現(xiàn)象稱為細(xì)菌干擾或定殖抗性[78]。病原菌入侵首先要粘附在腸粘膜表面,腸上皮細(xì)胞黏液層能夠阻止病原菌的粘附,作為防御病原菌定植的一道屏障[79]。研究表明腸上皮細(xì)胞黏液層的發(fā)展依賴腸道菌群,與正常小鼠相比,無菌小鼠腸上皮細(xì)胞黏液層更薄。腸道菌群還與病原菌競爭營養(yǎng)物質(zhì)產(chǎn)生定植抗性[80],例如,在無菌小鼠中,共生大腸桿菌與腸出血性大腸桿菌競爭脯氨酸,抑制其在盲腸定植[81]。腸道菌群也可通過競爭碳水化合物,對檸檬酸桿菌的感染,腸致病性大腸桿菌、腸出血性大腸桿菌感染的模型小鼠產(chǎn)生定植抗性[82]。然而,競爭營養(yǎng)只是腸道共生菌群對病原菌產(chǎn)生定植抗性的一種機(jī)制,某些病原菌能夠逃脫這種機(jī)制[80]。某些致病性大腸桿菌利用共生大腸桿菌不能利用的糖[83]。另外,腸道菌群還分泌抗菌肽和毒素對病原菌起到抑制作用[78]。一些共生腸桿菌分泌的抗微生物肽特異性殺死病原菌[84-85],雙歧桿菌分泌的細(xì)菌素表現(xiàn)出窄或?qū)挼囊志钚宰V[86]。

3.1.4 免疫佐劑活性 甘萍等[87]研究發(fā)現(xiàn)來源于芽胞桿菌的表面活性素促進(jìn)抗原的呈遞、激活 MAPKs信號轉(zhuǎn)導(dǎo)通路和核轉(zhuǎn)錄因子NF-κB、誘導(dǎo)ROS的產(chǎn)生和促進(jìn)炎癥小體的形成。López等[88]研究發(fā)現(xiàn)暴露于雙歧桿菌LMG13195膜囊泡的DC細(xì)胞顯著促進(jìn)功能性CD25highFOXP3highCD127-/lowTreg細(xì)胞的分化,提高IL-10的水平。

3.2免疫系統(tǒng)對腸道微生物的影響

研究表明免疫系統(tǒng)在塑造腸道微生物菌群的組成起到關(guān)鍵作用[17]。在缺乏IgA的模型小鼠中觀察到小腸中分段絲狀細(xì)菌異常擴(kuò)張,而模型小鼠IgA恢復(fù)正常后,腸道微生物群體的組成也恢復(fù)正常[89]。Larsson等[90]研究發(fā)現(xiàn)缺失MYD88的小鼠小腸含有更多分段絲狀細(xì)菌,表明MyD88信號的缺失改變腸道微生物組成。羅蘭等[91]用香菇多糖治療腸道微生態(tài)失調(diào)模型小鼠結(jié)果表明,香菇多糖顯著增殖模型小鼠腸道雙歧桿菌、乳酸桿菌,而腸桿菌和腸球菌數(shù)量顯著降低;脾臟指數(shù)和淋巴細(xì)胞轉(zhuǎn)化率增加,而胸腺指數(shù)無變化;小鼠菌群失調(diào)得到調(diào)整可能由于其免疫的提高。另外,腸固有層分泌的SIgA對革蘭陰性桿菌具有特殊親和力,能包被細(xì)菌,抑制細(xì)菌與腸上皮細(xì)胞特異性結(jié)合,阻止細(xì)菌在腸上皮細(xì)胞粘附,從而避免細(xì)菌穿透腸上皮發(fā)生移位[92]。

4 結(jié)語

本文綜述了多糖、腸道微生物與免疫之間的相互影響,多糖提高免疫,其調(diào)節(jié)機(jī)制包括:多糖激活巨噬細(xì)胞信號通路、激活T/B淋巴細(xì)胞信號通路[27];Wu等[93]研究發(fā)現(xiàn)香菇多糖PSCPL通過介導(dǎo)MyD88依賴信號通路和MAPK信號通路抑制LPS刺激的THP-1細(xì)胞內(nèi)MyD88、TRAF-6、NF-κB的表達(dá),抑制JNK和p38的活化、磷酸化和細(xì)胞因子TNF-α、IL-1α、IL-1β和IL-4的產(chǎn)生。多糖也可調(diào)節(jié)腸道微生物菌群,而腸道微生物則參與多糖代謝,發(fā)酵宿主自身不能消化、分解的糖類。腸道微生物通過促進(jìn)腸內(nèi)外免疫功能的形成、調(diào)節(jié)免疫功能、屏障作用及免疫佐劑活性等途徑提高機(jī)體免疫，而機(jī)體免疫功能又可塑造腸道微生物的組成。然而,多糖、腸道微生物、免疫三者之間的內(nèi)在關(guān)聯(lián)尚無文獻(xiàn)報(bào)道。其一,多糖是否通過調(diào)節(jié)腸道微生物菌群,進(jìn)而提高機(jī)體免疫功能。宗方方等[94]曾報(bào)道腸道菌群能通過調(diào)節(jié)免疫反應(yīng)增強(qiáng)腫瘤治療效果。其二,是否多糖及多糖的代謝產(chǎn)物提高機(jī)體免疫功能,隨后機(jī)體免疫功能又對腸道微生物產(chǎn)生積極影響。其三,上述兩個(gè)問題是否同時(shí)存在？因此,三者內(nèi)在聯(lián)系有待進(jìn)一步研究和明確。隨著腸道微生物群落分析方法,如焦磷酸測序分析、基因芯片分析和宏基因組測序與生物信息分析等各種技術(shù)方法的出現(xiàn)和革新,可更清楚的研究腸道微生物群落組成及其功能。另外,研究表明人體中許多疾病與免疫密切相關(guān),如類風(fēng)濕性關(guān)節(jié)炎系統(tǒng)性紅斑狼瘡、脊柱關(guān)節(jié)炎,而腸道微生物也與這些疾病存在著千絲萬縷的關(guān)系[95]。系統(tǒng)探究多糖、腸道微生物、免疫三者之間的內(nèi)在關(guān)系及作用機(jī)理,而非只單純研究兩兩之間的相互作用,將是該領(lǐng)域未來的著力方向,也有助于人們更有效預(yù)防和治療免疫性疾病、腸道或腸道微生物相關(guān)性疾病。

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Interactionofpolysaccharides,gutmicrobiotaandimmunity

WUJun-wen,ZHANGMin,YAOYun,ZHOUXue-fei,LIUKe-hai*

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

Polysaccharides exhibite immune activity and regulate gut microbiota. Gut microbiota can play an important role in metabolism of polysaccharides and immune function of human hosts. At the same time,it is influenced by the immune. In this paper,the related progress in interaction of polysaccharides,gut microbiota and immunity was summarized,which provided guidelines to explore the intrinsic relationship and action mechanism among polysaccharides,gut microbiota and immunity.

polysaccharides;gut microbiota;immunity;interaction

2017-04-01

鄔軍文(1991-)，男，碩士研究生，研究方向：功能性食品的開發(fā)利用，E-mail:1479949240@qq.com。

*

劉克海(1977-)，男，博士研究生，副教授，研究方向：食品新工藝與新劑型，E-mail:khliu@shou.edu.cn。

上海市教育委員會重點(diǎn)學(xué)科建設(shè)項(xiàng)目(J50704)。

TS201.4

A

1002-0306(2017)22-0315-07

10.13386/j.issn1002-0306.2017.22.061