微生物代謝產物在腸-腦軸中作用機制研究進展

2021-08-18 21:54石媛嫄侯琳張麗曹奕
青島大學學報(醫學版) 2021年3期
關鍵詞:神經遞質產物宿主

石媛嫄 侯琳 張麗 曹奕

[摘要] 腸道微生物群具有豐富的生物轉化能力,從而使宿主能接觸到一系列具有生物活性的代謝產物。這些代謝產物參與了胃腸道和中樞神經系統之間的信號傳遞,并具有調節中樞神經系統生理和病理過程的潛力。這種雙向交流可以通過各種直接和間接機制發生,包括與宿主腦中的受體結合、刺激腸道中的迷走神經、改變中樞神經傳遞以及調節神經炎癥。本文綜述了短鏈脂肪酸、膽汁酸、神經遞質等微生物代謝產物在腸-腦軸中的作用機制,從調控腸道微生物的角度為相關神經系統疾病的治療提供新思路。

[關鍵詞] 微生物群;代謝;腸-腦軸;脂肪酸類;膽汁酸類和鹽類;神經遞質;綜述

[中圖分類號] R329.35

[文獻標志碼] A

[文章編號] 2096-5532(2021)03-0470-05

doi:10.11712/jms.2096-5532.2021.57.066

[開放科學(資源服務)標識碼(OSID)]

[網絡出版] https://kns.cnki.net/kcms/detail/37.1517.R.20210201.1055.005.html;2021-02-01 16:02:16

RESEARCH ADVANCES IN THE MECHANISM OF ACTION OF MICROBIAL METABOLITES IN THE GUT-BRAIN AXIS

SHI Yuanyuan, HOU Lin, ZHANG Li, CAO Yi

(Organization and Personnel Office, Medical Department of Qingdao University, Qingdao 266071, China)

[ABSTRACT]Intestinal microflora has rich biotransformation abilities, which enables the host to come into contact with a series of bioactive metabolites. Such metabolites participate in the signal transduction between the gastrointestinal tract and the central nervous system and have the potential to regulate the physiological and pathological processes of the central nervous system. Such two-way communication can take place through a variety of direct and indirect mechanisms, which include binding to receptors in the host brain, stimulating the vagus nerve in the intestinal tract, altering central neurotransmission, and regulating neuroinflammation. This article reviews the mechanism of action of microbial metabolites, including short-chain fatty acids, bile acids, and neurotransmitters, in the gut-brain axis, in order to provide new ideas for the treatment of nervous system diseases from the perspective of the regulation of intestinal microflora.

[KEY WORDS]microbiota; metabolism; gut-brain axis; fatty acids; bile acids and salts; neurotransmitters; review

人的腸道微生物群包含500~1 000種細菌,共有約 200萬個基因,超過了人類基因總量的100倍[1],其中許多基因編碼執行代謝功能并產生微生物專有代謝物的蛋白質。微生物群的這種作用擴大了宿主生物轉化的利用范圍,以及可以處理的化合物的多樣性。這種廣泛的代謝潛力使得微生物群與進入腸道的一系列底物相結合,產生了大量的代謝產物,其中許多代謝產物對宿主來說是重要的分子前體。腸-腦軸(GBA)是胃腸道和中樞神經系統(CNS)之間的雙向信號網絡。該軸有幾種不同的信號途徑,包括自主神經系統(ANS)、下丘腦垂體腎上腺軸(HPA軸)和免疫系統。微生物相關的代謝產物通過這些不同途徑發生作用,調節CNS的功能和行為。先前研究已經觀察到,在自閉癥譜系障礙(ASD)、焦慮和抑郁等一系列CNS疾病中,腸道微生物群落結構發生顯著變化[2]。雖然微生物變化和神經疾病之間的因果關系仍未完全闡明,但嚙齒類動物的研究表明,微生物群的變化可以改變精神心理和行為[3]。本文主要綜述短鏈脂肪酸(SCFA)、膽汁酸(BA)、神經遞質等微生物來源的生物活性分子在腸道到大腦信號傳導中的作用及機制。

1 SCFA

SCFA是盲腸和結腸中微生物對膳食中碳水化合物厭氧發酵產生的小分子有機酸,其可以通過各種機制影響CNS。乙酸、丙酸和丁酸是主要的SCFA,而異丁酸、戊酸和異戊酸的生成量較小。研究發現,高生活質量人群的糞便具有高豐度糞桿菌屬(Faecalibacterium)和糞球菌屬(Coprococcus),這兩個菌屬是革蘭陽性厭氧細菌,可以發酵膳食纖維產生SCFA[4]。相反,與非抑郁對照相比,重度抑郁障礙(MDD)病人的糞便、尿液和血漿中的SCFA含量較低[5]。研究證實,益生元誘導的SCFA增加可以改善小鼠的抑郁和焦慮行為,并且能減輕癡呆模型小鼠的認知損害[6-7]。SCFA也被證明在亨廷頓癥、阿爾茨海默病、帕金森病和卒中等神經退行性疾病和腦血管疾病中起著重要作用[8-9]。

SCFA可以通過與細胞表達的受體結合以及改變宿主基因表達來實現與GBA的相互作用[10-12]。SCFA能夠結合并激活游離脂肪酸受體2(GPR43或FFAR2)、游離脂肪酸受體3(GPR41或FFAR3)和羥基羧酸受體2(GPR109A或HCAR2)[13]。這些受體在人體內的多種細胞中普遍表達,包括腸內分泌細胞、脂肪細胞、免疫細胞和神經元等。宿主對SCFA和GPR43的依賴效應可延伸到CNS,小膠質細胞是CNS的常駐巨噬細胞,其成熟和功能依賴于腸道菌群,維持小膠質細胞的穩態需要SCFA和GPR43[14]。此外,SCFA可以通過調節組蛋白乙酰化和甲基化來對基因表達施加表觀遺傳控制[15-16]。

SCFA可以通過刺激腸內分泌細胞釋放腸道激素和肽類來間接調節GBA。SCFA還可通過刺激胰高血糖素樣肽-1(GLP-1)、肽YY(PYY)和瘦素等厭食激素的分泌來調節攝食行為[11,17-19]。這些食欲激素除了可以作用于大腦中的受體,還可以作用于迷走神經。GOSWAMI等[20]研究證明了迷走神經在腸道微生物控制食欲中的作用,其中SCFA的厭食效應在迷走神經切斷的小鼠中明顯降低。SCFA也可以通過中樞機制參與食欲調節。腸源性乙酸鹽可以穿過血-腦脊液屏障,通過改變神經肽的表達對下丘腦控制食欲有直接影響[21]。

SCFA影響GBA的另一種機制是通過維持腸道和血-腦脊液屏障功能[22-23]。丁酸可以增強緊密連接蛋白的表達,穩定腸黏膜屏障功能,以限制細菌和其他微生物從腸道轉移到血液中[24-26]。當腸道屏障通透性增加時,宿主與細菌脂多糖(LPS)的接觸增加,從而導致慢性炎癥反應。慢性炎癥在包括抑郁癥和焦慮癥在內的一系列神經精神障礙中起著重要作用,促炎細胞因子能夠影響神經傳遞并改變行為。與它們在腸道中的作用一致,SCFA可以通過增加緊密連接表達來促進血-腦脊液屏障的完整性[8]。盡管已經發現SCFA通過各種直接和間接的途徑影響著CNS,但支持SCFA具有改善神經疾病潛力的結果仍不夠一致,故而還需更深入地了解其潛在機制。

2 BA

BA是膽固醇衍生的類固醇,可通過直接和間接途徑影響CNS。兩種主要的BA,膽酸(CA)和鵝去氧膽酸(CDCA)在肝臟中合成,并與甘氨酸或牛磺酸結合,然后分泌到膽汁中。進食刺激后,BA被釋放到腸道中,其中有95%被重新吸收。一小部分BA被運輸到結腸,在腸道菌群的7α-脫羥基作用下轉化為次級BA,即脫氧膽酸(DCA)和熊去氧膽酸(UDCA)。

與SCFA一樣,BA也可以作為信號分子激活法尼醇X受體(FXR)、G蛋白偶聯膽汁酸受體5(TGR5)、孕烷X受體(PXR)及維生素D受體(VDR)等。通過激活這些受體,BA控制葡萄糖穩態、脂質代謝和能量消耗等,對宿主新陳代謝有顯著影響。微生物群功能的變化可以改變BA池的組成,并改變其整體信號傳導能力[27]。已經在人類和嚙齒類動物的大腦中檢測到BA,并且它們的受體和轉運蛋白在CNS的細胞中表達[28-29]。這表明BA可能在CNS中起信號傳導作用。雖然目前對這種信號傳導潛能的了解有限,但在小鼠中發現FXR缺失擾亂了多種神經遞質系統,并改變了情感、認知和運動功能等[30]。

BA可以通過破壞緊密連接直接調節腸道和血-腦脊液屏障的通透性,從而直接影響腦功能[31]。DCA和CDCA可以增加血-腦脊液屏障的通透性,而UDCA可以通過減少腦內皮細胞的凋亡發揮保護作用[32]。BA也可以影響免疫反應,因為UDCA已被發現可以通過結合小膠質細胞上表達的TGR5來減輕小鼠的神經炎癥[33]。另外,BA也可以通過激活腸道中的FXR來向CNS發出信號,以促進中間分子如GLP-1和成纖維細胞生長因子19(FGF19)的釋放。GLP-1可以進入血液并激活腦中的受體,也可以通過激活迷走神經傳入纖維向CNS發出信號[34-35]。FGF19可以通過與下丘腦弓狀核(ARC)表達的受體結合來抑制刺鼠基因相關蛋白(AGRP)、神經肽Y(NPY)神經元,從而引發厭食效應[36]。

3 神經遞質

中樞神經遞質也存在于胃腸道中,在調節腸運動、腸細胞分泌以及細胞信號傳導中起著重要作用[37-38]。腸道微生物群可以合成多種神經遞質:乳酸桿菌和雙歧桿菌產生γ-氨基丁酸(GABA),大腸桿菌產生5-羥色胺(5-HT)和多巴胺(DA),乳酸桿菌產生乙酰膽堿,以及更多的微生物群合成和釋放具有神經活性的其他分子[39-41]。微生物群影響神經遞質水平已在嚙齒動物模型中被證明,微生物缺乏可顯著降低DA和GABA等神經遞質水平[42-43]。目前尚不清楚循環神經遞質是直接來自微生物群還是來自宿主,因為微生物代謝物(例如次級BA、SCFA)可以刺激腸嗜鉻細胞產生神經遞質并進入血液循環[42]。

調節神經遞質前體是微生物群影響宿主神經傳遞的另一種途徑。酪氨酸是左旋多巴胺(L-DOPA)前體,L-DOPA可以脫羧形成DA。反過來,DA可以代謝成其他兒茶酚胺,如去甲腎上腺素和腎上腺素。酪氨酸可以從飲食中獲得,也可以從苯丙氨酸中獲得,這兩種氨基酸都可以被腸道中的微生物分解成一系列分子,從而改變宿主對它們的利用度。L-DOPA轉化為DA也受微生物群的控制,腸球菌和乳酸桿菌通過表達酪氨酸脫羧酶參與L-DOPA的脫羧[44-45]。這對于帕金森病的治療具有重要意義,因為抑制外周L-DOPA代謝可以最大化提高大腦中的L-DOPA濃度。

微生物代謝產物還可以通過激活迷走神經來影響中樞神經傳遞。BRAVO等[46]研究證明,迷走神經參與了GBA交流,應用鼠李糖乳酸桿菌可改變中樞GABA受體的表達,同時減輕焦慮和抑郁癥樣癥狀,而在迷走神經切除小鼠中則沒有觀察到這種變化。腸道中產生的神經遞質還能通過調節免疫系統來影響大腦功能,已經發現5-HT能激活免疫細胞,以及GABA可減輕腸道炎癥[47-48]。這些研究表明,腸道微生物群直接或間接產生的神經遞質通過結合CNS中的特定受體或外周細胞上的受體而影響宿主心理和行為。可能存在更多的類似神經遞質的活性分子,有待于進一步發現和研究。腸道微生物群與宿主之間這種神經遞質代謝交流本質上是雙向的:除了合成能夠改變宿主生理的神經遞質外,腸道微生物還對宿主產生的神經遞質做出反應,從而影響微生物群的生長和豐富度[49]。

4 其他腸道微生物群代謝產物

來自腸道微生物群的其他幾種代謝產物也可以參與GBA通訊。膽堿是一種必需營養素,主要從飲食中的卵磷脂和肉堿中獲取,但是在人體內,肝臟中也可以合成少量膽堿[50]。膽堿具有參與生物膜構成、表觀遺傳和細胞信號傳導的功能。它參與乙酰膽堿的合成,并且是細胞膜成分磷脂酰膽堿和鞘磷脂的前體。盡管膽堿本身不是細菌產物,但腸道微生物可以將膽堿分解成一系列代謝產物,包括甜菜堿和三甲胺等。由于腸道微生物對膽堿的代謝會耗盡宿主體內可利用的膽堿,因此,利用膽堿的細菌過多將會導致膽堿的缺乏,這將增加代謝疾病的發生,增加心血管疾病的風險,改變宿主的神經精神行為。此外,膽堿是甲基的重要來源,它可以有效調節DNA甲基化。ROMANO等[51]在小鼠中發現,膽堿的細菌消耗降低了甲基供應,并減少了包括大腦在內的多個組織中的DNA甲基化。

乳酸是一種有機酸,產生于宿主代謝過程以及乳酸桿菌、雙歧桿菌和變形桿菌對膳食纖維的發酵[52]。盡管乳酸在腸道中水平很低,但它可以被吸收到血液中并穿過血-腦脊液屏障。乳酸在大腦信號傳導中起著確定的作用,它可以作為神經元的能量底物,有助于突觸可塑性,并在記憶形成過程中起重要作用[53-54]。乳酸調節情緒行為的潛在機制是通過直接激活海馬、新皮質和小腦中表達的G-蛋白偶聯受體81(GPR81),通過GPR81激活,乳酸可調節脂質和葡萄糖的代謝,發揮抗炎作用,并抑制GABA能神經傳遞[55-57]。盡管微生物對中樞乳酸濃度的影響已在無菌大鼠中得到證實,但其對乳酸和情緒中樞影響水平仍然難以評估[58]。

微生物群可以在腸道內合成維生素,人類的維生素代謝在很大程度上依賴于微生物的供應。在CNS功能中具有重要作用的B族維生素,如核黃素(B2)、葉酸(B9)和鈷胺(B12)等,作為中樞代謝反應的輔酶,其缺乏可以表現為各種神經系統癥狀,包括異常運動功能、睡眠記憶障礙以及精神情緒癥狀等[59]。據估計,微生物群可以為人類提供31%參考攝入量的B12,而B12缺乏與一系列精神和神經疾病有關,包括精神發育遲緩、記憶障礙、注意力缺陷和癡呆等[60]。

5 小結

在微生物群和哺乳動物宿主之間發生的雙向通信是這兩個互補系統協同進化的結果,這種信息交流可以通過各種機制來介導。微生物代謝產物可以通過直接和(或)間接方式調節CNS,最終影響宿主行為和認知功能。隨著微生物代謝產物與CNS疾病之間的多因素相互作用的深入探究,人們對GBA病理機制的認識將進一步增加。在未來,具有參與關鍵作用潛力的微生物代謝產物可能被用于治療和預防CNS疾病。

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(本文編輯 馬偉平)

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