肠道菌群对人体健康的作用及其应用

发布时间：2024-11-12 15:48

参考文献 1

GILBERT J A,BLASER M J,et al.Current understand‐ ing of the human microbiome[J].Nat Med,2018,24(4):392-400.

参考文献 2

HUMAN MICROBIOME PROJECT C.Structure,func‐ tion and diversity of the healthy human microbiome[J].Nature,2012,486(7402):207-214.

参考文献 3

YATSUNENKO T,REY F E,MANARY M J,et al.Hu‐ man gut microbiome viewed across age and geography[J].Nature,2012,486(7402):222-227.

参考文献 4

ROWLAND I,GIBSON G,HEINKEN A,et al.Gut mi‐ crobiota functions:metabolism of nutrients and other food components[J].Eur J Nutr,2017,57(1):1-24.

参考文献 5

SHETTY S A,HUGENHOLTZ F,LAHTI L,et al.Intesti‐ nal microbiome landscaping:insight in community assem‐ blage and implications for microbial modulation strate‐ gies[J].FEMS Microbiol Rev,2017,41(2):182-199.

参考文献 6

NOGACKA A M,GÓMEZ-MARTÍN,MARÍA S,et al.Xenobiotics formed during food processing their relation with the intestinal microbiota and colorectal cancer[J].INT J MOL SCI,2019,20(8):2051-2068.

参考文献 7

WAN M L Y,LING K H,EL-NEZAMI H,et al.Influ‐ ence of functional food components on gut health[J].Crit Rev Food Sci Nutr,2018,59(12):1927-1936.

参考文献 8

VERBEKE K A,BOOBIS A R,CHIODINI A,et al.To‐ wards microbial fermentation metabolites as markers for health benefits of prebiotics[J].Nutr Res Rev,2015,28(1):42-66.

参考文献 9

HILLS R D,PONTEFRACT B A,MISHCDN H R,et al.Gut microbiome:profound implications for diet and dis‐ ease[J].Nutrients,2019,11(7):1613-1653.

参考文献 10

SONG S J,DOMINGUEZ-BELLO M G,KNIGHT R.How delivery mode and feeding can shape the bacterial community in the infant gut[J].CMAJ,2013,185(5):384-394.

参考文献 11

LEE S A,LIM J Y,KIM B S,et al.Comparison of the gut microbiota profile in breast-fed and formula-fed Korean infants using pyrosequencing[J].Nutr Res Pract,2015,9(3):242-248.

参考文献 12

RAY K.Gut microbiota:filling up on fibre for a healthy gut[J].Nat Rev Gastro Hepat,2018,15(2):67.

参考文献 13

ZHAO L N,ZHANG F,DING X Y,et al.Gut bacteria selectively promoted by dietary fibers alleviate type 2 diabetes[J].Science,2018,359(6380):1151-1156.

参考文献 14

FOROUHI N G,KRAUSS R M,TAUBES G,et al.Di‐ etary fat and cardiometabolic health evidence,controver‐ sies,and consensus for guidance[J].BMJ,2018,361:K2139.

参考文献 15

JETHWANI P,GROVER K.Gut microbiota in health and diseases-a review[J].Int J Curr Microbiol Appl Sci,2019,8(8):1586-1599.

参考文献 16

DEL CHIERICO F,VERNOCCHI P,PETRUCCA A,et al.Phylogenetic and metabolic tracking of gut microbiota dur‐ing per-inatal development[J].PLoS One,2015,10(9):e0137347.

参考文献 17

SCHANCHE M,AVERSHINA E,DOTTERUD C,et al.High-resolution analyses of overlap in the microbiota between mothers and their children[J].Curr Microbiol,2015,71(2):283-290.

参考文献 18

HOLLISTER E B,RIEHLE K,LUNA R A,et al.Struc‐ ture and function of the healthy pre-adolescent pediatric gut microbiome[J].Microbiome,2015,3(1):36-45.

参考文献 19

REYES A,HAYNES M,HANSON N,et al.Viruses in the faecal microbiota of monozygotic twins and their mothers[J].Nature,2010,466(7304):334-338.

参考文献 20

THOMPSON A,MONTEAGUDO-MERA A,CADENAS M,et al.Milk-and solid-feeding practices and daycare attendance are associated with differences in bacterial diversity,predominant communities,and metabolic and immune function of the infant gut microbiome[J].Front Cell Infect Microbiol,2015,5(3):1-8.

参考文献 21

BIAGI E,RAMPELLI S,TURRONI S,et al.The gut microbiota of centenarians:signatures of longevity in the gut microbiota profile[J].Mech of Ageing and Dev,2017,165(Pt B):180-184.

参考文献 22

HUGHES R L.A review of the role of the gut microbi‐ ome in personalized sports nutrition[J].Front Nutr,2019,6:191.

参考文献 23

ALLEN J M,MAILING L J,NIEMIRO G M,et al.Exer‐ cise alters gut microbiota composition and function in lean and obese humans[J].Med Sci Sports Exerc,2018,50(4):747-757.

参考文献 24

KLINGENSMITH N J,COOPERSMITH C M.The gut as the motor of multiple organ dysfunction in critical illness[J].Crit Care Clin,2016,32(2):203-212.

参考文献 25

DETHLEFSEN L,RELMAN D A.Incomplete recovery and individualized responses of the human distal gut mi‐ crobiota to repeated antibiotic perturbation[J].Proc Natl Acad Sci USA,2011,108(Suppl 1):4554-4561.

参考文献 26

ISAAC S,SCHER J U,DJUKOVIC A,et al.Short-and long-term effects of oral vancomycin on the human intesti‐ nal microbiota[J].J Antimicrob Chemother,2017,72(1):128-136.

参考文献 27

JAKOBSSON H E,JERNBERG C,ANDERSSON A F,et al.Short-term antibiotic treatment has differing longterm impacts on the human throat and gut microbiome[J].PLoS One,2010,5(3):983-996.

参考文献 28

MARTÍNEZ I,STEGEN J C,MALDONADO-GÓMEZ M X,et al.The gut microbiota of rural papua new guin‐ eans composition,diversity patterns,and ecological pro‐ cesses[J].Cell Rep,2015,11(4):527-538.

参考文献 29

ZHU A,SUNAGAWA S,MENDE D R,et al.Inter-indi‐ vidual differences in the gene content of human gut bacte‐ rial species[J].Genome Biol,2015,16(1):82.

参考文献 30

LORENZO J M,MUNEKATA P E S,GÓMEZ B,et al.Bioactive peptides as natural antioxidants in food prod,ucts-a review[J].Trends in Food Scienc & Technolgy,2018,79:136-147.

参考文献 31

AL-SHERAJI S H,ISMAIL A,MANAP M Y,et al.Prebi‐ otics as functional foods:a review[J].J Funct Foods,2013,5(4):1542-1553.

参考文献 32

PENG M,TABASHSUM Z,ANDERSON M,et al.Effec‐ tiveness of probiotics,prebiotics,and prebiotic-like com‐ ponents in common functional foods[J].Compr Rev Food SCI F,2020,19(4):1908-1933.

参考文献 33

AGUILAR-TOALA J E,HALL F G,URBIZO-REYES U C,et al.In silico prediction and in vitro assessment of multifunctional properties of postbiotics obtained from two probiotic bacteria[J].Probiotics Antimicrob Proteins,2020,12(2):608-622.

参考文献 34

SANDERS M E,MERENSTEIN D J,REID G,et al.Pro‐ biotics and prebiotics in intestinal health and disease:from biology to the clinic[J].Nat Rev Gastro Hepat,2019,16(10):605-616.

参考文献 35

BIRKELAND E,GHARAGOZLIAN S,BIRKELAND K I,et al.Prebiotic effect of inulin-type fructans on faecal microbiota and short-chain fatty acids in type 2 diabetes:a randomised controlled trial[J].Eur J Nutr,2020,59(7):3325-3338.

参考文献 36

VULEVIC J,JURIC A,WALTON G E,et al.Influence of galacto-oligosaccharide mixture(B-GOS)on gut micro‐ biota,immune parameters and metabonomics in elderly persons[J].Brit J Nutr,2015,114(4):586-595.

参考文献 37

METZLER-ZEBELI B U,CANIBE N,MONTAGNE L,et al.Resistant starch reduces large intestinal pH and promotes fecal lactobacilli and bifidobacteria in pigs[J].Animal,2019,13(1):64-73.

参考文献 38

RIVERA-HUERTA M,LIZARRAGA-GRIMES V L,CASTRO-TORRES I G,et al.Functional effects of prebi‐ otic fructans in colon cancer and calcium metabolism in animal models[J].Biomed Res Int,2017,2017:9758982.

参考文献 39

SCHOLZ-AHRENS K E,SCHAAFSMA G,VAN DEN HEUVEL E G H M,et al.Effects of prebiotics on mineral metabolism[J].Am J Clin Nutr,2001,73(2):459-464.

参考文献 40

MAKKI K,DEEHAN E C,WALTER J,et al.The impact of dietary fiber on gut microbiota in host health and disease[J].Cell Host Microbe,2018,23(6):705-715.

参考文献 41

WHISNER C M,MARTIN B R,SCHOTERMAN M H,et al.Galacto-oligosaccharides increase calcium absorp‐ tion and gut bifidobacteria in young girls:a double-blind cross-over trial[J].Br J Nutr,2013,110(7):1292-1303.

参考文献 42

PRETORIUS R,PRESCOTT S L,PALMER D J.Taking prebiotic approach to early immunomodulation for aller‐ gy prevention[J].Expert Rev Clin Immu,2018,14:43-51.

参考文献 43

YAHFOUFI N,MALLET J F,GRAHAM E,et al.Role of probiotics and prebiotics in immunomodulation[J].Curr Opin Food SCI,2018,20:82-91.

参考文献 44

DANNESKIOLD-SAMSOE N B,DIAS DE FREITAS QUEIROZ BARROS H,SANTOS R,et al.Interplay be‐ tween food and gut microbiota in health and disease[J].Food Res Int,2019,115:23-31.

参考文献 45

HE Q,GAO Y,JIE Z,et al.Two distinct metacommuni‐ ties characterize the gut microbiota in Crohn's disease patients[J].GigaScience,2017,6(7):1-11.

参考文献 46

SHARMA M,SHUKLA G.Metabiotics:one step ahead of probiotics;an insight into mechanisms involved in anticancerous effect in colorectal cancer[J].Front Micro‐ biol,2016,7:1940.

参考文献 47

FEMIA A P,LUCERI C,DOLARA P,et al.Antitumori‐ genic activity of the prebiotic inulin enriched with oligo‐ fructose in combination with the probiotics lactobacillus rhamnosus and bifidobacterium lactis on azoxymethan[J].Carcinogenesis,2002,23(1):1953-1960.

参考文献 48

VERGHESE M,RAO D R,CHAWAN C B,et al.Dietary inulin suppresses azoxymethane-induced aberrant crypt foci and colon tumors at the promotion stage in young Fish‐ er 344 rats[J].J Nutr,2002,132(9):2809-2813.

参考文献 49

RAMAN M,AMBALAM P,KONDEPUDI K K,et al.Potential of probiotics,prebiotics and synbiotics for management of colorectal cancer[J].Gut Microbes,2013,4(3):181-192.

参考文献 50

WEN Y,WEN P,HU T G,et al.Encapsulation of phy‐ cocyanin by prebiotics and polysaccharides-based elec‐ trospun fibers and improved colon cancer prevention effects[J].Int J Biol Macromol 2020,149:672-681.

参考文献 51

ZITVOGEL L,DAILLERE R,ROBERTI M P,et al.Anticancer effects of the microbiome and its products[J].Nat Rev Microbiol,2017,15(8):465-478.

参考文献 52

SHENDEROV B A.Metabiotics:novel idea or natural development of probiotic conception[J].Microb Ecol Health Dis,2013,24:20399.

参考文献 53

RAY K.Gut microbiota:the gut virome and bacterial mi‐ crobiome-the early years[J].Nat Rev Gastro Hepat,2015,12(11):609.

参考文献 54

LA FATA G,WEBER P,MOHAJERI M H.Probiotics and the gut immune system:indirect regulation[J].Probi‐ otics Antimicro,2018,10(1):11-21.

参考文献 55

IKRAM S,HASSAN N,RAFFAT M A,et al.Systematic review and meta-analysis of double-blind,placebo-con‐ trolled,randomized clinical trials using probiotics in chronic periodontitis[J].J Investig Clin Dent,2018,9(3):e12338.

参考文献 56

HSIEH M.The microbiome and probiotics in childhood[J].Semin Reprod Med,2014,32(1):23-27.

参考文献 57

AMBALAM P,RAMAN M,PURAMA R K,et al.Probi‐ otics,prebiotics and colorectal cancer prevention[J].Best Pract Res Clin Gastroenterol,2016,30(1):119-131.

参考文献 58

HENDIJANI F,AKBARI V.Probiotic supplementation for management of cardiovascular risk factors in adults with type Ⅱdiabetes:a systematic review and meta-analy‐ sis[J].Clin Nutr,2018,37(2):532-541.

参考文献 59

KHORUTS A,SADOWSKY M J.Understanding the mechanisms of faecal microbiota transplantation[J].Nat Rev Gastro Hepat,2016,13(9):508-516.

参考文献 60

LI S S,ZHU A,BENES V,et al.Durable coexistence of donor and recipient strains after fecal microbiota trans‐ plantation[J].Science,2016,352(6285):586-589.

参考文献 61

HOLVOET T,JOOSSENS M,WANG J,et al.Assess‐ ment of faecal microbial transfer in irritable bowel syn‐ drome with severe bloating[J].Gut,2017,66(5):980-982.

参考文献 62

JOHNSEN P H,HILPÜSCH F,CAVANAGH J P,et al.Faecal microbiota transplantation versus placebo for moderate-to-severe irritable bowel syndrome:a doubleblind,randomised,placebo-controlled,parallel-group,sin‐ gle-centre trial[J].The Lancet Gastroenterology & Hepa‐ tology,2018,3(1):17-24.

参考文献 63

GIANOTTI R J,MOSS A C.Fecal microbiota transplanta‐ tion from clostridium difficile to inflammatory bowel disease[J].Gastroenterol Hepatol(NY),2017,13(4):209-213.

参考文献 64

SCARPELLINI E,IANIRO G,ATTILI F,et al.The hu‐ man gut microbiota and virome:potential therapeutic implications[J].Dig Liver Dis,2015,47(12):1007-1012.

参考文献 65

PARRACHO H,BURROWES B,ENRIGHT M,et al.The role of regulated clinical trials in the development of bacteriophage therapeutics[J].J Mol Med,2012,6:279-286.

摘要

人类肠道菌群复杂多样，在与人类长期的共同进化过程中，具备了调节人体免疫应答、影响疾病发展的作用。这种免疫调节作用与肠道菌群本身的多样性和关键菌种的存在与否具有紧密联系。然而肠道菌群结构和功能的特性在很大程度上受到肠道菌群宿主的饮食结构、年龄和生活环境等因素的影响。正常的肠道菌群能够调节肠上皮细胞的通透性，刺激物质代谢与免疫反应，使肠道微环境长期处于稳态；一旦肠道菌群失衡，引起肠道微环境稳态变化，则会提高许多疾病的发生风险，尤其是胃肠代谢疾病，以及免疫和神经性疾病。本文主要从肠道菌群与人体健康的关系、影响肠道菌群组成的因素、功能性食品对人体健康的影响以及如何维持肠道微生态平衡等几个方面，综述了人体肠道菌群的当前研究现状和相关产业应用，期望能够为肠道菌群与人体健康的相互关系研究及其成果转化提供新的思考。

Abstract

In the coevolutionary journey with humans, the complex and diverse human intestinal flora has evolved to regulate the human immune responses and affect the development of diseases. This immunomodulatory effect is closely related to the diversity of intestinal flora and the presence of key strains. The composition and function of the intestinal flora are greatly influenced by a variety of factors, including the diet, age and living envi‐ ronment of the host. Normal intestinal flora can regulate the permeability of intestinal epithelial cells, stimulate in‐ testinal metabolism and immunoreaction, and maintain local homeostasis in the intestinal microenvironment. When the intestinal flora is imbalanced and the intestinal homeostasis is disrupted, the risk of many diseases, such as the gastrointestinal metabolic diseases, as well as the immune and neurological diseases, will increase. Here we reviewed the current research progress and therapeutic applications of human intestinal flora in the following sec‐ tions: the relationship between intestinal flora and human health, the factors affecting the composition of intestinal flora, the impact of functional foods on human health, and how to maintain intestinal microecological balance. Hopefully this review will provide new thinking for future studies on the interaction between intestinal flora and human health and the related translational applications.

1 肠道菌群与人体健康

人类肠道菌群复杂多样，在维护人体健康和体内微生态平衡方面发挥着重要作用[1]。肠道菌群的结构组成具有明显的地域属性和个体特异性，已有研究表明，肠道菌群的特异性和人类的年龄、居住环境的气候、生活饮食、基因表达等的差异具有密切相关性[2, 3]。尽管存在差异，但核心肠道菌群（某物种健康个体的肠道内、长期与宿主互利共生并保持种群稳定的非特异性类群，如放线菌、拟杆菌、厚壁菌、变形菌等）一般比较保守[4]，而且这些核心微生物群与个体的年龄没有明显的相关性，只是在不同的时间阶段其物种丰度存在小范围、有规律的波动，这或许能够有利于肠道菌群与人类健康建立起一种微妙的平衡关系[5]。但也有研究指出，核心肠道菌群的“保守性”实际上具有一定的相对性，该类群依然受到特定且稳定的微生物家族基因、代谢途径等因素的调节，同时指出这对维持宿主肠道微生态环境的稳定性具有重要意义[6]。

在人体肠道中，生活着数以百万计的微生物动态群落，它们一般通过自身细胞壁表面的纤毛等附着于肠上皮细胞表面[6, 7]，且伴随着人体组织差异，局部区域的微生物呈现相对特异性[8]。例如在人体结肠中菌体个数达到峰值，单位质量（g）内容物中细菌个体数可达1013以上。从功能上看，肠道中的绝大多数微生物和参与转化食物组分的酶相关。食物经过肠道菌群的生物转化后，生成小分子的碳水化合物、有机酸和对人体健康、维持机体内稳态具有重要作用的微生物特异性代谢产物——维生素和短链脂肪酸（Short-Chain Fatty Acids，SCFAs）等[8]。但是，肠道菌群的代谢产物因人而异，且与人类年龄、饮食、居住环境、压力、精神状态等因素具有一定的相关性。研究表明，当肠道菌群稳态被打破时，肠道菌群物种多样性及其丰度变化显著，这会导致功能基因的表达、代谢相关酶等物质的水平发生显著变化，从而诱发肠道代谢紊乱，情况严重的则会引起炎症性肠病、结直肠癌等代谢疾病[6]。另外，尽管抗生素对治疗肠道疾病具有良好效果，但是面对抗生素的无差别攻击，部分有益微生物的丰度也会在抗生素的作用下大幅下降。因此，基于饮食调节的功能性食品的开发为改善人体肠道健康、维持肠道菌群与宿主之间的平衡提供了良好机会。

2 影响肠道菌群组成的因素

2.1 饮食

饮食对肠道菌群结构的调节具有至关重要的作用，直接影响了肠道菌群的优势物种及其代谢主要组分[9]。对于新生儿来说，饮食是塑造肠道菌群的关键驱动力，例如母乳喂养的新生儿表现出放线菌优势和厚壁菌门、变形菌门劣势，从代谢物的角度上整体表现出SCFAs水平增加，加强了免疫系统反应，使IgG表达量升高[10, 11]。随着新生儿年龄的增长，饮食成为影响肠道菌群结构、多样性发展的重要因素。饮食中膳食纤维的摄入能够确保肠道黏膜的完整性，在很大程度上降低了肠道疾病发生的风险[12]，富含纤维的饮食结构也能够改善人体血糖水平，促进人体健康代谢循环[13]。高蛋白的饮食结构能够使得肠道中的拟杆菌、嗜双胞杆菌大量增殖，这可能导致人体免疫力降低，增加疾病风险（包括代谢疾病）[14, 15]。

2.2 年龄

年龄是影响肠道菌群组成的另一个主要因素。新生儿出生后，变形菌等需氧型细菌首先定植在人体肠道中，随着肠道局部部位氧浓度的变化，厚壁菌门、拟杆菌门等细菌逐渐定植于氧浓度更低的肠道部位[16]。研究表明，新生儿肠道菌群的多样性最低，但随着年龄的增长，其物种多样性逐渐提高[17]。青春期时肠道菌群代谢物中叶酸和维生素B12的合成量显著升高，这表明某些肠道菌可能参与了人体的生长发育过程[18]。成年人肠道菌群以厚壁菌门、拟杆菌门的细菌为主，放线菌和变形菌的丰度相对较低[19]。而在老年人的肠道菌群中，多样性降低，兼性厌氧菌、梭杆菌、芽孢杆菌等的丰度相对较高，双歧杆菌、类杆菌等丰度降低[20]，SC‐ FAs表达量相对较低[21]。

2.3 其他因素

除了饮食和年龄能够显著影响肠道菌群的结构与功能外，运动、抗生素药物、生活环境等也能在一定程度上影响肠道菌群功能的发挥。Hughes等研究表明，规律的运动习惯能够丰富有益菌群的丰度和多样性[22]。与非运动员相比，运动员的肠道菌群显示出丰度更高的厚壁菌、乳杆菌和双歧杆菌等，SCFAs和丁酸盐等有益代谢产物的表达水平也显著高于非运动员的平均水平[23]，梭状芽胞杆菌、玫瑰芽孢杆菌等的丰度也在有益代谢产物的作用下明显提高，其他类群物种丰度均有不同程度的降低[22]。抗生素药物作为病原体灭活剂在进行病原体杀伤过程中具有“无差别”效应，即在杀灭病原菌的同时也能对肠道有益微生物进行灭活，从而导致肠道菌群代谢紊乱[24]。Dethlefsen等研究发现，抗生素对肠道菌群的影响主要取决于抗生素种类和给药时长[25]。例如万古霉素能够降低拟杆菌、烟曲霉菌和粪肠球菌的丰度，提高变形菌的丰度[26]，环丙沙星对乳球菌的抑制效果能够达到6个月以上，而克拉霉素灭活幽门螺杆菌的过程中，放线菌的丰度显著降低[27]。此外，基于气候、遗传、饮食等生活方式的不同，肠道菌群的结构功能也表现出一定的差异性[28]。有研究显示，在饮食结构相对接近的条件下，相比于发展中国家，工业化程度更高的西方发达国家人群的肠道菌群中，厚壁菌和拟杆菌的比例似乎更高[29]。

3 功能性食品对人体健康的作用

功能性食品是一类不仅能够提供多种营养物质，还能够提高人体健康水平、降低某些疾病风险的食物[30]，通常作为人类生长代谢调节剂，主要包括益生元、益生菌、膳食纤维、天然抗氧化剂和生物活性肽等[31]。已有研究表明，功能性食品中对人体有益的组分不仅仅局限于食物中活菌的补充，也包括这些有益菌的代谢产物。另外，我们个人的饮食结构对于有益菌的类群、代谢产物具有相当的决定作用[32]。为此，我们有必要了解功能性食品的代谢与人体健康之间的关系。

3.1 降低肠道病原菌的感染风险

饮食作为最容易造成肠道菌群个体差异性的因素，已成为当下研究肠道菌群代谢变化的主要热点之一。在饮食组分中，益生元等功能性食品有利于小肠和结肠的功能稳定[33]，肠道菌群对这些物质的代谢可以改善胃肠功能和屏障稳态，增强人体的矿物质吸收能力，调节能量代谢以及降低肠道病原菌的感染风险等[34]。相反，体内缺乏益生元则会引起体内生长因子多样性消失，导致糖尿病、结肠癌、心血管疾病等的发病风险增高，这一点在西方国家尤为明显[35]。

益生元作为功能性食品的常见形式进入人体后，能够通过自身的新陈代谢作用产生有机酸，降低肠道中的酸碱度，从而达到抑制病原菌生长的目的[34]。Vulevic等研究发现，65岁老年人每日服用低聚半乳糖5.5g，其自然杀伤性细胞和吞噬细胞的生物活性显著增强[36]。动物实验研究发现，膳食纤维可通过代谢产生酸性物质等以降低结肠微环境的酸碱度，从而达到预防致病菌感染的目的[37]。因此，摄入益生元等功能性食品有益于调节人体肠道功能，维持肠道微生态稳定，避免病原菌在肠道表面粘附、增殖、移位等。

3.2 改善矿物质吸收能力

在矿物质吸收方面，功能性食品也发挥了良好作用。研究显示，低聚糖、低聚半乳糖和糖醇等对改善维生素、抗氧化化合物、矿物质等微量元素的吸收能力具有良好效果[38]。这些物质被代谢后所产生的SCFAs等能刺激结合蛋白的表达，利于矿物复合物的降解，提高肠道对矿物小分子的吸收效率并改善肠道微环境[39]，这些小分子也被充当为辅因子参与到代谢循环中。另外，某些矿物质在特定的环境下具有抗菌特性，表现出利于预防肠道感染的特性[40]。

SCFAs作为益生元常见的降解产物，能够通过调节肠道内的酸碱平衡以促进肠上皮细胞对钙的溶解与吸收[34]。Abrams等已经证明，青少年每日补充适量的果聚糖（约8g）能够有效提高钙的吸收，每日钙吸收量超过250mg的人群达到65%以上。 Whisner等研究发现，低聚半乳糖也能通过肠道菌群的代谢产生SCFAs，进而促进肠上皮细胞对钙的吸收，同时肠道菌群中双歧杆菌的丰度显著升高[41]，他们在动物实验中得到了相似的结论。这些结果表明，益生元等功能性食品在经过肠道菌群的代谢后产生的小分子物质能够有效的调节肠道微环境的稳态，同时能够影响肠道菌群的多样性变化。

3.3 改善免疫调节

益生元对免疫调节的影响涉及多种代谢通路。通过微生物群的作用，益生元大部分被降解为SCFAs，通过肠上皮细胞的吸收，SCFAs参与到机体的代谢循环中，从而影响了抗炎细胞因子的基因表达[42]。已有研究表明，机体中的SCFAs水平同炎症性肠病（Inflammatory Bowel Disease，IBD）、糖尿病和动脉粥样硬化等疾病的发生具有一定的相关性[43]。

研究表明，SCFAs能够依赖丁酸盐结合树突细胞的GPR41、GPR43和GPR109A组分，并通过诱导组蛋白H3乙酰化、醛基脱氢酶的表达来促进结肠Treg细胞的产生[44]，间接影响了相关细胞免疫因子对免疫系统的调节。动物实验研究表明，SCFAs的水平降低和疾病的严重程度具有密切相关性。人们在临床研究中发现，高产SCFAs的菌群丰度的降低能够显著提高肠炎的发生风险[45]。由此可见，结肠中SCFAs的产生是调节并维持天然免疫系统和适应性免疫系统正常功能的关键因素[40]。

3.4 抗癌效果

影响细胞癌变的因素有很多，但其中最主要的是基因与环境（尤其是肠道微环境）的相互作用[46]。在癌症中，由肠炎引起的结直肠癌发病率长期居高不下，已有研究证明，结直肠癌的发病与肠道菌群的失衡有直接关系[40]。Femia等通过动物实验发现，乳双歧杆菌和鼠李糖乳杆菌混合物能够提高肠道丁酸盐水平，降低癌变细胞的增殖、直肠癌发生相关酶的活性，从而降低大鼠的结肠癌发病率[47]。后续研究表明，长链果聚糖和短链果糖能够通过调节肠道的酸碱度来间接影响结肠肿瘤的发病率[48]。

Raman等研究发现，盲肠、结肠和粪便中肠道菌基因表达的改变，增加了结肠中微量营养素的吸收，同时能够调节异种代谢酶的活性和免疫应答[49]。益生元在肠道菌群的作用下能够产生SCFAs，从而表现出一定的抗癌活性[40, 50]，而常规的低碳水化合物的饮食结构不仅会降低肠道内SCFAs的水平，还会提高潜在有害代谢物（如支链脂肪酸、亚硝基化合物、硫化物和吲哚化合物等）的水平，导致细胞组织出现毒性或促炎性，引起慢性疾病（如结直肠癌）的发展[40]。相比于SCFAs，丁酸盐更能促进结肠区域的代谢活动，降低细胞癌变风险，能够诱导结肠癌细胞的凋亡并抑制其增殖[51]。此外，乳酸、某些糖蛋白、胆汁酸等微生物胞外代谢物也对肠道菌群的代谢活性及特异性生理功能产生影响[52]。

4 肠道微生态平衡的维持策略

现今，关于维持肠道微生态平衡的方法有很多，比较成熟的有益生菌、粪菌移植和噬菌体策略。

4.1 益生菌

益生菌是一类可定植在人体内，通过调节宿主黏膜与系统免疫功能或肠道菌群的、对宿主有益的活性微生物。在日常生活中适当摄入益生菌对延长宿主寿命具有一定积极影响。目前已有研究证明，肠道中的益生菌对肠道微环境的稳定具有一定的调节作用，同时对肠道病原菌的防御也具有一定的促进作用[49]。目前最常用的益生菌主要有双歧杆菌、乳酸杆菌和酵母菌等，其应用范围广泛，涉及制药、乳制品发酵、非乳制品添加剂等领域[53]。

益生菌的功能灵活多样，能够通过产生SCFAs以调节肠道环境的酸碱平衡，也能够产生多种维生素（如维生素K），还能产生细菌素或其他具有抗菌活性的物质。另外，益生菌在代谢过程中，还能够调节巨噬细胞活性，细胞因子、免疫球蛋白水平以激活免疫反应，或者通过调节肠上皮细胞的通透性来间接激活免疫系统[54]。研究表明，益生菌对预防过大的精神压力以及某些慢性疾病（如动脉粥样硬化损伤、糖尿病等）也有一定的作用[55]，因此有针对性地开发以益生菌为基础的治疗药物已经成为热点之一，该研究方向主要聚焦于剂量、药效时长和菌株选择等方面[56]。

当前，已经有研究表明益生菌对癌症具有预防作用。益生菌在宿主体内的代谢过程能产生与细胞诱变剂结合的小分子，它们能促进这些潜在致癌因子的降解和代谢，避免正常细胞向癌细胞转化。与此同时，产生的SCFAs等分子能刺激抗炎因子的分泌，为适当的免疫应答[57] 做好准备。另外，也有研究证实益生菌能够减缓腹泻、肥胖等疾病症状[55]，对Ⅱ型糖尿病、心血管疾病等也有良好的预防效果[58]。尽管益生菌在调节肠道微生物稳态、人体免疫等方面具有很大潜力，但其实际应用仍然受到临床诊断等的多方阻碍。因此，基于多组学技术系统性地研究益生菌在人体代谢中的功能作用机制，是解决当下应用困境的主要方法。

4.2 粪菌移植

粪菌移植（Fecal Microbiota Transplantation， FMT），指的是将健康人的肠道菌移植到肠道感染者体内，以恢复患者肠道菌群结构及其功能的过程[59]。目前的研究及临床应用均已证明，FMT对炎症性肠病、肠易激综合征、结肠癌等肠道疾病导致的微生态失衡具有结构与功能的重建作用[60]。此外，FMT也已经广泛应用于对腹泻、过敏性疾病、肿瘤等疾病的治疗[61, 62]。

然而，FMT具体是如何影响肠道菌的结构与功能，它治疗某些疾病的具体机制是什么，这些问题仍有待进一步探究。比较容易接受的观点是FMT在肠道中基于自身的代谢，产生了许多有益的小分子（如有机酸、醇、醛等）和活性肽，这些物质一方面调节了肠道微环境的酸碱性，另一方面通过刺激宿主产生免疫反应，加快了肠道微生物结构与功能的恢复[63]。从实验室研究和临床的初步应用中可以判断，FMT对某些肠道疾病的治疗是有利的，但是在实际应用中往往存在许多瓶颈和问题。例如，如何规避FMT供体中病原菌的转移，如何降低与肠道菌群有关的疾病（糖尿病、心血管疾病等）产生的风险。由此可见，对FMT治愈目标疾病的具体机制的研究，将有助于开发和应用更加安全可靠有效的FMT药剂。

4.3 噬菌体策略

在人类疾病的产生中，病原菌并非是唯一的原因，噬菌体也是影响人类健康的重要类群[64]。噬菌体在人体中广泛存在，它能显著地影响肠道微生物的结构和功能。因此在理论上，我们可以通过影响噬菌体来间接影响肠道微生物的多样性及其功能的发挥，以达到维持肠道微环境“稳态”的目的[64]。然而，人们在临床指标中发现，给药后往往呈现噬菌体数量指数级扩增的现象，且在动力学的角度分析发现，噬菌体扩增规律是非恒定的，但与给药剂量、给药时间、宿主免疫反应强度具有密切相关性[65]。由于这种复杂的相关性，目前关于噬菌体介导的肠道微生物调节也仅停留在实验室研究阶段。

5 展望

近年来，人们对肠道菌群的研究愈发广泛和深入。肠道菌群能影响宿主的新陈代谢、生理和免疫系统。肠道菌群的组成受到多种因素的影响，如饮食、年龄、药物和生活方式等。肠道菌群结构和功能的改变直接影响人体的健康，对多种疾病的发生和发展起着重要作用。因此，对肠道菌群和宿主之间的关系进行进一步系统性的研究是非常必要的。此外，在临床应用中，如益生元辅助的食疗和粪菌移植等手段在肠道疾病的治疗过程中具有巨大潜力。结合不同学科的研究技术和方法，深入探究肠道菌群与人体健康的相互关系，开发应用基于肠道菌群功能的食品和药物，对胃肠道疾病的预防与治疗具有重要意义。

参考文献

[1] GILBERT J A,BLASER M J,et al.Current understand‐ ing of the human microbiome[J].Nat Med,2018,24(4):392-400.

[2] HUMAN MICROBIOME PROJECT C.Structure,func‐ tion and diversity of the healthy human microbiome[J].Nature,2012,486(7402):207-214.

[3] YATSUNENKO T,REY F E,MANARY M J,et al.Hu‐ man gut microbiome viewed across age and geography[J].Nature,2012,486(7402):222-227.

[4] ROWLAND I,GIBSON G,HEINKEN A,et al.Gut mi‐ crobiota functions:metabolism of nutrients and other food components[J].Eur J Nutr,2017,57(1):1-24.

[5] SHETTY S A,HUGENHOLTZ F,LAHTI L,et al.Intesti‐ nal microbiome landscaping:insight in community assem‐ blage and implications for microbial modulation strate‐ gies[J].FEMS Microbiol Rev,2017,41(2):182-199.

[6] NOGACKA A M,GÓMEZ-MARTÍN,MARÍA S,et al.Xenobiotics formed during food processing their relation with the intestinal microbiota and colorectal cancer[J].INT J MOL SCI,2019,20(8):2051-2068.

[7] WAN M L Y,LING K H,EL-NEZAMI H,et al.Influ‐ ence of functional food components on gut health[J].Crit Rev Food Sci Nutr,2018,59(12):1927-1936.

[8] VERBEKE K A,BOOBIS A R,CHIODINI A,et al.To‐ wards microbial fermentation metabolites as markers for health benefits of prebiotics[J].Nutr Res Rev,2015,28(1):42-66.

[9] HILLS R D,PONTEFRACT B A,MISHCDN H R,et al.Gut microbiome:profound implications for diet and dis‐ ease[J].Nutrients,2019,11(7):1613-1653.

[10] SONG S J,DOMINGUEZ-BELLO M G,KNIGHT R.How delivery mode and feeding can shape the bacterial community in the infant gut[J].CMAJ,2013,185(5):384-394.

[11] LEE S A,LIM J Y,KIM B S,et al.Comparison of the gut microbiota profile in breast-fed and formula-fed Korean infants using pyrosequencing[J].Nutr Res Pract,2015,9(3):242-248.

[12] RAY K.Gut microbiota:filling up on fibre for a healthy gut[J].Nat Rev Gastro Hepat,2018,15(2):67.

[13] ZHAO L N,ZHANG F,DING X Y,et al.Gut bacteria selectively promoted by dietary fibers alleviate type 2 diabetes[J].Science,2018,359(6380):1151-1156.

[14] FOROUHI N G,KRAUSS R M,TAUBES G,et al.Di‐ etary fat and cardiometabolic health evidence,controver‐ sies,and consensus for guidance[J].BMJ,2018,361:K2139.

[15] JETHWANI P,GROVER K.Gut microbiota in health and diseases-a review[J].Int J Curr Microbiol Appl Sci,2019,8(8):1586-1599.

[16] DEL CHIERICO F,VERNOCCHI P,PETRUCCA A,et al.Phylogenetic and metabolic tracking of gut microbiota dur‐ing per-inatal development[J].PLoS One,2015,10(9):e0137347.

[17] SCHANCHE M,AVERSHINA E,DOTTERUD C,et al.High-resolution analyses of overlap in the microbiota between mothers and their children[J].Curr Microbiol,2015,71(2):283-290.

[18] HOLLISTER E B,RIEHLE K,LUNA R A,et al.Struc‐ ture and function of the healthy pre-adolescent pediatric gut microbiome[J].Microbiome,2015,3(1):36-45.

[19] REYES A,HAYNES M,HANSON N,et al.Viruses in the faecal microbiota of monozygotic twins and their mothers[J].Nature,2010,466(7304):334-338.

[20] THOMPSON A,MONTEAGUDO-MERA A,CADENAS M,et al.Milk-and solid-feeding practices and daycare attendance are associated with differences in bacterial diversity,predominant communities,and metabolic and immune function of the infant gut microbiome[J].Front Cell Infect Microbiol,2015,5(3):1-8.

[21] BIAGI E,RAMPELLI S,TURRONI S,et al.The gut microbiota of centenarians:signatures of longevity in the gut microbiota profile[J].Mech of Ageing and Dev,2017,165(Pt B):180-184.

[22] HUGHES R L.A review of the role of the gut microbi‐ ome in personalized sports nutrition[J].Front Nutr,2019,6:191.

[23] ALLEN J M,MAILING L J,NIEMIRO G M,et al.Exer‐ cise alters gut microbiota composition and function in lean and obese humans[J].Med Sci Sports Exerc,2018,50(4):747-757.

[24] KLINGENSMITH N J,COOPERSMITH C M.The gut as the motor of multiple organ dysfunction in critical illness[J].Crit Care Clin,2016,32(2):203-212.

[25] DETHLEFSEN L,RELMAN D A.Incomplete recovery and individualized responses of the human distal gut mi‐ crobiota to repeated antibiotic perturbation[J].Proc Natl Acad Sci USA,2011,108(Suppl 1):4554-4561.

[26] ISAAC S,SCHER J U,DJUKOVIC A,et al.Short-and long-term effects of oral vancomycin on the human intesti‐ nal microbiota[J].J Antimicrob Chemother,2017,72(1):128-136.

[27] JAKOBSSON H E,JERNBERG C,ANDERSSON A F,et al.Short-term antibiotic treatment has differing longterm impacts on the human throat and gut microbiome[J].PLoS One,2010,5(3):983-996.

[28] MARTÍNEZ I,STEGEN J C,MALDONADO-GÓMEZ M X,et al.The gut microbiota of rural papua new guin‐ eans composition,diversity patterns,and ecological pro‐ cesses[J].Cell Rep,2015,11(4):527-538.

[29] ZHU A,SUNAGAWA S,MENDE D R,et al.Inter-indi‐ vidual differences in the gene content of human gut bacte‐ rial species[J].Genome Biol,2015,16(1):82.

[30] LORENZO J M,MUNEKATA P E S,GÓMEZ B,et al.Bioactive peptides as natural antioxidants in food prod,ucts-a review[J].Trends in Food Scienc & Technolgy,2018,79:136-147.

[31] AL-SHERAJI S H,ISMAIL A,MANAP M Y,et al.Prebi‐ otics as functional foods:a review[J].J Funct Foods,2013,5(4):1542-1553.

[32] PENG M,TABASHSUM Z,ANDERSON M,et al.Effec‐ tiveness of probiotics,prebiotics,and prebiotic-like com‐ ponents in common functional foods[J].Compr Rev Food SCI F,2020,19(4):1908-1933.

[33] AGUILAR-TOALA J E,HALL F G,URBIZO-REYES U C,et al.In silico prediction and in vitro assessment of multifunctional properties of postbiotics obtained from two probiotic bacteria[J].Probiotics Antimicrob Proteins,2020,12(2):608-622.

[34] SANDERS M E,MERENSTEIN D J,REID G,et al.Pro‐ biotics and prebiotics in intestinal health and disease:from biology to the clinic[J].Nat Rev Gastro Hepat,2019,16(10):605-616.

[35] BIRKELAND E,GHARAGOZLIAN S,BIRKELAND K I,et al.Prebiotic effect of inulin-type fructans on faecal microbiota and short-chain fatty acids in type 2 diabetes:a randomised controlled trial[J].Eur J Nutr,2020,59(7):3325-3338.

[36] VULEVIC J,JURIC A,WALTON G E,et al.Influence of galacto-oligosaccharide mixture(B-GOS)on gut micro‐ biota,immune parameters and metabonomics in elderly persons[J].Brit J Nutr,2015,114(4):586-595.

[37] METZLER-ZEBELI B U,CANIBE N,MONTAGNE L,et al.Resistant starch reduces large intestinal pH and promotes fecal lactobacilli and bifidobacteria in pigs[J].Animal,2019,13(1):64-73.

[38] RIVERA-HUERTA M,LIZARRAGA-GRIMES V L,CASTRO-TORRES I G,et al.Functional effects of prebi‐ otic fructans in colon cancer and calcium metabolism in animal models[J].Biomed Res Int,2017,2017:9758982.

[39] SCHOLZ-AHRENS K E,SCHAAFSMA G,VAN DEN HEUVEL E G H M,et al.Effects of prebiotics on mineral metabolism[J].Am J Clin Nutr,2001,73(2):459-464.

[40] MAKKI K,DEEHAN E C,WALTER J,et al.The impact of dietary fiber on gut microbiota in host health and disease[J].Cell Host Microbe,2018,23(6):705-715.

[41] WHISNER C M,MARTIN B R,SCHOTERMAN M H,et al.Galacto-oligosaccharides increase calcium absorp‐ tion and gut bifidobacteria in young girls:a double-blind cross-over trial[J].Br J Nutr,2013,110(7):1292-1303.

[42] PRETORIUS R,PRESCOTT S L,PALMER D J.Taking prebiotic approach to early immunomodulation for aller‐ gy prevention[J].Expert Rev Clin Immu,2018,14:43-51.

[43] YAHFOUFI N,MALLET J F,GRAHAM E,et al.Role of probiotics and prebiotics in immunomodulation[J].Curr Opin Food SCI,2018,20:82-91.

[44] DANNESKIOLD-SAMSOE N B,DIAS DE FREITAS QUEIROZ BARROS H,SANTOS R,et al.Interplay be‐ tween food and gut microbiota in health and disease[J].Food Res Int,2019,115:23-31.

[45] HE Q,GAO Y,JIE Z,et al.Two distinct metacommuni‐ ties characterize the gut microbiota in Crohn's disease patients[J].GigaScience,2017,6(7):1-11.

[46] SHARMA M,SHUKLA G.Metabiotics:one step ahead of probiotics;an insight into mechanisms involved in anticancerous effect in colorectal cancer[J].Front Micro‐ biol,2016,7:1940.

[47] FEMIA A P,LUCERI C,DOLARA P,et al.Antitumori‐ genic activity of the prebiotic inulin enriched with oligo‐ fructose in combination with the probiotics lactobacillus rhamnosus and bifidobacterium lactis on azoxymethan[J].Carcinogenesis,2002,23(1):1953-1960.

[48] VERGHESE M,RAO D R,CHAWAN C B,et al.Dietary inulin suppresses azoxymethane-induced aberrant crypt foci and colon tumors at the promotion stage in young Fish‐ er 344 rats[J].J Nutr,2002,132(9):2809-2813.

[49] RAMAN M,AMBALAM P,KONDEPUDI K K,et al.Potential of probiotics,prebiotics and synbiotics for management of colorectal cancer[J].Gut Microbes,2013,4(3):181-192.

[50] WEN Y,WEN P,HU T G,et al.Encapsulation of phy‐ cocyanin by prebiotics and polysaccharides-based elec‐ trospun fibers and improved colon cancer prevention effects[J].Int J Biol Macromol 2020,149:672-681.

[51] ZITVOGEL L,DAILLERE R,ROBERTI M P,et al.Anticancer effects of the microbiome and its products[J].Nat Rev Microbiol,2017,15(8):465-478.

[52] SHENDEROV B A.Metabiotics:novel idea or natural development of probiotic conception[J].Microb Ecol Health Dis,2013,24:20399.

[53] RAY K.Gut microbiota:the gut virome and bacterial mi‐ crobiome-the early years[J].Nat Rev Gastro Hepat,2015,12(11):609.

[54] LA FATA G,WEBER P,MOHAJERI M H.Probiotics and the gut immune system:indirect regulation[J].Probi‐ otics Antimicro,2018,10(1):11-21.

[55] IKRAM S,HASSAN N,RAFFAT M A,et al.Systematic review and meta-analysis of double-blind,placebo-con‐ trolled,randomized clinical trials using probiotics in chronic periodontitis[J].J Investig Clin Dent,2018,9(3):e12338.

[56] HSIEH M.The microbiome and probiotics in childhood[J].Semin Reprod Med,2014,32(1):23-27.

[57] AMBALAM P,RAMAN M,PURAMA R K,et al.Probi‐ otics,prebiotics and colorectal cancer prevention[J].Best Pract Res Clin Gastroenterol,2016,30(1):119-131.

[58] HENDIJANI F,AKBARI V.Probiotic supplementation for management of cardiovascular risk factors in adults with type Ⅱdiabetes:a systematic review and meta-analy‐ sis[J].Clin Nutr,2018,37(2):532-541.

[59] KHORUTS A,SADOWSKY M J.Understanding the mechanisms of faecal microbiota transplantation[J].Nat Rev Gastro Hepat,2016,13(9):508-516.

[60] LI S S,ZHU A,BENES V,et al.Durable coexistence of donor and recipient strains after fecal microbiota trans‐ plantation[J].Science,2016,352(6285):586-589.

[61] HOLVOET T,JOOSSENS M,WANG J,et al.Assess‐ ment of faecal microbial transfer in irritable bowel syn‐ drome with severe bloating[J].Gut,2017,66(5):980-982.

[62] JOHNSEN P H,HILPÜSCH F,CAVANAGH J P,et al.Faecal microbiota transplantation versus placebo for moderate-to-severe irritable bowel syndrome:a doubleblind,randomised,placebo-controlled,parallel-group,sin‐ gle-centre trial[J].The Lancet Gastroenterology & Hepa‐ tology,2018,3(1):17-24.

[63] GIANOTTI R J,MOSS A C.Fecal microbiota transplanta‐ tion from clostridium difficile to inflammatory bowel disease[J].Gastroenterol Hepatol(NY),2017,13(4):209-213.

[64] SCARPELLINI E,IANIRO G,ATTILI F,et al.The hu‐ man gut microbiota and virome:potential therapeutic implications[J].Dig Liver Dis,2015,47(12):1007-1012.

[65] PARRACHO H,BURROWES B,ENRIGHT M,et al.The role of regulated clinical trials in the development of bacteriophage therapeutics[J].J Mol Med,2012,6:279-286.

基本信息

中图分类号: R333.3
文献标识码: A
DOI: 10.13885/j.issn.2096-8965.20210206
文章编号: 2096-8965(2021)02-0039-07

基金信息

兰州大学第二医院萃英科技创新计划 (2020QN-08)；

引用信息

稿件历史

收稿日期: 2020-11-25