肠道菌群的分子致病机制及营养干预研究进展

罗绽; 陈磊

doi:10.13386/j.issn1002-0306.2022090055

肠道菌群的分子致病机制及营养干预研究进展

doi: 10.13386/j.issn1002-0306.2022090055

罗绽,
陈磊^*, ,

天津大学化工学院，天津 300350

基金项目: 国家重点研发计划（2020YFA0906800）。

详细信息

作者简介:
罗绽（2001−），女，本科，研究方向：分子生物学与生物化学，E-mail：roseluoz@foxmail.com

通讯作者:
陈磊（1979−），男，博士，教授，研究方向：微生物合成生物学，E-mail：lchen@tju.edu.cn

中图分类号: Q939.99
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- 文章访问数: 30
- HTML全文浏览量: 25
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- 被引次数: 0
出版历程
- 收稿日期: 2022-09-08
- 刊出日期: 2023-05-15

Research Progress of Molecular Pathogenic Mechanism and Nutritional Intervention of Gut Microbiome

LUO Zhan,
CHEN Lei^{*
, ,}

School of Chemical Engineering and Technology, Tianjin University, Tianjin 300350, China

摘要

摘要: 肠道菌群的丰度、种类发生变化能够导致疾病发生，许多基础疾病和神经系统疾病被证实与肠道菌群有关。探究肠道菌群的分子致病机制是定向调控肠道菌群从而治愈疾病的基础。本文综述了肠道菌群中功能基因差异导致代谢失调、促炎因子引发炎症级联反应、菌群介导免疫细胞分化和脑-肠轴影响大脑活动的4种分子致病机制，提出了从关联分析出发到分子机制研究的“自上而下”的研究模式，以及针对对应的致病机制发展出的营养干预策略。未来可基于“自上而下”的模式深入研究肠道菌群致病机制，并从致病机制出发，精准地进行营养干预。
- 肠道菌群 /
- 致病机制 /
- 营养干预
Abstract: Changes in the abundance and types of gut microbiome can lead to diseases, and many basic and nervous system diseases have been confirmed to be related to gut microbiome. Exploring the molecular pathogenic mechanism of gut microbiome is the basis of directed regulation of gut microbiome to cure diseases. In this review, four molecular pathogenic mechanisms, including metabolic disorder caused by functional gene difference in gut microbiome, inflammatory cascade caused by proinflammatory factors, immune cell differentiation mediated by flora, and brain gut axis affecting brain activity are summarized. A "top-down" research approach, beginning with association analysis to molecular mechanism investigation is proposed, and nutritional intervention strategies developed for the corresponding pathogenic mechanisms are also summarized. In the future, the pathogenic mechanism of gut microbiome can be further studied employing the "top-down" approach, and nutritional intervention can be carried out more accurately basing on the relative pathogenic mechanism.
- gut microbiome /
- pathogenic mechanism /
- nutritional intervention

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参考文献(69)

[1]	BÄCKHED F, LEY R E, SONNENBURG J L, et al. Host-bacterial mutualism in the human intestine[J]. Science,2005,307(5717):1915−1920. doi: 10.1126/science.1104816
[2]	METWALY A, REITMEIER S, HALLER D. Microbiome risk profiles as biomarkers for inflammatory and metabolic disorders[J]. Nat Rev Gastroenterol Hepatol,2022,19(6):383−397. doi: 10.1038/s41575-022-00581-2
[3]	XU X, OCANSEY D K W, HANG S, et al. The gut metagenomics and metabolomics signature in patients with inflammatory bowel disease[J]. Gut Pathog,2022,14(1):26. doi: 10.1186/s13099-022-00499-9
[4]	CANI P D, DEPOMMIER C, DERRIEN M, et al. Akkermansia muciniphila: Paradigm for next-generation beneficial microorganisms[J]. Nat Rev Gastroenterol Hepatol,2022(10):625−637.
[5]	ZHAO L, ZHANG F, DING X, et al. Gut bacteria selectively promoted by dietary fibers alleviate type 2 diabetes[J]. Science,2018,359(6380):1151−1156. doi: 10.1126/science.aao5774
[6]	IVANOV II, TUGANBAEV T, SKELLY A N, et al. T cell responses to the microbiota[J]. Annu Rev Immunol,2022,40:559−587. doi: 10.1146/annurev-immunol-101320-011829
[7]	PEREZ-PARDO P, DODIYA H B, ENGEN P A, et al. Role of TLR4 in the gut-brain axis in Parkinson's disease: A translational study from men to mice[J]. Gut,2019,68(5):829−843. doi: 10.1136/gutjnl-2018-316844
[8]	TAN A H, LIM S Y, LANG A E. The microbiome-gut-brain axis in Parkinson disease-from basic research to the clinic[J]. Nat Rev Neurol,2022,18(8):476−495. doi: 10.1038/s41582-022-00681-2
[9]	BISGAARD T H, ALLIN K H, KEEFER L, et al. Depression and anxiety in inflammatory bowel disease: Epidemiology, mechanisms and treatment[J]. Nat Rev Gastroenterol Hepatol,2022,19(11):717−726. doi: 10.1038/s41575-022-00634-6
[10]	WALTER J, ARMET A M, FINLAY B B, et al. Establishing or exaggerating causality for the gut microbiome: Lessons from human microbiota-associated rodents[J]. Cell,2020,180(2):221−232. doi: 10.1016/j.cell.2019.12.025
[11]	ZHAO L, ZHAO N. Demonstration of causality: Back to cultures[J]. Nat Rev Gastroenterol Hepatol,2021,18(2):97−98. doi: 10.1038/s41575-020-00400-6
[12]	HOU Y, WEI W, GUAN X, et al. A diet-microbial metabolism feedforward loop modulates intestinal stem cell renewal in the stressed gut[J]. Nat Commun,2021,12(1):271. doi: 10.1038/s41467-020-20673-4
[13]	ZHANG L, YUE Y, SHI M, et al. Dietary Luffa cylindrica (L.) Roem promotes branched-chain amino acid catabolism in the circulation system via gut microbiota in diet-induced obese mice[J]. Food Chem,2020,320:126648. doi: 10.1016/j.foodchem.2020.126648
[14]	VIOLI F, CAMMISOTTO V, BARTIMOCCIA S, et al. Gut-derived low-grade endotoxaemia, atherothrombosis and cardiovascular disease[J]. Nat Rev Cardiol, 2022: 1-14.
[15]	TURPIN W, DONG M, SASSON G, et al. Mediterranean-like dietary pattern associations with gut microbiome composition and subclinical gastrointestinal inflammation[J]. Gastroenterology,2022,163(3):685−698. doi: 10.1053/j.gastro.2022.05.037
[16]	YAO S, ZHANG M, DONG S S, et al. Bidirectional two-sample Mendelian randomization analysis identifies causal associations between relative carbohydrate intake and depression [J]. Nat Hum Behav, 2022,6(11):1569-1576.
[17]	FEI N, ZHAO L. An opportunistic pathogen isolated from the gut of an obese human causes obesity in germfree mice[J]. Isme J,2013,7(4):880−884. doi: 10.1038/ismej.2012.153
[18]	BLACHER E, BASHIARDES S, SHAPIRO H, et al. Potential roles of gut microbiome and metabolites in modulating ALS in mice[J]. Nature,2019,572(7770):474−480. doi: 10.1038/s41586-019-1443-5
[19]	SIDO B, HACK V, HOCHLEHNERT A, et al. Impairment of intestinal glutathione synthesis in patients with inflammatory bowel disease[J]. Gut,1998,42(4):485−492. doi: 10.1136/gut.42.4.485
[20]	CHENG M, ZHAO Y, CUI Y, et al. Stage-specific roles of microbial dysbiosis and metabolic disorders in rheumatoid arthritis[J]. Ann Rheum Dis, 2022,81(12):1669-1677.
[21]	FEI N, BRUNEAU A, ZHANG X, et al. Endotoxin producers overgrowing in human gut microbiota as the causative agents for nonalcoholic fatty liver disease[J]. mBio,2020,11(1):e03263−19.
[22]	LAMAS B, RICHARD M L, LEDUCQ V, et al. CARD9 impacts colitis by altering gut microbiota metabolism of tryptophan into aryl hydrocarbon receptor ligands[J]. Nat Med,2016,22(6):598−605. doi: 10.1038/nm.4102
[23]	SROUR B, KORDAHI M C, BONAZZI E, et al. Ultra-processed foods and human health: From epidemiological evidence to mechanistic insights[J]. Lancet Gastroenterol Hepatol,2022,S2468-1253(22):00169−8.
[24]	ECKBURG P B, BIK E M, BERNSTEIN C N, et al. Diversity of the human intestinal microbial flora[J]. Science,2005,308(5728):1635−1638. doi: 10.1126/science.1110591
[25]	PRYDE S E, DUNCAN S H, HOLD G L, et al. The microbiology of butyrate formation in the human colon[J]. FEMS Microbiol Lett,2002,217(2):133−139. doi: 10.1111/j.1574-6968.2002.tb11467.x
[26]	LOOMBA R, SANYAL A J. The global NAFLD epidemic[J]. Nat Rev Gastroenterol Hepatol,2013,10(11):686−690. doi: 10.1038/nrgastro.2013.171
[27]	LI J, CASANOVA J L, PUEL A. Mucocutaneous IL-17 immunity in mice and humans: Host defense vs. excessive inflammation[J]. Mucosal Immunol,2018,11(3):581−589. doi: 10.1038/mi.2017.97
[28]	OKADA S, MARKLE J G, DEENICK E K, et al. IMMUNODEFICIENCIES. Impairment of immunity to Candida and Mycobacterium in humans with bi-allelic RORC mutations[J]. Science,2015,349(6248):606−613. doi: 10.1126/science.aaa4282
[29]	HONDA K, LITTMAN D R. The microbiota in adaptive immune homeostasis and disease[J]. Nature,2016,535(7610):75−84. doi: 10.1038/nature18848
[30]	KAWANO Y, EDWARDS M, HUANG Y, et al. Microbiota imbalance induced by dietary sugar disrupts immune-mediated protection from metabolic syndrome[J]. Cell,2022,185(19):3501−3519. doi: 10.1016/j.cell.2022.08.005
[31]	GOTO Y, PANEA C, NAKATO G, et al. Segmented filamentous bacteria antigens presented by intestinal dendritic cells drive mucosal Th17 cell differentiation[J]. Immunity,2014,40(4):594−607. doi: 10.1016/j.immuni.2014.03.005
[32]	YANG Y, TORCHINSKY M B, GOBERT M, et al. Focused specificity of intestinal TH17 cells towards commensal bacterial antigens[J]. Nature,2014,510(7503):152−156. doi: 10.1038/nature13279
[33]	ATARASHI K, TANOUE T, ANDO M, et al. Th17 cell induction by adhesion of microbes to intestinal epithelial cells[J]. Cell,2015,163(2):367−380. doi: 10.1016/j.cell.2015.08.058
[34]	SANO T, HUANG W, HALL J A, et al. An IL-23R/IL-22 circuit regulates epithelial serum amyloid a to promote local effector Th17 responses[J]. Cell,2015,163(2):381−393. doi: 10.1016/j.cell.2015.08.061
[35]	LEE J Y, HALL J A, KROEHLING L, et al. Serum amyloid a proteins induce pathogenic th17 cells and promote inflammatory disease[J]. Cell,2020,180(1):79−91. doi: 10.1016/j.cell.2019.11.026
[36]	ZHOU W, ZHOU L, ZHOU J, et al. ZBTB46 defines and regulates ILC3s that protect the intestine[J]. Nature,2022,609(7925):159−165. doi: 10.1038/s41586-022-04934-4
[37]	GRIGG J B, SHANMUGAVADIVU A, REGEN T, et al. Antigen-presenting innate lymphoid cells orchestrate neuroinflammation[J]. Nature,2021,600(7890):707−712. doi: 10.1038/s41586-021-04136-4
[38]	ZHANG M, CHU Y, MENG Q, et al. A quasi-paired cohort strategy reveals the impaired detoxifying function of microbes in the gut of autistic children[J]. Sci Adv,2020,6(43):eaba3760. doi: 10.1126/sciadv.aba3760
[39]	SHARON G, CRUZ N J, KANG D W, et al. Human gut microbiota from autism spectrum disorder promote behavioral symptoms in mice[J]. Cell,2019,177(6):1600−1618. doi: 10.1016/j.cell.2019.05.004
[40]	LIU Y, YANG M, TANG L, et al. TLR4 regulates RORγt(+) regulatory T-cell responses and susceptibility to colon inflammation through interaction with Akkermansia muciniphila[J]. Microbiome,2022,10(1):98. doi: 10.1186/s40168-022-01296-x
[41]	ZHANG J H, XIN H L, XU Y M, et al. Morinda officinalis How. —A comprehensive review of traditional uses, phytochemistry and pharmacology[J]. J Ethnopharmacol,2018,213:230−255. doi: 10.1016/j.jep.2017.10.028
[42]	CHI L, CHEN L, ZHANG J, et al. Development and application of bio-sample quantification to evaluate stability and pharmacokinetics of inulin-type fructo-oligosaccharides from Morinda officinalis[J]. J Pharm Biomed Anal,2018,156:125−132. doi: 10.1016/j.jpba.2018.04.028
[43]	ZHANG Z W, GAO C S, ZHANG H, et al. Morinda officinalis oligosaccharides increase serotonin in the brain and ameliorate depression via promoting 5-hydroxytryptophan production in the gut microbiota[J]. Acta Pharm Sin B,2022,12(8):3298−3312. doi: 10.1016/j.apsb.2022.02.032
[44]	HUANG F, ZHENG X, MA X, et al. Theabrownin from Pu-erh tea attenuates hypercholesterolemia via modulation of gut microbiota and bile acid metabolism[J]. Nat Commun,2019,10(1):4971. doi: 10.1038/s41467-019-12896-x
[45]	BOLTE L A, VICH VILA A, IMHANN F, et al. Long-term dietary patterns are associated with pro-inflammatory and anti-inflammatory features of the gut microbiome[J]. Gut,2021,70(7):1287−1298. doi: 10.1136/gutjnl-2020-322670
[46]	KE S, WEISS S T, LIU Y Y. Rejuvenating the human gut microbiome[J]. Trends Mol Med,2022,28(8):619−630. doi: 10.1016/j.molmed.2022.05.005
[47]	CHEN D, WU J, JIN D, et al. Fecal microbiota transplantation in cancer management: Current status and perspectives[J]. Int J Cancer,2019,145(8):2021−2031. doi: 10.1002/ijc.32003
[48]	KEDIA S, VIRMANI S, S K V, et al. Faecal microbiota transplantation with anti-inflammatory diet (FMT-AID) followed by anti-inflammatory diet alone is effective in inducing and maintaining remission over 1 year in mild to moderate ulcerative colitis: A randomised controlled trial[J]. Gut, 2022,71(12):2401-2413.
[49]	FEDERICI S, KREDO-RUSSO S, VALDéS-MAS R, et al. Targeted suppression of human IBD-associated gut microbiota commensals by phage consortia for treatment of intestinal inflammation[J]. Cell,2022,185(16):2879−2898. doi: 10.1016/j.cell.2022.07.003
[50]	TANG S, CHEN Y, DENG F, et al. Xylooligosaccharide-mediated gut microbiota enhances gut barrier and modulates gut immunity associated with alterations of biological processes in a pig model[J]. Carbohydr Polym,2022,294:119776. doi: 10.1016/j.carbpol.2022.119776
[51]	HE X Q, LIU D, LIU H Y, et al. Prevention of ulcerative colitis in mice by sweet tea (Lithocarpus litseifolius) via the regulation of gut microbiota and butyric-acid-mediated anti-inflammatory signaling[J]. Nutrients,2022,14(11):2208. doi: 10.3390/nu14112208
[52]	ZHAO Y, JIANG Q. Roles of the polyphenol-gut microbiota interaction in alleviating colitis and preventing colitis-associated colorectal cancer[J]. Adv Nutr,2021,12(2):546−565. doi: 10.1093/advances/nmaa104
[53]	PANDEY K B, RIZVI S I. Plant polyphenols as dietary antioxidants in human health and disease[J]. Oxid Med Cell Longev,2009,2(5):270−278. doi: 10.4161/oxim.2.5.9498
[54]	CANTU-JUNGLES T M, BULUT N, CHAMBRY E, et al. Dietary fiber hierarchical specificity: The missing link for predictable and strong shifts in gut bacterial communities[J]. mBio,2021,12(3):e0102821. doi: 10.1128/mBio.01028-21
[55]	ZHANG X, MONNOYE M, MARIADASSOU M, et al. Glucose but not fructose alters the intestinal paracellular permeability in association with gut inflammation and dysbiosis in mice[J]. Front Immunol,2021,12:742584. doi: 10.3389/fimmu.2021.742584
[56]	MARTEL J, CHANG S H, KO Y F, et al. Gut barrier disruption and chronic disease[J]. Trends Endocrinol Metab,2022,33(4):247−265. doi: 10.1016/j.tem.2022.01.002
[57]	KOSINSKA A, ANDLAUER W. Modulation of tight junction integrity by food components[J]. Food Research International,2013,54(1):951−960. doi: 10.1016/j.foodres.2012.12.038
[58]	AMASHEH M, FROMM A, KRUG S M, et al. TNFalpha-induced and berberine-antagonized tight junction barrier impairment via tyrosine kinase, Akt and NFkappaB signaling[J]. J Cell Sci, 2010, 123(Pt 23): 4145-4155.
[59]	SUZUKI T, HARA H. Quercetin enhances intestinal barrier function through the assembly of zonula [corrected] occludens-2, occludin, and claudin-1 and the expression of claudin-4 in caco-2 cells[J]. J Nutr,2009,139(5):965−974. doi: 10.3945/jn.108.100867
[60]	MAYANGSARI Y, SUZUKI T. Resveratrol ameliorates intestinal barrier defects and inflammation in colitic mice and intestinal cells[J]. J Agric Food Chem,2018,66(48):12666−12674. doi: 10.1021/acs.jafc.8b04138
[61]	CANI P D, BIBILONI R, KNAUF C, et al. Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice[J]. Diabetes,2008,57(6):1470−1481. doi: 10.2337/db07-1403
[62]	DONG L, XIE J, WANG Y, et al. Mannose ameliorates experimental colitis by protecting intestinal barrier integrity[J]. Nat Commun,2022,13(1):4804. doi: 10.1038/s41467-022-32505-8
[63]	BAE M, CASSILLY C D, LIU X, et al. Akkermansia muciniphila phospholipid induces homeostatic immune responses[J]. Nature,2022,608(7921):168−173. doi: 10.1038/s41586-022-04985-7
[64]	BELKAID Y, HARRISON O J. Homeostatic immunity and the microbiota[J]. Immunity,2017,46(4):562−576. doi: 10.1016/j.immuni.2017.04.008
[65]	ANSALDO E, BELKAID Y. How microbiota improve immunotherapy[J]. Science,2021,373(6558):966−967. doi: 10.1126/science.abl3656
[66]	BEUKEMA M, JERMENDI É, OERLEMANS M M P, et al. The level and distribution of methyl-esters influence the impact of pectin on intestinal T cells, microbiota, and Ahr activation[J]. Carbohydr Polym,2022,286:119280. doi: 10.1016/j.carbpol.2022.119280
[67]	TCHITCHEK N, NGUEKAP TCHOUMBA O, PIRES G, et al. Low-dose interleukin-2 shapes a tolerogenic gut microbiota that improves autoimmunity and gut inflammation[J]. JCI Insight,2022,7(17):e159406. doi: 10.1172/jci.insight.159406
[68]	JENSEN S N, CADY N M, SHAHI S K, et al. Isoflavone diet ameliorates experimental autoimmune encephalomyelitis through modulation of gut bacteria depleted in patients with multiple sclerosis[J]. Sci Adv,2021,7(28):eabd4595. doi: 10.1126/sciadv.abd4595
[69]	EZRA-NEVO G, HENRIQUES S F, RIBEIRO C. The diet-microbiome tango: How nutrients lead the gut brain axis[J]. Curr Opin Neurobiol,2020,62:122−132. doi: 10.1016/j.conb.2020.02.005