Journal Home > Volume 12 , Issue 5

Akkermansia muciniphila, one of the most promising next-generation probiotics, was reported to exhibit beneficial modulatory effects on the gut barrier. However, the strain-specific and underlying regulatory mechanisms of this species on gut barrier function were not well studied. Therefore, this study evaluated the protective effect of A. muciniphila strains on the intestinal barrier and investigated the mode of action and material basis of this modulatory effect. We first confirmed the strain-specific effects of A. muciniphila on intestinal barrier regulation and found that this phenomenon may be explained by the different abilities of strains to affect tight junction protein expression in enterocytes. Comparative genomic analysis proved that the ability of A. muciniphila to regulate the intestinal barrier was exerted in part by the functional genes (such as COG0438, COG0463, and COG2244) related to the synthesis of cellular surface proteins. The role of these surface proteins in intestinal barrier regulation was further verified by strain-comparative experiments in animal and cell models and surface protein removal trials. This study confirmed the different effects of A. muciniphila strains on gut barrier modulation and provided molecular and genetic targets for the screening of A. muciniphila strains with superior protection against gut barrier dysfunction.


menu
Abstract
Full text
Outline
About this article

Strain-specific effects of Akkermansia muciniphila on the regulation of intestinal barrier

Show Author's information Yang Liua,bQing Liua,bChengcheng Zhanga,bJianxin Zhaoa,bHao Zhanga,b,cWei Chena,bQixiao Zhaia,b( )
State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi 214122, China
National Engineering Research Center for Functional Food, Jiangnan University, Wuxi 214122, China
Wuxi Translational Medicine Research Center and Jiangsu Translational Medicine Research Institute Wuxi Branch, Wuxi 214122, China

Peer review under responsibility of KeAi Communications Co., Ltd.

Abstract

Akkermansia muciniphila, one of the most promising next-generation probiotics, was reported to exhibit beneficial modulatory effects on the gut barrier. However, the strain-specific and underlying regulatory mechanisms of this species on gut barrier function were not well studied. Therefore, this study evaluated the protective effect of A. muciniphila strains on the intestinal barrier and investigated the mode of action and material basis of this modulatory effect. We first confirmed the strain-specific effects of A. muciniphila on intestinal barrier regulation and found that this phenomenon may be explained by the different abilities of strains to affect tight junction protein expression in enterocytes. Comparative genomic analysis proved that the ability of A. muciniphila to regulate the intestinal barrier was exerted in part by the functional genes (such as COG0438, COG0463, and COG2244) related to the synthesis of cellular surface proteins. The role of these surface proteins in intestinal barrier regulation was further verified by strain-comparative experiments in animal and cell models and surface protein removal trials. This study confirmed the different effects of A. muciniphila strains on gut barrier modulation and provided molecular and genetic targets for the screening of A. muciniphila strains with superior protection against gut barrier dysfunction.

Keywords: Comparative genomics, Akkermansia muciniphila, Intestinal barrier, Strain specificity, Bacterial surface components

References(74)

[1]

S. Citi, Intestinal barriers protect against disease, Science 359 (2018) 1097-1098. https://doi.org/10.1126/science.aat0835.

[2]

J. König, J. Wells, P.D. Cani, et al., Human intestinal barrier function in health and disease, Clin. Transl. Gastroenterol. 7 (2016) 196. https://doi.org/10.1038/ctg.2016.54.

[3]

Y. Liu, Y. Li, X. Yu, et al., Physiological characteristics of Lactobacillus casei strains and their alleviation effects against inflammatory bowel disease, J. Microbiol. Biotechnol. 31 (2021) 92-103. https://doi.org/10.4014/jmb.2003.03041.

[4]

V.T.E. Aho, M.C. Houser, P.A.B. Pereira, et al., Relationships of gut microbiota, short-chain fatty acids, inflammation, and the gut barrier in Parkinson's disease, Mol. Neurodegener. 16 (2021) 6. https://doi.org/10.1186/s13024-021-00427-6.

[5]

C. Sorini, I. Cosorich, M.L. Conte, et al., Loss of gut barrier integrity triggers activation of islet-reactive T cells and autoimmune diabetes, Proc. Natl. Acad. Sci. U.S.A. 116 (2019) 15140-15149. https://doi.org/10.1073/pnas.1814558116.

[6]

A. Nenci, C. Becker, A. Wullaert, et al., Epithelial NEMO links innate immunity to chronic intestinal inflammation, Nature 446 (2007) 557-561. https://doi.org/10.1038/nature05698.

[7]

C. Günther, E. Martini, N. Wittkopf, et al., Caspase-8 regulates TNF-α-induced epithelial necroptosis and terminal ileitis, Nature 477 (2011) 335-339. https://doi.org/10.1038/nature10400.

[8]

N. Takahashi, L. Vereecke, M.J. Bertrand, et al., RIPK1 ensures intestinal homeostasis by protecting the epithelium against apoptosis, Nature 513 (2014) 95-99. https://doi.org/10.1038/nature13706.

[9]

G.T. Brennan, S.D. Melton, S.J. Spechler, et al., Clinical implications of histologic abnormalities in ileocolonic biopsies of patients with Crohn's disease in remission, J. Clin. Gastroenterol. 51 (2017) 43-48. https://doi.org/10.1097/MCG.0000000000000507.

[10]

E.O. Glocker, D. Kotlarz, K. Boztug, et al., Inflammatory bowel disease and mutations affecting the interleukin-10 receptor, N. Engl. J. Med. 361 (2009) 2033-2045. https://doi.org/10.1056/NEJMoa0907206.

[11]

W. Shin, H.J. Kim, Intestinal barrier dysfunction orchestrates the onset of inflammatory host-microbiome cross-talk in a human gut inflammation-on-a-chip, Proc. Natl. Acad. Sci. U.S.A. 115 (2018) E10539-E10547. https://doi.org/10.1073/pnas.1810819115.

[12]

S.N. Casarotti, B.M. Carneiro, A.L. Penna, Evaluation of the effect of supplementing fermented milk with quinoa flour on probiotic activity, J. Dairy Sci. 97 (2014) 6027-6035. https://doi.org/10.3168/jds.2014-8197.

[13]

S.N. Spohn, F. Bianco, R.B. Scott, et al, Protective actions of epithelial 5-hydroxytryptamine 4 receptors in normal and inflamed colon, Gastroenterology 151 (2016) 933-944. https://doi.org/10.1053/j.gastro.2016.07.032.

[14]

L. van der Ploeg, H. Laken, S. Sharma, et al., Preclinical gastrointestinal prokinetic efficacy and endocrine effects of the ghrelin mimetic RM-131, Life Sci. 109 (2014) 20-29. https://doi.org/10.1016/j.lfs.2014.06.003.

[15]

A. Swidsinski, Y. Dörffel, V. Loening-Baucke, et al., Acute appendicitis is characterised by local invasion with Fusobacterium Nucleatum/necrophorum, Gut 60 (2011) 34-40. https://doi.org/10.1136/gut.2009.191320.

[16]

J. Li, F. Zhao, Y. Wang, et al., Gut microbiota dysbiosis contributes to the development of hypertension, Microbiome 5 (2017) 14. https://doi.org/10.1186/s40168-016-0222-x.

[17]

L. Wang, C.T. Christophersen, M.J. Sorich, et al., Low relative abundances of the mucolytic bacterium Akkermansia muciniphila and Bifidobacterium spp. in feces of children with autism, Appl. Environ. Microbiol. 77 (2011) 6718-6721. https://doi.org/10.1128/AEM.05212-11.

[18]

C.W. Png, S.K. Lindén, K.S. Gilshenan, et al., Mucolytic bacteria with increased prevalence in IBD mucosa augment in vitro utilization of mucin by other bacteria, Am. J. Gastroenterol. 105 (2010) 2420-2428. https://doi.org/10.1038/ajg.2010.281.

[19]

C. Chelakkot, Y. Choi, D.K. Kim, et al., Akkermansia muciniphila-derived extracellular vesicles influence gut permeability through the regulation of tight junctions, Exp. Mol. Med. 50 (2018) 450. https://doi.org/10.1038/emm.2017.282.

[20]

A. Everard, C. Belzer, L. Geurts, et al., Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity, Proc. Natl. Acad. Sci. U.S.A. 110 (2013) 9066-9071. https://doi.org/10.1073/pnas.1219451110.

[21]

N. Ottman, J. Reunanen, M. Meijerink, et al., Pili-like proteins of Akkermansia muciniphila modulate host immune responses and gut barrier function, PLoS ONE 12 (2017) 0173004. https://doi.org/10.1371/journal.pone.0173004.

[22]

S. Kim, Y.C. Shin, T.Y. Kim, et al., Mucin degrader Akkermansia muciniphila accelerates intestinal stem cell-mediated epithelial development, Gut Microbes. 13 (2021) 1-20. https://doi.org/10.1080/19490976.2021.1892441.

[23]

K. He, Y. Hu, H. Ma, et al., Rhizoma Coptidis alkaloids alleviate hyperlipidemia in B6 mice by modulating gut microbiota and bile acid pathways, Biochim. Biophys. Acta. 1862 (2016) 1696-1709. https://doi.org/10.1016/j.bbadis.2016.06.006.

[24]

C.S. Kang, M. Ban, E.J. Choi, et al., Extracellular vesicles derived from gut microbiota, especially Akkermansia muciniphila, protect the progression of dextran sulfate sodium-induced colitis, PLoS ONE 8 (2013) 76520. https://doi.org/10.1371/journal.pone.0076520.

[25]

C. Depommier, A. Everard, C. Druart, et al., Supplementation with Akkermansia muciniphila in overweight and obese human volunteers: a proof-of-concept exploratory study, Nat. Med. 25 (2019) 1096-1103. https://doi.org/10.1038/s41591-019-0495-2.

[26]

T. Secher, S. Kassem, M. Benamar, et al., Oral administration of the probiotic strain Escherichia coli Nissle 1917 reduces susceptibility to neuroinflammation and repairs experimental autoimmune encephalomyelitis-induced intestinal barrier dysfunction, Front. Immunol. 8 (2017) 1096. https://doi.org/10.3389/fimmu.2017.01096.

[27]

N.L. Mancini, S. Rajeev, T.S. Jayme, et al., Crohn's disease pathobiont adherent-invasive E. coli disrupts epithelial mitochondrial networks with implications for gut permeability, Cell Mol. Gastroenterol. Hepatol. 11 (2021) 551-571. https://doi.org/10.1016/j.jcmgh.2020.09.013.

[28]

L. Chung, E.O. Thiele, A.L. Geis, et al., Bacteroides fragilis toxin coordinates a pro-carcinogenic inflammatory cascade via targeting of colonic epithelial cells, Cell Host Microbe. 23 (2018) 203-214. https://doi.org/10.1016/j.chom.2018.01.007.

[29]

J.L. Chan, S. Wu, A.L. Geis, et al., Non-toxigenic Bacteroides fragilis (NTBF) administration reduces bacteria-driven chronic colitis and tumor development independent of polysaccharide A, Mucosal Immunol. 12 (2019) 164-177. https://doi.org/10.1038/s41385-018-0085-5.

[30]

R. Zhai, X. Xue, L. Zhang, et al., Strain-specific anti-inflammatory properties of two Akkermansia muciniphila strains on chronic colitis in mice, Front. Cell Infect. Microbiol. 9 (2019) 239. https://doi.org/10.3389/fcimb.2019.00239.

[31]

S. Feng, Y. Liu, Y. Huang, et al., Influence of oral administration of Akkermansia muciniphila on the tissue distribution and gut microbiota composition of acute and chronic cadmium exposure mice, FEMS Microbiol. Lett. 366 (2019) fnz160. https://doi.org/10.1093/femsle/fnz160.

[32]

S.J. Lahtinen, C.A. Haskard, A.C. Ouwehand, et al., Binding of aflatoxin B1 to cell wall components of Lactobacillus rhamnosus strain GG, Food Addit. Contam. 21 (2004) 158-164. https://doi.org/10.1080/02652030310001639521.

[33]

A. Hernandez-Mendoza, D. Guzman-de-Peña, H.S. Garcia, Key role of teichoic acids on aflatoxin B binding by probiotic bacteria, J. Appl. Microbiol. 107 (2009) 395-403. https://doi.org/10.1111/j.1365-2672.2009.04217.x.

[34]

Y. Shao, P.G. Wolf, S. Guo, et al., Zinc enhances intestinal epithelial barrier function through the PI3K/AKT/mTOR signaling pathway in Caco-2 cells, J. Nutr. Biochem. 43 (2017) 18-26. https://doi.org/10.1016/j.jnutbio.2017.01.013.

[35]

P.Y. Heredia-Castro, J.I. Méndez-Romero, A. Hernández-Mendoza, et al., Antimicrobial activity and partial characterization of bacteriocin-like inhibitory substances produced by Lactobacillus spp. isolated from artisanal Mexican cheese, J. Dairy Sci. 98 (2015) 8285-8293. https://doi.org/10.3168/jds.2015-10104.

[36]

K.W. Chang, C.Y. Kuo, 6-Gingerol modulates proinflammatory responses in dextran sodium sulfate (DSS)-treated Caco-2 cells and experimental colitis in mice through adenosine monophosphate-activated protein kinase (AMPK) activation, Food Funct. 6 (2015) 3334-3341. https://doi.org/10.1039/c5fo00513b.

[37]

Q. Zhai, J. Wang, S. Cen, et al., Modulation of the gut microbiota by a galactooligosaccharide protects against heavy metal lead accumulation in mice, Food Funct. 10 (2019) 3768-3781. https://doi.org/10.1039/c9fo00587k.

[38]

T.D. Schmittgen, K.J. Livak, Analyzing real-time PCR data by the comparative CT method, Nat. Protoc. 3 (2008) 1101-1108. https://doi.org/10.1038/nprot.2008.73.

[39]

S. Cen, R. Yin, B. Mao, et al., Comparative genomics shows niche-specific variations of Lactobacillus plantarum strains isolated from human, Drosophila melanogaster, vegetable and dairy sources, Food Biosci. 35 (2020) 100581.

[40]

Q. Zhai, S. Feng, N. Arjan, et al., A next generation probiotic, Akkermansia muciniphila, Crit. Rev. Food Sci. Nutr. 59 (2019) 3227-3236. https://doi.org/10.1080/10408398.2018.1517725.

[41]

C. Zhang, Y. Zhao, J. Jiang, et al., Identification of the key characteristics of Bifidobacterium longum strains for the alleviation of ulcerative colitis, Food Funct. 12 (2021) 3476-3492. https://doi.org/10.1039/d1fo00017a.

[42]

S.A. Frese, D.A. Mackenzie, D.A. Peterson, et al., Molecular characterization of host-specific biofilm formation in a vertebrate gut symbiont, PLoS Genet. 9 (2013) 1004057. https://doi.org/10.1371/journal.pgen.1004057.

[43]

J. Beganović, J. Frece, B. Kos, et al., Functionality of the S-layer protein from the probiotic strain Lactobacillus helveticus M92, Anton. Leeuw. Int. J. G. 100 (2011) 43-53. https://doi.org/10.1007/s10482-011-9563-4.

[44]

C. Wang, S. Li, K. Hong, et al., The roles of different Bacteroides fragilis strains in protecting against DSS-induced ulcerative colitis and related functional genes, Food Funct. 12 (2021) 8300-8313. https://doi.org/10.1039/D1FO00875G.

[45]

M.E. Johansson, G.C. Hansson, Immunological aspects of intestinal mucus and mucins. Nat. Rev. Immunol. 16 (2016) 639-649. https://doi.org/10.1038/nri.2016.88.

[46]

H.C. Clevers, C.L. Bevins, Paneth cells: maestros of the small intestinal crypts, Annu. Rev. Physiol. 75 (2013) 289-311. https://doi.org/10.1146/annurev-physiol-030212-183744.

[47]

M. Suzuki, O. Danilchanka, J.J. Mekalanos, Vibrio cholerae T3SS effector VopE modulates mitochondrial dynamics and innate immune signaling by targeting Miro GTPases, Cell Host Microbe. 16 (2014) 581-591. https://doi.org/10.1016/j.chom.2014.09.015.

[48]

F. Stavru, A.E. Palmer, C. Wang, et al., Atypical mitochondrial fission upon bacterial infection, Proc. Natl. Acad. Sci. U.S.A. 110 (2013) 16003-16008. https://doi.org/10.1073/pnas.1315784110.

[49]

S.C. Bischoff, G. Barbara, W. Buurman, et al., Intestinal permeability-a new target for disease prevention and therapy, BMC Gastroenterol. 14 (2014) 189. https://doi.org/10.1186/s12876-014-0189-7.

[50]

T.K. Lapointe, P.M. O'Connor, A.G. Buret, The role of epithelial malfunction in the pathogenesis of enteropathogenic E. coli-induced diarrhea, Lab. Invest. 89 (2009) 964-970. https://doi.org/10.1038/labinvest.2009.69.

[51]

P. Dowdell, S. Chankhamhaengdecha, W. Panbangred, et al., Probiotic activity of Enterococcus faecium and Lactococcus lactis isolated from Thai fermented sausages and their protective effect against clostridium difficile, Probiotics Antimicrob. Proteins 12 (2020) 641-648. https://doi.org/10.1007/s12602-019-09536-7.

[52]

H.Y. Liu, S. Roos, H. Jonsson, et al., Effects of Lactobacillus johnsonii and Lactobacillus reuteri on gut barrier function and heat shock proteins in intestinal porcine epithelial cells, Physiol. Rep. 3 (2015) 12355. https://doi.org/10.14814/phy2.12355.

[53]

X. Yang, X.C. Gao, J. Liu, et al. Effect of EPEC endotoxin and Bifidobacteria on intestinal barrier function through modulation of toll-like receptor 2 and toll-like receptor 4 expression in intestinal epithelial cell-18, World J. Gastroenterol. 23 (2017) 4744-4751. https://doi.org/10.3748/wjg.v23.i26.4744.

[54]

J.B. Ewaschuk, H. Diaz, L. Meddings, et al., Secreted bioactive factors from Bifidobacterium infantis enhance epithelial cell barrier function, Am. J. Physiol. Gastrointest. Liver Physiol. 295 (2008) G1025-G1034. https://doi.org/10.1152/ajpgi.90227.2008.

[55]

E. Miyauchi, H. Morita, S. Tanabe, Lactobacillus rhamnosus alleviates intestinal barrier dysfunction in part by increasing expression of zonula occludens-1 and myosin light-chain kinase in vivo, J. Dairy Sci. 92 (2009) 2400-2408. https://doi.org/10.3168/jds.2008-1698.

[56]

Q. Liu, Z. Yu, F. Tian, et al., Surface components and metabolites of probiotics for regulation of intestinal epithelial barrier, Microb. Cell Fact. 19 (2020) 23. https://doi.org/10.1186/s12934-020-1289-4.

[57]

Y. Wang, L. Liu, D.J. Moore, et al., An LGG-derived protein promotes IgA production through upregulation of APRIL expression in intestinal epithelial cells, Mucosal Immunol. 10 (2017) 373-384. https://doi.org/10.1038/mi.2016.57.

[58]

M. Kumar, R. Nagpal, V. Verma, et al., Probiotic metabolites as epigenetic targets in the prevention of colon cancer, Nutr. Rev. 71 (2013) 23-34. https://doi.org/10.1111/j.1753-4887.2012.00542.x.

[59]

Y. Zhao, C. Zhang, L. Yu, et al., Phylogenetic and comparative genomic analysis of Lactobacillus fermentum strains and the key genes related to their intestinal anti-inflammatory effects, Engineering 2021. https://doi.org/10.1016/j.eng.2020.09.016

[60]

J. Jiang, C. Wu, C. Zhang, et al., Strain-specific effects of Bifidobacterium longum on hypercholesterolemic rats and potential mechanisms, Int. J. Mol. Sci. 22 (2021) 1305. https://doi.org/10.3390/ijms22031305.

[61]

S.C. Chen, C.Y. Weng, M.C. Lai, et al., Comparative genomic analyses reveal trehalose synthase genes as the signature in genus Methanoculleus, Mar. Genomics. 47 (2019) 100673. https://doi.org/10.1016/j.margen.2019.03.008.

[62]

P. Vasudevan, J. McElligott, C. Attkisson, et al., Homologues of the Bacillus subtilis SpoVB protein are involved in cell wall metabolism, J. Bacteriol. 191 (2009) 6012-6019. https://doi.org/10.1128/JB.00604-09.

[63]

H. Mendes-Soares, H. Suzuki, R.J. Hickey, et al., Comparative functional genomics of Lactobacillus spp. reveals possible mechanisms for specialization of vaginal Lactobacilli to their environment, J. Bacteriol. 196 (2014) 1458-1470. https://doi.org/10.1128/JB.01439-13.

[64]

K.C. Johnson-Henry, K.E. Hagen, M. Gordonpour, et al., Surface-layer protein extracts from Lactobacillus helveticus inhibit enterohaemorrhagic Escherichia coli O157:H7 adhesion to epithelial cells, Cell Microbiol. 9 (2007) 356-367. https://doi.org/10.1111/j.1462-5822.2006.00791.x.

[65]

J. Li, S. Lin, P.M. Vanhoutte, et al., Akkermansia muciniphila protects against atherosclerosis by preventing metabolic endotoxemia-induced inflammation in Apoe-/- mice, Circulation 133 (2016) 2434-2446. https://doi.org/10.1161/CIRCULATIONAHA.115.019645.

[66]

H. Plovier, A. Everard, C. Druart, et al., A purified membrane protein from Akkermansia muciniphila or the pasteurized bacterium improves metabolism in obese and diabetic mice, Nat. Med. 23 (2017) 107-113. https://doi.org/10.1038/nm.4236.

[67]

S. Lebeer, P.A. Bron, M.L. Marco, et al., Identification of probiotic effector molecules: present state and future perspectives, Curr. Opin. Biotechnol. 49 (2018) 217-223. https://doi.org/10.1016/j.copbio.2017.10.007.

[68]

R.A. Siciliano, M.F. Mazzeo, Molecular mechanisms of probiotic action: a proteomic perspective, Curr. Opin. Microbiol. 15 (2012) 390-396. https://doi.org/10.1016/j.mib.2012.03.006.

[69]

R.P. Fagan, N.F. Fairweather, Biogenesis and functions of bacterial S-layers, Nat. Rev. Microbiol. 12 (2014) 211-222. https://doi.org/10.1038/nrmicro3213.

[70]

M. Abu-Qarn, J. Eichler, N. Sharon, Not just for Eukarya anymore: protein glycosylation in Bacteria and Archaea, Curr. Opin. Struct. Biol. 18 (2008) 544-550. https://doi.org/10.1016/j.sbi.2008.06.010.

[71]

Z. Liu, T. Shen, P. Zhang, et al., Lactobacillus plantarum surface layer adhesive protein protects intestinal epithelial cells against tight junction injury induced by enteropathogenic Escherichia coli, Mol. Biol. Rep. 38 (2011) 3471-3480. https://doi.org/10.1007/s11033-010-0457-8.

[72]

P.N. Li, J. Herrmann, B.B. Tolar, et al., Nutrient transport suggests an evolutionary basis for charged archaeal surface layer proteins, ISME J. 12 (2018) 2389-2402. https://doi.org/10.1038/s41396-018-0191-0.

[73]

S.B. Lewis, A. Prior, S.J. Ellis, et al., Flagellin induces β-defensin 2 in human colonic ex vivo infection with enterohemorrhagic Escherichia coli, Front. Cell Infect. Microbiol. 6 (2016) 68. https://doi.org/10.3389/fcimb.2016.00068.

[74]

M. Derrien, E.E. Vaughan, C.M. Plugge, et al., Akkermansia muciniphila gen. nov., sp. nov., a human intestinal mucin-degrading bacterium, Int. J. Syst. Evol. Microbiol. 54 (2004) 1469-1476. https://doi.org/10.1099/ijs.0.02873-0.

Publication history
Copyright
Acknowledgements
Rights and permissions

Publication history

Received: 17 July 2021
Revised: 17 August 2021
Accepted: 20 August 2021
Published: 21 March 2023
Issue date: September 2023

Copyright

© 2023 Beijing Academy of Food Sciences.

Acknowledgements

This work was supported by the Natural Science Foundation of Jiangsu Province (BK20200084); The National Natural Science Foundation of China (32021005 and 31871773); and Collaborative Innovation Center of Food Safety and Quality Control in Jiangsu Province.

Rights and permissions

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Return