Login Register Cart 0
Generic placeholder image

Current Stem Cell Research & Therapy

Editor-in-Chief

ISSN (Print): 1574-888X
ISSN (Online): 2212-3946

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Systematic Review Article

Impact of Mesenchymal Stem Cells on the Gut Microbiota and Microbiota Associated Functions in Inflammatory Bowel Disease: A Systematic Review of Preclinical Evidence on Animal Models

Author(s): Airu Liu, Chenyang Li, Chen Wang, Xiaonan Liang and Xiaolan Zhang*

Volume 19, Issue 7, 2024

Published on: 04 October, 2023

Page: [981 - 992] Pages: 12

DOI: 10.2174/011574888X250413230920051715

Price: $65

Abstract

Background: Inflammatory bowel disease (IBD) is a global health problem in which gut microbiota dysbiosis plays a pivotal pathogenic role. Mesenchymal stem cells (MSCs) therapy has shown promising application prospects for its powerful immune regulation and tissue repair ability. Recent experimental data suggest that MSCs also regulate the composition of gut microbiota. The current review analyzed, for the first time, the research data linking MSCs and gut microbiota modulation in IBD models aiming at assessing the role of gut microbiota in MSCs repair of IBD.

Methods: A comprehensive and structured literature search was performed up to January 2023 on the PubMed, Web of Science, and Scopus databases. The quality and risk of bias assessment followed the PRISMA guidelines and SYRCLE's tool.

Results: A total of nine pre-clinical studies on animal models were included. Although the dose and route of MSCs applied were quite heterogeneous, results showed that MSCs displayed protective effects on intestinal inflammation, including mice general assessment, immunoregulation, and intestinal barrier integrity. Meanwhile, studies showed positive effects on the composition of gut flora with MSCs administration, which had been characterized by restoration of Firmicutes/ Bacteroides balance and reduction of Proteobacteria. The beneficial bacteria Akkermansia, Bifidobacterium, and Lactobacillus were also distinctly enriched, and the pathogenic bacteria Escherichia-Shigella was conversely decreased. The alpha and beta diversity were also regulated to resemble those of healthy mice. Microbial metabolic functions, such as biosynthesis of secondary bile acid and sphingolipid metabolism, and some biological behaviors related to cell regeneration were also up-regulated, while cancer function and poorly characterized cellular function were down-regulated.

Conclusion: Current data support the remodeling effect on gut microbiota with MSC administration, which provides a potential therapeutic mechanism for MSCs in the treatment of IBD. Additional studies in humans and animal models are warranted to further confirm the role of gut microflora in MSCs repairing IBD.

« Previous
Graphical Abstract

[1]
Ng SC, Shi HY, Hamidi N, et al. Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: A systematic review of population-based studies. Lancet 2017; 390(10114): 2769-78.
[http://dx.doi.org/10.1016/S0140-6736(17)32448-0] [PMID: 29050646]
[2]
Kaplan GG, Ng SC. Understanding and preventing the global increase of inflammatory bowel disease. Gastroenterology 2017; 152(2): 313-321.e2.
[http://dx.doi.org/10.1053/j.gastro.2016.10.020] [PMID: 27793607]
[3]
Caruso R, Lo BC, Núñez G. Host–microbiota interactions in inflammatory bowel disease. Nat Rev Immunol 2020; 20(7): 411-26.
[http://dx.doi.org/10.1038/s41577-019-0268-7] [PMID: 32005980]
[4]
Sartor RB, Wu GD. Roles for intestinal bacteria, viruses, and fungi in pathogenesis of inflammatory bowel diseases and therapeutic approaches. Gastroenterology 2017; 152(2): 327-339.e4.
[http://dx.doi.org/10.1053/j.gastro.2016.10.012] [PMID: 27769810]
[5]
Schaubeck M, Clavel T, Calasan J, et al. Dysbiotic gut microbiota causes transmissible Crohn’s disease-like ileitis independent of failure in antimicrobial defence. Gut 2016; 65(2): 225-37.
[http://dx.doi.org/10.1136/gutjnl-2015-309333] [PMID: 25887379]
[6]
Burrello C, Garavaglia F, Cribiù FM, et al. Therapeutic faecal microbiota transplantation controls intestinal inflammation through IL10 secretion by immune cells. Nat Commun 2018; 9(1): 5184.
[http://dx.doi.org/10.1038/s41467-018-07359-8] [PMID: 30518790]
[7]
Lavelle A, Sokol H. Gut microbiota-derived metabolites as key actors in inflammatory bowel disease. Nat Rev Gastroenterol Hepatol 2020; 17(4): 223-37.
[http://dx.doi.org/10.1038/s41575-019-0258-z] [PMID: 32076145]
[8]
Weingarden AR, Vaughn BP. Intestinal microbiota, fecal microbiota transplantation, and inflammatory bowel disease. Gut Microbes 2017; 8(3): 238-52.
[http://dx.doi.org/10.1080/19490976.2017.1290757] [PMID: 28609251]
[9]
Che Z, Ye Z, Zhang X, et al. Mesenchymal stem/stromal cells in the pathogenesis and regenerative therapy of inflammatory bowel diseases. Front Immunol 2022; 13: 952071.
[http://dx.doi.org/10.3389/fimmu.2022.952071] [PMID: 35990688]
[10]
Soontararak S, Chow L, Johnson V, et al. Mesenchymal stem cells (MSC) derived from induced pluripotent stem cells (iPSC) equivalent to adipose-derived MSC in promoting intestinal healing and microbiome normalization in mouse inflammatory bowel disease model. Stem Cells Transl Med 2018; 7(6): 456-67.
[http://dx.doi.org/10.1002/sctm.17-0305] [PMID: 29635868]
[11]
Liu A, Wang X, Liang X, et al. Human umbilical cord mesenchymal stem cells regulate immunoglobulin a secretion and remodel the diversification of intestinal microbiota to improve colitis. Front Cell Infect Microbiol 2022; 12: 960208.
[http://dx.doi.org/10.3389/fcimb.2022.960208] [PMID: 36118029]
[12]
Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. BMJ 2021; 372(71): n71.
[http://dx.doi.org/10.1136/bmj.n71] [PMID: 33782057]
[13]
Kilkenny C, Browne WJ, Cuthill IC, Emerson M, Altman DG. Improving bioscience research reporting: The ARRIVE guidelines for reporting animal research. PLoS Biol 2010; 8(6): e1000412.
[http://dx.doi.org/10.1371/journal.pbio.1000412] [PMID: 20613859]
[14]
Hooijmans CR, Rovers MM, de Vries RBM, Leenaars M, Ritskes-Hoitinga M, Langendam MW. SYRCLE’s risk of bias tool for animal studies. BMC Med Res Methodol 2014; 14(1): 43.
[http://dx.doi.org/10.1186/1471-2288-14-43] [PMID: 24667063]
[15]
Ikarashi S, Tsuchiya A, Kawata Y, et al. Effects of human adipose tissue-derived and umbilical cord tissue-derived mesenchymal stem cells in a dextran sulfate sodiuminduced mouse model. Biores Open Access 2019; 8(1): 185-99.
[http://dx.doi.org/10.1089/biores.2019.0022] [PMID: 31720090]
[16]
Yang F, Ni B, Liu Q, et al. Human umbilical cord-derived mesenchymal stem cells ameliorate experimental colitis by normalizing the gut microbiota. Stem Cell Res Ther 2022; 13(1): 475.
[http://dx.doi.org/10.1186/s13287-022-03118-1] [PMID: 36104756]
[17]
Mar JS, Nagalingam NA, Song Y, Onizawa M, Lee JW, Lynch SV. Amelioration of DSS-induced murine colitis by VSL#3 supplementation is primarily associated with changes in ileal microbiota composition. Gut Microbes 2014; 5(4): 494-503.
[http://dx.doi.org/10.4161/gmic.32147] [PMID: 25144681]
[18]
He R, Han C, Li Y, Qian W, Hou X. Cancer-preventive role of bone marrow-derived mesenchymal stem cells on colitis-associated colorectal cancer: Roles of gut microbiota involved. Front Cell Dev Biol 2021; 9: 642948.
[http://dx.doi.org/10.3389/fcell.2021.642948] [PMID: 34150751]
[19]
Ocansey DKW, Zhang Z, Xu X, et al. Mesenchymal stem cell-derived exosome mitigates colitis via the modulation of the gut metagenomics–metabolomics–farnesoid X receptor axis. Biomater Sci 2022; 10(17): 4822-36.
[http://dx.doi.org/10.1039/D2BM00559J] [PMID: 35858469]
[20]
Kim DW, Jeong HS, Kim E, Lee H, Choi CH, Lee SJ. Oral delivery of stem-cell-loaded hydrogel microcapsules restores gut inflammation and microbiota. J Control Release 2022; 347: 508-20.
[http://dx.doi.org/10.1016/j.jconrel.2022.05.028] [PMID: 35597403]
[21]
Gu L, Ren F, Fang X, Yuan L, Liu G, Wang S. Exosomal microRNA-181a derived from mesenchymal stem cells improves gut microbiota composition, barrier function, and inflammatory status in an experimental colitis model. Front Med 2021; 8: 660614.
[http://dx.doi.org/10.3389/fmed.2021.660614] [PMID: 34249964]
[22]
Lloyd-Price J, Arze C, Ananthakrishnan AN, et al. Multi-omics of the gut microbial ecosystem in inflammatory bowel diseases. Nature 2019; 569(7758): 655-62.
[http://dx.doi.org/10.1038/s41586-019-1237-9] [PMID: 31142855]
[23]
Shi N, Li N, Duan X, Niu H. Interaction between the gut microbiome and mucosal immune system. Mil Med Res 2017; 4(1): 14.
[http://dx.doi.org/10.1186/s40779-017-0122-9] [PMID: 28465831]
[24]
Zhao LN, Ma SW, Xiao J, Yang LJ, Xu SX, Zhao L. Bone marrow mesenchymal stem cell therapy regulates gut microbiota to improve post-stroke neurological function recovery in rats. World J Stem Cells 2021; 13(12): 1905-17.
[http://dx.doi.org/10.4252/wjsc.v13.i12.1905] [PMID: 35069989]
[25]
Yang Z, Xia Q, Lu D, et al. Human mesenchymal stem cells treatment improved hepatic lesions and reversed gut microbiome disorder in non-alcoholic steatohepatitis. Aging 2020; 12(21): 21660-73.
[http://dx.doi.org/10.18632/aging.103962] [PMID: 33168782]
[26]
Li X, Lu C, Fan D, et al. Human umbilical mesenchymal stem cells display therapeutic potential in rheumatoid arthritis by regulating interactions between immunity and gut microbiota via the aryl hydrocarbon receptor. Front Cell Dev Biol 2020; 8: 131.
[http://dx.doi.org/10.3389/fcell.2020.00131] [PMID: 32232043]
[27]
Huldani H, Margiana R, Ahmad F, et al. Immunotherapy of inflammatory bowel disease (IBD) through mesenchymal stem cells. Int Immunopharmacol 2022; 107: 108698.
[http://dx.doi.org/10.1016/j.intimp.2022.108698] [PMID: 35306284]
[28]
Sala E, Genua M, Petti L, et al. Mesenchymal stem cells reduce colitis in mice via release of TSG6, independently of their localization to the intestine. Gastroenterology 2015; 149(1): 163-176.e20.
[http://dx.doi.org/10.1053/j.gastro.2015.03.013] [PMID: 25790743]
[29]
Wang M, Liang C, Hu H, et al. Intraperitoneal injection (IP), intravenous injection (IV) or anal injection (AI)? Best way for mesenchymal stem cells transplantation for colitis. Sci Rep 2016; 6(1): 30696.
[http://dx.doi.org/10.1038/srep30696] [PMID: 27488951]
[30]
Wallace KL, Zheng LB, Kanazawa Y, Shih DQ. Immunopathology of inflammatory bowel disease. World J Gastroenterol 2014; 20(1): 6-21.
[http://dx.doi.org/10.3748/wjg.v20.i1.6] [PMID: 24415853]
[31]
Neurath MF. Cytokines in inflammatory bowel disease. Nat Rev Immunol 2014; 14(5): 329-42.
[http://dx.doi.org/10.1038/nri3661] [PMID: 24751956]
[32]
Qiu P, Ishimoto T, Fu L, Zhang J, Zhang Z, Liu Y. The gut microbiota in inflammatory bowel disease. Front Cell Infect Microbiol 2022; 12: 733992.
[http://dx.doi.org/10.3389/fcimb.2022.733992] [PMID: 35273921]
[33]
Ruff WE, Greiling TM, Kriegel MA. Host–microbiota interactions in immune-mediated diseases. Nat Rev Microbiol 2020; 18(9): 521-38.
[http://dx.doi.org/10.1038/s41579-020-0367-2] [PMID: 32457482]
[34]
Ohkusa T, Koido S. Intestinal microbiota and ulcerative colitis. J Infect Chemother 2015; 21(11): 761-8.
[http://dx.doi.org/10.1016/j.jiac.2015.07.010] [PMID: 26346678]
[35]
Zhang Z, Taylor L, Shommu N, et al. A diversified dietary pattern is associated with a balanced gut microbial composition of faecalibacterium and escherichia/shigella in patients with crohn’s disease in remission. J Crohn’s Colitis 2020; 14(11): 1547-57.
[http://dx.doi.org/10.1093/ecco-jcc/jjaa084] [PMID: 32343765]
[36]
Peng L, Gao X, Nie L, et al. Astragalin attenuates dextran sulfate sodium (DSS)-induced acute experimental colitis by alleviating gut microbiota dysbiosis and inhibiting NF-κB activation in mice. Front Immunol 2020; 11: 2058.
[http://dx.doi.org/10.3389/fimmu.2020.02058] [PMID: 33042117]
[37]
Bae M, Cassilly CD, Liu X, et al. Akkermansia muciniphila phospholipid induces homeostatic immune responses. Nature 2022; 608(7921): 168-73.
[http://dx.doi.org/10.1038/s41586-022-04985-7] [PMID: 35896748]
[38]
Zhang T, Ji X, Lu G, Zhang F. The potential of Akkermansia muciniphila in inflammatory bowel disease. Appl Microbiol Biotechnol 2021; 105: 5785-94.
[http://dx.doi.org/10.1007/s00253-021-11453-1]
[39]
Cani PD, Depommier C, Derrien M, Everard A, de Vos WM. Akkermansia muciniphila: Paradigm for next-generation beneficial microorganisms. Nat Rev Gastroenterol Hepatol 2022; 19(10): 625-37.
[http://dx.doi.org/10.1038/s41575-022-00631-9]
[40]
Qu S, Fan L, Qi Y, et al. Akkermansia muciniphila alleviates dextran sulfate sodium (DSS)-induced acute colitis by NLRP3 activation. Microbiol Spectr 2021; 9(2): e00730-21.
[http://dx.doi.org/10.1128/Spectrum.00730-21] [PMID: 34612661]
[41]
Kim SW, Kim HM, Yang KM, et al. Bifidobacterium lactis inhibits NF-κB in intestinal epithelial cells and prevents acute colitis and colitis-associated colon cancer in mice. Inflamm Bowel Dis 2010; 16(9): 1514-25.
[http://dx.doi.org/10.1002/ibd.21262] [PMID: 20310012]
[42]
Yu P, Ke C, Guo J, Zhang X, Li B. Lactobacillus plantarum L15 Alleviates Colitis by Inhibiting LPS-Mediated NF-κB Activation and Ameliorates DSS-Induced Gut Microbiota Dysbiosis. Front Immunol 2020; 11: 575173.
[http://dx.doi.org/10.3389/fimmu.2020.575173] [PMID: 33123156]
[43]
Jakubczyk D, Leszczyńska K, Górska S. The effectiveness of probiotics in the treatment of inflammatory bowel disease (IBD)—A critical review. Nutrients 2020; 12(7): 1973.
[http://dx.doi.org/10.3390/nu12071973] [PMID: 32630805]
[44]
Sinha SR, Haileselassie Y, Nguyen LP, et al. Dysbiosis-induced secondary bile acid deficiency promotes intestinal inflammation. Cell Host Microbe 2020; 27(4): 659-670.e5.
[http://dx.doi.org/10.1016/j.chom.2020.01.021] [PMID: 32101703]
[45]
Hu L, Jin L, Xia D, et al. Nitrate ameliorates dextran sodium sulfate-induced colitis by regulating the homeostasis of the intestinal microbiota. Free Radic Biol Med 2020; 152: 609-21.
[http://dx.doi.org/10.1016/j.freeradbiomed.2019.12.002] [PMID: 31811920]
[46]
Bourgonje AR, Feelisch M, Faber KN, Pasch A, Dijkstra G, van Goor H. Oxidative stress and redox-modulating therapeutics in inflammatory bowel disease. Trends Mol Med 2020; 26(11): 1034-46.
[http://dx.doi.org/10.1016/j.molmed.2020.06.006] [PMID: 32620502]
[47]
Brown EM, Ke X, Hitchcock D, et al. Bacteroides-derived sphingolipids are critical for maintaining intestinal homeostasis and symbiosis. Cell Host Microbe 2019; 25(5): 668-680.e7.
[http://dx.doi.org/10.1016/j.chom.2019.04.002] [PMID: 31071294]
[48]
Schirmer M, Garner A, Vlamakis H, Xavier RJ. Microbial genes and pathways in inflammatory bowel disease. Nat Rev Microbiol 2019; 17(8): 497-511.
[http://dx.doi.org/10.1038/s41579-019-0213-6] [PMID: 31249397]
[49]
Cai J, Sun L, Gonzalez FJ. Gut microbiota-derived bile acids in intestinal immunity, inflammation, and tumorigenesis. Cell Host Microbe 2022; 30(3): 289-300.
[http://dx.doi.org/10.1016/j.chom.2022.02.004] [PMID: 35271802]
[50]
Sorrentino G, Perino A, Yildiz E, et al. Bile acids signal via TGR5 to activate intestinal stem cells and epithelial regeneration. Gastroenterology 2020; 159(3): 956-968.e8.
[http://dx.doi.org/10.1053/j.gastro.2020.05.067] [PMID: 32485177]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy