Skip to main content

Advertisement

SpringerLink
Log in

The Effect of Akkermansia muciniphila and Its Outer Membrane Vesicles on MicroRNAs Expression of Inflammatory and Anti-inflammatory Pathways in Human Dendritic Cells

  • Published:
Probiotics and Antimicrobial Proteins Aims and scope Submit manuscript

Abstract

Probiotics play a crucial role in immunomodulation by regulating dendritic cell (DC) maturation and inducing tolerogenic DCs. Akkermansia muciniphila affects inflammatory response by elevating inhibitory cytokines. We aimed to evaluate whether Akkermansia muciniphila and its outer membrane vesicles (OMVs) affect microRNA-155, microRNA-146a, microRNA-34a, and let-7i expression of inflammatory and anti-inflammatory pathways. Peripheral blood mononuclear cells (PBMCs) were isolated from the healthy volunteers. To produce DCs, monocytes were cultivated with granulocyte–macrophage colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4). DCs were allocated into six subgroups: DC + Lipopolysaccharide (LPS), DC + dexamethasone, DC + A. muciniphila (MOI 100, 50), DC + OMVs (50 µg/ml), and DC + PBS. The surface expression of human leukocyte antigen-antigen D related (HLA-DR), CD86, CD80, CD83, CD11c, and CD14 was examined using flow cytometry, and the expression of microRNAs was assessed using qRT-PCR, and the levels of IL-12 and IL-10 were measured using ELISA. A. muciniphila (MOIs 50, 100) could significantly decrease IL-12 levels relative to the LPS group. The IL-10 levels were decreased in the DC + LPS group than the DC + dexamethasone group. Treatment with A. muciniphila (MOI 100) and OMVs could elevate the concentrations of IL-10. DC treatment with LPS led to a significant increment in the expression of microRNA-155, microRNA-34a, and microRNA-146a. The expression of these microRNAs was reversed by A. muciniphilia and its OMVs treatment. Let-7i increased in treatment groups compared to the DC + LPS group. A. muciniphilia (MOI 50) had a substantial effect on the expression of HLA-DR, CD80, and CD83 on DCs. Therefore, DCs treatment with A. muciniphila led to induce tolerogenic DCs and the production of anti-inflammatory IL-10.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10
Fig. 11
Fig. 12

Similar content being viewed by others

Data Availability

All data generated or analyzed during this study are included in this published article

References

  1. Hrncir T (2022) Gut microbiota dysbiosis: triggers, consequences, diagnostic and therapeutic options. MDPI 10

  2. Bayer G, Ganobis CM, Allen-Vercoe E, Philpott DJ (2021) Defined gut microbial communities: promising tools to understand and combat disease. Microbes Infect 23(6–7):104816

    Article  CAS  PubMed  Google Scholar 

  3. Miller BM, Bäumler AJ (2021) The habitat filters of microbiota-nourishing immunity. Annu Rev Immunol 39:1–18

    Article  CAS  PubMed  Google Scholar 

  4. Yaghoubfar R, Behrouzi A, Zare Banadkoki E, Ashrafian F, Lari A, Vaziri F, Nojoumi SA, Fateh A, Khatami S, Siadat SD (2021) Effect of Akkermansia muciniphila, Faecalibacterium prausnitzii, and their extracellular vesicles on the serotonin system in intestinal epithelial cells. Probiotics and Antimicrobial Proteins 13(6):1546–1556

    Article  CAS  PubMed  Google Scholar 

  5. Belizário JE, Faintuch J (2018) Microbiome and gut dysbiosis. In: Metabolic interaction in infection. Springer, pp 459–476

  6. Bamola VD, Dubey D, Samanta P, Kedia S, Ahuja V, Madempudi RS, Neelamraju J, Chaudhry R (2022) Role of a probiotic strain in the modulation of gut microbiota and cytokines in inflammatory bowel disease

  7. Soltanmoradi H, Maniati M, Davoodabadi A, Mosapour A, Samavarchi Tehrani S, Pazhoohan M, Daemi F, Khaleghzadeh-Ahangar H (2021) A probiotic supplement, Lactobacillus rhamnosus GG, and kefir separately can improve mood and exhibit potential anti-depressant-like activities in mice. Acta Aliment 50(3):393–403

    Article  CAS  Google Scholar 

  8. Vancamelbeke M, Vermeire S (2017) The intestinal barrier: a fundamental role in health and disease. Expert Rev Gastroenterol Hepatol 11(9):821–834

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Lazar V, Ditu L-M, Pircalabioru GG, Gheorghe I, Curutiu C, Holban AM, Picu A, Petcu L, Chifiriuc MC (2018) Aspects of gut microbiota and immune system interactions in infectious diseases, immunopathology, and cancer. Front Immunol 9:1830

    Article  PubMed  PubMed Central  Google Scholar 

  10. Aslam MN, McClintock SD, Jawad-Makki MAH, Knuver K, Ahmad HM, Basrur V, Bergin IL, Zick SM, Sen A, Turgeon DK (2021) A multi-mineral intervention to modulate colonic mucosal protein profile: results from a 90-day trial in human subjects. Nutrients 13(3):939

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Liu R, Li J, Shao J, Lee J-H, Qiu X, Xiao Y, Zhang B, Hao Y, Li M, Chen Q (2021) Innate immune response orchestrates phosphoribosyl pyrophosphate synthetases to support DNA repair. Cell Metabolism 33(10):2076–2089. e2079

  12. Torres ACMG, Leite N, Tureck LV, de Souza RLR, Titski ACK, Milano-Gai GE, Lazarotto L, da Silva LR, Furtado-Alle L (2019) Association between Toll-like receptors (TLR) and NOD-like receptor (NLR) polymorphisms and lipid and glucose metabolism. Gene 685:211–221

    Article  Google Scholar 

  13. Steinman RM, Hemmi H (2006) Dendritic cells: translating innate to adaptive immunity. From innate immunity to immunological memory:17–58

  14. Douagi I, Gujer C, Sundling C, Adams WC, Smed-Sörensen A, Seder RA, Hedestam GBK, Loré K (2009) Human B cell responses to TLR ligands are differentially modulated by myeloid and plasmacytoid dendritic cells. J Immunol 182(4):1991–2001

    Article  CAS  PubMed  Google Scholar 

  15. Liu J, Zhang X, Cheng Y, Cao X (2021) Dendritic cell migration in inflammation and immunity. Cell Mol Immunol 18(11):2461–2471

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Rasquinha MT, Sur M, Lasrado N, Reddy J (2021) IL-10 as a Th2 cytokine: differences between mice and humans. J Immunol 207(9):2205–2215

    Article  CAS  PubMed  Google Scholar 

  17. Veenbergen S, Li P, Raatgeep H, Lindenbergh-Kortleve D, Simons-Oosterhuis Y, Farrel A, Costes L, Joosse M, van Berkel L, de Ruiter L (2019) IL-10 signaling in dendritic cells controls IL-1β-mediated IFNγ secretion by human CD4+ T cells: relevance to inflammatory bowel disease. Mucosal Immunol 12(5):1201–1211

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Baradaran Ghavami S, Asadzadeh Aghdaei H, Sorrentino D, Shahrokh S, Farmani M, Ashrafian F, Dore MP, Keshavarz Azizi Raftar S, Mobin Khoramjoo S, Zali MR (2021) Probiotic-induced tolerogenic dendritic cells: a novel therapy for inflammatory bowel disease? Int J Mol Sci 22(15):8274

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Wu X-D, Song Y-C, Cao P-L, Zhang H, Guo Q, Yan R, Diao D-M, Cheng Y, Dang C-X (2014) Detection of miR-34a and miR-34b/c in stool sample as potential screening biomarkers for noninvasive diagnosis of colorectal cancer. Med Oncol 31(4):1–6

    Article  Google Scholar 

  20. Movahedpour A, Khatami SH, Khorsand M, Salehi M, Savardashtaki A, Mirmajidi SH, Negahdari B, Khanjani N, Naeli P, Vakili O (2021) Exosomal noncoding RNAs: key players in glioblastoma drug resistance. Mol Cell Biochem 476(11):4081–4092

    Article  CAS  PubMed  Google Scholar 

  21. Zhou H, Wu L (2017) The development and function of dendritic cell populations and their regulation by miRNAs. Protein Cell 8(7):501–513

    Article  PubMed  PubMed Central  Google Scholar 

  22. Ebrahimpour A, Sarfi M, Rezatabar S, Tehrani SS (2021) Novel insights into the interaction between long non-coding RNAs and microRNAs in glioma. Mol Cell Biochem 476(6):2317–2335

    Article  CAS  PubMed  Google Scholar 

  23. Tehrani SS, Zaboli E, Sadeghi F, Khafri S, Karimian A, Rafie M, Parsian H (2021) MicroRNA-26a-5p as a potential predictive factor for determining the effectiveness of trastuzumab therapy in HER-2 positive breast cancer patients. Biomedicine 11(2):30

    PubMed  PubMed Central  Google Scholar 

  24. Stumpfova Z, Hezova R, Meli AC, Slaby O, Michalek J (2014) MicroRNA profiling of activated and tolerogenic human dendritic cells. Mediators of Inflammation 2014

  25. Ha CW, Lam YY, Holmes AJ (2014) Mechanistic links between gut microbial community dynamics, microbial functions and metabolic health. World J Gastroenterol: WJG 20(44):16498

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Raftar SKA, Ashrafian F, Abdollahiyan S, Yadegar A, Moradi HR, Masoumi M, Vaziri F, Moshiri A, Siadat SD, Zali MR (2022) The anti-inflammatory effects of Akkermansia muciniphila and its derivates in HFD/CCL4-induced murine model of liver injury. Sci Rep 12(1):1–14

    Article  Google Scholar 

  27. Zhang T, Li Q, Cheng L, Buch H, Zhang F (2019) Akkermansia muciniphila is a promising probiotic. Microb Biotechnol 12(6):1109–1125

    Article  PubMed  PubMed Central  Google Scholar 

  28. Shi M, Yue Y, Ma C, Dong L, Chen F (2022) Pasteurized Akkermansia muciniphila ameliorate the LPS-induced intestinal barrier dysfunction via modulating AMPK and NF-κB through TLR2 in Caco-2 cells. Nutrients 14(4):764

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Ghaderi F, Sotoodehnejadnematalahi F, Hajebrahimi Z, Fateh A, Siadat SD (2022) Effects of active, inactive, and derivatives of Akkermansia muciniphila on the expression of the endocannabinoid system and PPARs genes. Sci Rep 12(1):1–12

    Google Scholar 

  30. Kang C-s, Ban M, Choi E-J, Moon H-G, Jeon J-S, Kim D-K, Park S-K, Jeon SG, Roh T-Y, Myung S-J (2013) Extracellular vesicles derived from gut microbiota, especially Akkermansia muciniphila, protect the progression of dextran sulfate sodium-induced colitis. PLoS ONE 8(10):e76520

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Schwechheimer C, Kuehn MJ (2015) Outer-membrane vesicles from Gram-negative bacteria: biogenesis and functions. Nat Rev Microbiol 13(10):605–619

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Sundaram K, Mu J, Kumar A, Behera J, Lei C, Sriwastva MK, Xu F, Dryden GW, Zhang L, Chen S Oral administration of plant exosome-like nanoparticles inhibits brain inflammation by targeting microglial cells and gut Akkermansia muciniphila in obese mice

  33. Kang CS, Ban M, Choi EJ, Moon HG, Jeon JS, Kim DK, Park SK, Jeon SG, Roh TY, Myung SJ, Gho YS, Kim JG, Kim YK (2013) Extracellular vesicles derived from gut microbiota, especially Akkermansia muciniphila, protect the progression of dextran sulfate sodium-induced colitis. PLoS One 8(10):e76520. https://doi.org/10.1371/journal.pone.0076520

  34. Ashrafian F, Behrouzi A, Badi SA, Davari M, Jamnani FR, Fateh A, Vaziri F, Siadat SD (2019) Comparative study of effect of Akkermansia muciniphila and its extracellular vesicles on toll-like receptors and tight junction. Gastroenterology and hepatology from bed to bench 12(2):163

    PubMed  PubMed Central  Google Scholar 

  35. Ottman N, Reunanen J, Meijerink M, Pietilä TE, Kainulainen V, Klievink J, Huuskonen L, Aalvink S, Skurnik M, Boeren S (2017) Pili-like proteins of Akkermansia muciniphila modulate host immune responses and gut barrier function. PLoS ONE 12(3):e0173004

    Article  PubMed  PubMed Central  Google Scholar 

  36. Derrien M, Vaughan EE, Plugge CM, de Vos WM (2004) Akkermansia muciniphila gen. nov., sp. nov., a human intestinal mucin-degrading bacterium. International journal of systematic and evolutionary microbiology 54(5):1469–1476

  37. Diaz-Garrido N, Fábrega M-J, Vera R, Giménez R, Badia J, Baldomà L (2019) Membrane vesicles from the probiotic Nissle 1917 and gut resident Escherichia coli strains distinctly modulate human dendritic cells and subsequent T cell responses. Journal of Functional Foods 61:103495

    Article  CAS  Google Scholar 

  38. Díaz-Garrido N, Bonnin S, Riera M, Gíménez R, Badia J, Baldomà L (2020) Transcriptomic microRNA profiling of dendritic cells in response to gut microbiota-secreted vesicles. Cells 9(6):1534

    Article  PubMed  PubMed Central  Google Scholar 

  39. Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2−ΔΔCT method. methods 25(4):402–408

  40. Taganov KD, Boldin MP, Chang K-J, Baltimore D (2006) NF-κB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses. Proc Natl Acad Sci 103(33):12481–12486

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Song L, Zhou F, Cheng L, Hu M, He Y, Zhang B, Liao D, Xu Z (2017) MicroRNA-34a suppresses autophagy in alveolar type II epithelial cells in acute lung injury by inhibiting FoxO3 expression. Inflammation 40:927–936

    Article  CAS  PubMed  Google Scholar 

  42. Nejad C, Stunden HJ, Gantier MP (2018) A guide to miRNAs in inflammation and innate immune responses. FEBS J 285(20):3695–3716

    Article  CAS  PubMed  Google Scholar 

  43. Santos Rocha C, Gomes-Santos AC, Garcias Moreira T, de Azevedo M, Diniz Luerce T, Mariadassou M, Longaray Delamare AP, Langella P, Maguin E, Azevedo V (2014) Local and systemic immune mechanisms underlying the anti-colitis effects of the dairy bacterium Lactobacillus delbrueckii. PLoS One 9(1):e85923

    Article  PubMed  PubMed Central  Google Scholar 

  44. Hardy H, Harris J, Lyon E, Beal J, Foey AD (2013) Probiotics, prebiotics and immunomodulation of gut mucosal defences: homeostasis and immunopathology. Nutrients 5(6):1869–1912

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Diaz-Garrido N, Badia J, Baldomà L (2022) Modulation of dendritic cells by microbiota extracellular vesicles influences the cytokine profile and exosome cargo. Nutrients 14(2):344

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Esmaeili SA, Mahmoudi M, Rezaieyazdi Z, Sahebari M, Tabasi N, Sahebkar A, Rastin M (2018) Generation of tolerogenic dendritic cells using Lactobacillus rhamnosus and Lactobacillus delbrueckii as tolerogenic probiotics. J Cell Biochem 119(9):7865–7872

    Article  CAS  PubMed  Google Scholar 

  47. Engevik MA, Ruan W, Esparza M, Fultz R, Shi Z, Engevik KA, Engevik AC, Ihekweazu FD, Visuthranukul C, Venable S (2021) Immunomodulation of dendritic cells by Lactobacillus reuteri surface components and metabolites. Physiol Rep 9(2):e14719

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Pulendran B, Tang H, Manicassamy S (2010) Programming dendritic cells to induce TH2 and tolerogenic responses. Nat Immunol 11(8):647–655

    Article  CAS  PubMed  Google Scholar 

  49. Švajger U, Rožman P (2018) Induction of tolerogenic dendritic cells by endogenous biomolecules: an update. Front Immunol 2482

  50. Png CW, Lindén SK, Gilshenan KS, Zoetendal EG, McSweeney CS, Sly LI, McGuckin MA, Florin TH (2010) Mucolytic bacteria with increased prevalence in IBD mucosa augmentin vitroutilization of mucin by other bacteria. Official journal of the American College of Gastroenterology| ACG 105(11):2420–2428

  51. Han TH, Jin P, Ren J, Slezak S, Marincola FM, Stroncek DF (2009) Evaluation of three clinical dendritic cell maturation protocols containing lipopolysaccharide and interferon-gamma. Journal of immunotherapy (Hagerstown, Md: 1997) 32(4):399

  52. Zheng D, Wang Z, Sui L, Xu Y, Wang L, Qiao X, Cui W, Jiang Y, Zhou H, Tang L (2021) Lactobacillus johnsonii activates porcine monocyte derived dendritic cells maturation to modulate Th cellular immune response. Cytokine 144:155581

    Article  CAS  PubMed  Google Scholar 

  53. Scalavino V, Liso M, Serino G (2020) Role of microRNAs in the regulation of dendritic cell generation and function. Int J Mol Sci 21(4):1319

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. O’Connell RM, Taganov KD, Boldin MP, Cheng G, Baltimore D (2007) MicroRNA-155 is induced during the macrophage inflammatory response. Proc Natl Acad Sci 104(5):1604–1609

    Article  PubMed  PubMed Central  Google Scholar 

  55. Martinez-Nunez RT, Louafi F, Friedmann PS, Sanchez-Elsner T (2009) MicroRNA-155 modulates the pathogen binding ability of dendritic cells (DCs) by down-regulation of DC-specific intercellular adhesion molecule-3 grabbing non-integrin (DC-SIGN). J Biol Chem 284(24):16334–16342

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Ceppi M, Pereira PM, Dunand-Sauthier I, Barras E, Reith W, Santos MA, Pierre P (2009) MicroRNA-155 modulates the interleukin-1 signaling pathway in activated human monocyte-derived dendritic cells. Proc Natl Acad Sci 106(8):2735–2740

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. O’Connell RM, Chaudhuri AA, Rao DS, Baltimore D (2009) Inositol phosphatase SHIP1 is a primary target of miR-155. Proc Natl Acad Sci 106(17):7113–7118

    Article  PubMed  PubMed Central  Google Scholar 

  58. O’Connell RM, Kahn D, Gibson WS, Round JL, Scholz RL, Chaudhuri AA, Kahn ME, Rao DS, Baltimore D (2010) MicroRNA-155 promotes autoimmune inflammation by enhancing inflammatory T cell development. Immunity 33(4):607–619

    Article  PubMed  PubMed Central  Google Scholar 

  59. Jung, Baltimore David TKD, P BM, Kuang C (2006) NF-kappaB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses

  60. Tsitsiou E, Lindsay MA (2009) microRNAs and the immune response. Curr Opin Pharmacol 9(4):514–520

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Li W, Wang Y, Liu R, Kasinski AL, Shen H, Slack FJ, Tang DG (2021) MicroRNA-34a: potent tumor suppressor, cancer stem cell inhibitor, and potential anticancer therapeutic. Front Cell Dev Biol 9:640587

    Article  PubMed  Google Scholar 

  62. Taheri F, Ebrahimi SO, Shareef S, Reiisi S (2020) Regulatory and immunomodulatory role of miR-34a in T cell immunity. Life Sci 262:118209

    Article  CAS  PubMed  Google Scholar 

  63. Roggli E, Britan A, Gattesco S, Lin-Marq N, Abderrahmani A, Meda P, Regazzi R (2010) Involvement of microRNAs in the cytotoxic effects exerted by proinflammatory cytokines on pancreatic β-cells. Diabetes 59(4):978–986

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Kurowska-Stolarska M, Alivernini S, Melchor EG, Elmesmari A, Tolusso B, Tange C, Petricca L, Gilchrist DS, Di Sante G, Keijzer C (2017) MicroRNA-34a dependent regulation of AXL controls the activation of dendritic cells in inflammatory arthritis. Nat Commun 8(1):1–13

    Article  Google Scholar 

  65. Iliopoulos D, Hirsch HA, Struhl K (2009) An epigenetic switch involving NF-κB, Lin28, Let-7 microRNA, and IL6 links inflammation to cell transformation. Cell 139(4):693–706

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This work, as a PhD thesis, was financially supported by Tehran-Azad Islamic University (grant number: 123480793474175162621048).

Author information

Authors and Affiliations

  1. Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran

    Laya Zoghi Mofrad & Fattah Sotoodehnejadnematalahi

  2. Department of Mycobacteriology and Pulmonary Research, Microbiology Research Center, Pasteur Institute of Iran, Tehran, Iran

    Abolfazl  Fateh & Seyed Davar Siadat

  3. Head of NanoBiotechnology Department, Pasteur Institute of Iran, Tehran, Iran

    Dariush Norouzian Sham Asbi

Authors
  1. Laya Zoghi Mofrad
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Abolfazl  Fateh
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Fattah Sotoodehnejadnematalahi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Dariush Norouzian Sham Asbi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Seyed Davar Siadat
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

LZM and AF wrote the main manuscript text. FS and DNSA prepared figures, analyzed, and interpreted the data. SDS edited and reviewed the final article. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Seyed Davar Siadat.

Ethics declarations

Conflict of Interest

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mofrad, L.Z., Fateh, A., Sotoodehnejadnematalahi, F. et al. The Effect of Akkermansia muciniphila and Its Outer Membrane Vesicles on MicroRNAs Expression of Inflammatory and Anti-inflammatory Pathways in Human Dendritic Cells. Probiotics & Antimicro. Prot. 16, 367–382 (2024). https://doi.org/10.1007/s12602-023-10058-6

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12602-023-10058-6

Keywords

Search

Navigation