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2000
Volume 25, Issue 12
  • ISSN: 1566-5240
  • E-ISSN: 1875-5666

Abstract

Background

Previous studies have suggested that gut microbiota and immune system regulation have potential links with type 2 diabetes (T2D). However, the causal association between gut microbiota and T2D and whether immune cells mediate this interaction is unclear.

Methods

A two-sample, two-step Mendelian randomization (MR) study utilizing an initial inverse-variance weighted (IVW) method was performed to explore the causal impact of gut microbiota on T2D and the intermediary role of immune cells.

Results

The MR analysis assigned 4 gut microbiota and metabolic pathways that increase the risk of T2D (G_Prevotella, g_Anaerotruncus, g_Streptococcus.s_ Streptococcus_parasanguinis, and the pathway of PANTO-PWY) and 4 other gut microbiota and metabolic pathways that have a protective effect against T2D (PWY-5667, PWY-6892, PWY-7221, and the bacterial g_Paraprevotella.s_Paraprevotella_ clara). Furthermore, 17 immune cell traits have been identified as associated with T2D. The finding from mediation MR analysis revealed that PANTO-PWY increases T2D risk CD3 on HLA DR+ CD4+, whereas PWY-7221 reduces T2D risk through CD4 on CD4 Treg.

Conclusion

The research reveals a mediated causal link between the gut microbiota and T2D immune cells.

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References

  1. TeufelF. SeiglieJ.A. GeldsetzerP. Body-mass index and diabetes risk in 57 low-income and middle-income countries: A cross-sectional study of nationally representative, individual-level data in 685 616 adults.Lancet20213981029623824810.1016/S0140‑6736(21)00844‑8 34274065
     [Google Scholar]
  2. AnuradhaE.M. WangW.Y.C. MichaelM. Comprehensive factors for predicting the complications of diabetes mellitus: A systematic review.Curr. Diabetes Rev.2024
     [Google Scholar]
  3. DicksonI. Microbiome signatures for cirrhosis and diabetes.Nat. Rev. Gastroenterol. Hepatol.202017953210.1038/s41575‑020‑0351‑3 32704165
     [Google Scholar]
  4. TakeuchiT. KubotaT. NakanishiY. Gut microbial carbohydrate metabolism contributes to insulin resistance.Nature2023621797838939510.1038/s41586‑023‑06466‑x 37648852
     [Google Scholar]
  5. VatanenT. FranzosaE.A. SchwagerR. The human gut microbiome in early-onset type 1 diabetes from the TEDDY study.Nature2018562772858959410.1038/s41586‑018‑0620‑2 30356183
     [Google Scholar]
  6. ZhouW. SailaniM.R. ContrepoisK. Longitudinal multi-omics of host–microbe dynamics in prediabetes.Nature2019569775866367110.1038/s41586‑019‑1236‑x 31142858
     [Google Scholar]
  7. YangK. NiuJ. ZuoT. Alterations in the gut virome in obesity and type 2 diabetes mellitus.Gastroenterology2021161412571269.e1310.1053/j.gastro.2021.06.056 34175280
     [Google Scholar]
  8. WuZ. ZhangB. ChenF. Fecal microbiota transplantation reverses insulin resistance in type 2 diabetes: A randomized, controlled, prospective study.Front. Cell. Infect. Microbiol.202312108999110.3389/fcimb.2022.1089991 36704100
     [Google Scholar]
  9. NgS.C. XuZ. MakJ.W.Y. Microbiota engraftment after faecal microbiota transplantation in obese subjects with type 2 diabetes: A 24-week, double-blind, randomised controlled trial.Gut202271471672310.1136/gutjnl‑2020‑323617 33785557
     [Google Scholar]
  10. DingD. YongH. YouN. Prospective study reveals host microbial determinants of clinical response to fecal microbiota transplant therapy in type 2 diabetes patients.Front. Cell. Infect. Microbiol.20221282036710.3389/fcimb.2022.820367 35402293
     [Google Scholar]
  11. da Ponte NetoA.M. ClementeA.C.O. RosaP.W. Fecal microbiota transplantation in patients with metabolic syndrome and obesity: A randomized controlled trial.World J. Clin. Cases202311194612462410.12998/wjcc.v11.i19.4612 37469721
     [Google Scholar]
  12. GreenJ.E. DavisJ.A. BerkM. Efficacy and safety of fecal microbiota transplantation for the treatment of diseases other than Clostridium difficile infection: A systematic review and meta-analysis.Gut Microbes2020121185464010.1080/19490976.2020.1854640 33345703
     [Google Scholar]
  13. FujimotoK. KimuraY. AllegrettiJ.R. Functional restoration of bacteriomes and viromes by fecal microbiota transplantation.Gastroenterology2021160620892102.e1210.1053/j.gastro.2021.02.013 33577875
     [Google Scholar]
  14. AkdisC.A. Does the epithelial barrier hypothesis explain the increase in allergy, autoimmunity and other chronic conditions?Nat. Rev. Immunol.2021211173975110.1038/s41577‑021‑00538‑7 33846604
     [Google Scholar]
  15. RiedelS. PheifferC. JohnsonR. LouwJ. MullerC.J.F. Intestinal barrier function and immune homeostasis are missing links in obesity and type 2 diabetes development.Front. Endocrinol. (Lausanne)20221283354410.3389/fendo.2021.833544 35145486
     [Google Scholar]
  16. ZhangY. GaoX. GaoS. Effect of gut flora mediated‐bile acid metabolism on intestinal immune microenvironment.Immunology2023170330131810.1111/imm.13672 37317655
     [Google Scholar]
  17. BarbosaP. PinhoA. LázaroA. CD8+ Treg cells play a role in the obesity-associated insulin resistance.Life Sci.202433612230610.1016/j.lfs.2023.122306 38030055
     [Google Scholar]
  18. KattnerN. Immune cell infiltration in the pancreas of type 1, type 2 and type 3c diabetes.Ther. Adv. Endocrinol. Metab.2023142042018823118595810.1177/20420188231185958 37529508
     [Google Scholar]
  19. Yoon KimD. Kwon LeeJ. Type 1 and 2 diabetes are associated with reduced natural killer cell cytotoxicity.Cell. Immunol.202237910457810.1016/j.cellimm.2022.104578 35908302
     [Google Scholar]
  20. BurgessS. Davey SmithG. DaviesN.M. Guidelines for performing Mendelian randomization investigations: Update for summer 2023.Wellcome Open Res.2019418610.12688/wellcomeopenres.15555.3 32760811
     [Google Scholar]
  21. CarterA.R. SandersonE. HammertonG. Mendelian randomisation for mediation analysis: Current methods and challenges for implementation.Eur. J. Epidemiol.202136546547810.1007/s10654‑021‑00757‑1 33961203
     [Google Scholar]
  22. ChenJ. YuX. WuX. ChaiK. WangS. Causal relationships between gut microbiota, immune cell, and Non-small cell lung cancer: A two-step, two-sample Mendelian randomization study.J. Cancer20241571890189710.7150/jca.92699 38434967
     [Google Scholar]
  23. CaesarR. Pharmacologic and nonpharmacologic therapies for the gut microbiota in type 2 diabetes.Can. J. Diabetes201943322423110.1016/j.jcjd.2019.01.007 30929665
     [Google Scholar]
  24. GurungM. LiZ. YouH. Role of gut microbiota in type 2 diabetes pathophysiology.EBioMedicine20205110259010.1016/j.ebiom.2019.11.051 31901868
     [Google Scholar]
  25. ZhangL. ChuJ. HaoW. Gut microbiota and type 2 diabetes mellitus: Association, mechanism, and translational applications.Mediators Inflamm.2021202111210.1155/2021/5110276 34447287
     [Google Scholar]
  26. DuJ. YangM. ZhangZ. CaoB. WangZ. HanJ. The modulation of gut microbiota by herbal medicine to alleviate diabetic kidney disease - A review.Front. Pharmacol.202213103220810.3389/fphar.2022.1032208 36452235
     [Google Scholar]
  27. JiangZ. SunT. HeY. Dietary fruit and vegetable intake, gut microbiota, and type 2 diabetes: Results from two large human cohort studies.BMC Med.202018137110.1186/s12916‑020‑01842‑0 33267887
     [Google Scholar]
  28. TettA. PasolliE. MasettiG. ErcoliniD. SegataN. Prevotella diversity, niches and interactions with the human host.Nat. Rev. Microbiol.202119958559910.1038/s41579‑021‑00559‑y 34050328
     [Google Scholar]
  29. TsaiC.Y. LuH.C. ChouY.H. Gut microbial signatures for glycemic responses of GLP-1 receptor agonists in type 2 diabetic patients: A pilot study.Front. Endocrinol. (Lausanne)20221281477010.3389/fendo.2021.814770 35095773
     [Google Scholar]
  30. ZhaoL. LouH. PengY. ChenS. ZhangY. LiX. Comprehensive relationships between gut microbiome and faecal metabolome in individuals with type 2 diabetes and its complications.Endocrine201966352653710.1007/s12020‑019‑02103‑8 31591683
     [Google Scholar]
  31. LiuC. ShaoW. GaoM. Changes in intestinal flora in patients with type 2 diabetes on a low fat diet during 6 months of follow up.Exp. Ther. Med.2020205110.3892/etm.2020.9167 32952631
     [Google Scholar]
  32. WortelboerK. KoopenA.M. HerremaH. de VosW.M. NieuwdorpM. KemperE.M. From fecal microbiota transplantation toward next-generation beneficial microbes: The case of Anaerobutyricum soehngenii.Front. Med. (Lausanne)20229107727510.3389/fmed.2022.1077275 36544495
     [Google Scholar]
  33. MiaoZ. LinJ. MaoY. Erythrocyte n-6 polyunsaturated fatty acids, gut microbiota, and incident type 2 diabetes: A prospective cohort study.Diabetes Care202043102435244310.2337/dc20‑0631 32723842
     [Google Scholar]
  34. ThomèsL. LescureA. Mosaic evolution of the phosphopantothenate biosynthesis pathway in bacteria and archaea.Genome Biol. Evol.2021132evaa26210.1093/gbe/evaa262 33320181
     [Google Scholar]
  35. ZhangF. ZuoT. WanY. Multi-omic analyses identify mucosa bacteria and fecal metabolites associated with weight loss after fecal microbiota transplantation.Innovation (Camb.)20223510030410.1016/j.xinn.2022.100304 36091491
     [Google Scholar]
  36. ObaR. IsomuraM. IgarashiA. NagataK. Circulating CD3 + HLA-DR + extracellular vesicles as a marker for Th1/Tc1-Type immune responses.J. Immunol. Res.2019201911310.1155/2019/6720819 31205958
     [Google Scholar]
  37. MahmoudM. JuntunenM. AdnanA. Immunomodulatory functions of adipose mesenchymal stromal/stem cell derived from donors with type 2 diabetes and obesity on CD4 T cells.Stem Cells202341550551910.1093/stmcls/sxad021 36945068
     [Google Scholar]
  38. MartinezP.J. MathewsC. ActorJ.K. Impaired CD4+ and T-helper 17 cell memory response to Streptococcus pneumoniae is associated with elevated glucose and percent glycated hemoglobin A1c in Mexican Americans with type 2 diabetes mellitus.Transl. Res.20141631536310.1016/j.trsl.2013.07.005 23927943
     [Google Scholar]
  39. CarlosD. PérezM.M. LeiteJ.A. NOD2 deficiency promotes intestinal CD4+ T lymphocyte imbalance, metainflammation, and aggravates type 2 diabetes in murine model.Front. Immunol.202011126510.3389/fimmu.2020.01265 32774333
     [Google Scholar]
  40. ZhuY. LuoJ. YangZ. MiaoY. High-throughput sequencing analysis of differences in intestinal microflora between ulcerative colitis patients with different glucocorticoid response types.Genes Genomics202042101197120610.1007/s13258‑020‑00986‑w 32844358
     [Google Scholar]
  41. LiuR. PughG.H. TevonianE. Regulatory T cells control effector T cell inflammation in human prediabetes.Diabetes202271226427410.2337/db21‑0659 34737186
     [Google Scholar]
  42. Descalzi-MontoyaD.B. YangZ. FanningS. Cord blood-derived multipotent stem cells ameliorate in vitro/in vivo alloreactive responses, and this effect is associated with exosomal microvesicles in vitro.Transplant. Cell. Ther.2024304396.e1396.e1410.1016/j.jtct.2024.01.078 38307173
     [Google Scholar]
  43. LobmannR. IttensonA. SchiweckS. Expression of cell surface antigens in diabetic patients and healthy controls after injury.Diabetes Nutr. Metab.2004174244246 15575346
     [Google Scholar]
  44. ZouF. LaiX. LiJ. LeiS. HuL. Downregulation of cathepsin G reduces the activation of CD4+ T cells in murine autoimmune diabetes.Am. J. Transl. Res.201791151275137 29218110
     [Google Scholar]
  45. EarleK. TangQ. ZhouX. In vitro expanded human CD4+CD25+ regulatory T cells suppress effector T cell proliferation.Clin. Immunol.200511513910.1016/j.clim.2005.02.017 15870014
     [Google Scholar]
  46. PitmonE. MeehanE.V. AhmadiE. AdlerA.J. WangK. High glucose promotes regulatory T cell differentiation.PLoS One2023182e028091610.1371/journal.pone.0280916 36730267
     [Google Scholar]
  47. AnwaarI. GottsäterA. ErikssonK.F. JacobssonL. LindgärdeF. MattiassonI. Increased plasma endothelin-1 and intraplatelet cyclic guanosine monophosphate in men with disturbed glucose metabolism.Diabetes Res. Clin. Pract.200050212713610.1016/S0168‑8227(00)00190‑X 10960723
     [Google Scholar]
  48. ZappacostaB. De SoleP. Di SalvoS. De MicheleT. PennacchiettiL. GiardinaB. Resting and stimulated human polymorphonuclear leucocytes from type‐2 diabetic patients: Change in purine nucleotide pattern.Eur. J. Clin. Invest.199727319620110.1046/j.1365‑2362.1997.860638.x 9088854
     [Google Scholar]
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Role of Immune Cells in Mediating the Causal Effect of Gut Microbiota on Type 2 Diabetes
Current Molecular Medicine 25, 1497 (2025); https://doi.org/10.2174/0115665240322713241114051433
/content/journals/cmm/10.2174/0115665240322713241114051433
/content/journals/cmm/10.2174/0115665240322713241114051433
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  • Article Type:     Research Article
Keyword(s): Causal effects; Gut microbiota; Immune cells; inverse-variance weighted (IVW); Mendelian randomization analysis; Type 2 diabetes

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