Abstract
Type 2 diabetes mellitus (T2DM) has a major comorbidity known as diabetes-associated cognitive dysfunction (DACD). Studies have demonstrated that the gut microbiota is crucial in mediating the cognitive abnormalities that occur in diabetic individuals. Additionally, changes in dietary fatty acid intake levels, inflammatory cytokines, and microRNAs (miRs) have an effect on cognitive performance. However, further studies are needed to identify the link between gut microbiota and cognition in T2DM patients and the role that the above indicators play in this process. In order to provide a new rationale for the treatment of cognitive dysfunction in diabetes, this study was conducted in the middle-aged and elderly Beijing population to examine the differences in gut microbiota between DACD and T2DM patients as well as to further explore the role of erythrocyte membrane fatty acids, inflammatory cytokines, and miRs in gut microbiota-mediated cognitive impairment. According to the results, the abundance of norank_f_Eubacterium_coprostanoligenes_group, Acidaminococcus, Enterorhabdus, and norank_f_Clostridium_methylpentosum_group was higher in DACD patients compared to T2DM patients at the genus level. Compared with T2DM patients, plasma interleukin-12 (IL-12) concentrations were significantly higher in DACD patients than in T2DM patients, and IL-12 was significantly positively correlated with norank_f_Eubacterium_coprostanoligenes_group. In addition, plasma miR-142-5p was significantly positively correlated with Enterorhabdus and norank_f_Eubacterium_coprostanoligenes_group. We therefore hypothesize that cognitive impairment in T2DM patients is associated with altered gut microbial composition and that the effect of microbiota on cognition may be mediated through IL-12 and miR-142-5p.
Key points
• Type 2 diabetes with or without cognitive impairment differs in gut microbiota.
• Differential genera of gut microbiota were associated with inflammatory cytokines.
• Differential genera of gut microbiota were associated with plasma microRNAs.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Data availability
The sequences have been deposited in the NCBI Sequence Read Archive database under the bioproject number PRJNA978383.
References
Aschner P, Karuranga S, James S, Simmons D, Basit A, Shaw JE, Wild SH, Ogurtsova K, Saeedi P, International Diabetes Federation’s Diabetes Epidemiological Guide Writing G (2021) The International Diabetes Federation’s guide for diabetes epidemiological studies. Diabetes Res Clin Pract 172:108630. https://doi.org/10.1016/j.diabres.2020.108630
Beam A, Clinger E, Hao L (2021) Effect of diet and dietary components on the composition of the gut microbiota. Nutrients 13. https://doi.org/10.3390/nu13082795
Bi T, Feng R, Zhan L, Ren W, Lu X (2021) ZiBuPiYin recipe prevented and treated cognitive decline in ZDF rats with diabetes-associated cognitive decline via microbiota-gut-brain axis dialogue. Front Cell Dev Biol 9:651517. https://doi.org/10.3389/fcell.2021.651517
Biessels GJ, Despa F (2018) Cognitive decline and dementia in diabetes mellitus: mechanisms and clinical implications. Nat Rev Endocrinol 14:591–604. https://doi.org/10.1038/s41574-018-0048-7
Casagrande SS, Lee C, Stoeckel LE, Menke A, Cowie CC (2021) Cognitive function among older adults with diabetes and prediabetes, NHANES 2011–2014. Diabetes Res Clin Pract 178:108939. https://doi.org/10.1016/j.diabres.2021.108939
Cattaneo A, Cattane N, Galluzzi S, Provasi S, Lopizzo N, Festari C, Ferrari C, Guerra UP, Paghera B, Muscio C, Bianchetti A, Volta GD, Turla M, Cotelli MS, Gennuso M, Prelle A, Zanetti O, Lussignoli G, Mirabile D, Bellandi D, Gentile S, Belotti G, Villani D, Harach T, Bolmont T, Padovani A, Boccardi M, Frisoni GB, Group I-F (2017) Association of brain amyloidosis with pro-inflammatory gut bacterial taxa and peripheral inflammation markers in cognitively impaired elderly. Neurobiol Aging 49:60–68. https://doi.org/10.1016/j.neurobiolaging.2016.08.019
Chen KL, Xu Y, Chu AQ, Ding D, Liang XN, Nasreddine ZS, Dong Q, Hong Z, Zhao QH, Guo QH (2016) Validation of the Chinese version of montreal cognitive assessment basic for screening mild cognitive impairment. J Am Geriatr Soc 64:e285–e290. https://doi.org/10.1111/jgs.14530
Chen X, Zhang XL, Zhang GH, Gao YF (2019) Artesunate promotes Th1 differentiation from CD4+ T cells to enhance cell apoptosis in ovarian cancer via miR-142. Braz J Med Biol Res 52:e7992. https://doi.org/10.1590/1414-431X20197992
Custers, Emma EM, Kiliaan, Amanda J (2022) Dietary lipids from body to brain. Prog Lipid Res 85:101144. https://doi.org/10.1016/j.plipres.2021.101144
De Filippis F, Pellegrini N, Vannini L, Jeffery IB, La Storia A, Laghi L, Serrazanetti DI, Di Cagno R, Ferrocino I, Lazzi C, Turroni S, Cocolin L, Brigidi P, Neviani E, Gobbetti M, O’Toole PW, Ercolini D (2016) High-level adherence to a Mediterranean diet beneficially impacts the gut microbiota and associated metabolome. Gut 65:1812–1821. https://doi.org/10.1136/gutjnl-2015-309957
Ding B, Xiao R, Ma W, Zhao L, Bi Y, Zhang Y (2018) The association between macronutrient intake and cognition in individuals aged under 65 in China: a cross-sectional study. BMJ Open 8:e018573. https://doi.org/10.1136/bmjopen-2017-018573
Dong Y, Yean Lee W, Hilal S, Saini M, Wong TY, Chen CL, Venketasubramanian N, Ikram MK (2013) Comparison of the montreal cognitive assessment and the mini-mental state examination in detecting multi-domain mild cognitive impairment in a Chinese sub-sample drawn from a population-based study. Int Psychogeriatr 25:1831–1838. https://doi.org/10.1017/S1041610213001129
Du Y, Li X, An Y, Song Y, Lu Y (2022) Association of gut microbiota with sort-chain fatty acids and inflammatory cytokines in diabetic patients with cognitive impairment: a cross-sectional, non-controlled study. Front Nutr 9:930626. https://doi.org/10.3389/fnut.2022.930626
Ennis GE, Saelzler U, Umpierrez GE, Moffat SD (2020) Prediabetes and working memory in older adults. Brain Neurosci Adv 4:2398212820961725. https://doi.org/10.1177/2398212820961725
Franke A, Lante W, Kollig E, Koeller M, Schinkel C, Markewitz A (2009) Exogenous IL-12 and its effect on TH1/TH2 cell activity after cardiac surgery. Shock 32:366–373. https://doi.org/10.1097/SHK.0b013e31819d82ad
Galicia-Garcia U, Benito-Vicente A, Jebari S, Larrea-Sebal A, Siddiqi H, Uribe KB, Ostolaza H, Martin C (2020) Pathophysiology of type 2 diabetes mellitus. Int J Mol Sci 21. https://doi.org/10.3390/ijms21176275
Garrido-Mesa J, Rodriguez-Nogales A, Algieri F, Vezza T, Hidalgo-Garcia L, Garrido-Barros M, Utrilla MP, Garcia F, Chueca N, Rodriguez-Cabezas ME, Garrido-Mesa N, Galvez J (2018) Immunomodulatory tetracyclines shape the intestinal inflammatory response inducing mucosal healing and resolution. Br J Pharmacol 175:4353–4370. https://doi.org/10.1111/bph.14494
Gupta OP, Dahuja A, Sachdev A, Kumari S, Jain PK, Vinutha T, Praveen S (2019) Conserved miRNAs modulate the expression of potential transcription factors of isoflavonoid biosynthetic pathway in soybean seeds. Mol Biol Rep 46:3713–3730. https://doi.org/10.1007/s11033-019-04814-7
Hashemi S, Amani R, Cheraghian B, Neamatpour S (2020) Stress and anxiety levels are associated with erythrocyte fatty acids content in young women. Iran J Psychiatry 15:47–54
Hirko KA, Chai B, Spiegelman D, Campos H, Farvid MS, Hankinson SE, Willett WC, Eliassen AH (2018) Erythrocyte membrane fatty acids and breast cancer risk: a prospective analysis in the nurses’ health study II. Int J Cancer 142:1116–1129. https://doi.org/10.1002/ijc.31133
Hussein HM, Elyamany MF, Rashed LA, Sallam NA (2022) Vitamin D mitigates diabetes-associated metabolic and cognitive dysfunction by modulating gut microbiota and colonic cannabinoid receptor 1. Eur J Pharm Sci 170:106105. https://doi.org/10.1016/j.ejps.2021.106105
Karlsson FH, Tremaroli V, Nookaew I, Bergstrom G, Behre CJ, Fagerberg B, Nielsen J, Backhed F (2013) Gut metagenome in European women with normal, impaired and diabetic glucose control. Nature 498:99–103. https://doi.org/10.1038/nature12198
Larsen N, Vogensen FK, van den Berg FW, Nielsen DS, Andreasen AS, Pedersen BK, Al-Soud WA, Sorensen SJ, Hansen LH, Jakobsen M (2010) Gut microbiota in human adults with type 2 diabetes differs from non-diabetic adults. PLoS One 5:e9085. https://doi.org/10.1371/journal.pone.0009085
Lei S, He S, Li X, Zheng B, Zhang Y, Zeng H (2023) Effect of lotus seed resistant starch on small intestinal flora and bile acids in hyperlipidemic rats. Food Chem 404:134599. https://doi.org/10.1016/j.foodchem.2022.134599
Li Q, Chang Y, Zhang K, Chen H, Tao S, Zhang Z (2020a) Implication of the gut microbiome composition of type 2 diabetic patients from northern China. Sci Rep 10:5450. https://doi.org/10.1038/s41598-020-62224-3
Li, Rahman SU, Huang Y, Zhang Y, Ming P, Zhu L, Chu X, Li J, Feng S, Wang X, Wu J (2020b) Green tea polyphenols decrease weight gain, ameliorate alteration of gut microbiota, and mitigate intestinal inflammation in canines with high-fat-diet-induced obesity. J Nutr Biochem 78:108324. https://doi.org/10.1016/j.jnutbio.2019.108324
Li P, Gao Y, Ma X, Zhou S, Guo Y, Xu J, Wang X, Van Halm-Lutterodt N, Yuan L (2022) Study on the association of dietary fatty acid intake and serum lipid profiles with cognition in aged subjects with type 2 diabetes mellitus. Front Aging Neurosci 14:846132. https://doi.org/10.3389/fnagi.2022.846132
Liu X, Mo Y, Gong J, Li Z, Peng H, Chen J, Wang Q, Ke Z, Xie J (2016) Puerarin ameliorates cognitive deficits in streptozotocin-induced diabetic rats. Metab Brain Dis 31:417–423. https://doi.org/10.1007/s11011-015-9779-5
Liu Z, Dai X, Zhang H, Shi R, Hui Y, Jin X, Zhang W, Wang L, Wang Q, Wang D, Wang J, Tan X, Ren B, Liu X, Zhao T, Wang J, Pan J, Yuan T, Chu C, Lan L, Yin F, Cadenas E, Shi L, Zhao S, Liu X (2020) Gut microbiota mediates intermittent-fasting alleviation of diabetes-induced cognitive impairment. Nat Commun 11:855. https://doi.org/10.1038/s41467-020-14676-4
Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods 25:402–408. https://doi.org/10.1006/meth.2001.1262
Moens F, De Vuyst L (2017) Inulin-type fructan degradation capacity of Clostridium cluster IV and XIVa butyrate-producing colon bacteria and their associated metabolic outcomes. Benef Microbes 8:473–490. https://doi.org/10.3920/BM2016.0142
Mollon J, Curran JE, Mathias SR, Knowles EEM, Carlisle P, Fox PT, Olvera RL, Goring HHH, Rodrigue A, Almasy L, Duggirala R, Blangero J, Glahn DC (2020) Neurocognitive impairment in type 2 diabetes: evidence for shared genetic aetiology. Diabetologia 63:977–986. https://doi.org/10.1007/s00125-020-05101-y
Mukherjee A, Lordan C, Ross RP, Cotter PD (2020) Gut microbes from the phylogenetically diverse genus Eubacterium and their various contributions to gut health. Gut Microbes 12:1802866. https://doi.org/10.1080/19490976.2020.1802866
Nguyen HD, Oh H, Kim MS (2022) Higher intakes of nutrients are linked with a lower risk of cardiovascular diseases, type 2 diabetes mellitus, arthritis, and depression among Korean adults. Nutr Res 100:19–32. https://doi.org/10.1016/j.nutres.2021.11.003
Osborne G, Wu F, Yang L, Kelly D, Hu J, Li H, Jasmine F, Kibriya MG, Parvez F, Shaheen I, Sarwar G, Ahmed A, Eunus M, Islam T, Pei Z, Ahsan H, Chen Y (2020) The association between gut microbiome and anthropometric measurements in Bangladesh. Gut Microbes 11:63–76. https://doi.org/10.1080/19490976.2019.1614394
Pinart M, Dötsch A, Schlicht K, Laudes M, Bouwman J, Forslund SK, Pischon T, Nimptsch K (2021) Gut microbiome composition in obese and non-obese persons: a systematic review and meta-analysis. Nutrients 14. https://doi.org/10.3390/nu14010012
Qin J, Li Y, Cai Z, Li S, Zhu J, Zhang F, Liang S, Zhang W, Guan Y, Shen D, Peng Y, Zhang D, Jie Z, Wu W, Qin Y, Xue W, Li J, Han L, Lu D, Wu P, Dai Y, Sun X, Li Z, Tang A, Zhong S, Li X, Chen W, Xu R, Wang M, Feng Q, Gong M, Yu J, Zhang Y, Zhang M, Hansen T, Sanchez G, Raes J, Falony G, Okuda S, Almeida M, LeChatelier E, Renault P, Pons N, Batto JM, Zhang Z, Chen H, Yang R, Zheng W, Li S, Yang H, Wang J, Ehrlich SD, Nielsen R, Pedersen O, Kristiansen K, Wang J (2012) A metagenome-wide association study of gut microbiota in type 2 diabetes. Nature 490:55–60. https://doi.org/10.1038/nature11450
Qu Y, Wu Y, Cheng W, Wang D, Zeng L, Wang Y, Li T, Zhang L, Yang J, Sun L, Ai J (2022) Amelioration of cognitive impairment using epigallocatechin-3-gallate in ovariectomized mice fed a high-fat diet involves remodeling with Prevotella and Bifidobacteriales. Front Pharmacol 13:1079313. https://doi.org/10.3389/fphar.2022.1079313
Shahi SK, Zarei K, Guseva NV, Mangalam AK (2019) Microbiota analysis using two-step PCR and next-generation 16S rRNA gene sequencing. J Vis Exp. https://doi.org/10.3791/59980
Sharma G, Parihar A, Talaiya T, Dubey K, Porwal B, Parihar MS (2020) Cognitive impairments in type 2 diabetes, risk factors and preventive strategies. J Basic Clin Physiol Pharmacol 31. https://doi.org/10.1515/jbcpp-2019-0105
Shen J, Li J, Hua Y, Ding B, Zhou C, Yu H, Xiao R, Ma W (2022) Association between the erythrocyte membrane fatty acid profile and cognitive function in the overweight and obese population aged from 45 to 75 years old. Nutrients 14. https://doi.org/10.3390/nu14040914
Shi H, Ge X, Ma X, Zheng M, Cui X, Pan W, Zheng P, Yang X, Zhang P, Hu M, Hu T, Tang R, Zheng K, Huang XF, Yu Y (2021) A fiber-deprived diet causes cognitive impairment and hippocampal microglia-mediated synaptic loss through the gut microbiota and metabolites. Microbiome 9:223. https://doi.org/10.1186/s40168-021-01172-0
Song J, Kim YK (2017) Identification of the role of miR-142-5p in Alzheimer’s disease by comparative bioinformatics and cellular analysis. Front Mol Neurosci 10:227. https://doi.org/10.3389/fnmol.2017.00227
Srikanth V, Sinclair AJ, Hill-Briggs F, Moran C, Biessels GJ (2020) Type 2 diabetes and cognitive dysfunction-towards effective management of both comorbidities. Lancet Diabetes Endocrinol 8:535–545. https://doi.org/10.1016/S2213-8587(20)30118-2
Steffen BT, Steffen LM, Zhou X, Ouyang P, Weir NL, Tsai MY (2015) N-3 Fatty acids attenuate the risk of diabetes associated with elevated serum nonesterified fatty acids: the multi-ethnic study of atherosclerosis. Diabetes Care 38:575–580. https://doi.org/10.2337/dc14-1919
Turpin W, Espin-Garcia O, Xu W, Silverberg MS, Kevans D, Smith MI, Guttman DS, Griffiths A, Panaccione R, Otley A, Xu L, Shestopaloff K, Moreno-Hagelsieb G, Consortium GEMPR, Paterson AD, Croitoru K (2016) Association of host genome with intestinal microbial composition in a large healthy cohort. Nat Genet 48:1413–1417. https://doi.org/10.1038/ng.3693
Umegaki H, Hayashi T, Nomura H, Yanagawa M, Nonogaki Z, Nakshima H, Kuzuya M (2013) Cognitive dysfunction: an emerging concept of a new diabetic complication in the elderly. Geriatr Gerontol Int 13:28–34. https://doi.org/10.1111/j.1447-0594.2012.00922.x
Wang G, Zhang X, Lu X, Liu J, Zhang Z, Wei Z, Wu Z, Wang J (2020) Fish oil supplementation attenuates cognitive impairment by inhibiting neuroinflammation in STZ-induced diabetic rats. Aging (Albany NY) 12:15281–15289. https://doi.org/10.18632/aging.103426
Willmann C, Brockmann K, Wagner R, Kullmann S, Preissl H, Schnauder G, Maetzler W, Gasser T, Berg D, Eschweiler GW, Metzger F, Fallgatter AJ, Haring HU, Fritsche A, Heni M (2020) Insulin sensitivity predicts cognitive decline in individuals with prediabetes. BMJ Open Diabetes Res Care 8. https://doi.org/10.1136/bmjdrc-2020-001741
You Y, Liu Z, Chen Y, Xu Y, Qin J, Guo S, Huang J, Tao J (2021) The prevalence of mild cognitive impairment in type 2 diabetes mellitus patients: a systematic review and meta-analysis. Acta Diabetol 58:671–685. https://doi.org/10.1007/s00592-020-01648-9
Yu F, Han W, Zhan G, Li S, Xiang S, Zhu B, Jiang X, Yang L, Luo A, Hua F, Yang C (2019) Abnormal gut microbiota composition contributes to cognitive dysfunction in streptozotocin-induced diabetic mice. Aging (Albany NY) 11:3262–3279. https://doi.org/10.18632/aging.101978
Zhang W, Li Q, Shi L, Lu K, Shang Q, Yao L, Ye G (2009) Investigation of dietary intake of cadmium in certain polluted area of south in China. Wei Sheng Yan Jiu 38(552–4):557
Zhang Y, Lu S, Yang Y, Wang Z, Wang B, Zhang B, Yu J, Lu W, Pan M, Zhao J, Guo S, Cheng J, Chen X, Hong K, Li G, Yu Z (2021) The diversity of gut microbiota in type 2 diabetes with or without cognitive impairment. Aging Clin Exp Res 33:589–601. https://doi.org/10.1007/s40520-020-01553-9
Zhang L, Wang Z, Zhang X, Zhao L, Chu J, Li H, Sun W, Yang C, Wang H, Dai W, Yan S, Chen X, Xu D (2022) Alterations of the gut microbiota in patients with diabetic nephropathy. Microbiol Spectr 10:e0032422. https://doi.org/10.1128/spectrum.00324-22
Zheng Y, Zhou X, Wang C, Zhang J, Chang D, Zhuang S, Xu W, Chen Y, Wang X, Nan L, Sun Y, Lin X, Lin W, He C, Dai L, Zhang J, Chen J, Shi H, Huang M (2022) Effect of dendrobium mixture in alleviating diabetic cognitive impairment associated with regulating gut microbiota. Biomed Pharmacother 149:112891. https://doi.org/10.1016/j.biopha.2022.112891
Zhou H, Tai J, Xu H, Lu X, Meng D (2019) Xanthoceraside could ameliorate Alzheimer’s disease symptoms of rats by affecting the gut microbiota composition and modulating the endogenous metabolite levels. Front Pharmacol 10:1035. https://doi.org/10.3389/fphar.2019.01035
Funding
This research was funded by the Natural Science Foundation of Beijing (grant number 7222242) and the National Natural Science Foundation of China (grant number 81773406).
Author information
Authors and Affiliations
Contributions
HH: conceptualization, methodology, software, formal analysis, investigation, writing—original draft, writing—review and editing. JL and JS: software, validation, formal analysis, data curation, investigation. TZ: validation, data curation, investigation. RX: supervision, resources. WM: conceptualization, methodology, resources, writing—review and editing. All authors have read and agreed to the published version of the manuscript.
Corresponding author
Ethics declarations
Ethics approval
The study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Review Board of Capital Medical University (Z2019SY011).
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.
Supplementary Information
Below is the link to the electronic supplementary material.
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.
About this article
Cite this article
Huang, H., Zhao, T., Li, J. et al. Gut microbiota regulation of inflammatory cytokines and microRNAs in diabetes-associated cognitive dysfunction. Appl Microbiol Biotechnol 107, 7251–7267 (2023). https://doi.org/10.1007/s00253-023-12754-3
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00253-023-12754-3