{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,27]],"date-time":"2026-06-27T09:59:10Z","timestamp":1782554350081,"version":"3.54.5"},"reference-count":104,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2023,8,29]],"date-time":"2023-08-29T00:00:00Z","timestamp":1693267200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"MIUR Progetto Eccellenza and Intramural Grant Line-B from Universit\u00e0 degli Studi di Milano, Italy"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>The pathological consequences of type 2 diabetes mellitus (T2DM) also involve the central nervous system; indeed, T2DM patients suffer from learning and memory disabilities with a higher risk of developing dementia. Although several factors have been proposed as possible contributors, how neuroactive steroids and the gut microbiome impact brain pathophysiology in T2DM remain unexplored. On this basis, in male Zucker diabetic fatty (ZDF) rats, we studied whether T2DM alters memory abilities using the novel object recognition test, neuroactive steroid levels by liquid chromatography\u2013tandem mass spectrometry, hippocampal parameters using molecular assessments, and gut microbiome composition using 16S next-generation sequencing. Results obtained reveal that T2DM worsens memory abilities and that these are correlated with increased levels of corticosterone in plasma and with a decrease in allopregnanolone in the hippocampus, where neuroinflammation, oxidative stress, and mitochondrial dysfunction were reported. Interestingly, our analysis highlighted a small group of taxa strictly related to both memory impairment and neuroactive steroid levels. Overall, the data underline an interesting role for allopregnanolone and microbiota that may represent candidates for the development of therapeutic strategies.<\/jats:p>","DOI":"10.3390\/biom13091325","type":"journal-article","created":{"date-parts":[[2023,8,29]],"date-time":"2023-08-29T10:46:00Z","timestamp":1693305960000},"page":"1325","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Neuroactive Steroid\u2013Gut Microbiota Interaction in T2DM Diabetic Encephalopathy"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1454-2196","authenticated-orcid":false,"given":"Silvia","family":"Diviccaro","sequence":"first","affiliation":[{"name":"Dipartimento di Scienze Farmacologiche e Biomolecolari, Universit\u00e0 degli Studi di Milano, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5935-3597","authenticated-orcid":false,"given":"Lucia","family":"Cioffi","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze Farmacologiche e Biomolecolari, Universit\u00e0 degli Studi di Milano, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4198-9620","authenticated-orcid":false,"given":"Rocco","family":"Piazza","sequence":"additional","affiliation":[{"name":"Dipartimento di Medicina e Chirurgia, Universit\u00e0 di Milano\u2014Bicocca, 20126 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2115-778X","authenticated-orcid":false,"given":"Donatella","family":"Caruso","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze Farmacologiche e Biomolecolari, Universit\u00e0 degli Studi di Milano, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0861-8967","authenticated-orcid":false,"given":"Roberto Cosimo","family":"Melcangi","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze Farmacologiche e Biomolecolari, Universit\u00e0 degli Studi di Milano, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7741-826X","authenticated-orcid":false,"given":"Silvia","family":"Giatti","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze Farmacologiche e Biomolecolari, Universit\u00e0 degli Studi di Milano, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,8,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1253","DOI":"10.1016\/j.numecd.2018.07.008","article-title":"Brain imaging correlates of mild cognitive impairment and early dementia in patients with type 2 diabetes mellitus","volume":"28","author":"Groeneveld","year":"2018","journal-title":"Nutr. Metab. Cardiovasc. Dis."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"916","DOI":"10.1016\/j.jdiacomp.2018.05.017","article-title":"Relationships between cerebral structure and cognitive function in African Americans with type 2 diabetes","volume":"32","author":"Hughes","year":"2018","journal-title":"J. Diabetes Complicat."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"359","DOI":"10.15585\/mmwr.mm6712a2","article-title":"Prevalence of Diagnosed Diabetes in Adults by Diabetes Type\u2014United States, 2016","volume":"67","author":"Bullard","year":"2018","journal-title":"MMWR Morb. Mortal. Wkly. Rep."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1038\/s41574-018-0048-7","article-title":"Cognitive decline and dementia in diabetes mellitus: Mechanisms and clinical implications","volume":"14","author":"Biessels","year":"2018","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1002\/dmrr.1112","article-title":"Cognitive dysfunction in patients with type 2 diabetes","volume":"26","author":"Reijmer","year":"2010","journal-title":"Diabetes Metab. Res. Rev."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"969","DOI":"10.1016\/S1474-4422(11)70188-0","article-title":"Effects of intensive glucose lowering on brain structure and function in people with type 2 diabetes (ACCORD MIND): A randomised open-label substudy","volume":"10","author":"Launer","year":"2011","journal-title":"Lancet Neurol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2545","DOI":"10.1056\/NEJMoa0802743","article-title":"Effects of intensive glucose lowering in type 2 diabetes","volume":"358","author":"Gerstein","year":"2008","journal-title":"N. Engl. J. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1056\/NEJMoa0808431","article-title":"Glucose control and vascular complications in veterans with type 2 diabetes","volume":"360","author":"Duckworth","year":"2009","journal-title":"N. Engl. J. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1024","DOI":"10.1111\/dme.12467","article-title":"Diabetes and dementia in older people: A Best Clinical Practice Statement by a multidisciplinary National Expert Working Group","volume":"31","author":"Sinclair","year":"2014","journal-title":"Diabet. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2328","DOI":"10.1007\/s00125-009-1484-7","article-title":"Cognitive function and risks of cardiovascular disease and hypoglycaemia in patients with type 2 diabetes: The Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial","volume":"52","author":"Zoungas","year":"2009","journal-title":"Diabetologia"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1007\/s00125-007-0602-7","article-title":"Hippocampal damage and memory impairments as possible early brain complications of type 2 diabetes","volume":"50","author":"Gold","year":"2007","journal-title":"Diabetologia"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1017\/S1355617704104165","article-title":"Type 2 diabetes mellitus contributes to cognitive decline in old age: A longitudinal population-based study","volume":"10","author":"Hassing","year":"2004","journal-title":"J. Int. Neuropsychol. Soc."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1007\/s00125-009-1571-9","article-title":"A 4 year follow-up study of cognitive functioning in patients with type 2 diabetes mellitus","volume":"53","author":"Reijmer","year":"2010","journal-title":"Diabetologia"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"4036","DOI":"10.2337\/dc13-0143","article-title":"Brain atrophy in type 2 diabetes: Regional distribution and influence on cognition","volume":"36","author":"Moran","year":"2013","journal-title":"Diabetes Care"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.freeradbiomed.2021.09.006","article-title":"The interplay among oxidative stress, brain insulin resistance, and AMPK dysfunction contributes to neurodegeneration in type 2 diabetes and Alzheimer disease","volume":"176","author":"Barone","year":"2021","journal-title":"Free Radic. Biol. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1055\/s-0031-1275288","article-title":"Flattened circadian cortisol rhythm in type 2 diabetes","volume":"119","author":"Lederbogen","year":"2011","journal-title":"Exp. Clin. Endocrinol. Diabetes"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1016\/j.psyneuen.2015.08.021","article-title":"Diurnal salivary cortisol, glycemia and insulin resistance: The multi-ethnic study of atherosclerosis","volume":"62","author":"Joseph","year":"2015","journal-title":"Psychoneuroendocrinology"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1111\/nyas.13217","article-title":"Cortisol dysregulation: The bidirectional link between stress, depression, and type 2 diabetes mellitus","volume":"1391","author":"Joseph","year":"2017","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"3474","DOI":"10.1523\/JNEUROSCI.4893-07.2008","article-title":"Glucocorticoid Therapy-Induced Memory Deficits: Acute versus Chronic Effects","volume":"28","author":"Daniel","year":"2008","journal-title":"J. Neurosci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1212\/01.WNL.0000149523.35039.4C","article-title":"Effect of corticosteroids on short-term and long-term memory","volume":"64","author":"Brunner","year":"2005","journal-title":"Neurology"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/j.jsbmb.2016.11.019","article-title":"Short-term effects of diabetes on neurosteroidogenesis in the rat hippocampus","volume":"167","author":"Romano","year":"2017","journal-title":"J. Steroid Biochem. Mol. Biol."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Falvo, E., Giatti, S., Diviccaro, S., Cioffi, L., Herian, M., Brivio, P., Calabrese, F., Caruso, D., and Melcangi, R.C. (2023). Diabetic Encephalopathy in a Preclinical Experimental Model of Type 1 Diabetes Mellitus: Observations in Adult Female Rat. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24021196"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"100804","DOI":"10.1016\/j.yfrne.2019.100804","article-title":"Sex differences in steroid levels and steroidogenesis in the nervous system: Physiopathological role","volume":"56","author":"Giatti","year":"2020","journal-title":"Front. Neuroendocrinol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"S122","DOI":"10.1016\/S0924-977X(16)30893-8","article-title":"Neuroactive steroid levels in healthy and diseased","volume":"26","author":"Melcangi","year":"2016","journal-title":"Eur. Neuropsychopharmacol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3702","DOI":"10.1007\/s12035-018-1330-3","article-title":"Allopregnanolone Treatment Improves Plasma Metabolomic Profile Associated with GABA Metabolism in Fragile X-Associated Tremor\/Ataxia Syndrome: A Pilot Study","volume":"56","author":"Napoli","year":"2019","journal-title":"Mol. Neurobiol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e12996","DOI":"10.1111\/jne.12996","article-title":"Allopregnanolone: An overview on its synthesis and effects","volume":"34","author":"Diviccaro","year":"2022","journal-title":"J. Neuroendocrinol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"R125","DOI":"10.1530\/JME-12-0127","article-title":"Neuroactive steroids, their metabolites, and neuroinflammation","volume":"49","author":"Giatti","year":"2012","journal-title":"J. Mol. Endocrinol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/j.jsbmb.2015.03.002","article-title":"New steps forward in the neuroactive steroid field","volume":"153","author":"Giatti","year":"2015","journal-title":"J. Steroid Biochem. Mol. Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"169","DOI":"10.3389\/fendo.2019.00169","article-title":"Neurosteroid Actions in Memory and Neurologic\/Neuropsychiatric Disorders","volume":"10","author":"Ratner","year":"2019","journal-title":"Front. Endocrinol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1016\/j.jsbmb.2017.11.009","article-title":"Diabetes induces mitochondrial dysfunction and alters cholesterol homeostasis and neurosteroidogenesis in the rat cerebral cortex","volume":"178","author":"Romano","year":"2018","journal-title":"J. Steroid Biochem. Mol. Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1877","DOI":"10.1152\/physrev.00018.2018","article-title":"The Microbiota-Gut-Brain Axis","volume":"99","author":"Cryan","year":"2019","journal-title":"Physiol. Rev."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Diviccaro, S., Caputi, V., Cioffi, L., Giatti, S., Lyte, J.M., Caruso, D., O\u2019Mahony, S.M., and Melcangi, R.C. (2021). Exploring the Impact of the Microbiome on Neuroactive Steroid Levels in Germ-Free Animals. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222212551"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1111\/j.1365-2982.2010.01620.x","article-title":"Reduced anxiety-like behavior and central neurochemical change in germ-free mice","volume":"23","author":"Neufeld","year":"2011","journal-title":"Neurogastroenterol. Motil."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1007\/978-1-4939-0897-4_16","article-title":"Microbiota-gut-brain axis and cognitive function","volume":"817","author":"Gareau","year":"2014","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"109405","DOI":"10.1016\/j.neuropharm.2022.109405","article-title":"Gut microbiota composition is altered in a preclinical model of type 1 diabetes mellitus: Influence on gut steroids, permeability, and cognitive abilities","volume":"226","author":"Diviccaro","year":"2023","journal-title":"Neuropharmacology"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"855","DOI":"10.1038\/s41467-020-14676-4","article-title":"Gut microbiota mediates intermittent-fasting alleviation of diabetes-induced cognitive impairment","volume":"11","author":"Liu","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2278","DOI":"10.1016\/j.psyneuen.2013.04.016","article-title":"Comparison of plasma and cerebrospinal fluid levels of neuroactive steroids with their brain, spinal cord and peripheral nerve levels in male and female rats","volume":"38","author":"Caruso","year":"2013","journal-title":"Psychoneuroendocrinology"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"173513","DOI":"10.1016\/j.pbb.2022.173513","article-title":"Adolescent intermittent ethanol exposure enhances adult stress effects in male rats","volume":"223","author":"Healey","year":"2023","journal-title":"Pharmacol. Biochem. Behav."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1137","DOI":"10.1111\/j.1365-2826.2010.02064.x","article-title":"Effect of short-and long-term gonadectomy on neuroactive steroid levels in the central and peripheral nervous system of male and female rats","volume":"22","author":"Caruso","year":"2010","journal-title":"J. Neuroendocrinol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/j.jsbmb.2014.03.012","article-title":"Patients treated for male pattern hair with finasteride show, after discontinuation of the drug, altered levels of neuroactive steroids in cerebrospinal fluid and plasma","volume":"146","author":"Caruso","year":"2015","journal-title":"J. Steroid Biochem. Mol. Biol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"105364","DOI":"10.1016\/j.psyneuen.2021.105364","article-title":"Effects of paroxetine treatment and its withdrawal on neurosteroidogenesis","volume":"132","author":"Giatti","year":"2021","journal-title":"Psychoneuroendocrinology"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"467","DOI":"10.2144\/000112401","article-title":"Isolation and solubilization of proteins after TRIzol extraction of RNA and DNA from patient material following prolonged storage","volume":"42","author":"Hummon","year":"2007","journal-title":"Biotechniques"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"e12736","DOI":"10.1111\/jne.12736","article-title":"Sex differences in the brain expression of steroidogenic molecules under basal conditions and after gonadectomy","volume":"31","author":"Giatti","year":"2019","journal-title":"J. Neuroendocrinol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1186\/s13293-018-0164-z","article-title":"Axonal transport in a peripheral diabetic neuropathy model: Sex-dimorphic features","volume":"9","author":"Pesaresi","year":"2018","journal-title":"Biol. Sex Differ."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1159\/000381064","article-title":"Dihydrotestosterone as a Protective Agent in Chronic Experimental Autoimmune Encephalomyelitis","volume":"101","author":"Giatti","year":"2015","journal-title":"Neuroendocrinology"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"e1","DOI":"10.1093\/nar\/gks808","article-title":"Evaluation of general 16S ribosomal RNA gene PCR primers for classical and next-generation sequencing-based diversity studies","volume":"41","author":"Klindworth","year":"2013","journal-title":"Nucleic Acids Res."},{"key":"ref_47","unstructured":"(2023, July 11). GalSeq Srl. Available online: www.galseq.com."},{"key":"ref_48","unstructured":"(2023, July 11). FastQC. Available online: https:\/\/www.bioinformatics.babraham.ac.uk\/projects\/fastqc\/."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"10","DOI":"10.14806\/ej.17.1.200","article-title":"Cutadapt removes adapter sequences from high-throughput sequencing reads","volume":"17","author":"Martin","year":"2011","journal-title":"EMBnet. J."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"852","DOI":"10.1038\/s41587-019-0209-9","article-title":"Reproducible, interactive, scalable and extensible microbiome data science using QIIME 2","volume":"37","author":"Bolyen","year":"2019","journal-title":"Nat. Biotechnol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"D590","DOI":"10.1093\/nar\/gks1219","article-title":"The SILVA ribosomal RNA gene database project: Improved data processing and web-based tools","volume":"41","author":"Quast","year":"2013","journal-title":"Nucleic Acids Res."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"3514","DOI":"10.1038\/s41467-020-17041-7","article-title":"Analysis of compositions of microbiomes with bias correction","volume":"11","author":"Lin","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"3123","DOI":"10.1093\/bioinformatics\/btu494","article-title":"STAMP: Statistical analysis of taxonomic and functional profiles","volume":"30","author":"Parks","year":"2014","journal-title":"Bioinformatics"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1093\/ilar.47.3.186","article-title":"Animal models of type 2 diabetes: Clinical presentation and pathophysiological relevance to the human condition","volume":"47","author":"Cefalu","year":"2006","journal-title":"ILAR J."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"25","DOI":"10.2174\/1871530319666190626143832","article-title":"Future Perspective of Diabetic Animal Models","volume":"20","author":"Pandey","year":"2020","journal-title":"Endocr. Metab. Immune Disord. Drug Targets"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1457","DOI":"10.1002\/ejp.1235","article-title":"Behavioural, morphological and electrophysiological assessment of the effects of type 2 diabetes mellitus on large and small nerve fibres in Zucker diabetic fatty, Zucker lean and Wistar rats","volume":"22","author":"Sumalla","year":"2018","journal-title":"Eur. J. Pain"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1007\/s00221-013-3409-4","article-title":"Hyperinsulinemia in rats causes impairment of spatial memory and learning with defects in hippocampal synaptic plasticity by involvement of postsynaptic mechanisms","volume":"226","author":"Kamal","year":"2013","journal-title":"Exp. Brain Res."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"8566970","DOI":"10.1155\/2022\/8566970","article-title":"Enhancement of Mitochondrial Function by the Neurogenic Molecule NSI-189 Accompanies Reversal of Peripheral Neuropathy and Memory Impairment in a Rat Model of Type 2 Diabetes","volume":"2022","author":"Jolivalt","year":"2022","journal-title":"J. Diabetes Res."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"2291","DOI":"10.1016\/S0140-6736(12)60360-2","article-title":"Diabetes and cognitive dysfunction","volume":"379","author":"McCrimmon","year":"2012","journal-title":"Lancet"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1011","DOI":"10.2147\/CIA.S48926","article-title":"Type 2 diabetes as a risk factor for cognitive impairment: Current insights","volume":"9","author":"Umegaki","year":"2014","journal-title":"Clin. Interv. Aging"},{"key":"ref_61","first-page":"87","article-title":"Diabetes and the hypothalamo-pituitary-adrenal (HPA) axis","volume":"28","author":"Chan","year":"2003","journal-title":"Minerva Endocrinol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1016\/j.brainres.2007.09.036","article-title":"Gene expression of mineralocorticoid and glucocorticoid receptors in the limbic system is related to type-2 like diabetes in leptin-resistant rats","volume":"1184","author":"Dendorfer","year":"2007","journal-title":"Brain Res."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"815","DOI":"10.1016\/j.psyneuen.2008.12.010","article-title":"A blunted cortisol awakening response and hippocampal atrophy in type 2 diabetes mellitus","volume":"34","author":"Bruehl","year":"2009","journal-title":"Psychoneuroendocrinology"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1038\/nn2055","article-title":"Diabetes impairs hippocampal function through glucocorticoid-mediated effects on new and mature neurons","volume":"11","author":"Stranahan","year":"2008","journal-title":"Nat. Neurosci."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1016\/j.bbi.2006.11.006","article-title":"An inflammatory review of glucocorticoid actions in the CNS","volume":"21","author":"Sorrells","year":"2007","journal-title":"Brain Behav. Immun."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/j.jneuroim.2014.01.013","article-title":"Glucocorticoid sensitization of microglia in a genetic mouse model of obesity and diabetes","volume":"269","author":"Dey","year":"2014","journal-title":"J. Neuroimmunol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1016\/j.yhbeh.2009.04.008","article-title":"Sex differences in neuroactive steroid levels in the nervous system of diabetic and non-diabetic rats","volume":"57","author":"Pesaresi","year":"2010","journal-title":"Horm. Behav."},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"Talaei, F., Van Praag, V.M., Shishavan, M.H., Landheer, S.W., Buikema, H., and Henning, R.H. (2014). Increased protein aggregation in Zucker diabetic fatty rat brain: Identification of key mechanistic targets and the therapeutic application of hydrogen sulfide. BMC Cell Biol., 15.","DOI":"10.1186\/1471-2121-15-1"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1346","DOI":"10.2174\/1567205013666160401114751","article-title":"Glucagon-Like Peptide-1-Mediated Modulation of Inflammatory Pathways in the Diabetic Brain: Relevance to Alzheimer\u2019s Disease","volume":"13","author":"Qin","year":"2016","journal-title":"Curr. Alzheimer Res."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"824","DOI":"10.1179\/1743132814Y.0000000330","article-title":"Activation of microglia and induction of pro-inflammatory cytokines in the hippocampus of type 2 diabetic rats","volume":"36","author":"Hwang","year":"2014","journal-title":"Neurol. Res."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1241","DOI":"10.1159\/000373947","article-title":"Increased oxidative stress and mitochondrial dysfunction in zucker diabetic rat liver and brain","volume":"35","author":"Raza","year":"2015","journal-title":"Cell. Physiol. Biochem."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"104757","DOI":"10.1016\/j.jff.2021.104757","article-title":"Gum Arabic supplementation prevents loss of learning and memory through stimulation of mitochondrial function in the hippocampus of type 2 diabetic rats","volume":"87","author":"Rajab","year":"2021","journal-title":"J. Funct. Foods"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"3786","DOI":"10.1111\/j.1582-4934.2008.00493.x","article-title":"Oxidative stress in NPC1 deficient cells: Protective effect of allopregnanolone","volume":"13","author":"Zampieri","year":"2009","journal-title":"J. Cell. Mol. Med."},{"key":"ref_74","first-page":"13610","article-title":"Allopregnanolone attenuates A\u03b225-35-induced neurotoxicity in PC12 cells by reducing oxidative stress","volume":"8","author":"Qian","year":"2015","journal-title":"Int. J. Clin. Exp. Med."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1016\/j.bbadis.2016.12.007","article-title":"Allopregnanolone and its analog BR 297 rescue neuronal cells from oxidative stress-induced death through bioenergetic improvement","volume":"1863","author":"Lejri","year":"2017","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"9695412","DOI":"10.1155\/2019\/9695412","article-title":"Mitochondria- and Oxidative Stress-Targeting Substances in Cognitive Decline-Related Disorders: From Molecular Mechanisms to Clinical Evidence","volume":"2019","author":"Lejri","year":"2019","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.yfrne.2008.11.002","article-title":"Neurobiological and neuropsychiatric effects of dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS)","volume":"30","author":"Maninger","year":"2009","journal-title":"Front. Neuroendocrinol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"11300","DOI":"10.4238\/2015.September.22.24","article-title":"Effect of dehydroepiandrosterone treatment on hormone levels and antioxidant parameters in aged rats","volume":"14","author":"Yin","year":"2015","journal-title":"Genet. Mol. Res."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1111\/j.1527-3458.2003.tb00242.x","article-title":"Dehydroepiandrosterone (DHEA) and the aging brain: Flipping a coin in the \u201cfountain of youth\u201d","volume":"9","author":"Racchi","year":"2003","journal-title":"CNS Drug Rev."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"851","DOI":"10.1111\/j.1365-2826.2012.02284.x","article-title":"Neuroprotective Effects of Progesterone in Chronic Experimental Autoimmune Encephalomyelitis","volume":"24","author":"Giatti","year":"2012","journal-title":"J. Neuroendocrinol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"S1","DOI":"10.1016\/j.psyneuen.2009.11.001","article-title":"Neuroactive steroids: An update of their roles in central and peripheral nervous system","volume":"34","author":"Melcangi","year":"2009","journal-title":"Psychoneuroendocrinology"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1016\/j.yhbeh.2009.06.001","article-title":"Sex-Specific therapeutic strategies based on neuroactive steroids: In search for innovative tools for neuroprotection","volume":"57","author":"Cosimo","year":"2010","journal-title":"Horm. Behav."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"607240","DOI":"10.3389\/fendo.2020.607240","article-title":"Hypogonadism, Type-2 Diabetes Mellitus, and Bone Health: A Narrative Review","volume":"11","author":"Russo","year":"2021","journal-title":"Front. Endocrinol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1038\/nature11450","article-title":"A metagenome-wide association study of gut microbiota in type 2 diabetes","volume":"490","author":"Qin","year":"2012","journal-title":"Nature"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1038\/nature12198","article-title":"Gut metagenome in European women with normal, impaired and diabetic glucose control","volume":"498","author":"Karlsson","year":"2013","journal-title":"Nature"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"835","DOI":"10.2147\/DMSO.S240728","article-title":"Phocea, Pseudoflavonifractor and Lactobacillus intestinalis: Three Potential Biomarkers of Gut Microbiota That Affect Progression and Complications of Obesity-Induced Type 2 Diabetes Mellitus","volume":"13","author":"Wang","year":"2020","journal-title":"Diabetes Metab. Syndr. Obes."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"232","DOI":"10.3389\/fmicb.2019.00232","article-title":"Dynamic Development of Fecal Microbiome During the Progression of Diabetes Mellitus in Zucker Diabetic Fatty Rats","volume":"10","author":"Zhou","year":"2019","journal-title":"Front. Microbiol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"913002","DOI":"10.3389\/fnagi.2022.913002","article-title":"Integrated Analyses of Microbiomics and Metabolomics Explore the Effect of Gut Microbiota Transplantation on Diabetes-Associated Cognitive Decline in Zucker Diabetic Fatty Rats","volume":"14","author":"Bi","year":"2022","journal-title":"Front. Aging Neurosci."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1501025","DOI":"10.1002\/mnfr.201501025","article-title":"Obese ZDF rats fermented resistant starch with effects on gut microbiota but no reduction in abdominal fat","volume":"61","author":"Goldsmith","year":"2017","journal-title":"Mol. Nutr. Food Res."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"48941","DOI":"10.18632\/oncotarget.10597","article-title":"Deciphering bacterial community changes in zucker diabetic fatty rats based on 16S rRNA gene sequences analysis","volume":"7","author":"Gu","year":"2016","journal-title":"Oncotarget"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"G1","DOI":"10.1152\/ajpgi.00294.2021","article-title":"Gut feelings: The microbiota-gut-brain axis on steroids","volume":"322","author":"So","year":"2022","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"100815","DOI":"10.1016\/j.yfrne.2019.100815","article-title":"You\u2019ve got male: Sex and the microbiota-gut-brain axis across the lifespan","volume":"56","author":"Jaggar","year":"2020","journal-title":"Front. Neuroendocrinol."},{"key":"ref_93","doi-asserted-by":"crossref","unstructured":"Diviccaro, S., FitzGerald, J.A., Cioffi, L., Falvo, E., Crispie, F., Cotter, P.D., O\u2019Mahony, S.M., Giatti, S., Caruso, D., and Melcangi, R.C. (2022). Gut Steroids and Microbiota: Effect of Gonadectomy and Sex. Biomolecules, 12.","DOI":"10.3390\/biom12060767"},{"key":"ref_94","doi-asserted-by":"crossref","unstructured":"Lisco, G., Giagulli, V., De Pergola, G., Guastamacchia, E., Jirillo, E., Vitale, E., and Triggiani, V. (2023). Chronic Stress as a Risk Factor for Type 2 Diabetes: Endocrine, Metabolic, and Immune Implications. Endocr. Metab. Immune Disord. Drug Targets, Online ahead of print.","DOI":"10.2174\/1871530323666230803095118"},{"key":"ref_95","first-page":"1","article-title":"Composition, Diversity and Abundance of Gut Microbiome in Prediabetes and Type 2 Diabetes","volume":"2","author":"Lambeth","year":"2015","journal-title":"J. Diabetes Obes."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"1245","DOI":"10.1038\/ncomms2266","article-title":"Symptomatic atherosclerosis is associated with an altered gut metagenome","volume":"3","author":"Karlsson","year":"2012","journal-title":"Nat. Commun."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1080\/19490976.2017.1406584","article-title":"Low dietary fiber intake increases Collinsella abundance in the gut microbiota of overweight and obese pregnant women","volume":"9","author":"Barrett","year":"2018","journal-title":"Gut Microbes"},{"key":"ref_98","doi-asserted-by":"crossref","unstructured":"Nguyen, N.T., Sun, W.H., Chen, T.H., Tsai, P.C., Chen, C.C., and Huang, S.L. (2022). Gut Mucosal Microbiome Is Perturbed in Rheumatoid Arthritis Mice and Partly Restored after TDAG8 Deficiency or Suppression by Salicylanilide Derivative. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23073527"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1186\/s40168-021-01189-5","article-title":"Ageing and rejuvenation models reveal changes in key microbial communities associated with healthy ageing","volume":"9","author":"Shin","year":"2021","journal-title":"Microbiome"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1038\/nature15766","article-title":"Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota","volume":"528","author":"Forslund","year":"2015","journal-title":"Nature"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1017\/S0029665114001463","article-title":"Links between diet, gut microbiota composition and gut metabolism","volume":"74","author":"Flint","year":"2015","journal-title":"Proc. Nutr. Soc."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"1323","DOI":"10.1038\/ismej.2014.14","article-title":"Phylogenetic distribution of three pathways for propionate production within the human gut microbiota","volume":"8","author":"Reichardt","year":"2014","journal-title":"ISME J."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"580001","DOI":"10.3389\/fnagi.2020.580001","article-title":"Propionate and Alzheimer\u2019s Disease","volume":"12","author":"Killingsworth","year":"2020","journal-title":"Front. Aging Neurosci."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"165541","DOI":"10.1016\/j.bbadis.2019.165541","article-title":"Type 1 diabetes induces cognitive dysfunction in rats associated with alterations of the gut microbiome and metabolomes in serum and hippocampus","volume":"1865","author":"Gao","year":"2019","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/13\/9\/1325\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T20:41:32Z","timestamp":1760128892000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/13\/9\/1325"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,8,29]]},"references-count":104,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2023,9]]}},"alternative-id":["biom13091325"],"URL":"https:\/\/doi.org\/10.3390\/biom13091325","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,8,29]]}}}