{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T19:39:23Z","timestamp":1790883563555,"version":"4.1.0"},"reference-count":53,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2025,1,1]],"date-time":"2025-01-01T00:00:00Z","timestamp":1735689600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Dr. Yuan","award":["572"],"award-info":[{"award-number":["572"]}]}],"content-domain":{"domain":["www.mdpi.com"],"crossmark-restriction":true},"short-container-title":["Metabolites"],"abstract":"<jats:p>Background: Polysaccharides produced by the edible fungus Cordyceps cicadae can regulate blood sugar levels and may represent a suitable candidate for the treatment of diabetes and its complications. However, there is limited information available about the mechanism of how C. cicadae polysaccharide (CCP) might improve diabetic conditions. Methods: This study investigated its effects on the intestinal microbiota, intestinal mucosal barrier, and inflammation in mice with type 2 diabetes mellitus (T2DM) induced by streptozotocin, and its potential mechanisms. Results: Compared with the DC (diabetes model control group), CCPH oral treatment significantly increased the number of beneficial bifidobacteria, bifidobacteria, and lactobacilli (p &lt; 0.01), restored the diversity of intestinal microorganisms in diabetic mice, and the proportions of Firmicutes and Bacteroidetes (34.36%\/54.65%) were significantly lower than those of the DC (52.15%\/32.09%). Moreover, CCPH significantly reduced the content of endotoxin (lipopolysaccharide, LPS) and D-lactic acid(D-LA) (p &lt; 0.05), the activities of antioxidant enzymes and total antioxidant capacity were significantly increased (p &lt; 0.01), and the content of proinflammatory cytokines TNF-\u03b1, IL-6, and IL-1\u03b2 were reduced by 42.05%, 51.28%, and 52.79%, respectively, compared with the DC. The TLR4\/NF-\u03baB signaling pathway, as a therapeutic target for diabetic intestinal diseases, plays a role in regulating the inflammatory response and protecting the intestinal barrier function. Molecular mechanism studies showed that oral treatment with CCPH down-regulated the expression of NF-\u03baB, TLR-4, and TNF-\u03b1 genes by 18.66%, 21.58%, and 34.87%, respectively, while up-regulating the expression of ZO-1 and occludin genes by 32.70% and 25.11%, respectively. CCPH regulates the expression of short-chain fatty acid levels, increases microbial diversity, and ameliorates mouse colon lesions by inhibiting the TLR4\/NF-\u03baB signaling pathway. Conclusions: In conclusion, it is demonstrated that in this murine model, the treatment of diabetes with C. cicadae polysaccharide can effectively regulate intestinal microbiota imbalance, protect intestinal mucosal barrier function, and reduce inflammation in vivo, suggesting this natural product can provide a suitable strategy for the treatment of T2D-induced gut dysbiosis and intestinal health.<\/jats:p>","DOI":"10.3390\/metabo15010008","type":"journal-article","created":{"date-parts":[[2025,1,1]],"date-time":"2025-01-01T14:35:42Z","timestamp":1735742142000},"page":"8","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Effects of Cordyceps cicadae Polysaccharide on Gut Microbiota, the Intestinal Mucosal Barrier, and Inflammation in Diabetic Mice"],"prefix":"10.3390","volume":"15","author":[{"given":"Lijia","family":"Sun","sequence":"first","affiliation":[{"name":"School of Food and Biological Engineering, Hefei University of Technology, No. 193, Tunxi Road, Hefei 230009, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huaibo","family":"Yuan","sequence":"additional","affiliation":[{"name":"School of Food and Biological Engineering, Hefei University of Technology, No. 193, Tunxi Road, Hefei 230009, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huiqing","family":"Ma","sequence":"additional","affiliation":[{"name":"School of Food and Biological Engineering, Hefei University of Technology, No. 193, Tunxi Road, Hefei 230009, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yani","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Food and Biological Engineering, Hefei University of Technology, No. 193, Tunxi Road, Hefei 230009, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,1,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"267","DOI":"10.4239\/wjd.v5.i3.267","article-title":"Functional foods-based diet as a novel dietary approach for management of type 2 diabetes and its complications: A review","volume":"5","author":"Mirmiran","year":"2014","journal-title":"World J. Diabetes"},{"key":"ref_2","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_3","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_4","doi-asserted-by":"crossref","first-page":"1221","DOI":"10.1210\/me.2014-1108","article-title":"Minireview: Gut microbiota: The neglected endocrine organ","volume":"28","author":"Clarke","year":"2014","journal-title":"Mol. Endocrinol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1136\/gutjnl-2015-309990","article-title":"The gut microbiota and host health: A new clinical frontier","volume":"65","author":"Marchesi","year":"2016","journal-title":"Gut"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1016\/j.cmet.2020.06.011","article-title":"The gut microbiota in prediabetes and diabetes: A population-based cross-sectional study","volume":"32","author":"Wu","year":"2020","journal-title":"Cell Metab."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1966","DOI":"10.2337\/dc13-2018","article-title":"Involvement of oxidative stress-induced DNA damage, endoplasmic reticulum stress, and autophagy deficits in the decline of \u03b2-cell mass in Japanese type 2 diabetic patients","volume":"37","author":"Mizukami","year":"2014","journal-title":"Diabetes Care"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1016\/j.cyto.2016.06.028","article-title":"Adiponectin, TNF-\u03b1 and inflammatory cytokines and risk of type 2 diabetes: A systematic review and meta-analysis","volume":"86","author":"Liu","year":"2016","journal-title":"Cytokine"},{"key":"ref_9","first-page":"1","article-title":"Influence of IL-6, IL-10, IFN-\u03b3 and TNF-\u03b1 genetic variants on susceptibility to diabetic kidney disease in type 2 diabetes mellitus patients","volume":"31","author":"Fathy","year":"2018","journal-title":"Biomarkers"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1159\/000443356","article-title":"The gut bacteria-driven obesity development","volume":"34","author":"Compare","year":"2016","journal-title":"Dig. Dis."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Nedosugova, L.V., Markina, Y.V., Bochkareva, L.A., Kuzina, I.A., Petunina, N.A., Yudina, I.Y., and Kirichenko, T.V. (2022). Inflammatory Mechanisms of Diabetes and Its Vascular Complications. Biomedicines, 10.","DOI":"10.3390\/biomedicines10051168"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1016\/j.intimp.2018.03.002","article-title":"Toll-like receptors in immunity and inflammatory diseases: Past, present, and future","volume":"59","author":"Vijay","year":"2018","journal-title":"Int. Immunopharmacol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"C202","DOI":"10.1152\/ajpcell.00088.2022","article-title":"Proteoglycans in Toll-like receptor responses and innate immunity","volume":"323","author":"Garantziotis","year":"2022","journal-title":"Am. Physiol. Cell Physiol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"5265","DOI":"10.3390\/nu6115265","article-title":"Anti-inflammatory activity of fruit fractions in vitro, mediated through toll-like receptor 4 and 2 in the context of inflammatory bowel disease","volume":"6","author":"Nasef","year":"2014","journal-title":"Nutrients"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1257","DOI":"10.1159\/000430248","article-title":"Anti-Inflamm-Aging Effects of Long-Term Caloric Restriction via Overexpression of SIGIRR to Inhibit NF-\u03baB Signaling Pathway","volume":"37","author":"Xu","year":"2015","journal-title":"Cell. Physiol. Biochem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1016\/j.intimp.2017.01.033","article-title":"Isotrifoliol inhibits pro-inflammatory mediators by suppression of TLR\/NF-\u03baB and TLR\/MAPK signaling in LPS-induced RAW264.7 cells","volume":"45","author":"Li","year":"2017","journal-title":"Int. Immunopharmacol."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Lee, H.Y., Takeshita, T., Shimada, J., Akopyan, A., Woo, J.I., Pan, H., Moon, S.K., Andalibi, A., Park, R.K., and Kang, S.H. (2008). Induction of beta defensin 2 by NTHi requires TLR2 mediated MyD88 and IRAK-TRAF6-p38MAPK signaling pathway in human middle ear epithelial cells. BMC Infect. Dis., 8.","DOI":"10.1186\/1471-2334-8-87"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1038\/ni.2207","article-title":"Signaling via the kinase p38\u03b1 programs dendritic cells to drive TH17 differentiation and autoimmune inflammation","volume":"13","author":"Huang","year":"2012","journal-title":"Nat. Immunol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"109612","DOI":"10.1016\/j.intimp.2022.109612","article-title":"Oxymatrine ameliorated experimental colitis via mechanisms involving inflammatory DCs, gut microbiota and TLR\/NF-\u03baB pathway","volume":"115","author":"Liu","year":"2023","journal-title":"Int. Immunopharmacol."},{"key":"ref_20","first-page":"304","article-title":"Advances in research of polysaccharides in Cordyceps species","volume":"47","author":"Shi","year":"2009","journal-title":"Food Technol. Biotechnol."},{"key":"ref_21","first-page":"1000432","article-title":"Healthcare Functions of Cordyceps cicadae","volume":"5","author":"Hsu","year":"2015","journal-title":"J. Nutr. Food Sci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"3132","DOI":"10.1021\/jf053111w","article-title":"Comparison of Protective Effects between Cultured Cordyceps militaris and Natural Cordyceps sinensis against Oxidative Damage","volume":"54","author":"Yu","year":"2006","journal-title":"J. Agric. Food Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1016\/j.jep.2004.10.009","article-title":"Anti-inflammatory and related pharmacological activities of cultured mycelia and fruiting bodies of Cordyceps militaris","volume":"96","author":"Won","year":"2005","journal-title":"J. Ethnopharmacol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1248\/cpb.31.741","article-title":"Polysaccharides in fungi. Polysaccharides in fungi. XIII. Antitumor activity of various polysaccharides isolated from Dictyophora indusiata, Ganoderma japonicum, Cordyceps cicadae, Auricularia auricula-judae, and Auricularia species","volume":"31","author":"Ukai","year":"1983","journal-title":"Chem. Pharm. Bull."},{"key":"ref_25","first-page":"7912763","article-title":"Cordyceps cicadae Mycelia Ameliorate Cisplatin-Induced Acute Kidney Injury by Suppressing the TLR4\/NF-kappaB\/MAPK and Activating the HO-1\/Nrf2 and Sirt-1\/AMPK Pathways in Mice","volume":"1","author":"Deng","year":"2020","journal-title":"Oxid. Med. Cell Longev."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Wang, Y., Zeng, T., Li, H., Wang, Y., Wang, J., and Yuan, H. (2023). Structural Characterization and Hypoglycemic Function of Polysaccharides from Cordyceps cicadae. Molecules, 28.","DOI":"10.3390\/molecules28020526"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"7489","DOI":"10.1038\/ncomms8489","article-title":"Ganoderma lucidum reduces obesity in mice by modulating the composition of the gut microbiota","volume":"6","author":"Chang","year":"2015","journal-title":"Nat. Commun."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1136\/gutjnl-2017-315458","article-title":"Gut commensal Parabacteroides goldsteinii plays a predominant role in the anti-obesity effects of polysaccharides isolated from Hirsutella sinensis","volume":"68","author":"Wu","year":"2019","journal-title":"J. Gut."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1016\/j.indcrop.2019.03.054","article-title":"An environmentally friendly deproteinization and decolorization method for polysaccharides of Typha angustifolia based on a metal ion-chelating resin adsorption","volume":"134","author":"Shi","year":"2019","journal-title":"Ind. Crops Prod."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"100015","DOI":"10.1016\/j.prmcm.2021.100015","article-title":"Effect of water caltrop (Trapa bispinosa Roxb.) pericarp extract on improving insulin resistance in STZ-induced diabetic mice","volume":"1","author":"Wang","year":"2021","journal-title":"Pharmacol. Res.-Mod. Chin. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"154217","DOI":"10.1016\/j.phymed.2022.154217","article-title":"Berberine regulates short-chain fatty acid metabolism and alleviates the colitis-associated colorectal tumorigenesis through remodeling intestinal flora","volume":"102","author":"Yan","year":"2022","journal-title":"Phytomedicine"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Yu, Z., Li, D., and Sun, H. (2023). Herba Origani alleviated DSS-induced ulcerative colitis in mice through remolding gut microbiota to regulate bile acid and short-chain fatty acid metabolisms. Biomed. Pharmacother., 161.","DOI":"10.1016\/j.biopha.2023.114409"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1007\/s00204-009-0432-0","article-title":"Role of oxidative stress in alcohol-induced liver injury","volume":"83","author":"Cederbaum","year":"2009","journal-title":"Arch. Toxicol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1140","DOI":"10.1002\/med.21431","article-title":"Understanding the molecular mechanisms of the interplay between herbal medicines and gut microbiota","volume":"37","author":"Xu","year":"2017","journal-title":"Med. Res. Rev."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/j.smim.2006.10.002","article-title":"Use of axenic animals in studying the adaptation of mammals to their commensal intestinal microbiota","volume":"19","author":"Smith","year":"2007","journal-title":"Semin. Immunol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1022","DOI":"10.1038\/4441022a","article-title":"Microbial ecology: Human gut microbes associated with obesity","volume":"444","author":"Ley","year":"2006","journal-title":"Nature"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1694","DOI":"10.2174\/1389201024666230301100119","article-title":"Hypoglycemic Effect of Trichosanthes pericarpium to Type 2 Model Diabetic Mice via Intestinal Bacteria Transplantation","volume":"24","author":"Wang","year":"2023","journal-title":"Curr. Pharm. Biotechnol."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Qu, Y., Li, X., Xu, F., Zhao, S., Wu, X., Wang, Y., and Xie, J. (2021). Kaempferol Alleviates Murine Experimental Colitis by Restoring Gut Microbiota and Inhibiting the LPS-TLR4-NF-\u03baB Axis. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.679897"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Xue, M., Liu, Y., Xu, H., Zhou, Z., Ma, Y., Sun, T., Liu, M., Zhang, H., and Liang, H. (2019). Propolis modulates the gut microbiota and improves the intestinal mucosal barrier function in diabetic rats. Biomed. Pharmacother., 118.","DOI":"10.1016\/j.biopha.2019.109393"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Wang, Y., Ni, Z., Li, J., Shao, Y., Yong, Y., Lv, W., Zhang, S., Fu, T., and Chen, A. (2023). Cordyceps cicadae polysaccharides alleviate hyperglycemia by regulating gut microbiota and its mmetabolites in high-fat diet\/streptozocin-induced diabetic mice. Front. Nutr., 10.","DOI":"10.3389\/fnut.2023.1203430"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1038\/s41574-021-00480-7","article-title":"Do diet and microbes really \u2018PREDICT\u2019 cardiometabolic risks?","volume":"17","author":"Cani","year":"2021","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Cani, P.D., Moens de Hase, E., and Van Hul, M. (2021). Gut microbiota and host metabolism: From proof of concept to therapeutic intervention. Microorganisms, 9.","DOI":"10.3390\/microorganisms9061302"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1167","DOI":"10.1136\/gutjnl-2020-320781","article-title":"Mediterranean diet, gut microbiota and health: When age and calories do not add up!","volume":"69","author":"Cani","year":"2020","journal-title":"Gut"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"230014","DOI":"10.1098\/rsob.230014","article-title":"Short chain fatty acids: Key regulators of the local and systemic immune response in inflammatory diseases and infections","volume":"13","author":"Ney","year":"2023","journal-title":"Open Biol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1016\/j.cmet.2016.01.003","article-title":"The intestinal immune system in obesity and insulin resistance","volume":"23","author":"Winer","year":"2016","journal-title":"Cell Metab."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1310","DOI":"10.1056\/NEJMoa1107477","article-title":"C-reactive protein, fibrinogen, and cardiovascular disease prediction","volume":"367","author":"Kaptoge","year":"2012","journal-title":"N. Engl. J. Med."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"812","DOI":"10.2337\/diabetes.52.3.812","article-title":"Inflammatory cytokines and the risk to develop type 2 diabetes: Results of the prospective population-based European Prospective Investigation into Cancer and Nutrition (EPIC) Potsdam Study","volume":"52","author":"Spranger","year":"2003","journal-title":"Diabetes"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"114","DOI":"10.5808\/GI.2011.9.3.114","article-title":"Association of an Anti-inflammatory Cytokine Gene IL4 polymorphism with the risk of type 2 diabetes mellitus in Korean populations","volume":"9","author":"Go","year":"2011","journal-title":"Genom. Inform."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1007\/s11892-018-1110-5","article-title":"Inflammation markers in type 2 diabetes and the metabolic syndrome in the pediatric population","volume":"18","author":"Reinehr","year":"2018","journal-title":"Curr. Diab. Rep."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/j.jpeds.2016.02.055","article-title":"Inflammatory markers in obese adolescents with type 2 diabetes and their relationship to Hepatokines and Adipokines","volume":"173","author":"Reinehr","year":"2016","journal-title":"J. Pediatr."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"457","DOI":"10.4149\/BLL_2014_089","article-title":"Impact of glycemic control on advanced glycation and inflammation in overweight and obese patients with type 2 diabetes mellitus","volume":"115","author":"Kalninova","year":"2014","journal-title":"Bratisl. Med. J."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1016\/j.cca.2019.07.006","article-title":"Inflammatory markers in children and adolescents with type 2 diabetes mellitus","volume":"496","author":"Reinehr","year":"2019","journal-title":"Clin. Chim. Acta"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1016\/S0006-2952(02)01154-1","article-title":"Nuclear factor-kappa B and cancer: Its role in prevention and therapy","volume":"64","author":"Bharti","year":"2002","journal-title":"Biochem. Pharmacol."}],"updated-by":[{"DOI":"10.3390\/metabo16040233","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2025,1,1]],"date-time":"2025-01-01T00:00:00Z","timestamp":1735689600000}}],"container-title":["Metabolites"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-1989\/15\/1\/8\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T13:36:43Z","timestamp":1774964203000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-1989\/15\/1\/8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1,1]]},"references-count":53,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,1]]}},"alternative-id":["metabo15010008"],"URL":"https:\/\/doi.org\/10.3390\/metabo15010008","relation":{},"ISSN":["2218-1989"],"issn-type":[{"value":"2218-1989","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,1,1]]}}}