{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T02:11:17Z","timestamp":1777428677712,"version":"3.51.4"},"reference-count":47,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,4,25]],"date-time":"2026-04-25T00:00:00Z","timestamp":1777075200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"2022 Inner Mongolia Autonomous Region Grassland Talent Rolling Team Project","award":["201023"],"award-info":[{"award-number":["201023"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by persistent mucosal inflammation and dysregulated immune\u2013metabolic responses. Koumiss, a traditional fermented mare\u2019s milk, has long been used in ethnomedicine for gastrointestinal disorders; however, its molecular mechanisms in UC remain unclear. In this study, an integrated multi-omics approach combining network pharmacology, quantitative proteomics, and molecular docking was employed to elucidate the therapeutic mechanism of koumiss powder (KP) in a dextran sulfate sodium (DSS)-induced murine colitis model. Network pharmacology identified twelve bioactive compounds targeting fourteen UC-associated proteins, predominantly enriched in the peroxisome proliferator-activated receptor (PPAR) signaling pathway. In vivo experiments demonstrated that high-dose KP significantly alleviated disease activity, improved colon shortening and histopathological injury, reduced serum TNF-\u03b1 and IL-6 levels, and restored anti-inflammatory cytokines IL-4 and IL-10. Proteomic analysis further revealed activation of the PPAR signaling pathway, with significant upregulation of Plin4 and Sorbs1. Immunofluorescence staining further confirmed that KP restored the expression of PPARA and increased the levels of Plin4 and Sorbs1 in colonic tissues. Molecular docking confirmed strong binding affinities between key koumiss-derived lipid metabolites, including 13(S)-HOTrE and stearoyl ethanolamide, and PPAR-related target proteins. Collectively, these findings demonstrate that koumiss exerts protective effects against experimental UC primarily through activation of PPAR-mediated lipid metabolic and anti-inflammatory pathways. This study provides mechanistic insight into the biological activity of koumiss and highlights the value of multi-omics integration in natural product research.<\/jats:p>","DOI":"10.3390\/ijms27093821","type":"journal-article","created":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T11:33:37Z","timestamp":1777376017000},"page":"3821","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Integrated Multi-Omics Analysis Reveals Activation of the PPAR Signaling Pathway by Koumiss in Experimental Ulcerative Colitis"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-6995-1498","authenticated-orcid":false,"given":"Guanglin","family":"Guo","sequence":"first","affiliation":[{"name":"College of Mongolian Medicine and Pharmacy, Inner Mongolia Medical University, Hohhot 010110, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pinjie","family":"Bao","sequence":"additional","affiliation":[{"name":"Inner Mongolia Traditional Chinese and Mongolian Medical Research Institute, Hohhot 010010, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bolag","family":"Altan","sequence":"additional","affiliation":[{"name":"Inner Mongolia Traditional Chinese and Mongolian Medical Research Institute, Hohhot 010010, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bateer","family":"Siqin","sequence":"additional","affiliation":[{"name":"College of Mongolian Medicine and Pharmacy, Inner Mongolia Medical University, Hohhot 010110, China"},{"name":"Inner Mongolia Traditional Chinese and Mongolian Medical Research Institute, Hohhot 010010, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1187","DOI":"10.14309\/ajg.0000000000003463","article-title":"ACG clinical guideline update: Ulcerative colitis in adults","volume":"120","author":"Rubin","year":"2025","journal-title":"Am. J. Gastroenterol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"135","DOI":"10.7861\/clinmed.2021-0080","article-title":"Ulcerative colitis: An update","volume":"21","author":"Segal","year":"2021","journal-title":"Clin. Med."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Cao, F., Liu, Z.X., Liu, S., Liu, Y.W., Qi, Y., Cheng, Y.S., Wang, Y., and Xu, Y.Y. (2025). Proton pump inhibitors and gut microbiota dysbiosis: Insights into the pathogenesis of ulcerative colitis. Front. Microbiol., 16.","DOI":"10.3389\/fmicb.2025.1657865"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1016\/S0140-6736(23)00966-2","article-title":"Ulcerative colitis","volume":"402","author":"Honap","year":"2023","journal-title":"Lancet"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Cai, Z.B., Wang, S., and Li, J.N. (2021). Treatment of inflammatory bowel disease: A comprehensive review. Front. Med., 8.","DOI":"10.3389\/fmed.2021.765474"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"895","DOI":"10.3904\/kjim.2022.132","article-title":"Updates on conventional therapies for inflammatory bowel diseases: 5-aminosalicylates, corticosteroids, immunomodulators, and anti-TNF-\u03b1","volume":"37","author":"Park","year":"2022","journal-title":"Korean J. Intern. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2681","DOI":"10.1093\/ibd\/izaf036","article-title":"Efficacy and safety of etrasimod in patients with moderately to severely active ulcerative colitis stratified by baseline modified mayo score: A post hoc analysis from the phase 3 ELEVATE UC clinical program","volume":"31","author":"Sands","year":"2025","journal-title":"Inflamm. Bowel Dis."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1038\/s41572-020-0205-x","article-title":"Ulcerative colitis","volume":"6","author":"Kobayashi","year":"2020","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Wang, L., Xie, R.S., Xu, C.J., Luo, H.M., Hua, X.F., Yao, J.Y., Lu, M.Q., Zhou, S., Zhu, M., and Li, D.Y. (2025). Potential applications and mechanisms of natural products in mucosal-related diseases. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1594224"},{"key":"ref_10","unstructured":"Bai, Q.Y. (1987). Encyclopedia of Chinese Medicine: Mongolian Medicine (Part II), Inner Mongolia Science and Technology Press."},{"key":"ref_11","unstructured":"Wuliji, A.N. (2021). The Standard of Mongolian Medicinal Materials InInner Mongolia, Inner Mongolia Science and Technology Press."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Xue, W.K., Yuan, X.X., Ji, Z.J., Li, H., and Yao, Y.T. (2023). Nutritional ingredients and prevention of chronic diseases by fermented koumiss: A comprehensive review. Front. Nutr., 10.","DOI":"10.3389\/fnut.2023.1270920"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Shokrollahi, B., Choi, J.Y., Won, M., Kim, E.T., Lee, S.E., and Ham, J.S. (2025). Koumiss (Fermented Mare\u2019s Milk) as a functional food: Bioactive proteins, peptides, and future perspectives. Foods, 14.","DOI":"10.3390\/foods14223954"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"9420027","DOI":"10.26599\/FMH.2025.9420027","article-title":"Research progress on chemical composition, microbial diversity and effects on human health of koumiss","volume":"2","author":"Xilin","year":"2025","journal-title":"Food Med. Homol."},{"key":"ref_15","first-page":"6421","article-title":"Nutritional and ethnomedicinal scenario of koumiss: A concurrent review","volume":"9","author":"Afzaal","year":"2021","journal-title":"Food Sci. Technol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e0021825","DOI":"10.1128\/aem.00218-25","article-title":"ARTP mutagenesis for genome-wide identification of genes important for biofilm regulation in spoilage bacterium Pseudomonas fluorescens PF08","volume":"91","author":"Wang","year":"2025","journal-title":"Appl. Environ. Microbiol."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Su, M., Tang, T., Tang, W.W., Long, Y., Wang, L., and Liu, M.L. (2023). Astragalus improves intestinal barrier function and immunity by acting on intestinal microbiota to treat T2DM: A research review. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1243834"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1016\/j.jff.2018.11.023","article-title":"Koumiss consumption modulates gut microbiota, increases plasma high density cholesterol, decreases immunoglobulin G and albumin","volume":"52","author":"Hou","year":"2019","journal-title":"J. Funct. Foods"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"111584","DOI":"10.1016\/j.nut.2021.111584","article-title":"Lactobacillus paracasei from koumiss ameliorates diarrhea in mice via tight junctions modulation","volume":"98","author":"Ren","year":"2022","journal-title":"Nutrition"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2182","DOI":"10.3168\/jds.2024-25181","article-title":"Mare milk and fermented mare milk alleviate dextran sulfate sodium salt\u2013induced ulcerative colitis in mice by reducing inflammation and modulating intestinal flora","volume":"108","author":"Li","year":"2025","journal-title":"J. Dairy Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"3956504","DOI":"10.1155\/2021\/3956504","article-title":"Use of network pharmacology to investigate the mechanism by which allicin ameliorates lipid metabolism disorder in HepG2 Cells","volume":"2021","author":"Cheng","year":"2021","journal-title":"Evid. Based Complement. Alternat. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"104355","DOI":"10.1016\/j.jff.2021.104355","article-title":"Untargeted fecal metabolomics revealed biochemical mechanisms of the blood lipid-lowering effect of koumiss treatment in patients with hyperlipidemia","volume":"78","author":"Li","year":"2021","journal-title":"J. Funct. Foods"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"11","DOI":"10.5217\/ir.2025.00090","article-title":"Peroxisome proliferator-activated receptors in inflammatory bowel disease: Linking immunometabolism, lipid signaling, and therapeutic potential","volume":"24","author":"Bashiri","year":"2026","journal-title":"Intest. Res."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Grabacka, M., P\u0142onka, P.M., and Pierzchalska, M. (2022). The PPAR\u03b1 regulation of the gut physiology in regard to interaction with microbiota, intestinal immunity, metabolism, and permeability. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232214156"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"115068","DOI":"10.1016\/j.intimp.2025.115068","article-title":"Lovastatin alleviates DSS-induced colitis by modulating macrophage polarization via the PPAR\u03b3-NF-\u03baB pathway","volume":"161","author":"Zhu","year":"2025","journal-title":"Int. Immunopharmacol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"120910","DOI":"10.1016\/j.jep.2025.120910","article-title":"Shengjiang San attenuates sepsis-induced acute intestinal injury via Lactobacillus murinus derived IAAld-mediated macrophage polarization through NF-\u03baB and TGF-\u03b2 signaling","volume":"357","author":"Yan","year":"2026","journal-title":"J. Ethnopharmacol."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Pang, W.L., Li, T.G., Wang, Y.Y., Song, L.Y., Li, L., Li, X.Y., Qiu, Y., and Yang, Z.S. (2025). Saussurea costus alleviates ulcerative colitis by regulating the gut microbiota and improving intestinal barrier integrity. Front. Cell Infect. Microbiol., 15.","DOI":"10.3389\/fcimb.2025.1528578"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"101938","DOI":"10.1016\/j.molmet.2024.101938","article-title":"Crosstalk interactions between transcription factors ERR\u03b1 and PPAR\u03b1 assist PPAR\u03b1-mediated gene expression","volume":"84","author":"Desmet","year":"2024","journal-title":"Mol. Metab."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Li, S.J., Cui, Y., Li, X.R., Bai, X.F., Wang, D.H., Zhao, P.F., Wei, P.Q., Yu, S.J., and He, J.F. (2025). The role of PPAR\u03b2\/\u03b4-related lipid metabolism in high-altitude adaptation of yak coat based on proteomics and metabolomics. Cells, 14.","DOI":"10.3390\/cells14231843"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1186\/s12944-024-02212-y","article-title":"Roles of lipid droplets and related proteins in metabolic diseases","volume":"23","author":"Zhang","year":"2024","journal-title":"Lipids Health Dis."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"7865","DOI":"10.3168\/jds.2022-21877","article-title":"Anti-inflammation and gut microbiota regulation properties of fatty acids derived from fermented milk in mice with dextran sulfate sodium-induced colitis","volume":"105","author":"Lao","year":"2022","journal-title":"J. Dairy Sci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e03227\u201303220","DOI":"10.1128\/mBio.03227-20","article-title":"5-aminosalicylic acid ameliorates colitis and checks dysbiotic escherichia coli expansion by activating PPAR-\u03b3 signaling in the intestinal epithelium","volume":"12","author":"Cevallos","year":"2021","journal-title":"mBio"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Li, R., Cheng, L., Wang, Q., and Zhou, L.M. (2021). Comparative transcriptomic analysis reveals the immunosuppressive targets of mesalazine in dextran sulfate sodium-induced ulcerative colitis. Front. Genet., 12.","DOI":"10.3389\/fgene.2021.698983"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Rong, J.J., Zheng, H.F., Liu, M., Hu, X., Wang, T., Zhang, X.W., Jin, F., and Wang, L. (2015). Probiotic and anti-inflammatory attributes of an isolate Lactobacillus helveticus NS8 from Mongolian fermented koumiss. BMC Microbiol., 15.","DOI":"10.1186\/s12866-015-0525-2"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"31649","DOI":"10.1038\/srep31649","article-title":"15-Lipoxygenase metabolites of \u03b1-linolenic acid, [13-(S)-HPOTrE and 13-(S)-HOTrE], mediate anti-inflammatory effects by inactivating NLRP3 inflammasome","volume":"6","author":"Kumar","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1423","DOI":"10.1007\/s11030-023-10666-y","article-title":"Targeting lipid-sensing nuclear receptors PPAR (\u03b1, \u03b3, \u03b2\/\u03b4): HTVS and molecular docking\/dynamics analysis of pharmacological ligands as potential pan-PPAR agonists","volume":"28","author":"Mandal","year":"2024","journal-title":"Mol. Divers."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1186\/s12967-022-03623-0","article-title":"Integrated lipidomics and network pharmacology analysis to reveal the mechanisms of berberine in the treatment of hyperlipidemia","volume":"20","author":"Chen","year":"2022","journal-title":"J. Transl. Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1007\/s12602-025-10718-9","article-title":"Koumiss microbiome: Investigation of the microbial composition and functional potential of a unique beverage of fermented milk produced at kyrgyz mountains","volume":"18","author":"Sanli","year":"2026","journal-title":"Probiotics Antimicro. Prot."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"4058","DOI":"10.1002\/jsfa.13313","article-title":"Potential of fermented foods and their metabolites in improving gut microbiota function and lowering gastrointestinal inflammation","volume":"105","author":"Padhi","year":"2025","journal-title":"J. Sci. Food Agric."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/j.tifs.2021.01.054","article-title":"Trends in Probiotic(s)-Fermented milks and their in vivo functionality: A review","volume":"110","author":"Sakandar","year":"2021","journal-title":"Trends Food Sci. Technol."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Shizu, R., Otsuka, Y., Ishii, C., Ezaki, K., and Yoshinari, K. (2023). PPAR\u03b1 induces the expression of CAR that works as a negative regulator of PPAR\u03b1 functions in mouse livers. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24043953"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"119433","DOI":"10.1016\/j.ecoenv.2025.119433","article-title":"PPAR\u03b3-responsive luciferase reporter system for high-throughput screening of chemical toxins with potential pulmonary fibrosis effects","volume":"307","author":"Lin","year":"2025","journal-title":"Ecotoxicol. Environ. Saf."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"684","DOI":"10.1016\/j.cmet.2024.03.007","article-title":"Our extended microbiome: The human-relevant metabolites and biology of fermented foods","volume":"36","author":"Caffrey","year":"2024","journal-title":"Cell Metab."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1038\/s41575-023-00869-x","article-title":"Fermented foods and gastrointestinal health: Underlying mechanisms","volume":"21","author":"Mukherjee","year":"2024","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Li, Q.Y., Zhang, C.J., Xilin, T.Y., Ji, M.Y., Meng, X.X., Zhao, Y.L., Siqin, B., Zhang, N., and Li, M.H. (2022). Effects of koumiss on intestinal immune modulation in immunosuppressed rats. Front. Nutr., 9.","DOI":"10.3389\/fnut.2022.765499"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Huang, Y., Wang, S.Y., Ding, R., and Wu, S.H. (2025). Combined metabolomics and network pharmacology to reveal anti-diabetic mechanisms and potential pharmacological components of Synsepalum dulcificum. Plants, 14.","DOI":"10.3390\/plants14142132"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1038\/nmeth.1322","article-title":"Universal sample preparation method for proteome analysis","volume":"6","author":"Zougman","year":"2009","journal-title":"Nat. Methods"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/9\/3821\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T11:36:42Z","timestamp":1777376202000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/9\/3821"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,25]]},"references-count":47,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,5]]}},"alternative-id":["ijms27093821"],"URL":"https:\/\/doi.org\/10.3390\/ijms27093821","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,25]]}}}