Background and objectives Ulcerative colitis (UC) is a chronic autoimmune disease that mainly affects the rectum and colon. The symptoms primarily include abdominal pain, diarrhea, and bloody stools. The incidence of UC continues to increase each year. Bear bile powder (BBP) is a well-known traditional medicine that remains in use due to its outstanding efficacy. This study aimed to elucidate the therapeutic effects and molecular mechanisms of BBP on dextran sulfate sodium (DSS)-induced UC.
Methods DSS-induced UC model mice were created and then randomly assigned to the following groups: control, DSS-treated, 5-amino salicylic acid-treated, BBP low dose, and BBP high dose. Treatment was administered by gavage. Disease activity index, body weight loss, colon histopathology, colon length, and the expression of inflammatory cytokines were measured. Samples of the intestinal content were collected, and differences in the gut microbiota were analyzed by 16S rDNA sequencing.
Results The experimental results demonstrated that BBP significantly alleviated the symptoms and histopathological scores in UC mice, reduced the production of interleukin-6, interleukin-1β, tumor necrosis factor-α, malondialdehyde, nitric oxide, and myeloperoxidase, and upregulated the expression of cyclic adenosine monophosphate (cAMP), protein kinase A, and cAMP-response element binding protein. Moreover, 16S rRNA sequencing revealed that the gut microbiota of mice in the DSS-treated group was disordered compared to the control group. The abundance of gut microbiota in the treatment groups improved to varying degrees.
Conclusions Together, these results indicate that BBP significantly improves the inflammatory symptoms of mice with acute colitis, which may be related to its upregulation of the cAMP/protein kinase A/cAMP-response element binding protein signaling pathway, inhibition of NOD-like receptor thermal protein domain associated protein 3 inflammasome secretion, and regulation of gut microbiota.
Acknowledgments
None.
Funding
This work was supported by National Natural Science Foun-dation of China grants (No. 81773893); Hubei Province Key R&D Program (No. 2020BED017); Jiangxi Province “Thousand Talents Plan” of Scientific and Technological Innovation (No. JXSQ2019201105).
Conflict of interest
The authors declare no conflict of interest for this study.
Author contributions
Study concept and design (YR, HT), acquisition of data (HT, LC), analysis and interpretation of data (HT, LC), drafting of the manuscript (HT), critical revision of the manuscript for important intellectual content (YR, HT, LC, YL), administrative, technical, or material support (YR, YL), and study supervision (YR). All au-thors have made significant contributions to this study and have approved the final manuscript.
Ethical statement
All animal experimental procedures were performed in accordance with the Ethical Experimentation Committee of South-Central Minzu University and the National Act on Use of Experimental Animals (Permission ID: 2020-SCUEC-023). The study was ap-proved by the Institutional Animal Care and Use Committee of South-Central Minzu University, and all animals received human care in accordance with the guidelines from Directive 2010/63/EU of the European Parliament. Mice were sacrificed by CO2 inhala-tion or cervical dislocation at desired time-points, and all efforts were made to minimize suffering.
Data sharing statement
The datasets used and analyzed during the current study are avail-able from the corresponding author upon reasonable request.
| [1] |
Ordás I, Eckmann L, Talamini M, Baumgart DC, Sandborn WJ. Ulcera-tive colitis. Lancet 2012;380(9853):1606-1619. doi:10.1016/S0140-6736(12)60150-0, PMID:22914296.
|
| [2] |
Jie F, Xiao S, Qiao Y, You Y, Feng Y, Long Y, et al. Kuijieling decoc-tion suppresses NLRP3-Mediated pyroptosis to alleviate inflamma-tion and experimental colitis in vivo and in vitro. J Ethnopharmacol 2021;264:113243. doi:10.1016/j.jep.2020.113243,PMID:32781258.
|
| [3] |
Prideaux L, Kamm MA, De Cruz PP, Chan FK, Ng SC. Inflammatory bowel disease in Asia: a systematic review. J Gastroenterol Hepa-tol 2012; 27(8):1266-1280. doi:10.1111/j.1440-1746.2012.07150.x, PMID:22497584.
|
| [4] |
Yan PG, Li JN. [ The standard diagnosis and treatment of ulcerative colitis]. Zhonghua Nei Ke Za Zhi 2021; 60(6):567-570. doi:10.3760/cma.j.cn112138-20210316-00216,PMID:34058816.
|
| [5] |
Li M, Yeung K. Managing high-priced biologic agents: challenges and potential solutions. J Manag Care Spec Pharm 2021; 27(3):411-414. doi:10.18553/jmcp.2021.27.3.411,PMID:33645239.
|
| [6] |
Liu ZB, Ye X, Wu CJ, Wei DN. Bear Bile Powder Improves Ulcerative Colitis by Protecting the Intestinal Mechanical Barrier and Regulating Intestinal Flora. Curr Pharm Des 2024; 30:1530-1540. doi:10.2174/0113816128294893240403074953.
|
| [7] |
Li S, Tan HY, Wang N, Hong M, Li L, Cheung F, et al. Substitutes for Bear Bile for the Treatment of Liver Diseases: Research Progress and Future Perspective. Evid Based Complement Alternat Med 2016; 2016:4305074. doi:10.1155/2016/4305074,PMID:27087822.
|
| [8] |
Fernández-Sánchez L, Lax P, Noailles A, Angulo A, Maneu V, Cuenca N. Natural Compounds from Saffron and Bear Bile Prevent Vision Loss and Retinal Degeneration. Molecules 2015; 20(8):13875-13893. doi:10.3390/molecules200813875,PMID:26263962.
|
| [9] |
Chen DX, Chu JF, Lin S, Zhang L, Chen HW, Sun ZW, et al. Therapeutic Ef-fects of Different Animal Bile Powders on Lipid Metabolism Disorders and Their Composition Analysis. Chin J Integr Med 2022; 28(10):918-923. doi:10.1007/s11655-021-3441-3,PMID:33609233.
|
| [10] |
Wang LY, Gao X, Tong ZL, Wang XG. Summary on pharmacological action and clinical study of the chemical composition of bear bile. Inform Tradit Chin Med 2005; 22(4):30-33.
|
| [11] |
Guo C, Xie S, Chi Z, Zhang J, Liu Y, Zhang L, et al. Bile Acids Control Inflammation and Metabolic Disorder through Inhibition of NLRP3 Inflammasome. Immunity 2016; 45(4):802-816. doi:10.1016/j.im-muni.2016.09.008,PMID:27692610.
|
| [12] |
Tan Q, Hu J, Zhou Y, Wan Y, Zhang C, Liu X, et al. lactis HFY Inhibitory Effect of Lactococcus lactis subsp. 14 on Diphenoxylate-Induced Constipation in Mice by Regulating the VIP-cAMP-PKA-AQP3 Signal-ing Pathway. Drug Des Devel Ther 2021; 15:1971-1980. doi:10.2147/DDDT.S309675,PMID:34007157.
|
| [13] |
Chao G, Zhang S. Aquaporins 1, 3 and 8 expression and cytokines in irritable bowel syndrome rats’ colon via cAMP-PKA pathway. Int J Clin Exp Pathol 2018; 11(8):4117-4123. PMID:31949803.
|
| [14] |
Yang GH, Li XX, Dong L, Xu CL, Ling L, Liu QH. Bifidobacterium Ame-liorates Ulcerative Colitis in Mice by Modulating VIP/cAMP/PKA and mTOR Pathways Progress in Modern Biomedicine 2022; 22(20):3840-3847. (in Chinese).
|
| [15] |
Shreiner AB, Kao JY, Young VB. The gut microbiome in health and in disease. Curr Opin Gastroenterol 2015; 31(1):69-75. doi:10.1097/MOG.0000000000000139,PMID:25394236.
|
| [16] |
Cai J, Sun L, Gonzalez FJ. Gut microbiota-derived bile acids in in-testinal immunity, inflammation, and tumorigenesis. Cell Host Microbe 2022; 30(3):289-300. doi:10.1016/j.chom.2022.02.004,PMID:35271802.
|
| [17] |
Wirtz S, Popp V, Kindermann M, Gerlach K, Weigmann B, Fichtner-Feigl S, et al. Chemically induced mouse models of acute and chronic intestinal inflammation. Nat Protoc 2017; 12(7):1295-1309. doi:10.1038/nprot.2017.044,PMID:28569761.
|
| [18] |
Xuan-Qing CHEN, Xiang-Yu LV, Shi-Jia LIU. Baitouweng decoction al-leviates dextran sulfate sodium-induced ulcerative colitis by regu-lating intestinal microbiota and the IL-6/STAT3 signaling pathway. J Ethnopharmacol 2021;265:113357. doi:10.1016/j.jep.2020.113357,PMID:32891820.
|
| [19] |
Yang J, Liu XX, Fan H, Tang Q, Shou ZX, Zuo DM, et al. Extracellular Vesicles Derived from Bone Marrow Mesenchymal Stem Cells Pro-tect against Experimental Colitis via Attenuating Colon Inflammation, Oxidative Stress and Apoptosis. PLoS One 2015; 10(10):e0140551. doi:10.1371/journal.pone.0140551,PMID:26469068.
|
| [20] |
Huang S, Wang X, Xie X, Su Y, Pan Z, Li Y, et al. Dahuang Mudan decoc-tion repairs intestinal barrier in chronic colitic mice by regulating the function of ILC3. J Ethnopharmacol 2022;299:115652. doi:10.1016/j.jep.2022.115652, PMID:36038092.
|
| [21] |
Wang L, An J, Song S, Mei M, Li W, Ding F, et al. Electroacupuncture preserves intestinal barrier integrity through modulating the gut microbiota in DSS-induced chronic colitis. Life Sci 2020;261:118473. doi:10.1016/j.lfs.2020.118473,PMID:32971101.
|
| [22] |
Fan L, Zuo S, Tan H, Hu J, Cheng J, Wu Q, et al. Preventive effects of pectin with various degrees of esterification on ulcerative colitis in mice. Food Funct 2020; 11(4):2886-2897. doi:10.1039/c9fo03068a,PMID:32186298.
|
| [23] |
Yuan SN, Wang MX, Han JL, Feng CY, Wang M, Wang M, et al. Im-proved colonic inflammation by nervonic acid via inhibition of NF-κB signaling pathway of DSS-induced colitis mice. Phytomedi-cine 2023;112:154702. doi:10.1016/j.phymed.2023.154702,PMID:36764096.
|
| [24] |
Li F, Jiang C, Krausz KW, Li Y, Albert I, Hao H, et al. Microbiome re-modelling leads to inhibition of intestinal farnesoid X receptor signal-ling and decreased obesity. Nat Commun 2013; 4:2384. doi:10.1038/ncomms3384,PMID:24064762.
|
| [25] |
Wang T, Shi C, Wang S, Zhang Y, Wang S, Ismael M, et al. Protective Ef-fects of Companilactobacillus crustorum MN047 against Dextran Sul-fate Sodium-Induced Ulcerative Colitis: A Fecal Microbiota Transplan-tation Study. J Agric Food Chem 2022; 70(5):1547-1561. doi:10.1021/acs.jafc.1c07316,PMID:35077172.
|
| [26] |
Herp S, Brugiroux S, Garzetti D, Ring D, Jochum LM, Beutler M, et al. Mucispirillum schaedleri Antagonizes Salmonella Virulence to Pro-tect Mice against Colitis. Cell Host Microbe 2019; 25(5):681-694.e8. doi:10.1016/j.chom.2019.03.004,PMID:31006637.
|
| [27] |
Wang K, Liao M, Zhou N, Bao L, Ma K, Zheng Z, et al. Parabacteroides distasonis Alleviates Obesity and Metabolic Dysfunctions via Produc-tion of Succinate and Secondary Bile Acids. Cell Rep 2019; 26(1):222-235. e5. doi:10.1016/j.celrep.2018.12.028,PMID:30605678.
|
| [28] |
Mukherjee A, Lordan C, Ross RP, Cotter PD. Gut microbes from the phylogenetically diverse genus Eubacterium and their various contri-butions to gut health. Gut Microbes 2020; 12(1):1802866. doi:10.1080/19490976.2020.1802866,PMID:32835590.
|
| [29] |
Kalenyak K, Isaiah A, Heilmann RM, Suchodolski JS, Burgener IA. Comparison of the intestinal mucosal microbiota in dogs diagnosed with idiopathic inflammatory bowel disease and dogs with food-re-sponsive diarrhea before and after treatment. FEMS Microbiol Ecol 2018; 94(2):fix173. doi:10.1093/femsec/fix173,PMID:29228248.
|
| [30] |
Hall AB, Yassour M, Sauk J, Garner A, Jiang X, Arthur T, et al. A novel Ruminococcus gnavus clade enriched in inflammatory bowel disease patients. Genome Med 2017; 9(1):103. doi:10.1186/s13073-017-0490-5,PMID:29183332.
|
| [31] |
Lin Y, Su J, Wang M, Li Y, Zhao Z, Sun Z. Hypericumsampsonii at-tenuates inflammation in mice with ulcerative colitis via regula-tion of PDE4/PKA/CREB signaling pathway. J Ethnopharmacol 2022;296:115447. doi:10.1016/j.jep.2022.115447,PMID:35688258.
|
| [32] |
Adams SM, Bornemann PH. Ulcerative colitis. Am Fam Physician 2013; 87(10):699-705. PMID:23939448.
|
| [33] |
Chassaing B, Aitken JD, Malleshappa M, Vijay-Kumar M. Dextran sulfate sodium (DSS)-induced colitis in mice. Curr Protoc Immunol 2014; 104:15.25.1-15.25.14. doi:10.1002/0471142735.im1525s104,PMID:24510619.
|
| [34] |
Feng Y, Siu K, Wang N, Ng KM, Tsao SW, Nagamatsu T, et al. Bear bile: dilemma of traditional medicinal use and animal protec-tion. J Ethnobiol Ethnomed 2009; 5:2. doi:10.1186/1746-4269-5-2,PMID:19138420.
|
| [35] |
Sinha SR, Haileselassie Y, Nguyen LP, Tropini C, Wang M, Becker LS, et al. Dysbiosis-Induced Secondary Bile Acid Deficiency Promotes Intestinal Inflammation. Cell Host Microbe 2020; 27(4):659-670.e5. doi:10.1016/j.chom.2020.01.021,PMID:32101703.
|
| [36] |
Ward JBJ, Lajczak NK, Kelly OB, O’Dwyer AM, Giddam AK, Ní Gab-hann J, et al. Ursodeoxycholic acid and lithocholic acid exert anti-inflammatory actions in the colon. Am J Physiol Gastrointest Liver Physiol 2017; 312(6):G550-G558. doi:10.1152/ajpgi.00256.2016, PMID:28360029.
|
| [37] |
Martín AR, Villegas I, La Casa C, de la Lastra CA. Resveratrol, a poly-phenol found in grapes, suppresses oxidative damage and stimu-lates apoptosis during early colonic inflammation in rats. Biochem Pharmacol 2004; 67(7):1399-1410. doi:10.1016/j.bcp.2003.12.024,PMID:15013856.
|
| [38] |
Yadav V, Varum F, Bravo R, Furrer E, Bojic D, Basit AW. Inflammatory bowel disease: exploring gut pathophysiology for novel therapeutic targets. Transl Res 2016; 176:38-68. doi:10.1016/j.trsl.2016.04.009,PMID:27220087.
|
| [39] |
Guan Q, Zhang J. Recent Advances: The Imbalance of Cytokines in the Pathogenesis of Inflammatory Bowel Disease. Mediators Inflamm 2017; 2017:4810258. doi:10.1155/2017/4810258,PMID:28420941.
|
| [40] |
de Luca A, Smeekens SP, Casagrande A, Iannitti R, Conway KL, Gresnigt MS, et al. IL-1 receptor blockade restores autophagy and reduces inflammation in chronic granulomatous disease in mice and in humans. Proc Natl Acad Sci U S A 2014; 111(9):3526-3531. doi:10.1073/pnas.1322831111,PMID:24550444.
|
| [41] |
Liu J, Fang H, Hong N, Lv C, Zhu Q, Feng Y, et al. Gut Microbiome and Metabonomic Profile Predict Early Remission to Anti-Integrin Ther-apy in Patients with Moderate to Severe Ulcerative Colitis. Micro-biol Spectr 2023; 11(3):e0145723. doi:10.1128/spectrum.01457-23,PMID:37199618.
|
| [42] |
Zhen Y, Zhang H. NLRP3 Inflammasome and Inflammatory Bowel Dis-ease. Front Immunol 2019;10:276. doi:10.3389/fimmu.2019.00276,PMID:30873162.
|
| [43] |
Raker VK, Becker C, Steinbrink K. The cAMP Pathway as Therapeutic Target in Autoimmune and Inflammatory Diseases. Front Immunol 2016;7:123. doi:10.3389/fimmu.2016.00123,PMID:27065076.
|
| [44] |
Li H, Li J, Zhang X, Feng C, Fan C, Yang X, et al. DC591017, a phos-phodiesterase-4 (PDE4) inhibitor with robust anti-inflammation through regulating PKA-CREB signaling. Biochem Pharmacol 2020;177:113958. doi:10.1016/j.bcp.2020.113958,PMID:32251674.
|
| [45] |
Baars A, Oosting A, Knol J, Garssen J, van Bergenhenegouwen J. The Gut Microbiota as a Therapeutic Target in IBD and Metabolic Disease: A Role for the Bile Acid Receptors FXR and TGR5. Microor-ganisms 2015; 3(4):641-666. doi:10.3390/microorganisms3040641,PMID:27682110.
|
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