Taurodeoxycholic acid alleviates diquat-induced intestinal barrier function injury in mice through the upregulation of Nrf2-mediated signaling pathway

Abstract

Oxidative stress is an important contributor to gastrointestinal diseases in multiple ways. Taurodeoxycholic acid (TDCA) is a metabolite of bile acids and has anti-inflammatory and protective effects on the intestinal tract. However, whether TDCA can alleviate oxidative stress in the intestine is still unclear. Here, we investigated the effects of TDCA on diquat-induced oxidative stress in the jejunum and its mechanism. The results revealed that TDCA increased the concentrations of antioxidant enzymes in the serum, jejunal tissue and intestinal epithelial cells of the mice, as did the expression of tight junction-associated proteins and the Nrf2 protein in the jejunal epithelial tissue and intestinal epithelial cells. We then explored the mechanism of Nrf2 with ML385 (a specific Nrf2 inhibitor). The results showed that after ML385 treatment, the levels of antioxidant enzymes were significantly decreased in the serum, jejunum, and intestinal epithelial tissues of the mice. The expression of tight junction proteins in jejunum epithelial tissues and intestinal epithelial cells was also decreased. In conclusion, our study suggests that TDCA alleviates oxidative stress to improve intestinal barrier function through the Nrf2-mediated signaling pathway. These findings help elucidate the role of TDCA in protecting the intestinal barrier and its mechanism of action, providing insights for the prevention and treatment of intestinal diseases caused by oxidative stress.

References

[] BaiX, WeiH, LiuW, CokerOO, GouH, LiuC, ZhaoL, LiC, ZhouY, WangG, KangW, NgEK, YuJ. Cigarette smoke promotes colorectal cancer through modulation of gut microbiota and related metabolites. Gut, 2022, 71(12): 2439-2450

[] BalabanRS, NemotoS, FinkelT. Mitochondria, oxidants, and aging. Cell, 2005, 120(4): 483-495

[] Basilicata, P., M. Pieri, A. Simonelli, E. Capasso, C. Casella, T. Noto, F. Policino, and P. Di Lorenzo. 2022. Diquat poisoning: care management and medico-legal implications. Toxics 10 (4). https://doi.org/10.3390/toxics10040166.

[] BhattacharyyaA, ChattopadhyayR, MitraS, CroweSE. Oxidative stress: An essential factor in the pathogenesis of gastrointestinal mucosal diseases. Physiological Reviews, 2014, 94(2): 329-354

[] Chiang, J.Y., 2003. Bile acid regulation of hepatic physiology: III. Bile acids and nuclear receptors. Am J Physiol Gastrointest Liver Physiol 284 (3), G349–356. https://doi.org/10.1152/ajpgi.00417.2002.

[] CuiL, GuanX, DingW, LuoY, WangW, BuW, SongJ, TanX, SunE, NingQ, LiuG, JiaX, FengL. Scutellaria baicalensis Georgi polysaccharide ameliorates DSS-induced ulcerative colitis by improving intestinal barrier function and modulating gut microbiota. International Journal of Biological Macromolecules, 2021, 166: 1035-1045

[] Diaz De BarbozaG, GuizzardiS, MoineL, Tolosa De TalamoniN. Oxidative stress, antioxidants and intestinal calcium absorption. World Journal of Gastroenterology, 2017, 23(16): 2841-2853

[] EvansJL, GoldfineID, MadduxBA, GrodskyGM. Oxidative stress and stress-activated signaling pathways: A unifying hypothesis of type 2 diabetes. Endocrine Reviews, 2002, 23(5): 599-622

[] FormanHJ, ZhangH. Targeting oxidative stress in disease: Promise and limitations of antioxidant therapy. Nature Reviews. Drug Discovery, 2021, 20(9): 689-709

[] HayesJD, Dinkova-KostovaAT, TewKD. Oxidative Stress in Cancer. Cancer Cell, 2020, 38(2): 167-197

[] HeY, LiY, PanY, LiA, HuangY, MiQ, ZhaoS, ZhangC, RanJ, HuH, PanH. Correlation analysis between jejunum metabolites and immune function in Saba and Landrace piglets. Front Vet Sci, 2023, 10: 1069809

[] Hu, J., L. Ma, Y. Nie, J. Chen, W. Zheng, X. Wang, C. Xie, Z. Zheng, Z. Wang, T. Yang, et al. 2018. A Microbiota-derived bacteriocin targets the host to confer diarrhea resistance in early-weaned piglets. Cell Host Microbe 24 (6): 817–832 e818. https://doi.org/10.1016/j.chom.2018.11.006.

[] HuangF, ParianteCM, BorsiniA. From dried bear bile to molecular investigation: A systematic review of the effect of bile acids on cell apoptosis, oxidative stress and inflammation in the brain, across preclinical models of neurological, neurodegenerative and neuropsychiatric disorders. Brain, Behavior, and Immunity, 2022, 99: 132-146

[] LiJ, FengS, WangZ, HeJ, ZhangZ, ZouH, WuZ, LiuX, WeiH, TaoS. Limosilactobacillus mucosae-derived extracellular vesicles modulates macrophage phenotype and orchestrates gut homeostasis in a diarrheal piglet model. NPJ Biofilms Microbiomes, 2023, 9(1): 33

[] MaQ. Role of nrf2 in oxidative stress and toxicity. Annual Review of Pharmacology and Toxicology, 2013, 53: 401-426

[] MowatAM, AgaceWW. Regional specialization within the intestinal immune system. Nature Reviews Immunology, 2014, 14(10): 667-685

[] PerroneEE, ChenC, LongshoreSW, OkezieO, WarnerBW, SunCC, AlaishSM, StrauchED. Dietary bile acid supplementation improves intestinal integrity and survival in a murine model. Journal of Pediatric Surgery, 2010, 45(6): 1256-1265

[] SahooDK, HeilmannRM, PaitalB, PatelA, YadavVK, WongD, JergensAE. Oxidative stress, hormones, and effects of natural antioxidants on intestinal inflammation in inflammatory bowel disease. Front Endocrinol (Lausanne), 2023, 14: 1217165

[] Shah, V., R. Mittal, D. Shahal, P. Sinha, E. Bulut, J. Mittal, and A.A. Eshraghi. 2020. Evaluating the efficacy of taurodeoxycholic acid in providing otoprotection using an in vitro model of electrode insertion trauma. Frontiers in Molecular Neuroscience 13: 113. https://doi.org/10.3389/fnmol.2020.00113.

[] SiesH, BerndtC, JonesDP. Oxidative Stress. Annual Review of Biochemistry, 2017, 86: 715-748

[] SongD, ChengY, LiX, WangF, LuZ, XiaoX, WangY. Biogenic Nanoselenium Particles Effectively Attenuate Oxidative Stress-Induced Intestinal Epithelial Barrier Injury by Activating the Nrf2 Antioxidant Pathway. ACS Applied Materials & Interfaces, 2017, 9(17): 14724-14740

[] SongM, ZhangF, FuY, YiX, FengS, LiuZ, DengD, YangQ, YuM, ZhuC, ZhuX, WangL, GaoP, ShuG, MaX, JiangQ, WangS. Tauroursodeoxycholic acid (TUDCA) improves intestinal barrier function associated with TGR5-MLCK pathway and the alteration of serum metabolites and gut bacteria in weaned piglets. J Anim Sci Biotechnol, 2022, 13(1): 73

[] TangZ, YangY, WuZ, JiY. Heat Stress-Induced Intestinal Barrier Impairment: Current Insights into the Aspects of Oxidative Stress and Endoplasmic Reticulum Stress. Journal of Agriculture and Food Chemistry, 2023, 71(14): 5438-5449

[] TaoS, BaiY, LiT, LiN, WangJ. Original low birth weight deteriorates the hindgut epithelial barrier function in pigs at the growing stage. The FASEB Journal, 2019, 33(9): 9897-9912

[] Van Der PolA, Van GilstWH, VoorsAA, Van Der MeerP. Treating oxidative stress in heart failure: Past, present and future. European Journal of Heart Failure, 2019, 21(4): 425-435

[] WahlstromA, SayinSI, MarschallHU, BackhedF. Intestinal crosstalk between bile acids and microbiota and its impact on host metabolism. Cell Metabolism, 2016, 24(1): 41-50

[] WongAC, RyanAF. Mechanisms of sensorineural cell damage, death and survival in the cochlea. Front Aging Neurosci, 2015, 7: 58

[] XiangQ, ZhaoY, LinJ, JiangS, LiW. The Nrf2 antioxidant defense system in intervertebral disc degeneration: Molecular insights. Experimental & Molecular Medicine, 2022, 54(8): 1067-1075

[] Xu, L., Y. Li, Z. Wei, R. Bai, G. Gao, W. Sun, X. Jiang, J. Wang, X. Li, and Y. Pi. 2022a. Chenodeoxycholic acid (CDCA) promoted intestinal epithelial cell proliferation by regulating cell cycle progression and mitochondrial biogenesis in IPEC-J2 cells. Antioxidants (Basel) 11 (11). https://doi.org/10.3390/antiox11112285.

[] Xu, Q., M. Liu, X. Chao, C. Zhang, H. Yang, J. Chen, C. Zhao, and B. Zhou. 2022b. Acidifiers attenuate diquat-induced oxidative stress and inflammatory responses by regulating NF-kappaB/MAPK/COX-2 pathways in IPEC-J2 cells. Antioxidants (Basel) 11 (10). https://doi.org/10.3390/antiox11102002.

[] YinJ, LiuM, RenW, DuanJ, YangG, ZhaoY, FangR, ChenL, LiT, YinY. Effects of dietary supplementation with glutamate and aspartate on diquat-induced oxidative stress in piglets. PLoS ONE, 2015, 10(4)

[] YunB, KingM, DrazMS, KlineT, Rodriguez-PalaciosA. Oxidative reactivity across kingdoms in the gut: Host immunity, stressed microbiota and oxidized foods. Free Radical Biology & Medicine, 2022, 178: 97-110

[] ZahiriHR, PerroneEE, StrauchED. Bile salt supplementation acts via the farnesoid X receptor to alleviate lipopolysaccharide-induced intestinal injury. Surgery, 2011, 150(3): 480-489

[] ZhangP, ZhengL, DuanY, GaoY, GaoH, MaoD, LuoY. Gut microbiota exaggerates triclosan-induced liver injury via gut-liver axis. Journal of Hazardous Materials, 2022, 421

[] Zhang, X., S. Wang, Y. Wu, X. Liu, J. Wang, and D. Han. 2022b. Ellagic acid alleviates diquat-induced jejunum oxidative stress in C57BL/6 mice through activating Nrf2 mediated signaling pathway. Nutrients 14 (5). https://doi.org/10.3390/nu14051103.

[] ZhaoGP, WangXY, LiJW, WangR, RenFZ, PangGF, LiYX. Imidacloprid increases intestinal permeability by disrupting tight junctions. Ecotoxicology and Environmental Safety, 2021, 222

[] ZouY, GhaderpourA, MunkhbilegB, SeoSU, SeongSY. Taurodeoxycholate ameliorates DSS-induced colitis in mice. International Immunopharmacology, 2023, 122

Funding

National Natural Science Foundation of China(32272898)