Artificial Bear Bile: A Novel Approach to Balancing Medical Requirements and Animal Welfare

Yong Li; Yuhong Huang; Nan Feng; Heping Zhang; Jing Qu; Shuanggang Ma; Yunbao Liu; Jiang Li; Shaofeng Xu; Ling Wang; Mi Zhang; Jie Cai; Weiping Wang; Ru Feng; Hang Yu; Bo Yu; Dailiang Liang; Heping Qin; Suxiang Luo; Yanfen Li; Meifeng Li; Ruihua Wang; Chen Ma; Yan Wang; Xiaobo Cen; Xiaoxian Xu; Boli Zhang; Xiaoliang Wang; Shishan Yu

doi:10.1016/j.eng.2023.09.017

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Engineering ›› 2024, Vol. 38 ›› Issue (7) : 100-112. DOI: 10.1016/j.eng.2023.09.017

Research

Article

Artificial Bear Bile: A Novel Approach to Balancing Medical Requirements and Animal Welfare

Yong Li^a^,^#^,^* ,
Yuhong Huang^b^,^# ,
Nan Feng^a^,^# ,
Heping Zhang^c^,^# ,
Jing Qu^a ,
Shuanggang Ma^a ,
Yunbao Liu^a ,
Jiang Li^a ,
Shaofeng Xu^a ,
Ling Wang^a ,
Mi Zhang^a ,
Jie Cai^a ,
Weiping Wang^a ,
Ru Feng^a ,
Hang Yu^a ,
Bo Yu^d ,
Dailiang Liang^c ,
Heping Qin^c ,
Suxiang Luo^c ,
Yanfen Li^b ,
Meifeng Li^b ,
Ruihua Wang^b ,
Chen Ma^a ,
Yan Wang^a ,
Xiaobo Cen^e ,
Xiaoxian Xu^d ,
Boli Zhang^f^,^* ,
Xiaoliang Wang^a^,^* ,
Shishan Yu^a^,^*

Author information +

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Abstract

Bear bile has been a valuable and effective medicinal material in traditional Chinese medicine (TCM) for over 13 centuries. However, the current practice of obtaining it through bear farming is under scrutiny for its adverse impact on bear welfare. Here, we present a new approach for creating artificial bear bile (ABB) as a high-quality and sustainable alternative to natural bear bile. This study addresses the scientific challenges of creating bear bile alternatives through interdisciplinary collaborations across various fields, including resources, chemistry, biology, medicine, pharmacology, and TCM. A comprehensive efficacy assessment system that bridges the gap between TCM and modern medical terminology has been established, allowing for the systematic screening of therapeutic constituents. Through the utilization of chemical synthesis and enzyme engineering technologies, our research has achieved the environmentally friendly, large-scale production of bear bile therapeutic compounds, as well as the optimization and recomposition of ABB formulations. The resulting ABB not only closely resembles natural bear bile in its composition but also offers advantages such as consistent product quality, availability of raw materials, and independence from threatened or wild resources. Comprehensive preclinical efficacy evaluations have demonstrated the equivalence of the therapeutic effects from ABB and those from commercially available drained bear bile (DBB). Furthermore, preclinical toxicological assessment and phase I clinical trials show that the safety of ABB is on par with that of the currently used DBB. This innovative strategy can serve as a new research paradigm for developing alternatives for other endangered TCMs, thereby strengthening the integrity and sustainability of TCM.

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Keywords

Artificial bear bile / Chemical profile / Formula optimization / Pharmacodynamic consistency / Preclinical toxicological assessment

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Yong Li, Yuhong Huang, Nan Feng, Heping Zhang, Jing Qu, Shuanggang Ma, Yunbao Liu, Jiang Li, Shaofeng Xu, Ling Wang, Mi Zhang, Jie Cai, Weiping Wang, Ru Feng, Hang Yu, Bo Yu, Dailiang Liang, Heping Qin, Suxiang Luo, Yanfen Li, Meifeng Li, Ruihua Wang, Chen Ma, Yan Wang, Xiaobo Cen, Xiaoxian Xu, Boli Zhang, Xiaoliang Wang, Shishan Yu. Artificial Bear Bile: A Novel Approach to Balancing Medical Requirements and Animal Welfare. Engineering, 2024, 38(7): 100‒112 https://doi.org/10.1016/j.eng.2023.09.017

References

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[1]	Jiangsu New Medical College. Great dictionary of Chinese materia medica. People’s Publishing House of Shanghai, Shanghai (1977)

[2]	D.Q.H. Wang, M.C. Carey. Therapeutic uses of animal biles in traditional Chinese medicine: an ethnopharmacological, biophysical chemical and medicinal review. World J Gastroenterol, 20 (29) (2014), pp. 9952-9975

[3]	E. Roda, F. Bazzoli, A.M. Labate, G. Mazzella, A. Roda, C. Sama, et al.Ursodeoxycholic acid vs. chenodeoxycholic acid as cholesterol gallstone-dissolving agents: a comparative randomized study. Hepatology, 2 (6) (1982), pp. 804-810

[4]	M. Makishima, A.Y. Okamoto, J.J. Repa, H. Tu, R.M. Learned, A. Luk, et al. Identification of a nuclear receptor for bile acids. Science, 284 (5418) (1999), pp. 1362-1365

[5]	Y. Kawamata, R. Fujii, M. Hosoya, M. Harada, H. Yoshida, M. Miwa, et al. A G protein-coupled receptor responsive to bile acids. J Biol Chem, 278 (11) (2003), pp. 9435-9440

[6]	F. Yang, C. Mao, L. Guo, J. Lin, Q. Ming, P. Xiao, et al. Structural basis of GPBAR activation and bile acid recognition. Nature, 587 (7834) (2020), pp. 499-504

[7]	M. Makishima, T.T. Lu, W. Xie, G.K. Whitfield, H. Domoto, R.M. Evans, et al.Vitamin D receptor as an intestinal bile acid sensor. Science, 296 (5571) (2002), pp. 1313-1316

[8]	E. Kwong, Y. Li, P.B. Hylemon, H. Zhou. Bile acids and sphingosine-1-phosphate receptor 2 in hepatic lipid metabolism. Acta Pharm Sin B, 5 (2) (2015), pp. 151-157

[9]	P. Gustav, B. Ulrich. Ursodeoxycholic acid in cholestatic liver disease: mechanisms of action and therapeutic use revisited. Hepatology, 36 (3) (2002), pp. 525-531

[10]	T.R. Ahmad, R.A. Haeusler. Bile acids in glucose metabolism and insulin signalling—mechanisms and research needs. Nat Rev Endocrinol, 15 (12) (2019), pp. 701-712

[11]	A. Perino, K. Schoonjans. Metabolic messengers: bile acids. Nat Metab, 4 (4) (2022), pp. 416-423

[12]	L. Chen, T. Jiao, W. Liu, Y. Luo, J. Wang, X. Guo, et al. Hepatic cytochrome P 450 8B1 and cholic acid potentiate intestinal epithelial injury in colitis by suppressing intestinal stem cell renewal. Cell Stem Cell, 29 (9) (2022), pp. 1366-1381.e9

[13]	M.L. Chen, K. Takeda, M.S. Sundrud. Emerging roles of bile acids in mucosal immunity and inflammation. Mucosal Immunol, 12 (4) (2019), pp. 851-861

[14]	R.A. Quinn, A.V. Melnik, A. Vrbanac, T. Fu, K.A. Patras, M.P. Christy, et al. Global chemical effects of the microbiome include new bile-acid conjugations. Nature, 579 (7797) (2020), pp. 123-129

[15]	D. Paik, L. Yao, Y. Zhang, S. Bae, G.D. D’Agostino, M. Zhang, et al. Human gut bacteria produce T_H17-modulating bile acid metabolites. Nature, 603 (7903) (2022), pp. 907-912

[16]	X. Song, X. Sun, S.F. Oh, M. Wu, Y. Zhang, W. Zheng, et al. Microbial bile acid metabolites modulate gut RORγ+ regulatory T cell homeostasis. Nature, 577 (7790) (2020), pp. 410-415

[17]	M.L. Chen, X. Huang, H. Wang, C. Hegner, Y. Liu, J. Shang, et al. CAR directs T cell adaptation to bile acids in the small intestine. Nature, 593 (7857) (2021), pp. 147-151

[18]	L. Zangerolamo, J.F. Vettorazzi, L.R.O. Rosa, E.M. Carneiro, H.C.L. Barbosa. The bile acid TUDCA and neurodegenerative disorders: an overview. Life Sci, 272 (2021), Article 119252

[19]	T. Brevini, M. Maes, G.J. Webb, B.V. John, C.D. Fuchs, G. Buescher, et al. FXR inhibition may protect from SARS-CoV-2 infection by reducing ACE2. Nature, 615 (7950) (2023), pp. 134-142

[20]	L.Y. Wang, X. Gao, Z.L. Tong, X.G. Wang. Summary on pharmacological action and clinical study of the chemical composition of bear bile. Inf Tradit Chin Med, 22 (2005), pp. 30-33

[21]	A.J. Dutton, C. Hepburn, D.W. Macdonald. A stated preference investigation into the Chinese demand for farmed vs. wild bear bile. PLoS One, 6 (7) (2011), p. e21243

[22]	M.K.H. Bando, O.L. Nelson, C. Kogan, R. Sellon, M. Wiest, H.J. Bacon, et al. Metabolic derangements and reduced survival of bile-extracted Asiatic black bears (Ursus thibetanus). BMC Vet Res, 15 (1) (2019), p. 263

[23]	S. Li, H.Y. Tan, N. Wang, M. Hong, L. Li, F. Cheung, et al. Substitutes for bear bile for the treatment of liver diseases: research progress and future perspective. Evi-Based Compl Alt, 2016 (2016), p. 4305074

[24]	S. Appiah, P. Bremner, M. Heinrich, T. Kokubun, M. Simmonds, C. Bell. Herbal alternatives to bear bile: effects of Scutellaria baicalensis Georgi on IL-6 promoter and CYP3A4 activities. Focus Altern Complement Ther, 11 (2006), p. 3

[25]	Y. Feng, K. Siu, N. Wang, K.M. Ng, S.W. Tsao, T. Nagamatsu, et al. Bear bile: dilemma of traditional medicinal use and animal protection. J Ethnobiol Ethnomed, 5 (2009), p. 2

[26]	Y. Li, X. Zhu, P.P.H. But, H.W. Yeung. Ethnopharmacology of bear gall bladder: I. J Ethnopharmacol, 47 (1) (1995), pp. 27-31

[27]

The scientific basis for research on substitutes of endangered medicinal materials—the 713th Symposium of the Xiangshan Science Conferences [Internet]. Beijing: Office of Xiangshan Science Conferences, Bureau of Basic Research, Chinese Academy of Sciences; 2022 Jun 10 [cited 2023 Sep 26]. Available from: https://xssc.ac.cn/waiwangEng/index.html#/xsscEng/detailsEng/f0f902a1a45b2b1dde2c40430a88b3b8.

[28]	A.F. Hofmann, L.R. Hagey. Bile acids: chemistry, pathochemistry, biology, pathobiology, and therapeutics. Cell Mol Life Sci, 65 (16) (2008), pp. 2461-2483

[29]	F.G. Schaap, M. Trauner, P.L.M. Jansen. Bile acid receptors as targets for drug development. Nat Rev Gastroenterol Hepatol, 11 (1) (2014), pp. 55-67

[30]	T.Y. Jiao, Y.D. Ma, X.Z. Guo, Y.F. Ye, C. Xie. Bile acid and receptors: biology and drug discovery for nonalcoholic fatty liver disease. Acta Pharmacol Sin, 43 (5) (2022), pp. 1103-1119

[31]	Q. Zhang, X. Yin, K. Yan, S. Tian. Studies on analysis of tauroursodeoxycholic acid and taurochenodeoxycholic acid in bear biliary drainage powder and bear gall by HPLC. Chin J Pharm Anal, 13 (15) (1993), pp. 321-324

[32]	A. Uji, K. Takiura. Studies on bear gall. I. determination of bile acids in bear gall by gas chromatography. J Pharm Soc Jpn, 95 (1) (1975), pp. 114-119

[33]	T. Namba, S. Nunome, M. Hattori, S. Higashidate, T. Maekubo. Fundamental studies on the evaluation of crude drug. Ⅶ. on animal gall (1). J Pharm Soc Jpn, 102 (8) (1982), pp. 760-767

[34]	R.H. Dowling. Cheno and urso compared and contrasted. Acta Med Port, 4 (1) (1983), pp. 51-62

[35]	Y. Wu, F. Zhang, K. Yang, S. Fang, D. Bu, H. Li, et al. SymMap: an integrative database of traditional Chinese medicine enhanced by symptom mapping. Nucleic Acids Res, 47 (D1) (2019), pp. D1110-D1117

[36]	D.J. Shin, L. Wang. Bile acid-activated receptors: a review on FXR and other nuclear receptors. Handb Exp Pharmacol, 256 (2019), pp. 51-72

[37]	C.J. Jong, P. Sandal, S.W. Schaffer. The role of taurine in mitochondria health: more than just an antioxidant. Molecules, 26 (16) (2021), p. 4913

[38]	T. Eggert, D. Bakonyi, W. Hummel. Enzymatic routes for the synthesis of ursodeoxycholic acid. J Biotechnol, 191 (2014), pp. 11-21

[39]	Y. Xu, L. Yang, S. Zhao, Z. Wang. Large-scale production of tauroursodeoxycholic acid products through fermentation optimization of engineered Escherichia coli cell factory. Microb Cell Fact, 18 (1) (2019), p. 34

[40]	H.P. Li, B.Y. Yang, Y. Su, Z.N. You, W.T. Yin, C.X. Li, et al. Sustainable and robust closed-loop enzymatic platform for continuous/semi-continuous synthesis of ursodeoxycholic acid. ACS Sustainable Chem Eng, 10 (50) (2022), pp. 16916-16923