Gut Microbiota Modulation: A Viable Strategy to Address Medical Needs in Hepatocellular Carcinoma and Liver Transplantation

Ze Xiang, Jian Wu, Jiarui Li, Shusen Zheng, Xuyong Wei, Xiao Xu

Engineering ›› 2023, Vol. 29 ›› Issue (10) : 59-72.

PDF(1338 KB)
PDF(1338 KB)
Engineering ›› 2023, Vol. 29 ›› Issue (10) : 59-72. DOI: 10.1016/j.eng.2022.12.012
Research
Review

Gut Microbiota Modulation: A Viable Strategy to Address Medical Needs in Hepatocellular Carcinoma and Liver Transplantation

Author information +
History +

Abstract

Hepatocellular carcinoma (HCC) is the most common malignancy of the liver, posing a significant threat to public health. Although liver transplantation (LT) is an effective treatment for HCC, ischemia-reperfusion (I/R) injury, transplant rejection, and complications after LT can greatly reduce its effectiveness. In recent years, transplant oncology has come into being, a comprehensive discipline formed by the intersection and integration of surgery, oncology, immunology, and other related disciplines. Gut microbiota, an emerging field of research, also plays a crucial role. Through the microbiome-gut-liver axis, the gut microbiota has an impact on the onset and progression of HCC as well as LT. This review summarizes the mechanisms by which the gut microbiota affects HCC and its bidirectional interactions with chronic liver disease that can develop into HCC as well as the diagnostic and prognostic value of the gut microbiota in HCC. In addition, gut microbiota alterations after LT were reviewed, and the relationship between the gut microbiota and liver I/R injury, the efficacy of immunosuppressive drugs used, and complications after LT were discussed. In the era of LT oncology, the role of the gut microbiota in HCC and LT should be emphasized, which can provide new insights into the management of HCC and LT via gut microbiota modulation.

Graphical abstract

Keywords

Gut microbiota / Hepatocellular carcinoma (HCC) / Liver transplantation (LT) / Clinical value / Mediating mechanism

Cite this article

Download citation ▾
Ze Xiang, Jian Wu, Jiarui Li, Shusen Zheng, Xuyong Wei, Xiao Xu. Gut Microbiota Modulation: A Viable Strategy to Address Medical Needs in Hepatocellular Carcinoma and Liver Transplantation. Engineering, 2023, 29(10): 59‒72 https://doi.org/10.1016/j.eng.2022.12.012

References

[1]
J.M. Llovet, R.K. Kelley, A. Villanueva, A.G. Singal, E. Pikarsky, S. Roayaie, et al. Hepatocellular carcinoma. Nat Rev Dis Primers, 7 (1) ( 2021), p. 6.
[2]
R.L. Siegel, K.D. Miller, H.E. Fuchs, A. Jemal. Cancer statistics, 2022. CA Cancer J Clin, 72 (1) ( 2022), pp. 7-33
[3]
V. Mazzaferro, E. Regalia, R. Doci, S. Andreola, A. Pulvirenti, F. Bozzetti, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med, 334 (11) ( 1996), pp. 693-699
[4]
D.I. Tsilimigras, F. Bagante, D. Moris, K. Merath, A.Z. Paredes, K. Sahara, et al. Defining the chance of cure after resection for hepatocellular carcinoma within and beyond the Barcelona Clinic Liver Cancer guidelines: a multi-institutional analysis of 1,010 patients. Surgery, 166 (6) ( 2019), pp. 967-974
[5]
D.F. Mirza. Systematic review of outcome of downstaging hepatocellular cancer before liver transplantation in patients outside the Milan criteria (Br J Surg 2011; 98: 1201-1208). Br J Surg, 98 (9) ( 2011), p. 1209
[6]
X. Xu, D. Lu, Q. Ling, X. Wei, J. Wu, L. Zhou, et al. Liver transplantation for hepatocellular carcinoma beyond the Milan criteria. Gut, 65 (6) ( 2016), pp. 1035-1041
[7]
T. Hibi, M. Shinoda, O. Itano, Y. Kitagawa. Current status of the organ replacement approach for malignancies and an overture for organ bioengineering and regenerative medicine. Organogenesis, 10 (2) ( 2014), pp. 241-249
[8]
T. Hibi, O. Itano, M. Shinoda, Y. Kitagawa. Liver transplantation for hepatobiliary malignancies: a new era of “Transplant Oncology” has begun. Surg Today, 47 (4) ( 2017), pp. 403-415
[9]
N. Mehta, P. Bhangui, F.Y. Yao, V. Mazzaferro, C. Toso, N. Akamatsu, et al. Liver transplantation for hepatocellular carcinoma. Working group report from the ILTS Transplant Oncology Consensus Conference. Transplantation, 104 (6) ( 2020), pp. 1136-1142
1[ 10] B.O. Schroeder, F. B?ckhed. Signals from the gut microbiota to distant organs in physiology and disease. Nat Med, 22 (10) ( 2016), pp. 1079-1089
[11]
N. Kazemian, M. Mahmoudi, F. Halperin, J.C. Wu, S. Pakpour. Gut microbiota and cardiovascular disease: opportunities and challenges. Microbiome, 8 (1) ( 2020), p. 36
[12]
P.C. Konturek, I.A. Harsch, K. Konturek, M. Schink, T. Konturek, M.F. Neurath, et al. Gut-liver axis: how do gut bacteria influence the liver?. Med Sci, 6 (3) ( 2018), p. 79
[13]
X. Yang, D. Lu, J. Zhuo, Z. Lin, M. Yang, X. Xu. The gut-liver axis in immune remodeling: new insight into liver diseases. Int J Biol Sci, 16 (13) ( 2020), pp. 2357-2366
[14]
M. Deng, F. Qu, L. Chen, C. Liu, M. Zhang, F. Ren, et al. SCFAs alleviated steatosis and inflammation in mice with NASH induced by MCD. J Endocrinol, 245 (3) ( 2020), pp. 425-437
[15]
C. Ma, M. Han, B. Heinrich, Q. Fu, Q. Zhang, M. Sandhu, et al. Gut microbiome-mediated bile acid metabolism regulates liver cancer via NKT cells. Science, 360(6391):eaan5931 ( 2018)
[16]
N. Ohtani, E. Hara. Gut-liver axis-mediated mechanism of liver cancer: a special focus on the role of gut microbiota. Cancer Sci, 112 (11) ( 2021), pp. 4433-4443
[17]
Z. Ren, A. Li, J. Jiang, L. Zhou, Z. Yu, H. Lu, et al. Gut microbiome analysis as a tool towards targeted non-invasive biomarkers for early hepatocellular carcinoma. Gut, 68 (6) ( 2019), pp. 1014-1023
[18]
H. Huang, Z. Ren, X. Gao, X. Hu, Y. Zhou, J. Jiang, et al. Integrated analysis of microbiome and host transcriptome reveals correlations between gut microbiota and clinical outcomes in HBV-related hepatocellular carcinoma. Genome Med, 12 (1) ( 2020), p. 102
[19]
E. Thursby, N. Juge. Introduction to the human gut microbiota. Biochem J, 474 (11) ( 2017), pp. 1823-1836
[20]
X. Tian, Z. Yang, F. Luo, S. Zheng. Gut microbial balance and liver transplantation: alteration, management, and prediction. Front Med, 12 (2) ( 2018), pp. 123-129
[21]
B. Zhu, X. Wang, L. Li. Human gut microbiome: the second genome of human body. Protein Cell, 1 (8) ( 2010), pp. 718-725
[22]
A. Almeida, S. Nayfach, M. Boland, F. Strozzi, M. Beracochea, Z.J. Shi, et al. A unified catalog of 204,938 reference genomes from the human gut microbiome. Nat Biotechnol, 39 (1) ( 2021), pp. 105-114
[23]
C.A. Lozupone, J.I. Stombaugh, J.I. Gordon, J.K. Jansson, R. Knight. Diversity, stability and resilience of the human gut microbiota. Nature, 489 (7415) ( 2012), pp. 220-230
[24]
A. Adak, M.R. Khan. An insight into gut microbiota and its functionalities. Cell Mol Life Sci, 76 (3) ( 2019), pp. 473-493
[25]
F. Zhang, D. Aschenbrenner, J.Y. Yoo, T. Zuo. The gut mycobiome in health, disease, and clinical applications in association with the gut bacterial microbiome assembly. Lancet Microbe, 3 (12) ( 2022), pp. e969-e983
[26]
O.O. Coker, W.K.K. Wu, S.H. Wong, J.J. Sung, J. Yu. Altered gut archaea composition and interaction with bacteria are associated with colorectal cancer. Gastroenterology, 159 (4) ( 2020)
[27]
M. Gurung, Z. Li, H. You, R. Rodrigues, D.B. Jump, A. Morgun, et al. Role of gut microbiota in type 2 diabetes pathophysiology. EBioMedicine, 51 ( 2020), Article 102590
[28]
B.J.H. Verhaar, A. Prodan, M. Nieuwdorp, M. Muller. Gut microbiota in hypertension and atherosclerosis: a review. Nutrients, 12 (10) ( 2020), p. 2982
[29]
K. Sugihara, N. Kamada. Diet-microbiota interactions in inflammatory bowel disease. Nutrients, 13 (5) ( 2021), p. 1533
[30]
E.Y. Hsiao, S.W. McBride, S. Hsien, G. Sharon, E.R. Hyde, T. McCue, et al. Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders. Cell, 155 (7) ( 2013), pp. 1451-1463
[31]
C. Xia, X. Dong, H. Li, M. Cao, D. Sun, S. He, et al. Cancer statistics in China and United States, 2022: profiles, trends, and determinants. Chin Med J, 135 (5) ( 2022), pp. 584-590
[32]
S. Temraz, F. Nassar, F. Kreidieh, D. Mukherji, A. Shamseddine, R. Nasr. Hepatocellular carcinoma immunotherapy and the potential influence of gut microbiome. Int J Mol Sci, 22 (15) ( 2021), p. 7800
[33]
S. Ling, Q. Shan, Q. Zhan, Q. Ye, P. Liu, S. Xu, et al. USP22 promotes hypoxia-induced hepatocellular carcinoma stemness by a HIF1α/USP22 positive feedback loop upon TP53 inactivation. Gut, 69 (7) ( 2020), pp. 1322-1334
[34]
W.F. Doe. The intestinal immune system. Gut, 30 (12) ( 1989), pp. 1679-1685
[35]
R. Ahmad, M.F. Sorrell, S.K. Batra, P. Dhawan, A.B. Singh. Gut permeability and mucosal inflammation: bad, good or context dependent. Mucosal Immunol, 10 (2) ( 2017), pp. 307-317
[36]
O. Takeuchi, S. Akira. Pattern recognition receptors and inflammation. Cell, 140 (6) ( 2010), pp. 805-820
[37]
L. Wang, C. Llorente, P. Hartmann, A.M. Yang, P. Chen, B. Schnabl. Methods to determine intestinal permeability and bacterial translocation during liver disease. J Immunol Methods, 421 ( 2015), pp. 44-53
[38]
M. Venkatesh, S. Mukherjee, H. Wang, H. Li, K. Sun, A.P. Benechet, et al. Symbiotic bacterial metabolites regulate gastrointestinal barrier function via the xenobiotic sensor PXR and Toll-like receptor 4. Immunity, 41 (2) ( 2014), pp. 296-310
[39]
W.T. Liu, Y.Y. Jing, G.F. Yu, Z.P. Han, D.D. Yu, Q.M. Fan, et al. Toll like receptor 4 facilitates invasion and migration as a cancer stem cell marker in hepatocellular carcinoma. Cancer Lett, 358 (2) ( 2015), pp. 136-143
[40]
D.H. Dapito, A. Mencin, G.Y. Gwak, J.P. Pradere, M.K. Jang, I. Mederacke, et al. Promotion of hepatocellular carcinoma by the intestinal microbiota and TLR4. Cancer Cell, 21 (4) ( 2012), pp. 504-516
[41]
R.M. Ayling, K. Kok. Fecal calprotectin. Adv Clin Chem, 87 ( 2018), pp. 161-190
[42]
F.R. Ponziani, S. Bhoori, C. Castelli, L. Putignani, L. Rivoltini, F. Del Chierico, et al. Hepatocellular carcinoma is associated with gut microbiota profile and inflammation in nonalcoholic fatty liver disease. Hepatology, 69 (1) ( 2019), pp. 107-120
[43]
C. Bi, G. Xiao, C. Liu, J. Yan, J. Chen, W. Si, et al. Molecular immune mechanism of intestinal microbiota and their metabolites in the occurrence and development of liver cancer. Front Cell Dev Biol, 9 ( 2021), Article 702414
[44]
A. Visekruna, M. Luu. The role of short-chain fatty acids and bile acids in intestinal and liver function, inflammation, and carcinogenesis. Front Cell Dev Biol, 9 ( 2021), Article 703218
[45]
M. Luu, S. Pautz, V. Kohl, R. Singh, R. Romero, S. Lucas, et al. The short-chain fatty acid pentanoate suppresses autoimmunity by modulating the metabolic-epigenetic crosstalk in lymphocytes. Nat Commun, 10 (1) ( 2019), p. 760
[46]
N. McBrearty, A. Arzumanyan, E. Bichenkov, S. Merali, C. Merali, M. Feitelson. Short chain fatty acids delay the development of hepatocellular carcinoma in HBx transgenic mice. Neoplasia, 23 (5) ( 2021), pp. 529-538
[47]
C Hu, B Xu, X Wang, WH Wan, J Lu, D Kong, et al. Gut microbiota-derived short-chain fatty acids regulate group 3 innate lymphoid cells in HCC. Hepatology, 77 (1) ( 2023), pp. 48-64
[48]
V. Singh, B. San Yeoh, B. Chassaing, X. Xiao, P. Saha, R.A. Olvera, et al. Dysregulated microbial fermentation of soluble fiber induces cholestatic liver cancer. Cell, 175 (3) ( 2018). 679 94.e22
[49]
R. Mirzaei, A. Afaghi, S. Babakhani, M.R. Sohrabi, S.R. Hosseini-Fard, K. Babolhavaeji, et al. Role of microbiota-derived short-chain fatty acids in cancer development and prevention. Biomed Pharmacother, 139 ( 2021), Article 111619
[50]
M.V. Liberti, J.W. Locasale. The Warburg effect: how does it benefit cancer cells?. Trends Biochem Sci, 41 (3) ( 2016), pp. 211-218
[51]
K.G. De la Cruz-López, L.J. Castro-Mu?oz, D.O. Reyes-Hernández, A. García-Carrancá, J. Manzo-Merino. Lactate in the regulation of tumor microenvironment and therapeutic approaches. Front Oncol, 9 ( 2019), p. 1143
[52]
W. Zhang, Z. Chen, C. Xue, Y. Zhang, L. Wu, J. Zhu, et al. The applicability of ADA, AFU, and LAC in the early diagnosis and disease risk assessment of hepatitis B-associated liver cirrhosis and hepatocellular carcinoma. Front Med, 8 ( 2021), Article 740029
[53]
Y. Gu, F. Ji, N. Liu, Y. Zhao, X. Wei, S. Hu, et al. Loss of miR-192-5p initiates a hyperglycolysis and stemness positive feedback in hepatocellular carcinoma. J Exp Clin Cancer Res, 39 (1) ( 2020), p. 268
[54]
W. Cao, H. Kayama, M.L. Chen, A. Delmas, A. Sun, S.Y. Kim, et al. The xenobiotic transporter Mdr 1 enforces T cell homeostasis in the presence of intestinal bile acids. Immunity, 47 (6) ( 2017). 1182-96.e10
[55]
L. Conde de la Rosa, C. Garcia-Ruiz, C. Vallejo, A. Baulies, S. Nu?ez, M.J. Monte, et al. STARD 1 promotes NASH-driven HCC by sustaining the generation of bile acids through the alternative mitochondrial pathway. J Hepatol, 74 (6) ( 2021), pp. 1429-1441
[56]
R. Sun, Z. Zhang, R. Bao, X. Guo, Y. Gu, W. Yang, et al. Loss of SIRT 5 promotes bile acid-induced immunosuppressive microenvironment and hepatocarcinogenesis. J Hepatol, 77 (2) ( 2022), pp. 453-466
[57]
S. Yoshimoto, T.M. Loo, K. Atarashi, H. Kanda, S. Sato, S. Oyadomari, et al. Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. Nature, 499 (7456) ( 2013), pp. 97-101
[58]
J. Bruix, M. Sherman. the American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma: an update. Hepatology, 53 (3) ( 2011), pp. 1020-1022
[59]
H.B. El-Serag. Hepatocellular carcinoma. N Engl J Med, 365 (12) ( 2011), pp. 1118-1127
[60]
B. Liu, Z. Zhou, Y. Jin, J. Lu, D. Feng, R. Peng, et al. Hepatic stellate cell activation and senescence induced by intrahepatic microbiota disturbances drive progression of liver cirrhosis toward hepatocellular carcinoma. J Immunother Cancer, 10 (1) ( 2022), p. e003069
[61]
S. Li, W. Han, Q. He, W. Zhang, Y. Zhang. Relationship between intestinal microflora and hepatocellular cancer based on gut-liver axis theory. Contrast Media Mol Imaging, 2022 ( 2022), p. 6533628
[62]
B. Wang, X. Jiang, M. Cao, J. Ge, Q. Bao, L. Tang, et al. Altered fecal microbiota correlates with liver biochemistry in nonobese patients with non-alcoholic fatty liver disease. Sci Rep, 6 (1) ( 2016), p. 32002
[63]
H. Leung, X. Long, Y. Ni, L. Qian, E. Nychas, S.L. Siliceo, et al. Risk assessment with gut microbiome and metabolite markers in NAFLD development. Sci Transl Med ( 2022; 14(648):eabk0855.)
[64]
R. Loomba, V. Seguritan, W. Li, T. Long, N. Klitgord, A. Bhatt, et al. Gut microbiome-based metagenomic signature for non-invasive detection of advanced fibrosis in human nonalcoholic fatty liver disease. Cell Metab, 25 (5) ( 2017). 1054-62.e5
[65]
J.S. Yu, G.S. Youn, J. Choi, C.H. Kim, B.Y. Kim, S.J. Yang, et al. Lactobacillus lactis and Pediococcus pentosaceus-driven reprogramming of gut microbiome and metabolome ameliorates the progression of non-alcoholic fatty liver disease. Clin Transl Med, 11 (12) ( 2021), p. e634
[66]
B. Bj? rkholm, C.M. Bok, A. Lundin, J. Rafter, M.L. Hibberd, S. Pettersson. Intestinal microbiota regulate xenobiotic metabolism in the liver. PLoS One, 4 (9) ( 2009), p. e6958
[67]
I. Bergheim, S. Weber, M. Vos, S. Kr?mer, V. Volynets, S. Kaserouni, et al. Antibiotics protect against fructose-induced hepatic lipid accumulation in mice: role of endotoxin. J Hepatol, 48 (6) ( 2008), pp. 983-992
[68]
S. Thuy, R. Ladurner, V. Volynets, S. Wagner, S. Strahl, A. K? nigsrainer, et al. Nonalcoholic fatty liver disease in humans is associated with increased plasma endotoxin and plasminogen activator inhibitor 1 concentrations and with fructose intake. J Nutr, 138 (8) ( 2008), pp. 1452-1455
[69]
F. B? ckhed, J.K. Manchester, C.F. Semenkovich, J.I. Gordon. Mechanisms underlying the resistance to diet-induced obesity in Germ-free mice. Proc Natl Acad Sci USA, 104 (3) ( 2007), pp. 979-984
[70]
L. Bull-Otterson, W. Feng, I. Kirpich, Y. Wang, X. Qin, Y. Liu, et al. Metagenomic analyses of alcohol induced pathogenic alterations in the intestinal microbiome and the effect of Lactobacillus rhamnosus GG treatment. PLoS One, 8 (1) ( 2013), p. e53028
[71]
M. Llopis, A.M. Cassard, L. Wrzosek, L. Boschat, A. Bruneau, G. Ferrere, et al. Intestinal microbiota contributes to individual susceptibility to alcoholic liver disease. Gut, 65 (5) ( 2016), pp. 830-839
[72]
K. Brandl, P. Hartmann, L.J. Jih, D.P. Pizzo, J. Argemi, M. Ventura-Cots, et al. Dysregulation of serum bile acids and FGF 19 in alcoholic hepatitis. J Hepatol, 69 (2) ( 2018), pp. 396-405
[73]
L. Jiang, S. Lang, Y. Duan, X. Zhang, B. Gao, J. Chopyk, et al. Intestinal virome in patients with alcoholic hepatitis. Hepatology, 72 (6) ( 2020), pp. 2182-2196
[74]
C.L. Hsu, X. Zhang, L. Jiang, S. Lang, P. Hartmann, D. Pride, et al. Intestinal virome in patients with alcohol use disorder and after abstinence. Hepatol Commun, 6 (8) ( 2022), pp. 2058-2069
[75]
A.W. Yan, D.E. Fouts, J. Brandl, P. St?rkel, M. Torralba, E. Schott, et al. Enteric dysbiosis associated with a mouse model of alcoholic liver disease. Hepatology, 53 (1) ( 2011), pp. 96-105
[76]
C. Bode, V. Kugler, J.C. Bode. Endotoxemia in patients with alcoholic and non-alcoholic cirrhosis and in subjects with no evidence of chronic liver disease following acute alcohol excess. J Hepatol, 4 (1) ( 1987), pp. 8-14
[77]
C. Llorente, P. Jepsen, T. Inamine, L. Wang, S. Bluemel, H.J. Wang, et al. Gastric acid suppression promotes alcoholic liver disease by inducing overgrowth of intestinal Enterococcus. Nat Commun, 8 (1) ( 2017), p. 837
[78]
Y. Duan, C. Llorente, S. Lang, K. Brandl, H. Chu, L. Jiang, et al. Bacteriophage targeting of gut bacterium attenuates alcoholic liver disease. Nature, 575 (7783) ( 2019), pp. 505-511
[79]
A. Everard, C. Belzer, L. Geurts, J.P. Ouwerkerk, C. Druart, L.B. Bindels, et al. Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity. Proc Natl Acad Sci USA, 110 (22) ( 2013), pp. 9066-9071
[80]
C. Grander, T.E. Adolph, V. Wieser, P. Lowe, L. Wrzosek, B. Gyongyosi, et al. Recovery of ethanol-induced Akkermansia muciniphila depletion ameliorates alcoholic liver disease. Gut, 67 (5) ( 2018), pp. 891-901
[81]
Q. Liu, F. Li, Y. Zhuang, J. Xu, J. Wang, X. Mao, et al. Alteration in gut microbiota associated with hepatitis B and non-hepatitis virus related hepatocellular carcinoma. Gut Pathog, 11 (1) ( 2019), p. 1
[82]
X. Wang, M.M. Li, Y. Niu, X. Zhang, J.B. Yin, C.J. Zhao, et al. Serum zonulin in HBV-associated chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. Dis Markers, 2019 ( 2019), p. 5945721
[83]
S. Sultan, M. El-Mowafy, A. Elgaml, M. El-Mesery, A. El Shabrawi, M. Elegezy, et al. Alterations of the treatment-naive gut microbiome in newly diagnosed hepatitis C virus infection. ACS Infect Dis, 7 (5) ( 2021), pp. 1059-1068
[84]
P. Pérez-Matute, M. í? iguez, M.J. Villanueva-Millán, E. Recio-Fernández, A.M. Vázquez, S.C. Sánchez, et al. Short-term effects of direct-acting antiviral agents on inflammation and gut microbiota in hepatitis C-infected patients. Eur J Intern Med, 67 ( 2019), pp. 47-58
[85]
B. Heidrich, M. Vital, I. Plumeier, N. D? scher, S. Kahl, J. Kirschner, et al. Intestinal microbiota in patients with chronic hepatitis C with and without cirrhosis compared with healthy controls. Liver Int, 38 (1) ( 2018), pp. 50-58
[86]
E.J. Drenick, J. Fisler, D. Johnson. Hepatic steatosis after intestinal bypass—prevention and reversal by metronidazole, irrespective of protein-calorie malnutrition. Gastroenterology, 82 (3) ( 1982), pp. 535-548
[87]
J. Rehm, A.V. Samokhvalov, K.D. Shield. Global burden of alcoholic liver diseases. J Hepatol, 59 (1) ( 2013), pp. 160-168
[88]
M. Meroni, M. Longo, P. Dongiovanni. Alcohol or gut microbiota: who is the guilty?. Int J Mol Sci, 20 (18) ( 2019), p. 4568
[89]
G.A. Cresci, B. Glueck, M.R. McMullen, W. Xin, D. Allende, L.E. Nagy. Prophylactic tributyrin treatment mitigates chronic-binge ethanol-induced intestinal barrier and liver injury. J Gastroenterol Hepatol, 32 (9) ( 2017), pp. 1587-1597
[90]
Y. Chen, Z. Tian. HBV-induced immune imbalance in the development of HCC. Front Immunol, 10 ( 2019), p. 2048
[91]
P. Axley, Z. Ahmed, S. Ravi, A.K. Singal. Hepatitis C virus and hepatocellular carcinoma: a narrative review. J Clin Transl Hepatol, 6 (1) ( 2018), pp. 79-84
[92]
D.R. McGivern, S.M. Lemon. Virus-specific mechanisms of carcinogenesis in hepatitis C virus associated liver cancer. Oncogene, 30 (17) ( 2011), pp. 1969-1983
[93]
N. Fujiwara, S.L. Friedman, N. Goossens, Y. Hoshida. Risk factors and prevention of hepatocellular carcinoma in the era of precision medicine. J Hepatol, 68 (3) ( 2018), pp. 526-549
[94]
T. Deng, J. Li, B. He, B. Chen, F. Liu, Z. Chen, et al. Gut microbiome alteration as a diagnostic tool and associated with inflammatory response marker in primary liver cancer. Hepatol Int, 16 (1) ( 2022), pp. 99-111
[95]
S. Albhaisi, A. Shamsaddini, A. Fagan, S. McGeorge, M. Sikaroodi, E. Gavis, et al. Gut microbial signature of hepatocellular cancer in men with cirrhosis. Liver Transpl, 27 (5) ( 2021), pp. 629-640
[96]
R. Huang, T. Li, J. Ni, X. Bai, Y. Gao, Y. Li, et al. Different sex-based responses of gut microbiota during the development of hepatocellular carcinoma in liver-specific Tsc1-knockout mice. Front Microbiol, 9 ( 2018), p. 1008
[97]
Z. Liu, Y. Li, C. Li, G. Lei, L. Zhou, X. Chen, et al. Intestinal Candida albicans promotes hepatocarcinogenesis by up-regulating NLRP6. Front Microbiol, 13 ( 2022), Article 812771
[98]
A.X. Zhu, R.S. Finn, J. Edeline, S. Cattan, S. Ogasawara, D. Palmer, et al. the KEYNOTE-224 investigators. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial. Lancet Oncol, 19 (7) ( 2018), pp. 940-952
[99]
L. Li, J. Ye. Characterization of gut microbiota in patients with primary hepatocellular carcinoma received immune checkpoint inhibitors: a Chinese population-based study. Medicine, 99 (37) ( 2020), p. e21788
[100]
Y. Zheng, T. Wang, X. Tu, Y. Huang, H. Zhang, D. Tan, et al. Gut microbiome affects the response to anti-PD-1 immunotherapy in patients with hepatocellular carcinoma. J Immunother Cancer, 7 (1) ( 2019), p. 193
[101]
M. Lobanovska, G. Pilla. Focus: drug development: penicillin’s discovery and antibiotic resistance: lessons for the future?. Yale J Biol Med, 90 (1) ( 2017), pp. 135-145
[102]
T.M. Loo, F. Kamachi, Y. Watanabe, S. Yoshimoto, H. Kanda, Y. Arai, et al. Gut microbiota promotes obesity-associated liver cancer through PGE2-mediated suppression of antitumor immunity. Cancer Discov, 7 (5) ( 2017), pp. 522-538
[103]
V. Singh, B.S. Yeoh, A.A. Abokor, R.M. Golonka, Y. Tian, A.D. Patterson, et al. Vancomycin prevents fermentable fiber-induced liver cancer in mice with dysbiotic gut microbiota. Gut Microbes, 11 (4) ( 2020), pp. 1077-1091
[104]
P. Ginés, A. Rimola, R. Planas, V. Vargas, F. Marco, M. Almela, et al. Norfloxacin prevents spontaneous bacterial peritonitis recurrence in cirrhosis: results of a double-blind, placebo-controlled trial. Hepatology, 12 (4 Pt 1) ( 1990), pp. 716-724
[105]
P. Tandon, A. Delisle, J.E. Topal, G. Garcia-Tsao. High prevalence of antibiotic-resistant bacterial infections among patients with cirrhosis at a US liver center. Clin Gastroenterol Hepatol, 10 (11) ( 2012), pp. 1291-1298
[106]
Y. Fujinaga, H. Kawaratani, D. Kaya, Y. Tsuji, T. Ozutsumi, M. Furukawa, et al. Effective combination therapy of angiotensin-II receptor blocker and rifaximin for hepatic fibrosis in rat model of nonalcoholic steatohepatitis. Int J Mol Sci, 21 (15) ( 2020), p. 5589
[107]
L.X. Yu, R.F. Schwabe. The gut microbiome and liver cancer: mechanisms and clinical translation. Nat Rev Gastroenterol Hepatol, 14 (9) ( 2017), pp. 527-539
[108]
R.K. Dhiman, B. Rana, S. Agrawal, A. Garg, M. Chopra, K.K. Thumburu, et al. Probiotic VSL# 3 reduces liver disease severity and hospitalization in patients with cirrhosis: a randomized, controlled trial. Gastroenterology, 147 (6) ( 2014). 1327-37.e3
[109]
J. Li, C.Y.J. Sung, N. Lee, Y. Ni, J. Pihlajam?ki, G. Panagiotou, et al. Probiotics modulated gut microbiota suppresses hepatocellular carcinoma growth in mice. Proc Natl Acad Sci USA, 113 (9) ( 2016), pp. E1306-E1315
[110]
Z. Heydari, M. Rahaie, A.M. Alizadeh. Different anti-inflammatory effects of Lactobacillus acidophilus and Bifidobactrum bifidioum in hepatocellular carcinoma cancer mouse through impact on microRNAs and their target genes. J Nutr Intermed Metab, 16 ( 2019), p. 16100096
[111]
M. Mihailovi?, M. ?ivkovi? J. A. Jovanovi?, M. Tolina?ki, M. Sinadinovi?, J. Raji?, et al. Oral administration of probiotic Lactobacillus paraplantarum BGCG 11 attenuates diabetes-induced liver and kidney damage in rats. J Funct Foods, 38 ( 2017), pp. 38427-38437
[112]
H.L. Zhang, L.X. Yu, W. Yang, L. Tang, Y. Lin, H. Wu, et al. Profound impact of gut homeostasis on chemically-induced pro-tumorigenic inflammation and hepatocarcinogenesis in rats. J Hepatol, 57 (4) ( 2012), pp. 803-812
[113]
A.M. Elshaer, O.A. El-Kharashi, G.G. Hamam, E.S. Nabih, Y.M. Magdy, A.A. Abd El Samad. Involvement of TLR4/ CXCL9/ PREX-2 pathway in the development of hepatocellular carcinoma (HCC) and the promising role of early administration of lactobacillus plantarum in Wistar rats. Tissue Cell, 60 ( 2019), pp. 38-47
[114]
G.A. Nanis, L.S. Mohamed, E. Hassan, M.N. Maii. Lactobacillus acidophilus and Bifidobacteria spp having antibacterial and antiviral effects on chronic HCV infection. Afr J Microbiol Res, 13 (5) ( 2019), pp. 77-90
[115]
D.K. Lee, J.Y. Kang, H.S. Shin, I.H. Park, N.J. Ha. Antiviral activity of Bifidobacterium adolescentis SPM0212 against Hepatitis B virus. Arch Pharm Res, 36 (12) ( 2013), pp. 1525-1532
[116]
S.L. Gorbach, M. Barza, M. Giuliano, N.V. Jacobus. Colonization resistance of the human intestinal microflora: testing the hypothesis in normal volunteers. Eur J Clin Microbiol Infect Dis, 7 (1) ( 1988), pp. 98-102
[117]
D. Zhou, Q. Pan, F. Shen, H.X. Cao, W.J. Ding, Y.W. Chen, et al. Total fecal microbiota transplantation alleviates high-fat diet-induced steatohepatitis in mice via beneficial regulation of gut microbiota. Sci Rep, 7 (1) ( 2017), p. 1529
[118]
W.W. Wang, Y. Zhang, X.B. Huang, N. You, L. Zheng, J. Li. Fecal microbiota transplantation prevents hepatic encephalopathy in rats with carbon tetrachloride-induced acute hepatic dysfunction. World J Gastroenterol, 23 (38) ( 2017), pp. 6983-6994
[119]
C.R. Kelly, C. Ihunnah, M. Fischer, A. Khoruts, C. Surawicz, A. Afzali, et al. Fecal microbiota transplant for treatment of Clostridium difficile infection in immunocompromised patients. Am J Gastroenterol, 109 (7) ( 2014), pp. 1065-1071
[120]
A.K. Singal, P. Guturu, B. Hmoud, Y.F. Kuo, H. Salameh, R.H. Wiesner. Evolving frequency and outcomes of liver transplantation based on etiology of liver disease. Transplantation, 95 (5) ( 2013), pp. 755-760
[121]
S. Ling, Q. Zhan, G. Jiang, Q. Shan, L. Yin, R. Wang, et al. E2F 7 promotes mammalian target of rapamycin inhibitor resistance in hepatocellular carcinoma after liver transplantation. Am J Transplant, 22 (10) ( 2022), pp. 2323-2336
[122]
Z.W. Wu, Z.X. Ling, H.F. Lu, J. Zuo, J.F. Sheng, S.S. Zheng, et al. Changes of gut bacteria and immune parameters in liver transplant recipients. Hepatobiliary Pancreat Dis Int, 11 (1) ( 2012), pp. 40-50
[123]
M.H. Yu, X.L. Yu, C.L. Chen, L.H. Gao, W.L. Mao, D. Yan, et al. The change of intestinal microecology in rats after orthotopic liver transplantation. Chin J Surg, 46 (15) ( 2008), pp. 1139-1142. Chinese
[124]
J.S. Bajaj, G. Kakiyama, I.J. Cox, H. Nittono, H. Takei, M. White, et al. Alterations in gut microbial function following liver transplant. Liver Transpl, 24 (6) ( 2018), pp. 752-761
[125]
H.C. Xing, L.J. Li, K.J. Xu, T. Shen, Y.B. Chen, J.F. Sheng, et al. Intestinal microflora in rats with ischemia/reperfusion liver injury. J Zhejiang Univ Sci B, 6 (1) ( 2005), pp. 14-21
[126]
J. Yu, Z. Liu, C. Li, Q. Wei, S. Zheng, K. Saeb-Parsy, et al. Regulatory T cell therapy following liver transplantation. Liver Transpl, 27 (2) ( 2021), pp. 264-280
[127]
J. Zhou, J. Chen, Q. Wei, K. Saeb-Parsy, X. Xu. The role of ischemia/reperfusion injury in early hepatic allograft dysfunction. Liver Transpl, 26 (8) ( 2020), pp. 1034-1048
[128]
M.M. Wegorzewska, R.W.P. Glowacki, S.A. Hsieh, D.L. Donermeyer, C.A. Hickey, S.C. Horvath, et al. Diet modulates colonic T cell responses by regulating the expression of a Bacteroides thetaiotaomicron antigen. Sci Immunol, 4(32):eaau9079 ( 2019)
[129]
S.J. Aujla, P.J. Dubin, J.K. Kolls. Th 17 cells and mucosal host defense. Semin Immunol, 19 (6) ( 2007), pp. 377-382
[130]
I.I. Ivanov, K. Atarashi, N. Manel, E.L. Brodie, T. Shima, U. Karaoz, et al. Induction of intestinal Th 17 cells by segmented filamentous bacteria. Cell, 139 (3) ( 2009), pp. 485-498
[131]
D. Paik, L. Yao, Y. Zhang, S. Bae, G.D. D’Agostino, M. Zhang, et al. Human gut bacteria produce ΤΗ17-modulating bile acid metabolites. Nature, 603 (7903) ( 2022), pp. 907-912
[132]
N. Corbitt, S. Kimura, K. Isse, S. Specht, L. Chedwick, B.R. Rosborough, et al. Gut bacteria drive Kupffer cell expansion via MAMP-mediated ICAM-1 induction on sinusoidal endothelium and influence preservation-reperfusion injury after orthotopic liver transplantation. Am J Pathol, 182 (1) ( 2013), pp. 180-191
[133]
G. Kolios, V. Valatas, E. Kouroumalis. Role of Kupffer cells in the pathogenesis of liver disease. World J Gastroenterol, 12 (46) ( 2006), pp. 7413-7420
[134]
K. Nakamura, S. Kageyama, T. Ito, H. Hirao, K. Kadono, A. Aziz, et al. Antibiotic pretreatment alleviates liver transplant damage in mice and humans. J Clin Invest, 129 (8) ( 2019), pp. 3420-3434
[135]
K. Atarashi, T. Tanoue, K. Oshima, W. Suda, Y. Nagano, H. Nishikawa, et al. Treg induction by a rationally selected mixture of Clostridia strains from the human microbiota. Nature, 500 (7461) ( 2013), pp. 232-236
[136]
S.J. Han, M. Kim, E. Novitsky, V. D’Agati, H.T. Lee. Intestinal TLR9 deficiency exacerbates hepatic IR injury via altered intestinal inflammation and short-chain fatty acid synthesis. FASEB J, 34 (9) ( 2020), pp. 12083-12099
[137]
A.W. Thomson, J. Vionnet, A. Sanchez-Fueyo. Understanding, predicting and achieving liver transplant tolerance: from bench to bedside. Nat Rev Gastroenterol Hepatol, 17 (12) ( 2020), pp. 719-739
[138]
S.N. Sehgal. Sirolimus: its discovery, biological properties, and mechanism of action. Transplant Proc, 35 (3 Suppl) ( 2003), pp. 7S-14S
[139]
Y. Han, L. Wu, Q. Ling, P. Wu, C. Zhang, L. Jia, et al. Intestinal dysbiosis correlates with sirolimus-induced metabolic disorders in mice. Transplantation, 105 (5) ( 2021), pp. 1017-1029
[140]
J. Tourret, B.P. Willing, S. Dion, J. MacPherson, E. Denamur, B.B. Finlay. Immunosuppressive treatment alters secretion of ileal antimicrobial peptides and gut microbiota, and favors subsequent colonization by uropathogenic Escherichia coli. Transplantation, 101 (1) ( 2017), pp. 74-82
[141]
J.C. Swarte, Y. Li, S. Hu, J.R. Bj?rk, R. Gacesa, A. Vich Vila, et al. Gut microbiome dysbiosis is associated with increased mortality after solid organ transplantation. Sci Transl Med, 14(660):eabn7566 ( 2022)
[142]
C.Z. Han, Q. Wei, M.F. Yang, L. Zhuang, X. Xu. The critical role of therapeutic plasma exchange in ABO-incompatible liver transplantation. Hepatobiliary Pancreat Dis Int, 21 (6) ( 2022), pp. 538-542
[143]
R.L. Wei, G.H. Fan, C.Z. Zhang, K.C. Chen, W.H. Zhang, C.B. Li, et al. Prognostic implication of early posttransplant hypercholesterolemia in liver transplantation for patients with hepatocellular carcinoma. Hepatobiliary Pancreat Dis Int, S1499- 3872 (22) ( 2022), p. 00123
[144]
S.N. Lichtman, J. Keku, R.L. Clark, J.H. Schwab, R.B. Sartor. Biliary tract disease in rats with experimental small bowel bacterial overgrowth. Hepatology, 13 (4) ( 1991), pp. 766-772
[145]
R. Little, E. Wine, B.M. Kamath, A.M. Griffiths, A. Ricciuto. Gut microbiome in primary sclerosing cholangitis: a review. World J Gastroenterol, 26 (21) ( 2020), pp. 2768-2780
[146]
S. Lemoinne, A. Kemgang, K. Ben Belkacem, M. Straube, S. Jegou, C. Corpechot, et al. Fungi participate in the dysbiosis of gut microbiota in patients with primary sclerosing cholangitis. Gut, 69 (1) ( 2020), pp. 92-102
[147]
R. Tang, Y. Wei, Y. Li, W. Chen, H. Chen, Q. Wang, et al. Gut microbial profile is altered in primary biliary cholangitis and partially restored after UDCA therapy. Gut, 67 (3) ( 2018), pp. 534-541
[148]
Y. Li, R. Tang, P.S.C. Leung, M.E. Gershwin, X. Ma. Bile acids and intestinal microbiota in autoimmune cholestatic liver diseases. Autoimmun Rev, 16 (9) ( 2017), pp. 885-896
[149]
A. Isaacs-Ten, M. Echeandia, M. Moreno-Gonzalez, A. Brion, A. Goldson, M. Philo, et al. Intestinal microbiome-macrophage crosstalk contributes to cholestatic liver disease by promoting intestinal permeability in mice. Hepatology, 72 (6) ( 2020), pp. 2090-2108
[150]
J.H. Tabibian, S.P. O’Hara, C.E. Trussoni, P.S. Tietz, P.L. Splinter, T. Mounajjed, et al. Absence of the intestinal microbiota exacerbates hepatobiliary disease in a murine model of primary sclerosing cholangitis. Hepatology, 63 (1) ( 2016), pp. 185-196
[151]
Y.C. Kim, S.J. Lee. Temporal variation in hepatotoxicity and metabolism of acetaminophen in mice. Toxicology, 128 (1) ( 1998), pp. 53-61
[152]
C.A. Thaiss, D. Zeevi, M. Levy, G. Zilberman-Schapira, J. Suez, A.C. Tengeler, et al. Transkingdom control of microbiota diurnal oscillations promotes metabolic homeostasis. Cell, 159 (3) ( 2014), pp. 514-529
[153]
S. Gong, T. Lan, L. Zeng, H. Luo, X. Yang, N. Li, et al. Gut microbiota mediates diurnal variation of acetaminophen induced acute liver injury in mice. J Hepatol, 69 (1) ( 2018), pp. 51-59
[154]
Y. Li, L. Lv, J. Ye, D. Fang, D. Shi, W. Wu, et al. Bifidobacterium adolescentis CGMCC 15058 alleviates liver injury, enhances the intestinal barrier and modifies the gut microbiota in D-galactosamine-treated rats. Appl Microbiol Biotechnol, 103 (1) ( 2019), pp. 375-393
[155]
K. Wang, L. Lv, R. Yan, Q. Wang, H. Jiang, W. Wu, et al. Bifidobacterium longum R0175 protects rats against D-galactosamine-induced acute liver failure. MSphere, 5 (1) ( 2020)
[156]
L. Yu, X.K. Zhao, M.L. Cheng, G.Z. Yang, B. Wang, H.J. Liu, et al. Saccharomyces boulardii administration changes gut microbiota and attenuates D-galactosamine-induced liver injury. Sci Rep, 7 (1) ( 2017), p. 1359
[157]
J.S. Bajaj, H.E. Vargas, K.R. Reddy, J.C. Lai, J.G. O’Leary, P. Tandon, et al. Association between intestinal microbiota collected at hospital admission and outcomes of patients with cirrhosis. Clin Gastroenterol Hepatol, 17 (4) ( 2019). 756-65.e3
[158]
Y. Chen, J. Guo, G. Qian, D. Fang, D. Shi, L. Guo, et al. Gut dysbiosis in acute-on-chronic liver failure and its predictive value for mortality. J Gastroenterol Hepatol, 30 (9) ( 2015), pp. 1429-1437
[159]
R. Moreau, J. Clària, F. Aguilar, F. Fenaille, J.J. Lozano, C. Junot, et al. the CANONIC Study Investigators of the EASL Clif Consortium, the Grifols Chair, and the European Foundation for the Study of Chronic Liver Failure (EF Clif). Blood metabolomics uncovers inflammation-associated mitochondrial dysfunction as a potential mechanism underlying ACLF. J Hepatol, 72 (4) ( 2020), pp. 688-701
[160]
R. Moreau, R. Jalan, P. Gines, M. Pavesi, P. Angeli, J. Cordoba, et al. Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis. Gastroenterology, 144 (7) ( 2013), pp. 1426-1437. 1437.e1-9
[161]
S.J. Ott, N.E. El Mokhtari, M. Musfeldt, S. Hellmig, S. Freitag, A. Rehman, et al. Detection of diverse bacterial signatures in atherosclerotic lesions of patients with coronary heart disease. Circulation, 113 (7) ( 2006), pp. 929-937
[162]
S. Mitra, D.I. Drautz-Moses, M. Alhede, M.T. Maw, Y. Liu, R.W. Purbojati, et al. In silico analyses of metagenomes from human atherosclerotic plaque samples. Microbiome, 3 (1) ( 2015), p. 38
[163]
B.J. Bennett, T.Q. de Aguiar Vallim, Z. Wang, D.M. Shih, Y. Meng, J. Gregory, et al. Trimethylamine-N-oxide, a metabolite associated with atherosclerosis, exhibits complex genetic and dietary regulation. Cell Metab, 17 (1) ( 2013), pp. 49-60
[164]
R. Carnevale, C. Nocella, V. Petrozza, V. Cammisotto, L. Pacini, V. Sorrentino, et al. Localization of lipopolysaccharide from Escherichia coli into human atherosclerotic plaque. Sci Rep, 8 (1) ( 2018), p. 3598
[165]
W. Zhu, J.C. Gregory, E. Org, J.A. Buffa, N. Gupta, Z. Wang, et al. Gut microbial metabolite TMAO enhances platelet hyperreactivity and thrombosis risk. Cell, 165 (1) ( 2016), pp. 111-124
[166]
D. Duerschmied, M. Canault, D. Lievens, A. Brill, S.M. Cifuni, M. Bader, et al. Serotonin stimulates platelet receptor shedding by tumor necrosis factor-alpha-converting enzyme (ADAM17). J Thromb Haemost, 7 (7) ( 2009), pp. 1163-1171
[167]
S. J?ckel, K. Kiouptsi, M. Lillich, T. Hendrikx, A. Khandagale, B. Kollar, et al. Gut microbiota regulate hepatic von Willebrand factor synthesis and arterial thrombus formation via Toll-like receptor-2. Blood, 130 (4) ( 2017), pp. 542-553
[168]
J. Li, S. Lin, P.M. Vanhoutte, C.W. Woo, A. Xu. Akkermansia muciniphila protects against atherosclerosis by preventing metabolic endotoxemia-induced inflammation in Apoe-/- mice. Circulation, 133 (24) ( 2016), pp. 2434-2446
[169]
H. Wu, Y. Wang, Y. Zhang, F. Xu, J. Chen, L. Duan, et al. Breaking the vicious loop between inflammation, oxidative stress and coagulation, a novel anti-thrombus insight of nattokinase by inhibiting LPS-induced inflammation and oxidative stress. Redox Biol, 32 ( 2020), Article 101500
[170]
O.P. Mathew, K. Ranganna, S.G. Milton. Involvement of the antioxidant effect and anti-inflammatory response in butyrate-inhibited vascular smooth muscle cell proliferation. Pharmaceuticals, 7 (11) ( 2014), pp. 1008-1027
[171]
G. Kochhar, J.M. Parungao, I.A. Hanouneh, M.A. Parsi. Biliary complications following liver transplantation. World J Gastroenterol, 19 (19) ( 2013), pp. 2841-2846
[172]
J. Trebicka, P. Bork, A. Krag, M. Arumugam. Utilizing the gut microbiome in decompensated cirrhosis and acute-on-chronic liver failure. Nat Rev Gastroenterol Hepatol, 18 (3) ( 2021), pp. 167-180
[173]
F. Yang, H. Chen, Y. Gao, N. An, X. Li, X. Pan, et al. Gut microbiota-derived short-chain fatty acids and hypertension: mechanism and treatment. Biomed Pharmacother, 130 ( 2020), Article 110503
[174]
M. Tr?seid, G.?. Andersen, K. Broch, J.R. Hov. The gut microbiome in coronary artery disease and heart failure: current knowledge and future directions. EBioMedicine, 52 ( 2020), Article 102649
[175]
O.E. Kadri, M. Surblyte, V.D. Chandran, R.S. Voronov. Is the endothelial cell responsible for the thrombus core and shell architecture?. Med Hypotheses, 129 ( 2019), Article 109244
[176]
C.T. Esmon. The interactions between inflammation and coagulation. Br J Haematol, 131 (4) ( 2005), pp. 417-430.

This research gained support from the National Key Research and Development Program of China (2021YFA1100500), the Major Research Plan of the National Natural Science Foundation of China (92159202), the National Natural Science Foundation of China (82272396 and 81930016), the Key Research & Development Plan of Zhejiang Province (2019C03050), and the Construction Fund of Key Medical Disciplines of Hangzhou (OO20200093).

Funding
the National Key Research and Development Program of China(2021YFA1100500); the Major Research Plan of the National Natural Science Foundation of China(92159202); the National Natural Science Foundation of China(82272396); the National Natural Science Foundation of China(81930016); the Key Research & Development Plan of Zhejiang Province(2019C03050); the Construction Fund of Key Medical Disciplines of Hangzhou(OO20200093)
AI Summary AI Mindmap
PDF(1338 KB)

Accesses

Citations

Detail

Sections
Recommended

/