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Cited by 104Gut microbiota and healthLiver Disease Diagnosis and TreatmentLiver Diseases and Immunity

Disulfiram ameliorates nonalcoholic steatohepatitis by modulating the gut microbiota and bile acid metabolism

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Lei, Yuanyuan, Tang, Li, Chen, Qiao, Wu, Lingyi, He, Wei, Tu, Dianji, Wang, Sumin, Chen, Yuyang +5 more·2022·Nature Communications
DOI 10.1038/s41467-022-34671-1PMC PMC9651870
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Abstract

Nonalcoholic steatohepatitis (NASH) has been linked with the gut-liver axis. Here, we investigate the potential for repurposing disulfiram (DSF), a drug commonly used to treat chronic alcoholism, for NASH. Using a mouse model, we show that DSF ameliorates NASH in a gut microbiota-dependent manner. DSF modulates the gut microbiota and directly inhibits the growth of Clostridium. Administration of Clostridium abolishes the ameliorating effects of DSF on NASH. Mechanistically, DSF reduces Clostridium-mediated 7α-dehydroxylation activity to suppress secondary bile acid biosynthesis, which in turn activates hepatic farnesoid X receptor signaling to ameliorate NASH. To assess the effect of DSF on human gut microbiota, we performed a self-controlled clinical trial (ChiCTR2100048035), including 23 healthy volunteers who received 250 mg-qd DSF for 7 days. The primary objective outcomes were to assess the effects of the intervention on the diversity, composition and functional profile of gut microbiota. The pilot study shows that DSF also reduces Clostridium-mediated 7α-dehydroxylation activity. All volunteers tolerated DSF well and there were no serious adverse events in the 7-day follow-up period. Transferring fecal microbiota obtained from DSF-treated humans into germ-free mice ameliorates NASH. Collectively, the observations of similar ameliorating effects of DSF on mice and humans suggest that DSF ameliorates NASH by modulating the gut microbiota and bile acid metabolism.

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References 68 · Cited by 104

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  1. [1]Lazarus JV Advancing the global public health agenda for NAFLD: a consensus statement Nat. Rev. Gastroenterol. Hepatol. 2022 19 60 78 34707258
  2. [3]Vuppalanchi R Noureddin M Alkhouri N Sanyal AJ Therapeutic pipeline in nonalcoholic steatohepatitis Nat. Rev. Gastroenterol. Hepatol. 2021 18 373 392 33568794
  3. [4]Sheka AC Nonalcoholic steatohepatitis: a review JAMA 2020 323 1175 1183 32207804
  4. [6]Petroni ML Brodosi L Bugianesi E Marchesini G Management of non-alcoholic fatty liver disease BMJ 2021 372 m4747 33461969
  5. [8]Pan M Seesaw conformations of Npl4 in the human p97 complex and the inhibitory mechanism of a disulfiram derivative Nat. Commun. 2021 12 121 33402676 PMC7785736
  6. [9]Terashima Y Targeting FROUNT with disulfiram suppresses macrophage accumulation and its tumor-promoting properties Nat. Commun. 2020 11 609 32001710 PMC6992764
  7. [10]Shirley D-A Sharma I Warren CA Moonah S Drug repurposing of the alcohol abuse medication disulfiram as an anti-parasitic agent Front Cell Infect. Microbiol 2021 11 633194 33777846 PMC7991622
  8. [11]Lee YM Using an old drug to target a new drug site: application of disulfiram to target the Zn-site in HCV NS5A protein J. Am. Chem. Soc. 2016 138 3856 3862 26928525
  9. [13]Tamburin S COVID-19 and related symptoms in patients under disulfiram for alcohol use disorder Intern Emerg. Med. 2021 16 1729 1731 33464469 PMC7814518
  10. [14]Elliott JH Short-term administration of disulfiram for reversal of latent HIV infection: a phase 2 dose-escalation study Lancet HIV 2015 2 e520 e529 26614966 PMC5108570
  11. [16]Liu T Diethyldithiocarbamate, an anti-abuse drug, alleviates steatohepatitis and fibrosis in rodents through modulating lipid metabolism and oxidative stress Br. J. Pharm. 2018 175 4480 4495 PMC6255958 30266038
  12. [17]Schwartz JJ Amelioration of hepatic inflammation in a mouse model of NASH using a dithiocarbamate derivative Hepatol. Int 2013 7 600 609 26201793
  13. [19]Sharpton SR Schnabl B Knight R Loomba R Current concepts, opportunities, and challenges of gut microbiome-based personalized medicine in nonalcoholic fatty liver disease Cell Metab. 2021 33 21 32 33296678 PMC8414992
  14. [20]Zhou HJ He KJ Chen J Zhang XY LinDA: linear models for differential abundance analysis of microbiome compositional data Genome Biol. 2022 23 95 35421994 PMC9012043
  15. [21]Segata N Metagenomic biomarker discovery and explanation Genome Biol. 2011 12 R60 21702898 PMC3218848
  16. [22]Ma C Gut microbiome-mediated bile acid metabolism regulates liver cancer via NKT cells Science 2018 360 eaan5931 29798856 PMC6407885
  17. [23]The Gene Ontology Consortium. The Gene Ontology Oesource: 20 years and still GOing strong Nucleic Acids Res. 2018 47 D330 D338 PMC6323945 30395331
  18. [24]Krautkramer KA Fan J Bäckhed F Gut microbial metabolites as multi-kingdom intermediates Nat. Rev. Microbiol. 2020 19 77 94 32968241
  19. [25]Ridlon JM The ‘in vivo lifestyle’ of bile acid 7alpha-dehydroxylating bacteria: comparative genomics, metatranscriptomic, and bile acid metabolomics analysis of a defined microbial community in gnotobiotic mice Gut Microbes 2020 11 381 404 31177942 PMC7524365
  20. [26]Sun L Cai J Gonzalez FJ The role of farnesoid X receptor in metabolic diseases, and gastrointestinal and liver cancer Nat. Rev. Gastroenterol. Hepatol. 2021 18 335 347 33568795
  21. [27]Kolodziejczyk AA Zheng D Shibolet O Elinav E The role of the microbiome in NAFLD and NASH EMBO Mol. Med. 2019 11 e9302 30591521 PMC6365925
  22. [28]Tripathi A The gut–liver axis and the intersection with the microbiome Nat. Rev. Gastroenterol. Hepatol. 2018 15 397 411 29748586 PMC6319369
  23. [29]Arrieta MC Walter J Finlay BB Human microbiota-associated mice: a model with challenges Cell Host Microbe 2016 19 575 578 27173924
  24. [30]Hu H Intestinal microbiota regulates anti-tumor effect of disulfiram combined with Cu(2+) in a mice model Cancer Med. 2020 9 6791 6801 32750218 PMC7520343
  25. [31]Rom O Glycine-based treatment ameliorates NAFLD by modulating fatty acid oxidation, glutathione synthesis, and the gut microbiome Sci. Transl. Med. 2020 12 eaaz2841 33268508 PMC7982985
  26. [32]Matsumoto K Fructo-oligosaccharides and intestinal barrier function in a methionine-choline-deficient mouse model of nonalcoholic steatohepatitis PloS one 2017 12 e0175406 28632732 PMC5478096
  27. [33]Qin N Alterations of the human gut microbiome in liver cirrhosis Nature 2014 513 59 64 25079328
  28. [34]Li CC Tomato powder inhibits hepatic steatosis and inflammation potentially through restoring SIRT1 activity and adiponectin function independent of carotenoid cleavage enzymes in mice Mol. Nutr. Food Res. 2018 62 e1700738 29266812
  29. [35]Bomhof MR Histological improvement of non-alcoholic steatohepatitis with a prebiotic: a pilot clinical trial Eur. J. Nutr. 2019 58 1735 1745 29779170
  30. [36]Horita Y Antitubercular activity of disulfiram, an antialcoholism drug, against multidrug- and extensively drug-resistant Mycobacterium tuberculosis isolates Antimicrob. Agents Chemother. 2012 56 4140 4145 22615274 PMC3421551
  31. [37]Hamblin KA Disulfiram, an alcohol dependence therapy, can inhibit the in vitro growth of Francisella tularensis Int J. Antimicrob. Agents 2019 54 85 88 31029736
  32. [39]Kobatake T Antibacterial effects of disulfiram in Helicobacter pylori Infect. Drug Resist 2021 14 1757 1764 34012274 PMC8126873
  33. [40]Stokes JM Lopatkin AJ Lobritz MA Collins JJ Bacterial metabolism and antibiotic efficacy Cell Metab. 2019 30 251 259 31279676 PMC6990394
  34. [41]Foti James J Devadoss B Winkler Jonathan A Collins James J Walker Graham C Oxidation of the guanine nucleotide pool underlies cell death by bactericidal antibiotics Science 2012 336 315 319 22517853 PMC3357493
  35. [42]Lei Y Parabacteroides produces acetate to alleviate heparanase-exacerbated acute pancreatitis through reducing neutrophil infiltration Microbiome 2021 9 115 34016163 PMC8138927
  36. [44]Ridlon JM Alves JM Hylemon PB Bajaj JS Cirrhosis, bile acids and gut microbiota: unraveling a complex relationship Gut Microbes 2013 4 382 387 23851335 PMC3839982
  37. [46]Schmitt J Protective effects of farnesoid X receptor (FXR) on hepatic lipid accumulation are mediated by hepatic FXR and independent of intestinal FGF15 signal Liver Int. 2015 35 1133 1144 25156247 PMC4146754
  38. [48]Neuschwander-Tetri BA Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial Lancet 2015 385 956 965 25468160 PMC4447192
  39. [49]Harrison SA Efficacy and safety of aldafermin, an engineered FGF19 analog, in a randomized, double-blind, placebo-controlled trial of patients with nonalcoholic steatohepatitis Gastroenterology 2021 160 219 231.e211 32781086
  40. [50]Loomba R GS-0976 reduces hepatic steatosis and fibrosis markers in patients with nonalcoholic fatty liver disease Gastroenterology 2018 155 1463 1473.e1466 30059671 PMC6318218
  41. [51]Kitahara M Sakamoto M Benno Y PCR detection method of Clostridium scindens and C. hiranonis in human fecal samples Microbiol Immunol. 2001 45 263 266 11345537
  42. [53]Bolyen E Reproducible, interactive, scalable and extensible microbiome data science using QIIME 2 Nat. Biotechnol. 2019 37 852 857 31341288 PMC7015180
  43. [54]Callahan BJ DADA2: High-resolution sample inference from Illumina amplicon data Nat. Methods 2016 13 581 583 27214047 PMC4927377
  44. [55]Quast C The SILVA ribosomal RNA gene database project: improved data processing and web-based tools Nucleic Acids Res. 2013 41 D590 D596 23193283 PMC3531112
  45. [56]Parks DH Tyson GW Hugenholtz P Beiko RG STAMP: statistical analysis of taxonomic and functional profiles Bioinformatics 2014 30 3123 3124 25061070 PMC4609014
  46. [58]Langmead B Salzberg SL Fast gapped-read alignment with Bowtie 2 Nat. Methods 2012 9 357 359 22388286 PMC3322381
  47. [59]Bolger AM Lohse M Usadel B Trimmomatic: a flexible trimmer for Illumina sequence data Bioinformatics 2014 30 2114 2120 24695404 PMC4103590
  48. [60]Wood DE Lu J Langmead B Improved metagenomic analysis with Kraken 2 Genome Biol. 2019 20 257 31779668 PMC6883579
  49. [61]Lu J Breitwieser FP Thielen P Salzberg SL Bracken: estimating species abundance in metagenomics data PeerJ Comput. Sci. 2017 3 e104 PMC12016282 40271438
  50. [63]Buchfink B Xie C Huson DH Fast and sensitive protein alignment using DIAMOND Nat. Methods 2015 12 59 60 25402007
  51. [64]Suzek BE Wang Y Huang H McGarvey PB Wu CH Consortium tU. UniRef clusters: a comprehensive and scalable alternative for improving sequence similarity searches Bioinformatics 2014 31 926 932 25398609 PMC4375400
  52. [65]Huang F Theabrownin from Pu-erh tea attenuates hypercholesterolemia via modulation of gut microbiota and bile acid metabolism Nat. Commun. 2019 10 4971 31672964 PMC6823360
  53. [66]Lei Y Disulfiram ameliorates nonalcoholic steatohepatitis by modulating the gut microbiota and bile acid metabolism Zenodo 2022 10.5281/zenodo.7247972 PMC9651870 36369291 · DOI

Authors
Lei, Y., Tang, L., Chen, Q., Wu, L., He, W., Tu, D., Wang, S., Chen, Y., Liu, S., Xie, Z., Wei, H., Yang, S., & Tang, B.
Affiliations
Army Medical University (CN)
Corresponding author
  • Wei, Hong
  • Yang, Shiming
  • Tang, Bo
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2022-11-11
Volume
13
Issue
1
Pages
6862-6862
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-022-34671-1
PMC
PMC9651870
OpenAlex
W4309046772
Cited by
104
References
68
Citations by year
2026: 23 · 2025: 25 · 2024: 39 · 2023: 16 · 2022: 1
FWCI
7.51
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Natural Science Foundation of China (NSFC)
  • the Key Project of National Natural Science Foundation of China (NSFC)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
  • Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
  • Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
Keywords
disulfiram, nonalcoholic steatohepatitis, gut microbiota, bile acid metabolism, 7α-dehydroxylation, Clostridium, farnesoid X receptor, gut-liver axis, drug repurposing, fecal microbiota transplantation, germ-free mice, human gut microbiome
MeSH terms
Gastrointestinal Microbiome, Bile Acids and Salts, Clostridium, Disulfiram, Humans, Liver, Pilot Projects, Non-alcoholic Fatty Liver Disease

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