Idiosyncratic Drug-Induced Liver Injury and Amoxicillin-Clavulanate: Spotlight on Gut Microbiota, Fecal Metabolome and Bile Acid Profile in Patients

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2024 Jul 13

PMID 38999973

Authors

Sara Roman-Saguillo

Raisa Quinones Castro

Maria Juarez-Fernandez

Polina Soluyanova

Camilla Stephens

Mercedes Robles-Diaz

Francisco Jorquera Plaza

Javier Gonzalez-Gallego

Susana Martinez-Florez

Maria Victoria Garcia-Mediavilla

Esther Nistal

Ramiro Jover

Sonia Sanchez-Campos

Affiliations

Soon will be listed here.

Abstract

Several hepatic disorders are influenced by gut microbiota, but its role in idiosyncratic drug-induced liver injury (iDILI), whose main causative agent is amoxicillin-clavulanate, remains unknown. This pioneering study aims to unravel particular patterns of gut microbiota composition and associated metabolites in iDILI and iDILI patients by amoxicillin-clavulanate (iDILI-AC). Thus, serum and fecal samples from 46 patients were divided into three study groups: healthy controls (n = 10), non-iDILI acute hepatitis (n = 12) and iDILI patients (n = 24). To evaluate the amoxicillin-clavulanate effect, iDILI patients were separated into two subgroups: iDILI non-caused by amoxicillin-clavulanate (iDILI-nonAC) (n = 18) and iDILI-AC patients (n = 6). Gut microbiota composition and fecal metabolome plus serum and fecal bile acid (BA) analyses were performed, along with correlation analyses. iDILI patients presented a particular microbiome profile associated with reduced fecal secondary BAs and fecal metabolites linked to lower inflammation, such as dodecanedioic acid and pyridoxamine. Moreover, certain taxa like , and spp. correlated with significant metabolites and BAs. Additionally, comparisons between iDILI-nonAC and iDILI-AC groups unraveled unique features associated with iDILI when caused by amoxicillin-clavulanate. In conclusion, specific gut microbiota profiles in iDILI and iDILI-AC patients were associated with particular metabolic and BA status, which could affect disease onset and progression.

References

Sinha S, Haileselassie Y, Nguyen L, Tropini C, Wang M, Becker L . Dysbiosis-Induced Secondary Bile Acid Deficiency Promotes Intestinal Inflammation. Cell Host Microbe. 2020; 27(4):659-670.e5. PMC: 8172352. DOI: 10.1016/j.chom.2020.01.021. View

Mao B, Guo W, Liu X, Cui S, Zhang Q, Zhao J . Potential Probiotic Properties of Blautia producta Against Lipopolysaccharide-Induced Acute Liver Injury. Probiotics Antimicrob Proteins. 2023; 15(3):785-796. DOI: 10.1007/s12602-023-10044-y. View

Fu L, Qian Y, Shang Z, Sun X, Kong X, Gao Y . Antibiotics enhancing drug-induced liver injury assessed for causality using Roussel Uclaf Causality Assessment Method: Emerging role of gut microbiota dysbiosis. Front Med (Lausanne). 2022; 9:972518. PMC: 9500153. DOI: 10.3389/fmed.2022.972518. View

Nistal E, Saenz de Miera L, Pomar M, Sanchez-Campos S, Garcia-Mediavilla M, Alvarez-Cuenllas B . An altered fecal microbiota profile in patients with non-alcoholic fatty liver disease (NAFLD) associated with obesity. Rev Esp Enferm Dig. 2019; 111(4):275-282. DOI: 10.17235/reed.2019.6068/2018. View

Ferreira I, Gouveia C, Vasques Sr C, Faria C, Pedroso A . Drug-Induced Liver Injury Caused by Amoxicillin/Clavulanate. Cureus. 2021; 12(12):e12234. PMC: 7819498. DOI: 10.7759/cureus.12234. View

. EASL Clinical Practice Guidelines: Drug-induced liver injury. J Hepatol. 2019; 70(6):1222-1261. DOI: 10.1016/j.jhep.2019.02.014. View

Smith L, Ignacio J, Winesett M, Kaiser G, Lacson A, Gilbert-Barness E . Vanishing bile duct syndrome: amoxicillin-clavulanic acid associated intra-hepatic cholestasis responsive to ursodeoxycholic acid. J Pediatr Gastroenterol Nutr. 2005; 41(4):469-73. DOI: 10.1097/01.mpg.0000178086.44155.73. View

Porras D, Nistal E, Martinez-Florez S, Olcoz J, Jover R, Jorquera F . Functional Interactions between Gut Microbiota Transplantation, Quercetin, and High-Fat Diet Determine Non-Alcoholic Fatty Liver Disease Development in Germ-Free Mice. Mol Nutr Food Res. 2019; 63(8):e1800930. DOI: 10.1002/mnfr.201800930. View

Khan H, Aamir K, Jusuf P, Sethi G, Sisinthy S, Ghildyal R . Lauric acid ameliorates lipopolysaccharide (LPS)-induced liver inflammation by mediating TLR4/MyD88 pathway in Sprague Dawley (SD) rats. Life Sci. 2020; 265:118750. DOI: 10.1016/j.lfs.2020.118750. View

10.

Dang J, Mocanu V, Park H, Laffin M, Hotte N, Karmali S . Roux-en-Y gastric bypass and sleeve gastrectomy induce substantial and persistent changes in microbial communities and metabolic pathways. Gut Microbes. 2022; 14(1):2050636. PMC: 8942407. DOI: 10.1080/19490976.2022.2050636. View

11.

Abu Shanab A, Scully P, Crosbie O, Buckley M, OMahony L, Shanahan F . Small intestinal bacterial overgrowth in nonalcoholic steatohepatitis: association with toll-like receptor 4 expression and plasma levels of interleukin 8. Dig Dis Sci. 2010; 56(5):1524-34. DOI: 10.1007/s10620-010-1447-3. View

12.

Winston J, Theriot C . Diversification of host bile acids by members of the gut microbiota. Gut Microbes. 2019; 11(2):158-171. PMC: 7053883. DOI: 10.1080/19490976.2019.1674124. View

13.

Andrade R, Chalasani N, Bjornsson E, Suzuki A, Kullak-Ublick G, Watkins P . Drug-induced liver injury. Nat Rev Dis Primers. 2019; 5(1):58. DOI: 10.1038/s41572-019-0105-0. View

14.

Huang L, Zheng J, Sun G, Yang H, Sun X, Yao X . 5-Aminosalicylic acid ameliorates dextran sulfate sodium-induced colitis in mice by modulating gut microbiota and bile acid metabolism. Cell Mol Life Sci. 2022; 79(8):460. PMC: 11071811. DOI: 10.1007/s00018-022-04471-3. View

15.

Philips C, Augustine P, Ganesan K, Ranade S, Chopra V, Patil K . The role of gut microbiota in clinical complications, disease severity, and treatment response in severe alcoholic hepatitis. Indian J Gastroenterol. 2022; 41(1):37-51. DOI: 10.1007/s12664-021-01157-9. View

16.

Chu H, Ai Y, Cheng Z, Yang L, Hou X . Contribution of gut microbiota to drug-induced liver injury. Hepatobiliary Pancreat Dis Int. 2023; 22(5):458-465. DOI: 10.1016/j.hbpd.2023.06.008. View

17.

Park M, DAlecy L, Anderson M, Basrur V, Feng Y, Brady G . Constitutive release of CPS1 in bile and its role as a protective cytokine during acute liver injury. Proc Natl Acad Sci U S A. 2019; 116(18):9125-9134. PMC: 6500125. DOI: 10.1073/pnas.1822173116. View

18.

Petrov P, Soluyanova P, Sanchez-Campos S, Castell J, Jover R . Molecular mechanisms of hepatotoxic cholestasis by clavulanic acid: Role of NRF2 and FXR pathways. Food Chem Toxicol. 2021; 158:112664. DOI: 10.1016/j.fct.2021.112664. View

19.

Wang B, Wu G, Zhou Z, Dai Z, Sun Y, Ji Y . Glutamine and intestinal barrier function. Amino Acids. 2014; 47(10):2143-54. DOI: 10.1007/s00726-014-1773-4. View

20.

Wu G, Win S, Than T, Chen P, Kaplowitz N . Gut Microbiota and Liver Injury (I)-Acute Liver Injury. Adv Exp Med Biol. 2020; 1238:23-37. DOI: 10.1007/978-981-15-2385-4_3. View