Introduction
Recent research has revealed a close association between drug-induced liver injury (DILI) and gut microbiota. However, the specific mechanisms of gut microbiota involvement in DILI remain unclear. This review examines how gut microbiota interacts with common hepatotoxic drugs and its potential role in DILI pathogenesis, offering a comprehensive reference for the interplay between DILI and gut microbiota.
Drug-Induced Liver Injury
Drug-induced liver injury refers to liver damage caused by chemicals, biologics, proprietary medicines, and other drugs, including over-the-counter products, herbal medicines, and dietary supplements. In the past, viral hepatitis was the leading cause of acute liver failure in the United States, but now DILI is the primary cause. At least 1000 drugs have been reported to cause liver injury, with detailed information available on LiverTox and Hepatox websites. The drugs responsible for DILI vary by country due to differences in disease epidemiology, prescribing habits, and population heterogeneity.
Mechanisms of Gut Microbiota–Mediated Drug-Induced Liver Injury
Gut microbiota dysregulation is widely recognized as playing a key role in the development of DILI. The main mechanisms explored include the involvement of lipopolysaccharide (LPS) based on the leaky gut hypothesis, influencing intestinal metabolite homeostasis, directly affecting drug metabolism, and promoting inflammation or oxidative stress.
Gut Microbiota Participation in Drug-Induced Liver Injury Through LPS
The LPS pathway, based on the «leaky gut» hypothesis, is a significant mechanism by which gut microbiota is involved in DILI. Studies have shown that gut microbiota homeostasis is altered in mice given triclosan, leading to increased hepatic inflammatory cytokines, disruption of the intestinal barrier, and high levels of intestinal-derived LPS detected in serum. This pathway disrupts gut microbiota homeostasis, increases intestinal inflammation and permeability, and leads to liver injury.
Gut Microbiota: Intestinal Metabolites and Drug-Induced Liver Injury
Drug-induced liver injury is considered to result from a combination of variable host and nonhost risk factors, which may act by influencing the composition and metabolites of gut microbiota. Numerous studies have indicated that reductions in the abundance of gut microbiota species and genes play a driving role in individual susceptibility to DILI. Microbiota-rich genes encode various enzymes that influence drug metabolism and increase the likelihood of liver injury.
Bile Acid Metabolism
Studies have shown that abnormal bile acid (BA) metabolism is closely related to DILI. BAs are generated in the liver and converted by gut microbiota to secondary BAs. Approximately 95% of BAs in the intestine can be reabsorbed back to the liver, causing significant changes in BA metabolism when gut microbiota homeostasis is imbalanced. Alterations in the BA metabolic pathway can also cause gut microbiota disorders, contributing to DILI.
Lipid Metabolism
Lipid metabolism interacts with gut microbiota, affecting the composition and function of gut microbiota. The liver plays a crucial role in lipid metabolism, and aberrant lipid metabolism is strongly associated with hepatocyte mitochondrial dysfunction. Studies have shown that abnormalities in gut microbiota and lipid metabolism play a pivotal role in the hepatotoxicity process induced by certain drugs.
Common Liver Injury–Causing Drugs Linked to Gut Microbiota
Antibiotics
Antibiotics are a significant public health concern due to their association with DILI. Recent reports indicate that antibiotics are the primary causative agent of DILI in patients with novel coronavirus pneumonia. Antibiotic use can affect gut microbiota, inducing liver injury. However, antibiotics can also protect against DILI by ameliorating liver inflammation through gut microbiota depletion.
Psychotropic Drugs
Psychotropic drugs, including antidepressants and antiepileptics, carry a risk of hepatotoxicity. Studies have shown that antidepressants and antiepileptics can alter gut microbiota, contributing to DILI. The bidirectional relationship between psychotropic drugs and gut microbiota highlights the need for further research to elucidate specific mechanisms.
Acetaminophen
Acetaminophen is a common antipyretic and analgesic medication, but excessive consumption can result in significant hepatotoxicity. Studies have shown that gut microbiota plays a role in acetaminophen-induced hepatic injury by producing metabolites that compete for glutathione, leading to severe acute liver injury.
Antituberculosis Drugs
Antituberculosis drugs, such as isoniazid, ethambutol, pyrazinamide, and rifampin, can induce liver injury. Research indicates that gut microbiota can impact drug metabolism, influencing drug efficacy and toxicity. Studies have shown that antituberculosis drugs can perturb gut microbiota balance, contributing to DILI.
Antithyroid Drugs
Antithyroid drugs, such as methimazole and propylthiouracil, are associated with DILI. Studies have shown that antithyroid drugs can induce changes in gut microbiota structure, leading to liver injury. The correlation between gut microbiota dysregulation, intestinal barrier disruption, increased LPS, and liver injury highlights the need for further research.
Discussion and Future Directions
Drug-induced liver injury is a prevalent adverse drug reaction that poses significant challenges to patient treatment and the development of new medications. Recent research indicates that gut microbiota plays a significant role in DILI pathogenesis. However, comprehensive research into the mechanisms of gut microbiota involvement in DILI is lacking, and there are no targeted approaches for DILI prevention and treatment. Future research should focus on elucidating the relationship between gut microbiota and DILI to develop novel hepatoprotective drugs targeting gut microbiota.
Conclusion
Gut microbiota is a promising target for the prevention and treatment of drug-induced liver injury. Maintaining gut microbiota homeostasis is crucial in the pathogenesis of DILI. Future research should focus on developing specific drugs targeting gut microbiota to prevent and treat DILI, promoting the advancement of medical science.
References
1. Li X, Tang J, Mao Y. Incidence and risk factors of drug-induced liver injury. Liver Int 2022;42:1999–2014.
2. Shen T, Liu Y, Shang J, et al. Incidence and etiology of drug-induced liver injury in mainland China. Gastroenterology 2019;156:2230–2241.e11.
3. Vega M, Verma M, Beswick D, et al. The incidence of drug- and herbal and dietary supplement-induced liver injury: preliminary findings from gastroenterologist-based surveillance in the population of the state of Delaware. Drug Saf 2017;40:783–787.
Authors: Guolin Li, Yifu Hou, Changji Zhang, Xiaoshi Zhou, Furong Bao, Yong Yang, Lu Chen, Dongke Yu