Gut Microbiota and Drug-Induced Liver Injury: An Update
The gut microbiota, composed of trillions of microorganisms, plays a crucial role in maintaining host health. While most of these microorganisms are non-pathogenic and contribute to the host’s immune defense, an imbalance in the bacterial community can lead to various diseases, including fatty liver, metabolic syndromes, inflammatory bowel disease, and colon cancer. The liver, anatomically and physiologically connected to the gut, is exposed to gut microbiota products through the portal vein. This connection underscores the significant influence of gut microbiota on liver pathophysiology.
Drug-induced liver injury (DILI) is a severe adverse drug reaction that can lead to liver dysfunction and is a major global health concern. According to the World Health Organization, DILI is the fifth most common cause of liver disease-associated death. The pathophysiological process of DILI involves drug-related metabolic processes that lead to cellular oxidative stress, inflammation activation, and ultimately hepatocyte necrosis. Despite the identification of over 1200 agents that can potentially cause liver injury, the detailed mechanisms of DILI remain poorly understood. Increasing evidence suggests that gut microbiota plays a significant role in drug-induced hepatotoxicity.
Gut microbiota influences drug metabolism, thereby affecting drug efficacy and toxicity. For instance, gut microbial products can compete with drugs during the metabolizing process. P-cresol, a product of gut microbiota secreted by Clostridium difficile, competes with acetaminophen (APAP) for sulfotransferase 1A1. Elevated p-cresol production reduces APAP sulfonation, leading to APAP accumulation in the liver. Additionally, bacterially-derived metabolites can directly modulate the expression of hepatic cytochrome P450 enzymes.
Recent studies have explored the diurnal variation of APAP hepatotoxicity, revealing that the gut microbiota’s composition changes throughout the day, influencing the severity of liver damage. For example, mice challenged with APAP at zeitgeber time (ZT)12 (8:00 pm) exhibited more severe liver damage than those challenged at ZT0 (8:00 am). Metabolomics analysis identified 1-phenyl-1,2-propanedione (PPD) as a microbial metabolite that synergistically augments APAP-induced liver damage. Intestinal bacterial strains such as Escherichia coli and Citrobacter freundii were confirmed to produce PPD, while beneficial microbiota like Lactobacillus casei and Bacteroides thetaiotaomicron did not. PPD directly depletes hepatic glutathione and increases APAP-adduct accumulation, highlighting the gut microbiota’s impact on DILI through the “gut microbiota-liver axis.”
The role of gut microbiota in tacrine-induced hepatotoxicity has also been investigated. Tacrine, a reversible acetylcholinesterase inhibitor used to treat Alzheimer’s dementia, is known for its hepatic toxicity. Studies classified rats into strong responder (StrR) and non-responder (NonR) groups based on their susceptibility to tacrine-induced hepatotoxicity. The StrR group exhibited higher fecal excretion of tacrine, suggesting increased enterohepatic recycling and secondary intestinal drug absorption. 16S rDNA sequencing revealed an enrichment of Bacteroides and Enterobacteriaceae, which exhibit β-glucuronidase activity, in the StrR group. Treatment with β-glucuronidase or antibiotics confirmed the association between gut microbiota and tacrine hepatotoxicity, as antibiotic treatment reduced susceptibility to liver damage, while β-glucuronidase enhanced it.
Herbal medicines also interact with gut microbiota, affecting drug metabolism and potentially causing liver injury. For example, Huanglian Jiedu decoction influences short-chain fatty acids-producing microbiota, while Lactobacillus and Bifidobacterium participate in the deglycosylation of ginsenoside. However, overdose administration of herbal medicines can lead to liver injury, emphasizing the need for further exploration of the relationship between herbal medicines and gut microbiota.
The diagnosis and treatment of DILI remain challenging due to the lack of specific diagnostic markers and treatments. Elevated plasma aminotransferase levels are common signs of liver injury, but fecal microbial metabolite profiles may offer a more efficient diagnostic approach in the future. However, metabolomics studies face challenges in distinguishing between metabolites synthesized by microbiota and those synthesized by the host. Advances in multi-omics technologies are expected to further elucidate the functions of gut microbiota.
Probiotics and prebiotics are emerging as potential therapeutic approaches for preventing and treating liver diseases. They may exert therapeutic effects by reconstructing gut microbiota composition and modulating host immunity. However, their role in DILI requires further investigation.
In summary, the gut microbiota plays a significant role in the development of DILI through various mechanisms, including drug metabolism modulation, diurnal variation, and interactions with herbal medicines. Targeting the gut microbiota-liver axis offers a promising approach for preventing and managing DILI progression.
doi.org/10.1097/CM9.0000000000000651
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