Liver failure (LF) is characterized by a constellation of clinical syndromes, including ascites, coagulopathy, hepatic encephalopathy, and renal insufficiency, which arise from severe liver dysfunction resulting from multiple insults to the liver. The etiology of LF is complex, with viruses, drugs or toxins, autoimmune disorders, bacterial infections, and genetic defects being the major contributors to its development.1 LF is generally classified into four categories: (1) acute LF (ALF), (2) subacute LF, (3) acute-on-chronic LF (ACLF), and (4) chronic LF, based on the speed at which liver dysfunction progresses. LF-associated mortality remains high. For instance, approximately 40% of patients with ACLF die within 90 days of admission in a US cohort.2 Among patients with ALF lacking liver transplantation, the mortality rate is over 50%.3 Although liver transplantation has significantly improved survival rates among patients with LF, the ongoing shortage of available donors markedly limits clinical practice. Gut microbiota is recognized as a key modulator in the development of various diseases, including liver pathologies. In chronic liver diseases, particularly during the progression of fatty liver, gut commensal microbiota—including bacteria, fungi, and viruses—can profoundly influence liver injury. Currently, several potential interventions targeting intestinal commensal microbiota (ICM) are under evaluation.4,5 However, the extent to which ICM regulates the progression of LF is still not clear. Recent literature has uncovered the potential link between ICM and LF,6,7 with a focus on alterations in intestinal microecology, the role of gut microbial bioactive metabolites, and gut barrier modulation during LF development. These preliminary findings indicate an interplay between ICM and LF that may facilitate the development of novel therapeutic approaches to combat LF based on ICM investigation. “Infection”-related LF: Viruses and other pathogens: Clinically, hepatitis B virus (HBV)-related ACLF is associated with changes in the overall composition of gut microbiota when compared with individuals suffering from chronic HBV or HBV-related cirrhosis. Specifically, Enterococcus is enriched in the HBV-ACLF group, whereas Faecalibacterium was decreased in the HBV-ACLF progression group.8 Another cohort confirmed that Enterococcus abundance may be elevated in HBV-ACLF patients while indicating that other bacteria, such as Veillonella, Streptococcus, and Klebsiella, may also be enriched.9 These findings suggest that gut microbiota may serve as a potential biomarker for predicting the progression of HBV-related LF. However, the causality between dysbiosis and LF is still poorly understood. Gut microbial composition is also shifted upon (HCV) infection, for example, Clostridiales was decreased while Lactobacillus was increased after HCV infection.10 Moreover, HCV eradication could partially rescue the gut dysbiosis,11 indicating HCV progression is also tightly associated with gut microbiota. HCV infection alone is rare related to ALF,12 but HCV may aggravate LF upon other insults co-existing, thus the exact contribution of HCV-related dysbiosis on LF progression is complex and requires deeper research. Gut eubiosis is also linked with the therapeutic status of HBV-ACLF. For example, artificial liver support systems (ALSSs) treated patients showed improved microecological disorders, with a decrease in potential pathogens and an increase in microbial diversity, compared to those not receiving ALSSs.13 This evidence further supports the strong association between gut microbial status and ACLF progression. However, not all phenotypes of end-stage liver disease are modulated by gut microbiota. For instance, portal vein thrombosis occurrence was not associated with significant alterations in gut microbial diversity alteration,14 indicating the need for more precise investigations into the regulatory roles of gut microbiota. Bacterial infection is one of the key inducers of LF. For example, sepsis resulting from bacterial dissemination can cause multiple-organ failure, including the liver. Intestinal microbiota and microbial products are implicated in sepsis-induced liver injury.15,16 These products were found to exhibit anti-inflammatory effects during sepsis and suppress inflammation-associated liver damage.16,17 Meanwhile, endogenous infection due to impaired gut barrier is a key driver of ACLF in cirrhotic individuals.18 Our findings indicate that gut microbiota-derived panose can restore gut barrier dysfunction and improve ACLF-associated mortality.19 Notably, these microbial products exhibit dual effects in the context of LF; they can inflict damage via pathogen-associated molecular patterns but can also yield beneficial metabolites that aid in the recovery of liver injury. This requires us to recognize the function of ICM precisely during LF progression, potentially guiding the discovery of more effective compounds to treat patients with LF. It is noteworthy that there is strong evidence to demonstrate microbial bile acids metabolism is closely associated with LF progression, for example, patients with ACLF showed abnormal bile acids profile in the blood. Furthermore, microbial-derived bile acid taurochenodeoxycholic acid was linked with clinical outcome, disclosing that the pathways involved in taurochenodeoxycholic acid generation may play a key role in LF development.20 However, more detailed causal research should be carried out in the future. “Noninfection”-related LF: toxins, drugs, and rare disease. It is well established that liver damage resulting from alcohol abuse is significantly influenced by gut microbiota.21 In cases of alcohol-induced LF, ICM exerted therapeutic potential. For example, fecal transplants from healthy donors into patients with alcohol-associated ACLF have been shown to improve LF-associated pathologies, such as ascites, and significantly prolong survival in an Indian cohort.22 However, unlike chronic alcoholic liver disease, the specific impacts of ICM on alcohol-associated LF remain largely unclear, particularly regarding mechanistic investigations, which require further systemic basic research. Drug-induced LF is another life-threatening condition. Acetaminophen overdose is a leading cause of ALF worldwide. Historically, the pathogenesis of acetaminophen-induced liver injury was primarily attributed to hepatic factors. Recent findings, however, demonstrate that ICM also plays a critical role in this process. For example, acetaminophen intake rapidly impairs gut barrier function and promotes commensal bacteria translocation, resulting in continued damage to the liver.23 Additionally, microbial metabolites can modulate various pathological processes associated with acetaminophen-induced liver damage.24 Finally, targeting ICM metabolism, such as through oral magnesium intake, has been shown to prevent acetaminophen-induced liver injury.25 Therefore, ICM is deeply involved in the pathogenesis of acetaminophen-induced liver injury; such modulations are not only based on the compositional changes but also based on the microbial functional alterations. LF can also result from genetic disorders. For instance, fumarylacetoacetate hydrolase deficiency leads to tyrosine metabolism disorders, resulting in toxin accumulation and fatal LF, a condition known as hereditary tyrosinemia type 1 (HT1). Theoretically, the consumption of tyrosine in the intestine may relieve “metabolic stress” during HT1 progression. We developed an engineered bacterium, Escherichia coli nissle 1917-hereditary tyrosinemia type 1, which was demonstrated to protect against HT1-associated LF in a murine model.26 This illustrates that manipulating gut microbiota presents a promising strategy to cure HT1. It is noteworthy that many forms of noninfection-related LF, including alcohol- and drug-associated LF, may also involve microbial infections, complicating the pathogenesis of these cases. Conclusion and future perspective: With advancements in microbial technologies, an increasing body of evidence supports the notion that ICM may play a critical role in the progression of LF. An imbalance in gut eubiosis may cause systemic immune disturbances, further influencing LF development. Additionally, ICM-derived bioactive compounds could modulate various aspects of LF progression and impact disease outcomes. Therefore, manipulations of ICM could be considered as a novel and effective approach for preventing and curing LF in clinical settings. However, several considerations warrant further investigation. First, beyond bacteria, how do other microbiota influence LF? Gut commensal fungi and viruses may also play important roles during LF, yet little is currently known about their contributions. Second, the causality should be clarified, namely, the compositional and functional changes of gut microbiota are the cause or result of LF? Third, how can we effectively and precisely cure LF in clinical practice? As LF can progress rapidly, targeted interventions addressing specific symptoms and events related to ICM are urgently required. Moreover, prevention of chronic LF by targeting ICM may hold promise for further translation in the future. Finally, the multifaceted contributions of ICM to LF development must be recognized, as LF occurrence and progression result from a complex interplay of numerous pathological events involving both host and microbiota factors. The specific contributions of ICM to LF must not be overestimated. Overall, the investigation of ICM holds promise for combating LF and improving clinical prognoses, despite the future challenges. Continued in-depth basic and clinical research using advanced technologies is essential to advance our understanding in this field. Funding This study was supported by the Natural Science Foundation of Guangdong Province of China (No. 2024A1515011256) and the National Natural Science Foundation of China (No. 32271230). Conflicts of interest None.
Peng Chen (Fri,) studied this question.