Gut-liver axis in sepsis-associated liver injury: Epidemiology, challenges and clinical practice

Abstract

Although the liver has a remarkable regenerative capacity, sepsis-associated liver injury (SLI) is a complication often seen in intensive care units. Due to its role in immune and inflammatory regulation, the liver is particularly vulnerable during severe infections. Understanding the global prevalence, causes, and management of SLI is essential to improve outcomes and reduce healthcare costs. This paper aims to explore these factors, with an emphasis on identifying effective strategies for clinical management. Zhang et al’s bibliometric analysis of 787 publications (745 original articles and 42 reviews, mostly in animal models) from 2000 to 2023 highlights the growing interest in SLI, focusing on oxidative stress, gut microbiota, and inflammatory processes. Key components such as nuclear factor-kappa B and the NOD-like receptor thermal protein domain associated protein 3 inflammasome pathway, along with their links to gut microbiota imbalance and oxidative stress, are crucial for understanding SLI pathogenesis. The gut-liver axis, particularly the role of intestinal permeability and bacterial translocation in liver inflammation, is emphasized. In this context, bacterial translocation is especially relevant for critically ill patients, as it can exacerbate liver inflammation. The findings underscore the need for integrated care in intensive care units, prioritizing gut health and careful antibiotic use to prevent dysbiosis. Despite extensive research, there remains a lack of clinical trials to validate therapeutic approaches. The abundance of experimental studies highlights potential therapeutic targets, stressing the need for high-quality randomized clinical trials to translate these findings into clinical practice.

Key Words: Dysbiosis; Oxidative stress; Inflammation; Microbiota; Sepsis-associated liver injury

Core Tip: Liver-gut axis balance, with dysbiosis, oxidative stress and pro-inflammatory activity control, is linked to sepsis-associated liver injury onset and progression. Therefore, the search for therapeutics targeting these metabolic pathways should be carried out through well-designed clinical trials in order to find ways to support effective clinical treatments.

TO THE EDITOR

Sepsis is the dysregulated host response to infections closely linked to immune system dysfunctions. It is a common clinical condition associated with high mortality rates in intensive care units (ICUs). The liver, which is an organ directly involved in regulating immune and inflammatory systems, is significantly affected by sepsis; it has an impact on 34%-46% sepsis patients, although its regenerative capacity somehow protects it from acute damage. However, immune regulation fails in sepsis-associated liver injury (SLI) and it leads to increased morbidity and mortality rates, and healthcare costs[1,2]. Therefore, understanding the global prevalence of SLI, its causes, and how it is identified and managed is crucial for disseminating knowledge and minimizing SLI-related damage. Accordingly, Zhang et al[3] carried out a bibliometric analysis of SLI. They analyzed 787 publications on SLI (745 original articles and 42 reviews) published between 2000 and 2023. Notably, there has been increased interest in this topic in recent years, and discussions on it involve oxidative stress, gut microbiota, as well as their connections to the inflammatory process. This bibliometric analysis provided a comprehensive view of recent trends and highlighted gaps in current knowledge, mainly in information on inflammation and oxidative stress.

Inflammation and the role of nuclear factor-kappa B and NOD-like receptor thermal protein domain associated protein 3 inflammasome signaling pathway

NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome is a complex of proteins that play essential role in regulating inflammation processes and the innate immune system. Furthermore, it is a primary research target in inflammatory bowel diseases. Its activation involves two steps: (1) Activation of toll-like receptors, which are pattern recognition receptors inducing NLRP3 and pro-interleukin-1β (IL-1β) expression mediated by nuclear factor-kappa B (NF-κB); and (2) Activation by pathogen-associated molecular patterns and danger-associated molecular patterns, which leads to NLRP3 inflammasome assembly, and IL-1β and IL-18 secretion mediated by caspase-1[4,5].

This pathway is also linked to oxidative stress. Reactive oxygen species, for example, play a significant role in damaging cellular structures, proteins and DNA, and it contributes to SLI[1,6]. NLRP3 inflammasome activation in the liver plays a key role in SLI pathogenesis, which is perpetuated by the influence of lipopolysaccharides (LPS) from gut gram-negative bacteria. These bacterial components stimulate NF-κB and induce the production of pro-inflammatory cytokines, such as IL-1, IL-6 and tumor necrosis factor-α, a fact that exacerbates the liver injury[7,8].

Gut-liver axis

The gut-liver-axis is critical for SLI. Microbiota, mainly Gram-negative organisms, trigger systemic inflammation in patients, particularly in critically ill patients, due to increased intestinal permeability caused by LPS. Intestinal permeability allows bacterial translocation in critically ill patients, significantly contributing to liver injury. Kupffer cells and hepatic Ito cells are activated by this influx of bacterial components, which leads to persistent inflammation and liver damage[7,9,10]. Zhang et al[3] highlighted key terms such as oxidative stress, inflammation, LPS, tumor necrosis factor-α, NF-κB and Kupffer cell among the top 20 keywords, and it underscored the relevance of these mechanisms in SLI research.

In addition to these keywords, other top 20 terms, such as “sepsis”, “liver injury”, “gene expression”, “rat”, “activation”, “nitric oxide”, “cecal ligation and puncture”, “cell”, “inhibition”, “apoptosis”, “mechanism”, and “dysfunction” also emphasize the complexity of SLI. These terms are not only intrinsically linked to oxidative stress but also to dysfunction severity, which leads to high mortality rates in ICUs. These authors draw attention to intricate pathophysiological factors involved in SLI by highlighting these often-cited keywords, and they suggested the need for a multifaceted approach to be adopted by ICU professionals. This process includes efforts to prevent SLI, early symptom recognition, accurate diagnosis and comprehensive treatment strategies. Tackling SLI requires coordinated efforts across various domains, from keeping gut health to investigating cell mechanisms to reduce the heavy burden this condition places on healthcare systems.

Challenges in ICU

Preventing and treating SLI presents several challenges in the ICU: (1) Careful antibiotic selection: Choosing the appropriate antibiotics is vital to avoid disrupting gut microbiota and worsening dysbiosis in critically ill patients; (2) Minimizing bacterial translocation: Ensuring gut health in the ICU is essential. Unstimulated intestines, such as in total parenteral nutrition or low-prebiotic enteral diets, can lead to bacterial overgrowth and dysbiosis; and (3) Adjunctive pharmacotherapy: Understanding cellular mechanisms opens new therapeutic possibilities, including inhibitors and molecular pathway blockers to protect the gut-liver axis[11].

CONCLUSION

Sepsis remains the leading cause of death in non-coronary ICUs[12]. The liver is somewhat protected from sepsis-related damage in comparison to organs like kidneys, but its exhaustion increases mortality rates and the risk of reinfection and readmission. The bibliometric review by Zhang et al reflected the growing interest in SLI[3], mainly in recent years, providing important insights into the global research on SLI and highlighting the growing interest in this field from 2000 to 2023, particularly in countries such as China, the United States, and Germany. Key contributing institutions include Shanghai Jiao Tong University and Huazhong University of Science and Technology, and top journals like Critical Care Medicine, Shock, and Hepatology lead this conversation.

The review emphasized critical factors, such as the role of oxidative stress, gut microbiota and inflammatory pathways such as NF-κB and NLRP3 inflammasome. The abundance of experimental studies has suggested promising therapeutic targets, more specifically, trials focused on assessing the effectiveness of antioxidant therapies or microbiota-targeting treatments are necessary to translate these findings into clinical practice. High-quality randomized clinical trials are urgently needed to validate these therapeutic targets and translate basic research into clinical practice. Trials assessing antioxidant therapies and microbiota-targeting treatments are essential to improve SLI clinical management and to help move towards evidence-based care. Integrating these research findings into healthcare guidelines could lead to cost-saving interventions and to improved patient outcomes if one bears in mind the high healthcare costs associated with SLI. Strategies to promote gut health and to manage oxidative stress should be prioritized in critically ill patients to help mitigate the impact of SLI and reduce its heavy burden on healthcare systems.

ACKNOWLEDGEMENTS

The authors gratefully acknowledge the financial support of the Fundação de Amparo à Pesquisa do Estado de Alagoas/Programa Pesquisa para o SUS, Ministério da Saúde.