REGISTRO DOI: 10.69849/revistaft/cs10202409171440
Fabiana Andréa Moura1,2*
Aryana Isabelle de Almeida Neves Siqueira1
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. Key components such as nuclear factor-kappa B (NF-κB) and the NLRP3 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. 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
Introduction
Sepsis, a dysregulated host response to infection closely linked to immune system dysfunctions, is a common clinical condition associated with high mortality in intensive care units. The liver, an organ directly involved in regulating the immune and inflammatory systems, is significantly affected in cases of sepsis (34-46%), though its regenerative capacity offers some protection from acute damage. However, when sepsis-associated liver injury (SLI) occurs, immune regulation fails, leading to increased morbidity, mortality, 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.
In this context, there has been increased interest in recent years, with discussions involving oxidative stress, gut microbiota, and their connections to the inflammatory process.
Inflammation and the Role of Nuclear Factor-Kappa B (NF-κB) and NLRP3 Inflammasome Signaling Pathway
The NLRP3 inflammasome, a multimeric protein complex, is crucial for innate immune system regulation of inflammation and is a primary research target in inflammatory bowel diseases (IBD). Its activation involves two steps: (1) activation of Toll-like receptors (TLR), which are pattern recognition receptors (PPR) inducing NLRP3 and pro-IL-1β expression mediated by NF-κB, and (2) activation by pathogen-associated molecular patterns (PAMP) and danger-associated molecular patterns (DAMP), leading to NLRP3 inflammasome assembly and secretion of IL-1β and IL-18, mediated by caspase-1 [4, 5].
NLRP3 activation is linked to the generation of reactive oxygen species (ROS). This involves ion influx, such as potassium and calcium, stimulating the mitochondrial electron transport chain, producing superoxide radicals, which can lead to other ROS like hydrogen peroxide and hydroxyl radicals. These ROS can damage cellular membranes, proteins, and DNA, or react with nitric oxide to produce peroxynitrite, a reactive nitrogen species causing tissue damage [1, 6].
One of the PAMPs recognized by TLRs is lipopolysaccharide (LPS) from gut Gram-negative bacteria. LPS-activated TLRs stimulate the MyD88 pathway, activating NF-κB, which increases pro-inflammatory cytokines like IL-1, IL-6, and TNF-α. ROS presence alone can activate NF-κB, and NF-κB inhibits nuclear factor erythroid 2-related factor 2 (Nrf-2), reducing antioxidant enzyme expression and perpetuating oxidative stress [7, 8].
Gut-Liver Axis
The gut microbiota, a major source of PAMPs and DAMPs, plays a critical role. LPS from gut bacteria recognized by TLR4 can amplify the inflammatory response systemically. Increased intestinal permeability, common in critically ill patients, allows bacterial translocation to the liver, initiating inflammation through Kupffer cells and hepatic Ito cells, further perpetuating liver injury [7, 9, 10].
Challenges in Intensive Care Units (ICU)
Preventing and treating SLI presents several challenges in the ICU:
1) Antibiotic Selection: Combating infections in critical patients requires careful antibiotic choice to avoid intestinal microbiota imbalance and dysbiosis.
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.
3) Adjunctive Pharmacotherapy: Understanding cellular mechanisms opens new therapeutic possibilities, including inhibitors and molecular pathway blockers to protect the gut-liver axis.
Conclusion
Sepsis remains the leading cause of death in non-coronary intensive care units [11]. While the liver is somewhat protected from sepsis-related damage compared to organs like the kidneys, its exhaustion increases mortality and risks of reinfection and readmission.
References
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1Pós-Graduação em Ciências Médicas (PPGCM), Universidade Federal de Alagoas (UFAL), 57072-970 Maceió, AL, Brasil: FAM (fabiana.moura@fanut.ufal.br; ORCID: 0000-0003-0625-0193); AIANS (aryana.siqueia@ebserh.gov.br; ORCID: 0000-0002-0412-0451)
2Pós-Graduação em Nutrição (PPGNUT), Universidade Federal de Alagoas (UFAL), 57072-970 Maceió, AL, Brasil:
*Correspondence: fabiana.moura@fanut.ufal.br