Organ Crosstalk and Dysfunction in Sepsis 🌟🩺

Introduction✨

Sepsis disrupts homeostasis by causing a dysregulated immune response that leads to multi-organ dysfunction. The phenomenon of organ crosstalk—where dysfunction in one organ triggers a cascade of failures in other organs—has been extensively studied in recent years. Despite significant advances, septic shock and multiple organ dysfunction syndrome (MODS) remain major contributors to ICU mortality. Today's focus is on the mechanisms of organ crosstalk in sepsis, specifically in heart-lung-kidney, gut-microbiome-liver-brain, and adipose-muscle-bone systems. It also highlights how interventions such as mechanical ventilation, antibiotics, and extracorporeal organ support influence this dynamic, and proposes metabolomics as a promising tool for understanding and monitoring sepsis-induced organ dysfunction.

Background 🧬

Sepsis affects multiple systems in the body, stemming from a dysregulated immune response to infection. It progresses through systemic inflammation, immune suppression, and metabolic alterations, ultimately leading to MODS. ICU sepsis rates range from 13.6% to 39.3%, with associated hospital mortality of 35.3%. Organ crosstalk is a key concept in understanding sepsis, involving bidirectional signaling between organs mediated by cytokines, hormones, extracellular vesicles, and metabolites. However, the exact mechanisms remain elusive, necessitating further research into this intricate network.

The Inflammatory Response and Metabolic Reprogramming in Sepsis 🔥⚙️

Hyperinflammation and Immune Dysregulation

• Triggering Factors: Sepsis begins with an infection that activates the innate immune system, leading to the release of proinflammatory cytokines such as IL-6, TNF-α, and IFN-γ. This hyperinflammatory phase can lead to refractory shock and MODS if not regulated.
• Immune Counterregulation: Adaptive immunity, via cortisol and anti-inflammatory cytokines, tempers this response. However, Critical Illness-Related Corticosteroid Insufficiency (CIRCI) exacerbates inflammation and immune suppression, as highlighted in meta-analyses suggesting corticosteroids reduce mortality in sepsis.

Metabolic Reprogramming

• Energy Shift: Cells switch from oxidative phosphorylation (OXPHOS) to glycolysis during sepsis. This adaptation conserves energy but reduces ATP production, impairing cellular and organ function. Reversing this metabolic shift is crucial for restoring normal function.
• Persistent Inflammation and Catabolism Syndrome (PICS): Survivors of the hyperinflammatory phase may progress to PICS, characterized by chronic inflammation, immune dysfunction, and protein catabolism.

Therapeutics and Challenges

• Extracorporeal Therapies: Techniques such as hemoadsorption and plasma filtration aim to remove inflammatory mediators but lack sufficient evidence of efficacy in organ crosstalk modulation.
• Knowledge Gaps: The interaction between artificial organ support and native organ function in sepsis remains underexplored, requiring more targeted research.

Heart–Lung–Kidney Crosstalk in Sepsis 💓🫁🩺

Cardiovascular System

• Mechanisms of Injury: Septic shock triggers endothelial dysfunction, causing refractory hypotension mediated by nitric oxide and prostacyclin. Neurohormonal pathways like the renin-angiotensin-aldosterone system (RAAS) and β-adrenergic signaling are activated to compensate.
• Cardiokines: The heart functions as an endocrine organ, releasing cardiokines like IL-6, ANF, and BNP, which regulate organ crosstalk. Dysregulated cardiokine release exacerbates MODS by impairing autonomic function and reducing heart rate variability.

Kidney

• Sepsis-Induced Acute Kidney Injury (AKI): AKI releases uremic toxins such as indoxyl sulfate, which affect the heart, lungs, and central nervous system. AKI also leads to volume overload, metabolic acidosis, and electrolyte imbalances that worsen cardiovascular and pulmonary outcomes.
• Therapeutics: Renal Replacement Therapy (RRT) mitigates uremic toxin accumulation but requires further research into its role in restoring organ crosstalk.

Lungs

• ARDS in Sepsis: Acute Respiratory Distress Syndrome (ARDS) is a common complication, driven by systemic inflammation and biotrauma from mechanical ventilation.
• Brain-Lung Axis: The vagus nerve modulates pulmonary inflammation via the cholinergic anti-inflammatory pathway (CAP), but overactivation worsens lung injury.
• Extracorporeal Membrane Oxygenation (ECMO): VV-ECMO supports oxygenation in severe ARDS but increases the risk of AKI.

Gut–Microbiome–Liver–Brain Crosstalk in Sepsis 🦠🧠

Gut and Microbiome

• Barrier Dysfunction: Sepsis damages the gut barrier through ischemia, cytokine release (IL-6, TNF-α), and altered microbiota. This leads to endotoxemia and systemic inflammation.
• Dysbiosis: Antibiotics and PPIs further disrupt the gut microbiome, reducing diversity and impairing immune modulation. This disruption contributes to liver and brain dysfunction.

Liver

• Hepatokines: Mediators like FGF-21 and LECT2 regulate inflammation, metabolism, and glucose homeostasis. Dysregulated hepatokine release exacerbates cardiovascular dysfunction and MODS.
• Extracorporeal Liver Support: Devices like MARS® remove cytokines and bilirubin but show limited efficacy in altering clinical outcomes.

Brain

• Sepsis-Associated Encephalopathy (SAE): Gut dysbiosis and altered neurotransmitter production (e.g., serotonin) drive cognitive dysfunction. SAE manifests as delirium, memory loss, and impaired executive function.
• Circadian Disruption: Sepsis alters circadian rhythms, exacerbating neuroinflammation and immune dysfunction.

Adipose Tissue–Muscle–Bone Crosstalk in Sepsis 🦵💪

Adipose Tissue

• Adipokines: Leptin promotes inflammation, while adiponectin has anti-inflammatory effects. Brown adipose tissue (BAT) secretes batokines, such as FGF-21, that regulate systemic metabolism and immune responses.

Muscle and Bone

• Myokines and Osteokines: Myokines (e.g., IL-6, myostatin) and osteokines (e.g., osteocalcin) influence energy metabolism and inflammation. Muscle atrophy and osteoporosis in septic patients exacerbate metabolic dysfunction.

Forward to the Future: Monitoring Organ Crosstalk 🌟🔍

• Metabolomics: This emerging field enables the identification of biomarkers reflecting impaired organ crosstalk. Metabolic profiling offers potential for precision medicine in sepsis but requires more integration with clinical data.
• Computational Models: Data fusion and systems biology approaches can help decipher the complex language of organ crosstalk, paving the way for individualized therapies.

Conclusion 🛑🩺

Sepsis-induced organ dysfunction is a result of disrupted interorgan communication. Understanding these interactions through advanced tools like metabolomics and artificial intelligence can enhance prediction models and therapeutic strategies. While the path forward remains challenging, improving our grasp of organ crosstalk could revolutionize sepsis management and reduce mortality.

Reference 📖

Borges A, Bento L. Organ crosstalk and dysfunction in sepsis. Ann Intensive Care. 2024;14:147. doi:10.1186/s13613-024-01377-0.