Immunometabolism in Critical Care: Bridging Metabolism and Immunity in the Critically Ill Patient

Dr Neeraj Manikath , claude.ai

Abstract

Background: Immunometabolism, the intersection between immune function and cellular metabolism, has emerged as a critical determinant of outcomes in critically ill patients. Understanding metabolic reprogramming during critical illness provides novel therapeutic targets for conditions such as sepsis and acute respiratory distress syndrome (ARDS).

Objective: This review synthesizes current evidence on immunometabolic alterations in critical care, focusing on cross-talk between immune and metabolic pathways, metabolic reprogramming in sepsis and ARDS, and clinical implications for nutrition and targeted therapies.

Methods: Comprehensive literature review of peer-reviewed articles from 2015-2024 examining immunometabolism in critical care settings.

Results: Critical illness induces profound metabolic reprogramming characterized by enhanced glycolysis, altered fatty acid oxidation, and dysregulated glutamine metabolism. These changes significantly impact immune cell function, organ dysfunction, and patient outcomes.

Conclusions: Immunometabolic dysfunction represents a key pathophysiological mechanism in critical illness. Targeted metabolic interventions may offer novel therapeutic approaches to improve outcomes in critically ill patients.

Keywords: immunometabolism, sepsis, ARDS, glycolysis, fatty acid oxidation, glutamine, critical care

1. Introduction

The traditional view of metabolism as merely a provider of cellular energy has been revolutionized by the emergence of immunometabolism—a field that recognizes metabolism as an active regulator of immune function. In critical care medicine, this paradigm shift has profound implications for understanding disease pathophysiology and developing targeted interventions.

Critical illness, particularly sepsis and ARDS, triggers dramatic metabolic reprogramming that extends far beyond simple energy production. These metabolic alterations directly influence immune cell phenotype, function, and ultimately, patient outcomes. Understanding these immunometabolic networks provides clinicians with novel therapeutic targets and biomarkers for managing critically ill patients.

2. Fundamentals of Immunometabolism

2.1 Historical Perspective

The concept of immunometabolism emerged from the recognition that immune cells undergo metabolic reprogramming during activation, similar to cancer cells. Otto Warburg's observation of aerobic glycolysis in proliferating cells laid the groundwork for understanding how metabolic pathways support immune function beyond ATP generation.

2.2 Key Metabolic Pathways in Immune Cells

Glycolysis: The conversion of glucose to pyruvate, generating ATP rapidly but inefficiently. This pathway supports biosynthetic demands of activated immune cells and provides metabolic intermediates for biosynthesis.

Oxidative Phosphorylation (OXPHOS): Mitochondrial ATP production through the electron transport chain. More efficient than glycolysis but slower to respond to changing energy demands.

Fatty Acid Oxidation (FAO): β-oxidation of fatty acids in mitochondria, supporting memory T cell formation and M2 macrophage polarization.

Glutamine Metabolism: Central to immune cell biosynthesis, providing carbon and nitrogen for nucleotide synthesis and supporting TCA cycle anaplerosis.

Pentose Phosphate Pathway (PPP): Generates NADPH for antioxidant defense and provides ribose for nucleotide synthesis.

3. Cross-talk Between Immune System and Metabolic Pathways

3.1 Metabolic Control of Immune Cell Function

Immune cells exhibit distinct metabolic profiles that correlate with their functional states:

T Cell Subsets:

Effector T cells: Preferentially utilize glycolysis and glutamine metabolism to support rapid proliferation and cytokine production
Memory T cells: Rely primarily on fatty acid oxidation and OXPHOS for long-term survival and maintenance
Regulatory T cells (Tregs): Utilize fatty acid oxidation and maintain high mitochondrial spare respiratory capacity

Macrophage Polarization:

M1 (Classical) Macrophages: Exhibit enhanced glycolysis, reduced OXPHOS, and increased pentose phosphate pathway activity. This metabolic profile supports pro-inflammatory cytokine production and antimicrobial activity.
M2 (Alternative) Macrophages: Rely on fatty acid oxidation and OXPHOS, supporting tissue repair and anti-inflammatory functions.

3.2 Metabolic Sensors and Signaling

mTOR (Mechanistic Target of Rapamycin): Integrates growth signals and nutrient availability, promoting glycolysis and biosynthesis in activated immune cells.

AMPK (AMP-activated Protein Kinase): Energy sensor that promotes catabolic pathways and suppresses anabolic processes during energy stress.

HIF-1α (Hypoxia-Inducible Factor-1α): Transcription factor that promotes glycolysis and is stabilized during inflammation and hypoxia.

SIRT1 (Sirtuin 1): NAD+-dependent deacetylase that promotes fatty acid oxidation and mitochondrial biogenesis.

3.3 Metabolites as Signaling Molecules

Beyond serving as fuel sources, metabolites act as signaling molecules that directly influence immune function:

Lactate: Previously considered a waste product, lactate now emerges as an immunosuppressive metabolite that promotes M2 macrophage polarization and Treg expansion.

Succinate: Accumulates in M1 macrophages and acts as a danger signal, promoting IL-1β production through HIF-1α stabilization.

Itaconate: Produced by activated macrophages, this immunomodulatory metabolite limits inflammatory responses and promotes tissue repair.

α-Ketoglutarate: Supports Th17 differentiation while inhibiting Treg development through epigenetic modifications.

4. Metabolic Reprogramming in Sepsis

4.1 Early Metabolic Changes

Sepsis triggers immediate metabolic reprogramming characterized by:

Enhanced Glycolysis: Mediated by HIF-1α stabilization and mTOR activation, supporting rapid immune cell activation and cytokine production.

Mitochondrial Dysfunction: Bacterial toxins and inflammatory mediators impair mitochondrial respiration, leading to cellular energy crisis and organ dysfunction.

Amino Acid Depletion: Particularly glutamine, which becomes conditionally essential during critical illness for immune cell function and intestinal barrier maintenance.

4.2 Metabolic Heterogeneity in Sepsis

Recent evidence suggests that sepsis involves distinct metabolic phenotypes rather than uniform metabolic dysfunction:

Hypermetabolic Phenotype: Characterized by increased energy expenditure, enhanced glycolysis, and elevated inflammatory mediators. Often associated with younger patients and better outcomes when appropriately managed.

Hypometabolic Phenotype: Features reduced metabolic rate, impaired mitochondrial function, and immunosuppression. More common in elderly patients and associated with prolonged ICU stays and poor outcomes.

4.3 Temporal Evolution of Metabolic Changes

Phase 1 (0-24 hours): Hyperinflammatory response with enhanced glycolysis and cytokine production.

Phase 2 (1-7 days): Transition period with mixed inflammatory and anti-inflammatory responses.

Phase 3 (>7 days): Immunosuppressive phase characterized by metabolic exhaustion, T cell dysfunction, and increased susceptibility to secondary infections.

5. Metabolic Reprogramming in ARDS

5.1 Pulmonary Epithelial Cell Metabolism

ARDS involves significant metabolic alterations in pulmonary epithelial cells:

Alveolar Epithelial Cells: Shift from fatty acid oxidation to glycolysis during injury, impairing surfactant production and epithelial barrier function.

Metabolic Support for Repair: Resolution of ARDS requires restoration of fatty acid oxidation to support epithelial cell regeneration and surfactant synthesis.

5.2 Immune Cell Metabolism in the Lung

Alveolar Macrophages: Undergo metabolic reprogramming from M2 (homeostatic) to M1 (inflammatory) phenotype, characterized by enhanced glycolysis and reduced fatty acid oxidation.

Neutrophil Metabolism: Neutrophils in ARDS exhibit enhanced glycolysis and reduced apoptosis, contributing to prolonged inflammation and tissue damage.

5.3 Metabolic Biomarkers in ARDS

Emerging evidence suggests that metabolic biomarkers may predict ARDS outcomes:

Lactate-to-Pyruvate Ratio: Reflects tissue hypoxia and metabolic dysfunction.

Fatty Acid Metabolites: Altered levels correlate with disease severity and resolution potential.

6. Key Metabolic Targets in Critical Care

6.1 Glycolysis: The Double-Edged Sword

Pathophysiology

Enhanced glycolysis in critical illness serves dual functions:

Beneficial: Provides rapid ATP for immune cell activation and antimicrobial functions
Detrimental: Contributes to lactate accumulation, metabolic acidosis, and immunosuppression

Clinical Implications

Glucose Control: Moderate glycemic control (140-180 mg/dL) balances metabolic demands with avoiding hyperglycemia-associated complications.

Lactate Monitoring: Serial lactate measurements serve as biomarkers of tissue perfusion and metabolic dysfunction.

Therapeutic Targets

Glycolytic Modulators:

2-Deoxy-D-glucose: Glycolytic inhibitor showing promise in modulating excessive inflammation
Dichloroacetate: Pyruvate dehydrogenase kinase inhibitor that shifts metabolism from glycolysis to oxidative phosphorylation

6.2 Fatty Acid Oxidation: Fueling Recovery

Pathophysiology

FAO supports:

Memory T cell formation and maintenance
M2 macrophage polarization and tissue repair
Epithelial cell regeneration in ARDS
Cardiac and skeletal muscle function

Clinical Evidence

Studies demonstrate that patients with preserved FAO capacity show:

Improved immune function recovery
Reduced secondary infection rates
Better long-term outcomes

Therapeutic Approaches

Nutritional Strategies:

Medium-chain triglycerides (MCTs): Readily oxidized fatty acids that bypass carnitine-dependent transport
Ketogenic nutrition: May enhance FAO and provide alternative fuel source

Pharmacological Interventions:

Carnitine supplementation: Supports fatty acid transport into mitochondria
PPAR agonists: Transcriptional regulators of fatty acid oxidation genes

6.3 Glutamine Pathway: The Conditionally Essential Amino Acid

Pathophysiology

Glutamine becomes conditionally essential during critical illness due to:

Increased consumption by immune cells for nucleotide synthesis
Enhanced intestinal utilization for barrier function
Depletion of endogenous glutamine stores

Clinical Benefits

Glutamine supplementation in critically ill patients:

Reduces infection rates
Improves nitrogen balance
Supports intestinal barrier function
Enhances immune cell function

Implementation Strategies

Dosing: 0.3-0.5 g/kg/day of glutamine or glutamine dipeptides Route: Enteral preferred when tolerated; parenteral when enteral nutrition contraindicated Duration: Throughout critical illness phase, typically 7-14 days

7. Clinical Pearls and Practical Applications

7.1 Metabolic Assessment in Critical Care

Bedside Tools

Indirect Calorimetry: Gold standard for measuring energy expenditure and respiratory quotient (RQ)

RQ <0.7: Predominant fat oxidation
RQ 0.7-0.85: Mixed substrate utilization
RQ >0.85: Predominant carbohydrate oxidation

Metabolic Biomarkers:

Lactate: Tissue hypoxia and metabolic dysfunction
Prealbumin: Protein synthesis capacity
Transferrin: Iron metabolism and inflammatory status

Clinical Decision Making

Nutrition Prescription:

Hypermetabolic patients: Higher caloric targets (25-30 kcal/kg)
Hypometabolic patients: Conservative caloric approach (15-20 kcal/kg)
Substrate mix: 30-40% fat, 15-20% protein, remainder carbohydrates

7.2 Oysters (Common Pitfalls)

Over-feeding during acute phase: May worsen metabolic dysfunction and increase CO2 production
Ignoring metabolic phenotype: One-size-fits-all approach fails to address patient heterogeneity
Focusing solely on calories: Substrate quality and timing are equally important
Neglecting micronutrients: Vitamins and minerals essential for metabolic enzyme function

7.3 Clinical Hacks

RQ Trending: Use serial RQ measurements to guide substrate provision and weaning protocols
Lactate Clearance: Target >10% lactate clearance in first 6 hours as metabolic resuscitation endpoint
Glutamine Loading: Consider higher glutamine doses (0.5 g/kg) in patients with prolonged mechanical ventilation
Metabolic Flexibility: Alternate between glucose and lipid-based nutrition to maintain metabolic adaptability

8. Emerging Therapeutic Targets

8.1 Metabolic Modulators

Metformin: Beyond glucose control, metformin activates AMPK and may improve mitochondrial function in sepsis.

Nicotinamide Riboside: NAD+ precursor that supports sirtuins and may restore mitochondrial function.

Itaconate Derivatives: Synthetic analogs of this endogenous metabolite show anti-inflammatory properties.

8.2 Precision Medicine Approaches

Metabolomics-Guided Therapy: Using metabolic profiles to guide personalized nutrition and drug therapy.

Pharmacometabolomics: Predicting drug responses based on individual metabolic signatures.

Biomarker-Driven Interventions: Using metabolic biomarkers to identify patients most likely to benefit from specific interventions.

8.3 Mitochondrial-Targeted Therapies

Mitochondrial Antioxidants: MitoQ and other mitochondria-targeted compounds to reduce oxidative stress.

Mitochondrial Biogenesis Promoters: PGC-1α activators to enhance mitochondrial mass and function.

Metabolic Enzyme Modulators: Targeting specific enzymes in metabolic pathways affected by critical illness.

9. Future Directions and Research Priorities

9.1 Technological Advances

Real-time Metabolic Monitoring: Development of continuous metabolic monitoring systems for ICU use.

Artificial Intelligence Integration: Machine learning approaches to interpret complex metabolic data and guide therapy.

Point-of-Care Metabolomics: Rapid metabolic profiling at the bedside for immediate clinical decision-making.

9.2 Clinical Trial Priorities

Personalized Nutrition Trials: Testing metabolically-guided nutrition strategies in critically ill patients.

Metabolic Intervention Studies: Evaluating specific metabolic modulators in sepsis and ARDS.

Biomarker Validation Studies: Confirming metabolic biomarkers for prognosis and treatment response.

9.3 Mechanistic Understanding

Single-Cell Metabolomics: Understanding metabolic heterogeneity at the cellular level during critical illness.

Temporal Metabolic Profiling: Characterizing dynamic changes in metabolism throughout critical illness trajectory.

Multi-Omics Integration: Combining metabolomics with genomics, proteomics, and transcriptomics for comprehensive understanding.

10. Conclusion

Immunometabolism represents a paradigm shift in critical care medicine, moving beyond traditional supportive care to targeted metabolic interventions. The intricate cross-talk between immune function and cellular metabolism offers novel therapeutic opportunities for improving outcomes in critically ill patients.

Key takeaways for clinical practice include:

Recognition of metabolic heterogeneity in critical illness requires personalized approaches rather than standardized protocols
Metabolic reprogramming is both adaptive and maladaptive, requiring careful balance in therapeutic interventions
Substrate quality and timing are as important as total caloric delivery in metabolic support
Emerging metabolic targets offer promise for precision medicine approaches in critical care

As our understanding of immunometabolism continues to evolve, clinicians must integrate these insights into practice while awaiting definitive clinical trial evidence. The future of critical care medicine will likely involve metabolically-guided therapies that optimize both immune function and cellular energetics for improved patient outcomes.

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Conflicts of Interest: The authors declare no conflicts of interest.

Funding: Nil

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Thursday, September 18, 2025