Immunometabolism in Sepsis: How Metabolic Pathways Regulate Immune Dysfunction and Therapeutic Targets

Dr Neeraj Manikath , claude.ai

Abstract

Background: Sepsis represents a complex host response to infection characterized by profound metabolic reprogramming that directly influences immune cell function. The emerging field of immunometabolism has revealed intricate relationships between cellular metabolism and immune responses, offering novel therapeutic targets for sepsis management.

Objectives: To review the current understanding of immunometabolic pathways in sepsis, their role in immune dysfunction, and potential therapeutic interventions.

Methods: Comprehensive review of literature from 2018-2025 focusing on metabolic regulation of immune responses in sepsis.

Key Findings: Sepsis triggers metabolic reprogramming in immune cells, shifting from oxidative phosphorylation to aerobic glycolysis. This metabolic switch affects T-cell anergy, macrophage polarization, and neutrophil dysfunction. Key pathways include mTOR, AMPK, HIF-1α, and fatty acid oxidation, presenting actionable therapeutic targets.

Conclusions: Understanding immunometabolism provides a mechanistic framework for sepsis pathophysiology and identifies promising therapeutic interventions targeting metabolic-immune circuits.

Keywords: sepsis, immunometabolism, glycolysis, oxidative phosphorylation, immune dysfunction, therapeutic targets

Introduction

Sepsis affects over 49 million people globally with mortality rates ranging from 15-30% despite advances in supportive care¹. The traditional paradigm of sepsis as an overwhelming inflammatory response has evolved to recognize a complex, dynamic process involving both hyper-inflammatory and immunosuppressive phases². Central to this understanding is the recognition that cellular metabolism profoundly influences immune cell function—a field termed immunometabolism³.

The concept that "metabolism fuels immunity" has transformed our understanding of sepsis pathophysiology. Immune cells undergo dramatic metabolic reprogramming during sepsis, shifting energy production pathways that directly impact their functional capacity⁴. This metabolic-immune crosstalk offers novel therapeutic targets beyond traditional anti-inflammatory approaches.

This review examines the mechanistic basis of immunometabolic dysregulation in sepsis, its contribution to immune dysfunction, and emerging therapeutic strategies targeting these pathways.

Fundamental Principles of Immunometabolism

The Metabolic-Immune Interface

Immune cells exhibit remarkable metabolic plasticity, adapting their energy production to match functional demands⁵. Resting immune cells primarily utilize oxidative phosphorylation (OXPHOS) for efficient ATP production. Upon activation, most immune cells undergo a metabolic switch to aerobic glycolysis (the Warburg effect), prioritizing rapid ATP generation and biosynthetic precursors over efficiency⁶.

This metabolic reprogramming supports:

Rapid proliferation and activation
Biosynthesis of effector molecules
Redox balance maintenance
Epigenetic modifications affecting gene expression

Pearl: The metabolic switch from OXPHOS to glycolysis isn't just about energy—it fundamentally rewires cellular function, affecting everything from cytokine production to cell survival.

Key Metabolic Pathways in Immune Function

Glycolysis: The conversion of glucose to pyruvate provides rapid ATP and biosynthetic intermediates. Enhanced glycolysis supports pro-inflammatory responses and T-cell activation⁷.

Oxidative Phosphorylation: Mitochondrial respiration generates ATP efficiently and supports anti-inflammatory responses and memory T-cell formation⁸.

Fatty Acid Oxidation (FAO): β-oxidation of fatty acids fuels anti-inflammatory macrophage polarization and regulatory T-cell function⁹.

Glutaminolysis: Glutamine catabolism supports rapidly dividing cells and contributes to inflammatory mediator production¹⁰.

Pentose Phosphate Pathway (PPP): Generates NADPH for biosynthesis and antioxidant defense¹¹.

Metabolic Reprogramming in Sepsis

Early Hyperinflammatory Phase

During initial sepsis, innate immune cells undergo rapid metabolic reprogramming characterized by:

Enhanced Glycolysis: Pattern recognition receptor (PRR) activation triggers glycolytic upregulation through mTOR and HIF-1α pathways¹². This supports:

Rapid ATP production for immediate energy demands
Lactate production contributing to tissue acidosis
Biosynthetic precursor generation for cytokine synthesis

Suppressed OXPHOS: Mitochondrial dysfunction occurs through multiple mechanisms:

Direct bacterial toxin effects
Reactive oxygen species (ROS) damage
Inflammatory cytokine-mediated inhibition
Nitric oxide-induced cytochrome c oxidase inhibition¹³

Altered Fatty Acid Metabolism: Sepsis disrupts normal lipid metabolism:

Impaired FAO in cardiac and skeletal muscle
Increased lipolysis and free fatty acid release
Altered ketogenesis affecting brain metabolism¹⁴

Late Immunosuppressive Phase

The immunosuppressive phase involves distinct metabolic changes:

Metabolic Exhaustion: Prolonged glycolytic activation leads to:

T-cell anergy and exhaustion
Impaired NK cell cytotoxicity
Reduced antigen presentation capacity¹⁵

Mitochondrial Biogenesis Dysfunction: Impaired mitochondrial recovery prevents:

Effective immune memory formation
Adequate energy production for immune surveillance
Proper cellular repair mechanisms¹⁶

Cell-Specific Immunometabolic Dysfunction

T-Cell Metabolism in Sepsis

Naive T-Cell Activation: Healthy T-cell activation requires metabolic reprogramming from OXPHOS to glycolysis, supported by mTOR signaling¹⁷. In sepsis:

Persistent inflammatory signals exhaust metabolic capacity
Chronic mTOR activation leads to T-cell anergy
Impaired amino acid availability limits protein synthesis

Memory T-Cell Formation: Effective memory requires metabolic flexibility and mitochondrial spare respiratory capacity¹⁸. Sepsis impairs:

Mitochondrial biogenesis
FAO capacity
Long-term survival signals

Regulatory T-Cells (Tregs): Tregs depend on FAO and OXPHOS for function¹⁹. Sepsis-induced metabolic dysregulation:

Enhances Treg suppressive activity
Contributes to immunosuppression
Impairs effector T-cell responses

Clinical Pearl: Monitor lymphocyte count recovery as a marker of metabolic immune recovery. Persistent lymphopenia often indicates ongoing immunometabolic dysfunction.

Macrophage Polarization and Metabolism

M1 (Pro-inflammatory) Macrophages: Utilize glycolysis and have impaired TCA cycle function²⁰. In sepsis:

Enhanced glycolysis supports inflammatory cytokine production
Accumulated succinate activates HIF-1α
Increased ROS production contributes to tissue damage

M2 (Anti-inflammatory) Macrophages: Depend on OXPHOS and FAO²¹. During sepsis recovery:

Impaired mitochondrial function limits M2 polarization
Reduced IL-4/IL-13 signaling affects alternative activation
Compromised tissue repair and resolution

Metabolic Flexibility: Healthy macrophages exhibit metabolic flexibility. Sepsis reduces this adaptability, leading to:

Inappropriate inflammatory responses
Impaired pathogen clearance
Poor wound healing

Neutrophil Metabolism

Neutrophils are primarily glycolytic but sepsis affects their metabolic capacity:

Enhanced glycolysis supports initial antimicrobial responses
Metabolic exhaustion leads to impaired chemotaxis
Reduced NET formation capacity in prolonged sepsis²²
Impaired apoptosis contributes to tissue damage

Hack: Consider neutrophil-to-lymphocyte ratio not just as an inflammatory marker, but as an indirect indicator of immunometabolic balance.

Key Regulatory Pathways

mTOR Signaling

The mechanistic target of rapamycin (mTOR) integrates nutrient, energy, and growth factor signals²³:

mTORC1 in Sepsis:

Promotes glycolysis and protein synthesis
Initially beneficial for immune activation
Chronic activation leads to T-cell exhaustion
Inhibits autophagy, preventing cellular clearance

mTORC2 Functions:

Regulates lipid synthesis and glucose metabolism
Controls cytoskeletal organization
Less well-studied in sepsis context

Therapeutic Implications: mTOR inhibition (rapamycin) shows promise in preventing T-cell exhaustion but timing is critical²⁴.

AMPK Pathway

AMP-activated protein kinase (AMPK) serves as a cellular energy sensor²⁵:

AMPK in Sepsis:

Initially activated by energy depletion
Promotes FAO and OXPHOS
Inhibits inflammatory responses
Becomes dysfunctional with prolonged sepsis

Clinical Relevance: AMPK activators (metformin) may preserve metabolic flexibility and reduce sepsis severity²⁶.

HIF-1α Signaling

Hypoxia-inducible factor 1α (HIF-1α) coordinates metabolic responses to hypoxia and inflammation²⁷:

HIF-1α Functions:

Promotes glycolytic gene expression
Suppresses OXPHOS
Enhances inflammatory responses
Stabilized by succinate and inflammatory signals

Oyster: While HIF-1α stabilization initially supports immune responses, prolonged activation contributes to metabolic dysfunction and poor outcomes.

Therapeutic Targets and Interventions

Direct Metabolic Interventions

Glucose and Insulin Management:

Moderate glucose control (140-180 mg/dL) balances metabolic support with avoiding hyperglycemia-induced dysfunction²⁸
Insulin sensitivity changes dynamically during sepsis
Consider continuous glucose monitoring in severe cases

Nutritional Support:

Early enteral nutrition preserves gut barrier function
Glutamine supplementation may support immune metabolism but evidence is mixed²⁹
Omega-3 fatty acids can modulate inflammatory responses

Metabolic Substrates:

Ketone bodies (β-hydroxybutyrate) may provide alternative fuel and anti-inflammatory effects³⁰
Succinate inhibition under investigation
Lactate clearance as both biomarker and potential therapeutic target

Pharmacological Approaches

Metformin:

AMPK activator with anti-inflammatory properties
May reduce sepsis incidence and severity in diabetic patients²⁶
Potential concerns about lactic acidosis in severe sepsis

Dichloroacetate (DCA):

Pyruvate dehydrogenase kinase inhibitor
Shifts metabolism from glycolysis to OXPHOS
Early trials show mixed results³¹

2-Deoxy-D-glucose (2-DG):

Glycolysis inhibitor
May prevent T-cell exhaustion
Requires careful dosing to avoid energy depletion³²

Rapamycin:

mTOR inhibitor
May prevent T-cell anergy if given early
Immunosuppressive effects require careful timing²⁴

Mitochondrial-Targeted Therapies

Coenzyme Q10 and Idebenone:

Support electron transport chain function
Limited clinical evidence in sepsis

SS-31 (Elamipretide):

Mitochondria-targeted peptide
Stabilizes cardiolipin and improves OXPHOS
Promising preclinical data³³

NAD+ Precursors:

Nicotinamide riboside and nicotinamide mononucleotide
Support mitochondrial biogenesis
Early clinical investigation³⁴

Clinical Pearls and Practical Applications

Biomarker Integration

Lactate/Pyruvate Ratio: Reflects cellular metabolic state beyond just perfusion. Elevated ratios suggest impaired OXPHOS even with adequate oxygen delivery³⁵.

Ketone Bodies: β-hydroxybutyrate levels may indicate metabolic adaptation and potential for recovery.

Amino Acid Profiles: Altered branched-chain amino acid metabolism correlates with outcomes and may guide nutritional therapy³⁶.

Timing Considerations

Phase-Specific Therapy: Early sepsis may benefit from supporting glycolytic metabolism, while later phases require OXPHOS restoration.

Personalized Approach: Metabolic profiles vary significantly between patients based on:

Comorbidities (diabetes, obesity, malnutrition)
Age and functional status
Infection source and organism
Genetic polymorphisms affecting metabolism

Monitoring Strategies

Indirect Calorimetry: When available, provides real-time metabolic information to guide nutritional support.

Muscle Ultrasound: May detect metabolic myopathy associated with mitochondrial dysfunction.

Immune Cell Phenotyping: Flow cytometry analysis of T-cell activation markers and metabolic indicators³⁷.

Emerging Concepts and Future Directions

Epigenetic Regulation

Metabolic intermediates serve as cofactors for epigenetic enzymes, creating lasting changes in gene expression:

Histone modifications affect immune cell programming
DNA methylation patterns influence long-term immune dysfunction
Potential targets for reversal of sepsis-induced immune suppression³⁸

Microbiome-Metabolism Interactions

The gut microbiome profoundly influences host metabolism:

Short-chain fatty acid production affects immune responses
Dysbiosis in sepsis disrupts metabolic homeostasis
Microbiome-targeted therapies under investigation³⁹

Sex-Specific Differences

Emerging evidence suggests sex-specific differences in immunometabolism:

Estrogen influences mitochondrial function and immune responses
Male-female differences in sepsis outcomes may relate to metabolic factors
Personalized approaches should consider sex-specific biology⁴⁰

Precision Medicine Applications

Future approaches may integrate:

Metabolomic profiling for patient stratification
Real-time metabolic monitoring
AI-driven prediction of metabolic trajectories
Combination therapies targeting multiple pathways

Hacks for Clinical Practice

The "Metabolic Sepsis Bundle":
- Monitor lactate clearance AND lactate/pyruvate ratio
- Consider moderate (not tight) glucose control
- Early enteral nutrition when possible
- Assess and correct micronutrient deficiencies (B vitamins, magnesium, phosphate)
Timing-Based Approach:
- Days 0-3: Support initial inflammatory response while preventing excess
- Days 4-7: Focus on metabolic recovery and mitochondrial function
- Beyond day 7: Address persistent immunosuppression and metabolic dysfunction
Red Flags for Metabolic Dysfunction:
- Persistent lymphopenia beyond day 3-5
- Failure of lactate clearance despite adequate resuscitation
- New onset hyperglycemia without obvious cause
- Unexplained fatigue or weakness during recovery
Simple Metabolic Assessment:
- Calculate respiratory quotient when indirect calorimetry available
- Monitor ketone levels in prolonged critical illness
- Consider muscle wasting as indicator of metabolic dysfunction

Conclusions

Immunometabolism represents a paradigm shift in understanding sepsis pathophysiology, moving beyond simple inflammatory models to recognize the fundamental role of metabolic-immune interactions. Key insights include:

Metabolic reprogramming is central to sepsis pathophysiology, affecting all aspects of immune function from initial activation to long-term memory formation.
Phase-specific metabolic changes require tailored therapeutic approaches, with early support of inflammatory metabolism transitioning to recovery-focused interventions.
Multiple therapeutic targets exist across metabolic pathways, from traditional glucose management to novel mitochondrial therapies.
Clinical integration requires new biomarkers, monitoring strategies, and treatment algorithms that incorporate metabolic principles.
Personalized approaches will likely emerge based on individual metabolic profiles, comorbidities, and genetic factors.

The field of immunometabolism in sepsis is rapidly evolving, with numerous clinical trials in progress. Success will require integration of basic science discoveries with pragmatic clinical approaches, always remembering that metabolism and immunity are inextricably linked in the critically ill patient.

Future research priorities include validation of metabolic biomarkers, development of combination therapies targeting multiple pathways, and establishment of optimal timing and dosing for metabolic interventions. As our understanding deepens, immunometabolism-guided therapy may transform sepsis care from supportive management to precision, mechanism-based treatment.

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Tuesday, September 23, 2025