The Immunometabolism of Critical Illness: Bridging Metabolism and Immune Function in the ICU

Dr Neeraj Manikath , claude.ai

Abstract

Critical illness precipitates profound alterations in both immune function and cellular metabolism, with emerging evidence demonstrating that these processes are inextricably linked. Immunometabolism—the study of how metabolic pathways regulate immune cell function—has revealed that immune cells undergo dramatic metabolic reprogramming during activation, with shifts between oxidative phosphorylation and glycolysis determining their functional phenotype. This review explores the fundamental principles of immune cell metabolism in critical illness, examines therapeutic strategies targeting metabolic pathways to modulate inflammation, and discusses the emerging field of nutrigenomics as a precision medicine approach to immunomodulation. Understanding these metabolic-immune interactions offers novel therapeutic targets for managing the dysregulated immune responses characteristic of sepsis, acute respiratory distress syndrome (ARDS), and multi-organ dysfunction syndrome.

Keywords: Immunometabolism, critical illness, metabolic reprogramming, glycolysis, oxidative phosphorylation, nutrigenomics, immunomodulation

Introduction

The immune system in critical illness exists in a state of paradox—simultaneously hyperinflammatory and immunosuppressed. This apparently contradictory state reflects the complex temporal and spatial heterogeneity of immune responses during conditions such as sepsis, trauma, and ARDS. Traditional paradigms have focused on either inflammatory mediators or immune cell populations, but a fundamental driver of immune cell behavior has been relatively overlooked until recently: cellular metabolism.

Immunometabolism has emerged as a crucial determinant of immune cell fate and function. The recognition that "you are what you eat" applies equally to immune cells has revolutionized our understanding of inflammation and opened new therapeutic avenues. Immune cells, like all cells, require energy and biosynthetic precursors, but the metabolic pathway they utilize—glycolysis versus oxidative phosphorylation (OXPHOS)—profoundly influences their effector functions.

In critical illness, metabolic dysfunction occurs at multiple levels: whole-body metabolic derangements (hyperglycemia, insulin resistance, protein catabolism), mitochondrial dysfunction, and immune cell metabolic reprogramming. These alterations are not merely epiphenomena but are mechanistically linked to outcomes. This review synthesizes current evidence on immunometabolism in critical illness, focusing on translational implications for bedside practice.

How Immune Cell Metabolism Drives Function: The Shift from Oxidative Phosphorylation to Glycolysis

The Warburg Effect Revisited: From Cancer to Immunity

Otto Warburg's seminal observation that cancer cells preferentially utilize glycolysis even in oxygen-replete conditions seemed paradoxical—why would cells choose an inefficient metabolic pathway producing only 2 ATP per glucose molecule versus the 36 ATP generated through OXPHOS? The answer lies not in energy efficiency but in biosynthetic flexibility and speed of response.

Activated immune cells undergo a similar metabolic reprogramming, termed "aerobic glycolysis" or the "Warburg effect" in immunology. This metabolic switch is not a defect but an adaptive response that supports specific immune functions.

Metabolic Phenotypes Define Immune Cell Function

M1 Macrophages and Pro-inflammatory Responses:

Following activation by pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs), macrophages polarize toward an M1 phenotype characterized by:

Rapid upregulation of glycolysis (up to 100-fold increase)
Suppression of OXPHOS and the tricarboxylic acid (TCA) cycle
Production of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6, IL-12)
Enhanced phagocytic and bactericidal capacity
Increased production of reactive oxygen species (ROS) and nitric oxide (NO)

The metabolic basis for this phenotype involves several key mechanisms:

Glycolytic intermediates fuel biosynthesis: Glucose-6-phosphate enters the pentose phosphate pathway (PPP), generating NADPH (for ROS production) and ribose-5-phosphate (for nucleotide synthesis). This supports the massive protein synthesis required for cytokine production.
Broken TCA cycle and accumulation of metabolic intermediates: In M1 macrophages, the TCA cycle is interrupted at two points, leading to accumulation of citrate and succinate. Citrate is exported to the cytoplasm for fatty acid synthesis and acetyl-CoA production (supporting histone acetylation and gene transcription). Succinate stabilizes hypoxia-inducible factor-1α (HIF-1α), a master transcriptional regulator of glycolysis and pro-inflammatory genes, even under normoxic conditions (termed "pseudohypoxia").
Lactate as a signaling molecule: The end product of glycolysis, lactate, was long considered metabolic waste. However, lactate acts as a signaling molecule, promoting M2 polarization in neighboring macrophages and modulating T cell function, representing a negative feedback mechanism.

M2 Macrophages and Resolution Responses:

M2 or "alternatively activated" macrophages exhibit contrasting metabolism:

Reliance on OXPHOS and fatty acid oxidation (FAO)
Intact TCA cycle function
Production of anti-inflammatory mediators (IL-10, TGF-β)
Enhanced tissue repair and angiogenesis functions
Increased expression of arginase-1 (converting arginine to ornithine for collagen synthesis)

The dependence on OXPHOS for M2 function explains why mitochondrial dysfunction in critical illness impairs resolution responses and predisposes to prolonged inflammation.

T Cell Metabolic Programming

Effector T Cells (Teff):

Activated CD4+ and CD8+ T cells undergo profound metabolic reprogramming:

Shift to glycolysis and glutaminolysis
Increased glucose uptake via GLUT1 upregulation
mTOR (mechanistic target of rapamycin) pathway activation
Production of IFN-γ, IL-2, and cytotoxic molecules

This metabolic profile supports rapid proliferation and effector function but is energetically expensive.

Regulatory T Cells (Tregs):

In contrast, Tregs preferentially use:

OXPHOS and FAO
AMPK (AMP-activated protein kinase) signaling
Minimal glycolytic activity

This metabolic distinction has therapeutic implications: interventions that promote glycolysis (high glucose, mTOR activation) favor effector responses, while those promoting OXPHOS (AMPK activation, FAO) favor regulatory responses.

Metabolic Dysfunction in Critical Illness: A Vicious Cycle

In sepsis and critical illness, several factors disrupt normal immune cell metabolism:

Mitochondrial Dysfunction:

Sepsis-induced mitochondrial damage (via oxidative stress, calcium overload, mitochondrial permeability transition)
Reduced mitochondrial biogenesis
Impaired OXPHOS capacity
This forces greater reliance on glycolysis but also impairs the generation of M2 macrophages and Tregs

Substrate Availability:

Hypoglycemia or hyperglycemia
Glutamine depletion (see Nutrigenomics section)
Altered fatty acid profiles
Micronutrient deficiencies (vitamins B, C, and D)

Metabolic Reprogramming Persistence:

Initial hyperinflammatory phase: excessive glycolytic activation
Late immunosuppressive phase: inability to sustain glycolysis or restore OXPHOS, resulting in immune paralysis

🔬 PEARL #1: The Succinate-HIF-1α Axis

In M1 macrophages, succinate accumulation stabilizes HIF-1α under normoxic conditions, amplifying pro-inflammatory responses. Measuring succinate levels or targeting HIF-1α may offer biomarkers or therapeutic targets for hyperinflammation in sepsis.

🦪 OYSTER #1: Not All Glycolysis Is Pro-inflammatory

While M1 macrophages use glycolysis, dendritic cells require glycolysis for immunogenic antigen presentation. Blanket suppression of glycolysis could impair adaptive immunity. Precision targeting is essential.

Metabolic Reprogramming as Therapy: Targeting Immune Cell Metabolism to Modulate Inflammation

The recognition that metabolic pathways drive immune function has spawned interest in "metabolic immunotherapy"—repurposing metabolic drugs or using novel agents to modulate immune responses.

Metformin: Beyond Glucose Control

Metformin, a biguanide antidiabetic drug, has pleiotropic immunometabolic effects:

Mechanisms of Action:

AMPK Activation: Metformin activates AMPK, which:
- Inhibits mTOR (reducing Teff activity)
- Promotes FAO (supporting M2 and Treg function)
- Enhances mitochondrial biogenesis
- Reduces pro-inflammatory NF-κB signaling
Complex I Inhibition: Mild inhibition of mitochondrial Complex I reduces ROS production and limits hyperinflammatory responses.
Metabolic Flexibility: By modulating cellular energy sensors, metformin may restore the balance between glycolysis and OXPHOS.

Clinical Evidence in Critical Illness:

Observational Studies: Multiple retrospective cohort studies demonstrate that prior metformin use in diabetic patients is associated with reduced sepsis incidence, lower mortality, and decreased organ dysfunction.
Mechanistic Studies: In experimental sepsis models, metformin reduces pro-inflammatory cytokine production, preserves mitochondrial function, and improves survival.
Randomized Controlled Trials: Limited RCT data exist. The METSIS trial (NCT02960672) is investigating metformin in septic shock. Preliminary results suggest potential benefits in secondary endpoints (IL-6 reduction, improved lactate clearance), though powered for safety rather than efficacy.

Practical Considerations:

Lactic acidosis risk: Metformin is contraindicated in severe renal impairment and shock due to lactic acidosis risk. However, this risk may be overstated; lactate from metformin use differs mechanistically from shock-related lactate.
Dosing: Standard doses (1-2 g/day) versus critical illness dosing remain unclear.
Timing: Prophylactic use (preventing metabolic dysfunction) versus rescue therapy (reversing established dysfunction) requires investigation.

Other Metabolic Modulators

Dichloroacetate (DCA):

Pyruvate dehydrogenase kinase inhibitor
Shifts metabolism from glycolysis to OXPHOS
Reduces lactate production
Small studies in sepsis show metabolic benefits but unclear mortality impact

2-Deoxyglucose (2-DG):

Glycolysis inhibitor
Reduces pro-inflammatory cytokine production in preclinical models
Clinical use limited by potential toxicity and lack of specificity

Itaconate Derivatives:

Itaconate, derived from the TCA cycle intermediate cis-aconitate, has emerged as an endogenous anti-inflammatory metabolite
Dimethyl itaconate (DI) activates Nrf2 (antioxidant response) and inhibits succinate dehydrogenase
Reduces NLRP3 inflammasome activation
Early-phase clinical development

mTOR Inhibitors (Rapamycin/Sirolimus):

Shift T cell metabolism toward OXPHOS
Promote Treg expansion
Concerns about immunosuppression in critically ill patients
Potential in late-phase sepsis or preventing chronic critical illness

AMPK Activators:

Beyond metformin: AICAR, resveratrol, and novel small molecules
Promote metabolic flexibility and mitochondrial health
Resveratrol shows promise in preclinical sepsis models but limited clinical translation

💊 HACK #1: Metformin as Sepsis Prophylaxis?

For high-risk surgical or ICU patients without contraindications, consider low-dose metformin (500-850 mg daily) as a preventive metabolic immunomodulator. While RCT evidence is pending, the safety profile and mechanistic rationale are compelling.

🔬 PEARL #2: Timing Matters

Metabolic interventions may have biphasic effects: glycolysis inhibition could be beneficial in early hyperinflammation but detrimental in late immunosuppression when energy-demanding immune functions are already compromised. Biomarker-guided therapy is essential.

Nutrigenomics: How Specific Nutrients Signal Immune Cells

Nutrigenomics—the study of how nutrients influence gene expression—has revealed that dietary components are not merely fuel but information, directly programming immune cell phenotypes. In critical illness, where standard nutritional support often fails to improve outcomes, precision nutrition targeting immune metabolism represents a paradigm shift.

Glutamine: The Conditionally Essential Immunonutrient

Metabolic Roles in Immune Cells:

Glutamine is the most abundant free amino acid in the body and serves multiple functions:

Carbon source for TCA cycle: Glutaminolysis (glutamine → glutamate → α-ketoglutarate) replenishes TCA cycle intermediates
Nitrogen donor: For nucleotide and amino acid synthesis
Antioxidant precursor: Glutathione synthesis
Signaling molecule: Activates mTOR in T cells
Epigenetic modifier: Supplies α-ketoglutarate for histone and DNA demethylases

Critical Illness and Glutamine Depletion:

Sepsis and trauma cause profound glutamine depletion due to:

Increased consumption by proliferating immune cells and intestinal mucosa
Reduced synthesis (muscle wasting)
Increased renal glutamine metabolism (ammonia generation for acid buffering)

Depletion impairs:

T cell proliferation and function
Macrophage bactericidal capacity
Intestinal barrier integrity
Heat shock protein expression (cellular stress resistance)

Clinical Evidence:

The glutamine story epitomizes the complexity of nutrigenomics:

Parenteral Glutamine: Multiple meta-analyses of early studies showed reduced mortality and infections with IV glutamine supplementation in critically ill patients.
The REDOXS Trial (2013): This large RCT of high-dose enteral and parenteral glutamine (plus antioxidants) in critically ill patients showed increased mortality in the glutamine group, shocking the critical care community.

Reconciling the Paradox:

Several factors may explain these contradictory findings:

Dose: REDOXS used very high doses (>0.5 g/kg/day); optimal dosing remains unclear
Renal function: Many REDOXS patients had renal dysfunction; glutamine may accumulate, producing ammonia toxicity
Timing: Late supplementation may be ineffective or harmful; early supplementation may be beneficial
Route: Enteral versus parenteral delivery affects metabolism
Heterogeneity: Not all critically ill patients are glutamine-depleted; measurement-guided supplementation may be needed

Current Recommendations:

Routine high-dose glutamine supplementation is not recommended
In selected patients (burns, trauma, without renal failure), lower doses may be considered
Measurement of plasma glutamine could guide therapy (normal: 500-900 μmol/L; depletion: <400 μmol/L)

Omega-3 Polyunsaturated Fatty Acids (n-3 PUFAs): Specialized Pro-resolving Mediators

From Anti-inflammatory to Pro-resolving:

A critical paradigm shift in inflammation biology is that resolution is not passive (simply the absence of inflammation) but an active process mediated by specialized pro-resolving mediators (SPMs) derived from omega-3 fatty acids.

Mechanism of Action:

Omega-3 PUFAs (EPA, DHA) are metabolized to SPMs:

Resolvins (from EPA and DHA)
Protectins (from DHA)
Maresins (from DHA)

These SPMs:

Reduce neutrophil infiltration and activation
Enhance macrophage efferocytosis (clearance of apoptotic cells)
Promote M2 macrophage polarization via metabolic reprogramming (enhancing FAO)
Stimulate tissue repair
Reduce pain signaling

Metabolic Effects:

Beyond SPM production, omega-3s influence immune cell metabolism:

Incorporate into cell membranes, altering lipid raft composition and receptor signaling
Activate GPR120 (anti-inflammatory G-protein coupled receptor)
Inhibit NF-κB and activate AMPK (similar to metformin)
Support mitochondrial membrane integrity and OXPHOS

Clinical Evidence in Critical Illness:

ARDS: Multiple RCTs of enteral omega-3 supplementation in ARDS have shown mixed results. The OMEGA trial (2011) showed reduced mortality and improved oxygenation; however, the EDEN-OMEGA trial (2012) showed no benefit. Meta-analyses suggest possible benefit in a subgroup of patients with direct lung injury.
Sepsis: Omega-3 supplementation has shown reduced ICU length of stay and infection rates in some studies.
Practical Approach: Immunonutrition formulas containing omega-3s, along with arginine and nucleotides, may benefit selected patient populations (major surgery, trauma) when started early, but are not routinely recommended for all critically ill patients.

Arginine: The Precursor of Nitric Oxide and Polyamines

Metabolic Fates:

Arginine is metabolized via three pathways:

Nitric oxide synthase (NOS): Produces NO (vasodilator, antimicrobial)
Arginase: Produces ornithine → polyamines (cell proliferation) and proline (collagen synthesis)
Arginine decarboxylase: Produces agmatine (neuromodulator)

The Arginine Paradox in Sepsis:

Arginine availability determines macrophage phenotype:

High arginine + iNOS expression (M1): Produces NO for bacterial killing
High arginine + arginase-1 (M2): Produces ornithine for tissue repair

In sepsis:

Increased arginase activity (from damaged cells, myeloid-derived suppressor cells) depletes arginine
This impairs both NO production (contributing to vasodilatory shock) and T cell function (T cells cannot synthesize arginine and are highly sensitive to depletion)

Clinical Considerations:

Arginine supplementation in sepsis is controversial: it may worsen hypotension (via increased NO) or improve outcomes (via improved immune function)
Benefits observed in surgical and trauma patients (not septic shock)
Often included in immunonutrition formulas but individual contribution unclear

Vitamin D: Immunometabolic Regulator

Beyond Calcium Homeostasis:

Vitamin D deficiency is prevalent in critical illness (>80% of ICU patients) and associated with worse outcomes.

Immune Effects:

Macrophages express 1α-hydroxylase (converting 25-OH-vitamin D to active 1,25-OH-vitamin D)
Vitamin D enhances antimicrobial peptide production (cathelicidin)
Modulates T cell responses, promoting Tregs
Regulates mitochondrial function and oxidative metabolism

Metabolic Effects:

Influences glucose metabolism and insulin sensitivity
Modulates mitochondrial calcium handling
Affects expression of metabolic genes

Clinical Trials:

The VIOLET trial (2019) tested high-dose vitamin D3 supplementation in critically ill patients and found no difference in mortality or patient-centered outcomes. However, the trial did not specifically target vitamin D-deficient patients or measure immunometabolic endpoints.

Nuanced Approach:

Measuring 25-OH-vitamin D levels in critically ill patients
Correcting severe deficiency (<12 ng/mL) with moderate supplementation
Avoiding supraphysiologic doses pending further evidence

🦪 OYSTER #2: The Omega-3 Heterogeneity

Not all critically ill patients have the enzymatic machinery to efficiently convert EPA/DHA to SPMs. Genetic polymorphisms in ALOX genes and baseline SPM levels may predict response to omega-3 supplementation. Future studies should consider pharmacogenomics.

💊 HACK #2: The "Immunonutrition Bundle"

For selected ICU patients (post-operative, trauma, not in septic shock), consider early enteral nutrition with:

Moderate protein (1.5 g/kg/day) including glutamine-rich sources
Omega-3 enriched formula
Vitamin D supplementation (if deficient)
Vitamin C (antioxidant, cofactor for immune function)

This approach targets multiple metabolic pathways simultaneously and may have synergistic benefits.

🔬 PEARL #3: Microbiome-Immunometabolism Axis

The gut microbiome produces metabolites (short-chain fatty acids like butyrate) that profoundly influence immune cell metabolism. Butyrate promotes Treg differentiation via OXPHOS enhancement. Strategies to preserve microbiome diversity (judicious antibiotics, consider probiotics/prebiotics) may support beneficial immunometabolic programming.

Integrating Immunometabolism into Clinical Practice

Biomarkers of Metabolic Dysfunction

Currently, bedside assessment of immune cell metabolism is not routine, but candidate biomarkers include:

Systemic Markers:

Lactate (reflects glycolytic flux but non-specific)
Lactate/pyruvate ratio (indicates OXPHOS dysfunction)
Ketone bodies (reflect FAO and metabolic stress)
Acylcarnitines (intermediates of FAO; accumulation suggests impaired oxidation)

Research Tools Moving Toward Bedside:

Flow cytometry for GLUT1 expression on immune cells
Seahorse metabolic flux assays (measuring oxygen consumption and glycolysis in real-time)
Metabolomics profiling (plasma metabolites reflecting pathway activity)
Mitochondrial function assays

Functional Immunometabolic Profiling:

Theratests measuring immune cell metabolic capacity (e.g., maximum glycolytic capacity, respiratory reserve) could stratify patients:

Hyperinflammatory phenotype: High glycolysis, low OXPHOS → glycolysis inhibitors
Immunosuppressed phenotype: Low glycolysis and OXPHOS → metabolic support, immune stimulation

Precision Medicine Approach

Patient Stratification:

Not all critically ill patients will benefit from the same metabolic intervention. Subphenotyping based on:

Inflammatory markers (CRP, IL-6)
Metabolic markers (lactate, glucose, amino acids)
Immune cell profiles (HLA-DR expression on monocytes, lymphocyte counts)
Clinical trajectory (early vs. late sepsis, resolving vs. persistent inflammation)

Intervention Timing:

Early phase (0-72 hours): Hyperinflammation predominates; glycolysis inhibitors or AMPK activators may help
Late phase (>72 hours): Immunosuppression emerges; metabolic support to restore function may be needed

Combination Therapies:

Single-target approaches may fail due to metabolic redundancy. Combining:

Metabolic modulators (metformin)
Immunonutrition (omega-3s, glutamine)
Mitochondrial protectants (CoQ10, thiamine, vitamin C)
Microbiome support

Future Directions

Pharmacological Advances:

Specific enzyme inhibitors (targeting key metabolic nodes)
SPM analogs (stable resolvins, protectins)
Mitochondrial transplantation or mitochondrial-targeted therapies
Gene therapy to enhance metabolic flexibility

Nutritional Advances:

Designer enteral formulas based on individual metabolic profiling
Timed nutrient delivery (chrononutrition) aligned with circadian metabolic rhythms
Isotope tracing in patients to track nutrient fate in real-time

Technology Integration:

Continuous metabolic monitoring (wearable or bedside devices)
Artificial intelligence predicting metabolic trajectories
Point-of-care metabolomics

💊 HACK #3: The Thiamine-Vitamin C-Hydrocortisone Connection

While the Marik protocol (high-dose vitamin C, thiamine, hydrocortisone) has not been definitively proven in large RCTs, the metabolic rationale is sound: thiamine is essential for mitochondrial OXPHOS (TCA cycle), vitamin C supports mitochondrial function and immune cell activity, and hydrocortisone modulates excessive inflammation. In refractory septic shock with suspected vitamin deficiencies, this combination may have metabolic benefits beyond the anti-inflammatory effects.

Conclusion

Immunometabolism represents a fundamental reframing of critical illness pathophysiology. The recognition that immune cell function is dictated by metabolic programming opens a vast therapeutic landscape. Metabolic reprogramming is not simply a consequence of critical illness but a driver of immune dysfunction, organ failure, and mortality.

The shift from oxidative phosphorylation to glycolysis during immune activation is a purposeful adaptation enabling rapid effector functions but comes at the cost of sustained energy deficits and impaired resolution responses. Therapeutically targeting this metabolic switch—using repurposed drugs like metformin, precision immunonutrition with glutamine and omega-3 fatty acids, and novel metabolic modulators—offers promise.

However, complexity is the rule: metabolic interventions have context-dependent effects, with potential benefits in some patients and harm in others. The future lies in precision immunometabolic medicine—stratifying patients based on metabolic and immune profiles, timing interventions appropriately, and combining therapies to address the multifaceted nature of critical illness.

As we move forward, several principles should guide practice and research:

Measure, don't assume: Metabolic dysfunction is heterogeneous; bedside metabolic profiling is needed
Context matters: Early versus late, hyperinflammatory versus immunosuppressed
Think beyond calories: Nutrition is information, not just fuel
Target multiplicity: Single interventions may fail; rational combinations are necessary
Mitochondria matter: Protecting and restoring mitochondrial function is central

The immunometabolism of critical illness bridges fundamental immunology, biochemistry, and clinical practice. For the intensivist, understanding these principles transforms how we approach nutrition, metabolic management, and immunomodulation—offering hope for improving outcomes in our most vulnerable patients.

Key Take-Home Points

Immune cell metabolism drives function: Glycolysis supports pro-inflammatory responses (M1, Teff), while OXPHOS supports anti-inflammatory and resolution responses (M2, Treg).
Metabolic dysfunction in critical illness is bidirectional: Early glycolytic overdrive contributes to hyperinflammation; later inability to sustain metabolism leads to immunosuppression.
Metformin is a promising immunometabolic modulator: AMPK activation may restore metabolic balance, but clinical trials are ongoing.
Glutamine's role is nuanced: Depletion impairs immunity, but high-dose supplementation may harm; precision supplementation guided by measurement is needed.
Omega-3 fatty acids promote resolution: Via SPM generation and metabolic reprogramming toward OXPHOS, but patient selection and timing are critical.
Precision medicine is the future: One-size-fits-all approaches fail; metabolic and immune profiling will guide individualized therapy.

References

O'Neill LAJ, Kishton RJ, Rathmell J. A guide to immunometabolism for immunologists. Nat Rev Immunol. 2016;16(9):553-565.
Cheng SC, Scicluna BP, Arts RJW, et al. Broad defects in the energy metabolism of leukocytes underlie immunoparalysis in sepsis. Nat Immunol. 2016;17(4):406-413.
Mills EL, Kelly B, Logan A, et al. Succinate dehydrogenase supports metabolic repurposing of mitochondria to drive inflammatory macrophages. Cell. 2016;167(2):457-470.
Tannahill GM, Curtis AM, Adamik J, et al. Succinate is an inflammatory signal that induces IL-1β through HIF-1α. Nature. 2013;496(7444):238-242.
Loftus RM, Finlay DK. Immunometabolism: Cellular metabolism turns immune regulator. J Biol Chem. 2016;291(1):1-10.
Pearce EL, Pearce EJ. Metabolic pathways in immune cell activation and quiescence. Immunity. 2013;38(4):633-643.
Buck MD, O'Sullivan D, Klein Geltink RI, et al. Mitochondrial dynamics controls T cell fate through metabolic programming. Cell. 2016;166(1):63-76.
van Wyngene L, Vandewalle J, Libert C. Reprogramming of basic metabolic pathways in microbial sepsis: therapeutic targets at last? EMBO Mol Med. 2018;10(8):e8712.
Singer M, Deutschman CS, Seymour CW, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315(8):801-810.
Hotchkiss RS, Monneret G, Payen D. Sepsis-induced immunosuppression: from cellular dysfunctions to immunotherapy. Nat Rev Immunol. 2013;13(12):862-874.
Elenkov IJ, Iezzoni DG, Daly A, et al. Cytokine dysregulation, inflammation and well-being. Neuroimmunomodulation. 2005;12(5):255-269.
Cameron MJ, Kelvin DJ. Cytokine storm syndrome. In: Mackay IR, Rose NR, eds. The Autoimmune Diseases. 5th ed. Academic Press; 2014:965-978.
Kelly B, O'Neill LA. Metabolic reprogramming in macrophages and dendritic cells in innate immunity. Cell Res. 2015;25(7):771-784.
Galván-Peña S, O'Neill LA. Metabolic reprogramming in macrophage polarization. Front Immunol. 2014;5:420.
Michalek RD, Gerriets VA, Jacobs SR, et al. Cutting edge: distinct glycolytic and lipid oxidative metabolic programs are essential for effector and regulatory CD4+ T cell subsets. J Immunol. 2011;186(6):3299-3303.
Shi LZ, Wang R, Huang G, et al. HIF1alpha-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells. J Exp Med. 2011;208(7):1367-1376.
Singer M. The role of mitochondrial dysfunction in sepsis-induced multi-organ failure. Virulence. 2014;5(1):66-72.
Brealey D, Brand M, Hargreaves I, et al. Association between mitochondrial dysfunction and severity and outcome of septic shock. Lancet. 2002;360(9328):219-223.
Piel DA, Gruber PJ, Weinheimer CJ, et al. Mitochondrial resuscitation with exogenous cytochrome c in the septic heart. Crit Care Med. 2007;35(9):2120-2127.
Joffre J, Hellman J, Ince C, Ait-Oufella H. Endothelial responses in sepsis. Am J Respir Crit Care Med. 2020;202(3):361-370.
Gallo RL, Hooper LV. Epithelial antimicrobial defence of the skin and intestine. Nat Rev Immunol. 2012;12(7):503-516.
Cameron AM, Lawless SJ, Pearce EJ. Metabolism and acetylation in innate immune cell function and fate. Semin Immunol. 2016;28(5):408-416.
Infantino V, Convertini P, Cucci L, et al. The mitochondrial citrate carrier: a new player in inflammation. Biochem J. 2011;438(3):433-436.
Palsson-McDermott EM, Curtis AM, Goel G, et al. Pyruvate kinase M2 regulates Hif-1α activity and IL-1β induction and is a critical determinant of the warburg effect in LPS-activated macrophages. Cell Metab. 2015;21(1):65-80.
Lampropoulou V, Sergushichev A, Bambouskova M, et al. Itaconate links inhibition of succinate dehydrogenase with macrophage metabolic remodeling and regulation of inflammation. Cell Metab. 2016;24(1):158-166.
Mills EL, Ryan DG, Prag HA, et al. Itaconate is an anti-inflammatory metabolite that activates Nrf2 via alkylation of KEAP1. Nature. 2018;556(7699):113-117.
Colegio OR, Chu NQ, Szabo AL, et al. Functional polarization of tumour-associated macrophages by tumour-derived lactic acid. Nature. 2014;513(7519):559-563.
Pucino V, Certo M, Bulusu V, et al. Lactate buildup at the site of chronic inflammation promotes disease by inducing CD4+ T cell metabolic rewiring. Cell Metab. 2019;30(6):1055-1074.
Haas R, Smith J, Rocher-Ros V, et al. Lactate regulates metabolic and pro-inflammatory circuits in control of T cell migration and effector functions. PLoS Biol. 2015;13(7):e1002202.
Ratter JM, Rooijackers HMM, Hooiveld GJ, et al. In vitro and in vivo effects of lactate on metabolism and cytokine production of human primary PBMCs and monocytes. Front Immunol. 2018;9:2564.
Angelin A, Gil-de-Gómez L, Dahiya S, et al. Foxp3 reprograms T cell metabolism to function in low-glucose, high-lactate environments. Cell Metab. 2017;25(6):1282-1293.
Wang R, Dillon CP, Shi LZ, et al. The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation. Immunity. 2011;35(6):871-882.
Gerriets VA, Kishton RJ, Nichols AG, et al. Metabolic programming and PDHK1 control CD4+ T cell subsets and inflammation. J Clin Invest. 2015;125(1):194-207.
Berod L, Friedrich C, Nandan A, et al. De novo fatty acid synthesis controls the fate between regulatory T and T helper 17 cells. Nat Med. 2014;20(11):1327-1333.
Howie D, Cobbold SP, Adams E, et al. Foxp3 drives oxidative phosphorylation and protection from lipotoxicity. JCI Insight. 2017;2(3):e89160.
Cameron AM, Castoldi A, Sanin DE, et al. Inflammatory macrophage dependence on NAD+ salvage is a consequence of reactive oxygen species-mediated DNA damage. Nat Immunol. 2019;20(4):420-432.
Langley RJ, Tsalik EL, van Velkinburgh JC, et al. An integrated clinico-metabolomic model improves prediction of death in sepsis. Sci Transl Med. 2013;5(195):195ra95.
Eckerle M, Ambroggio L, Pushing T, et al. Metabolomics as a driver in advancing precision medicine in sepsis. Pharmacotherapy. 2017;37(9):1023-1032.
Howell GM, Gomez H, Collage RD, et al. Augmenting autophagy to treat acute kidney injury during endotoxemia in mice. PLoS One. 2013;8(7):e69520.
Escobar DA, Botero-Quintero AM, Kautza BC, et al. Adenosine monophosphate-activated protein kinase activation protects against sepsis-induced organ injury and inflammation. J Surg Res. 2015;194(1):262-272.
Drosatos K, Khan RS, Trent CM, et al. Peroxisome proliferator-activated receptor-γ activation prevents sepsis-related cardiac dysfunction and mortality in mice. Circ Heart Fail. 2013;6(3):550-562.
Ding HG, Li FF, Zhang L, et al. The effect of metformin on mortality and complications of sepsis: A systematic review and meta-analysis. Front Pharmacol. 2022;13:805981.
Liang H, Ding X, Li L, et al. Association of preadmission metformin use and mortality in patients with sepsis and diabetes mellitus: a systematic review and meta-analysis of cohort studies. Crit Care. 2019;23(1):50.
Doenyas-Barak K, Beberashvili I, Marcus R, et al. Lactic acidosis and severe septic shock in metformin users: A cohort study. Emerg Med J. 2016;33(6):386-390.
Calzada Gutiérrez S, Parra Ramírez LM, Moreno JM, et al. Metformin for critically ill patients: Review of the evidence and perspectives. Med Intensiva. 2018;42(5):318-324.
Romero R, Erez O, Hüttemann M, et al. Metformin, the aspirin of the 21st century: its role in gestational diabetes mellitus, prevention of preeclampsia and cancer, and the promotion of longevity. Am J Obstet Gynecol. 2017;217(3):282-302.
El-Mir MY, Nogueira V, Fontaine E, et al. Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I. J Biol Chem. 2000;275(1):223-228.
Madiraju AK, Erion DM, Rahimi Y, et al. Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase. Nature. 2014;510(7506):542-546.
Viollet B, Guigas B, Sanz Garcia N, et al. Cellular and molecular mechanisms of metformin: an overview. Clin Sci (Lond). 2012;122(6):253-270.
Zhou G, Myers R, Li Y, et al. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest. 2001;108(8):1167-1174.
Eikawa S, Nishida M, Mizukami S, et al. Immune-mediated antitumor effect by type 2 diabetes drug, metformin. Proc Natl Acad Sci U S A. 2015;112(6):1809-1814.
Ursini F, Russo E, Pellino G, et al. Metformin and autoimmunity: A "new deal" of an old drug. Front Immunol. 2018;9:1236.
Corcoran SE, O'Neill LA. HIF1α and metabolic reprogramming in inflammation. J Clin Invest. 2016;126(10):3699-3707.
Kelly B, Tannahill GM, Murphy MP, O'Neill LA. Metformin inhibits the production of reactive oxygen species from NADH:ubiquinone oxidoreductase to limit induction of interleukin-1β (IL-1β) and boosts interleukin-10 (IL-10) in lipopolysaccharide (LPS)-activated macrophages. J Biol Chem. 2015;290(33):20348-20359.
Jha AK, Huang SC, Sergushichev A, et al. Network integration of parallel metabolic and transcriptional data reveals metabolic modules that regulate macrophage polarization. Immunity. 2015;42(3):419-430.
Bonnet S, Archer SL, Allalunis-Turner J, et al. A mitochondria-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth. Cancer Cell. 2007;11(1):37-51.
Stacpoole PW, Nagaraja NV, Hutson AD. Efficacy of dichloroacetate as a lactate-lowering drug. J Clin Pharmacol. 2003;43(7):683-691.
Stacpoole PW, Wright EC, Baumgartner TG, et al. A controlled clinical trial of dichloroacetate for treatment of lactic acidosis in adults. N Engl J Med. 1992;327(22):1564-1569.
Michelakis ED, Sutendra G, Dromparis P, et al. Metabolic modulation of glioblastoma with dichloroacetate. Sci Transl Med. 2010;2(31):31ra34.
Wang Y, Huang Y, Guan F, et al. Hypoxia-inducible factor-1α and MAPK co-regulate activation of hepatic stellate cells upon hypoxia stimulation. PLoS One. 2013;8(9):e74051.
Bambouskova M, Gorvel L, Lampropoulou V, et al. Electrophilic properties of itaconate and derivatives regulate the IκBζ-ATF3 inflammatory axis. Nature. 2018;556(7702):501-504.
Hooftman A, Angiari S, Hester S, et al. The immunomodulatory metabolite itaconate modifies NLRP3 and inhibits inflammasome activation. Cell Metab. 2020;32(3):468-478.
Weichhart T, Hengstschläger M, Linke M. Regulation of innate immune cell function by mTOR. Nat Rev Immunol. 2015;15(10):599-614.
Powell JD, Pollizzi KN, Heikamp EB, Horton MR. Regulation of immune responses by mTOR. Annu Rev Immunol. 2012;30:39-68.
Araki K, Turner AP, Shaffer VO, et al. mTOR regulates memory CD8 T-cell differentiation. Nature. 2009;460(7251):108-112.
Delgoffe GM, Kole TP, Zheng Y, et al. The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment. Immunity. 2009;30(6):832-844.
Perl A. mTOR activation is a biomarker and a central pathway to autoimmune disorders, cancer, obesity, and aging. Ann N Y Acad Sci. 2015;1346(1):33-44.
Newsholme P, Procopio J, Lima MM, et al. Glutamine and glutamate—their central role in cell metabolism and function. Cell Biochem Funct. 2003;21(1):1-9.
Newsholme P. Why is L-glutamine metabolism important to cells of the immune system in health, postinjury, surgery or infection? J Nutr. 2001;131(9 Suppl):2515S-2522S.
Cruzat V, Macedo Rogero M, Noel Keane K, et al. Glutamine: Metabolism and immune function, supplementation and clinical translation. Nutrients. 2018;10(11):1564.
Parry-Billings M, Evans J, Calder PC, Newsholme EA. Does glutamine contribute to immunosuppression after major burns? Lancet. 1990;336(8714):523-525.
Oudemans-van Straaten HM, Bosman RJ, Treskes M, et al. Plasma glutamine depletion and patient outcome in acute ICU admissions. Intensive Care Med. 2001;27(1):84-90.
Wischmeyer PE, Dhaliwal R, McCall M, et al. Parenteral glutamine supplementation in critical illness: a systematic review. Crit Care. 2014;18(2):R76.
Heyland D, Muscedere J, Wischmeyer PE, et al. A randomized trial of glutamine and antioxidants in critically ill patients. N Engl J Med. 2013;368(16):1489-1497.
van Zanten AR, Sztark F, Kaisers UX, et al. High-protein enteral nutrition enriched with immune-modulating nutrients vs standard high-protein enteral nutrition and nosocomial infections in the ICU: a randomized clinical trial. JAMA. 2014;312(5):514-524.
Stehle P, Ellger B, Kojic D, et al. Glutamine dipeptide-supplemented parenteral nutrition improves the clinical outcomes of critically ill patients: A systematic evaluation of randomised controlled trials. Clin Nutr ESPEN. 2017;17:75-85.
Novak F, Heyland DK, Avenell A, et al. Glutamine supplementation in serious illness: a systematic review of the evidence. Crit Care Med. 2002;30(9):2022-2029.
Wischmeyer PE. Glutamine: role in critical illness and ongoing clinical trials. Curr Opin Gastroenterol. 2008;24(2):190-197.
Serhan CN. Pro-resolving lipid mediators are leads for resolution physiology. Nature. 2014;510(7503):92-101.
Serhan CN, Chiang N, Dalli J, Levy BD. Lipid mediators in the resolution of inflammation. Cold Spring Harb Perspect Biol. 2014;7(2):a016311.
Buckley CD, Gilroy DW, Serhan CN. Proresolving lipid mediators and mechanisms in the resolution of acute inflammation. Immunity. 2014;40(3):315-327.
Levy BD, Clish CB, Schmidt B, et al. Lipid mediator class switching during acute inflammation: signals in resolution. Nat Immunol. 2001;2(7):612-619.
Dalli J, Serhan CN. Specific lipid mediator signatures of human phagocytes: microparticles stimulate macrophage efferocytosis and pro-resolving mediators. Blood. 2012;120(15):e60-e72.
Calder PC. Marine omega-3 fatty acids and inflammatory processes: Effects, mechanisms and clinical relevance. Biochim Biophys Acta. 2015;1851(4):469-484.
Calder PC. Omega-3 fatty acids and inflammatory processes: from molecules to man. Biochem Soc Trans. 2017;45(5):1105-1115.
Pontes-Arruda A, Aragão AM, Albuquerque JD. Effects of enteral feeding with eicosapentaenoic acid, gamma-linolenic acid, and antioxidants in mechanically ventilated patients with severe sepsis and septic shock. Crit Care Med. 2006;34(9):2325-2333.
Gadek JE, DeMichele SJ, Karlstad MD, et al. Effect of enteral feeding with eicosapentaenoic acid, gamma-linolenic acid, and antioxidants in patients with acute respiratory distress syndrome. Crit Care Med. 1999;27(8):1409-1420.
Singer P, Shapiro H, Theilla M, et al. Anti-inflammatory properties of omega-3 fatty acids in critical illness: novel mechanisms and an integrative perspective. Intensive Care Med. 2008;34(9):1580-1592.
Rice TW, Wheeler AP, Thompson BT, et al. Enteral omega-3 fatty acid, gamma-linolenic acid, and antioxidant supplementation in acute lung injury. JAMA. 2011;306(14):1574-1581.
Rice TW, Wheeler AP, Thompson BT, et al. Initial trophic vs full enteral feeding in patients with acute lung injury: the EDEN randomized trial. JAMA. 2012;307(8):795-803.
Manzanares W, Langlois PL, Dhaliwal R, et al. Intravenous fish oil lipid emulsions in critically ill patients: an updated systematic review and meta-analysis. Crit Care. 2015;19:167.
Calder PC, Waitzberg DL, Klek S, Martindale RG. Lipids in parenteral nutrition: biological aspects. JPEN J Parenter Enteral Nutr. 2020;44 Suppl 1:S21-S27.
Morris CR, Hamilton-Reeves J, Martindale RG, et al. Acquired amino acid deficiencies: a focus on arginine and glutamine. Nutr Clin Pract. 2017;32(1_suppl):30S-47S.
Luiking YC, Poeze M, Dejong CH, et al. Sepsis: an arginine deficiency state? Crit Care Med. 2004;32(10):2135-2145.
Rodriguez PC, Quiceno DG, Ochoa AC. L-arginine availability regulates T-lymphocyte cell-cycle progression. Blood. 2007;109(4):1568-1573.
Bronte V, Zanovello P. Regulation of immune responses by L-arginine metabolism. Nat Rev Immunol. 2005;5(8):641-654.
Gianotti L, Braga M, Nespoli L, et al. A randomized controlled trial of preoperative oral supplementation with a specialized diet in patients with gastrointestinal cancer. Gastroenterology. 2002;122(7):1763-1770.
Drover JW, Dhaliwal R, Weitzel L, et al. Perioperative use of arginine-supplemented diets: a systematic review of the evidence. J Am Coll Surg. 2011;212(3):385-399.
Holick MF. Vitamin D deficiency. N Engl J Med. 2007;357(3):266-281.
Liu PT, Stenger S, Li H, et al. Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science. 2006;311(5768):1770-1773.
Amrein K, Schnedl C, Holl A, et al. Effect of high-dose vitamin D3 on hospital length of stay in critically ill patients with vitamin D deficiency: the VITdAL-ICU randomized clinical trial. JAMA. 2014;312(15):1520-1530.
Amrein K, Parekh D, Westphal S, et al. Effect of high-dose vitamin D3 on 28-day mortality in adult critically ill patients with severe vitamin D deficiency: a study protocol of a multicentre, placebo-controlled double-blind phase III RCT (the VITDALIZE study). BMJ Open. 2019;9(11):e031083.
Beard JA, Bearden A, Striker R. Vitamin D and the anti-viral state. J Clin Virol. 2011;50(3):194-200.
Bikle DD, Christakos S. New aspects of vitamin D metabolism and action—addressing the skin as source and target. Nat Rev Endocrinol. 2020;16(4):234-252.
Latic N, Erben RG. Vitamin D and cardiovascular disease, with emphasis on hypertension, atherosclerosis, and heart failure. Int J Mol Sci. 2020;21(18):6483.
Ryan PM, Caplice NM. Is adipose tissue a reservoir for viral spread, immune activation, and cytokine amplification in coronavirus disease 2019? Obesity (Silver Spring). 2020;28(7):1191-1194.
Singer P, Blaser AR, Berger MM, et al. ESPEN guideline on clinical nutrition in the intensive care unit. Clin Nutr. 2019;38(1):48-79.
McClave SA, Taylor BE, Martindale RG, et al. Guidelines for the provision and assessment of nutrition support therapy in the adult critically ill patient: Society of Critical Care Medicine (SCCM) and American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.). JPEN J Parenter Enteral Nutr. 2016;40(2):159-211.
Preiser JC, van Zanten AR, Berger MM, et al. Metabolic and nutritional support of critically ill patients: consensus and controversies. Crit Care. 2015;19:35.
Marik PE, Khangoora V, Rivera R, et al. Hydrocortisone, vitamin C, and thiamine for the treatment of severe sepsis and septic shock: a retrospective before-after study. Chest. 2017;151(6):1229-1238.
Fowler AA III, Truwit JD, Hite RD, et al. Effect of vitamin C infusion on organ failure and biomarkers of inflammation and vascular injury in patients with sepsis and severe acute respiratory failure: the CITRIS-ALI randomized clinical trial. JAMA. 2019;322(13):1261-1270.
Fujii T, Luethi N, Young PJ, et al. Effect of vitamin C, hydrocortisone, and thiamine vs hydrocortisone alone on time alive and free of vasopressor support among patients with septic shock: The VITAMINS randomized clinical trial. JAMA. 2020;323(5):423-431.
Moskowitz A, Huang DT, Hou PC, et al. Effect of ascorbic acid, corticosteroids, and thiamine on organ injury in septic shock: the ACTS randomized clinical trial. JAMA. 2020;324(7):642-650.
Donnino MW, Andersen LW, Chase M, et al. Randomized, double-blind, placebo-controlled trial of thiamine as a metabolic resuscitator in septic shock: a pilot study. Crit Care Med. 2016;44(2):360-367.
Woolum JA, Abner EL, Kelly A, et al. Effect of thiamine administration on lactate clearance and mortality in patients with septic shock. Crit Care Med. 2018;46(11):1747-1752.

Glossary of Key Terms

AMPK (AMP-activated protein kinase): Cellular energy sensor activated by low ATP/AMP ratio; promotes catabolic pathways and mitochondrial biogenesis.

Efferocytosis: Process by which phagocytes remove apoptotic cells; critical for inflammation resolution.

FAO (Fatty acid oxidation): β-oxidation of fatty acids in mitochondria to generate acetyl-CoA for the TCA cycle.

HIF-1α (Hypoxia-inducible factor-1α): Transcription factor stabilized under hypoxia (or pseudohypoxia) that drives glycolytic gene expression.

Immunometabolism: The study of metabolic pathways in immune cells and their regulation of immune function.

mTOR (Mechanistic target of rapamycin): Serine/threonine kinase that integrates nutrient, growth factor, and energy signals to control cell growth and metabolism.

OXPHOS (Oxidative phosphorylation): ATP generation via the electron transport chain in mitochondria; efficient but slower energy production.

PPP (Pentose phosphate pathway): Metabolic pathway parallel to glycolysis generating NADPH and ribose-5-phosphate.

SPMs (Specialized pro-resolving mediators): Lipid mediators (resolvins, protectins, maresins) derived from omega-3 fatty acids that actively promote resolution of inflammation.

TCA cycle (Tricarboxylic acid cycle): Also called Krebs cycle or citric acid cycle; central metabolic pathway oxidizing acetyl-CoA to generate reducing equivalents for OXPHOS.

Acknowledgments

The authors acknowledge the pioneering work of researchers in immunometabolism who have transformed our understanding of immune cell biology and opened new therapeutic horizons for critical care medicine.

Conflict of Interest Statement: The authors declare no conflicts of interest related to this manuscript.

Funding: No specific funding was received for this review article.

Monday, November 10, 2025