Sepsis as an Energy Crisis: Why the Immune System Fails Without Fuel

Sepsis remains one of medicine’s greatest challenges. Patients often arrive in intensive care with infections that spiral into two seemingly opposite dangers: first, a destructive cytokine storm, and then, paradoxically, a state of dangerous immune paralysis where they can no longer fight infection.

A 2024 review in Biomedicines by Padovani and Yin (2024), “Immunosuppression in Sepsis: Biomarkers and Specialized Pro-Resolving Mediators,” takes us deep into this puzzle. The authors outline how sepsis progresses from hyperinflammation into immune collapse, focusing on three hallmarks:

• Lymphocyte apoptosis – vital immune cells die prematurely through mitochondrial and caspase-driven pathways.

• Macrophage exhaustion – frontline immune cells lose the ability to present antigens, phagocytose microbes, or release inflammatory cytokines.

• Myeloid-derived suppressor cell (MDSC) expansion – immature myeloid cells flood into the bloodstream, dampening immunity through enzymes like arginase-1 and cytokines like IL-10.

These changes are now measurable. Biomarkers such as low HLA-DR expression, high IL-10, altered GPR18 signaling, and lymphopenia are emerging tools to identify when the immune system has tipped into collapse.

The review also highlights a fascinating therapeutic angle: specialized pro-resolving mediators (SPMs), lipid molecules like resolvins and lipoxins derived from omega-3 fatty acids. Unlike steroids or immune suppressants, SPMs don’t silence immunity—they guide it back to balance, enhancing macrophage “cleanup” functions while reducing collateral damage.

But here’s the bigger story: why does the immune system fail to complete resolution in the first place?

Resolution Is Not Free

For years, scientists thought inflammation faded passively once the trigger was gone. We now know that resolution is an active, highly choreographed process. Counterregulatory immune programs work to:

• Switch macrophages from a pro-inflammatory “M1” state to tissue-repairing and pro-resolving phenotypes.

• Expand regulatory T cells (Tregs) that release IL-10 and TGF-β to calm excessive responses.

• Produce SPMs that enhance efferocytosis (the removal of apoptotic neutrophils) and restore tissue homeostasis.

• Activate genes that restrain NF-κB, stabilize mitochondria, and boost antioxidant defenses.

All of these require energy and substrates—fatty acids for SPMs, amino acids for lymphocyte survival, NADPH for redox balance, ATP for mitochondrial reprogramming.

When Energy Runs Out: The ERM Perspective

This is where the framework of Exposure-Related Malnutrition (ERM) helps connect the dots. ERM describes a state where chronic stressors or acute illness force the body to divert scarce energy and nutrients toward short-term survival, leaving nothing in reserve for repair.

In sepsis, the early hyperinflammatory phase consumes extraordinary amounts of energy. If nutrient and energy stores aren’t replenished, the immune system cannot afford the costly work of resolution. Counterregulatory pathways stall, and the system tips into maladaptation:

• Lymphocytes undergo apoptosis instead of surviving.

• Macrophages remain “exhausted,” unable to switch into pro-resolving modes.

• MDSCs dominate, shutting down adaptive immunity.

Sepsis thus becomes not just an infection, but an energy crisis.

Vitamin D: A Case in Point

One clear example is vitamin D, a nutrient with powerful roles in immune regulation.

• Deficiency is common: 30–50% of the global population has insufficient vitamin D, and in ICU patients—including those with sepsis—the rate can reach 70–80%. Deficiency correlates with higher mortality.

  
  

• Molecular role: Vitamin D acts through the vitamin D receptor (VDR), which binds DNA and regulates the transcription of hundreds of genes. Many of these are counterregulatory genes:

  • IL-10 → supports Treg expansion and immune tolerance.

  • Cathelicidin (LL-37) and defensins → antimicrobial peptides that clear pathogens without escalating inflammation.

  • IκBα → inhibits NF-κB, limiting runaway cytokine production.

  • Bcl-2 family regulators → prevent unnecessary lymphocyte apoptosis.

    
    

• In ERM framing: Without sufficient vitamin D, the transcriptional “fuel” for counterregulation runs out. The immune system is left unable to produce its own brakes or cleanup crews.

  
  

  Vitamin D is just one example. Omega-3 fatty acids, glutamine, and redox cofactors like NADPH are also critical substrates for resolution.

  
  

Beyond Fighting Infection

Padovani and Yin argue that new therapies for sepsis should focus not only on blunting inflammation or reviving immune cells, but on supporting the body’s intrinsic resolution programs. The ERM perspective reinforces this: immune recovery depends on restoring the bioenergetic balance needed to complete the cycle of inflammation and repair.

SPMs may prove to be powerful tools here—resolvin D2, for example, boosts macrophage clearance of bacteria while reducing damage, and even improves survival in animal models of late sepsis. But just as importantly, substrate support—ensuring adequate vitamin D, amino acids, fatty acids, and mitochondrial cofactors—may be what allows these molecules to work in the first place.

Take-Home Message

Sepsis shows us the immune system at its most extreme: burning out in a storm of inflammation, then collapsing into silence. The transition isn’t just an accident of immunity—it’s a failure of energy supply.

Counterregulatory immune responses—SPMs, Tregs, macrophage reprogramming—are like gears that shift the body from defense to repair. But gears can’t turn without fuel.

By framing sepsis through Exposure-Related Malnutrition (ERM), we can see these hallmarks of immunosuppression not only as immune defects, but as signatures of bioenergetic depletion. This opens the door to new strategies: pairing immune modulation with nutrient and metabolic support to restore the body’s most powerful healing program—successful resolution.

Padovani, C. M., & Yin, K. (2024). Immunosuppression in sepsis: Biomarkers and specialized pro-resolving mediators. Biomedicines, 12(1), 175. https://doi.org/10.3390/biomedicines12010175

#Sepsis immunosuppression, #Exposure-Related Malnutrition (ERM), #Counterregulatory immune responses, #Specialized pro-resolving mediators (SPMs), #Vitamin D deficiency