When the Skin Remembers: How Everyday Exposures Strengthen Our Defenses

A new review in eLife by Gres et al. (2025), “Trained Immunity in Skin Infections: Macrophages and Beyond,” offers a fascinating glimpse into how our skin learns from experience.

Long thought to be a simple physical barrier, the skin is now recognized as a metabolically intelligent organ—one that can “remember” mild microbial encounters and use that memory to respond faster and heal better the next time.

Skin Immunity Learns Like the Gut

What happens on our skin closely mirrors what happens in our gut.

Both are mucosal frontlines, constantly exposed to harmless microbes and occasional invaders. In both places, tiny doses of microbial or metabolic signals—without real tissue damage—teach local immune cells to respond more effectively later.

This process, called trained immunity, is the innate immune system’s version of memory.

In the skin, common bacteria such as Staphylococcus aureus can trigger this training. Macrophages—the big eaters that patrol tissue—briefly shift their metabolism toward glycolysis, the fast-burning energy pathway that fuels inflammation. This short burst creates the cellular equivalent of a rehearsal: genes for defense are marked and ready to activate quickly if infection strikes again.

In the gut, the same pattern holds true. Short-chain fatty acids from friendly bacteria act as mild stress signals, fine-tuning immune tolerance and protecting against overreaction. In both organs, the dialogue between microbes and metabolism defines resilience.

Hormesis: Strength Through Small Stress

This principle is a textbook example of hormesis—the idea that small, controlled stressors make us stronger.

Just as exercise or brief fasting trains our cells to handle future stress, mild microbial exposure trains our immune metabolism.

The key is dose and context: a nudge, not an injury. When the exposure comes without an overload of damage signals (DAMPs), the system adapts instead of inflaming. The immune cells “practice” defense without paying the full energetic cost of battle.

The Metabolic Switch Between Alarm and Tolerance

Every immune response walks a metabolic tightrope:

• Glycolysis fuels the alarm phase—quick energy, pro-inflammatory cytokines, and microbe killing.

• Oxidative phosphorylation (OXPHOS) powers the resolution phase—efficient ATP production, antioxidant defense, and tissue repair.

When energy and nutrients are plentiful, the system smoothly transitions from glycolysis back to OXPHOS. But when resources run low—or exposures become chronic—the switch sticks. Cells stay glycolytic, inflammation lingers, and repair stalls.

Where ERM Fits In

This is precisely the dynamic described by the Exposure-Related Malnutrition (ERM) framework.ERM proposes that chronic, unrelenting exposure—whether microbial, toxic, or psychological—can trap the body in a bioenergetic debt.

Instead of resolving stress, the system remains half-activated: inflamed yet undernourished, fighting but not healing.

In this light, trained immunity represents the adaptive face of stress—a hormetic rehearsal that strengthens resilience.ERM represents the exhausted face of the same process—when the energy needed for resolution runs out.

Both arise from how our body manages the metabolic cost of adaptation.

Why It Matters

The lesson from the skin is universal:

Our barriers—skin, gut, lung—are not passive walls but living teachers. They learn from every exposure, tune their metabolism, and decide when to fight and when to repair.

Supporting this rhythm—through nourishment, rest, and balanced microbial contact—may be the key to restoring resilience in modern chronic conditions.

Reference:

Gres V, Göcer M, Kolter J, & Henneke P. (2025). Trained immunity in skin infections: macrophages and beyond. eLife, 14, e106688. https://doi.org/10.7554/eLife.106688

#Trained immunity, #Hormesis, #Glycolysis / OXPHOS switch, #Mucosal resilience, #Exposure-Related Malnutrition