How does fermentation (aerobic glycolysis) contribute to the pathogenesis and therapeutic targeting of autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, and inflammatory bowel disease?

Fermentation (Aerobic Glycolysis) in Autoimmune Disease Pathogenesis

Aerobic glycolysis and its downstream product lactate drive autoimmune disease pathogenesis through lactylation-mediated immune cell activation, making metabolic reprogramming a critical therapeutic target across rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, and multiple sclerosis.

The Metabolic-Inflammatory Axis

Autoimmune diseases share a common metabolic signature: immune cells shift from oxidative phosphorylation to aerobic glycolysis (the Warburg effect) even when oxygen is available 1, 2, 3. This metabolic switch is not merely an energy adaptation—it fundamentally alters immune cell function and drives chronic inflammation.

Key Mechanistic Insights

Lactate functions as both metabolic byproduct and active signaling molecule 4, 5. The process works through this pathway:

• Inflammatory microenvironments create local hypoxia
• Immune cells upregulate glycolytic enzymes (HK2, PFKFB3, PKM2)
• Increased lactate production occurs
• Lactate drives lactylation—a post-translational modification where lactate molecules attach to lysine residues on proteins
• Lactylation modifies transcription factors, enzymes, and immune regulatory proteins
• This perpetuates inflammatory responses and tissue damage

Disease-Specific Manifestations

Rheumatoid Arthritis

In RA, enhanced glycolytic metabolism in synovial tissues and immune cells directly promotes joint destruction 4, 5. The evidence shows:

• Synovial fibroblasts and infiltrating immune cells (macrophages, T cells, B cells, dendritic cells) exhibit abnormally elevated glycolysis
• Key glycolytic enzymes (HK2, PFK-1/PFKFB3, PKM2) show aberrant expression
• Lactate accumulation drives synovial hyperplasia, pannus formation, and bone erosion
• Lactylation enhances inflammatory cytokine production and immune cell infiltration
• This creates a self-perpetuating cycle: inflammation → hypoxia → glycolysis → lactate → lactylation → more inflammation

The primary treatment goal remains clinical remission defined as absence of inflammatory disease activity 6, 7, with abrogation of inflammation as the most important mechanism 6.

Systemic Lupus Erythematosus

SLE demonstrates similar metabolic reprogramming with lactylation driving autoantibody production and tissue damage 1, 2, 3. Patients show:

• Altered gut microbiota with reduced beneficial bacteria and increased pathobionts 8
• Enhanced glycolysis in lymphocytes
• Elevated lactate levels exacerbating immune responses
• Lactylation promoting chronic inflammation and multi-organ involvement

Multiple Sclerosis and Inflammatory Bowel Disease

Both conditions exhibit the metabolic switch toward aerobic glycolysis with lymphocyte reprogramming 3. The pattern includes:

• Increased glycolysis and mitochondrial dysfunction
• Enhanced mTOR signaling
• Dysregulated glutamine metabolism
• Fatty acid synthesis alterations
• These changes critically shape lymphocyte activation, differentiation, and pathogenicity

Therapeutic Implications

Targeting the Glycolysis-Lactylation Axis

The most promising therapeutic approach involves inhibiting specific glycolytic enzymes 4, 5:

• HK2 inhibitors: Block the first committed step of glycolysis
• PKM2 inhibitors: Target the rate-limiting enzyme
• PFKFB3 inhibitors: Reduce glycolytic flux
• LDH inhibitors: Prevent lactate production

Critical Considerations

The challenge lies in cell-specific targeting without systemic toxicity 3. Current evidence derives primarily from preclinical models, though the mechanistic understanding is robust 1, 2.

Dietary modification may provide adjunctive benefit 8:

• Mediterranean-style diets with anti-inflammatory and antioxidant properties show association with reduced disease risk
• High-fiber diets support beneficial gut microbiota
• Omega-3 fatty acids demonstrate anti-inflammatory effects
• Avoid processed foods, saturated fats, and refined sugars that promote pathogenic bacteria and inflammation

Integration with Standard Care

For RA specifically, treatment must target remission through measuring disease activity and adjusting therapy at least every 3 months until target achieved 6, 7. Metabolic interventions should complement, not replace, standard immunosuppressive therapy.

Common Pitfalls

Do not assume metabolic changes are merely consequences of inflammation—they are active drivers of disease pathogenesis 1, 2, 3. The bidirectional relationship between metabolism and immunity means addressing metabolic reprogramming may break the inflammatory cycle.

Avoid overlooking the gut-joint axis 9. Microbial dysbiosis contributes to metabolic alterations and immune activation across multiple autoimmune conditions, particularly in spondyloarthritis, RA, and IBD.

Future Directions

Lactylation-associated genes and modification levels show potential as disease biomarkers 1. Clinical trials are needed to validate targeting lactate metabolic pathways or involved enzymes as therapeutic strategies. The metabolic-epigenetic crosstalk represents a fundamental mechanism linking cellular metabolism to immune tolerance failure 3.