New research into Lyme arthritis (joint pain due to an infection with Borrelia burgdorferi) is challenging long-standing assumptions about what causes persistent symptoms after treatment. For years, many clinicians believed that when patients continued to experience swollen joints, even after treatment with antibiotics, the inflammation was simply due to an overactive immune system. The body’s immune system was believed to be reacting to “leftover” bacterial debris and not an ongoing infection.

But that explanation may not be the full story.

A recent study published in Science Translational Medicine examined the synovial fluid of patients with Lyme arthritis—often weeks or months after their initial diagnosis and antibiotic treatment. Researchers found peptidoglycan, a key structural molecule from the cell wall of Borrelia burgdorferi, still present in the joint fluid.

Peptidoglycan is known to trigger a strong immune response. Its presence has been proposed as a driver of continued inflammation in Lyme arthritis, even when live bacteria are no longer detectable. But that finding raises a critical question:

Is this truly inert debris—or could it be a marker of persistent infection?

The Assumption: Inflammation Without Infection

The current mainstream view is that antibiotic-refractory Lyme arthritis (cases where joint pain and swelling persists after treatment) is due to an overactive immune system responding to bacterial remnants. The identification of peptidoglycan supports this hypothesis, suggesting that even after the bacteria are gone, pieces of their cell wall may remain and continue to stimulate the immune system.

If this is, in fact, what is happening, treatment should focus on immune modulation (like NSAIDs, corticosteroids, or DMARDs) rather than prescribing additional antibiotics.

But it relies on an assumption that deserves closer scrutiny.

The Limitation: Testing for Live Bacteria Is Inherently Difficult

In the study, researchers did not detect live Borrelia organisms in the joint fluid. But absence of evidence is not evidence of absence. Detecting Borrelia in synovial fluid or tissue is notoriously challenging. The spirochete can exist in low numbers, in difficult-to-access niches, and in forms that evade conventional PCR or culture methods.

That means the peptidoglycan seen in joint fluid could, in some cases, reflect ongoing bacterial turnover—not just sterile remnants. This would imply that in at least a subset of patients, the infection persists despite antibiotic treatment.

Such cases could still benefit from additional or combination antibiotic therapy—not just anti-inflammatory or immunosuppressive approaches.

Clinical Implications: Why This Distinction Matters

Understanding whether peptidoglycan signals active infection or immune debris matters deeply for treatment. If inflammation is being driven by an ongoing, hard-to-detect infection, suppressing the immune system without addressing the infection may worsen the condition or delay recovery.

On the other hand, if the inflammation is truly sterile and immune-driven, unnecessary antibiotic use could increase risks without benefit.

Both scenarios likely exist in different patients—which may explain the wide variability in treatment outcomes. Some improve with a second course of antibiotics. Others need immune-focused therapies. Without a reliable test to distinguish between these cases, treatment remains uncertain and often delayed.

A Call for More Nuanced Understanding

The discovery of peptidoglycan is a step forward in understanding the biology of Lyme arthritis—but it also underscores how much we still don’t know. Treating persistent Lyme symptoms as if they’re always post-infectious could leave some patients undertreated. Treating everyone with extended antibiotics risks overtreatment.

A more individualized, evidence-informed approach is needed—one that acknowledges the limitations of current testing, the biology of bacterial persistence, and the diverse experiences of patients.

Until we can reliably tell whether inflammation means debris or active disease, the question of lingering infection remains open—and critical.