When Lyme Goes Quiet: Persister Cells and the Embers That Remain

One of the most frustrating experiences in Lyme disease is getting better, sometimes clearly better, and then watching that progress stall. The treatment seemed to be working. The pain eased, your thinking improved, your energy started to come back, and for a while you began to believe you might finally be turning a corner.

Then something changed.

One possible reason is surprisingly simple: the treatment may not have changed, but the bacteria may have changed what they were doing.

Think about a forest fire. When flames are racing through the trees, the fire is obvious and relatively easy to find. Once the flames disappear, however, experienced firefighters know that heat can remain buried beneath ash and burned wood. Those embers survive not by burning harder, but by burning less.

Bacteria can use a similar strategy.

A small portion of a bacterial population can dramatically slow its growth and metabolism when conditions become hostile. These organisms are called persister cells. They are not necessarily genetically resistant to the antibiotic. Instead, many of the cellular processes that antibiotics normally attack have become much quieter.[1]

That matters because many antibiotics work best against bacteria that are actively growing. If the organism slows down enough, the drug may still be perfectly capable of killing Borrelia, but there is less active bacterial machinery for it to disrupt.

The fire has changed.

Borrelia Can Form Persister Populations

Researchers have demonstrated this behavior with Borrelia burgdorferi.

In one important study, Sharma and colleagues exposed growing Borrelia cultures to antibiotics commonly used in Lyme disease. Most of the organisms died relatively quickly, while a much smaller population survived. When those survivors were later allowed to grow again, they remained susceptible to the same antibiotics. They had not simply become genetically resistant.[2]

Other researchers found a similar pattern. As Borrelia cultures became older and growth slowed, the organisms became harder to eliminate with doxycycline and were more likely to grow back after treatment was removed.[3]

For me, this helps explain why the simple question, “Does this antibiotic kill Borrelia?” is not always enough.

A rapidly growing Borrelia organism and a metabolically quiet persister may be the same species, but they are presenting very different treatment targets.

That is why we place Persister Cell Formation within the Precision Lyme Management Stealth Pathology domain of Metabolic Flexibility and Dormancy. We are not only interested in whether the organism is present. We are interested in what biological state it is in.

Why Treatment Can Work Well at First

This gives us a useful way to think about the person who improves early in treatment and then plateaus.

Imagine starting with a forest in which there are large areas of active flame. Treatment may reduce that part of the microbial population substantially. What remains behind can be increasingly enriched with slower-growing organisms, organisms in protected tissue environments, and persister-like forms that tolerate conditions that were much more effective against their actively growing neighbors.

That means the population after treatment may not look biologically like the population before treatment.

We often respond to a plateau by asking whether we need a stronger treatment. Persister biology suggests another question: Are we still treating the same biological state?

That is a much more useful question.

The Environment Around the Organism Matters

Bacteria also do not become metabolically quiet in isolation. Their behavior is influenced by the environment around them.

Nutrient availability, immune pressure, antimicrobial exposure, oxygen, pH, and the physical location of the organism can all affect bacterial metabolism. This is where the different parts of Stealth Pathology begin to connect.

An organism living within a protected tissue niche may behave differently from one freely exposed in the bloodstream. An organism embedded within an organized microbial community may receive different signals and nutrients. Changes in blood flow or extracellular matrix may further alter the local environment.

So when we talk about persisters, we are really talking about more than a single unusual bacterial form. We are talking about the ability of microorganisms to adapt their metabolism to the conditions around them.

That is part of what makes persistent infection so difficult to reduce to a single drug or protocol.

This Is Where Some Botanicals Become Interesting

Several botanicals commonly used in Functional Medicine have been tested against both actively growing and non-growing Borrelia.

Researchers at Johns Hopkins evaluated a group of plant extracts against different Borrelia growth states. Several showed activity against the non-growing population, including Cryptolepis, Japanese knotweed, Chinese skullcap, cat’s claw, sweet wormwood, black walnut, and Cistus.[4]

The two that interest me most are Cryptolepis and Japanese knotweed.

Both showed activity against actively growing and non-growing Borrelia. Cryptolepis was particularly notable because, at the highest concentration tested, the treated cultures did not regrow after the herb was removed.[4]

That gives us a reason to think about these plants differently than simply calling them “natural antibiotics.” Their activity appears to extend across more than one microbial growth state.

Japanese knotweed is also interesting because it contains compounds such as resveratrol and other polyphenols that affect inflammation, vascular biology, and host signaling. In other words, its relevance may extend beyond direct antimicrobial activity.

There is also laboratory work showing activity of several essential oils, particularly oregano, cinnamon bark, and clove, against stationary-phase Borrelia.[5] I find that research biologically interesting, although concentrated essential oils require much more attention to dose, formulation, and tolerance than the phrase “natural treatment” sometimes implies.

The Point Is Not to Build a Bigger Antimicrobial Stack

Persister biology can easily lead us in the wrong direction.

Once we learn that some organisms are harder to kill, the instinct is to add more agents: something for growing Borrelia, something for persisters, something for biofilms, something intracellular, and then perhaps several herbs on top of that.

But chronic illness is not just a microbial problem. The person receiving the treatment matters just as much.

Someone who is sleeping reasonably well, eating well, recovering from activity, and tolerating treatment has a very different capacity from someone who crashes after minor exertion, reacts strongly to every new supplement, has poor gastrointestinal function, and takes days to recover from each treatment change.

This is why PLM separates Stealth Pathology from Resilience. We want to understand what the organism may be doing, but we also want to know how much intervention the person can successfully use.

That often changes sequencing. Sometimes reducing microbial burden is the priority. At another point, improving sleep, circulation, nutrition, gut function, autonomic stability, or recovery capacity may create a better opportunity for the next phase of treatment.

The goal is not the largest possible antimicrobial attack. It is a strategy that matches both the microbial state and the person carrying the illness.

Looking for the Embers

Return to the forest one last time.

When the flames disappear, an experienced firefighter does not assume the fire never existed, nor do they simply continue attacking the same patch of ground with more force. They look for what remains, where it is hiding, and how the fire has changed.

That is how I think about persister biology.

A treatment can work. A person can improve. The microbial population can change. What remains may behave differently from what was present at the beginning.

For someone who has lived through the confusing experience of getting better and then stalling, that is an important distinction.

The question is no longer only, “What kills Borrelia?”

It becomes, “What state is the organism in now, and what strategy makes sense for that state?”

That is why Persister Cell Formation belongs on the Stealth Pathology map.

Sometimes the part of the fire that matters most is no longer the flame you can see.

It is the ember beneath the ash.

References

1. Balaban NQ, Helaine S, Lewis K, et al. Definitions and guidelines for research on antibiotic persistence. Nature Reviews Microbiology. 2019;17:441-448.
2. Sharma B, Brown AV, Matluck NE, Hu LT, Lewis K. Borrelia burgdorferi, the causative agent of Lyme disease, forms drug-tolerant persister cells. Antimicrobial Agents and Chemotherapy. 2015;59(8):4616-4624. PMID: 26014929.
3. Caskey JR, Embers ME. Persister development by Borrelia burgdorferi populations in vitro. Antimicrobial Agents and Chemotherapy. 2015;59(10):6288-6295. PMID: 26248368.
4. Feng J, Leone J, Schweig S, Zhang Y. Evaluation of natural and botanical medicines for activity against growing and non-growing forms of Borrelia burgdorferi. Frontiers in Medicine. 2020;7:6. PMID: 32154254.
5. Feng J, Zhang S, Shi W, et al. Selective essential oils from spice or culinary herbs have high activity against stationary-phase and biofilm Borrelia burgdorferi. Frontiers in Medicine. 2017;4:169. PMID: 29075628.