Fragments of Lyme Disease Bacteria Linked to Liver Dysfunction

In the United States and Canada, the incidence of Lyme disease has risen steadily in recent years, driven by climate change and a host of other interconnected factors. Lyme disease, which is caused by the spiral-shaped bacterium Borrelia burgdorferi, can manifest as severe headaches, nerve pain, arthritis, and cardiac dysfunction if it is left untreated. Even after antibiotic treatment, however, as many as 15 percent of people may continue to experience symptoms like fatigue and pain, due to a condition known as post-treatment Lyme disease syndrome (PTLDS).

The underlying cause of these persistent problems has been a matter of debate, with researchers variously proposing that they are due to an unresolved, low-level infection, an autoimmune response triggered by the initial infection, or bacterial antigens that have somehow avoided clearance by the immune system. Back in 2019, a team of microbiologists at Yale University, including then-postdoctoral scholar Brandon Jutras, discovered that most patients with Lyme arthritis had B. burgdorferi peptidoglycan (PG), a bacterial cell wall component, in the fluid of their inflamed joints.¹ However, it was not clear how these cell wall fragments were able to persist in the body for so long, or whether they might be involved in pathological processes outside of the joints.

New research from Jutras and his team at Northwestern University, published in Science Translational Medicine, sheds light on these questions.² The researchers identified unique cell wall components that enable B. burgdorferi fragments to persist in the liver, perturbing protein expression and increasing markers of liver dysfunction in the blood. Although more work is needed, establishing the causative agent of PTLDS, is an important step towards developing effective treatments.

“Trying to decipher what mechanisms lead to the inflammation, which is at the core of it, is really, really important,” said Monica Embers, a vector-borne disease researcher at Tulane University. “I think this work that Dr. Jutras has done is truly groundbreaking, and it's also the kind of science—which is the best kind of science—that leads to more questions.”

In the present study, the scientists created two different forms of B. burgdorferi PG: small pieces to simulate how the bacteria shed bits of the cell wall as they grow, and larger chunks to mimic debris created as the bacteria die. They marked the pieces with a fluorescent dye and tracked how the fragments moved through the bodies of mice over time. While the smaller pieces were eliminated within four days, the larger pieces accumulated in the liver and were detectable four weeks later. Furthermore, this persistence was unique to B. burgdorferi cell wall debris; PG from other bacterial species were cleared in just a few days.

“The chemical components of the peptidoglycan in Borrelia burgdorferi are just fundamentally different from virtually all other bacteria,” said Jutras. One of the unusual features of B. burgdorferi’s cell wall is a component that doesn’t seem to be produced by the bacteria itself.³ Instead, said Jutras, “They appear to be taking up a tick sugar, and changing their peptidoglycan using that sugar.” This borrowed sugar also seemed to contribute to the persistence of PG in the body: Strains with lower levels of this strange sugar modification were eliminated more rapidly than normal B. burgdorferi PG.

Researchers also found elevated serum levels of two enzymes that are indicative of liver dysfunction and persisted for at least 35 days after PG administration. Proteomic analysis of the liver itself identified a suite of differentially expressed proteins, about 70 percent of which were linked to immune processes.

Finally, researchers compared how human blood cells reacted to PG from different bacterial species. While thousands of gene transcripts were commonly affected by PG from all five species of bacteria, many were unique to B. burgdorferi PG. “Almost all of the genes are in particular pathways associated with energy metabolism,” said Jutras. “Obviously, a lot more [research] is needed in order to understand this, but it reminded us of some patients with post-treatment Lyme disease: The major feature that they all have in common is chronic fatigue.” Dysregulation of metabolic processes could be a plausible explanation for this fatigue.

In the future, Jutras hopes to explore how human genetic differences contribute to the pathology of the disease. “We suspect—and we have some preliminary evidence already—that how patients respond to the lingering peptidoglycan is the most important part,” he said. Jutras said his team is also exploring how monoclonal antibodies that specifically target these B. burgdorferi fragments could be used to help eliminate these persistent immune stimulators and potentially resolve the symptoms of PTLDS.