Inflammation, biofilms and dietary measures in post treatment Lyme disease syndrome

Introduction

A meta-analysis of post-Lyme symptoms [1] has provided strong evidence that after having Lyme disease some patients report fatigue, cognitive disorders and musculoskeletal pain that may last for years. This array of symptoms is known as post-treatment Lyme disease syndrome (PTLDS). The fatigue from PTLDS has been variously described in the literature as profound, notable, unusual, debilitating, and extreme, not as a vague symptom of tiredness. Concurrent musculoskeletal pain is often roving with asymmetrical pain in the limbs. Memory problems, particularly for verbal memory, as well as poor concentration are also observed [1]. Shapiro et al. [2] have attempted to dismiss this meta-analysis [1] by arguing that the studies cited preceded the publication of official diagnostic criteria and treatment recommendations, and that patients would be unlikely to have persistent symptoms because antibiotics can effectively eradicate the actively dividing bacteria. Shapiro [2] also noted that further antibiotic treatment after the initial course for Lyme disease does not appear to help these patients. Separately, Stricker et al. [3] claimed that PTLDS is due to persistent infection because of the presence of nonreplicating forms of the Lyme disease spirochete that may have contributed to the failure of simple antibiotic regimens. Another explanation for PTLDS is that some patients may have symptom-producing bacterial debris remaining after effective antibiotic treatment of the spirochete Borrelia burgdorferi. This editorial provides an overview of possible pathophysiological factors in PTLDS and suggests dietary measures that may be helpful.

Inflammation and immune dysregulation in PTLDS

In a study of the expression of C-reactive protein (CRP) in patients with PTLDS or with early to late objective manifestations of Lyme disease, Uhde et al [4] concluded that antibiotic-refractory Lyme arthritis and PTLDS are associated with elevated CRP responses driven by inflammatory mechanisms distinct from those in active infection. From the chemokines involved in immunoregulatory and inflammatory processes, Aucott et al [5] identified CCL19 as a chemokine risk factor, speculating that the persistently elevated CCL19 levels among the study participants with PTLDS may reflect ongoing, immune-driven reactions at sites distal to secondary lymphoid tissue. PTLDS may also be linked to immune response in the central nervous system. In a neuroimaging pilot study of patients with PTLDS symptoms [6], positron emission tomography to quantify the 18 kDa translocator protein, a marker of activated microglia, yielded findings suggesting that PTLDS pathophysiology may be linked to an aberrant activation of immune cells in the brain.

Immune abnormalities were also suggested by Strle et al. [7] who found that patients with post-Lyme symptoms such as fatigue and arthralgias had no objective signs of disseminated disease, but their type 17 helper T cell-associated immune responses, often accompanied by autoantibodies, were correlated with their post-Lyme symptoms. These authors concluded that a subset of patients may have immune dysregulation associated with presenting symptoms. Also implicated in PTLDS arthralgias, the spirochete aggrecanase can damage joint tissue, which in turn can elicit an inflammatory response that may then stimulate human cartilage to produce its own aggrecanase. That means that the finding of aggrecanase in joint tissue may not be taken as an indication of the presence of actively dividing bacteria. However, Stricker et al. [8] attempted to use the finding of aggrecanase in joint tissue to defend their idea that long-term symptoms are due to persistent infection. In contrast to Stricker, Swiss guidelines [9] write that the potential aetiologies of PTLDS include antineural antibodies, bacterial debris and tissue destruction.

Biofilms, Lyme disease antigens and DNA

A biofilm is a thin but robust layer of mucilage adhering to a solid surface and containing a community of bacteria and other microorganisms. Lyme disease bacteria were first seen in biofilms in a study of autopsy tissues of a patient who died after having had many years of antibiotic treatment for Lyme disease [10]. These investigators found evidence of Lyme disease antigens and DNA in biofilms in many parts of the body and the presence of infiltrating lymphocytes in the vicinity of the Borrelia burgdorferi biofilms. Their autopsy findings suggested that bacterial debris remaining in the biofilm may trigger chronic inflammation.

A review of bacterial biofilms [11] noted that the mechanisms that different bacteria employ to form biofilms vary, frequently depending on environmental conditions and specific strain attributes, but the ability to form biofilms is a universal attribute of bacteria. This review further pointed out that bacteria can profoundly change their physiology by increasing production of secondary metabolites, and these secondary metabolites can function as signaling molecules to initiate the process of biofilm formation. In a review of triggers of autoimmunity, Qiu et al. [12] highlighted the role of bacterial biofilms in the generation of autoantibodies, and the ability of biofilms to stimulate an autoreactive immune response. A study of a well-defined group of patients with PTLDS [13] found that longer-term symptoms were associated with increased severity of the acute illness and a delay in initial treatment. Eikeland et al. [14] found that, in patients who had been treated for Lyme neuroborreliosis, higher fatigue scores were associated with a pre-treatment symptom duration of more than six weeks. During the pre-treatment period there may have been a slow formation of Borrelia burgdorferi biofilms that may then shield the bacteria from antibiotic effects but may nevertheless cause ongoing host immune responses resulting in inflammation.

Unnecessary antibiotic treatment

Antibiotics may have anti-inflammatory effects as well as antibacterial effects, and thus it is not surprising that some patients have noticed slight improvements in symptoms if antibiotic treatment is continued beyond a standard course. The US Centers for Disease Control and Prevention [15] concluded that long-term antibiotic treatment for Lyme disease is associated with serious, sometimes deadly complications, noting that long-term outcomes are no better for PTLDS patients who received additional prolonged antibiotic treatment than for those who received placebo. The expression ‘chronic Lyme disease’ may be misunderstood, and some patients may mistakenly think they have ongoing active infection requiring extensive antibiotic treatment. Furthermore, antibiotics can damage the natural, healthy intestinal bacteria and so have negative effects on the host intestinal microbiota and immune system. Dysbiosis of gut microbiota can contribute to various chronic inflammation-related diseases [16]. The challenge can be in determining whether previous antibiotic treatment has effectively killed the actively dividing Lyme disease spirochete, as direct tests are not always accurate or available to clinicians. The oral antibiotic doxycycline is usually effective for early Lyme disease, leaving the patient with no further problems, but oral antibiotics may not be effective if the infection has reached the later stages of the disease when intravenous ceftriaxone may be recommended.

US guidelines on Lyme disease [17] recommend intravenous antibiotics for acute neurologic manifestations but recommend against additional antibiotic therapy for patients with persistent nonspecific symptoms (fatigue, pain, or cognitive impairment) following recommended treatment and without objective evidence of reinfection or treatment failure.

The UK National Institute for Health and Care Excellence [18] recommends no further antibiotics for individuals with ongoing symptoms following two courses of antibiotic treatment for Lyme disease and that patients with ongoing symptoms should be told that continuing symptoms may take months or years to resolve and may not indicate active infection. In a long-term assessment of PTLDS patients carried out over many years [19], Weitzner et al found that, in a large majority of patients, the symptoms of PTLDS did eventually disappear.

Possible dietary measures for PTLDS

PTLDS symptoms can fade away very slowly over time, which may suggest possible mechanisms such as neurological recovery, eventual breakdown of bacterial debris, and/or a slow cessation of the chronic inflammation. Symptomatic recovery may be manifested by very subtle improvement from one year to the next with no apparent improvement in shorter time periods of months.

Certain food supplements may help to some extent with recovery. Omega-3 fatty acids found in natural fish oil have anti-inflammatory properties [20] and have been shown to help with minor cognitive impairment [21]. Vitamin B12 has been shown to be beneficial in nerve regeneration [22]. Sirtuin 3 has been identified as a key regulator of mitochondrial fission, and it may help reduce neuroinflammation [23]. The Sirtuin enzymes are activated by foods like green tea, dark chocolate, and blueberries. Vitamin D has been found to play an important role in the modulation of the immune/inflammation system via regulating the production of inflammatory cytokines and inhibiting the proliferation of proinflammatory cells [24].

In addition, probiotics are beneficial bacteria found in certain foods or supplements while prebiotics are types of fiber that feed the good bacteria in the digestive system. In a recent meta-analysis [25], probiotics improved cognitive performance in patients with Alzheimer’s disease or mild cognitive impairment, possibly through decreasing levels of inflammatory biomarkers. Also, Shokryazdan et al [26] reported on the beneficial effects of prebiotics in increasing the expression of anti-inflammatory cytokines, while reducing the expression of proinflammatory cytokines.

Although there have been no studies on the effects of an anti-inflammatory diet on PTLDS symptoms, there is evidence of inflammation in these patients, and it seems reasonable for PTLDS patients to follow an anti-inflammatory diet similar to that recommended for patients with some inflammatory autoimmune diseases. Patients with PTLDS may be helped by these anti-inflammatory foods and food supplements, while certain other foods can be avoided. Inflammation is thought to be increased by high-energy Western-style diets, which are typically high in salt, animal fat, red meat, sugar-sweetened drinks, and fried food, and low in fiber [27]. Recovery from PTLDS, regardless of dietary approach, can take a long time and acceptance and patience are necessary.

Conclusion

It is estimated that approximately 10% to 20% of patients optimally treated for early Lyme disease develop persistent symptoms of PTLDS [5]. Many patients do recover with time, but there is considerable variability in the course of the disease. Unnecessary anxiety can be avoided if patients understand that further medical treatment with antibiotics may not be needed and may even be counterproductive. Also, patients may feel empowered by taking the small dietary steps that could help with their gradual recovery.