Elsevier

Medical Hypotheses

Volume 74, Issue 5, May 2010, Pages 895-897
Medical Hypotheses

Microbial endocrinology as a basis for improved l-DOPA bioavailability in Parkinson’s patients treated for Helicobacter pylori

https://doi.org/10.1016/j.mehy.2009.11.001Get rights and content

Summary

Antibiotic therapy to eradicate Helicobacter pylori, the causative agent of gastric and duodenal ulcers, has been suggested to improve l-DOPA bioavailability in Parkinson’s and thereby improve patient symptomology. To date, there has been no proven mechanism to explain the purported benefit of treatment of H. pylori in the management of Parkinson’s disease. I propose the hypothesis, and provide initial data, that the mechanism of action is due to direct utilization of l-DOPA by H. pylori to maintain its ecological niche within the gastrointestinal tract. In support of this hypothesis, data is presented which demonstrates for the first time the ability of l-DOPA to influence the in vitro growth of H. pylori in an iron-restricted minimal medium. H. pylori utilization of l-DOPA for its own growth requirement reduces the amount of per orally administered l-DOPA that would be available to the patient for the treatment of Parkinson’s disease-related pathology. Neuroendocrine-mediated interactions with bacteria represent the emerging interdisciplinary field of microbial endocrinology. Thus, microbial endocrinology provides for a mechanism between l-DOPA and H. pylori with which to explain the purported benefit of H. pylori-directed antibiotic therapy to improve l-DOPA bioavailability in Parkinson’s patients and thereby improve drug therapy management. Further, if other bacterial species within the gastrointestinal tract depend on the availability of l-DOPA or other similar neuroendocrine-based drugs for their survival, then the efficacy of such neuroendocrine-based drugs not restricted solely for the management of parkinsonian symptomology may also be adversely affected and may therefore justify the use of an antibiotic regimen to eradicate them.

Introduction

The ability of bacteria to directly interact with neuroendocrine hormones, especially those which belong to the catecholamine family, is increasingly being recognized as a newly emerging interdisciplinary field in microbiology known as microbial endocrinology [1], [2]. Both commensal and pathogenic bacteria have now been shown to directly utilize neuroendocrine hormones as part of their normal physiological processes including growth [3], [4], [5], [6]. This intersection of the scientific disciplines of microbiology and neurophysiology has critical implications for the drug therapy management of patients who utilize neuroendocrine-based drugs such as l-3,4-dihydroxyphenylalanine (l-DOPA) to ameliorate their clinical condition.

Support for an interaction between l-DOPA and Helicobacter pylori comes from two fronts: firstly, from theoretical papers that have drawn upon the clinical observation first noted by Schwab in 1961 [7] of the incidence of H. pylori-induced peptic ulceration in patients with Parkinson’s disease to secondly, a recent clinical study which noted improvement of symptomology in Parkinson’s patients who were treated with a standard antibiotic regimen against H. pylori [8]. Altschuler [9] initially proposed in 1996 a direct casual association between Parkinson’s and H. pylori. For a putative mechanism of action Altschuler proposed the biosynthesis of the neurotoxin 1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine by H. pylori [9]. Others noting the association between the incidence of H. pylori infection and occurrence of Parkinson’s have also suggested possible cause and effect relationships including the proposal by Dobbs et al. [10] who theorized that H. pylori-induced autoimmunity served as the casual mechanism resulting in neuronal damage leading to eventual Parkinsonism. This was based on the observation of an age-associated increase the levels of antibodies against H. pylori in Parkinson’s patients as they approached the latter parts of their lives [10]. Interestingly, while Dobbs et al. further proposed, but did not test, the idea that dopaminergic agents may actually act in a protective manner by direct inhibition of H. pylori growth, the data contained in the report contradicted this by showing lowered dopaminergic status resulting from infection with H. pylori. Other clinical reports have similarly noted an association between Parkinson’s disease and H. pylori infection such as the finding of such an association in siblings [11]. A more recent review which examined through statistical modeling the overall evidence for a role of gut inflammation, and H. pylori infection in particular, concluded that idiopathic Parkinsonism may be directly related to the infectious and inflammatory status of the gastrointestinal tract [12].

The first clinical trial which examined a direct cause and effect relationship of H. pylori in Parkinson’s disease was conducted by Pierantozzi et al. [8]. They demonstrated that Parkinson’s patients who were positive for H. pylori at the time of enrollment had improved clinical status and motor fluctuations following a standard course of antibiotic therapy for H. pylori. Importantly, the improvement in clinical status of these patients was accompanied by increased l-DOPA absorption that was evident even after the administration of a single antibiotic dosing. These positive clinical effects were also shown to last for at least 3 months following initial antibiotic therapy [8]. Importantly, none of the prior studies regarding the association and putative role of H. pylori in Parkinson’s disease has suggested the more direct role for the bacterium – one that envisions H. pylori depending upon l-DOPA therapy for its own survival.

Section snippets

Relevance of microbial endocrinology to H. pylori in Parkinson’s disease

That H. pylori should be able to directly utilize l-DOPA for its own survival should not seem that surprising given that vertebrate neurotransmitters, neurohormones, and related receptors, are in fact widely dispersed throughout nature extending from bacteria to plants to mammals [13]. The range of neuroendocrine hormones and the variety of microorganisms in which they have been identified is very large including gamma-aminobutyric acid, somatostatin, corticotropin and most importantly dopamine

Hypothesis

I hypothesize that the purported ability of a H. pylori-specific antibiotic regimen to improve l-DOPA bioavailability in Parkinson’s is due to the eradication of the H. pylori bacterium which actively utilizes l-DOPA to maintain its ecological niche in the gastrointestinal tract. According to this microbial endocrinology-based-hypothesis, neuroendocrine-bacterial interactions between l-DOPA and H. pylori result in increased growth and persistence of H. pylori in the stomach, as well as upper

Evaluation of feasibility

In order to evaluate the feasibility of the hypothesis, initial experiments were conducted in which very low amounts of H. pylori (American Type Culture Collection #43504) were cultured in the presence of norepinephrine, l-DOPA or vehicle in a minimal medium to more closely mimic the in vivo milieu [18]. As can be seen in Table 1, the presence of either norepinephrine or l-DOPA dramatically increased the growth of H. pylori. That norepinephrine was able to increase growth was expected given the

Conclusions

The demonstration that l-DOPA can directly increase the growth of H. pylori strongly suggests that microbial endocrinology-based interactions play a role in the pathogenesis of Parkinson’s disease and specifically in the need to progressively increase drug dosage over the course of the disease. The utilization of l-DOPA by H. pylori would mean that therapeutic levels l-DOPA would be less available for the alleviation of Parkinson’s disease-related pathology. Thus, the microbial

Conflict of interest statement

None declared.

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