Microbial endocrinology as a basis for improved l-DOPA bioavailability in Parkinson’s patients treated for Helicobacter pylori
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.
References (23)
- et al.
Microbial endocrinology: how stress influences susceptibility to infection
Trends Microbiol
(2008) - et al.
Catecholamine induced growth of gram negative bacteria
Life Sci
(1992) - et al.
Stimulation of Staphylococcus epidermidis growth and biofilm formation by catecholamine inotropes
Lancet
(2003) - et al.
Norepinephrine as a growth stimulating factor in bacteria – mechanistic studies
Life Sci
(2000) Gastric Helicobacter pylori infection as a cause of idiopathic Parkinson disease and non-arteric anterior optic ischemic neuropathy
Med Hypotheses
(1996)- et al.
Link between Helicobacter pylori infection and idiopathic Parkinsonism
Med Hypotheses
(2000) - et al.
Role of inflammation in gastrointestinal tract in aetiology and pathogenesis of idiopathic Parkinsonism
FEMS Immunol Med Microbiol
(2005) Microbial endocrinology and infectious disease in the 21st century
Trends Microbiol
(2004)- et al.
Microbial endocrinology: experimental design issues in the study of interkingdom signalling in infectious disease
Adv Appl Microbiol
(2008) - et al.
Iron regulated genes of Salmonella enterica serovar Typhimurium in response to norepinephrine and the requirement of fepDGC for norepinephrine-enhanced growth
Microbes Infect
(2008)