Higher exposure to commonly used oral antibiotics is linked to an increased risk of Parkinson’s disease according to a recently published study by researchers from the Helsinki University Hospital, Finland.
The strongest associations were found for broad-spectrum antibiotics and those that act against anaerobic bacteria and fungi. The timing of antibiotic exposure also seemed to matter.
The study suggests that excessive use of certain antibiotics can predispose to Parkinson’s disease with a delay of up to 10 to 15 years. This connection may be explained by their disruptive effects on the gut microbial ecosystem.
“The link between antibiotic exposure and Parkinson’s disease fits the current view that in a significant proportion of patients the pathology of Parkinson’s may originate in the gut, possibly related to microbial changes, years before the onset of typical Parkinson motor symptoms such as slowness, muscle stiffness and shaking of the extremities.
It was known that the bacterial composition of the intestine in Parkinson’s patients is abnormal, but the cause is unclear.
Our results suggest that some commonly used antibiotics, which are known to strongly influence the gut microbiota, could be a predisposing factor,” says research team leader, neurologist Filip Scheperjans MD, PhD from the Department of Neurology of Helsinki University Hospital.
In the gut, pathological changes typical of Parkinson’s disease have been observed up to 20 years before diagnosis.
Constipation, irritable bowel syndrome and inflammatory bowel disease have been associated with a higher risk of developing Parkinson’s disease.
Exposure to antibiotics has been shown to cause changes in the gut microbiome and their use is associated with an increased risk of several diseases, such as psychiatric disorders and Crohn’s disease.
However, these diseases or increased susceptibility to infection do not explain the now observed relationship between antibiotics and Parkinson’s.
The study suggests that excessive use of certain antibiotics can predispose to Parkinson’s disease with a delay of up to 10 to 15 years. This connection may be explained by their disruptive effects on the gut microbial ecosystem.
“The discovery may also have implications for antibiotic prescribing practices in the future. In addition to the problem of antibiotic resistance, antimicrobial prescribing should also take into account their potentially long-lasting effects on the gut microbiome and the development of certain diseases,” says Scheperjans.
The possible association of antibiotic exposure with Parkinson’s disease was investigated in a case-control study using data extracted from national registries.
The study compared antibiotic exposure during the years 1998-2014 in 13,976 Parkinson’s disease patients and compared it with 40,697 non-affected persons matched for the age, sex and place of residence.
Antibiotic exposure was examined over three different time periods: 1-5, 5-10, and 10-15 years prior to the index date, based on oral antibiotic purchase data.
Exposure was classified based on number of purchased courses. Exposure was also examined by classifying antibiotics according to their chemical structure, antimicrobial spectrum, and mechanism of action.
Funding: The authors have received funding from The Finnish Parkinson Foundation, The Finnish Medical Foundation, The Maire Taponen Foundation, and The Academy of Finland (295724, 310835). The funders had no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or the decision to submit the article for publication.
Relevant conflicts of interests/financial disclosures: F.S. is listed as inventor on patents FI127671B and US10139408B2 and patent applications EP3149205A4 and US16/186,663. F.S. is founder and chief executive officer of NeuroInnovation Oy. The authors report no other conflicts of interest relative to the research covered in this manuscript.
Parkinson’s disease (PD) is a debilitating neuromotor disorder affecting the nigrostriatal pathway in the midbrain. In the United States, PD is the second most common neurodegenerative disease. It has an incidence of 14 per 100 000 people in the total population, however, the incidence increases to 160 per 100 000 in individuals 65 years and older.1
The lifetime risk of the disease is estimated to be 4.4% for men and 3.7% for women in the United States at birth.2 An estimated 1 million people are affected by this progressive disorder of the central nervous system (CNS). Globally, it is estimated that over 3 million patients may suffer from PD.3,4
PD is characterized by an array of motor symptoms ranging from tremors, rigidity, bradykinesia (often akinesia), and postural abnormalities (characterized by a shuffling gait).
Very common neuropsychiatric symptoms include depression, anxiety, apathy, cognitive decline, dementia, and psychosis. In addition, many non-neurological and non-motor symptoms of the gastrointestinal (GI) tract such as constipation, bloating, urinary incontinence, anosmia, and blunted affect are also observed.5–7
Histopathologically, the disease is associated with an accumulation of Lewy bodies, which are intra-cytoplasmic eosinophilic deposits composed of a misfolded protein, α-synuclein, in the basal ganglia neurons, especially in the caudate nucleus and the putamen.5
Based on available evidence, it has been postulated that depletion of the dopaminergic neurons in the substantia nigra in the midbrain results in a defect in the thalamic signaling to the cerebral cortex.5 This presumably results in the characteristic signs and symptoms of PD. The multiple factors associated with the pathogenesis and progression of PD are summarized in Table 1.
Table 1
Factors Associated With Pathogenesis and Progression of Parkinson’s Disease
| Phenomenon | Description | Degree of Association | Reference |
|---|---|---|---|
| Loss of dopaminergic activity | Silencing of neuronal dopamine generation in the substantia nigra | High: proximate cause, potentially reversible | Siderowf and Stern,8 2003 |
| Inclusion of Lewy bodies | Aggregation of α-synuclein | High: appears in the gut in the prodromal phase | |
| Sex differences | Greater prevalence among men | High: brain sex dimorphism | Gillies et al,9 2014 |
| Gut dysbiosis | Prodromal symptoms of PD | High: strong association with the microbiome | Minato et al,10 2017 |
| Aging | Advancing age | High-Moderate | |
| Environmental factors | Exposure to neurotoxins in the gut lead to loss of dopaminergic activity | Moderate | Yadav et al,11 2013 |
| Parkin ligase | Loss linked to mutations in the PRKN gene | Moderate: familial form of PD | Kitada et al,12 1998 |
| Glucagon-like peptide synthetic homolog: exenatide | Insulinotropic gut hormone; may have a protective function in the gut-brain axis | Moderate: ameliorates PD symptoms | Kim et al,13 2017 |
| SRY gene in the male Y chromosome | Regulates expression of tyrosine hydroxylase, rate-determining step to dopamine | Indeterminate | Dewing et al,14 2006 |
| Ultrasound thalamotomy | Effective in medication-refractory tremor-dominant PD | Indeterminate: may disrupt Lewy bodies | Bond et al,15 2017 |
PD, Parkinson’s disease; PRKN, parkin RBR E3 ubiquitin protein ligase; SRY, sex determining region Y.
The currently available treatment modalities for PD fall under medical, surgical or supplementary therapies. The cornerstone of medical therapies for the treatment of PD include the combination of levodopa-carbidopa, which increases dopamine levels for neural transmission in the diseased areas of the brain.16
Additional pharmacological options include synthetic dopamine receptor agonists (eg, ropinirole and pramipexole) which stimulate dopamine receptor and catechol-O-methyl transferase inhibitors, and reduce dopamine and levodopa degradation outside the brain to increase its availability at the site of action at the midbrain.16
Similarly, monoamine oxidase inhibitors (eg, selegiline and rasagiline) prolong the duration of action of dopamine and its analogues, and leads to an improvement in the symptoms of PD.16
The current surgical options available for the treatment of PD are limited and rarely used. However, surgery is considered for patients who have fluctuating responses to levodopa treatment, intractable tremor, or dyskinesia.
Deep brain stimulation is a novel surgical method that involves an implant of electrodes in certain areas of the brain such as the sub-thalamic nuclei, and a pulse generator similar to an artificial pacemaker located just below the clavicle.17 Once in place, the pacemaker generates impulses to stimulate the implanted electrodes that in turn block the subthalamic signals, which improves motor symptoms of PD.17
The role of diet and nutritional supplements in the management of PD has also been studied. Mischley et al18 conducted a cross-sectional analysis study conducted in 1053 patients, which concluded that foods associated with a reduction in the progression of PD include fresh (uncanned or non-frozen) vegetables, fruits, nuts, seeds, herbs, non-fried fish, olive oil, coconut oil, and spices (P < 0.05).
Supplements enacting a similar reduction in PD progression included CoQ10 and fish oil (P < 0.05). Foods associated with the worsening of PD (P < 0.05) included canned fruits and vegetables, diet and non-diet soda, fried foods, beef, ice cream, yogurt, and cheese. Similarly, iron supplementation was associated with a faster progression of PD (P < 0.05).18 Polyphenols and flavonoids have been studied in a wide range of in vitro and in vivo models of neurological diseases.
These nutrients, found in plants and microbes, have showcased a neuroprotective role in PD.19 Another prospective study in Sweden was conducted by Yang et al20 in 2 population-based cohorts (38 937 women and 45 837 men) to understand dietary antioxidants and the risk of PD. During a 14.9 year follow-up, 1329 PD cases were identified. The intake of vitamin E and beta-carotene was associated with a lower risk of PD in the identified patients.20
Natural History of Parkinson’s Disease
PD is a slowly progressing disorder, but this progression is highly variable from patient to patient. Life expectancy is marginally reduced.23 Death is usually the result of complications from impaired movement such as a fall with fracture leading to immobility, aspiration from severe dysphagia, and bowel obstruction from poor gut motility. Prognosis is generally based on favorable indicators, which include prominent tremors without significant rigidity, absence of gait disorder or bradykinesia, normal cognition, and positive attitude. Negative indicators include postural instability and bradykinesia without tremor, recurrent episodes of falling, apathy, cognitive decline, depression and/or anxiety, dysphagia, and orthostatic hypotension. In the last decade, there has been an increase of research demonstrating the benefit of exercise on managing the motor symptoms of PD. There is a need for early identification of these indicators to provide therapy that can modulate the disease process favorably. Probiotics and FMT may play a role in reducing the progression of the disease and improve psychomotor and neurological symptoms.
Role of Inflammation in the Central Nervous System in Parkinson’s Disease
A possible role of glial cell dysregulation and its association with inflammation has also been demonstrated in the CNS of patients with PD.24 Devos et al25 evaluated 19 PD patients and 14 age-matched controls to look for inflammatory and glial cell markers in their intestinal biopsies. They found evidence of increased inflammatory cytokines such as IL-6 and IL-1β and enhanced expression of glial cell markers (ie, glial fibrillary acidic protein [GFAP] and SRY-Box 10 [Sox-10]) using real time polymerase chain reaction. These findings have pointed towards the involvement of the gut-brain axis in the pathogenesis of PD.25 These investigators however, did not find a correlation between the levels of pro-inflammatory cytokines or glial cell markers with disease severity, GI symptoms or cumulative lifetime dose of L-dopa.25 Several factors such as the presence of glial cell markers in the myenteric and Auerbach’s plexus in the intestinal mucosa, and increased glial cell dysfunction and oxidative stress in the Substantia Nigra pars compacta of patients of PD provide possible links between the development of inflammation in the nervous system and PD.24
Increased levels of pro-inflammatory cytokines such as IL-6 and TNF-α have been observed in the cerebrospinal fluid of patients with PD.26–28 There has been growing evidence to show that oxidative stress and cytokine-dependent toxicity could play a role in the pathogenesis of neuronal damage in the substantia nigra.29,30 Brochard et al29 have reported increased infiltration of reactive lymphocytes in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treated mice, which has further strengthened this claim.
A study conducted by Sampson et al31 provides in vivo evidence to support a similar hypothesis of colonic inflammation in the pathogenesis of PD. The study involved germ-free mice and wild type mice. Each category was further subdivided to either specific pathogen free or α-synuclein overexpressing (ASO) mice. A series of tests of gross motor and fine motor function indicated a significantly higher risk of motor impairment and development of disease symptoms in the specific pathogen free and the ASO varieties.31 Moreover, it was shown that transplanting fecal microbiota from PD patients demonstrating gut dysbiosis to mice leads to a significantly higher chance of developing disease symptoms as compared to transplanting fecal microbiota from healthy donors.31 The risk was significantly higher in ASO varieties as compared to the wild type varieties. The study thus concluded that both genetic (ASO overexpression) and environmental (gut dysbiosis) factors play a role in the pathogenesis of PD.31
These emerging pieces of evidence suggest that inflammation may have a substantial role in the development and progression of PD. Furthermore, gut dysbiosis may precede glial cell dysfunction several years before the onset of the disease.25
Source:
University of Helsinkir
Media Contacts:
Filip Scheperjans – University of Helsinki
Image Source:
The image is in the public domain.
Original Research: Closed access
“Antibiotic exposure and risk of Parkinson’s disease in finland: A nationwide case‐control study”. Tuomas H. Mertsalmi MD, Eero Pekkonen MD, PhD, Filip Scheperjans MD, PhD.
Movement Disorders doi:10.1002/mds.27924.
