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What's Hot in PD? Accumulating Evidence for a Role of Gut Microbiota in Parkinson’s Disease

What's Hot in PD? - December 2016

Considerable evidence has been mounting in support of a relationship between the gastrointestinal (GI) system and Parkinson’s disease (PD). Many pathologists and neurologists even believe that Parkinson’s may start in the gut, but this view remains speculative. Many GI symptoms, such as constipation, occur as prominent and disabling PD symptoms. In the July 2013 What’s Hot in PD? column, I addressed H. Pylori gut infection, and in January 2015, I wrote about the gut and H. Pylori. This month I’ll bring it all together with gut microbiota and its relationship to PD.

The discovery that a bug in the gut called H. Pylori could underpin gastrointestinal disease and lead to ulcers was one of the most important observations in modern GI medicine. But why is H. Pylori infection relevant to Parkinson’s patients, especially if two of every three people already live with the infection? If left untreated, H. Pylori may affect the absorption of PD medications and the overall response to treatment.

In 2006, an important paper by Pierantozzi and colleagues in Rome was published in Neurology. The researchers identified and treated patients with H. Pylori infections, either with an anti-oxidant pill or with eradicate H, an antibiotic regimen. The absorption of levodopa in these patients improved, as did the hours of “on” time. Later, a 2008 article by Lee and colleagues from Samsung Medical Center in Korea confirmed these results. The onset of action of levodopa, the “on” duration and the PD scales improved more in the group treated for H. Pylori infection.

The subject of H. Pylori infection and the risk of PD remained relevant, as in 2012 another study was published by Nielsen and colleagues. They collected data from 4,484 Danish patients. The use of H. Pylori-eradicating drugs was associated with a 45% increased risk of developing Parkinson’s. Similarly, the use of proton pump inhibitors showed a 23% increased risk for the development of PD. The researchers speculated that chronic H. Pylori infections and gastritis could be related to the risk of developing Parkinson’s, though there were many methodological issues that questioned the study itself.

In a presentation at the International Movement Disorders Society Congress held in Sydney, Australia, a group from Malaysia brought up the issue again. 27 of 76 PD patients in their clinic were found to have the H. Pylori infection. After treatment with oral clarithromycin, amoxicillin and esomeprazole, their response to levodopa improved, as did “on” time. PD rating scales and questionnaires measuring quality of life also showed positive trends following treatment (unpublished data from the Movement Disorders Society, Ibrahim, et. al. National University of Malaysia).

So what about other gut bacteria and Parkinson’s? A 2013 study by Fasano and colleagues showed that patients with isolated small intestinal bacterial overgrowth had associated clinical issues that may have been underpinned by bacteria. This group observed more dopaminergic “off” time, more delayed “on” time and more dose failures. They also reported that removing bacterial overgrowth improved the symptoms without disrupting the pharmacokinetics of the Parkinson’s medication.

A recent study on gut bacteria and PD, published by a Finnish group led by Dr. Scheperjans, points out that the “intestinal microbiota interact with the autonomic and central nervous system via diverse pathways and that these areas are susceptible to Parkinson’s pathology… (i.e., alpha synuclein protein deposition).” They studied 72 PD patients and 72 controls and found that the bacteria in feces (called Prevotellaceae) reduced by 77.6%. Additionally, another bacteria called Enterobacteriaceae was associated with balance and gait issues, though this finding was much less robust. Whether these changes were due to the disease itself, Parkinson’s medications or other factors should be determined in future, more robust studies.

In November 2016, Sampson and colleagues published an important paper in the journal Cell, where they performed a series of experiments to demonstrate the importance of the gut microbiota and the relationship to PD indicators. Mice were designed to overexpress alpha synuclein, the protein that deposits into the guts and brains of PD patients. The mice showed that the microbiota in the intestines was related to the motor deficits in Parkinson’s, as the bacteria in the gut seemed to activate the microglia (the scavengers of the immune system). This activation means that inflammation plays a likely role in the pathology of Parkinson’s. The mice improved after they were given antibiotics. The authors hypothesize the presence of an important and previously unknown signaling between the stomach and the brain. In a final experiment, researchers introduced the microbiota from people with PD into the mice with Parkinson’s, and the symptoms in the mice worsened. Transplants of bacteria from healthy humans without Parkinson’s, however, did not worsen the movement manifestations. The authors speculated that the human microbiome could be a risk factor for the later development of Parkinson’s disease.

Below are key points about the relationship between gut bacteria and Parkinson’s:

  1. It is still unknown if H. Pylori or other gut bacteria are a risk factor for the later development of PD.
  2. If a person with Parkinson’s is experiencing motor fluctuations that cannot be controlled by medication adjustment, ask your doctor (or GI specialist) for a C-urea breath test to test for H. Pylori infection.
  3. Because H. Pylori is such a common infection (occurring in two out of every three people), the decision to treat it should be made in consultation with a GI specialist and neurologist. A GI specialist may need to perform follow-up tests.
  4. Changes in your Parkinson’s symptoms, motor fluctuations and medications should all be managed by your neurologist before and after H. Pylori treatment.
  5. The new findings on Prevotellaceae and Enterobacteriaceau will need further investigation and have not shown to interfere with current PD treatment.
  6. The human microbiome may be a risk factor for PD, but until clinical studies are conducted we do not recommend that people with PD seek treatment with antibiotics, which could advance drug resistance and other issues.
  7. We do not know what causes changes in the microbiome in Parkinson’s, theorized factors include: intestinal absorption, problems with gastric motility or diet. The exact causes remain unknown.

*Cartoon provided courtesy of Marty Bee http://katekelsall.typepad.com/my_weblog/2011/11/the-dopamine-chronicles...

Selected References:

Pierantozzi M, Pietroiusti A, Brusa L, Galati S, Stefani A, Lunardi G, Fedele E, Sancesario G, Bernardi G, Bergamaschi A, Magrini A, Stanzione P, Galante A. Helicobacter pylori eradication and l-dopa absorption in patients with PD and motor fluctuations. Neurology. 2006 Jun 27;66(12):1824-9.

Lee WY, Yoon WT, Shin HY, Jeon SH, Rhee PL. Helicobacter pylori infection and motor fluctuations in patients with Parkinson's disease. Mov Disord. 2008 Sep 15;23(12):1696-700.

Dobbs SM, Dobbs RJ, Weller C, Charlett A, Bjarnason IT, Lawson AJ, Letley D, Harbin L, Price AB, Ibrahim MA, Oxlade NL, Bowthorpe J, Leckstroem D, Smee C, Plant JM, Peterson DW. Differential effect of Helicobacter pylori eradication on time-trends in brady/hypokinesia and rigidity in idiopathic parkinsonism. Helicobacter. 2010 Aug;15(4):279-94.

Nielsen HH, Qiu J, Friis S, Wermuth L, Ritz B. Treatment for Helicobacter pylori infection and risk of Parkinson's disease in Denmark. Eur J Neurol. 2012 Jun;19(6):864-9. doi: 10.1111/j.1468-1331.2011.03643.x. Epub 2012 Jan 17.

Fasano A, Bove F, Gabrielli M, Petracca M, Zocco MA, Ragazzoni E, Barbaro F,
Piano C, Fortuna S, Tortora A, Di Giacopo R, Campanale M, Gigante G, Lauritano EC, Navarra P, Marconi S, Gasbarrini A, Bentivoglio AR. The role of small intestinal bacterial overgrowth in Parkinson's disease. Mov Disord. 2013
Aug;28(9):1241-9. doi: 10.1002/mds.25522. Epub 2013 May 27. PubMed PMID:
23712625.

Scheperjans F, Aho V, Pereira PA, Koskinen K, Paulin L, Pekkonen E, Haapaniemi E, Kaakkola S, Eerola-Rautio J, Pohja M, Kinnunen E, Murros K, Auvinen P. Gut microbiota are related to Parkinson's disease and clinical phenotype. Mov Disord. 2014 Dec 5. doi: 10.1002/mds.26069. [Epub ahead of print] PubMed PMID: 25476529.

Sampson TR et al., Gut Microbiota Regulate Motor Deficits and Neuroinflammation in a Model of Parkinson’s Disease, Cell (2016), http://dx.doi.org/10.1016/j.cell.2016.11.018

You can find out more about PF's National Medical Director, Dr. Michael S. Okun, by also visiting the Center of Excellence, University of Florida Health Center for Movement Disorders and Neurorestoration. Dr. Okun is also the author of the Amazon #1 Parkinson's Best Seller 10 Secrets to a Happier Life and 10 Breakthrough Therapies for Parkinson's Disease. You can read more from Dr. Okun in the What's Hot in PD? archives.