In today’s post we will review recent research regarding one particular family of bacteria, Helicobacter pylori, and what they might be doing in relations to Parkinson’s disease.
In his magnificent book, I contain multitudes, science writer/journalist Ed Yong writes that we – every single one of us – release approximately 37 million bacteria per hour. By talking, breathing, touching, or simply being present in the world, we are losing and also picking up the little passengers everywhere we go.
Reminds me of that Pascal Mercier book “Night Train to Lisbon” – We leave something of ourselves behind when we leave a place,… I’m not sure if this is what he was referring to though.
Yong also points out that: 80% of the bacteria on your right thumb are different to the bacteria on your left thumb.
It’s a fascinating book (and no, I am not receiving any royalties for saying that).
Microbes. Source: NYmag
We have discussed microbes several times on this blog, particularly in the context of the gut and its connection to Parkinson’s disease (Click here, here and here to read some of those posts). Today we are going to re-visit one particular type of microbe that we have also discussed in a previous post: Helicobacter pylori.
Helicobacter pylori. Source: Helico
In the world of scientific research, if you publish your research in one of the top peer-reviewed journals (eg. Cell, Nature, or Science) that means that it is pretty important stuff.
This week a research report was published in the journal Cell, dealing with the bacteria in our gut and Parkinson’s disease. If it is replicated and confirmed, it will most certainly be considered REALLY ‘important stuff’.
In today’s post we review what the researchers found in their study.
Bacteria in the gut. Source: Huffington Post
Although we may think of ourselves as individuals, we are not.
We are host to billions of microorganisms. Ours bodies are made up of microbiomes – that is, collections of microbes or microorganisms inhabiting particular environments and creating “mini-ecosystems”. Most of these bacteria have very important functions which help to keep us healthy and functioning normally. Without them we would be in big trouble.
One of the most important microbiomes in our body is that of the gut (Click here for a nice short review on this topic). And recently there has been a lot of evidence that the microbiome of our gut may be playing a critical role in Parkinson’s disease.
What does the gut have to do with Parkinson’s disease?
We have previously written about the connections between the gut and Parkinson’s disease (see our very first post, and subsequent posts here, here and here), and there are now many theories that this debilitating condition may actually start in the gastrointestinal system. This week a new study was published which adds to the accumulating evidence.
So what does the new study say?
Title: Gut Microbiota Regulate Motor Deficits and Neuroinflammation in a Model of Parkinson’s Disease
Authors: Sampson TR, Debelius JW, Thron T, Janssen S, Shastri GG, Ilhan ZE, Challis C, Schretter CE, Rocha S, Gradinaru V, Chesselet MF, Keshavarzian A, Shannon KM, Krajmalnik-Brown R, Wittung-Stafshede P, Knight R, Mazmanian SK
Journal: Cell, 167 (6), 1469–1480
PMID: 27912057 (this article is available here)
The researchers (who have previously conducted a great deal of research on the microbiome of the gut and it’s interactions with the host) used mice that have been genetically engineered to produce abnormal amounts of alpha synuclein – the protein associated with Parkinson’s disease (Click here for more on this). They tested these mice and normal wild-type mice on some behavioural tasks and found that the alpha-synuclein producing mice performed worse.
A lab mouse. Source: USNews
The researchers then raised a new batch of alpha-synuclein producing mice in a ‘germ free environment’ and tested them on the same behavioural tasks. ‘Germ free environment’ means that the mice have no microorganisms living within them.
And guess what happened:
The germ-free alpha-synuclein producing mice performed as well as on the behavioural task as the normal mice. There was no difference in the performance of the two sets of mice.
How could this be?
This is what the researchers were wondering, so they decided to have a look at the brains of the mice, where they found less aggregation (clustering or clumping together) of alpha synuclein in the brains of germ-free alpha-synuclein producing mice than their ‘germ-full’ alpha-synuclein producing mice.
This result suggested that the microbiome of the gut may be somehow involved with controlling the aggregation of alpha-synuclein in the brain. The researchers also noticed that the microglia – helper cells in the brain – of the germ-free alpha-synuclein producing mice looked different to their counterparts in the germ-full alpha-synuclein producing mice, indicating that in the absence of aggregating alpha synuclein the microglia were not becoming activated (a key feature in the Parkinsonian brain).
The researchers next began administering antibiotics to see if they could replicate the effects that they were seeing in the germ-free mice. Remarkably, alpha-synuclein producing mice injected with antibiotics exhibited very little dysfunction in the motor behaviour tasks, and they closely resembling mice born under germ-free conditions.
How antibiotics work. Source: MLB
Antibiotics kill bacteria via many different mechanisms (eg. disrupting the cell membrane or targeting protein synthesis; see image above), and they have previously demonstrated efficacy in models of Parkinson’s disease. We shall come back to this in a section below.
The researchers in the study next asked if the microbiome of people with Parkinson’s disease could affect the behaviour of their germ free mice. They took samples of gut bacteria from 6 people who were newly diagnosed (and treatment naive) with Parkinson’s disease and from 6 healthy age matched control samples. These samples were then injected into the guts of germ free mice… and guess what happened.
The germ-free mice injected with gut samples from Parkinsonian subjects performed worse on the behavioural tasks than those injected with samples from healthy subjects. This finding suggested that the gut microbiome of people with Parkinson’s disease has the potential to influence vulnerable mice.
Note the wording of that last sentence.
Importantly, the researchers noted that when they attempted this experiment in normal mice they observed no difference in the behaviour of the mice regardless of which gut samples were injected (Parkinsonian or healthy). This suggests that an abundance of alpha synuclein is required for the effect, and that the microbiome of the gut is exacerbating the effect.
So what does it all mean?
If it can be replicated (and there will now be a frenzy of research groups attempting this), it would be a BIG step forward for the field of Parkinson’s disease research. Firstly, it could represent a new and more disease-relevant model of Parkinson’s disease with which drugs can be tested (it should be noted however that very little investigation of the brain was made in this study. For example, we have no idea of what the dopamine system looks like in the affected mice – we hope that this analysis is ongoing and will form the results of a future publication).
The results may also explain the some of the environmental factors that are believed to contribute to Parkinson’s disease. Epidemiological evidence has linked certain pesticide exposure to the incidence Parkinson’s disease, and the condition is associated with agricultural backgrounds (for more on this click here). It is important to reinforce here that the researchers behind this study are very careful in not suggesting that Parkinson’s disease is starting in the gut, merely that the microbiome may be playing a role in the etiology of this condition.
The study may also mean that we should investigate novel treatments focused on the gut rather than the brain. This approach could involve anything from fecal transplants to antibiotics.
EDITORIAL NOTE HERE: While there are one or two anecdotal reports of fecal transplants having beneficial effect in Parkinson’s disease, they are few and far between. There have never been any comprehensive, peer-reviewed preclinical or clinical studies conducted. Such an approach, therefore, should be considered EXTREMELY experimental and not undertaken without seeking independent medical advice. We have mentioned it here only for the purpose of inserting this warning.
Has there been any research into antibiotics in Parkinson’s disease?
You might be surprised to hear this, but ‘Yes there has’. Numerous studies have been conducted. In particular, this one:
Title: Minocycline prevents nigrostriatal dopaminergic neurodegeneration in the MPTP model of Parkinson’s disease.
Author: Du Y, Ma Z, Lin S, Dodel RC, Gao F, Bales KR, Triarhou LC, Chernet E, Perry KW, Nelson DL, Luecke S, Phebus LA, Bymaster FP, Paul SM.
Journal: Proc Natl Acad Sci U S A. 2001 Dec 4;98(25):14669-74.
PMID: 11724929 (This article is OPEN ACCESS if you would like to read it)
In this research study, the researchers gave the antibiotic ‘Minocycline’ to mice in which Parkinson’s disease was being modelled via the injection of a neurotoxin that specifically kills dopamine neurons (called MPTP).
Minocycline is a tetracycline antibiotic that works by inhibiting bacterial protein synthesis. It has also been shown to exert neuroprotective effects in different models of neurodegeneration via several pathways, primarily anti-inflammatory and inhibiting microglial activation.
The researchers found that Minocycline demonstrated neuroprotective properties in cell cultures so they then tested it in mice. When the researchers gave Minocycline to their ‘Parkinsonian’ mice, they found that it inhibited inflammatory activity of glial cells and thus protected the dopamine cells from dying (compared to control mice that did not receive Minocycline).
Have there been any clinical trials of antibiotic?
Again (surprisingly): Yes.
Title: A pilot clinical trial of creatine and minocycline in early Parkinson disease: 18-month results.
Authors: NINDS NET-PD Investigators..
Journal: Clin Neuropharmacol. 2008 May-Jun;31(3):141-50.
PMID: 18520981 (This article is OPEN ACCESS if you would like to read it)
This research report was the follow up of a 12 month clinical study that can be found by clicking here. The researchers had taken two hundred subjects with Parkinson’s disease and randomly sorted them into the three groups: creatine (an over-the-counter nutritional supplement), minocycline, and placebo (control). All of the participants were diagnosed less than 5 years before the start of the study.
At 12 months, both creatine and minocycline were noted as not interfering with the beneficial effects of symptomatic therapy (such as L-dopa), but a worrying trend began with subjects dropping out of the minocycline arm of the study.
At the 18 month time point, approximately 61% creatine-treated subjects had begun to take additional treatments (such as L-dopa) for their symptoms, compared with 62% of the minocycline-treated subjects and 60% placebo-treated subjects. This result suggested that there was no beneficial effect from using either creatine or minocycline in the treatment of Parkinson’s disease, as neither exhibited any greater effect than the placebo.
Was that the only clinical trial?
Another clinical trial, targeted a particular type of gut bacteria: Helicobacter pylori (which we have discussed in a previous post – click here for more on that).
Title: Eradication of Helicobacter pylori infection improves levodopa action, clinical symptoms and quality of life in patients with Parkinson’s disease.
Authors: Hashim H, Azmin S, Razlan H, Yahya NW, Tan HJ, Manaf MR, Ibrahim NM.
Journal: PLoS One. 2014 Nov 20;9(11):e112330.
PMID: 25411976 (This article is OPEN ACCESS if you would like to read it)
In this study, the researchers recruited 82 people with Parkinson’s disease. A total of 27 (32.9%) of those subjects had positive tests for Helicobacter pylori, and those participants had significantly poorer clinical scores compared to Helicobacter pylori-negative subjects. The researcher gave the participants a drug that kills Helicobacter pylori, and then twelve weeks later the researchers found improvements in levodopa onset time and effect duration, as well as better scores in motor performance and quality of life measures.
The researchers concluded that the screening and eradication of Helicobacter pylori is inexpensive and should be recommended for people with Parkinson’s disease, especially those with minimal responses to levodopa. Other experiments suggest that Helicobacter pylori is influencing some people’s response to L-dopa (click here for more on that).
Some concluding thoughts
While we congratulate the authors of the microbiome study published in the journal Cell for an impressive piece of work, we are cautious in approaching the conclusions of the study.
All really good research will open the door to lots of new questions, and the Cell paper published last week has certainly done this. But as we have suggested above, the results need to be independently replicated before we can get to excited about them. So while the media may be making a big fuss about this study, we’ll wait for (and report here) the follow-up, replication studies by independent labs before calling this REALLY ‘important stuff’.
The banner for today’s post was sourced from the Huffington Post
In her best selling book, ‘Gut’, author Giulia Enders wrote the following:
‘Although doctors had known since the 1960s that patients with Parkinson’s disease have an increased incidence of stomach problems they did not know the nature of the connection between sore stomachs and trembling hands. It took a study of different population groups on the Pacific island of Guam to throw light on the subject. In some parts of the island, there was an astonishingly high incidence of Parkinson-like symptoms among the population. Those affected suffered from trembling hands, facial paralysis and motor problems. Researchers realised that the symptoms were most common in areas where people’s diets included cycad seeds. These seeds contain neurotoxins – substances that damage the nerves. Helicobacter pylori can produce an almost identical substance. When laboratory mice were fed with an extract of the bacteria without being infected with the living bacterium itself, the displayed very similar symptoms to the cycad eating Guamanians.’
While finding her book a very interesting read, we here at the Science of Parkinson’s were a little worried as to how the general audience would interpret this passage (“So Helico… whatever causes Parkinson’s disease?!?”).
But then this week a new study was published regarding Helicobacter pylori and Parkinson’s disease. And so we thought we’d do a post on it.
In 1982, two Australian scientists – Robin Warren and Barry Marshall – made an interesting discovery.
Barry Marshall (left) and Robin Warren. Source: AustraliaUnlimited
They were studying the association between bacterial infection and peptic ulcers. Their research was ridiculed by the establishment who did not believe that bacteria could even live in the harsh acidic environment of the gut let alone influence or affect it. The general consensus was that stomach ulcers were caused by stress, fatigue, and too much acid.
After some unsuccessful initial experiments, Marshall took the rather bold step of making himself a guinea pig in his own study: he drank a petri dish containing cultured Helicobacter pylori.
A petri dish of Helicobacter pylori. Yummy! Source: Liofilchem
Yes, I know how crazy that sounds, but that is what happened. And the resulting events changed the way we look at the intestinal system forever.
Marshall had expected the bacteria to take months (if not years) to embed and start to grow, so it came as a bit of a surprise when several days later he began feeling nausea and his mother commented about his bad breath. After a week, Marshall had a biopsy, which demonstrated severe inflammation and the growing of Helicobacter pylori bacteria in his gut. Warren and Marshall were awarded the Nobel prize in Medicine in 2005 for this work.
Since their discovery, we have discovered a small universe of microbes living in our intestinal system (and most of it is still waiting to be discovered). Importantly – as Miss Elders’ book emphasises – we are learning more and more about how the biological system living in our gut is influencing our bodies, both our normal and abnormal states of being.
There are even theories of Parkinson’s disease arising from our growing knowledge of the ‘microbiota’ (what scientists called the eco-system in our guts) and how it could be playing a role in the disease. And many of those theories involve Helicobacter pylori.
What is Helicobacter pylori?
Helicobacter pylori is a spiral shaped bacterium that lives in the stomach and duodenum (that is the section of intestine just below stomach). Don’t be disturbed by that, the population of all microbes outnumber the cells in our body by approximately 10 to 1, and without them we wouldn’t last very long. And Helicobacter pylori are present in the gut of at least 50% of us (though 85% of people never display the symptoms of an infection).
Helicobacter pylori. Source: Helico
So are Helicobacter pylori involved in Parkinson’s disease?
There have been numerous studies that have assessed the Helicobacter pylori populations in the guts of people with Parkinson’s disease (for a very good open access review on this, please click here). These studies are difficult to judge, however, as the rate of Helicobacter pylori is very high and varies somewhat around the world. Different strains of Helicobacter pylori may be having different effects, but this is yet to be determined.
Helicobacter pylori does appear to have an effect, however, with regards to the standard treatment of Parkinson’s disease: L-dopa.
In 2001, Italian researchers noticed fluctuations in the absorption of L-dopa in six Helicobacter pylori infected people with Parkinson’s disease, but not in Helicobacter pylori-negative people with Parkinson’s disease. This was interesting, but even more interesting was that the ratings of these subjects (their UPDRS scores) decreased when they were treated with medication to eradicate Helicobacter pylori.
Title: Reduced L-dopa absorption and increased clinical fluctuations in Helicobacter pylori-infected Parkinson’s disease patients.
Authors: Pierantozzi M, Pietroiusti A, Sancesario G, Lunardi G, Fedele E, Giacomini P, Frasca S, Galante A, Marciani MG, Stanzione P.
Journal: Neurol Sci. 2001 Feb;22(1):89-91.
Other studies have reported similar observations, including this study:
Title: Helicobacter pylori infection and motor fluctuations in patients with Parkinson’s disease.
Authors: Lee WY, Yoon WT, Shin HY, Jeon SH, Rhee PL.
Journal: Mov Disord. 2008 Sep 15;23(12):1696-700.
The researchers in this study found that the onset time of L-dopa was longer, and the duration of the effect was shorter in people with Parkinson’s disease who also have an Helicobacter pylori infection (compared to people with Parkinson’s disease who are Helicobacter pylori negative). This data supports the idea that Helicobacter pylori may be disrupting the absorption of L-dopa. And again, after administering antibiotic treatment to people with Parkinson’s disease to eradicate Helicobacter pylori, the ‘onset’ time decreased and the duration of the L-dopa effect increased when compared to the pretreatment measures.
So there appears to be some indication that Helicobacter pylori may be affecting the situation in Parkinson’s disease.
But is there any evidence that Helicobacter pylori causes Parkinson’s disease?
To our knowledge, there has been one study that has suggested any kind of causative role for Helicobacter pylori in Parkinson’s disease. That study was presented at the Annual general meeting of the American Society for Microbiology at New Orleans in 2011:
Title: Helicobacter pylori Infection Induces Parkinson’s Disease Symptoms in Aged Mice.
Authors: Block: M. F. Salvatore, S. L. Spann, D. J. Mcgee, O. A. Senkovich, T. L. Testerman;
University: Louisiana State Univ. Hlth.Sci. Ctr.- Shreveport, Shreveport, LA.
Poster Presentation Number: 136
Background: H. pylori has long been known to cause gastritis and ulcers, but mounting evidence suggests that this organism contributes to several extragastric diseases, including idiopathic Parkinson’s disease. It has been hypothesized that cholesteryl glucosides produced by H. pylori are the cause of neurotoxicity; however chronic inflammation may also cause neurological damage. We have recently developed a mouse model of H. pylori-mediated Parkinson’s disease which approximates many features of human disease, including locomotor dysfunction, decreased dopamine in certain brain regions, and increased susceptibility of older animals to Parkinsonian symptoms. Our experiments also revealed that a mutant strain causes more severe disease than the isogenic wild-type strain. AlpA and AlpB have previously been identified as adhesins.
Methods: We measured five locomotor activity parameters in aged mice persistently colonized with H. pylori SS1 AlpAB and in mice fed whole, killed H. pylori. Following euthanasia, we measured dopamine and tyrosine hydroxylase content in the substantia nigra and dorsal striatum. We also measured effects of the AlpAB mutation on H. pylori adherence and pathogenesis.
Results: Long-term administration of food containing killed H. pylori causes locomotor deficits similar to those seen in H. pylori-infected animals. We found that AlpA and AlpB bind host laminin. Contrary to expectations, the AlpAB mutant causes severe inflammation in gerbils.
Conclusions: The finding that feeding killed H. pylori causes locomotor deficits similar to those seen with active infection supports the hypothesis that products produced by H. pylori are neurotoxic. Our results also suggest alterations in laminin binding by the AlpAB strain could impact interactions with the host. This new mouse model offers an unprecedented opportunity to examine the mechanisms through which H. pylori contributes to Parkinson’s disease in humans.
(Click here for the original abstract)
Unfortunately this research has not been formally published (in a peer-reviewed fashion or otherwise), so many of the details regarding the study are unknown to us. The implications, however, are very interesting and exciting. It would be a worthwhile endeavour for the study to be independently replicated.
But there was a study published last week that raised some interesting possibilities regarding a role for Helicobacter pylori in the onset of Parkinson’s disease:
Title: Augmentation of Autoantibodies by Helicobacter pylori in Parkinson’s Disease Patients May Be Linked to Greater Severity.
Authors: Suwarnalata G, Tan AH, Isa H, Gudimella R, Anwar A, Loke MF, Mahadeva S, Lim SY, Vadivelu J.
Journal: PLoS One. 2016 Apr 21;11(4):e0153725.
PMID: 27100827 (this research article is OPEN ACCESS if you want to read it)
The researchers in this study took blood from 30 Helicobacter pylori-positive people with Parkinson’s disease and 30 age- and gender-matched Helicobacter pylori-negative people with Parkinson’s disease. They then analysed the blood for autoantibodies (we’ve discussed these before in a previous post). Interestingly, some of the autoantibodies that were found to be elevated in Helicobacter pylori-positive group included antibodies that recognize proteins essential for normal brain function (such as Nuclear factor I subtype A (NFIA), Platelet-derived growth factor B (PDGFB) and Eukaryotic translation initiation factor 4A3 (eIFA3)). This suggests that Helicobacter pylori may be causing the immune system to attack proteins that are required, thus making people with Parkinson’s more vulnerable.
Finally, back to Miss Elder’s passage in her book ‘Gut’:
In the passage at the start of this post, we would suggest that Miss Elders may have been referring to ‘Lytico-bodig’ (also known as amyotrophic lateral sclerosis-parkinsonism-dementia complex (ALS-PDC) – coined by Hirano and colleagues in 1961). ALS-PDC is a neurodegenerative disease of unknown causes that exists in the United States territory of Guam. In fact, during 1950s, it was one of the leading causes of death for the Chamorros people of of Guam.
As the name suggests the disease has elements of several neurodegenerative conditions, and it is considered a separate condition to Parkinson’s disease. There is no treatment for ALS-PDC. The Parkinsonian drug L-DOPA alleviates only some of the symptoms of ALS-PDC, and window of efficacy is a lot shorter (only 1-2 hours) than that of Parkinson’s disease. ALS-PDC occurs within families, but no genetic connection has been found yet, so most scientists believe it is predominantly environment-based.
β-Methylamino-L-alanine (BMAA), is a neurotoxin produced by a bacteria called cyanobacteria and it has long been considered the culprit behind ALS-PDC. Miss Elders is correct that cycad seeds contain high levels of BMAA, and so too do animals that like eating the fleshy covering of the cycad seeds, such as flying foxes. Flying foxes were a popular dinner in Guam, but little did those consuming the meat realise that their meal probably contained high levels of BMAA. One theory of ALS-PDC causation is basically ‘Eat enough of those dinners across a lifetime and…’. But this theory is not supported by the evidence – flying foxes have been hunted to near extinction in Guam, but the rates of ALS-PDC have disappeared in parallel.
It is also interesting to note that high concentrations of BMAA are present in shark fins. Ignore any comments about the ‘libido enhancing properties’ and avoid shark fin soup.
While we here are very excited by the largely unexplored depths the gastrointestinal system and of the role that it could be playing in Parkinson’s disease, we think that Miss (soon to be Dr) Giulia Enders’ suggestion that Helicobacter pylori and Parkinson’s disease are intimately connected is a bit flimsy. Certainly unproven.
It is dangerous to write definitely about medically related research as it will often result in some individuals going off and self-testing all manner of different treatments in a desperate attempt to ‘cure themselves’.Sometimes this ‘definitive style’ is the suggestion of the editorial staff, hoping to cause something sensational and sell more books.
We are of the mind that more research is required in order to determine the role of bacteria (not just Helicobacter pylori) in Parkinson’s disease.
Having said all this, we still think that soon-to-be-Dr Enders’ book is a good read!