frontiers in Pediatrics: ME/CFS in the era of the human microbiome... Amy D. Proal et al - 2018

[Kalliope]

Review article which is provisionally accepted. Full text published soon.

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome in the era of the human microbiome: persistent pathogens drive chronic symptoms by interfering with host metabolism, gene expression and immunity

ME/CFS may be driven by this pathogen-induced dysfunction, with the nature of dysbiosis and symptom presentation varying based on a patient’s unique infectious and environmental history. Under such conditions, patients would benefit from treatments that support the human immune system in an effort to reverse the infectious disease process.

 

[Kalliope]

Full text available now: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome in the Era of the Human Microbiome: Persistent Pathogens Drive Chronic Symptoms by Interfering With Host Metabolism, Gene Expression, and Immunity

 

[Sly Saint]

 

[Trish]

Congratulations @Amy Proal.

 

[Hutan]

This paper is speculative and I'm sure people will find bits or even lots to disagree with. But the main idea that I got from the paper is, I think, valid. That is, there's an awful lot more to find out about how the huge number of organisms that make up the human holobiont interact in sickness and health, and over time. And some of that knowledge may be the answer to the cause of ME/CFS. And for that alone, I think it's worth a read - as a reminder of how hubristic it is to think that if a simple biological explanation can't be found for an illness right now, then the answer can only be that the patient's symptoms are a result of faulty thoughts and behaviours, fixable with positive thinking and sleep hygiene.

The overall success of ME/CFS research also hinges on the scientific community's willingness to embrace the concept of the human holobiont. In ME/CFS, the immune response, metabolism, central nervous system, and human gene expression are all linked by the activity of the microbiome and its associated proteins/metabolites. A greater focus on these interconnected systems is necessary, which will require increased collaboration between separate research teams.

Some of the complications might be the effect of series of infections on the immune system; organisms being benign in some tissues and pathogenic in others, or being benign in some people and pathogenic in others; and interactions between different microbiome species.

This paper sounded worth looking up:

Schutzer et al. (94) demonstrated that the ME/CFS cerebrospinal proteome differs substantially from that of healthy controls (Figure 2). Indeed, 738 of 2,783 identified proteins (26.5%) were unique to patients with ME/CFS, providing strong evidence that ME/CFS is indeed characterized by microbiome dysbiosis in tissue and blood.

A typo(dauer)

This dour-like state can be driven by exposure to adverse environmental conditions, as would be expected if the ME/CFS immune system struggles to manage microbiome dysbiosis and associated pathogens.

It was suggested that investigating the common ways that organisms evade immune systems might be an efficient way to understand ME/CFS. e.g. the Vitamin D nuclear receptor

The fungus Aspergillus fumigatus secretes a gliotoxin that significantly downregulates VDR expression (133). Because disabling the innate immune system via the VDR pathway is such a logical survival mechanism, other uncharacterized bacteria, viruses or fungi may have also evolved to dysregulate receptor activity.

Similarly, composition of the ME/CFS microbiome, proteome and metabolome should be expected to differ somewhat from study to study. Instead of worrying about these inconsistencies, the ME/CFS research community should strive to better characterize even more common mechanisms of pathogen survival and persistence.

There's a discussion of how the way an organism interacts with the human host might change over time:

Another study found that Candida albicans's transition from extracellular to intracellular pathogen was accompanied by a coordinated, time-dependent shift in gene expression for both host and fungus (135). These gene expression changes led to a gradual decline in pro-inflammatory cytokine activation by the host immune system.

These findings shed light on a recent ME/CFS study. Hornig et al. (5) reported distinct alterations in plasma immune signatures—including prominent activation of both pro-and anti-inflammatory cytokines—early in the course of ME/CFS. However, these alterations were not observed in subjects with a longer duration of illness.

Another typo (patients):

A number of brain abnormalities have been reported in patents with ME/CFS (187).

This paragraph summarises many of the ideas:

Different pathogens have evolved similar survival mechanisms to disable the host immune response and/or host metabolic pathways. The metabolic dysfunction driven by these different microbes can result in similar clusters of inflammatory symptoms. ME/CFS may be driven by this pathogen-induced dysfunction, with the nature of dysbiosis and symptom presentation varying based on a patient's unique infectious and environmental history. An initial infection or environmental exposure weakens the host immune system. This makes it easier for pathobionts to subvert the immune response and interfere with host gene expression and metabolism. A snowball effect begins, in which the microbiome becomes increasingly dysbiotic as the strength of the immune response weakens over time

The authors note that ME/CFS is a nasty illness and that treatments are needed. Their suggested treatment is probably taking a leap at this point in time, but I appreciate the desire for action.

This suggests that immunostimulative therapies should be administered in a predictive and even preventative fashion.

[a couple of minor edits made for clarity]

 

[Amy Proal]

Hey Science for ME,

This is Amy, the lead author of the paper. I joined the group to post the paper and see if you guys have any feedback. I'm excited to see Kalliope already posted it!

Hutan, thanks for pointing out those spelling errors. That frustrates me lot. One difficult thing about this journal (Frontiers) is they use spellcheck (which definitely turned "dauer" into "dour" ahhhhhh!) "Patients" is on me. I'm going to see if the journal can make changes to the online version...

In the meantime, do any of you have questions about the paper? My goal was to connect different findings on ME/CFS as viewed through the lens of persistent infection. Also, to take data on infection + microbiome in inflammatory conditions related to ME/CFS and see how they might better inform our understanding of infectious processes in patients with ME/CFS.

Let me know and thanks,
Amy

 

[Hutan]

Welcome to the forum @Amy Proal. We love it when researchers share their ideas with us and are open to feedback. Best wishes.

 

[Milo]

Hey Science for ME,

This is Amy, the lead author of the paper. I joined the group to post the paper and see if you guys have any feedback. I'm excited to see Kalliope already posted it!

Hutan, thanks for pointing out those spelling errors. That frustrates me lot. One difficult thing about this journal (Frontiers) is they use spellcheck (which definitely turned "dauer" into "dour" ahhhhhh!) "Patients" is on me. I'm going to see if the journal can make changes to the online version...

In the meantime, do any of you have questions about the paper? My goal was to connect different findings on ME/CFS as viewed through the lens of persistent infection. Also, to take data on infection + microbiome in inflammatory conditions related to ME/CFS and see how they might better inform our understanding of infectious processes in patients with ME/CFS.

Let me know and thanks,
Amy

Thank you for coming and hanging out with us @Amy Proal and thank you so very much for your work. Your paper was dense and referring to good papers which showed that you did your homework!

My brain is totally out of it tonight but i noted from your past work made comments about Vitamin D that would be great to discuss here (well in a new thread so it can be tracked properl). Many patients here take D supplementation and it would be great to review what you wrote.

As a sort of, paper related question, when you mention microbiome, should we assume gut microbiome? And has the concept of brain microbiome, or CSF microbiome been explored, would it be relevant in the context of our disease?

 

[Robert 1973]

Hi @Amy Proal. Thanks for joining the forum. Great to have you here. I’ve not managed to read the paper yet but just looking at what @Hutan posted above, one sentence caught my attention:

“A snowball effect begins, in which the microbiome becomes increasingly dysbiotic as the strength of the immune response weakens over time.”

Apologies if I have misunderstood from reading out of context, but if there is a snowball effect in which the microbiome becomes increasingly dysbiotic, would we not expect the illness to be progressive? Given that most ME patients seems to stabilise without recovering, is it not more likely that something(s) may cause some sort of dybiosis which in most cases then becomes a new stable state?

 

[Amy Proal]

Milo hey - Thanks for reading the paper and for your nice comments! Vitamin D is actually a very complicated topic. But I would be happy to write about it later in a separate thread. I’ll try to see if I can do that this coming week.

In the meantime, yes! My paper contends that microbiome communities outside the gut are extremely important in ME/CFS. Researchers at Harvard (that I know personally) are currently working on what’s called the “Brain Microbiome Project.” They are studying human brains to identify the bacteria that can persist in them. While they haven’t yet published their data, I’m allowed to tell you that they have found that all human brains (even healthy childhood brains) contain a bacteria microbiome. Then, when this team has studied this brain microbiome in patients with Alzheimer’s, the microbe communities are very different than in healthy subjects. The implications of that are huge. We know ME/CFS is characterized by neuroinflammation. The presence of microbes in the brain could mean that certain brain pathogens may directly drive that neuroinflammation. If that’s the case, it would explain why microglia and astrocytes are often activated in ME/CFS. So I think studying the brain microbiome in ME/CFS is one of the most important things we could do as a research community.

Here is a video where I talk about neuroinflammation, the immune response and brain infection:



Also, even healthy humans appear to have a blood microbiome (bacteria, viruses, fungi etc). A major questions is: does this blood microbiome change in ME/CFS? Blood microbes are also important because they often persist inside the cells of the immune system. And any pathogen able to persist inside a human immune cell can directly change how the human cell expresses its own genes (in simple terms, these pathogens can best “hack” our human pathways).

So, yes, one of the main messages of my paper is that in ME/CFS we must better study microbes + viruses + fungi etc that live in microbiome communities outside the human gut.

Robert hey - Successive infection and the “snowball effect” are part of a model that seeks to explain how ME/CFS develops in the first place (not necessarily how it continues over time). The main point of the model is that several different environmental factors (chemicals, infections, stress etc) could combine to cause final ME/CFS symptoms. Here’s a video I recently recorded on successive infection. What do you think? Thanks!:

 

[Amy Proal]

Welcome to the forum @Amy Proal. We love it when researchers share their ideas with us and are open to feedback. Best wishes.

Thanks Hutan!

 

[adambeyoncelowe]

Milo hey - Thanks for reading the paper and for your nice comments! Vitamin D is actually a very complicated topic. But I would be happy to write about it later in a separate thread. I’ll try to see if I can do that this coming week.

In the meantime, yes! My paper contends that microbiome communities outside the gut are extremely important in ME/CFS. Researchers at Harvard (that I know personally) are currently working on what’s called the “Brain Microbiome Project.” They are studying human brains to identify the bacteria that can persist in them. While they haven’t yet published their data, I’m allowed to tell you that they have found that all human brains (even healthy childhood brains) contain a bacteria microbiome. Then, when this team has studied this brain microbiome in patients with Alzheimer’s, the microbe communities are very different than in healthy subjects. The implications of that are huge. We know ME/CFS is characterized by neuroinflammation. The presence of microbes in the brain could mean that certain brain pathogens may directly drive that neuroinflammation. If that’s the case, it would explain why microglia and astrocytes are often activated in ME/CFS. So I think studying the brain microbiome in ME/CFS is one of the most important things we could do as a research community.

Here is a video where I talk about neuroinflammation, the immune response and brain infection:



Also, even healthy humans appear to have a blood microbiome (bacteria, viruses, fungi etc). A major questions is: does this blood microbiome change in ME/CFS? Blood microbes are also important because they often persist inside the cells of the immune system. And any pathogen able to persist inside a human immune cell can directly change how the human cell expresses its own genes (in simple terms, these pathogens can best “hack” our human pathways).

So, yes, one of the main messages of my paper is that in ME/CFS we must better study microbes + viruses + fungi etc that live in microbiome communities outside the human gut.

Robert hey - Successive infection and the “snowball effect” are part of a model that seeks to explain how ME/CFS develops in the first place (not necessarily how it continues over time). The main point of the model is that several different environmental factors (chemicals, infections, stress etc) could combine to cause final ME/CFS symptoms. Here’s a video I recently recorded on successive infection. What do you think? Thanks!:

I really enjoyed your videos. Thanks for coming and sharing them with us.

 

[Snow Leopard]

This manuscript is quite interesting, though inconclusive due to lack of research.

I must admit I was quite put off by the fact that it was coauthored by Trevor Marshall. I'm expecting this article was mostly written by Amy, rather than Trevor... Also, "Autoimmunity Research Foundation Thousand Oaks, United States" appears to be someone's house...

 

[Invisible Woman]

An aside & a nitpicking one at that -

Given that most ME patients seems to stabilise without recovering, is it not more likely that something(s) may cause some sort of dybiosis which in most

Do we know that this is true? I seem to be on a gradual downward trajectory and I know of others who have similar experiences. Of course, some of that might be to do with aging.

I do know some people who, temporary fluctuations aside, seem fairly stable, but they ate at the much milder end of the spectrum.

 

[Andy]

I do know some people who, temporary fluctuations aside, seem fairly stable, but they ate at the much milder end of the spectrum.

So something like a chicken korma then??

 

[unicorn7]

Very interesting this article! I like the hypotheses that are put forward.

The snowball-effect really corresponds with my case, as I have had a lot of successive infections, lots (!) of antibiotics in my life (about 40 courses..) and then a few operations.

Would low-dose immunoglobulins (scIg) be considered an immune strengthening medication?

This hypothesis would also correspond with the observation that early on people seem to have an overactive immune system and later on in the disease the immune system seems to slow down. There was also an observation I heard Ron Davis about, that some people seem to get better after a massive infection. It seems like this happened to me as well this year.

@AmyProal: I watched your youtube video, really like your idea's! I find the microbiome immensely interesting. For some reason I found it mind blowing that the bladder is not sterile

 

[Amy Proal]

Hey! Glad some of you find my videos helpful! I'm going to record more after the holidays, because I have several key project proposals to finalize before the new year.

And yes isn't it amazing how many organisms (and persistent pathogens) can persist in just the bladder alone? One thing I realize is that the public needs more access to the actual data on these findings. Because the number of microbes + viruses + fungi + archea + bacteriophages + mycoviruses (viruses that infect fungi) + virophages (viruses that infect viruses) capable of persisting in human tissue and blood etc is huge. And MOST of these organisms are pathobionts: organisms capable of changing their gene expression to act as pathogens under conditions of imbalance + immunosuppression.

A key thing I emphasize in my paper is that even healthy human blood harbors way more organisms than most people realize. Attached is a figure from this study which searched for just bacteria in the blood of healthy controls, and patients with schizophrenia, ALS, and bipolar disorder. Look at how many bacterial phyla were detected in the healthy controls!:

https://www.nature.com/articles/s41398-018-0107-9

Or take this Steven Quake study (Stanford) which identified over 3,000 novel organisms in the blood of immunocompromised patients. Look at the attached figure. It shows just the novel anelloviruses the study found in blood. All the viruses in white are new anelloviruses never before understood to persist in human before the study was performed:

https://www.pnas.org/content/114/36/9623

I argue in my paper that a basic acceptance of these organisms in human blood (plus the recognition that key pathogens can also persist in brain tissue) should form a starting point for ALL ME/CFS research. If you don't account for these organisms it's hard to correctly interpret your data or search for reliable biomarkers (for example red blood cell shape can change in response to microbe-driven changes in the blood: are we accounting for that??)

Best,
Amy

 

[Amy Proal]

Also if any of you better want to understand my background and how I got into researching infection + ME/CFS..I talk about it in this recent interview (start listening at minute 13:15):

https://vloggest.com/watch/amy-proa...ribiome-affect-autoimmune-disease-1076404399/

I had a severe case of ME/CFS when I was 19. Today I still have symptoms, but not nearly as severe. I got into ME/CFS research out of a desire to get to the bottom of what's going on in the condition. Also, my best friend is severely bedridden with ME/CFS and cannot even speak out loud.

The reason I'm sharing my paper here and elsewhere is out a determination that research on this disease move forward ASAP, with urgency, and in the most proactive fashion possible.

 

[Unable]

Just found this thread this evening.

So I know what I’ll be doing tomorrow. (Too sleepy to watch videos now )

Thanks Amy - much food for thought.

 

[Sly Saint]

This may be of interest:

"New RNA sequencing strategy provides insight into microbiomes
December 17, 2018

Researchers from the University of Chicago have developed a high-throughput RNA sequencing strategy to study the activity of the gut microbiome.

The new tools analyze transfer RNA (tRNA), a molecular Rosetta Stone that translates the genetic information encoded in DNA into proteins that perform basic biological functions. Developing a clear picture of tRNA dynamics will allow scientists to understand the activity of naturally occurring microbiomes, and study their responses to environmental changes, such as varying temperatures or changing availability of nutrients."

full article here:
https://www.brightsurf.com/news/art...rategy-provides-insight-into-microbiomes.html