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The Role of Toll-Like Receptors In CFS/ME: A Promising New Therapeutic Approach?

shannah

Senior Member
Messages
1,429
Courtesy of Jan Van Roijen
Research from Italy

Anyone have access to the whole paper or know of the therapeutic approaches they're referring to?

Abstract
Perturbations in immune processes play an important role in chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME), a multifactorial disorder mainly characterized by severe and prolonged fatigue and tipically affecting a variety of bodily systems including the immune system.

Recent reports have shown that CFS/ME is an inflammatory disorder may be associated with autoimmune responses, mainly characterized by reduced functional activity of most immune cells, including neutrophils, natural killer cells, monocytes/macrophage and dendritic cells, together with dysregulations in cytokine levels, responsible for changes in the adaptive immune system.

Interactions between gut microorganisms and host immune function have been shown to contribute to aberrant inflammation in CFS/ME patients.
 Commensal and/or pathogen-associated molecular patterns detected by Toll-like receptors (TLRs) expressed on intestinal epithelial cells appear to trigger inflammatory signaling cascade leading to neuroinflammation and neurodegeneration.

This paper examines the role of TLR-mediated innate immunity in CFS/ME with evaluation of the current literature, also discussing about innovative therapeutic approaches represented by immunomodulators TLR-targeting.


http://www.ncbi.nlm.nih.gov/pubmed/25808894
 
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Bob

Senior Member
Messages
16,455
Location
England (south coast)
Of course they go directly to immunomodulators, instead of focusing on the gut dysbiosis.
Isn't that a chicken or egg question? i.e. which comes first? Gut dysbiosis or intestinal epithelial cell dysfunction? (BTW, I'm not sure this study is suggesting gut dysbiosis.)
 

Jonathan Edwards

"Gibberish"
Messages
5,256
I wonder what @Jonathan Edwards thinks of this study?

Not a lot so far. This isn't really a journal. It is a place where people put ideas that they think somebody might invest money in for drug company projects. The abstract contains a lot of dogmatic introductory statements that look tendentious and no actual content. I am not sure why bacteria binding to toll-like receptors in the gut should cause neuroinflammation. It sounds like a word salad of trendy ideas to be honest.
 

adreno

PR activist
Messages
4,841
I am not sure why bacteria binding to toll-like receptors in the gut should cause neuroinflammation.
I don't understand it as bacteria binding directly to the TLRs. But bacteria can regulate the expression of TLRs. Wouldn't this have an effect on inflammation?
 

Jonathan Edwards

"Gibberish"
Messages
5,256
I don't understand it as bacteria binding directly to the TLRs. But bacteria can regulate the expression of TLRs. Wouldn't this have an effect on inflammation?

They say bacterial molecular patterns being detected by TLRs - which means bacteria binding to TLRs to my understanding. I cannot see how this makes your brain unhappy. And gut epithelial cells are normally exposed to shedloads of bacterial molecular patterns. Maybe in the article there is a novel or plausible idea but this looks to me like rent-a-hypothesis!
 

MeSci

ME/CFS since 1995; activity level 6?
Messages
8,231
Location
Cornwall, UK
They say bacterial molecular patterns being detected by TLRs - which means bacteria binding to TLRs to my understanding. I cannot see how this makes your brain unhappy. And gut epithelial cells are normally exposed to shedloads of bacterial molecular patterns. Maybe in the article there is a novel or plausible idea but this looks to me like rent-a-hypothesis!

It seems consistent with a lot of studies I've read on interactions between the gut microbiome and the immune system, although I admit I don't have an in-depth understanding of this. I'd love to see the full text.

EDIT: the phrase "evaluation of the current literature" suggests that it is to some extent a review, which seems worth a read.
 

Marco

Grrrrrrr!
Messages
2,386
Location
Near Cognac, France
They say bacterial molecular patterns being detected by TLRs - which means bacteria binding to TLRs to my understanding. I cannot see how this makes your brain unhappy. And gut epithelial cells are normally exposed to shedloads of bacterial molecular patterns. Maybe in the article there is a novel or plausible idea but this looks to me like rent-a-hypothesis!

You're probably right about the rent a hypothesis but isn't LPS often used in models to induce neuroinflammation?
 

adreno

PR activist
Messages
4,841
You're probably right about the rent a hypothesis but isn't LPS often used in models to induce neuroinflammation?
It is, and activation of TLR4 increases intestinal permeability and endotoxins in plasma. See:

Taken together, all the data presented here suggest a bifunctional role of TLR-4 signaling pathway after stress exposure by triggering neuroinflammation at PFC level and regulating gut barrier function/permeability. Furthermore, our data suggest a possible protective role of antibiotic decontamination in stress-related pathologies presenting increased intestinal permeability (leaky gut) such as depression, showing a potential therapeutic target that deserves further consideration.
http://www.ncbi.nlm.nih.gov/pubmed/22906518
 

adreno

PR activist
Messages
4,841
They say bacterial molecular patterns being detected by TLRs - which means bacteria binding to TLRs to my understanding.
You are right about this:

Intestinal epithelial cells (IECs) and gut associated immune cells recognize the bacterial components via pattern-recognition receptors (PRRs) and are responsible for maintaining tolerance to the large communities of resident luminal bacteria while being also able to mount inflammatory responses against pathogens. Toll-like receptors (TLRs) are a major class of PRRs that are present on IECs and immune cells which are involved in the induction of both tolerance and inflammation.
http://journal.frontiersin.org/article/10.3389/fimmu.2013.00512/full
 

Jonathan Edwards

"Gibberish"
Messages
5,256
I am sorry but I cannot make head or tail of any of this really. If you simply think in terms of 'if this goes up that goes up and that goes down' you can build any hypothesis about inflammation you like, and you can always find a transgenic mouse that will illustrate it. But a story about a human disease has to have the right sort of beginning, middle and end in relation to primary causal factors, plausible feedback mechanisms and specific clinical result. As far as I can see the psychiatrists have decided to play with these pathways in the lab because it is trendy and they can get grant money but in terms of real human illness it makes no sense whatever. I may be wrong but I have been in this game a long time. The microbiome is trendy in everything, including RA, but I have yet to see anything that makes sense come out of studying it, other than the very specific and atypical case of Helicobacter.
 

Crux

Senior Member
Messages
1,441
Location
USA
As an anecdote ; I can induce neuritis, and a shingles outbreak, simply by having a serving of naturally fermented food, a probiotic, or anything with commensal bacteria.

I realize all food is teeming with microbes, so the 'dose makes the poison', in my case.

Since the shingles, herpes zoster virus, resides in my spine, and my symptoms are neurological ; I believe that commensals can cause neuroinflammation in some people.

I'm only one example, but I suspect this is happening to many folks, especially those with ME/CFS. ( Lactic acid has been found in the CSF of people with MS. Some people with Parkinson's have been found to have SIBO.)
 

MeSci

ME/CFS since 1995; activity level 6?
Messages
8,231
Location
Cornwall, UK
As an anecdote ; I can induce neuritis, and a shingles outbreak, simply by having a serving of naturally fermented food, a probiotic, or anything with commensal bacteria.

I realize all food is teeming with microbes, so the 'dose makes the poison', in my case.

Since the shingles, herpes zoster virus, resides in my spine, and my symptoms are neurological ; I believe that commensals can cause neuroinflammation in some people.

I'm only one example, but I suspect this is happening to many folks, especially those with ME/CFS. ( Lactic acid has been found in the CSF of people with MS. Some people with Parkinson's have been found to have SIBO.)

My understanding of 'commensal bacteria' or 'commensal microflora' is the micro-organisms present on and in our bodies, as described here. They are essential to our survival.
 

Crux

Senior Member
Messages
1,441
Location
USA
My understanding of 'commensal bacteria' or 'commensal microflora' is the micro-organisms present on and in our bodies, as described here. They are essential to our survival.

Yes, commensal bacteria are essential, and symbiotic with us as their host.
Although,if their numbers are overgrown, then they can become infectious and inflammatory.

A search for reports regarding infections from many types of commensals is pretty easy to find.

Edit: I hope this doesn't seem snarky, apologies if so.
 
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MeSci

ME/CFS since 1995; activity level 6?
Messages
8,231
Location
Cornwall, UK
Yes, commensal bacteria are essential, and symbiotic with us as their host.
Although,if their numbers are overgrown, then they can become infectious and inflammatory.

A search for reports regarding infections from many types of commensals is pretty easy to find.

Edit: I hope this doesn't seem snarky, apologies if so.

No problem. As you can see from some of my blogposts, e.g. this one, the role of the gut in ME/SEID is an area of great interest to me.
 

Sea

Senior Member
Messages
1,286
Location
NSW Australia
As an anecdote ; I can induce neuritis, and a shingles outbreak, simply by having a serving of naturally fermented food, a probiotic, or anything with commensal bacteria.

I realize all food is teeming with microbes, so the 'dose makes the poison', in my case.

Since the shingles, herpes zoster virus, resides in my spine, and my symptoms are neurological ; I believe that commensals can cause neuroinflammation in some people.

I'm only one example, but I suspect this is happening to many folks, especially those with ME/CFS. ( Lactic acid has been found in the CSF of people with MS. Some people with Parkinson's have been found to have SIBO.)
Interesting Crux. Also, I've heard parents of kids with PANDAS (pediatric autoimmune neuropsychiatric disorder associated with streptococcus) say that their child reacts with a flare of symptoms to some or all strep family probiotics
 

Crux

Senior Member
Messages
1,441
Location
USA