The microbiome hypothesis: Lipkin's collaborative, part 1 (Simon McGrath blog)

[Simon M]

New blog at ME/CFS Research Review

The microbiome hypothesis: Dr Ian Lipkin's collaborative, part 1​

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A gut reaction is the problem in ME/CFS – that’s the main idea being pursued by Dr Ian W. Lipkin of the Center for Infection and Immunity at Columbia University. He believes that the body’s response to changes in the gut could be what’s driving ME/CFS for at least some patients.

Lipkin’s collaborative group, the Center for Solutions for ME/CFS, will test this theory as part of a $9.6 million, five-year research programme, which Lipkin was good enough to discuss with me via phone and email.

This huge research programme, which is funded by the National Institutes of Health (NIH), is made up of three main projects. This blog looks at the first two, which will use high-tech approaches to see if changes in the gut are causing changes in the body, particularly in the immune system. The third project, which looks at the biological response to exertion in ME/CFS, will be covered in the next blog.

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Read the full blog

 

[Simon M]

 

[Aimossy]

Thank you @Simon M !!

 

[Barry]

Only very quickly skimmed so far, but to me there would be no great surprise at all for a connection between ME/auto-immune/gut issues. My wife has the lot and I suspect is far from alone. Research into this area is very worthwhile I think.

 

[mariovitali]

It is a big surprise to me that since the Gut and the Liver work very closely together ("enterohepatic circulation","Gut-Liver Axis") , no one is paying attention to the Liver.

Some interesting excerpts from https://www.nature.com/articles/s41575-018-0011-z :


Title : The Gut-Liver Axis and the intersection with the microbiome

• Alcoholic and nonalcoholic fatty liver diseases share key characteristics, such as intestinal dysbiosis, gut permeability and shifts in levels of bile acids, ethanol and choline metabolites

Interestingly Dr Lipkin reports the following :

We confirm reports of altered plasma levels of choline, carnitine and complex lipid metabolites and demonstrate that patients with ME/CFS and IBS have increased plasma levels of ceramide.

<......>

Increased levels of ceramides were reported in mucosal samples from IBS patients29 as well as in plasma and tissue samples in diabetes, cardiomyopathy, insulin resistance, atherosclerosis and steatohepatitis.

Next, recall that Maureen hanson has found impaired Bile Acids (BAs) Metabolism. Interestingly BAs are very much connected with the Gut Microbiome :

BAs and the gut microbiota closely interact and modulate each other; BAs exert direct control on the intestinal microbiota. By binding to FXR, they induce production of antimicrobial peptides (AMPs) such as angiogenin 1 and RNase family member 4, which are directly involved in inhibiting gut microbial overgrowth and subsequent gut barrier dysfunction

and

Intestinal permeability is characterized by compromised tight junctions between enterocytes and is consistently seen across the spectrum of liver diseases66,67. Liver damage is associated with small intestinal bacterial overgrowth (SIBO) and dysbiosis of the lower gastrointestinal tract

There are more reasons for increased gut permeability of course such as impaired N-Linked Glycosylation.


I e-mailed to Ron Davis, Robert Phair, Maureen Hanson and Derya Unutmaz (among others) Fibroscan Results showing Liver Fibrosis.


Also interestingly :

All experimental models of liver fibrosis result in gut microbial dysbiosis and increased intestinal permeability, and treatment of the gastrointestinal tract with nonabsorbable antibiotics (such as rifaximin and neomycin) improved survival by immuno-modulation, reducing translocation and incidence of infection

This is a Fibroscan of an ME/CFS patient with F3 Fibrosis and completely normal Liver Function Tests :

 

[Forbin]

This 2018 paper found that respiratory viruses can alter the gut microbiome (in mice).

Both RSV and influenza virus infection resulted in significantly altered gut microbiota diversity, with an increase in Bacteroidetes and a concomitant decrease in Firmicutes phyla abundance.

Respiratory Disease following Viral Lung Infection Alters the Murine Gut Microbiota

Assuming that something similar can happen in humans, perhaps the non-specific "viral triggers" apparent in many ME cases are actually only important in that the immune response to them disrupts the gut microbiome (even when they're lung infections). A predisposition, or just blind chance, may account for the form that the altered microbiome takes.

Our observation that different families within the Bacteroidetes phylum increase in abundance suggests that rather than the specific targeting of certain microbiota members by the immune system, respiratory infection causes a change in the gut environment, favoring the expansion of Bacteroidetes, and whichever Bacteroidetes family gains the advantage first increases in abundance. [same source]

 

[Sunshine3]

Anyone have any idea what Lipkin's ' bullish views' might be in relation to ME/CFS that Simon refers to for upcoming blog.... I'm intrigued!!

 

[Simon M]

Anyone have any idea what Lipkin's ' bullish views' might be in relation to ME/CFS that Simon refers to for upcoming blog.... I'm intrigued!!

Good to see that the teaser worked . Coming next week

 

[Amw66]

Thank you @Simon M . A great explanation and hopefully a silver lining - a crap disease to get now, but hope that things can change soon.

 

[Sean]

Excellent, Simon. Made it about as clear as one could with this stuff. Looking forward very much to the next blog.

My favourite bits:

The real bite of this study is that it won’t just use proteomics; it’s also using epigenomics to probe gene regulation, transcriptomics to see which genes are active, and metabolomics to probe which cellular chemical reactions are taking place.

These four omics approaches cover almost all fundamental levels of a cell’s molecular biology, providing a detailed map of activity in immune cells. This should give researchers extraordinary insight into the problems in the biology of ME/CFS patients.

To make this aspect of Project 2 happen, Lipkin has recruited an impressive roster of omics experts to his collaborative, namely Dr John Greally for the epigenomics and transcriptomics work, Dr Ben Garcia for the proteomics, and Dr Oliver Fiehn, who leads one of the largest metabolomics labs in the world, to analyse metabolites. All of them are relatively new to ME/CFS and will bring fresh perspectives.

In addition to the microbiome and related immune work, Lipkin’s team will also use elegant new technology that he developed to look for potential autoimmune problems and past infections that might have triggered the illness.

And there’s more. The team will use additional technology – based on Lipkin’s high-tech way of detecting just about any human virus – to check the gut, saliva and blood for fungal or bacterial infections.

 

[Andy]

Simon McGrath has written a very nice blog article on study plans from W. Ian Lipkin and his Collaborative Research Center for ME/CFS at Columbia University.

https://jaxmecfs.com/2018/07/23/the-microbiome-hypothesis-lipkins-collaborative/

 

[mariovitali]

cc : @JaimeS

I just had a look to @Simon M 's blog post on Ian Lipkin's Research. As stated in the text :

Evidence from research supports the idea that gut problems could lead to ill health. Inside the gut, trillions of microbes – viruses, bacteria and fungi – form an ecosystem. Some are hitching a free ride, but many are useful, crowding out harmful microbes, helping us to digest our food or providing essential nutrients such as vitamin K.

Also of interest is the following text taken from here:

Vitamin K is unique among the vitamins in several respects. It is the only vitamin that can be produced within the human body, but not by the body (to be defined as a vitamin, a substance cannot be produced by human tissue).7 Beneficial bacteria in the human intestine produce about 75% of the vitamin K the body absorbs each day, with the other 25% coming from dietary sources.8 The amount of vitamin K absorbed each day from both sources usually is equal to the minimum amount required for normal bodily function.9

Like the body’s absorption of other fat-soluble vitamins (A, D, and E), vitamin K absorption depends on healthy liver and gallbladder function.10-13

Referencing the following post, please see below a Network Analysis graph (some more nodes are disclosed here (this is the graph version sent to Ron Davis in October 2017) . Interestingly, Vitamin K, Liver issues (NAFLD), Bile acid-related Metabolism Genes (CYP27A1, CYP7B1) are there. Also it is interesting to see that Choline Deficiency (Ian Lipkin found altered levels) is there. Unfortunately no data about Gut Microbiome was part of the Input at that point in time.






As stated in the document i circulated to Professor Ron Davis in October 2017 (and then Derya Unutmaz, Maureen Hanson and others), there are several Vitamin K-related Genes (GAS6, MERTK, GGCX and others) that have many critical roles potentially relevant to ME/CFS (Hypothesis)

 

[JaimeS]

@mariovitali -- write a paper and publish it. You've been on this awhile -- you have devoted many, many hours to this. PM me and I'll help you construct and edit it if you want.

 

[mariovitali]

Thank you @JaimeS , your help is very much appreciated and needed. I will PM you

 

[boolybooly]

IMHO this is an issue of cause and effect. I can only draw on my own experience and it is subjective and limited evidence from which to extrapolate, besides which I may be one subtype and there may be others. I await empirical illumination with interest.

That said I got ME quickly at the same time as a viral infection which became atypically recurrent. I became strongly allergic to grass pollen at the same time, to my mind this matches Dr Paul Cheney's TH2 shift hypothesis and indicates to me the viral infection was somehow causal due to the evident triggering effect for all the other symptoms.

Consequently I remain open minded on the one hand but doubtful on the other about the microbiome study as a search for a cause, as I think an HSV (on top of previous EBV) triggered my CFIDS, not gut dysbiosis, but I do think dysbiosis developed sometime later and that the microbiome is a very important contributor to the way the disease developes, especially over the longer timescales involved in chronic illness. I think we can learn a lot by studying the microbiome in ME/CFS and perhaps do a lot for the palliative care of ME patients.

I am sorry to say that reports of several serious cases of ME I have read include difficulty with digestion and sensitivity to food, which is no stranger to me either, though I struggle against degradation of my condition as best I can, it strikes me the more we know about this the better.

I agree @mariovitali the liver is an important factor in the affect of ME on digestion and the microbiome, low liver function has long been a helpful working hypothesis for me in dealing with my difficulties with food intolerance and hypersensitivity. The liver needs a lot of energy to function and if energy deprivation is a feature of ME then that might explain a few things. Interestingly the tight junctions between epithelial cells in the gut may also be important. I learned recently (working my way through this) that maintaining the tight junctions is an energy dependent process. Its an obvious speculation that metabolic problems with energy production could potentially have knock on effects on the liver's ability to deal with the load in the hepatic circulation from the bowel and the magnitude of the hepatic load itself through a tendency to exacerbate "leaky gut" by affecting the efficacy of tight junctions.

It seems to me the gut and the microbiome are important to understand in the search to unravel ME. So I wish Dr Lipkin success in his work and thank @Simon M for breaking it down for us into digestible portions in his blog.