Webinar: Massachusetts ME/CFS & FM research update - 23 October 2021

I sent my first muscle biopsy years ago to Baylor for viral testing. It didn’t turn up anything. Local pathologist looked for red ragged fibers. Nothing to explain the constant chronic pain in my legs and random widespread muscle fasciculations.
A sports medicine doctor utilized an algorithm using muscle ultrasound to estimate muscle glycogen stores noninvasively. He reported my glycogen stores were very low in my quadriceps despite being physically inactive.

It’s beyond frustrating and even if something is uncovered at the NIH, I am not hopeful that it will lead to meaningful treatment.

I wonder whether they can use MR Spectroscopy similar to how Jared Younger PhD is studying the brain in MECFS patients for evidence of neuro inflammation to look at muscle tissue in patient subset with prominent muscle symptoms (before and after exercise).

 

https://twitter.com/user/status/1453811335133863938

 

Six significant findings?​

Following a migraine interlude, I'm now focusing on what looks to me to be the most interesting findings and I will be interested to know if others agree with my choices.

Metabolomics

1. PEM-linked metabolites. Dr Maureen Hanson highlighted work by Dr Arnaud Germain who found changes in particular metabolites that matched those of PEM symptoms following exercise. (Hanson mentioned metabolism of the amino acids cysteine and methionine, glycerol lipid and primary bile acid biosynthesis).

2. Aryl hydrocarbon pathway. Unutmuz was excited about something obscure called AHR pathways https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6039966/. This relates to the uptake of a type of organic molecule called aryl hydrocarbons into the cell. When they bind to their receptor (AhR), it directly leads to changes in gene expression i.e. longer-term biological changes i.e. these hydrocarbons are signalling molecules.

Unutmuz said they could be involved in connecting the microbiota, the immune system and metabolism. However, more work is planned to look at metabolism in a larger cohort.

Immunology

3. Overactive MAIT cells. Dr Derya Unutmuz highlighted that type of gut immune cells called MAIT (mucosal invariant T cells) are overactive in patients. He also said that they make up 30% of all T cells in some patients, but only 1% in others. MAIT cells respond to a narrow range of antigens produced by bacteria and can kill intracellular parasites. Though any role in ME/CFS is not yet known.

4. Unutmaz has previously reported activated TH17 immune cells: these are a type of highly inflammatory T helper cells. See microbiome/butyrate below.

5. B cell clonal expansion. Dr Ian Lipkin highlighted his recent paper looking at plamsa proteins that pointed to B-cell clonal expansion, at after subgrouping by IBS status. He said the findings had been independently confirmed by Sato.

Microbiome

6. Reduced levels of butyrate-producing bacteria. Lipkin found lower levels of butyrate-producing bacteria in the guts of people with ME/CFS. Similar findings were seen by Nath, Unutmuz and, in previous work, Hanson. Hanson was sceptical of the significance of this finding because similar things are seen in other diseases including inflammatory bowel disease, Parkinson's disease and fatty liver disease. Also, she said butyrate levels were not reduced in found to be reduced in blood Metabolomics - though Unutmuz apparently did see butyrate differences in metabolomic work.

I'm mentioning this because butyrate from gut bacteria play an important role in reducing the levels of inflammatory TH17 cells mentioned in point 4 above. They are also believed to play a causal role in inflammatory bowel disease, including Crohn's disease. However, Unutmaz apparently didn't mention this and he is the expert in immunology and the microbiome and so would be aware.

Credit: My sources for this post are the reports from @Hutan on this thread and the blog by @Michiel Tack - thank you both, I trust your note-taking.

My next post will cover things that the researchers are excited about but have yet to report on.

 

Jam tomorrow, and important general points
Promising areas but no firm results yet...

The importance of cell subtypes and subgroups

Unutmuz stressed the importance of looking in detail at different immune types and subtypes, particularly for T cells. Nath found mitochondrial deficits looking at white blood cells (i.e. blood immune cells) but said they now needed to look at results by cell type. Hanson said she had similar results to Nath and also stressed the importance of looking at different cell types.

An analogy for this problem is comparing a fruit smoothie with a bowl of fruit. A fruit smoothie gives you an average, 'bulk' fruit taste, much like looking at all white blood cells together. The bowl of fruit contains the individual cell types and looking at (tasting) these individually is likely to tell you far more about fruit. If the fruit smoothie has an 'off' taste, what is really going on?
I



The ultimate approach is to study each individual cell separately, and that's happening here:

Detailed examination of gene expression by cell type (and beyond). Hanson was clearly excited by Dr Andrew Grimson's gene expression study using white blood cells. Previous studies looking at gene expression in all cells together have been inconclusive (the fruit smoothie approach). @Hutan said Grimson was looking at 270,000 individual cells, which makes it sound to me like single-cell RNA sequencing (scRNA-seq). This is much more expensive but gives the most detail and the most robust results. So far, Hanson said the researchers have established what is "normal" in gene expression following exercise. Next, they compare with ME/CFS.

Gene expression analysis can probe results by cell types (e.g. T cells, T-helper cells and Th subtypes: these can be identified by particular gene transcripts). It can also look in even greater detail, down to the level of the individual cell.


Inflammation in the brain? The long awaited brain PET study looking for microglia activation, by Dr Dikoma Shengu in Hanson's group, has been delayed by Covid. Microglia are the brain's immune cells and their activation (aka inflammation) was first seen in that small Japanese study in about 2015. (However, another equally small but slightly better done more recent study failed to replicate this.) Shengu's study is much bigger and looks both before, during and after exercise.

Metabolomics... Most of the results are still to come, including a 90 patients/90 controls cohort from Hanson's team, more from Unutmuz and Dr Oliver Fiehn in Lipkin's team. I am particularly interested in Fiehn's work because he is a metabolomics specialist, one of the tope ones in the US (he heads up the NIH's West Coast metabolomics lab).

At last, replication (sort of)

Finally, different groups are starting to look at the same problem, such as metabolomics, mitochondria and microbiome - giving the chance to gain real understanding rather than just producing shiny new findings that often don't go anywhere . This isn't entirely an accident: the NIH, I believe, encouraged the different groups to take overlapping approaches.

 

Dr. Maureen Hanson directs the National Institutes of Health (NIH) ME/CFS Collaborative Research Center at Cornell University, the Cornell Center for Enervating Neuroimmune Disease, where she and her colleagues investigate the biological mechanisms underlying ME/CFS (myalgic encephalomyelitis/chronic fatigue syndrome) by obtaining blood samples and conducting brain scans on individuals with ME/CFS before and after they undergo an exercise test designed to bring on symptoms of post-exertional malaise (PEM). Dr. Hanson’s team uses a wide range of tools and technologies to test the role of genes, inflammationm and the immune system in this disease. Recorded on October 23, 2021 as part of the Massachusetts ME/CFS & FM Association's 2021 Annual Meeting.

https://www.youtube.com/watch?v=_M06T5SQoFM

 

Researcher Q&A and Wrap-Up | MassME 2021 Annual Meeting Part 12/12

https://www.youtube.com/watch?v=PNTFA85Y-Yo

 

Playlist of all the videos from this event can be found here, https://www.youtube.com/playlist?list=PLz31KwoUbYrEqidEmr-wCJzPI19hQMn_A