As already discussed in part 1, the talks at the Invest in ME Research conference reflected the complex and multi-system nature of ME/CFS. This was particularly clear from evidence relating to differences between people with ME/CFS and healthy people (known as ‘controls’), as well as some differences that are still theoretical.
Four areas emerged, and the main takeaway messages from each are summarised below, before we look at them in more detail. Invest in ME Research have also provided videos of each talk which are available on their website.
Takeaway messages
- Cardiovascular system, respiratory function and energy metabolism
Dr David Systrom: People with ME/CFS had impairments in the maximum amount of oxygen that could be used by the body one time during intense exercise (aerobic capacity). - Identification of metabolic profiles
Prof. Karl Johan Tronstad: Differences in compounds related to metabolism that may indicate a level of energetic strain were identified in people with ME/CFS; these changes were grouped into three distinct profiles that may be associated with disease severity. - Immune system and energy metabolism
Prof. Maureen Hanson: One form of T-cells from people with ME/CFS showed evidence of metabolic changes compared with those from healthy controls, indicating T-cell exhaustion which may be indicative of chronic immune alterations in people with ME/CFS. - Immune system and mitochondrial dysfunction
Dr Bhupesh Prusty: Reactivation of a specific human herpes virus in only a few cells could lead to an inflammatory response across multiple systems in the body in people with ME/CFS.
Cardiovascular system, respiratory function and energy metabolism
Dr David Systrom presented work which considered results from invasive cardiopulmonary exercise testing (or iCPET) in people with ME/CFS. This test allows researchers to look at cardiovascular, respiratory and metabolic function during exercise. The study, published in 2021, included 160 people, predominantly women, who met the Institute of Medicine’s (now known as the National Academy of Medicine) 2015 criteria for ME/CFS. The participants all underwent iCPET in an upright position; Dr Systrom clarified that signs of autonomic dysfunction are missed if the test is carried out lying down.
The results showed that people with ME/CFS had impairments in the maximum amount of oxygen that could be used by the body at one time during intense exercise (aerobic capacity). When undergoing this intense exercise, two groups of observable characteristics (exercise phenotypes) were identified: one with high, and another with low levels of blood flow to the lungs (pulmonary blood flow). The two groups had the following characteristics:
- Low blood flow group – Low filling pressure in both chambers of the heart (known as low biventricular filling pressure, or preload failure) during upright cycling.
- High blood flow group – Impairment of the ability of muscle to use the blood delivered to it.
The study also found that a high proportion of those with ME/CFS in both groups had evidence of damage to the small fibres of the nerves which lie outside the brain and the spinal cord (peripheral nervous system), something that has also been seen in fibromyalgia and POTS research. Dr Systrom suggested that, while more research is needed, these findings could explain post-exertional malaise following physical exercise, rather than ‘deconditioning’ as has been suggested by some.
Identification of metabolic profiles
Prof. Karl Johan Tronstad spoke about work which aimed to investigate changes to the system that generates energy for the body (metabolic changes) in people with ME/CFS. Prof. Tronstad considered one exploratory study he published with colleagues in 2021 which looked at changes of ‘energy fuels’ in the blood (metabolomics). The study included 83 people fulfilling the Canadian Consensus Criteria for ME/CFS, all of whom had been ill for two or more years with mild to severe ME/CFS, and 35 healthy controls who had similar distributions of age, body mass index, and numbers of men and women.
The results were complex, but in summary showed that there were significant differences in compounds related to metabolism, particularly those relating to the metabolism of lipid (fat) and amino acid (molecules that make up proteins). Prof. Tronstad suggested that these changes may indicate a level of ‘energetic strain’ in people with ME/CFS.
In addition, the study found that the metabolic changes in people with ME/CFS could be grouped into three distinct profiles (metabolic phenotypes). The authors referred to these as ME-M1, ME-M2 and ME-M3. The results showed that while two of these phenotypes, ME-M1 and ME-M2, were almost completely distinct from healthy controls, the other, ME-M3, was not.
- ME-M1 – Suggested that the body had started using less efficient fuels to provide energy.
- ME-M2 – Suggested that there were low levels of insulin resistance and increased inflammatory response.
- ME-M3 – Although having some similarities with the other two phenotypes, grouped with the healthy controls.
The study also considered the ability of participants to perform activities related to daily living, and found that those in the ME-M2 group had the lowest scores for physical function, followed by ME-M1 then ME-M3. The authors stated that this pattern corresponded with trends in the severity of ME/CFS, indicating that the metabolic phenotypes may be associated with disease severity. However, it was unclear from the results whether the disease severity was affecting changes in metabolism, or if the changes in metabolism were affecting the disease severity. Prof. Tronstad highlighted that the clustering of metabolites into these three distinct profiles in those with ME/CFS was not explained by factors such as age, sex, body mass index or medication.
Immune system and energy metabolism
In her presentation, Prof. Maureen Hanson drew upon published work from her research team which aimed to investigate energy metabolism in T-cells from people with ME/CFS. T-cells, or T-lymphocytes, are an essential part of the immune system.
The study included 53 people who fulfilled the Canadian Consensus Criteria for ME/CFS and 45 healthy controls. Distributions of age and sex were similar across the two groups, and the average length of illness was 21.7 years in those with ME/CFS. Blood samples were collected from participants and used to investigate mitochondrial metabolism (the process by which cells generate energy) in two types of T-cells: helper T-cells, which help control the immune response upon infection, and cytotoxic T-cells, which work to destroy harmful cells in the body.
The results showed the following:
- Helper T-cells from people with ME/CFS did not show impairment in mitochondrial metabolsim, nor did they show difficulty increasing energy production in response to cell activation.
- Cytotoxic T-cells from people with ME/CFS did show metabolic changes compared with those from healthy controls, and these changes indicated T-cell exhaustion.
In summation, Dr Hanson stated that T-cell exhaustion is something that is seen following chronic viral infection and suggested that it may be indicative of chronic immune alterations in people with ME/CFS.
Immune system and mitochondrial dysfunction
Research from Dr Bhupesh Prusty, who has ongoing work funded by ME Research UK, was mentioned in part one of the highlights from the conference article, in relation to viruses and viral reactivation, but his work in relation to the immune system and mitochondrial dysfunction warrants greater exploration.
Dr Prusty presented research relating to human herpes virus (HHV) reactivation and how this may act as a trigger for ME/CFS and long COVID. He discussed a study which aimed to investigate potential infectious causes and mechanisms behind mitochondrial dysfunction. The study and the methods used were highly complex, as were the findings.
In brief, the study used blood samples from people who were diagnosed with ME/CFS using the Canadian Consensus Criteria and healthy controls matched for age and sex in order to consider a number of research questions. The following findings were observed:
| Question | Observation | What does it mean? |
| How does HHV-6 reactivation affect the mitochondria of the infected cell? | Reactivation of a particular HHV (HHV-6) led to changes in the structure of mitochondria (mitochondrial fragmentation). | This change in mitochondrial structure was associated with decreased energy production and decreased immune response. |
| Could HHV potentially be a factor involved in causing ME/CFS? | Low levels of genetic material from HHV (or HHV viral genome) were present in cells from people with ME/CFS. | The levels of HHV viral material detected were not enough to suggest a direct role of active viral infection in ME/CFS – something that Dr Prusty noted was confusing. |
| Could the liquid part of blood (serum) from people with ME/CFS alter mitochondria in healthy cells? | Changes in the structure of mitochondria were observed in heathy cells following exposure to blood serum from people with ME/CFS but not from healthy controls. | Serum from people with ME/CFS contains something that leads to changes in mitochondrial structure in healthy cells, which is associated with an inflammatory response. |
Dr Prusty’s observations suggest that reactivation of a specific HHV (HHV-6) in only a few cells in people with ME/CFS could lead to an inflammatory response across multiple systems in the body. Dr Prusty explained that while this inflammatory response in the body aims to protect against certain viral infections, it also leads to disruption in the energy production of cells, potentially through mitochondrial fragmentation.
Dr Prusty highlighted that more research is needed to investigate these findings further, and particularly to study people with ME/CFS in different age groups. Following the conference, Dr Prusty spoke to the TLC living with long COVID podcast in more detail about his research, and some preliminary findings that are yet to be published.
Summary
One of the common links that ran through all the presentations at the conference was metabolism, and how altered metabolism in different systems of the body, such as the immune system, can lead to a disease state, such as that seen in ME/CFS.
The research presented at the conference was highly complex, and each study came with its own set of limitations meaning all findings must be interpreted with caution. Much of the work was in the early stages of development, known as pilot or exploratory work, including that from Prof. Tronstad and Dr Prusty.
These early phases of research are essential building blocks for future, larger studies, with all presenters highlighting the need for more biomedical research to better understand the mechanisms underlying the disease process and abnormalities identified in those with ME/CFS.
