Dr. Rosamund Vallings
        
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microbiome andmetabolome Lipkin

9/15/2018

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Sci Rep. 2018 Jul 3;8(1):10056. doi: 10.1038/s41598-018-28477-9.Insights into myalgic encephalomyelitis/chronic fatigue syndrome phenotypes through comprehensive metabolomics.  Nagy-Szakal D1, Barupal DK2, Lee B1, Che X1, Williams BL1, Kahn EJR1, Ukaigwe JE1, Bateman L3, Klimas NG4,5, Komaroff AL6, Levine S7, Montoya JG8, Peterson DL9, Levin B10, Hornig M1, Fiehn O11, Lipkin WI12.
After striking that rich vein, the Lipkin group expanded their research effort – incorporating metabolomics for the first time into their studies. (Lipkin and the Simmaron Research Foundation are also currently engaged in the first metabolomics spinal fluid study.) Once again incorporating a wide variety of doctors from different locations (Peterson, Bateman, Klimas, Levine, Montoya) and using a fairly large sample set (n=100) Nagy-Szakal/Lipkin, the Lipkin group fused together blood metabolomic, fecal bacterial metagenomic, and clinical data to paint a new picture of ME/CFS.
The study represented the first attempt to meld two potentially important fields in ME/CFS – metabolomics and gut microbiome findings- together.  Lipkin and Hornig have proposed that the gut issues play an important role in ME/CFS, and several studies have found evidence of dysbiosis (pro-inflammatory gut bacteria) in ME/CFS.  Unutmaz is chasing down a T-cell gut connection, and past studies have suggested that bacterial leakage from the gut could help explain at least some of the post-exertional malaise present.
Given the group’s past gut findings – that significant differences in gut bacteria, immune profiles and possibly energy production exist between ME/CFS + IBS patients and ME/CFS patients without IBS, it made sense for the Lipkin group to once again split the ME/CFS group into subsets with and without IBS and analyze the heck out of them.
Study Results
Energy Production Problems Highlighted
The study confirmed past general findings of decreased levels of phospholipids and sphingomyelins – two important findings by Naviaux- and increased levels of triglycerides (TG’s). (Triglycerides have been associated with metabolic problems and hypothyroidism.)
That both the ME/CFS + IBS group and the ME/CFS without IBS group had reduced levels of metabolites associated with the choline-carnitine energy pathway suggested that both groups had similar core metabolic problems.  (Carnitine participates in the TCA cycle, ATP production and energy metabolism).
More Was Better
The Lipkin group’s decision to integrate metabolomics, microbiome and clinical data worked. Not only did incorporating all this data together illuminate a possibly important subset – the ME/CFS IBS subset – but it also allowed the group to better differentiate ME/CFS patients from controls. It suggested that studies which combine multisystemic data together will do a better job in describing this multisystemic disease.
As with the 2017 study, having or not having IBS was the biggest driver in determining the kind of bacterial profile (and bacterial metabolic pathways) present. This time the study found that the metabolomics of the ME/CFS + IBS group were significantly different from the ME/CFS only group as well. That suggested these two subsets of ME/CFS patients might be quite different indeed.
In contrast to Naviaux, the study did not find a “consistent decrease” in ceramide metabolites – the most commonly disrupted metabolite Naviaux found in his ME/CFS group.  When Lipkin controlled for IBS, he found increased levels of ceramides in the ME/CFS plus IBS group but decreased levels of ceramides in the ME/CFS only group. That suggested that key metabolites in ME/CFS might be different in these two ME/CFS subsets.
Bacterial Toxins Highlighted
Nagy/Lipkin suggested that increased levels of bacterial toxins (IBS connection) in ME/CFS may be triggering an enzyme called sphingomyelinase to produce the ceramides which then may damage the gut lining and possibly interfere with energy production.
Ceramides are waxy fats that figure in a number of processes that may be important in ME/CFS. Not only can they produce many free radicals (reactive oxygen species) that can damage the gut lining (the IBS connection), they can also interfere with electron transport (the energy connection) as well as contribute to insulin and leptin resistance (metabolism issues).
The authors also proposed that the higher mannitol levels found in the ME/CFS could reflect the breakdown of two important barriers in the body: the gut barrier and the blood-brain barrier.
Several studies suggest a breach in the gut barrier could be contributing to systemic inflammation in ME/CFS, and one suggests that exercise may further widen that breach. Several researchers, including Jarred Younger and Avindra Nath, have also postulated that the suspected neuroinflammation in ME/CFS results from immune cells entering the brain through a weakened blood-brain barrier.
The Gut Shines in Distinguishing ME/CFS Patients From Healthy Controls
Interestingly, for all the focus on metabolomics, a network analysis using differences in gut bacterial abundance was better able to distinguish ME/CFS patients from healthy controls than did metabolomic results.
That suggested that gut bacterial differences may be more prominent than metabolomics differences in ME/CFS patients. That was a surprise, and we’ll see how this all turns out. It stands to reason that the closer we get to the core of the problem, the more striking the differences we’ll see between healthy people and people with ME/CFS.  (Will the gut play a bigger role than we thought?)
Possible Treatment Options
The group suggested that their findings, if validated, could present some possible treatment options. They included using SMAse blockers to reduce ceramide levels and giving carnitine supplementation to increase the low levels of metabolites in the choline-carnitine pathway.  One open-label study found that carnitine supplementation helped over half of ME/CFS patients.
Given the unrevealing cytokine data from Lipkin’s cytokine data and his recent turn to metabolomics I asked Lipkin how important a role cytokines were likely to play in future ME/CFS research and treatment. Lipkin felt they may yet play an important role in ME/CFS indeed:
“Cytokine disturbances can result in fatigue, cognitive and other disturbances. The observation that other biomarkers such as metagenomic or metabolomic profiles are highly associated with disease does not diminish their (cytokines) importance. There may be people who would benefit from drugs, including antibody therapies, that modulate cytokine responses.”
Scheibenbogen is pursuing antibody therapies in ME/CFS, and Nancy Klimas is reportedly using Enbrel (etanercept) – a cytokine (TNF) blocker – plus mifepristone in her Gulf War Illness trial. Other biologics are available and more are coming on the market.  Recent findings in POTS suggest that antibody drugs will probably play an important role in that disease as well.
Since the study also found that taking Vit. B supplements was associated with higher levels of pantothenic acid and lower fatigue scores, taking Vit. B supplements may be a good idea.
The 5-MT Question
Decreased levels of 5-MT, a metabolite associated with tryptophan, serotonin and melatonin metabolism could reflect problems with serotonin/melatonin conversion. This finding, however, was confounded by the high use of antidepressants (50% of the ME/CFS group) which could have produced the decrease.
Correlation studies do suggest, though, that low 5-MT levels could contribute to problems with cognition, sleep and fatigue. Larger studies are needed to determine if the low 5-MT levels are associated with those symptoms in ME/CFS – and if they are – if it might be beneficial to modulate that pathway using drugs in ME/CFS.
Next Up for the Simmaron Research Foundation and Ian Lipkin
The next phase in the Simmaron Research Foundation’s ongoing collaboration with Ian Lipkin is an expanded study which will, for the first time in ME/CFS, analyze the metabolomics of ME/CFS patients cerebral spinal fluid. The study, which will also include immune analyses is the third Simmaron/Lipkin CSF study to date. The first two studies found dramatic evidence of immune activation and the presence of a potential new subset.
Lipkin also reported rapid progress from his new NIH research center and a new collaborative effort with ME/CFS researcher and NIH ME/CFS research center leader Derya Unutmaz. The idea of two top labs in the country collaborating in a complementary fashion is an exciting one – one we will hopefully see much more of in this field.


Lipkin and Unutmaz are merging their respective strengths in a collaboration – something we could use much more of in ME/CFS.
We are completing analysis of saliva, blood, and feces for bacteria, viruses and fungi from ME/CFS and control subjects using powerful new sequencing methods. This will be the largest and most comprehensive study to date on the microbiome in ME/CFS. We will soon begin metabolomic, proteomic, and transcriptomic analyses of ME/CFS and control subjects before and after exercise. We are deeply grateful to the patients who are contributing to this work despite the implications for their health. They are true heroes.
We have begun a new collaboration with Derya Unutmaz and Jackson Laboratories that builds on the complementary expertise of our teams in cellular immunology and molecular microbiology and biochemistry.
Dana March and Tony Komaroff are building an app to help ME/CFS subjects and their caregivers track their status. We have had great support in this effort from people in the community.
Conclusions
In the past three years Lipkin’s identified three potential subsets (early/late duration patients, the “Peterson subset”, ME/CFS + IBS subset) and his explorations into the ME/CFS IBS subset continues to reap dividends.
His metabolomic study found signs of energy production problems in all ME/CFS patients, but when Lipkin separated out the ME/CFS + IBS patients, he found altered, even at times opposite metabolic findings that could suggest a different source of fatigue was present in the ME/CFS + IBS patients. His earlier study suggested more severe energy production problems may be present in ME/CFS patients with IBS.
The importance of the gut bacteria in ME/CFS perhaps rose to a new level of significance when a network analysis found larger differences in gut bacteria than metabolites. Lipkin’s ability to better differentiate ME/CFS patients from healthy controls using gut bacteria, metabolomic and clinical data suggests that large studies which tie together multiple systems will be the most helpful.
In short, the latest study from the Lipkin group indicates that the gut does matter in ME/CFS and that in those with gut problems it may matter more than we think.
The Simmaron Research Foundation and Lipkin are employing metabolomics in the study of cerebral spinal fluid for the first time, and Lipkin has launched a new collaborative ME/CFS effort with fellow NIH ME/CFS Research Center leader Derya Unutmaz.
 ​
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Epigenetics: System Reset? Study Suggests Pro-Inflammatory / Autoimmune Reset Occurred in Chronic Fatigue Syndrome (ME/CFS)

9/15/2018

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Cort Johnson
August 4, 2018
Epigenetics research holds the fascinating possibility of figuring out what shifted at the very beginning of chronic fatigue syndrome (ME/CFS).  For many with ME/CFS a sudden change occurred – some sort of biological reset quickly happened – which never relinquished itself.
Finding out what “reset” occurred is what epigenetics is all about.  Epigenetics identifies changes in the expression of our genes that occur after we meetup with biological stressors such as pathogens, drug, toxin or even foods.   Most of our genes that produce proinflammatory cytokines, for instance, have a kind of a lock on them. Removing that lock leaves them free to express themselves and leaves us open to poor health.
Epigenetics explores how the biological challenges we encounter in life can remove those locks (or add to them) resulting in an entirely new genetic landscape – one that could perhaps cause something like ME/CFS.
Many people’s ME/CFS/FM starts with an infection, and viruses can exert major epigenetic changes to our genome.  Herpes simplex virus (the virus Dr. Pridgen is targeting in fibromyalgia) engineers changes to our genome which help the virus avoid destruction and enhance its replication. Those changes include a suppression of our immune system, which can result in an increased risk of cancer.
What goes around comes around, though.  Epigenetic News recently reported that an epigenetic modifying cancer drug was able to return the parts of the immune system that the  herpes simplex virus had disturbed to normal. The drug was able to effectively fill in the immune hole created by the herpes virus by boosting a number of immune factors (IFN-a, IL-8, IL-6, transcription factors, stress response factors). Mouse studies revealed that the drug also reduced reactivation of the virus.
That suggests that some similar drugs now in clinical trials could help in the fight against herpes and other viruses or could perhaps simply return to normal epigenetically modified genes that have suppressed immune functioning.
 “A new class of antivirals based on this study might be useful for patients who are resistant to existing antivirals like acyclovir and ganciclovir….. (or in) viral infections for which there aren’t pharmaceuticals to boost an individual’s immune response.” Dr Kristie
If epigenetics turns out to play the major role in ME/CFS that it does in cancer and other diseases, a cancer drug could someday be in store for ME/CFS treatment.
Epigenetics Study Highlights Immune Alterations in ME/CFS
The epigenetics story begins with gene transcription – the first step in the process of translating our genes into proteins.  Gene expression gets enabled by the removal of methyl groups that block transcription and/or by the addition of methyl groups that stop genes from being expressed.
Malay Trivedi and Lubov Nathanson at Dr. Klimas’s Institute of Neuroimmune Research at Nova Southeastern University recently published the most comprehensive study yet on epigenetics in chronic fatigue syndrome .
Just a few epigenetic studies have been done in ME/CFS and none like this one. For one, the group took advantage of a new breakthrough in genetic testing (an advanced Illumina array) to almost double the number of testing sites (from 450,000 to 850,000 sites). For another, the larger sample size (64 participants from two geographically distant locations) ensured a more comprehensive look at the epigenetic changes in ME/CFS. This allowed the group to produce what they called “consensus hypomethylated sites” they believe could be used in future studies.
The general findings of the study agreed with those from past ME/CFS epigenetic studies. Hypomethylation – the deletion of methyl groups, which make it easier for the genes to be expressed – was the theme, with 98% of differentially methylated sites in ME/CFS hypomethylated compared to controls. (Only 2% were hypermethylated compared to controls.)  The hypomethylation was most prominent in genes associated with immune cell regulation.
The high degree of hypomethylation was intriguing for several reasons. For one, Epstein-Barr Virus – presumably a common trigger in ME/CFS – overwhelmingly triggers hypomethylation and almost no hypermethylation of genes. Hypomethylation is also associated with pro-inflammatory gene expression in autoimmune diseases as well as in cancer promotion.
Multiple Sclerosis Breakthrough
A “global” hypomethylation, for instance, is also found in lupus and rheumatoid arthritis. The hypomethylation of a promoter gene for IL-6 in rheumatoid arthritis causes an overexpression of pro-inflammatory cytokines and other immune factors which ultimately results in joint damage.
The recently uncovered hypomethylation of an HLA gene in multiple sclerosis (MS) prompted researchers to state that epigenetic changes may even be “caus(ing) the disease”. That bold statement reflected the findings of a recent large study, which indicated that epigenetic changes were directly causing the largest risk factor found yet for MS.
That finding may have implications that go far beyond MS and could conceivably reach ME/CFS/FM.  Since the HLA region of the genome is associated with almost all autoimmune diseases, the authors believe their finding will impact other autoimmune diseases.
(Several years ago Ron Davis pegged the HLA region as a potential study area for ME/CFS. His Stanford Genome Lab has developed new methods of assessing this complex region of our genome, and he and Mike Snyder at Stanford are doing an intensive analysis of that HLA region in ME/CFS.)
Back to Chronic Fatigue Syndrome (ME/CFS)
The highest degree of hypomethylation in a genetic region in ME/CFS occurred in gene promoters associated with natural killer cell functioning, no less – the most consistent finding in ME/CFS.  That suggested that some sort of epigenetic reset – perhaps triggered by an infection – occurred in the NK cells of ME/CFS patients.
With regard to single genes, the authors highlighted the hypomethylation of genes associated with muscle hypotonia (low muscle tone) and cognitive impairment (MED13L), problems with protein synthesis (metabolism), and glucocorticoids (SGK3 gene – inflammation).
It was the immune genes, though, where the hypomethylation really came to the fore. Immune genes that regulate the adaptive immune response (T & B cells) and the production of immunoglobulins were hypomethylated. The authors asserted that those findings were in sync with reports of improvement from Rituximab.
Promoters (MMP14, MAP4K4, MAPK12 and CREB5), which may be activating tumor necrosis factor signaling pathways and thus contributing to the pro-inflammatory problems believed present in ME/CFS, were hypomethylated as well.
A gene (miRNA-148a) that impairs the innate immune response was also hypomethylated. Several of the hypomethylated genes were also found in prior ME/CFS studies.
Then there’s the IL21R gene. The hypomethylation of the IL21R gene promoter in ME/CFS could promote inflammation, autoimmunity, thyroid disease, intestinal inflammation, and others.  IL-21 also plays a critical role in triggering spontaneous experimental autoimmune encephalomyelitis – an animal model of brain inflammation.
Conclusion
Epigenetics is a relatively new science which is already proving to be a boon to the study of autoimmunity and cancer. Larger studies will be needed in ME/CFS for epigenetics to reach its potential, but the study from Dr. Klimas’s group suggested that, just as in some autoimmune diseases, enhanced hypomethylation may be increasing the expression of genes which promote inflammation and autoimmunity in ME/CFS.
The most encouraging thing about epigenetics is the possibility of reversing the epigenetic changes a pathogen, toxin or drug has caused. Much more study is needed to isolate any epigenetic culprits in ME/CFS, but epigenetic altering drugs are being developed for other diseases. One intriguing drug seeks to reverse the epigenetic changes caused by herpes simplex virus – thus returning the immune system to normal.  Another breakthrough suggests that epigenetic changes may be major drivers of multiple sclerosis.

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Unique blood and microbiome profiles pave way for test for chronic fatigue syndrome

9/15/2018

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Rich Haridy   July 10th, 2018
  • A new blood metabolic profile for chronic fatigue syndrome may be a step towards a tool to help diagnose the disorder
 
  • In the world of medicine there are still many biological mysteries yet to be solved. Chronic fatigue syndrome (CFS) is one of those big unsolved mysteries but a team from Columbia University is bringing us closer to understanding this elusive disorder, finding a specific metabolic fingerprint for the condition that could lead to a new diagnostic tool for doctors.
 
  • Chronic fatigue syndrome (CFS), also known as myalgic encephalomyelitis (ME), is a controversial condition identified by a variety of symptoms, from severe fatigue and muscle pain, to allergies, depression and impaired memory. Other than targeting specific symptoms, there is no effective treatment for CFS, and despite a growing body of strong physiological evidence, some in the medical community still persist in labeling it a psychological condition.
  • Last year, a team of researchers from the Center for Infection and Immunity at Columbia University's Mailman School of Public Health revealed sufferers of CFS displayed microbiome profiles that were unique to the disorder. Compared to a healthy control group, the researchers found that CFS patients could be identified by having abnormally high levels of certain bacteria in the gut.
  • Following on from that research the team moved to studying the particular blood metabolite profile of CFS patients and analyzed plasma samples from 50 CFS sufferers compared to 50 healthy control subjects. Over 500 different metabolic biomarkers were examined and the researchers homed in on several that were significantly altered in relation to the healthy control group. 
  • When a predictive model was generated to diagnose CFS using these blood biomarkers the researchers reached an accuracy rate of over 80 percent. A comprehensive model was then generated combining the metabolic markers and the previously studied microbiome markers. This model could accurately predict the presence of CFS with 84 percent certainty.
  • "This is a strong predictive model that suggests we're getting close to the point where we'll have lab tests that will allow us to say with a high level of certainty who has this disorder," says Dorottya Nagy-Szakal, first author on the new study.
  • Other than offering a pathway towards a much-needed diagnostic tool for the disorder, it's hoped this research will lead to a better understanding of what causes this devastating condition. One outcome the researchers suggest is that animal models be developed that simulate these same metabolic and microbiome footprints. If those animals subsequently display CFS symptoms and behaviours it means that those specific parameters are playing a causal role in the disorder. 
  • "We're getting close to the point where we can develop animal models that will allow us to test various hypotheses, as well as potential therapies, says W. Ian Lipkin, director of the Center for Infection and Immunity. "For instance, some patients might benefit from probiotics to retune their gastrointestinal microflora or drugs that activate certain neurotransmitter systems."​
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RBC Rheology

9/15/2018

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On this #OMFScienceWednesday we are pleased to introduce you to a central member of the OMF-funded ME/CFS Collaborative Research Center team at the Stanford Genome Technology Center (SGTC), Mohsen Nemat-Gorgani, PhD. Dr. Nemat-Gorgani is leading a team to investigate the Red Blood Cells (RBC) in ME/CFS patients. Mohsen shared his story with OMF:

"I was born and raised in Iran, and did my undergraduate and graduate studies in U.K. In 1974, I obtained a PhD in biochemistry from Warwick University, and after a year of postdoctoral training at Vanderbilt, I returned to Iran. In October 2003, I came to the Stanford Genome Technology Center (SGTC) as a Visiting Professor from Tehran University, and continued working as a Research Associate upon termination of the sabbatical leave. During my time at the Center, I participated in various technology development projects, and about two years ago, after a brief absence from the Center, I started working on ME/CFS.

Upon participation in the ME/CFS project, and during the first few months of my presence at the Center, I learnt, mainly by talking to Ron Davis, Laurel Crosby and a number of patients, that inadequate blood flow to tissues could be the cause of some of the symptoms reported in ME/CFS. It also became known to me that red blood cells (RBCs) and their mechanical properties may largely determine the rheological (deformation and flow) behavior of blood in normal and disease states.

Interestingly, a few years before working on ME/CFS, I was somewhat involved in a study on the mechanical properties of breast cancer cells at the Center. This work was conducted by Shane Crippen, a graduate student under the guidance of Ron Davis, Roger Howe and Stefanie Jeffrey (Electrical Engineering and Stanford Medical School, respectively). In the course of subsequent discussions (in June 2016) with Ron and Roger, it was decided that we should look at the mechanical properties of RBCs related to ME/CFS, and we started exploring different technical approaches to achieve this goal.

In January 2017, during a visit to SJSU, I met Anand Ramasubramanian who had recently taken up a faculty position in the Chemical and Materials Engineering Department. Anand had previously looked at deformability of monocytes using a microfluidic platform, and during the course of our discussions, it became obvious that a collaboration with his team (involving Amit Saha, who had worked with Anand on monocyte deformability as a part of his Ph.D. thesis, and graduate students) would be an effective way of going forward. Few months later, the studies were initiated, and with the outstanding technical support provided by Julie Wilhelmy and Layla Cervantes, samples from a large number (over 30) of CFS patients and healthy controls were collected at the SGTC, and later analyzed at SJSU.


RBC deformability is believed to play an important role in their main function - the transport of oxygen and carbon dioxide via blood circulation. They are highly elastic, which allows them to flow easily. The reason for this exceptional property is found in the composition of the membrane and the membrane-cytoskeleton interaction. A healthy RBC is approximately 8.0 µm in diameter, which needs to undergo large deformations in order to pass through capillaries, around 2-3 µm in diameter. A slight decrease in deformability has been shown to cause a significant increase in microvascular flow resistance, with important physiological implications. 

RBC deformability has been shown to be impaired in various pathologies including inflammatory conditions such as sepsis. Recent studies have clearly indicated that inflammation is involved in ME/CFS. Moreover, RBCs are highly susceptible to oxidative stress due to the high contents of polyunsaturated fatty acids in the cell membrane, a process that may impair deformability, and some studies have indicated RBC oxidative damage occurring in ME/CFS.

Using the microfluid platform, the mechanical properties of RBCs from ME/CFS and healthy control samples have been compared by determination of the time taken to enter the channels as well as transit velocity, and elongation capacity. Our preliminary results suggest clear differences in deformability of RBCs from ME/CFS and healthy control blood samples using this platform. A manuscript has recently been submitted for publication describing these observations. 


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