All posts tagged gut

“The Subset Maker”: Lipkin Chronic Fatigue Syndrome Study Highlights Energy Issues In Gut Subset

Looking for clues to the cause of chronic fatigue syndrome (ME/CFS), Ian Lipkin has, over the years, poked his fingers into a number of different areas. His 2012 XMRV study showed that the virus was not infecting people with ME/CFS. (It was a contaminant). His pathogen studies (unpublished) found no evidence of a viral infection in ME/CFS.

Subsets

Lipkin may have uncovered more potential subsets than any other researcher and has long emphasized the need to break ME/CFS up into its constituent parts.

lipkin subsets ME/CFS

Lipkin believes identifying subsets is critical to the progress in this field

Lipkin and Mady Hornig’s 2015 cytokine study  which found the immune system going gangbusters early in ME/CFS but then pooping out, exhausted, later identified two possible subsets (early and long duration patients.) Lipkin then teamed with the Simmaron Research Institute to document similar findings in chronic fatigue syndrome (ME/CFS) patients’ spinal fluid.  Dr. Peterson, Lipkin and the Simmaron Research Institute then uncovered an atypical ME/CFS subset (the “Peterson subset”.)

In an email Lipkin emphasized the critical need to identify the subsets he believes must be present in this disease.

ME/CFS is not a single disorder and is unlikely to have  single cause or a single treatment. As we learn more about ME/CFS, we are beginning to define subtypes. This is critical to understanding how people become ill and developing practical solutions for management. The challenge is not unique to ME/CFS. It is representative of the Precision Medicine initiative that is sweeping clinical medicine and public health. Just as there is no one cause or cure for all cancers, all forms of heart disease, or all infections, there will be more than one path to ME/CFS and more than one treatment strategy.

Over the past couple of years Lipkin – who has been intensely interested in the role that gut bacteria plays in this illness – has been digging into an ME/CFS plus irritable bowel subset. We’ve learned in the past ten years just how influential the gut is. Gut bacteria and the metabolites they produce don’t stop at the gut. If they leak out of the gut they can directly affect the immune and central nervous system functioning. Some of the metabolites showing up in ME/CFS metabolomic studies originate in the gut.

Last year Lipkin’s group published the most comprehensive gut bacteria study in ME/CFS yet done, which incorporated immune and clinical findings. This year he repeated the gut bacterial analysis and added metabolomics  and clinical findings to the mix. The man clearly likes large, complex studies.

The 2017 Gut Study

The large 2017 Nagy-Szakal/Lipkin gut study was notable for it’s size (n=100) and it’s breadth – it included patients from no less than six ME/CFS practitioners including Dr. Peterson. It found, amongst other things, increased levels of bacteria from a family (Clostridiaceae) known for its abundance of toxic and disease causing bacteria.

One of the few gut studies that’s actually been able to identify individual bacterial species, the study found increased abundances of several bacterial species (Faecalibacterium & Coprococcus spp.) that have been associated in other studies with IBS-like symptoms, including colonic pain, bloating, and GI discomfort.

Using a type of data analysis called topological data analysis (TDA) which is able to incorporate metagenomic, metabolic pathway, immune and clinical data, the Lipkin group found that the presence of irritable bowel syndrome (IBS) was having a major effect on disease severity, gut microbiota, and immune profiles.

That finding led the Lipkin group to split the ME/CFS patient cohort into ME/CFS with IBS and ME/CFS without IBS subsets and examine the differences in microbiota (gut bacteria).

gut bacteria ME/CFS

The gut bacteria in the ME/CFS plus IBS subset was different from the ME/CFS only group and the healthy controls

The results were astonishing. A dissimilarity measure found that gut bacteria differed as much between the ME/CFS + IBS patients and the ME/CFS – IBS patients as between the ME/CFS group as a whole and the healthy controls. That analysis suggested that the guts of the ME/CFS patients with and without IBS featured significantly different bacteria.

The cytokine data in the study did not add to the analysis but the microbiome analysis revealed a number of interesting possibilities,

Metabolic pathway analyses revealed the ME/CFS + IBS and the ME/CFS – IBS groups differed in some important ways. Both groups featured enriched metabolic pathways that produced Vit. B6, but an important part of the energy production process (the pyrimidine ribonucleoside degradation pathway) was enriched in the ME/CFS only group. That same pathway was hit hard in the ME/CFS plus IBS group.

Plus, the abnormalities found in the urea cycle, which is closely linked to aerobic energy production (Krebs or TCA cycle)  occurred mostly in the ME/CFS + IBS group.

The data suggested that people with ME/CFS and IBS group had different bacterial gut makeups and might have more problems with energy production than people with ME/CFS, and it set the stage for Lipkin’s next effort.

The 2018 Gut and Metabolomics Study

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.

The Core Problem in Chronic Fatigue Syndrome Identified? Naviaux’s Metabolomics Study Breaks Fresh Ground

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.

gut metabolomics ME/CFS

The metabolomic analysis suggest unique metabolic problems may be present in the ME/CFS plus IBS group

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.

Simmaron’s Spinal Fluid Study Finds Dramatic Differences in Chronic Fatigue Syndrome

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.

Lipkin has been a vocal advocate for ME/CFS

Dr. Ian Lipkin, Center for Infection and Immunity, Columbia University

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.

 

Tea-Time at Simmaron I: Mady Hornig on the “Peterson Subsets”, Immune Exhaustion and New Gut Findings In ME/CFS

The Simmaron Research Foundation is out to redefine ME/CFS scientifically.  In an recent event called A Simmaron Tea, collaborators talked with patients about their recent work to propel discovery in our disease. Part 1 of our summary will review Dr. Mady Hornig’s presentation, including some early results from Columbia’s ongoing gut studies. Part 2 will summarize Dr. Konstance Knox’s study of mosquito and tick-borne pathogens in ME/CFS patients. Stay tuned!

Simmaron has collaborated with Dr. Hornig on half a dozen studies unfolding the immuological anomalies in ME/CFS. A doctor-scientist by training, she is Associate Professor of Epidemiology and Director of Translational Research at Columbia University’s Mailman School of Public Health.Simmaron Research | Scientifically Redefining ME CFS | #ShakeTheCFSstigmaSimmaron’s collaborations with Columbia on spinal fluid studies mark our signature contribution to ME/CFS research. Simmaron is continuing this research by funding a second phase of this work to compare metabolomics and proteomics in ME/CFS and MS patients.

Mady Hornig

“We now know that the same changes to the immune system that we recently reported in the blood of people with ME/CFS with long-standing disease are also present in the central nervous system,” Dr. Hornig

In her presentation, Dr. Hornig first reviewed the recent finding from the Chronic Fatigue Initiative-funded study run by the Columbia team: massive immune up regulation in short duration ME/CFS patients and immune down regulation in longer duration ME/CFS patients.  The same immune factors, interestingly enough, that were upregulated early in the illness were squashed later in the illness. One key viral fighter called IFN-y that was hugely important in early ME/CFS but significantly down regulated in later ME/CFS pointed an arrow at a process called “immune exhaustion”.

Immune Exhaustion

collaboration

The blood and spinal fluid findings matched

The first cerebrospinal fluid study using Dr. Peterson’s carefully collated samples found a similar pattern of immune system down regulation. That study (supported by CFI and Evans Foundation) included only longer duration patients.  These two studies – the first to find similar issues in these two different compartments of the body – suggested that the immune system had taken a system wide punch to the gut.

What could cause this kind of immune exhaustion?  Dr. Hornig stated it’s usually associated with chronic infections. In a scenario reminiscent of the wired and tired problem in ME/CFS, the immune system gets revved up, stays revved up and ultimately crashes.

That nice concurrence between immune findings in the spinal fluid and in the blood was encouraging, and the group is digging deeper into those CSF samples. Thus far a factor called cortisol binding globulin (CBG) has popped up in protein analyses. This intriguing factor which facilitates the transport of cortisol in the blood, has shown up in chronic fatigue syndrome before and families with certain polymorphisms in their CBG genes have increased fatigue and low blood pressure.

The Peterson Subsets

Earlier, Dr. Hornig noted Dr. Peterson’s exceptional foresight at collecting cerebrospinal fluid samples over many years and his skill at characterizing them. Now she appeared almost dumbfounded at his ability to pluck out subsets in his patients. At Dr. Peterson’s urging, the Columbia team examined the cerebrospinal fluid of what he called “classical” ME/CFS patients and “complex atypical” patients. Dr. Peterson has been talking about the “classical” set of ME/CFS patients vs other types of patients for years, but this was the first time his intuition was put to the test.

subsets ME/CFS

Finding subsets was crucial to the success of both studies

The classical patients typically present with infectious onset while ME/CFS in the atypical patients has been associated with post transfusion illness, cancers and other factors. No one before has suggested or attempted to determine if these patients differ biologically.

Dr. Peterson’s intuition that they would be different biologically proved to be correct. Columbia found dramatic differences in the CSF of classical versus atypical patients. Virtually all the immune factors tested were higher in the complex atypical vs the classical patients. The researchers are taking a deeper look at the cerebrospinal fluid in these two types of patients.

The findings also demonstrates how vital it is to tease out subsets. Without breaking patients up into early and longer duration subsets the findings of the CFI’s big immune study would have been negative.  Similarly, without excluding Peterson’s subset of  atypical patients, the cerebral spinal fluid study findings would have been insignificant. Given the size, expense and prominence of the CFI blood study, in particular, the negative results would have provided a significant impetus for the field to move away from the immune system.

Instead, there is now great interest in immune alterations in ME/CFS. The inability to ferret out biologically important subsets has undoubtedly smothered potentially important findings in ME/CFS in the past. In a short period of time the CFI investigators and Dr. Peterson have added two factors ME/CFS researchers need to consider in their studies: duration of illness and classical vs non-classical patients.

This is an example of “translational medicine” – going from the bench (lab) to the bedside (clinic) and vice-versa – at its best. It can only occur when researchers interact closely with practitioners they trust and vice-versa.

The Gut Work

gut chronic fatigue syndrome

Mady Hornig believes the gut may hold answers to ME/CFS. The preliminary gut results suggest she may be right.

Columbia’s Center for Infection and Immunity has  completed the testing of samples from 50 patients and 50 healthy controls started in the CFI study and extended in an NIH-funded study to analyze ME/CFS microbiome. They are completing analysis of the samples now.

They’re finding evidence of significant changes in the gut flora of ME/CFS patients vs healthy controls. For one, altered levels of butyrate producing bacteria have been found in the ME/CFS patients. Noting that similar differences have been found in autoimmune diseases, Dr. Hornig proposed that an autoimmune process may be fueling the symptoms in a subset of patients.

Another finding suggests substantial serotonin dysregulation may be present in ME/CFS. (Most of the serotonin in our body is found in our gut.) Dr. Hornig described serotonin as a major immune regulator. Thus far they’ve found that serotonin is more likely to be undetectable in shorter duration patients than longer duration patients, and those reduced serotonin levels are associated with increased immune activity including a very significant increase in IFN-Y – an important antiviral factor.

Tryptophan is metabolized to either serotonin or kynurenine.  If serotonin levels are low, the levels of kynurenine are likely high. Plentiful serotonin results in feelings of well-being, emotional resilience, and immune balance. High levels of kynurenine, on the other hand, have been associated with a host of neurological and neuropsychiatric disorders. Dr. Hornig has called the kynurenine pathway her favorite pathway because it’s been implicated in so many diseases.

The low serotonin findings in ME/CFS were apparently significant enough for Columbia to begin developing new tests to more accurately assess the presence of kynurenine metabolites. It appears that they’ve been successful in doing that, and we can expect more fine-tuned analyses of the role that pathway plays in ME/CFS.

In discussion afterward the presentation, Dr. Hornig said she was struggling a bit how to relay ideas of low resilience to stress in ME/CFS – some of which low serotonin levels could play a role in – without ruffling feathers.  She’s certainly not advocating the SNRI’s or other antidepressants in ME/CFS. In fact, she noted that she was sure ME/CFS patients were amongst the “treatment resistant depression” patients she’d seen when working as a psychiatrist early in her career.

The fix for the serotonin problem – if it is validated in a subset of ME/CFS patients – will clearly come from another direction. A recent review article suggested using the gut flora to affect serotonin-based brain disorders and that is probably the track Dr. Hornig will take. She said she is especially keen to look at the effects of nutraceuticals, probiotics and fecal transplants in ME/CFS.

Dr. Hornig is clearly intellectually excited by her work, but one thing that happened during her presentation indicated her strong emotional connection to it as well.  The presentation of a small quilt to her from ME/CFS patients strongly affected her and left her having to momentarily gather herself emotionally.  It was a surprisingly moving moment.

Dr. Hornig sounded confident about the direction of their research and stated that they were veSimmaron Research | Give | Donate | Scientifically Redefining ME/CFSry much looking forward to what the next few years will bring.  She said she was cautiously optimistic that the IOM and P2P reports, the positive immune study, plus the signs that the National Institute of Neurological Disorders and Stroke (NINDS) may be interested in taking ME/CFS on, indicate that a turnaround for ME/CFS funding is in store.

Help Simmaron continue to fund this pivotal work, as we seek to deepen immune findings in ME/CFS and turn them into potential treatments.

Infection, Autoimmunity and PANDA’s: Dr. Hornig on Chronic Fatigue Syndrome at Dr. Klimas’ NSU Conference

Quite the Resume

Dr Mady Hornig comes with quite a resume. She and Dr. Ian Lipkin MD direct the Center for Infection and Immunity at Columbia University in New York, and Dr. Hornig is directing the Pathogen Discovery and Pathogenesis Program at the Chronic Fatigue Initiative (CFI).

The Hornig/Lipkin lab at Columbia University is involved in numerous ME/CFS studies

The Hornig/Lipkin lab at Columbia University is involved in numerous ME/CFS studies

An MD and immunologist with a background in neuropsychiatry, Dr. Hornig’s been focused throughout her career on uncovering immune dysfunctions associated with mood and developmental disorders such as autism, PANDA’s, ADHD and schizophrenia. Her current work on the MIND (Microbiology and Immunology of Neuropsychiatric Disorders) Project constitutes the largest examination yet of the role the immune system and viruses play in mood disorders and schizophrenia. She’s currently a lead investigator for  the Autism Birth Cohort study determining how development, genes and environmental factors combine to produce autism.

Dr. Hornig has quickly become a major chronic fatigue syndrome investigator and said she and Dr. Ian Lipkin were using all the tools available to them including gene expression studies, immune and stress markers and proteomics using mass spectroscopy.Check out the ME/CFS studies her lab is or has been involved in….

Chronic Fatigue Syndrome Studies at Dr. Hornig’s Laboratory

  • 200/200 Cases and controls with Chronic Fatigue Initiative  – 18 pathogens identified, then unbiased high throughput sequencing – pretty much tell us anything that is in there
  • 150/150 cases/controls in XMRV study
  • 400/400 cases/controls in huge Montoya Stanford study
  • 60 cases/60 controls Simmaron Spinal Fluid Study

Dr. Hornig focused in on the Simmaron Institute spinal fluid study calling it ‘really intriguing’, calling the number of well-characterized spinal fluid samples  ‘unparalleled’, and stating the study was a ‘unique opportunity’.

We’ll get another chance to see her at the 2013 Invest In ME Conference in May.

The Talk – Infection, Autoimmunity and Illnesses

Placing chronic fatigue syndrome into the category of ‘neuropsychiatric disorders’ (disorders that effect cognition and mood among other things) Dr Hornig started off her talk demonstrating how attacks of insanity seem to have swept over populations, not suggesting that she’s studying a group of insane people, but demonstrating how infections can generate symptoms we don’t generally associate with them.

Mom???

Dr. Hornig believes three factors, timing – a window of opportunity,  a genetic predisposition, and an environmental insult probably come  together to cause chronic fatigue syndrome.  That window of vulnerability could have occurred at any time but Dr. Hornig zeroed in on pregnancy:  a time, it appears, when many chronic disorders are  set into motion.

Mom? The roots of some chronic illnesses appear as far back as pregnancy

Mom? The roots of some chronic illnesses appear as far back as pregnancy

She suggested, but did not say, that chronic fatigue syndrome could be triggered as early as pregnancy and then not show up for 20 or  40 or 50 years until  another window of vulnerability opens up – perhaps during a stressful period, another infection, toxic overexposure. (She noted that the stress response is similar in all these cases).   Indeed, that model of disease, she said,  could apply to outbreaks of autism and ADHD in early life, multiple sclerosis, schizophrenia and ME/CFS in middle life and Parkinson’s and Alzheimer’s disease in later life.

Cannabis triggered schizophrenia during adolescence is an example of the three factors combining in a perfect storm to cause a devastating  disease.  It turns out that bringing together one form of a COMT gene (the COMT gene, oddly enough is implicated in ME/CFS), the tumultuous physiological time of  adolescence, and an environmental factor (cannabis) you get an increased risk of (gulp) schizophrenia.  Basically smoking pot when you’re an adolescent increases your risk of  schizophrenia (it happened to one of the my best friends) but smoking it when you’re an adult – even if you have this particular form of this gene- doesn’t increase your risk at all.

She described an incredible and rather frightening study in which researchers examined pro-inflammatory cytokine levels (IL-6 and IL-1b) in the blood of mothers collected 40-50 years ago. Skipping  forward they found that women whose mothers had high cytokine levels during pregnancy  tended to be depressed and have reduced  brain activation in middle age. This suggested those high levels of pro-inflammatory cytokines changed the circuitry of female fetus’s brain enough to make those women more vulnerable to depression later on.  She noted that some of the same stress-circuitry showing up  in those women is implicated in ME/CFS as well.

The Immune Side of Neuopsychiatric Disorders

Hornig is an immunologist and she  explained that many ‘neuropsychiatric disorders’ may be explained by immune problems; the list  she presented was not a particularly pretty on; besides fibromyalgia and ME/CFS it included Tourette’s syndrome, autism, obsessive compulsive syndrome, ADHD, anorexia nervosa, narcolepsy, major depressive disorder, bipolor disorder and schizophrenia (and probably should have included irritable bowel syndrome, interstitial cystitis and other disorders that co-occur with ME/CFS. ).

There are several  groups in here; the heavy psychiatric disorders – depression, bi-polar disorder, compulsive obssessive disorder and schizophrenia; the CFS-like disorders (ME/CFS, FM….IBS, IC, etc.) and then autism and ADHD.

The Infection Autoimmune Connection

The infection/autoimmune connection is a strong one with many autoimmune disorders showing up shortly after infections…but..(there’s always a but :))  she noted that other autoimmune disorders  can take years to show up making it difficult to determine the trigger.  If it was a pathogen, it could’ve  and may very well have done it’s damage and then disappeared, leaving a chronically disrupted immune system in its wake.

PANDAS – A Possible  Model for ME/CFS

“Several studies suggest autoimmunity may play a role…”

PANDA's - a childhood disorder associated with Streptooccus infection could be a model for ME/CFS

PANDA’s – a childhood disorder associated with Streptooccus infection could be a model for ME/CFS

Hornig  then described an infection triggered neuropsychiatric disorder called PANDAS that could be a model for ME/CFS.  Children with PANDAS don’t eat eucalyptus leaves for lunch, but they do display dramatic changes in behavior including obsessive-compulsive behavior, tics, mood swings and anxiety soon after a staphyloccus infection. They also display the kind  of ‘ vigilance’ and arousal that shows up in some people with chronic fatigue syndrome.

Hornig has become deeply involved in PANDAS. Much is controversial about PANDAS but it’s believed to be an autoimmune disorder that targets the basal ganglia in the brain (which is, yes, also under consideration in ME/CFS…). Working with Dr. Lipkin, Dr. Hornig found that mice injected with strep   engage in obsessive compulsive behaviors (they flip themselves over backwards again and again) and that simply injecting  antibodies to streptococcus  into mice caused problems with learning and memory, coordination, and social interactions.  Then, in a nice Koch-like test, they found that  removing the antibodies from the mice  resulted in the return of  normal behavior.

General Stress Response Affected

That made it pretty clear  it’s the antibodies; eg. the immune response that’s the problem and what they found next confirmed that; they found that the antibodies to strep mistakenly cross-react (ie  target  for destruction) two important parts of  the  immune system; C4 complement and heat shock proteins.

Why would we, with ME/CFS, be interested in these factors?  Because both  appear, Dr. Hornig said, to be general responses to infections and stressors of all sorts, with all its different triggers, chronic fatigue syndrome could be associated with a basic derangement of the stress response (to  infection, trauma, etc.).

Dr. Hornig didn’t mention it both C4 and heat shock proteins  have (yes, yes, yes :)) been implicated in chronic fatigue syndrome at one time or the other

Dr Hornig noted that children with  PANDAS can respond to IVIG, antibiotics and other immune agents.  That’s a bit controversial (no surprise there) with  the American Heart Association (AHA)  recommending that strep not be tested for in children with PANDAS or that they attempt IVIG  treatment despite the fact that one preliminary  study has found IVIG effective.

It’s more of the old, we need more studies before we do or recommend anything without providing the money to do them leaving potential helpful treatments on the shelf while patients suffer (sound familiar?). (PANDAS is way down on the NIH’s priority list.

Key Partners – The Stress Hormone-Immune System Interactions

Hornig noted the immune- stress response connection with PANDAS and now she enlarged on it. Proper central nervous system functioning is dependent on having  balanced immune and stress responses; throw those responses in just one part of the system-  tryptophan degredation – into disarray can cause you to not be able to lay down a memory. Tryptophan is a possible candidate with ME/CFS but she was most interested in the biggest bundle of nerves outside the brain – the enteric nervous system or gut….

Getting Down With The Gut

Hornig then directed us out of the brain and downwards into the gut.  On a very, very basic level this makes sense since  everything  that our bodies run on (except for the gases) comes from our food which means we better be able to digest it well. Stopping the flow of anti-oxidants  (selenium, cysteine, glutathione) from our food out of the gut into our body, for instance, results in increased levels of oxidative stress,  pro-inflammatory cytokines and auto-antibodies  (autoimmune reactions).

Get increased auto-antibodies and you can have problems showing up in literally any part of the body. Just to get our attention, Dr. Hornig noted that an  autoantibody attack of folate receptors could show up in problems with  metabolism,  methylation and B-12.

Then she shifted upwards – back to the brain.  So far our dysfunctional gut has left us with low levels of anti-oxidants, high levels of pro-inflammatory cytokines,  and high levels of autoantibodies in our blood.  Send all that stuff up to the precious (and fragile) blood-brain barrier  protecting our brain and….you have the possibility of a rip exposing the brain to all sorts of bad actors. Depending on which part of your brain gets attacked there goes your  sex drive, appetite, motivation, energy levels, etc….and to think it all could have started with bad flora in your gut.

More Floral Than Viral?

Lest we think this is some researcher’s fantasy, Hornig described her work with autistic kids.  Hornig’s group did not find evidence of measles in autistic children but they did find levels of digestive enzymes so low to be almost non-existent. The autistic kids couldn’t break down milk products because they were lacking the enzyme for that but that hardly mattered as their guts were so deficient they couldn’t have gotten the milk protein into their bodies even they could have broken it down.

Not only was their gut flora massively different but they also they harbored a rare bacteria called Sutterella not present at all in the healthy controls.  Sutterella was not just present,  it was flourishing, accounting for up to  7% of all gut bacteria. Usually a very minor component of the gut microbiome, Suttarella was the third most common bacteria found in these kids.  That really raised some eyebrows.

Could ME/CFS be More Floral than Viral? An upcoming CAA study should be revealing. These bacteria were cultured from yogurt

Could ME/CFS be More Floral than Viral? An upcoming CAA study should be revealing. These bacteria were cultured from yogurt

Still, it’s not clear if Sutterella itself is whacking the kids or if its crowding out good gut flora or if its doing nothing but  we do know that Sutterella thrives in low oxygen  environments and has been linked to inflammatory bowel disorder, Crohn’s disease and ulcerative colitis. (It  can also, though, sometimes be found in healthy individuals.) Hornig’s ability to find an antibody to Sutterella in about 50% of the children indicated they had mounted an immune response to it.

Bacterial imbalances in the gut have been observed in gut disorders such as irritable bowel syndrome (IBS) and inflammatory bowel disease but its become clear that  bad gut bacteria could wreak havoc far outside the gut. The first non-gut disorder associated with bad bacteria appears to have been arthritis.  (Check out a horrifying and fascinating New York Times story of  young child’s battle with rheumatoid arthritis.)  Cesareans appear to  put children at increased risk for asthma because they prevent children from picking up important gut bacteria as they pass they through the birth canal.   Bacterial imbalances in the gut appear to be associated with increased obesity in people with  type two  diabetes .

Researchers have identified three main types of gut composition in humans and they know that diet can influence gut flora. They know that  cutting out sweets and processed foods and using prebiotics and probiotics can help some people reduce or eliminate  inflammation.  Fecal transplants may actually be more effective because they contain more of the bacteria that’s actually populating our guts.

Hornig noted how  important the small intestine is for so many different type of phenomena – for cognition, anxiety and even for sleep. Did you know that if you’re not getting peristalsis (small gut movements pushing the food along)  during the night then you’re missing some sleep enhancing molecules.

Major Chronic Fatigue Syndrome Gut Study Out This Year

The Shukla CFIDS Association gut metagenome study is looking more exciting all the time. This study, which study started several years ago and should be published soon, sought to characterize the entire  gut microbriome before and after exercise in people with ME/CFS.

By studying the gastrointestinal microbiome, Shukla’s work will determine if the ratio of normal to pathogenic (illness-causing) bacteria is off-kilter in CFS patients and if exercise causes harmful bacteria to travel into the body from the gut, creating the postexertional symptoms that are such a prominent feature of the illness. The results have the potential to yield microbial biomarkers for CFS as well as targeted treatments aimed at rebalancing the ratio of bacteria. From CFIDS Chronicle Winter 2009

  • Xafaxan: Gut Rebalancer Extraordinaire –  Suffering from gut issues? Check out a new page Health Rising has on Xafaxan, a gut antibiotic used to snuff out small intestine bacterial overgrowth (SIBO) problems. One person with ME/CFS ended six years of gut turmoil with one short course of Xafaxan…

 Q & A Period

Is Chronic Fatigue Syndrome Infectious?

She thought perhaps, but if so probably mostly during the initial stage of the illness, and that it was highly unlikely it was  infectious in later stages of the illness.  Hornig is following the same model as Klimas in her research; she’s  looking for an infectious agent but finding  immune and stress response factors indicative of a pathogenic attack (at some point) is a major focus.

With a kind of immune system hypervigilance twist she stated its possible an initial infection sensitized the system so that further infections, even very mild ones, might be  throwing it  into a tizzy.   If ME/CFS patients have a problem with infection in general; that is, if any infection has the potential to trigger a kind of overwrought immune response, then she felt it was more important the source of that than to look for a specific virus.  With all the known infectious triggers for ME/CFS she believes some genetic susceptibility/immune issue was present.

One reason for Hornig’s interest in ME/CFS may be due to her work in autism. Hornig believes innate immune system problems during maternity may play a role in the development of autism, and the innate immune system  – the early immune response system involving NK cells, dendritic cells and others – is getting more and more attention in ME/CFS.  Interestingly, Hornig found that infection induced inhibition of the same Toll-like receptors (TLR3) Ampligen effects lead problems with sensorimotor gating responses as adult.  Check out this blog for a treatment of sensory gating issues in chronic fatigue syndrome.

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