Dr Chia finds Double-stranded RNA in stomach biopsies

[adreno]

The answer, as always, probably lies somewhere in between. Recent research is talking about genome-microbiome associations:

Our findings indicate that host genetics are part of a complex web of host-associated factors influencing microbiome composition. We performed a meta-analysis of interactions between clinical host factors and bacterial taxa using the above 474 subjects and an additional 55 subjects who had recently taken antibiotics. This analysis included NOD2 as one of the host factors. We identified an additional 99 significant associations of non-genetic factors with relative abundance of specific bacterial taxa, largely in agreement with previous analyses of the IBD microbial environment.

This analysis revealed a web of complex overlapping linkages between numerous host factors and bacterial taxa. For example, recent antibiotic usage is associated with systematic shifts in many major taxonomic groups (Figure 6; FDR <0.05); immunosuppressants are associated with decreased Firmicutes, and Ruminococcaceae. Biopsy location and cohort membership had similarly broad effects; age, gender, and disease phenotype had measurable, although less broad, effects; genotype, as represented by the NOD2 subtype, had a modest effect in relation to other factors. Inflammatory status of the biopsied tissue was associated with increased relative abundance of unclassified members of Lactobacillus, and with decreased relative abundance of Bacteroides uniformis (Figure S5 in Additional file 1). This analysis demonstrates the comprehensive and intermingled effects of treatment history, gastrointestinal biogeography, and other host and environmental factors on gut microbiome profile and makes clear the need to account for host factors when linking host genotype to microbial composition in a phenotypically heterogeneous population. We confirmed that host genetics as a whole do have a significant effect on microbiome profile by correlating overall between-subject genetic distance (Manhattan distance) with overall between-subject microbiome distance (unweighted UniFrac distance) (P < 5.0 × 10-10; Figure S6 in Additional file 1), but that it is only a minor contributor in the context of other sources of variation. A recent study of treatment-naïve pediatric patients with CD identified consistent microbiome shifts in patients with recent antibiotic exposure toward the disease-related state 20]. That study exemplified the need to control for the potentially confounding effects of antibiotics when attempting to identify bacterial profiles associated with disease. Based on several studies linking short- and long-term dietary exposure to microbiome profile, it is also likely to be useful to include food intake diaries or dietary recall questionnaires in future genotype-microbiome research.

So this is how complex these interactions are. The authors made a diagram of these interactions:

The conclusion:

Taken together, our findings indicate a complex set of associations between the mucosal-adherent microbiome and genetic impairment of several host immune pathways. Although we have been living and evolving with our microbial symbionts throughout human evolution, we have only been aware of their existence for a few centuries, and the genetic and functional diversity of our so-called 'second genome' has only become apparent in the last few decades. Also in recent decades incidence of IBDs and other autoimmune and autoinflammatory diseases has increased dramatically 42], and a rapidly growing set of these diseases has been linked to shifts both in taxonomic carriage and functional potential of host-associated microbial communities. Although our data are cross-sectional and therefore cannot define causality, our analyses demonstrate complex host genetic associations with taxonomic and metabolic dysbiosis in humans. These include implications of microbiome-wide associations with TNFSF15, IL12B, and with innate immune response, inflammatory response, and the JAK-STAT pathway, as well as NOD2-related increases in Enterobacteriaceae relative abundance. Future studies may be warranted to account for the effects of copy number variation, pleiotropic genes and epigenetic modifications. It is also possible that certain genotype-microbiome associations observed in IBD patients may be disease-independent and may be relevant to healthy individuals and individuals with other diseases. The methods we employed were validated on independent cohorts and make possible well-powered false-positive-controlled testing of microbiome-wide host genetic associations.

http://genomemedicine.com/content/6/12/107

 

[oceiv]

When a low virulent strain carrier gets infected with a high virulent strain it can cause an extremne response.

Can you expand on how this would apply to ME/CFS? I'm not sure I understand what would happen.

But would there be any evolutionary purpose to having genes predisposing you to ME from common pathogens? Why would such genes have survived through a human history where having ME would most likely equal being dead, or at least not reproducing?

Some known reasons are endogamy, local populations' intermarrying for many generations and populations being isolated for periods of time. Under these conditions, there are genetic bottlenecks. Also, because people used to marry, have children and die earlier, these genes could quite easily pass through the generations.

But, it could be that both genetic and non-hereditary factors influence ME/CFS susceptibility. I was just reading how some MS cases are known to be genetically-influenced, but many aren't. At least, with the genetic info we currently have. Could be that ME/CFS future sub-groups will be defined in this way. We know that autoimmune diseases are more likely when family members also have autoimmune disease. But many cases have no familial association.

There is so much we don't yet know about immune systems and how/which genes influence disease susceptibility.

 

[lansbergen]

Can you expand on how this would apply to ME/CFS? I'm not sure I understand what would happen.

What eems to be the worst flu ever can be an extreme reaction when a high virulent strain infects a low virulent strain carrier (basic virology). The agent I suspect causes a chronic infection and can survive in soil for decades. Low virulent strains seem not to cause the terminal disease in humans but high virulent strains do. When infection pressure is lowered the lethal form decreases. Low virulent strains can partly protect against high virulent strains.

I think in my case there is an ongoing battle between low virulent strains and a high virulent strain wich alerts the cell danger response.

The innate system responses but the adaptive system fails.

 

[Antares in NYC]

Thank you.
In my family, there are several with CFS/ME and/or the usual co-morbid disorders. We grew up and live in different cities and countries. I also have a relative in the same branch of the family who battled lymphoma. This and related conditions are too prevalent in my family not to be genetic, especially without other common factors (such as local diet, places of birth, places of living). But I agree in part: microbiome will turn out to be one influential factor.

Basically, I think all of the physical prerequisites need to happen all together in genetically susceptible people to create the perfect immune storm. I realize now that @halcyon pointed out, that Dr, Chia has focused mostly on enteroviruses as the cause.

I will look at @halcyon 's Dr. Chia links and your micribiota/viral susceptibility link. I'm definitely curious to read them. I'm also reading through Dr. Chia's site and found this:

From this explanation, it seems he thinks there's an underlying immune problem, which makes patients more susceptible to the infections. Only more research will tell us what causes that underlying susceptibility. He acknowledges non-enterovirus cases though, it seems.

Interesting stuff, glad @halcyon got me looking further into Chia. Thanks for posting this study, @thegodofpleasure .

I find this very interesting, but my family history seems to be the complete opposite: nobody in my family or extended family (spanning two continents) has this thing but me. I'm the 'lucky one', apparently.

That said, on my mother's side there are a number of family members with what seem like weaker immune systems, and that includes me. By that I mean being more susceptible to getting sick, and to do so for longer periods of time.

When I was in my teens I used to get sick all the time, with repeated bouts of bronchitis, over and over again, and was treated with strong antibiotics on a regular basis. After my teens, I used to get major colds and bouts of flu at least once a year, which would leave me bedridden for days. All this was part of my 'normal', and may have contributed to a weakened microbiome and paved the way for that brutal ME/CFS 'flu' that changed my life forever.

It's interesting that nobody else in my family has this thing, but a few of us have a predisposition to getting brutal colds and stay sick for long periods of time.

 

[alex3619]

If gut microbiota explain it, why don't people who have fecal transplants recover?

There is a long history of case studies where these patients improve or recover, going back decades. Its just never been done in a large scale RCT.

Also in such a transplant you need to know what bacteria you need. Not just any poop will do.

 

[oceiv]

I find this very interesting, but my family history seems to be the complete opposite: nobody in my family or extended family (spanning two continents) has this thing but me. I'm the 'lucky one', apparently.

That said, on my mother's side there are a number of family members with what seem like weaker immune systems, and that includes me. By that I mean being more susceptible to getting sick, and to do so for longer periods of time.

When I was in my teens I used to get sick all the time, with repeated bouts of bronchitis, over and over again, and was treated with strong antibiotics on a regular basis. After my teens, I used to get major colds and bouts of flu at least once a year, which would leave me bedridden for days. All this was part of my 'normal', and may have contributed to a weakened microbiome and paved the way for that brutal ME/CFS 'flu' that changed my life forever.

It's interesting that nobody else in my family has this thing, but a few of us have a predisposition to getting brutal colds and stay sick for long periods of time.

It is really fascinating how you have those familial immune patterns. I see some other familial patterns of symptoms, but not diseases, too. For example, my immediate family all have different sleep issues. Even though you and I have different familial profiles, your teenage years sound like mine. Lots of throat and some lung infections. Frequent antibiotics. They repeatedly tested me for mono, but found nothing, Later, I had frequent sinus infections. Those got worse after my illness onset. I read that Dr. Chia believes that enteroviruses can cause sinus infections. As an addition to that theory, sinus infections can in turn cause lung infections.

This may not be the case, but ME/CFS could fit a recessive gene illness pattern. So, maybe if a family member has a weak immune system, then they have shades of the the illness, but not a full-blown illness. They might have one copy of a faulty gene, But let's say if you and I got a pair of faulty genes plus had the right circumstances (other infections, enteroviruses, altered gut microbiome, injury, etc.) in our lives (non-herditary factors), then we would both get ME/CFS. Just a theory I've had for a while, which might fit with Dr. Chia saying an underlying weak immune system may set the stage for getting ME/CFS. I'm sure it's more complicated than just one gene, maybe a group of them. Or maybe like the various BRCA mutations, which increase a person's odds of getting a variety of cancers.

It would be interesting to compare symptoms of those with and without family associations.

 

[adreno]

Interestingly, a new large study of autism found no connection between phenotypical symptom presentation and genotype:

A large group of collaborating scientists used data from the Simons Simplex Collection, a project that extensively characterized 2576 autism simplex families, the largest such cohort amassed to date and for which the data is now available in a permanent repository.

"This study did not provide good evidence that selecting patients with similar symptoms results in a greater ability to find autism genes," said Dr. John Krystal, Editor of Biological Psychiatry. "This might suggest that some of the clinical variability in autism arises from causes other than genetic vulnerability, such as epigenetic changes or other responses to the environment."

I suspect the same would be the case for ME. Now, if genome-microbiome associations were factored in, the results might have been different. Imagine that only certain combinations of genotype and "microbiome phenotype" would present as certain clinical phenotypes...

 

[natasa778]

Interestingly, a new large study of autism found no connection between phenotypical symptom presentation and genotype:

I suspect the same would be the case for ME. Now, if genome-microbiome associations were factored in, the results might have been different. Imagine that only certain combinations of genotype and "microbiome phenotype" would present as certain clinical phenotypes...

Yes but imo even more important than both of those is what happens during pregnancy, what types (if any) of immune/infectious and toxic insults, and how those will shape and prime both neuronal function AND immune function and microbiome composition.

This prenatal or perinatal priming by environmental factors is almost certainly a major etiological factor in autism (and shizophrenia) but I suspect in ME and many other 'later onset' diseases

 

[adreno]

Yes but imo even more important than both of those is what happens during pregnancy, what types (if any) of immune/infectious and toxic insults, and how those will shape and prime both neuronal function AND immune function and microbiome composition.

This is likely true. Most of us weren't born with ME so this might not pertain to us in the same degree as autism.

Microbiome composition happens only after birth, first through swallowing bacteria in the birth canal, and later through breastfeeding, diet and environment. During pregnancy babies have no microbiome.

 

[natasa778]

This is likely true. Most of us weren't born with ME so this might not pertain to us in the same degree as autism.

Microbiome composition happens only after birth, first through swallowing bacteria in the birth canal, and later through breastfeeding, diet and environment. During pregnancy babies have no microbiome.

I didn't mean to say that what happens prenatally will necessarily have immediate effects, on the contrary (lots of kids are not born with autism but develop normally then regress later suddenly, also shizo does not develop till much later in life etc). What happens prenatally can prime the immune system, so that it reacts (or doesn't react) to things differently later in life.

One example is that immune systems of animals exposed to infections prenatally tend to be not as effective at controlling certain infections later on in adulthood, while at the same time having the tendency for producing chronic pro-inflammatory states compared to control animals. This can all manifest later in their lives, not cause symptoms in early life.

Re microbiome, again animals who suffer immune insults prenatally have different microbiome composition from control animals with the same genetic make up, same litter conditions and maternal microbiome etc. (look up work by Patterson and Hsiao and many others). Long story short the immune priming by environmental factors BEFORE birth clearly influences the acquisition of microbiome AFTER birth. Both of course can be changed and manipulated