Clostridium Butyricum - A Game Changer?

[Hutan]

Yes, I've just quoted that very same 2012 paper you quote in another thread. I found it confusing because this paragraph about Lupus is also from it:

IL-10 functions as a potent B cell stimulator that enhances activation, proliferation, and differentiation of B cells. This relates to SLE, which is characterized by high autoantibody production and decreased cellular immune responses. In SLE, high levels of autoantibodies generate immune complexes that exacerbate tissue damage. Compared with healthy individuals, levels of IL-10 in SLE patients are significantly higher and there is a correlation between IL-10 levels and clinical manifestation.77 Depletion of IL-10 by anti-IL-10 antibody in vitro treatment of SLE patient–derived PBMC significantly decreased autoantibody production.

 

[Hutan]

@adreno, given the paragraph from the paper that I quote, I think the paragraph you quote can be read as 'deficient or aberrant expression' (which includes over-expression) can enhance inflammatory response but also lead to persistent infections and autoimmune disease.

Clearly, it's complicated. It's an interesting paper though.

 

[adreno]

@adreno, given the paragraph from the paper that I quote, I think the paragraph you quote can be read as 'deficient or aberrant expression' (which includes over-expression) can enhance inflammatory response but also lead to persistent infections and autoimmune disease.

Clearly, it's complicated. It's an interesting paper though.

This might be key:

Here, we discuss the role of IL-10 in autoimmune diseases and examine its beneficial effects in cellular-based autoimmune diseases such as multiple sclerosis (MS) or its involvement in humoral-based autoimmune diseases such as systemic lupus erythematosus (SLE).

http://www.ncbi.nlm.nih.gov/pubmed/12220553

 

[JPV]

@Hutan and @adreno. Not sure if this was brought up before but here's another study from 2011...

Immunological abnormalities as potential biomarkers in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis

This study supports the presence of a possible imbalance in Th1/Th2 response in CFS/ME characterised by a significant increase in IL-10 together with significant increases in IFN-γ and TNF-α. Such increases in IL-10 are suggestive of a persistent chronic infectious state and may be associated with a dampening of the NK and CD8+T cell immune response 22]. Others have shown that IL-10RA is differentially expressed in CFS/ME patients, highlighting a potential compromise in IL-10 function or its receptor in CFS/ME patients 35,36]. Nonetheless, increased levels of IL-10, IFN-γ and TNF-α indicate the presence of fungal, bacterial or viral infection 37]. Incidentally in HIV elevation in IL-10, IFN-γ and TNF-α denote the presence of a chronic infection and this correlated with viral load 38]. Similarly in CFS such alterations in these cytokines may also suggest an increase in viral load and the occurrence of flu-like symptoms. An increase in IL-10 also may contribute to decreased cytotoxic activity observed in the NK and CD8+T cells 39,40]. The increase in pro-inflammatory cytokines such as TNF-α, may also depict the presence of an inflamed gut or irritable bowel syndrome in some CFS/ME patients 41]. Inflammation in the gut can alter the central nervous system 42,43] and affects various physiological mechanisms including neuropeptides.

 

[mariovitali]

Without wanting to derail the subject :

Interleukin-10 Blocked Endoplasmic Reticulum Stress in Intestinal Epithelial Cells: Impact on Chronic Inflammation


Results:
Primary IEC from IL-10−/− mice as well as inflammatory bowel disease patients revealed increased expression levels of the glucose-regulated ER stress protein (grp)-78 under conditions of chronic inflammation. Consistent with the observation that TNF induced ER stress responses through grp-78 redistribution from the ER lumen to the cytoplasmic IκB kinase complex, grp-78 knockdown completely abolished TNF-induced nuclear factor-κB RelA phosphorylation in epithelial cell cultures. Interestingly, IL-10 inhibited grp-78 protein and messenger RNA expression in IL-10R reconstituted IEC. Chromatin immunoprecipitation analysis and immunofluorescence microscopy revealed that IL-10-mediated p38 signaling inhibited TNF-induced recruitment of the ER-derived activating transcription factor (ATF)-6 to the grp-78 promoter likely through the blockade of ATF-6 nuclear translocation. Conclusions: Primary IEC from inflamed IL-10−/− mice and inflammatory bowel disease patients revealed activated ER stress responses in the intestinal epithelium. IL-10 inhibits inflammation-induced ER stress response mechanisms by modulating ATF-6 nuclear recruitment to the grp-78 gene promoter.

Could the reason behind elevated IL-10 levels in CFS sufferers is an attempt to ameliorate inflammation originated by the Unfolded Protein Response and ER Stress?


Edit : There is a possible two-way relationship between ER Stress and Inflammation :

The relationship between ER stress and inflammation is not likely to be one-sided. Inflammatory mediators and activation of cellular stress pathways, such as the JNK and IKK pathways, may have a negative impact on ER function. However, the interplay between inflammation and ER stress may depend on the cell type, and a great deal of work is still needed to understand the major parameters that determine a cell's susceptibility to inflammatory signals and subsequent effects on ER homeostasis. Indeed, much of the work done to date is based on in vitro experiments. However, recent studies in the brain provide in vivo evidence supporting the model that both ER stress and inflammation are able to activate each other and to inhibit normal cellular metabolism (Zhang et al., 2008). In this setting, activation of IKK-β can lead to ER stress, and activation of ER stress can stimulate IKK-β. One can speculate that the cell may have a central node through which different stress responses send their signals. This central node may then, in turn, “decide” which responses to elicit and may activate specific pathways related to the intrinsic status of the organelle. For example, the inflammatory response may be activated and may signal to this node, which then activates the UPR. Depending upon the cell type, these responses and the components of such a node may differ. In the adipocyte, for instance, inflammatory signals may not cause UPR activation (or may do so only when the cell is under metabolic stress), but activation of the UPR may elicit an inflammatory response.

Please see here for more : http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2887297/

 

[Avengers26]

I find these IL-10 studies very interesting. Thanks for posting these. For me, TNF-a, IL2, IL10 are high while IFN-y & several others are low. It's food for thought & reflection.

 

[Violeta]

Without wanting to derail the subject :





Could the reason behind elevated IL-10 levels in CFS sufferers is an attempt to ameliorate inflammation originated by the Unfolded Protein Response and ER Stress?


Edit : There is a possible two-way relationship between ER Stress and Inflammation :




Please see here for more : http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2887297/

IL-10 also inhibits mast cell degranulation.
http://www.jimmunol.org/content/180/5/2848.full

 

[mariovitali]

OK so i am preparing a new major round of "CFS Analytics" and wanted to add my 2 cents regarding IL-10.


Here is the output of one type of the analysis : Below you see the percentage that "IL-10" has matched to several topics of interest regarding CFS. Each *.csv is a file in my disk that contains PubMed entries for the relevant subject.

So the entry pbmc.csv below contains PubMed Abstracts entries for peripheral blood mononuclear cells (PBMCs). "IL-10" keyword has been found in 10.10% of PubMed Abstract entries of PBMCs.

Anything over 0.1% deserves a look in my opinion. I will soon post a file that contains similar information for all CFS Topics of interest (almost 50000 lines)

@Violeta, @Avengers26 notice the fact that mast_cell_activation.csv entry below is on the top positions

*********Topic : il-10 ***************
il_10.csv : 74.09 %
pbmc.csv : 10.10 %
mcp-1.csv : 9.97 %
inflammatory_response.csv : 5.27 %
inducible_nos.csv : 3.61 %
probiotics.csv : 3.24 %
vcam-1.csv : 2.21 %
mast_cell_activation.csv : 1.53 %
microbiome_humans.csv : 1.07 %
hsp70.csv : 0.79 %
cortisol_levels.csv : 0.72 %
scfa.csv : 0.71 %
heat_shock_protein.csv : 0.69 %
omega3.csv : 0.65 %
oxidative_stress_markers.csv : 0.65 %
irritable_bowel.csv : 0.61 %
vitamin_d3.csv : 0.61 %
benfotiamine.csv : 0.60 %
hpa_axis.csv : 0.59 %
cfs.csv : 0.56 %
mastocytosis.csv : 0.54 %
curcumin.csv : 0.54 %
xbp1.csv : 0.48 %
ngf.csv : 0.47 %
ros.csv : 0.44 %
glycoproteins.csv : 0.43 %
resveratrol.csv : 0.42 %
caspase_human.csv : 0.42 %
rxr.csv : 0.41 %
d-limonene.csv : 0.41 %
hepatotoxicity.csv : 0.40 %
tocotrienol.csv : 0.39 %
oxidative_stress_protection.csv : 0.38 %
advanced_glycation_end.csv : 0.38 %
creatine_supplementation.csv : 0.38 %
gluten.csv : 0.35 %
l-arginine.csv : 0.35 %
protease_inhibitor.csv : 0.35 %
amyloid.csv : 0.35 %
nafld.csv : 0.34 %
testosterone_production.csv : 0.34 %
rituximab.csv : 0.34 %
rar.csv : 0.33 %
endothelial_nos.csv : 0.32 %
nlinkedglycosylation.csv : 0.31 %
er_stress.csv : 0.31 %
acetylcholine.csv : 0.29 %
histone_deacetylase.csv : 0.29 %
peroxynitrite.csv : 0.28 %
zinc_supplementation.csv : 0.28 %
asymmetric_dimethylarginine.csv : 0.26 %
l_tryptophan.csv : 0.25 %
ckd.csv : 0.25 %
anhedonia.csv : 0.25 %
pxr.csv : 0.23 %
excitotoxicity.csv : 0.22 %
floaters.csv : 0.22 %
resistant_starch.csv : 0.22 %
hmgcoa.csv : 0.21 %
steatohepatitis.csv : 0.21 %
pgc1.csv : 0.21 %
insulin_resistance.csv : 0.21 %
human_semen.csv : 0.20 %
cyp2e1.csv : 0.20 %
choline_deficiency.csv : 0.19 %
serotonin_levels.csv : 0.19 %
nadph_human.csv : 0.19 %
trpv.csv : 0.19 %
tetrahydrobiopterin.csv : 0.18 %
phospholipid_human.csv : 0.18 %
coenzymeq10.csv : 0.18 %
p450scc.csv : 0.17 %
taurine.csv : 0.17 %
ginkgo.csv : 0.17 %
butyrate.csv : 0.17 %
glycosylation.csv : 0.16 %
gtp_cyclohydrolase.csv : 0.16 %
sinusitis.csv : 0.14 %
tau.csv : 0.14 %
human_proteinuria.csv : 0.14 %
cyp2d6.csv : 0.14 %
cholestasis.csv : 0.14 %
upr.csv : 0.14 %
mthfr.csv : 0.13 %
glutamate.csv : 0.13 %
hgh.csv : 0.12 %
iron_deficiency.csv : 0.12 %
dht.csv : 0.12 %
lipoic_acid.csv : 0.12 %
glycerylphosphorylcholine.csv : 0.12 %
n-acetylglucosamine.csv : 0.12 %
mitochondrial_dysfunction.csv : 0.11 %
uric_acid.csv : 0.11 %
nadh_human.csv : 0.10 %
dopamine_levels.csv : 0.10 %
tmao.csv : 0.10 %
freet3.csv : 0.10 %
calcium_homeostasis.csv : 0.09 %
selenium.csv : 0.09 %
triiodothyronine_levels.csv : 0.08 %
cyp1a2.csv : 0.08 %
vitamin_b6.csv : 0.08 %
sirt1.csv : 0.08 %
cyp3a4.csv : 0.08 %
neuronal_nos.csv : 0.08 %
steroidogenesis_human.csv : 0.07 %
magnesium_deficiency.csv : 0.07 %
autism.csv : 0.07 %
monosodium_glutamate.csv : 0.07 %
neurite_outgrowth.csv : 0.07 %
cimetidine.csv : 0.07 %
star.csv : 0.06 %
dolichol.csv : 0.06 %
adrenal_insufficiency.csv : 0.06 %
5-htp.csv : 0.06 %
phosphatidylcholine.csv : 0.05 %
cyp1b1.csv : 0.05 %
dysautonomia.csv : 0.05 %
selenium_deficiency.csv : 0.05 %
hydroxysteroid_dehydrogenase.csv : 0.05 %
acetyl-coa.csv : 0.05 %
3betahsd.csv : 0.05 %
vitamin_k2.csv : 0.05 %
p450oxidoreductase.csv : 0.05 %
atrial_fibrillation.csv : 0.04 %
hexosamine.csv : 0.04 %
sshl.csv : 0.04 %
dopamine.csv : 0.04 %
finasteride.csv : 0.04 %
l_carnitine.csv : 0.04 %
cyp1a1.csv : 0.04 %
amyloidosis.csv : 0.04 %
l_tyrosine.csv : 0.03 %
udpgluc.csv : 0.03 %
accutane.csv : 0.03 %
p5p.csv : 0.03 %
systemic_amyloidosis.csv : 0.02 %
gaba_human.csv : 0.02 %
5alphareductase.csv : 0.02 %
social_anxiety.csv : 0.02 %
misfolded_proteins.csv : 0.02 %
insomnia.csv : 0.02 %
urea_cycle.csv : 0.02 %
limbic_system.csv : 0.02 %
pregnenolone.csv : 0.01 %
adhd.csv : 0.01 %
tinnitus.csv : 0.01 %
l-dopa.csv : 0.01 %
oxalates.csv : 0.01 %
tudca.csv : 0.00 %
adrenal_hyperplasia.csv : 0.00 %
5mthf.csv : 0.00 %
panic_disorder.csv : 0.00 %
dpagt1.csv : 0.00 %
phenylketonuria.csv : 0.00 %
ire1.csv : 0.00 %
orthostatic_intolerance.csv : 0.00 %
cerebrovascular_amyloidosis.csv : 0.00 %
udpglcnac.csv : 0.00 %
fmo3.csv : 0.00 %
pqq.csv : 0.00 %
beta-alanine.csv : 0.00 %
car.csv : 0.00 %
mucuna.csv : 0.00 %
allopregnanolone.csv : 0.00 %
dihydroprogesterone.csv : 0.00 %
osmolytes.csv : 0.00 %
subclinicalhypo.csv : 0.00 %
o-glcnac.csv : 0.00 %
srd5a3.csv : 0.00 %

This is another example of a sample run for Histone deacetylase :

*********Topic : histone deacetylase ***************
histone_deacetylase.csv : 87.16 %
sirt1.csv : 14.29 %
butyrate.csv : 7.37 %
scfa.csv : 3.05 %
rar.csv : 1.93 %
resveratrol.csv : 1.55 %
pgc1.csv : 1.47 %
nadh_human.csv : 1.42 %
caspase_human.csv : 1.35 %
o-glcnac.csv : 1.10 %
rxr.csv : 1.09 %
misfolded_proteins.csv : 0.93 %
curcumin.csv : 0.91 %
car.csv : 0.67 %
er_stress.csv : 0.56 %
pxr.csv : 0.53 %
heat_shock_protein.csv : 0.53 %
star.csv : 0.50 %
xbp1.csv : 0.48 %
hsp70.csv : 0.44 %
cyp1b1.csv : 0.43 %
urea_cycle.csv : 0.42 %
tudca.csv : 0.38 %
upr.csv : 0.35 %
resistant_starch.csv : 0.33 %
excitotoxicity.csv : 0.33 %
ros.csv : 0.32 %
acetyl-coa.csv : 0.31 %
cyp1a1.csv : 0.29 %
...
....

 

[mariovitali]

My theory is that people who try CB and feel worse is because they lower TMAO. TMAO has great refolding capabilities (=it helps misfolded proteins to fold back correctly, thus saving the cell from UPR and ER Stress) BUT too much of TMAO is proatherogenic.

A growing number of biologically important proteins have been identified as fully unfolded or partially disordered. Thus, an intriguing question is whether such proteins can be forced to fold by adding solutes found in the cells of some organisms. Nature has not ignored the powerful effect that the solution can have on protein stability and has developed the strategy of using specific solutes (called organic osmolytes) to maintain the structure and function cellular proteins in organisms exposed to denaturing environmental stresses (Yancey, P. H., Clark, M. E., Hand, S. C., Bowlus, R. D., and Somero, G. N. (1982)Science 217, 1214–1222). Here, we illustrate the extraordinary capability of one such osmolyte, trimethylamineN-oxide (TMAO), to force two thermodynamically unfolded proteins to fold to native-like species having significant functional activity. In one of these examples, TMAO is shown to increase the population of native state relative to the denatured ensemble by nearly five orders of magnitude. The ability of TMAO to force thermodynamically unstable proteins to fold presents an opportunity for structure determination and functional studies of an important emerging class of proteins that have little or no structure without the presence of TMAO.

TMAO and Choline is lowered by butyrate :

An NMR-based metabolomics approach was used to investigate the differentiation between subjects consuming cheese or milk and to elucidate the potential link to an effect on blood cholesterol level. Fifteen healthy young men participated in a full crossover study during which they consumed three isocaloric diets with similar fat contents that were either (i) high in milk, (ii) high in cheese with equal amounts of dairy calcium, or (iii) a control diet for 14 days. Urine and feces samples were collected and analyzed by NMR-based metabolomics. Cheese and milk consumption decreased urinary choline and TMAO levels and increased fecal excretion of acetate, propionate, and lipid. Compared with milk intake, cheese consumption significantly reduced urinary citrate, creatine, and creatinine levels and significantly increased the microbiota-related metabolites butyrate, hippurate, and malonate. Correlation analyses indicated that microbial and lipid metabolism could be involved in the dairy-induced effects on blood cholesterol level.

Read more at: http://phys.org/news/2015-04-piece-french-paradox-puzzlecheese-metabolism.html#jCp

 

[Violeta]

Yes, I've just quoted that very same 2012 paper you quote in another thread. I found it confusing because this paragraph about Lupus is also from it:

IL-10 functions as a potent B cell stimulator that enhances activation, proliferation, and differentiation of B cells. This relates to SLE, which is characterized by high autoantibody production and decreased cellular immune responses. In SLE, high levels of autoantibodies generate immune complexes that exacerbate tissue damage. Compared with healthy individuals, levels of IL-10 in SLE patients are significantly higher and there is a correlation between IL-10 levels and clinical manifestation.77 Depletion of IL-10 by anti-IL-10 antibody in vitro treatment of SLE patient–derived PBMC significantly decreased autoantibody production.

I wonder if they are finding higher levels of IL 10 in SLE because of not distinguishing between human IL 10 and ebv IL 10. The reason I'm wondering that is because it doesn't appear that the IL 10 is reducing inflammation.

http://www.ncbi.nlm.nih.gov/pubmed/22692218

http://www.hindawi.com/journals/jir/2013/535738/

And ebv causes unfolded protein response.
"
Erle S. Robertson - 2010 - ‎Preview - ‎More editions
Lee, D.Y., and Sugden, B. (2008a). e LMP1 oncogene of EBV activates PERK and the unfolded protein response to drive its own synthesis. Blood 111, 2280–2289. Lee, D.Y., and Sugden, B. (2008b). e latent membrane protein 1 oncogene ...
Erle S. Robertson - 2010 - "

And then there's this, and the butyrate they are referring to is sodium/arginine butyrate, so I don't know if it applies to clostridium butyrate.
"Butyrate facilitates reactivation of latent EBV by allowing remodeling of the chromatin-like structure of the EBV genome, through its histone deacetylase (HDAC) inhibitory activity [67, 68]. The recent discovery that butyrate and other HDAC inhibitors (HDACi) can also induce demethylation and reactivation of methylated, silenced genes through repression of DNA methyltransferase 1 DNMT1 [69] may also contribute to their activity in inducing EBV lytic-phase gene expression. Combination therapy using a chemical inducer of EBV lytic-phase gene expression (arginine butyrate) and the anti-herpesvirus prodrug GCV was first tested on lymphoma cells derived from the EBV-positive lymphoma from a lung transplantation patient."

I don't know if anyone would find this interesting, but autoantibodies to IL 10, yikes.

http://www.ncbi.nlm.nih.gov/pubmed/24581234

What if that were going on in your vagus nerve?

 

[Gondwanaland]

BUT too much of TMAO is proatherogenic.

You can say that again

 

[Avengers26]

Do a lot of people here have increased IL10? I have several high viral titres. Am I understanding it right that high IL10 points more towards chronic infection than autoimmunity?

@mariovitali Where does histone deacetylase fit in this? I googled & see it's a class of enzymes. So, it's not a lab parameter. How can one correlate it's relevance to one's condition? Thanks.

If, TMAO is proatherogenic, then wouldn't vit K2 help with it?

Also, does that csv list indicate that there are that many % of pubmed studies which include both IL10 & the other parameter together? For eg, 0.6% of pubmed studies on benfotiamine mention IL10 in them.

 

[Bdeep86]

Anyone ever get constipation taking Clostridium butyricum?

 

[Sushi]

Anyone ever get constipation taking Clostridium butyricum?

Yes, and loss of appetite too.

 

[Bdeep86]

How long can it take for the constipation to subside, I quit taking it about 4 days ago and nothing is moving starting to get kind of concerned.

 

[Avengers26]

I am still on hold with miyarisan. I will probably add it back in the next 1-2 weeks. My sleep continues to be an issue. I am still looking into what other changes i might have made which might be contributing to it. On another note, i came across this article recently -

http://www.cortjohnson.org/blog/2015/03/09/being-patient-excited-institute-neuro-immune-medicine/

I felt it has a lot of important nuggets. Take for instance,

"For all the complexity of the immune networks Broderick has uncovered in ME/CFS, the good news is that they appear to be driven by just a few factors. Impacting just a few cytokines might allow him to impact large immune networks that are responsible for producing the pain, fatigue, etc. we are experiencing. Broderick’s ability to tease out these factors suggests that relatively small tweaks could have significant effects on our health."

Also, this -

"He has a list of 16 cytokines all of which may respond to IL-2 modification in ME/CFS. Then there’s IL-15 – an NK cell activator – which keeps showing up. The combination that’s performed best for him is an IL-2 and IL-17 one-two punch. First you take down IL-2 and then you pump up IL-17. According to his models that should help ME/CFS patients recover from exercise. In fact, his models indicate they might get them very close to having a normal response to it. Then there are the sex hormones. Their role in modulating the immune system has turned out to be surprisingly significant. Broderick’s is trying to put it all together. His models right now are suggesting he can get the system back to normal – for a while – but then the effect fades."

I have high IL2.

 

[out2lunch]

Yes, and loss of appetite too.

Sushi and other CB supplementers… any idea why it promotes constipation? Do you folks have any other constipation-related symptoms with other probiotics? Or just this one?

I started CB/Miyarisan over the weekend; started w/one tablet, held at two tablets for a few days, went to three this AM. I've been cursed with IBS-C for several decades, but CB doesn't seem to be making this worse, at least so far. Perhaps my dose is too low?

Just curious where the tipping point is/was for fellow CB users. Thanks!

 

[Scarecrow]

@out2lunch You may find it improves your IBS-C.

I can very nearly tell the time now just from my bowels!

 

[Bdeep86]

@out2lunch Careful increasing and keep an eye on your movements because it wasn't having much of an effect on me then all of a sudden it hit me like a ton bricks with constipation.

 

[Sushi]

Sushi and other CB supplementers… any idea why it promotes constipation? Do you folks have any other constipation-related symptoms with other probiotics? Or just this one?

For me, just this one.