TUDCA dampens neuroinflammation

[S-VV]

Tauroursodeoxycholic acid reduces glial cell activation in an animal model of acute neuroinflammation
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4000131/

"TUDCA specifically reduces microglial reactivity in the hippocampus of mice treated by icv injection of LPS. TUDCA treatment reduced the production of nitrites by microglial cells and astrocytes induced by proinflammatory stimuli that led to transcriptional and translational diminution of the iNOS. This effect might be due to inhibition of the NFκB pathway, activated by proinflammatory stimuli. TUDCA decreased in vitro microglial migration induced by both IFN-γ and astrocytes treated with LPS plus IFN-γ. TUDCA inhibition of MCP-1 expression induced by proinflammatory stimuli could be in part responsible for this effect. VCAM-1 inmunoreactivity in the hippocampus of animals treated by icv LPS was reduced by TUDCA treatment, compared to animals treated with LPS alone."

'TUDCA is a neuroprotective agent in different animal models of stroke and neurological diseases. Nevertheless, little is known about the anti-inflammatory properties of TUDCA in the CNS. Our results suggest that TUDCA reduced glial cell activation induced by proinflammatory stimuli through inhibition of NFκB activity. TUDCA has a triple inhibitory effect on glial cells in the CNS parenchyma, inhibiting NFκB by i) reducing glial cell activation, ii) reducing microglial cell migratory capacity, and iii) reducing the expression of chemoattractants (e.g., MCP-1) and vascular adhesion proteins (e.g., VCAM-1) required for microglial migration and blood monocyte invasion of the CNS inflammation site. Our results suggest a novel TUDCA anti-inflammatory mechanism with therapeutic implications for inflammatory diseases of the CNS."

The figures in the study are well worth a watch. T/UDCA, which accounts for 50% of the bike on bears, has been suggested as a factor that allows them to survive hibernation.

 

[ljimbo423]

It looks like TUDCA is also good for dysbiosis and a leaky gut. Many studies have shown both a leaky gut and dysbiosis in ME/CFS.

I think it's very possible it's these dysfunctions that lead to the neuro-inflammation Jarred Younger has found. TUDCA is now on my list of supplements to buy! It's expensive but it might be worth it.

Tauroursodeoxycholic acid inhibits intestinal inflammation and barrier disruption in mice with non-alcoholic fatty liver disease.

Abstract
BACKGROUND AND PURPOSE:
The gut-liver axis is associated with the progression of non-alcoholic fatty liver disease (NAFLD). Targeting the gut-liver axis and bile acid-based pharmaceuticals are potential therapies for NAFLD.

The effect of tauroursodeoxycholic acid (TUDCA), a candidate drug for NAFLD, on intestinal barrier function, intestinal inflammation, gut lipid transport and microbiota composition was analysed in a murine model of NAFLD.

EXPERIMENTAL APPROACH:
The NAFLD mouse model was established by feeding mice a high-fat diet (HFD) for 16 weeks. TUDCA was administered p.o. during the last 4 weeks.

The expression levels of intestinal tight junction genes, lipid metabolic and inflammatory genes were determined by quantitative PCR. Tissue inflammation was evaluated by haematoxylin and eosin staining.

The gut microbiota was analysed by 16S rRNA gene sequencing.

KEY RESULTS:
TUDCA administration attenuated HFD-induced hepatic steatosis, inflammatory responses, obesity and insulin resistance in mice.

Moreover, TUDCA attenuated gut inflammatory responses as manifested by decreased intestinal histopathology scores and inflammatory cytokine levels. In addition, TUDCA improved intestinal barrier function by increasing levels of tight junction molecules and the solid chemical barrier.

The components involved in ileum lipid transport were also reduced by TUDCA administration in HFD-fed mice. Finally, the TUDCA-treated mice showed a different gut microbiota composition compared with that in HFD-fed mice but similar to that in normal chow diet-fed mice.

CONCLUSIONS AND IMPLICATIONS:
TUDCA attenuates the progression of HFD-induced NAFLD in mice by ameliorating gut inflammation, improving intestinal barrier function, decreasing intestinal fat transport and modulating intestinal microbiota composition.

https://www.ncbi.nlm.nih.gov/pubmed/29139555

 

[wigglethemouse]

According to the recent Hanson metabolic paper patients have higher levels of TUDCA

All the other metabolites identified in the volcano plot had higher abundances in patients
compared to controls (Figure S1). These included tauroursodeoxycholate (TUDCA), reported both as a
cytoprotective agent and a chemical chaperone;

 

[ljimbo423]

According to the recent Hanson metabolic paper patients have higher levels of TUDCA

I couldn't find in that paper how much higher TUDCA was in ME/CFS. Was it high enough to be at a therapeutic level? I think the study also needs to be replicated for it to be considered a valid finding. I think it's still possible that higher levels of TUDCA could be beneficial.

@mariovitali , got big benefits from TUDCA. I think he even considers it one of the main reasons he went into full recovery. Although I think his view is that it helped support his liver and that lead to his recovery.

 

[wigglethemouse]

I couldn't find in that paper how much higher TUDCA was in ME/CFS.

Hansons paper has a supplementary data section with a hyperlink to zipped raw data in an Excel file. Here is TUDCA plotted (C=Control, P=Patient).

Looking at the raw data has been an eye opener. When you closely look at the data in ME/CFS biological research papers you see only a subset of patients are outside the control range (except for the recent RBC deformability paper, but that was a low number of patients). At quick glance of an abstract you think trends refer to all patients. Teasing out subsets is going to be important. To do that we need much larger cohorts as 32 patients is not enough.

 

[Celandine]

Could it be that the higher levels observed in patients is the body trying to help itself? But maybe there's no way to make enough so supplementation could help. Maybe the high levels are a signpost for what the body wants/needs? Disclaimer: I have very limited understanding of the biology here!

 

[wigglethemouse]

Here is a plot with the y-axis limited arbitrarily.

Rough percentages of those > 80,000
Controls 2 out of 19 = 11%
Patients 14 out of 32 = 44%

 

[wigglethemouse]

Could it be that the higher levels observed in patients is the body trying to help itself? But maybe there's no way to make enough so supplementation could help. Maybe the high levels are a signpost for what the body wants/needs? Disclaimer: I have very limited understanding of the biology here!

Interesting thought.

Wikipedia has this interesting snippet. I wondered what chemical chaperone was when mentioned in the Hanson paper

Apoptosis, or programmed cell death, is largely influenced by the mitochondria. If the mitochondria are distressed, they release the molecule cytochrome C (cyC). Cytochrome C initiates enzymes called caspases to propagate a cascade of cellular mechanisms to cause apoptosis. TUDCA prevents apoptosis with its role in the Bax pathway. Bax, a molecule that is translocated to the mitochondria to release cytochrome C, initiates the cellular pathway of apoptosis.[5] TUDCA prevents Bax from being transported to the mitochondria. This protects the mitochondria from perturbation and the activation of caspases.[7] TUDCA acts as a chemical chaperone.

Link : https://en.wikipedia.org/wiki/Tauroursodeoxycholic_acid

 

[S-VV]

Yes, tudca is related to apoptosis inhibition. It's does this mainly by suppressing ER stress. In fact, it's so good at suppressing apoptosis, that you can get anomalous cell growth from too much tudca:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3168684/

High-Dose Ursodeoxycholic Acid Is Associated With the Development of Colorectal Neoplasia in Patients With Ulcerative Colitis and Primary Sclerosing Cholangitis

 

[S-VV]

Could it be that the higher levels observed in patients is the body trying to help itself? But maybe there's no way to make enough so supplementation could help. Maybe the high levels are a signpost for what the body wants/needs? Disclaimer: I have very limited understanding of the biology here!

I though that too, but in humans tudca is only synthesized by gut bacteria. The question then becomes if the body can selectively absorb tudca over other bile acids, or if elevations in tudca reveal elevations in whole bile acids

 

[S-VV]

Hansons paper has a supplementary data section with a hyperlink to zipped raw data in an Excel file. Here is TUDCA plotted (C=Control, P=Patient).
View attachment 30843

Looking at the raw data has been an eye opener. When you closely look at the data in ME/CFS biological research papers you see only a subset of patients are outside the control range (except for the recent RBC deformability paper, but that was a low number of patients). At quick glance of an abstract you think trends refer to all patients. Teasing out subsets is going to be important. To do that we need much larger cohorts as 32 patients is not enough.

YESS. Take for example the new transcriptome study they did.

https://journals.sagepub.com/doi/abs/10.1177/2058738418820402

Most of the pwME are WITHIN the range.

These are the genes for which they found the *biggest* difference

 

[mariovitali]

I wanted to give my two cents in this thread and i hope that Ron Davis through @Janet Dafoe (Rose49) is still listening :


1) First of all TUDCA is used for cholestasis. It is the same compound as UDCA but with a Taurine molecule added.

I believe that the paper from Hanson is important in many ways despite its small sample. Of course, findings need to be replicated on a much larger sample.

I believe though that there are many "signals" that point towards liver function. I recently made a presentation in London at a EUROMENE meeting where i described my hypothesis that a Liver Injury is responsible for setting the stage of ME/CFS ( and also other syndromes such as Gulf war ilness syndrome, Post Accutane syndrome and others).


2) Let's see some interesting findings from Hanson's work. We see that Bile acid metabolism is being disrupted and signs of Liver damage :

3) What is the common factor of EBV, Cytomegalovirrus, HHV-6, echovirus, Parvovirus B19? They are all Hepatotropic viruses which means that they can disrupt liver function and cause liver injury :

4) Also incidentally (?) when an infection of a virus occurs we have Endoplasmic reticulum stress (ER Stress) taking place and TUDCA as a chaperone ameliorates it (please see that two causes of ER stress are viral infections and chemical insults) below :

5) Moreover 3 new research papers (for ME/CFS, Fibromyalgia and Gulfwar Ilness) may be pointing our attention to the Liver :


https://www.s4me.info/threads/chang...-me-cfs-2019-sweetman-et-al.7694/#post-136218


and


https://www.s4me.info/threads/gulf-...oblem-2018-mawson-and-croft.7533/#post-133877


and


https://www.s4me.info/threads/a-pre...controls-2018-saliqan-et-al.7239/#post-129182

 

[S-VV]

Hey @mariovitali , I have been following your research on the forums and algogenomics for quite some time. It's very interesting.

In fact, I just saw this study about FM patients and thought about you:

A predictive algorithm to identify genes that discriminate individuals with fibromyalgia syndrome diagnosis from healthy controls

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6255277/

But I do have a problem. How does liver damage translate to fatigue and low levels of erratic inflammation? I say erratic because no study to date has been able to pinpoint an inflammatory profile for me cfs

 

[pattismith]

Hey @mariovitali , I have been following your research on the forums and algogenomics for quite some time. It's very interesting.

In fact, I just saw this study about FM patients and thought about you:

A predictive algorithm to identify genes that discriminate individuals with fibromyalgia syndrome diagnosis from healthy controls

you missed it:

https://forums.phoenixrising.me/ind...individuals-with-fibromyalgia-syndrome.62536/

 

[S-VV]

Whoops

 

[pattismith]

 

[prioris]

TUDCA does practically the same thing as UltraThistle silybin. It is for therapeutic purposes and powerful. It is mainly designed to keep bile clean of sludge. Either is good. If bile becomes too sludgy, it can cause liver, gallbladder and pancreas problems. I use either of those daily to keep any potential bile problems at bay.

Nice thing about TUDCA is that it is able to piggyback off the pharmaceutical research of UDCA too. Silybin research won't get much funding.

 

[mariovitali]

Hey @mariovitali

But I do have a problem. How does liver damage translate to fatigue and low levels of erratic inflammation? I say erratic because no study to date has been able to pinpoint an inflammatory profile for me cfs

This is a very good question and i tried looking at what actually causes fatigue.

First we look at a post of a user called "Andy" in S4ME where he states that his fatigue is significantly better after he widened his bile ducts :

https://www.s4me.info/threads/gulf-...oblem-2018-mawson-and-croft.7533/#post-133946



Here is an interesting paper from which i provide some interesting -IMO- excerpts :

https://pmj.bmj.com/content/78/921/404

There is evidence to show that fatigue is associated with an altered serotoninergic neurotransmission. Fatigued rats during prolonged exercise have raised levels of brain 5-hydroxytryptamine (5HT) and treatment with a 5HT2 antagonist prolonged the exercise period, whereas treatment with a 5HT agonist shortened the exercise period.39 Serotonin reuptake inhibitor (paroxetine), that acts as a serotonin agonist centrally, does indeed decrease exercise tolerance in male athletes.40 Altered serotoninergic neurotransmission has also been implicated in the pathogenesis of fatigue in diseased states like chronic fatigue syndrome and postviral fatigue.23,24

It is important to understand the pathogenesis of fatigue in cholestatic liver disease before any therapeutic breakthrough can be achieved. The role of serotoninergic neurotransmission, IL-1 and nitric oxide in the pathogenesis of fatigue, as suggested in rat experiments, may provide a rationale for treatment in future as these can be modulated using specific antagonists. In this respect, the reports of reversal of fatigue in cholestatic rats using 5-HT1A receptor antagonist33 and similarly, reversal of sickness behaviour using IL-1ra29 are encouraging.

Antioxidants were found to reduce fatigue in a pilot study.59 However, the role of antioxidants in amelioration of fatigue needs further evaluation by larger controlled trials.

Tagging also @ScottTriGuy for this :


On my recent presentation at the EUROMENE i specifically mentioned the possibility that a trial using a personalised regimen must take place. This regimen is directed to manage problems on certain biological pathways on a patient level and create the necessary environment for recovery using supplementation and treating any underlying disorders that impair liver / gallbladder function.

I believe it is interesting that Hanson found impaired bile acids metabolism -as well as Naviaux- and that fatigue is a major symptom of cholestasis (=increased total bile acids). I can confirm that some ME Patients were found having increased total bile acids hence we need to see if this holds on a larger ME patient cohort.

For the inflammation part, i do not know the answer unfortunately. What i can say anecdotally is that i had flare ups on places where inflammation i knew existed in my body : In specific points at my gums, a tooth that has root inflammation -confirmed by X ray testing- i would feel pain whenever i had other ME symptoms. I do not think this is a coincidence at least for me.

 

[prioris]

the major problem is NOT too much bile ... but too little ... it's great they had increased bile acids ... maybe they were taking supplements for their liver too ... too little bile will reverberate negatively to other organs downstream ... it's dead end research ...

bile is what keeps the liver gallbladder bile duct pancreas clean of cholesterol build up ... once cholesterol makes it to intestine, a lot of health problems have been removed ... 4 organs are much healthier ... then cholesterol can do it's job of keeping a person healthy ... the more cholesterol a person has correlates with a longer lifespan ... the less cholesterol they have, the faster they die ...

reminds me of research where they find increased hyaluronic acid with so and so condition so they conclude that HA is be bad for people with so and so ... noooooo .... the conclusions of this research is a dead end too

 

[perrier]

So is it advisable to try to take TUDCA or say, milk thistle.

This illness has driven me around the bend, truly. We try all kinds of supplements, have tall towers of supplements, and nothing changes things into a positive direction.