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Sunday, 24 March 2013

More lessons from Naltrexone and TLR4; Astragalus

The naltrexone story I covered in the last post has turned up other insights into its mode of action in Hepatitis C.

(music: Steely Dan live from 1974)

Most importantly, naltrexone is antifibrotic. TLR4 agonism stimulates the activation of hepatic stellate cells (HSC) into myofibroblasts that lay down collagen-rich matrix all over the place like a one-armed plasterer on meth. A little of this is part of the repair process but excess is like DIY repairs gone bad. Sooner or later there's so much plaster you can't get in or out of your own cells. Hilarity doesn't ensue.

Mechanisms of Hepatic Fibrogenesis

Among the most compelling pathways of injury are those recently uncovered for innate immune signaling in liver. Specifically, the discovery of TLRs has led to major advances in understanding how the human organism responds to pathogens. The identification of TLR4, the receptor for bacterial lipopolysaccharide, on Kupffer cells, was therefore not a surprise, but its expression on stellate cells was unexpected. Moreover, although TLR4 signaling in macrophages may be essential for inflammatory responses, recent studies have indicated that signaling by stellate cells in response to lipopolysaccharide and possibly endogenous ligands of TLR4 (eg, high-mobility group box 1, biglycan, and heparan sulfate) may be more important than in Kupffer cells in eliciting a fibrogenic response by down-regulating bone morphogenic protein (BMP) and activin membrane-bound inhibitor, a transmembrane suppressor of transforming growth factor β1 (TGFβ1), which is the major fibrogenic cytokine in the liver. This finding has converged with evidence that specific single-nucleotide polymorphisms of TLR4 contribute to the rate of fibrosis progression in HCV infection, thereby linking a genetic risk marker to disease pathogenesis.

Naltrexone prevents gliosis (inflammation of neuroglial cells) caused by opiates through TLR4 agonism. HSCs are hepatic glial cells. Glial cells are "caretaker" cells that protect and repair nerves, blood vessels and the like and maintain the appropriate spaces between cells and the extra-cellular matrix. So this link between gliosis and fibrosis doesn't surprise me. Even in the dizzying and scarcely ever linear world of immunology, sometimes the correct answer can be the simplest.

What are the relevant TLR4 agonists in liver fibrosis? Lipopolysaccharide (LPS) from gram-negative bacteria, and alcohol. Opiates too maybe (methadone use is associated with fibrosis in Whites Only in this study, but methadone can always be either substituting for, or encouraging the use of, something worse).

Naltrexone antagonizes TLR4 and increases receptor numbers (decreasing sensitivity).

Naltrexone, an opioid receptor antagonist, attenuates liver fibrosis in bile duct ligated rats

This is the first study to demonstrate that administration of an opioid antagonist prevents the development of hepatic fibrosis in cirrhosis. Opioids can influence liver fibrogenesis directly via the effect on HSCs and regulation of the redox sensitive mechanisms in the liver.
Comparative Study between the Effect of Atorvastatin and Naltrexone on Hepatic Fibrosis Induced by Bile Duct Ligation in Rats (pdf)
Another TLR4 antagonist seems to be the polysaccharide-A from astragalus root. Astragalus is a common Chinese herb which is well-tolerated and used in many anti-inflammatory preparations including liver-protecting and immune-boosting formulas. I like it myself and have had good results with either astragalus alone, or a mixture of astragalus and the super-weird cordyceps fungus, which also contains an active polysaccharide but much else besides.

TLR4 expression in chronic UTI patients after astragalus treatment was higher than pre-treatment.
The pattern with these agents seems to be that sensitivity to "bad" LPS is reduced, but that macrophage activity is enhanced. This should see some clearing of the immune complexes (cryoglobulinaemia) associated with hepatitis C and a reduction in the various extra-hepatic autoimmune symptoms they cause. Hepatic LPS sensitivity is also reduced by the presence of highly-saturated fats in the diet (beef tallow, coconut oil, etc) and the restriction of polyunsaturated fatty acids.

Probiotics (such as the anti-inflammatory Rhamnosus LGG) have a comparable  effect on TLR4: activation after LPS exposure is decreased.
LGG attenuates LPS induced inflammation, and this may be associated with TLR4/NF-κB down-regulation.

Lactobacillus GG Treatment Ameliorates Alcohol-induced Intestinal Oxidative Stress, Gut Leakiness, and Liver Injury in a Rat Model of Alcoholic Steatohepatitis

I think it's a good idea to take probiotics if you have hepatitis C, and the L. Rhamnosus plus Reuterii combination was my favourite long before I knew this TLR immunology stuff.
J Am Coll Nutr. 2012 Feb;31(1):14-23.
Probiotics in the treatment of the liver diseases.
Kirpich IA, McClain CJ.


Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Louisville, KY 40202, USA.


The concept that interactions between the gut, the liver, and the immune system play an important role in liver diseases is an old concept that has recently seen a resurgence in interest. Altered intestinal bacterial flora and gut-associated endotoxemia are increasingly recognized as critical components in both nonalcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD). Probiotics have been proposed in the treatment and prevention of many conditions, including the liver diseases. Probiotics are live microorganisms that, when consumed in adequate amounts, confer a health benefit to the host. There are many mechanisms by which probiotics enhance intestinal health and influence the gut-liver axis, including modulation of the intestinal microflora, modification of intestinal barrier function, and immunomodulation. The present review summarizes the recent studies highlighting the role of the intestinal microflora in the development of NAFLD and ALD and the potential efficacy of probiotics as a therapeutic strategy for liver diseases.

Oh, BTW, what's another TLR4 antagonist? Niacinamide (nicotinamide). I've told you that's antifibrotic in an earlier post, for quite different reasons.
I could go on all day, all year maybe, but I have stuff to do now.
Cordyceps in action (The one in this video is a relative of C. Sinensis, the herbal one, which parasitizes Tibetan moth larvae):



Puddleg said...

Hepatology. 2013 Jan 8. doi: 10.1002/hep.26234. [Epub ahead of print]

TLR4 activity protects against hepatocellular tumorigenesis and progression via regulating the expression of DNA repair protein Ku70(1).

Hepatocellular carcinoma (HCC) is a devastating consequence of chronic inflammatory liver diseases. We recently find that inhibition of TLR4 promotes tumor metastases. We aimed to investigate whether TLR4 activity contributes to HCC initiation and progression in mice. A mouse model of diethylnitrosamine (DEN)-induced HCC was generated with wild type and TLR4 mutant mice and the development and progression of HCC and senescent responses were assessed by morphologic, immunological and biochemical criteria. We found that genetic or pharmacologic blocking of TLR4 increased susceptibility to DEN-induced HCC carcinogenesis and progression, which was indicated by the increases in tumor nodules, tumor volume and animal death. The enhanced HCC associated with a broad-spectrum reduction of immune response to DEN liver injury as indicated by decreases in the liver-infiltrating F4/80+ macrophages, the ASK1/p38 MAPK/NF-κB and IRF3 signaling activities, and the expression of inflammatory cytokines. Suppressed immune networks resulted in a halt of cellular senescence induction in TLR4 mutant liver tissue, which promoted proliferation and suppressed programmed cell death. Moreover, TLR4 mutation resulted in a suppressed capacity of DNA repair due to a decrease in TLR4-mediated expression of DNA repair proteins Ku70/80 in liver tissue and cells. Isotopic expression of Ku70 in TLR4 mutant mouse restored senescence and interrupted the positive feedback loop of DNA damage and oxidative stress, which reversed TLR4 mutation-deteriorated HCC carcinogenesis and progression.
CONCLUSIONS: TLR4 plays an integrated defense role against HCC carcinogenesis by enhancing the expression and function of DNA repair protein Ku70. Our studies provide novel insights into understanding of TLR4 activity in the regulation of HCC tumorigenesis which may be useful for the prevention of HCC development. (HEPATOLOGY 2013.).

Peter said...

Excellent George. I keep being driven to the importance of fibroblasts in cancer nourishment and PUFA in the same, especially in the liver. This is all way above the level of physiology I've been picking at for the last few months but you can see how they might fit together...


Puddleg said...

Indeed I do.
Both PUFA and carbohydrate seem to be drivers for these processes.
FFAs are TLR4 ligands hence DM2 is an added risk factor.
NF-kappa beta downstream from TLR4is driven by mito ROS...

Puddleg said...

LPS is implicated in elevated ferritin:

Cytokines also regulated ferritin postranscriptionally. In the Hep G 2 hepatic cell line, induction of ferritin synthesis was observed with a number of cytokines: IL-Iβ, IL-6, TNF-α [2324].

Secretion of ferritin is stimulated by cytokines. In primary cultured human hepatocytes, IL-1α and IL-6 induced a transient secretion of ferritin at 24 hr followed by a decline to baseline, whereas TNF treatment result in a sustained increase in ferritin secretion, reaching a level 10 times that found in untreated cells. Cytokines play a pivotal role in the cellular response to infection and ferritin plays a prominent role in the cytokine response. Lipopolysaccharide (LPs), a component of the outer membrane of gram-negative bacteria, elicits a variety of reactions that involve ferritin LPS administered endotracheally to rats induced ferrritin protein expression.

Insulin also promotes ferritin expression.

Un Kim said...

Hi George, you suggest that red meats are protective of liver disease. However, red meats are rich in iron, which we all know promote the progression of chronic hepatitis (apparently, the hepatitic viruses will try to raise your iron stores). Can you explain why you recommend consumption of red meats (i.e beef)?

This is not an attack, but just my expression of concerns. I am recenlty limiting my consumption of red meat, and try to get saturated fat from dairy sources.

Puddleg said...

This is a good point Un Kim.
I recommend consumption of beef and lamb fat (dripping) or dairy fat(I see them as interchangable, fat is better than butter for some types of cooking). As for meat, I tend to follow the Perfect Health Diet protein recommendations these days. So I might have 2 bacon rashers with breakfast and one large chop at dinner; most calories would come from fats including cream and butter used to cream puree and sautee vegetables. I choose fattier meats like lamb. I would have red meats for dinner perhaps 4 nights a week.
I did eat much more meat at one time, but my ferritin rose above 200, it is decreasing now. Like you I find dairy fats a great source of energy, and limit meat to my protein needs. I also eat fish, pork, eggs, chicken, tahini, cheese, offal, and occasionally well-cooked dahl as protein foods.

Puddleg said...

Most of the benefit of the red meat is probably due to its fat, but it is also a source of zinc and selenium, carnitine and carnosine, and omega 3s.
Iron is just one factor, and though I like to see it low, I don't want to give it too much importance if everything else is going fine.

karismac said...

Hi George,

Thank you so much for all of your recommendations on this blog. You have really done your research.

I have commenced a high fat very low carb diet, am taking spirulina every day and have thrown out the brahmi supplements I was taking that had Ginko and B6 (pyridoxin) in them along with eating breakfast. I am eating a lot of lamb, pate, avocados, eggs, mackerel and other great food. (I cheat and have a carb meal once a week)

I feel great and have a very good feeling about this regime but as I cannot understand any of this article above I wonder if you can tell me - should I be asking my doctor if she will put me on lose dose Naltrexon? I also wonder if I should be taking Niacin?

I used to take about 250 mg a day but I have run out and don't know what you think about Niacin and the dosage?

I also have asthma but can't bring myself to consider eating shit!!!! I wish I had a well :-)

Anyway thanks again- you are a real life saver.

karismac said...

Oh and I am taking Selinium, ALA, Milk thistle, Calcium magnesium vitamin D and C. I will also start taking E again soon when I find a good mixed tocoferols one.
I don't know what my viral load is yet but am asking the doctor on Monday.

Puddleg said...

My own experience has been that niacin or niacinamide are fine to take. Just stay away from high-dose time-release niacin. Niacinamide has an antifibrotic profile, the way niacin works is more obscure but it can definitely help at lower doses (such as 250mg a day). The no-flush niacin is good too. It's not essential but OK if it works for you, especially around moods, comfort, and (niacinamide) sleep.

The article is technical background stuff and relates more to good probiotics, some herbs like astragalus/cordyceps, and getting the right fibre (and amount thereof) for your needs.
Naltrexone is especially valuable when HCV causes autoimmune problems, mood problems, low immunity.

karismac said...

Thanks George, Yes probiotics are great and I found the strain you recommend in Vaalia yoghurt and am culturing it myself with raw milk. That and the Spirulina are so potent - who needs drugs when you can feel like superman everyday :)

I wonder is asthma an auto immune disease? Do you think low dose Naltrexone would help with that?

Anyway thanks again for all your amazing research and I like the music too :) I used to sing in a post punk band back in the day - good to see that some folk are still at it!

Puddleg said...

Yes asthma is an auto-immune disease. It is rare in children raised on farms who are exposed to more microbes, and in people who test positive for hepatitis A. A dirtier lifestyle might protect against it.
TLR2 and TLR4 are involved which are targets of spirulina (TLR2) and probiotics (TLR2 and TLR4), but experiments with probiotics don't produce much result except in newborns. Hopefully shifting to a lower-carb, more saturated fat diet will help, as breathing is one of the areas that benefits. On a high-fat diet cellular respiration produces less CO2 (per calorie) so the impulse to exhale is lessened and breathing can be slower and steadier.

karismac said...

Okay what you say about the C02 explains something weird I had noticed since going on the high fat low carb diet.

The best help I have had with breathing is a site you might like

The Russian doctor whose site that is teaches that C02 actually heals our lungs and allows our blood to carry more oxygen. So doing his exercises I had already slowed down my breathing by raising my bodies natural trigger level to C02. I guess a way to describe it would be that I have trained myself to be tolerant to higher levels of C02, which has helped my lungs and slowed down my breathing.

So when I started this diet a few weeks ago I noticed right away that to get the same breath holding time each day only took me about 5 minutes instead of 12.

I don't really enjoy the exercise so I thought oh great I am done now and I have just been stopping when my breath holding time gets to the same duration that it used to after 12 minutes.

But even though my breath holding time (or it is also called your control pause -- meaning how long a time you can pause with your lungs empty between breaths) is higher than ever my lung inflammation (asthma) has been worse than it has been in a long time.

So what you say explains all of that. Since you say my respiration is producing less C02 I will still need to do the exercises for the full 12 minutes and expect my breath holding time to be much higher than before to get the same positive results for my lung inflammation.

I am getting up to about 50 seconds right now - so I will see how high my BHT gets when I start doing the full exercise again. I have never been over a minute so this will be interesting.

BTW - This is not the amount of time you can hold your breath once - but repeatedly with controlled breathing. When I started the exercises a year ago my BHT was only about 9 seconds!

Anyway I thought I would share this in case anyone with asthma on this diet finds it useful.

Hey but George you haven't mentioned LDN and if you think it is worth trying for my asthma? I have a friendly doctor now but I would still have to give her some research etc. as to why I want to try it.

Normally I avoid prescription drugs unless they are absolutely necessary but I have heard so much about LDN being a wonder cure for so many things I can't help but be curious?

Puddleg said...

That's very interesting. Asthma may be worse because you are introducing more of some allergen (dairy protein, milk white, beef) you avoided before. Or because there are cells dependent on glucose and carbs are too low to feed these (if you are very low-carb it might take time to adjust, it's often not easy nor necessary to go very low).
LDN I can't find much data on LDN and asthma. In theory it could help, and it's not very toxic even at normal high doses. Some good data here:

Orthomolecular treatment of asthma uses high-dose vitamin C: 1,000mg per hour until "bowel tolerance". I don't know anyone who's tried this. Most of my friends smoked pot for it.

Puddleg said...

Sorry I meant "egg white", a common allergen (unfortunately).

karismac said...

Cool I will have a look at the link.

Your hypothesis about possible increase in allergens in my diet is sound - but I don't think it is the problem. It may be that the last batch of Natto I made has gone a bit mouldy (I am throwing it out and starting over tomorrow) but my main allergy is dust mites which often play up when getting blankets and jumpers out of storage. Still I think the C02 factor could be a part of it. The Exercises they teach on are pretty amazing so I will go back to doing them religiously and let you know what happens. I went from someone whose loud breathing used to draw a lot of embarrassing comments and who was bed ridden a lot of the time with allergies and flu symptoms to being very active all day and my breathing being nearly invisible (and hardly ever using my puffer). I am sure I can get back there - I just needed that key bit of info (about the C02) you gave me to get me doing the exercises properly again. It is a PITA to do every day but well worth the benefits!

I stopped smoking anything last time I had pneumonia from smoking only one joint after nearly two years off it! I know people say smoking pot helps but they must not have the same kind of lung disease I do!

Puddleg said...

Have a look at this.
it would be much better with butter and marge consumption split into quintiles or other groupings, the method they use doesn't tell us much.
But still.

karismac said...

Wow - what a shame I ate so much margarine as a child! Pity that not having eaten it for the past 20 years hasn't fixed the damage done :(