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
Naltrexone, an opioid receptor antagonist, attenuates liver fibrosis in bile duct ligated rats
Lactobacillus GG Treatment Ameliorates Alcohol-induced Intestinal Oxidative Stress, Gut Leakiness, and Liver Injury in a Rat Model of Alcoholic Steatohepatitis
(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.
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.
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.
Probiotics in the treatment of the liver diseases.
Source
Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Louisville, KY 40202, USA.
Abstract
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.
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):