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Tuesday, 22 October 2013

How do you fix a leaky gut? New twists on old ideas.

Leaky gut, AKA intestinal permeability, is one of the determining factors in diseases of the liver, which should be tolerant of the normal adaptive quantities of lipopolysaccharides (LPS, fragments of Gram-negative bacterial cell walls) that reach it (other parts of the immune system need to be more sensitive to LPS). If too much LPS reaches the liver because the gut barrier is weakened, or if the liver is made over-sensitive to LPS by factors such as steatosis and cholesterol accumulation, LPS activation of TLR4 can set in motion the immune cascades that lead to fibrosis and necrosis.

TLRs are sensors that amongst other things help orchestrate responses to both potential pathogens and symbiotic organisms. Having just had to replace one of the many sensors in my car that keeps the engine in tune and alerts me to problems, I'm thinking that might be an acceptable analogy for now. A defective sensor crippling the engine to alert me to a problem that doesn't exist is a bit like an allergic reaction, maybe.

Gut integrity is modulated by TLR2

Our findings suggest that dietary saturated fat plays a protective role against MCDD-induced steatohepatitis, whereas TLR-2 deficiency exacerbated NASH. The mechanism underlying the response to dietary fat and TLR-2 likely involves altered signalling via the TLR-4 pathway.

TLR2 is activated by saturated fat, inhibited by polyunsaturated fat.

Dietary saturated fat protects against LPS (endotoxin) activation of TLR4 in hepatic immune cells, but different SFAs achieve this in different ways.

 2013 Oct 10. [Epub ahead of print]

Dietary fat sources differentially modulate intestinal barrier and hepatic inflammation in alcohol-induced liver injury in rats.

Zhong W, Li Q, Xie G, Sun X, Tan X, Sun X, Jia W, Zhou Z.


1University of North Carolina at Greensboro.


Endotoxemia is a causal factor in the development of alcoholic liver injury. The present study aimed at determining the interactions of ethanol with different fat sources at the gut-liver axis. Male Sprague Dawley rats were pair-fed control or ethanol liquid diets for 8 weeks. The liquid diets were based on the Lieber-DeCarli formula, with 30% total calories derived from corn oil (rich in polyunsaturated fatty acids). To test the effects of saturated fats, corn oil in the ethanol diet was replaced by either cocoa butter (CB, rich in long chain saturated fatty acids) or medium chain triglycerides (MCT, exclusively medium chain saturated fatty acids). Ethanol feeding increased hepatic lipid accumulation and inflammatory cell infiltration, and perturbed hepatic and serum metabolite profiles. Ethanol feeding with CB or MCT alleviated ethanol-induced liver injury and attenuated ethanol-induced metabolic perturbation. Both CB and MCT also normalized ethanol-induced hepatic macrophage activation, cytokine expression and neutrophil infiltration. Ethanol feeding elevated serum endotoxin level, which was normalized by MCT but not CB. In accordance, ethanol-induced downregulations of intestinal occludin and ZO-1 were normalized by MCT but not CB. However, CB normalized ethanol-increased hepatic endotoxin level in association with upregulation of the endotoxin detoxifying enzymes argininosuccinate synthase 1 (ASS1). Knockdown ASS1 in H4IIEC3 cells resulted in impaired endotoxin clearance and upregulated cytokine expression. These data demonstrate that the protection of saturated fats against alcohol-induced liver injury occur via different actions at the gut-liver axis and are chain length dependent.

Meaning: Coconut oil MCTs (also found in butter/ghee and palm oil) normalised serum LPS level by repairing gut integrity, whereas cocoa butter protected the liver by enhancing the clearance or detoxification of LPS.
Spirulina is a TLR2 agonist and protects against inflammation in chronic hepatitis C. Probiotic (Gram-positive) bacteria also protect the intestinal epithelium via TLR2;

All the Gram(+) strains increased the number of TLR-2+ cells and the Gram(−) strains [
increased the number] of the TLR-4+ cells. 
VSL#3 is a popular probiotic mix approved for medical use in Europe ("VSL#3 is a probiotic  mixture which has been frequently referred to in the literature, and contains live lyophilized  Bifidobacterium breve, Bifidobacterium longum, Bifidobacterium infantis, Lactobacillus  acidophilus, Lactobacillus plantarum, Lactobacillus paracasei, Lactobacillus bulgaricus and  Streptococcus thermophilus.").
Here is a very interesting new paper which compares, in a alcohol model of liver/gut disease, combinations of live VSL#3, heat-killed VSL#3, and l-glutamine (amino acid fuel preferred by enterocytes and protective thereof).


First, compared with control group, endotoxin and TNFalpha in alcohol group was obviously high. At the same time, in VSL#3 group, the expression of endotoxin and TNFalpha obviously lower than the alcohol group. And the trends of the expression of tight junction proteins in these groups were reversed with the change of endotoxin and TNFalpha. Second, compared the groups of VSL#3 with glutamine, VSL#3+glutamine and heat-killed VSL#3, we found that both VSL#3 and heat-killed VSL#3+glutamine were as effective as VSL#3+glutamine in the treatment of acute alcohol liver disease, the expression of endotoxin and TNFalpha were lower than the alcohol group, and tight junction proteins were higher than the alcohol group whereas the expression of tight junction proteins were higher in VSL#3 + glutamine group than either agent alone, but have no significant difference.
Did you get that? The full text is a little different:
We found that both VSL#3 and heat-killed VSL#3 were as effective as 
glutamine in the treatment of acute alcohol liver disease, whereas the combination of VSL#3 
and glutamine therapy efficacy was more effective than either agent alone

So maybe - and this is backed up by other research - for some purposes the viability or resistance or age or condition of a probiotic supplement can be less important than the strains and number of organisms it contains. And yoghurt cooked into meals, which appears to be a common thing in countries where yogurt is a traditional food, with only Western faddists consistently fetishizing rawness, might have its medicinal uses too.

Lamb baked in yogurt

Certainly, a probiotic need not make it alive all the way through the digestive tract to influence host immunity, and some of the objections commonly made in "evidence based" criticisms of probiotics are simply not relevant to some important probiotic modes of action.

"The probiotic paradox is that both live and dead cells in probiotic products can generate beneficial biological responses. The action of probiotics could be a dual one. Live probiotic cells influence both the gastrointestinal microflora and the immune response whilst the components of dead cells exert an anti-inflammatory response in the gastrointestinal tract."

So here we have a mixture of strategies to combine to repair a leaky gut and reduce consequent hepatic inflammation;
1) dietary saturated fats of both MCT and long-chain classes

2) l-glutamine
3) spirulina
4) viable live probiotic cultures (and prebiotic fibres)
5) killed probiotics, as well as live commensal species that do not easily colonise the gut


lissjeanrosa said...

Your enlightening shows are a delight to log in to. Being a fellow HCV G3 F4, I had been researching nutritional pathways to reduce inflammation & fibrosis and found myself here! Don't mind a slice of 'medicinally' enhanced brownie myself ;-)....regards.

George Henderson said...


it's my considered opinion that oral consumption of green medicine is where it's at.

Regarding fibrosis, still a lot of guesswork. I've started taking zinc (gluconate in my case) because the evidence for that is getting pretty good.

Progression of liver disease seemed to vary, depending on serum albumin concentrations. In the group with baseline serum albumin concentrations of 4.0 g/dl or more, the change and rate of change of serum zinc concentrations increased significantly, and the cumulative incidence of HCC tended to decrease, in the treated group. According to multivariate analysis, the factors that contribute to a reduction in the incidence of HCC are zinc therapy (risk ratio: 0.113, 95% CI: 0.015–0.870, p = 0.0362), and platelet counts (0.766, 0.594–0.989, 0.0409). Zinc supplementation therapy seems to improve liver pathology and reduce the incidence of HCC.

Drinking coffee ditto, though that is all observational still.

mfairchild said...

Thank you for this post. I don't have Hep C but I want a happy liver. I've seen great improvement in my gut health since adding the RS suggestions at FTA..big change from decades of frequent dysbiosis. I added the "Pearl" probiotic suggestion from Woo and much improvement clicked into place. Still have a problem or two so just added some glutamine. Thanks for the list. I think gut health is huge. Loved the allergy as a car sensor, limp mode analogy. Truth! I get painful allergic reactions to ant bites but not always or delayed a day...why? I want to unravel that!

shtove said...

Orthodox view at Livestrong:
"The most common form of supplemental glutamine is L-glutamine. Glutamine supplements are contraindicated if you have liver disease. This is not because they will cause further damage to your liver but because a damaged liver is unable to properly process the glutamine."

They give a list of links to sources of variable quality. Blaylock is in there. I had a look at the renal ammonia paper, but clear as mud.

George Henderson said...

One reason possible allergies might be delayed concerns the arthus or type 3 allergic reaction, where (from memory) immune complexes will build up in the bloodstream then be deposited in soft tissue, triggering inflammation there, a process which takes time. It's also possible something in the bite suppresses the reaction till it wears off. If it's a local reaction this seems more likely. Or you are allergic to a metabolite of the toxin, not the toxin itself. Or you are reacting to the allergen plus breakdown products of your damaged tissues (DAMPs) - the possibilities are endless. In fact you may never know.
It could be worse - I reckon this is as bad as an insect allergy can get
I call it the Heart Foundation Tick, because they are both equally unreasonable about stopping you enjoying red meat.

@ shtove, you would need to have decompensated cirrhosis before glutamine supps became a problem, and even then I have anecdotal reports they are fine. The idea would be to consume the dose that the gut will metabolise without sending much to the liver. But it represents a small % of a daily protein quota.
It is always possible that something that will slow the decline of the liver significantly can become a problem at the same amount if the liver is already seriously damaged and decompensating.

lissjeanrosa said...

Well...being a 'girl' I am tending to embrace the statistics that I will not become victim of the Cluthlu of Cancer, HCC. However my recent fall in albumin & platelets, rise in bilirubin, low cholesterol & low HDL has added to my concerns that hepatic function is declining and that unless I take treatment, Inf/Rib, I am but piling stupidity onto an already burdened body.I will however take heed of the zinc study. PS The home Bezzera espresso machine charges me a daily dose of common ground.

George Henderson said...

@ lisjeanrosa,

Combos of Sofosbuvir and other second-generation DAAs (directly acting antivirals), perhaps with Riba, will be the future gold standard. There will be no need for Interferon. I think it is worth holding out for this to become the norm. These combos work very well in untreated HCV and they are working on combos for non-responders.

Galina L. said...

I can't resist a chance to post a culinary comment - yogurt is great for marinating meat. I like the combination of yogurt, garlic,black pepper and salt.Many would add carry,flakes of hot pepper, mustard and what not, but I like minimalist approach when it comes to a seasoning. I suspect in a hot climate such marinade could delay a bacteria growth.