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Farnesoid X receptor and bile acids regulate vitamin A storage
The nuclear receptor Farnesoid X Receptor (FXR) is activated by bile acids and controls multiple metabolic processes, including bile acid, lipid, carbohydrate, amino acid and energy metabolism. Vitamin A is needed for proper metabolic and immune control and requires bile acids for efficient intestinal absorption and storage in the liver. Here, we analyzed whether FXR regulates vitamin A metabolism. Compared to control animals, FXR-null mice showed strongly reduced (>90%) hepatic levels of retinol and retinyl palmitate and a significant reduction in lecithin retinol acyltransferase (LRAT), the enzyme responsible for hepatic vitamin A storage. Hepatic reintroduction of FXR in FXR-null mice induced vitamin A storage in the liver. Hepatic vitamin A levels were normal in intestine-specific FXR-null mice. Obeticholic acid (OCA, 3 weeks) treatment rapidly reduced (>60%) hepatic retinyl palmitate levels in mice, concurrent with strongly increased retinol levels (>5-fold). Similar, but milder effects were observed in cholic acid (12 weeks)-treated mice. OCA did not change hepatic LRAT protein levels, but strongly reduced all enzymes involved in hepatic retinyl ester hydrolysis, involving mostly post-transcriptional mechanisms. In conclusion, vitamin A metabolism in the mouse liver heavily depends on the FXR and FXR-targeted therapies may be prone to cause vitamin A-related pathologies.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6925179/
Three weeks of obeticholic acid, a synthetic bile acid, reduced hepatic retinyl palmitate by more than 60%. Hepatic retinol levels increased 5x but since the majority of Vitamin A in the liver is in the retinyl palmitate form total hepatic Vitamin A still dropped by about 50%. During this time they were fed a diet containing 10 IU of retinyl acetate/g, standard chow diet and yet the hepatic Vitamin A dropped rapidly.
Obeticholic acid is a synthetic analogue of Chenodeoxycholic acid which is a primary bile acid and is considered the most potent natural bile acid at stimulating FXR. There are many other FXR agonists including milk thistle, chicory, curcumin, procyanidins(apple, blueberry, grapes, cocoa, wine, etc.), saffron, melatonin, cafestol(in coffee),various probiotics, and others.
Bile acid composition and FXR and other nuclear receptor activity are inextricably linked to gut health and the microbiome. I think gut health is far more important than Vitamin A intake.
If you want to research this more there are a few things to be aware of. FXR is expressed in both the ileum(small intestine) and the liver and they have different affects. In this paper and others liver FXR is what you want to stimulate to improve Vitamin A metabolism. Many papers make no mention of which type they are testing which is ridiculous. It's also not clear that FXR itself is what's important it may be the bile salt export pump(BSEP) or other downstream affects. Different FXR agonists have differing downstream affects on things like BSEP, FGF19, CYP7A1, etc. It seems nuclear receptors are poorly understood.
Interesting. So, would UDCA or TUDCA be a useful tool or would it cause the body to "store more poisons" as a certain doctor suggests?
Looks like FXR activation from bile acids may be dangerous.
https://www.sciencedirect.com/science/article/pii/S0303720722001265
It looks like the VDR and FXR interact and Vitamin D 1,25 D shuts down FXR downstream effects.
From the study above, it said that FXR-null mice had much lower vitamin A stored in the liver. Wouldn't this be the opposite of an agonized receptor? Or am I missing something?
This suggests that FXR antagonists could help liver health.
https://www.sciencedirect.com/science/article/abs/pii/S096808961930375X
This is indeed very fascinating.
Thanks for the mention!
I have been wondering if the recycling of fat-soluble things from the small intestine might be to avoid excess unbound toxins in the large intestine damaging the microbiome. Protecting the microbiome might a main function behind the enterohepatic circulation. Food additives like carrageenan I think are generally poorly absorbed but when they are broken down, which mainly seems to be done by the gut microbiome, the food additives creates inflammatory toxic compounds. Though minimal real research exists on most food additives which is insane in and of itself.
A quote from a 2021 in vitro study on common emulsifiers in a bioreactor filled with the microbiome from one healthy donor. At the end they call for clinical trials of these very common food additives since they say they didn't know that any clincial trials had been done for all these emulsifiers.
"Direct impact of commonly used dietary emulsifiers on human gut microbiota"
https://microbiomejournal.biomedcentral.com/articles/10.1186/s40168-020-00996-6#Tab2
"While various factors have potential to alter intestinal microbiota, dietary components, especially food additives whose advent associates with the post-mid twentieth century increase non-infectious inflammatory diseases, are particularly suspicious [5, 6]. Such food additives are frequently non-absorbed and thus will likely directly interact with the microbiota. Several studies have reported that artificial sweeteners and polysaccharides can promote intestinal inflammation and metabolic dysregulation [7,8,9,10]. Another example of this concept is our observation that dietary emulsifiers can promote chronic intestinal inflammation in mice [5, 11]. Emulsifiers are chemicals that enable homogenization of immiscible liquids and are incorporated into many processed foods in order to improve texture and extend shelf life [12]. While the limited testing of food additives indicates that these compounds generally lack over toxicity and are not mutagenic, there is, nonetheless, considerable basis to question their safety, particularly in the context of chronic inflammatory diseases. For example, carrageenan induces chronic intestinal inflammation in rodents [13], and our studies of carboxymethylcellulose (CMC, E466) and polysorbate 80 (P80, E433) revealed that these compounds detrimentally alter intestinal microbiota composition and function, in ways that promoted chronic intestinal inflammation [5]. Mechanistically, we found, using mice and in vitro models, that intestinal microbiota is a direct target of CMC and P80. Moreover, germfree animals are completely protected against CMC- and P80-induced inflammation, while in vitro microbiota treated with CMC or P80 are detrimentally impacted in ways that can lead to chronic intestinal inflammation when transferred to germfree recipient animals [5, 11, 14]. Such studies indicate the central role of direct microbiota disturbances in mediating the detrimental impacts of CMC and P80."
I think you’re right about the importance of avoiding food additives, @david. It doesn’t help that they’re often present in processed products made with other questionable “food” ingredients, as well (like hydrogenated cottonseed oil, gmo modified starch, and protein isolates).
From “Dysregulated Microbial Fermentation of Soluble Fiber Induces Cholestatic Liver Cancer:”
...further study has led us to appreciate that consumption of processed foods enriched with purified fibers may have dire consequences in certain contexts. For instance, we observed that mice consuming inulin-enriched CDD [purified, compositionally defined diet] develop severe colitis upon exposure to the chemical colitogen DSS (Miles et al., 2017). We herein report that prolonged feeding of fermentable fiber-enriched CDD to mice with pre-existing microbiota dysbiosis such as, but by no means limited to, T5KO mice, resulted in development of cholestatic HCC. In contrast, there were no indications of liver disease in T5KO mice that consumed similar amounts of inulin added to grain-based rodent chow (data not shown), which is a relatively unrefined conglomerate of food scraps that has classically served as the standard diet for rodents used in research. These results suggest that the dietary context (i.e., refined or unrefined diet) in which a fermentable fiber is consumed is of great importance and, in particular, caution against enriching highly refined foods with fermentable fibers.
It’s like the more gross fake “food” you combine, the worse outcome you get, unsurprisingly.
I have wondering if the recycling of fat-soluble things from the small intestine might be to avoid excess unbound toxins in the large intestine damaging the microbiome. Protecting the microbiome might a main function behind the enterohepatic circulation.
That makes so much sense! Thank you for your insightful posts, btw, David. I always find them thought-provoking.
Dysbiosis and endotoxin production in the gut doesn’t help anyone dealing with a toxic bile problem, that’s for sure.
Thank you for the lovely compliment!
I like the curiousity and compassion that permates all of your post.
On the topic of the enterohepatic circulation possibly being there to help the gut microbiome to avoid the most hydrophobic (fat-soluble) toxic compounds. Many of these compounds are leave the body through large intesitnal cells that are rubbed off the intestinal walls. I think it points towards the enterohepatic circulation having a microbiome saving function.
The 1985 paper has previously been available at sci-hub and it is called:
"Intestinal Excretion of Toxic Substances"
https://doi.org/10.1007/978-3-642-69928-3_10
Abstract:
"Chemicals can be eliminated from body via feces by two major mechanisms, namely biliary and intestinal excretion. The relative importance of these processes in the elimination of a highly lipophilic xenobiotic such as hexachlorobenzene (HCB) has been studied. It has been demonstrated that fecal (90%) rather than urinary (10%) excretion is the major route of elimination of HCB in most species. It has been shown also that the bile of HCB dosed animals contained HCB metabolites only whereas fecal excretion consisted primarily of the parent compound. These findings suggested that the bile could not be the source of fecal HCB. Indeed, bild duct ligation in rats increased rather than decreased the fecal excretion of HCB. Experiments in rhesus monkeys with complete biliary bypass confirmed the conclusion that the source of fecal HCB is not the bile, suggesting that most of the fecal HCB originated from intestinal excretion. Exfoliation of intestinal epithelium and exudation across the intestinal mucosa are the two major nonbiliary mechanisms whereby xenobiotics can enter the intestinal lumen. The contribution of desquamation and exudation to fecal excretion of HCB was estimated in jejunectomized and hemicolectomized rats. Removal of 50% of the jejunum did not influence fecal excretion of HCB, whereas excision of 50% of the large intestine reduced it by 40%. These data suggest that the source of fecal HCB is nonbiliary, intestinal transfer (exudation) from blood into the intestinal contents, which occurs primarily in the large intestine. Fecal elimination of HCB is significantly enhanced by dietary treatments with mineral oil or hexadecane. Jejunectomy and hemicolectomy affected fecal excretion of HCB in hexadecane stimulated rats in a similar fashion as in the untreated animals. Thus, it is concluded that hexadecane specifically stimulated exudation of HCB into the large intestine."
On the topic of the importance of the microbiome, which is probably connected to FXR receptor in several ways as well.
Here is an absorption study on alpha- and beta-carotene in germ-free rats and rats with a human gut microbiome. This 1998 study is called:
"The bioavailability of α- and β-carotene is affected by gut microflora in the rat" by Grolier, P. et al.
https://www.cambridge.org/core/journals/british-journal-of-nutrition/article/bioavailability-of-and-carotene-is-affected-by-gut-microflora-in-the-rat/0111C2BB41D5F0CD5F0C04C85F87A332
Table 2 from the study is attached and here is a short quote from the study about it:
"Germ-free rats accumulated approximately twice as much vitamin A, α-carotene and β-carotene in the liver as their heteroxenic [human fecal microbiome] and conventional counterparts (P < 0:001).
...
Vitamin A concentrations in serum, lungs and kidneys were similar for all the experimental groups."
Here is a quote from the discussion about how the longer stool transit time of germ-free rats might be one explaination for why they had about 2x higher carotenoid absorption:
"Finally, because the absorption of carotenes occurs through passive diffusion, factors increasing the carotene concentration in the lumen of the jejunum would increase their absorption. The intestinal transit time was found to be slower in germ-free rats (Riottot et al. 1980) and could explain the two-fold increase in the small intestinal lumen concentration of bile salts in these animals as compared with controls (Sacquet et al. 1976). Thus, we suggest that the absence of intestinal microflora results in a more efficient solubilization of β-carotene in mixed micelles and a longer interaction between these particles and the jejunal mucosa. Both these factors are capable of promoting the absorption of α- and β-carotene.
...
In conclusion, the bioavailability of both α- and β-carotene was improved when the intestinal microflora was absent or decreased in the rat. We suggest that intestinal microflora do not act directly on carotenes, but rather diminish their intestinal absorption by decreasing the intestinal transit time and the pool of bile salts in the jejunum."
Lactoferrin is a FXR inhibitor. I’ve been using grass fed whey protein recently which contains lactoferrin and immunoglobulins it fixes biles issues completely for me. Dark brown stools a few times a day. The easily available amino acids also help a lot with bile acid synthesis much more than meat.
TUDCA I used for my gallbladder issues before Vit A toxicity it was helpful but never fixed anything. Then when I tried it after I had developed bad Vit A toxicity the TUDCA caused bad confusion for me. And the confusion also happened when I ate carrots or rutagaba too.
Quote from AlexM on July 23, 2023, 11:53 amLactoferrin is a FXR inhibitor. I’ve been using grass fed whey protein recently which contains lactoferrin and immunoglobulins it fixes biles issues completely for me. Dark brown stools a few times a day. The easily available amino acids also help a lot with bile acid synthesis much more than meat.
TUDCA I used for my gallbladder issues before Vit A toxicity it was helpful but never fixed anything. Then when I tried it after I had developed bad Vit A toxicity the TUDCA caused bad confusion for me. And the confusion also happened when I ate carrots or rutagaba too.
I'm currently thinking inhibitors are the way vs agonizing the FXR receptors.
1,25 Vitamin D is an inhibitor as well. Not to be confused with D3 supplements.