Over Activation of Farnesoid X Receptor In the Ilium Driving Liver and Gut Disharmony

[Bdeep86]

Cimetidine, phytoceramides, bile acids, and TUDCA seem to be making a real difference for me @Bdeep86 and btw I ordered a gram of Obeticholic Acid. Pm me for details.

Yeah you have somethings that will be hitting this system pretty hard. Not sure how much you are getting from the phytoceramides I don't know much about those. TUDCA is a powerful powerful agent.

 

[eljefe19]

Yup that's the regimen. TEMPOL and riboflavin for BSH too.

 

[Bdeep86]

Yup that's the regimen. TEMPOL and riboflavin for BSH too.

Take the TEMPOL slow.

 

[eljefe19]

Take the TEMPOL slow.

What dosing strategy do you suggest?

 

[Gondwanaland]

Please take a look at microbiome and bile !
E.g.

Gastroenterol Res Pract. 2015;2015:398585. doi: 10.1155/2015/398585. Epub 2015 Mar 3.
The interplay of the gut microbiome, bile acids, and volatile organic compounds.

Sagar NM1, Cree IA2, Covington JA3, Arasaradnam RP2.
Author information
Abstract
Background. There has been an increasing interest in the use of volatile organic compounds (VOCs) as potential surrogate markers of gut dysbiosis in gastrointestinal disease. Gut dysbiosis occurs when pathological imbalances in gut bacterial colonies precipitate disease and has been linked to the dysmetabolism of bile acids (BA) in the gut. BA metabolites as a result of microbial transformations act as signaling molecules and have demonstrated regulation of intestinal homeostasis through the TGR5 and FXR receptors by inhibiting inflammation, preventing pathogen invasion, and maintaining cell integrity. The presence of VOC footprints is the resultant effect to gut microbiome substrate fermentation. Aim. To review the role of the gut microbiome and bile acid signaling in intestinal homeostasis and the resultant use of VOCs as potential noninvasive surrogate biomarkers in gut dysbiosis. Methods. A systematic search on PubMed and Medline databases was performed to identify articles relevant to gut dysbiosis, BA metabolism, and VOCs. Conclusions. The host and presence of the gut microbiome appear to regulate the BA pool size. A dysbiotic gut microbiome results in disrupted intestinal homeostasis, which may be reflected by VOCs, differentiating those who are healthy and those with disease.
PMID: 25821460 PMCID: PMC4363917 DOI: 10.1155/2015/398585

 

[Bdeep86]

What dosing strategy do you suggest?

I can't advise on dosages but if it were me I would take the smallest possible. You are using it to manipulate the microbiome and this won't be done over night. Its a powerful detoxing agent and you need to take it along side some other nutrients.

 

[Bdeep86]

Please take a look at microbiome and bile !
E.g.

Yep two are crucial to each other.

 

[Tunguska]

I'm always interested to read theories involving gut since mine is an untamable beast I plain give up on, and it's a black box in (my) understanding.

Did you investigate how this might tie into Lipopolysaccharide signaling? Along with inflammation it's a bit of a boogeyman nowadays but there's some clear acute effects on FXR in liver:
http://www.jbc.org/content/278/11/8988.full
https://www.ncbi.nlm.nih.gov/pubmed/18972444
It goes with the idea of under-activated FXR, but specifically in the liver.

What would be interesting to know is the net effect of the different possible combinations of FXR agonism/antagonist in gut vs liver, and the timing. Could gut and liver FXR even oppose each other? (from black box to pandora's box) There's an article (either in above or a third, can't remember) that tries to describe a possible progression but doesn't go very far.

The CYP7A1 expression looks hard to get a handle on because it can get repressed by non-FXR mechanisms.

I looked at this stuff only a little in the context of retinoic acid, which also gets involved (as a CYP7A1 repressor with and without FXR).

The overarching question being which of these modulators have the most impact (normally and in this disease).

(sorry I might forgo regular forum courtesies today)

 

[eljefe19]

I'm always interested to read theories involving gut since mine is an untamable beast I plain give up on, and it's a black box in (my) understanding.

Did you investigate how this might tie into Lipopolysaccharide signaling? Along with inflammation it's a bit of a boogeyman nowadays but there's some clear acute effects on FXR in liver:
http://www.jbc.org/content/278/11/8988.full
https://www.ncbi.nlm.nih.gov/pubmed/18972444
It goes with the idea of under-activated FXR, but specifically in the liver.

What would be interesting to know is the net effect of the different possible combinations of FXR agonism/antagonist in gut vs liver, and the timing. Could gut and liver FXR even oppose each other? (from black box to pandora's box) There's an article (either in above or a third, can't remember) that tries to describe a possible progression but doesn't go very far.

The CYP7A1 expression looks hard to get a handle on because it can get repressed by non-FXR mechanisms.

I looked at this stuff only a little in the context of retinoic acid, which also gets involved (as a CYP7A1 repressor with and without FXR).

The overarching question being which of these modulators have the most impact (normally and in this disease).

(sorry I might forgo regular forum courtesies today)

That first source you gave says FXR activation inhibits Bile Acid synthesis by downregulating CYP7A1 but that doesn't sound like what we want..

 

[nandixon]

It would work out better all around, I think, to have the problem be that FXR is under-activated rather than over-activated.

That would fit with the low ceramides found in the Naviaux study (activation of FXR increases ceramide synthesis).

I've had to rethink what I wrote above, because I forgot that PPAR delta (PPARd) was found to be upregulated in the recent Fluge & Mella study.

I think the finding of increased PPARd is actually the strongest support (in terms of metabolic findings) for an argument of FXR being over-activated in ME/CFS, rather than the increased PDK4 that Fluge & Mella also found. (FXR increases PPARd which in turn increases PDK4, but PDK4 could have been increased in a number of other ways, and other PDKs were found to be increased by Fluge & Mella as well.)

But if FXR is being over-activated, then I can't currently explain why ceramides are low. Conversely, if FXR is being under-activated, I can't explain why PPARd is high.

So I guess for now it might be somewhat of a toss-up whether FXR is under- or over-activated (or neither) in ME/CFS. Hopefully @eljefe19's experiment will be revealing one way or the other.

FWIW, there are a couple of interesting mouse studies, one of which might support under-activation, the other over-activation - assuming the same thing happens in humans.

For under-activation:

In this study looking at the effects of the synthetic FXR antagonist, glycine-β-muricholic acid (Gly-MCA), on the mouse intestinal microbiome, that antagonist caused a reduction in the ratio of Firmicutes to Bacteroidetes bacteria. That effect was blocked when an FXR agonist was used in combination with Gly-MCA, i.e., their opposite actions cancelled each other out.

This type of reduced ratio of Firmicutes to Bacteroidetes is what has been found in ME/CFS in at least 3 different studies, I think. (See, e.g., Reference.)

So that mouse study may be suggesting that an FXR antagonist could take the ratio in the wrong direction in ME/CFS, and that the use of an agonist instead might increase the ratio of Firmicutes to Bacteroidetes phyla, perhaps then helping to normalize the microbiome.

And if it's true that FXR has a significant effect on ceramide levels, then agonism may fix the problem of the low ceramides found in Naviaux's study and the downstream consequences.

On the other hand, in favor of the over-activation scenario:

This study used the FXR agonist, obeticholic acid, in a common mouse model of multiple sclerosis known as "experimental autoimmune encephalomyelitis." Obeticholic acid was found to reduce the symptoms of the disease.

And MS and ME/CFS appear to be sort of opposite diseases in major respects, with an over-activated mTORC1 pathway and decreased Tregs in MS (i.e., too much immunostimulation), and the opposite in ME/CFS (i.e., too much immunosuppression).

The study is indicating that obeticholic acid had an immunosuppressive effect helpful for the MS model and therefore possibly bad for ME/CFS, suggesting that an FXR antagonist might be the correct therapy. Unfortunately, there are no antagonists that are both specific to FXR and also very potent that have been trialed in humans. The Gly-MCA mentioned above might be a candidate, though. (Note that humans don't make the tauro-beta-muricholic acid mentioned in the original post of this thread.)

Again, though, whether either of those studies seemingly supporting over- or under-activation of FXR apply to humans is another matter.

 

[Bdeep86]

I'm always interested to read theories involving gut since mine is an untamable beast I plain give up on, and it's a black box in (my) understanding.

Did you investigate how this might tie into Lipopolysaccharide signaling? Along with inflammation it's a bit of a boogeyman nowadays but there's some clear acute effects on FXR in liver:
http://www.jbc.org/content/278/11/8988.full
https://www.ncbi.nlm.nih.gov/pubmed/18972444
It goes with the idea of under-activated FXR, but specifically in the liver.

What would be interesting to know is the net effect of the different possible combinations of FXR agonism/antagonist in gut vs liver, and the timing. Could gut and liver FXR even oppose each other? (from black box to pandora's box) There's an article (either in above or a third, can't remember) that tries to describe a possible progression but doesn't go very far.

The CYP7A1 expression looks hard to get a handle on because it can get repressed by non-FXR mechanisms.

I looked at this stuff only a little in the context of retinoic acid, which also gets involved (as a CYP7A1 repressor with and without FXR).

The overarching question being which of these modulators have the most impact (normally and in this disease).

(sorry I might forgo regular forum courtesies today)

I'm not totally sure whats being asked here, I check in here during the day from work and can only pop in for a minute or two.

 

[Bdeep86]

I've had to rethink what I wrote above, because I forgot that PPAR delta (PPARd) was found to be upregulated in the recent Fluge & Mella study.

I think the finding of increased PPARd is actually the strongest support (in terms of metabolic findings) for an argument of FXR being over-activated in ME/CFS, rather than the increased PDK4 that Fluge & Mella also found. (FXR increases PPARd which in turn increases PDK4, but PDK4 could have been increased in a number of other ways, and other PDKs were found to be increased by Fluge & Mella as well.)

But if FXR is being over-activated, then I can't currently explain why ceramides are low. Conversely, if FXR is being under-activated, I can't explain why PPARd is high.

So I guess for now it might be somewhat of a toss-up whether FXR is under- or over-activated (or neither) in ME/CFS. Hopefully @eljefe19's experiment will be revealing one way or the other.

FWIW, there are a couple of interesting mouse studies, one of which might support under-activation, the other over-activation - assuming the same thing happens in humans.

For under-activation:

In this study looking at the effects of the synthetic FXR antagonist, glycine-β-muricholic acid (Gly-MCA), on the mouse intestinal microbiome, that antagonist caused a reduction in the ratio of Firmicutes to Bacteroidetes bacteria. That effect was blocked when an FXR agonist was used in combination with Gly-MCA, i.e., their opposite actions cancelled each other out.

This type of reduced ratio of Firmicutes to Bacteroidetes is what has been found in ME/CFS in at least 3 different studies, I think. (See, e.g., Reference.)

So that mouse study may be suggesting that an FXR antagonist could take the ratio in the wrong direction in ME/CFS, and that the use of an agonist instead might increase the ratio of Firmicutes to Bacteroidetes phyla, perhaps then helping to normalize the microbiome.

And if it's true that FXR has a significant effect on ceramide levels, then agonism may fix the problem of the low ceramides found in Naviaux's study and the downstream consequences.

On the other hand, in favor of the over-activation scenario:

This study used the FXR agonist, obeticholic acid, in a common mouse model of multiple sclerosis known as "experimental autoimmune encephalomyelitis." Obeticholic acid was found to reduce the symptoms of the disease.

And MS and ME/CFS appear to be sort of opposite diseases in major respects, with an over-activated mTORC1 pathway and decreased Tregs in MS (i.e., too much immunostimulation), and the opposite in ME/CFS (i.e., too much immunosuppression).

The study is indicating that obeticholic acid had an immunosuppressive effect helpful for the MS model and therefore possibly bad for ME/CFS, suggesting that an FXR antagonist might be the correct therapy. Unfortunately, there are no antagonists that are both specific to FXR and also very potent that have been trialed in humans. The Gly-MCA mentioned above might be a candidate, though. (Note that humans don't make the tauro-beta-muricholic acid mentioned in the original post of this thread.)

Again, though, whether either of those studies seemingly supporting over- or under-activation of FXR apply to humans is another matter.

It doesn't matter either way. It is the same therapy. Bile has to get flowing, dysbiosis has to be resolved. It is the environment around the receptors that is influencing them.

 

[Tunguska]

@eljefe19
Well first and foremost the FXR inhibiting CYP7A1 is the normal response, it should occur, it's only a problem if it's exaggerated, chronic or happens at the wrong time of day.

@nandixon
Great points there. To me suggest this might be more complex than one-or-the-other.

One of the articles I read (sorry can't find the passage) alluded to a FXR under-activation followed by (not-really-)paradoxical decrease in CYP7A1. So I could imagine a scenario like this (along the lines of what they wrote): given someone with serious dysbiosis, at time of feeding, they produce exaggerated LPS, which under-activates liver FXR during feeding, and leads to too much bile acid. Assuming they have no bile duct blockage or substitute (in which case it just results in cholestatis), then the gut overgrowth produces too much de-conjugation from the bile acids, which would lead to FXR over-activation afterward (in gut; liver?). But the timing might be affected, such that FXR is being under-activated during feeding, and the overload leads to FXR over-activation after feeding.

This is speculation on top of speculation, just to communicate the timing problem (still ignoring the question of whether gut and liver might oppose each other at the same time).

(I will look at those links later too, but the expectation of MS treatment being the opposite of desirable is the way I would normally think too)

@Bdeep86
No worries I don't log in much either.

 

[nandixon]

It doesn't matter either way. It is the same therapy. Bile has to get flowing, dysbiosis has to be resolved. It is the environment around the receptors that is influencing them.

It does matter for purposes of trying to determine which supplements or drugs might be most useful because, for example, if you agonize FXR then that ultimately decreases bile production - which you're implying you wouldn't want to happen.

But the mouse study I cited is suggesting that increasing bile acids (e.g., by using an FXR antagonist) would make the microbiome even more dysregulated in ME/CFS.

And we don't know if the bile supplements people commonly take, which it's important to note are all conjugated forms, are helpful for some people in ME/CFS because they are activating the S1P receptor (i.e., S1PR2), which is activated by both the predominant conjugated forms found in supplements (e.g., taurocholic acid) and also by TUDCA, or if they're helpful because they are improving a low bile acid problem (after they are de-conjugated) related to FXR.

 

[Bdeep86]

It does matter for purposes of trying to determine which supplements or drugs might be most useful because, for example, if you agonize FXR then that ultimately decreases bile production - which you're implying you wouldn't want to happen.

But the mouse study I cited is suggesting that increasing bile acids (e.g., by using an FXR antagonist) would make the microbiome even more dysregulated in ME/CFS.

And we don't know if the bile supplements people commonly take, which it's important to note are all conjugated forms, are helpful for some people in ME/CFS because they are activating the S1P receptor (i.e., S1PR2), which is activated by both the predominant conjugated forms found in supplements (e.g., taurocholic acid) and also by TUDCA, or if they're helpful because they are improving a low bile acid problem (after they are de-conjugated) related to FXR.

Many things are going in to even how well the receptors themselves are functioning. Even body temperature is influencing this. Why i'm saying it doesn't matter is because the therapy that I have in mind overrides the liver-gut disharmony all together. The bile acids themselves are doing so many things outside of stimulating the receptors. With the amount of resource available for research, I just feel that utilizing a therapy that over-rides this regardless is probably best. Who knows, the fxr antagonism maybe triggering more bile which maybe stimulating the S1P receptor. Could be both receptors that are dysfunction. I would say that taking nonconjugated bile acids would probably not be the desired route if you were to utilize bile acid therapy. Many things could be going on. I have something in mind that could fix all of this, it has many moving parts and I need to understand it better myself before I write about it. But I do have experience with TUDCA/UDCA and I have seen these do some great things for people. Particularly TUDCA.

I'll write more tonight.

 

[Gondwanaland]

Not sure if this study has already been mentioned or if it applies:

PLoS One. 2014 Jan 14;9(1):e85344. doi: 10.1371/journal.pone.0085344. eCollection 2014.
Discovery of bile salt hydrolase inhibitors using an efficient high-throughput screening system.
Smith K1, Zeng X1, Lin J1.
Author information

Abstract
The global trend of restricting the use of antibiotic growth promoters (AGP) in animal production necessitates the need to develop valid alternatives to maintain productivity and sustainability of food animals. Previous studies suggest inhibition of bile salt hydrolase (BSH), an intestinal bacteria-produced enzyme that exerts negative impact on host fat digestion and utilization, is a promising approach to promote animal growth performance. To achieve the long term goal of developing novel alternatives to AGPs, in this study, a rapid and convenient high-throughput screening (HTS) system was developed and successfully used for identification of BSH inhibitors. With the aid of a high-purity BSH from a chicken Lactobacillus salivarius strain, we optimized various screening conditions (e.g. BSH concentration, reaction buffer pH, incubation temperature and length, substrate type and concentration) and establish a precipitation-based screening approach to identify BSH inhibitors using 96-well or 384-well microplates. A pilot HTS was performed using a small compound library comprised of 2,240 biologically active and structurally diverse compounds. Among the 107 hits, several promising and potent BSH inhibitors (e.g. riboflavin and phenethyl caffeate) were selected and validated by standard BSH activity assay. Interestingly, the HTS also identified a panel of antibiotics as BSH inhibitor; in particular, various tetracycline antibiotics and roxarsone, the widely used AGP, have been demonstrated to display potent inhibitory effect on BSH. Together, this study developed an efficient HTS system and identified several BSH inhibitors with potential as alternatives to AGP. In addition, the findings from this study also suggest a new mode of action of AGP for promoting animal growth.
PMID: 24454844 PMCID: PMC3891821 DOI: 10.1371/journal.pone.0085344

 

[Gondwanaland]

Appl Environ Microbiol. 2006 Mar; 72(3): 1729–1738.
doi: 10.1128/AEM.72.3.1729-1738.2006
PMCID: PMC1393245
Bile Salt Hydrolase Activity in Probiotics

IS BSH ACTIVITY A DESIRABLE TRAIT IN PROBIOTICS?
Overall, the data strongly support the hypothesis that microbial BSHs function in the detoxification of bile salts and in doing so increase the intestinal survival and persistence of producing strains. Therefore, BSH activity by a probiotic bacterium may be desirable since it could maximize its prospects of survival in the hostile environment of the gastrointestinal tract. Increased intestinal survival is likely to increase the overall beneficial effects associated with the strain.

Since large amounts of deconjugated bile salts may have undesirable effects for the human host (described earlier), concerns may arise over the safety of administering a BSH-positive probiotic strain. However, the bacterial genera that would most likely be used as probiotics (bifidobacteria and lactobacilli) are not capable of dehydroxylating deconjugated bile salts (1, 36, 87), and so the majority of the breakdown products of BSH activity by a probiotic strain may be precipitated and excreted in feces (this may vary from person to person depending on colonic pH and intestinal transit time [97, 98, 105]). In addition, work performed by two groups has shown that it may be possible to prevent further modification of deconjugated products by other intestinal microorganisms (e.g., certain strains of Clostridium and Eubacterium, which are the only strains that have been shown to possess dehydroxylating activity [19, 25]). First, Jones et al. (46) investigated the ability of a BSH-positive L. plantarum strain encapsulated in an artificial membrane to hydrolyze bile salts. The experiments of Jones et al. demonstrated that the microencapsulated strain was able to effectively break down physiologically relevant concentrations of bile in vitro, but the products of BSH deconjugation were trapped within the membrane. In addition to increasing the safety of the strain by rendering these products less bioavailable, microencapsulation would also protect entrapped bacteria from harsh environmental conditions encountered during gastric transit. Second, studies by Kurdi et al. (57, 58) revealed that cholic acid, the main free bile acid produced by BSH activity in the intestine, could accumulate inside the bifidobacterium and lactobacillus strains examined so long as the bacteria were energized. The amount of accumulation increased at decreasing external pH values, suggesting that factors which decrease the intestinal pH (the presence of short-chain fatty acids or lactic acid produced by intestinal microbes) may enhance the accumulation of cholic acid by lactobacilli in vivo (57).

In summary, BSH activity may benefit a probiotic bacterium required to survive and perform in the intestinal milieu. Microencapsulating the bacterium or selection of a strain that is not capable of further modifying unconjugated bile salts or one that may accumulate them would address the medical concerns about the possible side effects associated with BSH activity.
...........
Impaired digestive functions.
Since unconjugated bile acids are less efficient than conjugated molecules in the emulsification of dietary lipids and the formation of micelles, BSH activity may compromise normal lipid digestion, and the absorption of fatty acids and monoglycerides could be impaired (22). Microbial BSH activity has been related to growth defects in chickens (32, 33) but not in mice (2).

Disruption of normal intestinal conditions and/or gallstones.
It has been proposed that secondary bile acids resulting from the subsequent modification of unconjugated bile salts may cause DNA damage, promote colon cancer, or result in impaired colonic mucosal function that would lead to diarrhea or inflammation (7, 47, 65, 69, 71). In addition, since the solubilization of cholesterol in bile depends on the ratio of cholesterol to bile salts and lecithin, alterations in the concentrations of bile acids may result in bile being supersaturated with cholesterol. This cholesterol may precipitate together with calcium salts and bile pigments to form concretions termed gallstones, which may grow and obstruct the biliary ducts (62, 64, 104). It is noteworthy that an increase in secondary bile acids has been observed in gallstone sufferers (8, 63).

 

[Gondwanaland]

Does it all come down to glucose tolerance?

An Intestinal Farnesoid X Receptor-Ceramide Signaling Axis Modulates Hepatic Gluconeogenesis in Mice
Diabetes 2016 Nov; db160663. https://doi.org/10.2337/db16-0663

Abstract

Increasing evidence supports the view that intestinal farnesoid X receptor (FXR) is involved in glucose tolerance and that FXR signaling can be profoundly impacted by the gut microbiota. Selective manipulation of the gut-microbiota-FXR signaling axis was reported to significantly impact glucose intolerance, but the precise molecular mechanism remains largely unknown. Here, caffeic acid phenethyl ester (CAPE), an over-the-counter dietary supplement and an inhibitor of bacterial bile salt hydrolase, increased levels of intestinal tauro-β-muricholic acid, which selectively suppresses intestinal FXR signaling. Intestinal FXR inhibition decreased ceramide levels by suppressing expression of genes involved in ceramide synthesis specifically in the intestinal ileum epithelial cells. The lower serum ceramides mediated decreased hepatic mitochondrial acetyl-CoA levels and pyruvate carboxylase activities, and attenuated hepatic gluconeogenesis, independent of body weight change and hepatic insulin signaling in vivo; this was reversed by treatment of mice with ceramides or the FXR agonist GW4064. Ceramides substantially attenuated mitochondrial citrate synthase activities primarily through the induction of endoplasmic reticulum stress, which triggers increased hepatic mitochondrial acetyl-CoA levels and pyruvate carboxylase activities. These results reveal a mechanism by which the dietary supplement CAPE and intestinal FXR regulates hepatic gluconeogenesis, and suggest that inhibiting intestinal FXR is a strategy for treating hyperglycemia.

Implications for Farnesoid X Receptor Signaling on Bile Acid Metabolism as a Potential Therapeutic Strategy for Nonalcoholic Fatty Liver Disease
Korean J Obes 2016;25:167-175
https://doi.org/10.7570/kjo.2016.25.4.167

Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in both developed and developing countries and is an important risk factor for both hepatic and cardiometabolic mortality. Despite decades of clinical trials, effective treatment options for NAFLD are limited, requiring novel therapeutic approaches to prevent disease development and progression to cirrhosis and cancer. Recently, bile acids have emerged as signaling molecules and metabolic regulators that can activate signaling mediated by nuclear receptors and G protein-coupled receptors to regulate hepatic lipid, glucose, and energy homeostasis, as well as its own synthesis and transport in the liver and intestine. Many recent studies have reported that the activation or modulation of bile acid signaling mediated by bile acid receptors favorably affects both insulin sensitivity and NAFLD pathogenesis at multiple levels, suggesting that these approaches hold promise as novel therapies. In this review, we provide an overview of the role of bile acids, in particular, their signaling related to the nuclear receptor farnesoid X receptor in NAFLD and new insights into the possible approach of targeting bile acid-related pathways in the treatment of this serious disease.
Keywords : Bile acids, Farnesoid X receptor, Farnesoid X receptor agonists, Gut microbiota, Non-alcoholic fatty liver disease

Proc Nutr Soc. 2016 Nov 16:1-11. [Epub ahead of print]
Intestinal bile acid receptors are key regulators of glucose homeostasis.

Abstract
In addition to their well-known function as dietary lipid detergents, bile acids have emerged as important signalling molecules that regulate energy homeostasis. Recent studies have highlighted that disrupted bile acid metabolism is associated with metabolism disorders such as dyslipidaemia, intestinal chronic inflammatory diseases and obesity. In particular, type 2 diabetes (T2D) is associated with quantitative and qualitative modifications in bile acid metabolism. Bile acids bind and modulate the activity of transmembrane and nuclear receptors (NR). Among these receptors, the G-protein-coupled bile acid receptor 1 (TGR5) and the NR farnesoid X receptor (FXR) are implicated in the regulation of bile acid, lipid, glucose and energy homeostasis. The role of these receptors in the intestine in energy metabolism regulation has been recently highlighted. More precisely, recent studies have shown that FXR is important for glucose homeostasis in particular in metabolic disorders such as T2D and obesity. This review highlights the growing importance of the bile acid receptors TGR5 and FXR in the intestine as key regulators of glucose metabolism and their potential as therapeutic targets.
KEYWORDS:
BAS bile acid sequestrants; CA cholic acid; CDCA chenodeoxycholic acid; ChREBP carbohydrate response element-binding protein; DCA deoxycholic acid; FGF15/19 fibroblast growth factor 15/19; FXR farnesoid X receptor; GF germ-free; GLP; GLP glucagon-like peptide; IP insulinotropic polypeptide; KO knockout; MCA muricholic acids; NR nuclear receptors; T2D type 2 diabetes; TCA taurocholate; WT wild type; glucagon-like peptide; TGR5 G-protein-coupled bile acid receptor 1; Bile acid sequestrants; Bile acids; Glucagon-like peptide 1; Intestine; Type 2 diabetes
PMID: 27846919 DOI: 10.1017/S0029665116002834

 

[adreno]

Intestinal FXR inhibition decreased ceramide levels by suppressing expression of genes involved in ceramide synthesis specifically in the intestinal ileum epithelial cells. The lower serum ceramides mediated decreased hepatic mitochondrial acetyl-CoA levels and pyruvate carboxylase activities, and attenuated hepatic gluconeogenesis, independent of body weight change and hepatic insulin signaling in vivo

This would certainly indicate that we need FXR agonism rather than inhibition.

 

[Bdeep86]

This would certainly indicate that we need FXR agonism rather than inhibition.

Adreno I have revised my theory to say it is overall a general FXR dysfunction in the intestine, it is very hard to say without more resource if it needs agonism or antagonism. It realistically could be either. However, it doesn't change the protocol on how to correct this issue. It is the same for either.