Leaky Gut and Metabolic Health

The ‘endotoxemia’, which results from intestinal permeability (leaky gut), is a crucially important physiological event which, I will argue here, underlies a large number of the modern ‘western’ diseases.
Preventing ‘leaky gut’ and endotoxemia is a very important target, if we are to prevent and/or reverse many of the ‘western’ diseases.
It has been called ‘metabolic endotoxemia’ since one aspect of the dysregulation induced by endotoxemia is the exacerbation of disrupted insulin regulation of glucose levels.

Other health disorders which are argued to be either the result of, or exacerbated by, endotoxemia are: fatty liver, cardiovascular disease, stroke, autoimmune disorders, allergies, skin disorders, depression, anxiety and even the progression of cancer.

The subject of endotoxemia is a vast one, but I am presenting here some of the most important elements which, I argue, have been elucidated.

What is Endotoxemia (Leaky Gut)?

Endotoxemia refers to the escape of cell wall components of gram negative bacteria from the intestine into the blood.
Endotoxin literally means toxin produced by the body.
These bacterial cell wall components are called lipopolysaccharide (LPS) and they are highly immunogenic, which means that they activate the immune system leading to inflammation and increased lipolysis.
The LPS only detrimentally activate the immune system, causing inflammation, when they escape from the intestine.
Confined to the intestinal lumen, they do not generally appear to cause problems.

What causes Endotoxemia (Leaky Gut )? 

Accumulating evidence indicates that the escape of LPS from the intestine is due to a pathological increase in intestinal permeability, commonly referred to as ‘leaky gut’.
In this post I will examine some of the factors which increase intestinal permeability, paying particular attention to the largely unknown role of bile in the pathogenesis of ‘leaky gut’ and endotoxemia.
I will argue that alterations in bile signalling is the mechanism behind the usefulness of dietary macronutrient manipulation (low carb, low fat or intermittent fasting) to increase or decrease ‘leaky gut’.

The Effects of Leaky Gut-Induced Inflammation on Health 

Lipolysis and Insulin Resistance, Hyperinsulinemia, Type 2 Diabetes and Fatty Liver 

Oral antibiotics that prevented endotoxemia and the CD14−/− genotype with defective LPS signalling ameliorated nearly every inflammatory, oxidative, and metabolic derangement in both high-fat-fed and leptin-deficient mice.
This strongly implicates LPS signalling as a key, crucial initiator of a vast array of health disorders.

A direct link between postprandial endotoxemia, inflammation, and metabolic disease has been strongly supported by other animal experiments.
In these studies, mice fed a high fat diet (72% fat, 28% protein) consumed twice the energy as controls, exhibited elevated plasma LPS, and acquired features of metabolic disease.
The very same features of metabolic dysregulation could be reproduced by a 4-week infusion of low-dose LPS. R]

Consistent with the theory that endotoxemia is a crucial mechanism responsible for many of the disorders associated with metabolic syndrome; is the observation that levels of endotoxin in the blood correspond with atherosclerosis risk.

Subjects with endotoxin levels beyond 50 pg/ml faced a threefold risk of incident atherosclerosis.
Notably, smokers with low endotoxin levels and non-smokers did not differ in their atherosclerosis risk, whereas smokers with high levels almost invariably developed new lesions. All findings emerged as independent of vascular risk factors and similar results were obtained for incident cardiovascular disease. R]

With regard to the effects of endotoxemia to induce blood sugar dysregulation and fatty liver; it appears that the effects of endotoxemia to increase lipolysis are key.

Endotoxemia (leakage of LPS from the intestine into the blood) activates the immune system, which creates inflammation.
Inflammation increases basal lipolysis. 10] 11]

LPS stimulated lipolysis in adipose tissue combined with a trend toward decreased insulin signalling... increased lipolysis is observed in the early stages of acute inflammation....’

Lipolysis is the breakdown of fat cell triglycerides.
Anti-lipolytic drugs, which inhibit lipolysis, prevent systemic insulin resistance. 12]

As I will argue later, alcohol induced metabolic dysregulation and fatty liver is induced by endotoxemia and the role of lipolysis in the pathological chain of events is elucidated in a recent study.
Chronic alcohol exposure reduced adipose tissue mass and adipocyte size due to lipolysis.
Fatty acid release from adipose tissue explants was significantly increased in alcohol-fed mice in association with the activation of adipose triglyceride lipase and hormone-sensitive lipase. Alcohol exposure induced insulin intolerance...
Alcohol exposure up-regulated fatty acid transport proteins and caused lipid accumulation in the liver...’

To demonstrate that triglycerides from the adipose tissue were being deposited in the liver, during the development of fatty liver, mice were administered heavy water for 5 weeks to label adipose triglycerides with deuterium.
They were then pair-fed alcohol or a control diet for 2 weeks. ‘Alcohol exposure increased more than a dozen deuterium-labelled triglyceride molecules in the liver by up to 6.3-fold. These data demonstrate for the first time that adipose triglycerides due to alcohol-induced hyper-lipolysis are reverse transported and deposited in the liver.’ R]

This study thoroughly demonstrates the contribution of lipolysis (which is induced by endotoxemic inflammation) to the development of fatty liver.
And since we know that lipolysis also induces insulin resistance and the deterioration of the pancreas, it would be safe to assume that a similar process (of reverse transport of triglycerides) occurs during the development of endotoxemic–induced pancreatic dysfunction and insulin resistance.

Certain individuals, such as those with less subcutaneous fat storage capacity, (which buffers metabolic dysregulation) and therefore higher levels of visceral fat storage; appear to have exaggerated immune and inflammatory responses. REF
In these individuals, endotoxemia appears to result in more extreme immune reactions, manifested as auto-immune disorders, mucus production, headaches, aches and pains, skin reactions, insulin resistance and a more rapid progression of other disorders which are implicated to be the result of endotoxemic inflammation.

Accumulating evidence has led researchers to conclude that ‘loss of intestinal barrier function (leaky gut) is necessary to develop autoimmunity’. R]

What Causes leaky Gut? 

It appears that there are several contributing factors:
Intestinal oxidative stress and inflammation can directly destabilise the tight junctions of the intestine, leading to increased ‘leakiness’. R]

Certain food components, including gluten and food allergens, are also reported to contribute to intestinal permeability in those susceptible.
This appears to be due to inflammatory responses in the intestine having a direct negative effect on the tight junctions. R]

Stress also appears to exert negative effects on intestinal permeability via inducing an increase in inflammatory mediators in the intestine. R]
However, the ‘tolerance’ for factors such as gluten, food allergens and stress appears to be regulated by AMPK activation.
This means that AMPK activation is the most important factor which controls ‘leaky gut’ and endotoxemia.
It appears that if we can optimise AMPK activation, tolerance for stress and food allergens is greatly improved and even completely corrected. REF?

How AMPK Activation Prevents Leaky Gut-Induced Inflammatory Disorders 

When AMPK is optimally activated; inflammatory reactions to food allergens and stress in the intestine will be dampened. R]

Many inflammatory disorders are also prevented due to the ability of AMPK to preserve the integrity of the intestinal tight junctions 8.] R]; to increase anti-inflammatory responses in the intestine and in the blood R] ; and also to directly inhibit lipolysis R]

If AMPK activation is the most vital regulator of ‘leaky gut’; the priority must then be optimal AMPK signalling.
As argued in THIS POST; the most important regulator of whole body AMPK activation is the signals which are received by the hypothalamus from the intestine.

The most vital AMPK activating signals are intestinal gluconeogenesis and intestinal GLP-1.
And the most important regulators of intestinal gluconeogenesis and GLP-1 are; protein, fibre and optimal bile signalling.
And optimal bile signalling appears to be achieved, in those with metabolic dysfunction, by low carb diets, intermittent fasting and also low fat diets with certain ‘whole food’ carbohydrates.

It is argued in THIS POST that carbohydrate-induced flourishes of bacteria play a role in maintaining poor AMPK activation.
Poor AMPK activation reduces the tolerance for food components, such as gluten.
This mechanism is supported by studies which have found that the state of the microbiome determines the ‘tolerance’ to gluten, and presumably the other factors which are have been found to increase ‘leaky gut’. R]

Macronutrient-Induced Alterations to Bile Signalling –Regulate ‘Leaky Gut’

Clearly, if we want to reduce intestinal permeability and endotoxemia; AMPK activation and therefore bile manipulation is a crucial target.

As well as exerting effects on endotoxemia via AMPK activation or inhibition; bile also appears to exert effects directly by creating inflammation in the intestine, in some circumstances (such as during binge drinking of alcohol).

The amount and type of bile crucially influences metabolic endotoxemia (leaky gut).
Hydrophilic bile has a protective effect against intestinal permeability and endotoxemia, whilst an excess of hydrophobic bile has a devastating effect to increase ‘leaky gut’ and endotoxemia.

Researchers studying diet-induced fatty liver concluded that ‘excessive dietary fat and/or increased levels of luminal bile juice are responsible for the increase in small intestinal permeability resulting from the suppression of TJ protein expression. R]

The secondary bile acid deoxycholic acid (DCA) is one of the most hydrophobic bile acids and it has been shown to disrupt epithelial integrity dose dependently at a dose which corresponds to physiological concentrations on a high-fat diet.
Low-fat diet-related concentrations of DCA had no effect.
In vivo, the DCA-containing diet increased intestinal permeability 1.5-fold compared with control.
Studies have found ‘a clear disruption of the epithelial barrier by 3 mM DCA in vitro.’
This shows that high concentrations of hydrophobic bile can have a DIRECT effect on the epithelial barrier, presumably due to its detergent-like inflammatory effects.

The hydrophilic bile acid, UDCA, instead had a protective effect, ‘ameliorating DCA-induced barrier disruption at a 0.6 mM concentration.’
LPS by itself had no significant effect on barrier function at physiological concentrations.
The researchers ‘suggest a novel mechanism for barrier dysfunction on a high-fat diet involving the effect of hydrophobic luminal bile acids.’ R]

Other results show that the hydrophobic unconjugated bile acid, chenodeoxycholate, significantly enhanced IP and ‘loosened’ tight junctions in a dose-related manner in the ileum of the small intestine. R]
Unless via direct inflammatory action, bile exerts its negative or positive effects on intestinal permeability and endotoxemia via activation or inhibition of the bile receptors; TGR5 and FXR.
And these bile receptors exert their effects via activating or inhibiting AMPK.

Mice which lack TGR5 receptors have greatly increased intestinal permeability. R]

The activation of TGR5 also has a more direct and localized effect to decrease ‘leaky gut’ via the activation of epidermal growth factor.

Epidermal Growth Factor (EGF) - Key Regulator of Leaky Gut

It regulates tight junction expression, stimulates an increase of the goblet cells (which produce the protective mucus layer of the intestine); increases the secretion of protective mucins, as well as reducing bacterial colonization and translocation into the blood. R]

Researchers studying the effects of bile on ‘leaky gut’ concluded that bile acid metabolism was the best candidate mechanism responsible for high-fat-feeding-induced increased intestinal permeability.

The mechanism they specified was ‘namely a decreased proportion of fecal (hydrophilic) UDCA and increased FXR expression (which is induced by increased hydrophobic bile).’ R]
FXR activation has the opposite effect to TGR5.
Its activation reduces EGF and AMPK activation. R]

Researchers showed that the hydrophobic unconjugated bile acids; chenodeoxycholic acid, deoxycholic acid and cholic acid, but not the hydrophilic Ursodeoxycholic acid (UDCA), induced an increase in intestinal permeability through changes in tight junction proteins which was epithelial growth factor receptor (EGFR)-dependent. R]
In fact, hydrophilic bile acids, such as taurine conjugated bile and UDCA have been shown to increase EGF due to enhanced TGR5 activation. R] R]

As well as improving the integrity of the intestinal barrier, TGR5 activation prevents endotoxemic inflammation due to potent anti-inflammatory and LPS detoxifying effects. R]

‘Several research groups have extended the functions of TGR5 to more than metabolic regulation, which include inflammatory response, cancer and liver regeneration.’

‘Bile acids and TGR5 activation have been demonstrated to inhibit NLRP3 inflammasome activation including lipopolysaccharide-induced systemic inflammation, R]

Why a High- Fat/High- Refined Carbohydrate Diet Causes Leaky Gut

As outlined; hydrophobic bile is the primary culprit in the development of diet-induced leaky gut and endotoxemia.
To induce hydrophobic bile, we need a dietary source of fat to induce bile secretion into the intestine.
However, we also need to ensure that the bile is hydrophobic.
This is the role of refined carbohydrates and sugars.
As described in detail IN THIS POST; refined carbohydrates and sugars ‘feed’ the intestinal bacteria which ‘overgrow’ in this fertile environment.
The type of bacteria which grow on sugars are the type of bacteria which deconjugate bile.
Therefore refined carbohydrates and sugars create an excessive increase in the bacteria which deconjugate bile resulting in excessive bile deconjugation.
Since deconjugated bile is more hydrophobic and FXR activating, the mechanistic link between refined carbs/sugars and a detrimental increase in hydrophobic bile becomes clear.

The fact that a COMBINATION of fat WITH refined carbohydrates/sugars are required to induce health dysregulation is supported by the many studies which result in general health IMPROVEMENT when high fat diets are administered which are simultaneously low in carbohydrates.
The diet which is used to reliably initiate health dysregulation and obesity is always high in fat AND refined carbohydrates and preferably, sugar.

Supportive of the role of bacteria in the model of diet-induced endotoxemia: ‘In animals consuming a high- fat diet, antibiotic treatment ameliorated the adverse effects of diet on intestinal permeability, endotoxemia and inflammation’. R]

More evidence which supports the fact that high fat/high sugar diets induce dysregulation VIA alterations to bile comes from a study which analysed the effects of bile acid reuptake inhibitors on fatty liver and metabolic syndrome.

Bile acid reuptake inhibitors prevent the re-absorption of bile from the small intestine for recycling back to the liver.

During the study, mice were given a high fat/ high sugar diet, which caused them to develop all the signs of metabolic syndrome, including fat depositions and inflammation in the liver.

A separate group of mice were given the high fat, high sugar diet in conjunction with an ASBT inhibitor.
Giving the mice an ASBT inhibitor for 16 weeks along with the high-fat/high-sugar diet prevented the fat accumulation and inflammation in their livers.
The levels of triglycerides and cholesterol in the livers of drug-treated mice were more than ten times less than untreated mice, and similar to levels in mice fed a regular low fat diet.
The drug also restored their glucose tolerance and improved insulin resistance. When bile acid uptake was blocked – so were all the symptoms of diet-induced metabolic endotoxemia. R]

This helps to elucidate the mechanism by which FXR activation/inhibition regulates metabolic endotoxemia.
FXR activation activates ASBT to increase bile acid re-absorption.
So strategies which cause FXR inhibition mimic ASBT inhibitors and are preventative of metabolic dysregulation and endotoxemia.

There is a vicious cycle which occurs when firmicutes bacteria expand in response to sugars and refined carbohydrates.
The increase in firmicutes bacteria in the small intestine increases deconjugation of bile.
An increase of unconjugated bile increases FXR activation, which decreases the ratio of chenodeoxycholic acid and increases the ratio of cholic acid in the bile.
This leads to a reduction in the immune control of intestinal bacteria via the TGR5 gut/brain axis. 7.]
A study has found that administration of unconjugated bile (in this case, cholic acid) causes the proliferation of firmicutes and the inhibition of Bacteroidetes.
Firmicutes vastly expanded from 54% of the microbiome in control rats to between 93-98% of the microbiome. R]

This highlights the vicious cycle of unconjugated bile activation of FXR which decreases innate immunity via the hypothalamus.
Reduced immune control of the microbiome results in an increase of firmicutes.
Increases of firmicutes results in further increases of deconjugated bile, which further increases the activation of FXR, which leads to even worse immune control of firmicutes and so on in a spiralling of worsening hypothalamic regulation of health and body composition.
Upon administration of unconjugated hydrophobic cholic acid; ‘of the firmicutes, the Clostridia expanded from 39% in controls to roughly 70%.’
This is important since clostridia are responsible for converting cholic acid to the most potently hydrophobic secondary bile acid of all; deoxycholic acid (DCA). R]

and within the Clostridia, the genus Blautia expanded from 8.3% in control rats to between 55-62%.

Bile Hero - Hydrophilic Taurine Conjugated Bile 

Taurine–conjugated bile acids are emerging as heroic in the bile acid realm.
Taurine conjugated bile is more hydrophilic than either glycine conjugated or unconjugated bile and is therefore more FXR inhibiting and a more specific activator of TGR5.
Taurolithocholic acid is, in fact, the most potent and specific activator of TGR5 of all the types of bile acids known.

As well as effects exerted via activation or inhibition of bile receptors; taurine conjugation of bile has an effect to reduce metabolic endotoxemia due to its propensity to directly activate LPS detoxification enzymes.

Alkaline Phosphatase is an enzyme which detoxifies LPS.

The taurine conjugate of the bile acid chenodeoxycholic acid has been shown to induce a 75-fold increase in alkaline phosphatase enzyme secretion!

Whereas tauroursodeoxycholate caused only a 3-fold and taurocholate induced only a 14-fold increase in alkaline phosphatase enzyme secretion. R]

What this study also highlights is that the TYPE of bile acid matters.
Taurine conjugation of chenodeoxycholic acid was dramatically more effective at inducing the LPS detoxifying enzyme than the taurine conjugate of Ursodeoxycholic acid or cholic acid.
As discussed in THIS POST; chenodeoxycholic acid increases when FXR is inhibited and dietary cholesterol is increased.
As also argued in this post, the dietary strategies which increase the ratio of chenodeoxycholic acid are; low carb diets, intermittent fasting and low fat/’healthy carb’ diets.
It may be that low carb diets rich in meat/fish/eggs and cholesterol have the edge on increasing the ratio of Taurochenodeoxycholic acid, due to the contribution of dietary taurine and cholesterol and the ‘starvation’ of the bacteria which deconjugate bile.

Taurochenodeoxycholic acid (TCDCA) has been found to ameliorate intestinal inflammation and ‘significantly normalize the clinical inflammatory parameters’ R]

Consistent with the model being proposed here; that metabolic endotoxemia and fatty liver is caused by the deconjugation of bile and particularly a reduction of taurine conjugated bile; dietary taurine supplementation significantly reduced hepatic lipid accumulation, liver injury, inflammation, plasma triglycerides, and insulin levels.

A high-sucrose diet resulted in an induction of liver ER stress, which was ameliorated by taurine supplementation.

Treatment with an FXR antagonist also prevented ‘high-fat diet’ induced NAFLD which again supports the model that increased FXR activation due to an increase of deconjugated hydrophobic bile is the primary mechanism behind HFD induced NAFLD. R]

Taurine was effective in treating fatty liver of children with simple obesity regardless of the success/failure of weight control. R]

Evidence indicates that dietary taurine supplementation is able to prevent and/or reverse the problematic deconjugation of bile which occurs during high sugar, high fat diets.

It HAS been shown that dietary taurine DOES increase the ratio of taurine conjugated bile and that this DOES increase bile synthesis (which increases the ratio of chenodeoxycholic acid) and lithocholic acid.

‘Oral administration of taurine for 10 days (to guinea pigs) increased taurine-conjugated bile acids and bile acid synthesis from 4.28 to 7.27.
Also, taurine feeding increased the amount of lithocholic acid in the caecum and large intestine by about 40%. R] (Recall from THIS POST that lithocholic acid is an FXR antagonist and is indicated as a potent promoter of optimal health and longevity)

Other researchers also found that ‘taurine supplementation increases the synthesis and excretion of taurine-conjugated bile acids’ and they concluded that the increased bile acid synthesis was the mechanism behind the reduction in serum and liver cholesterol levels.
This is because of an increase in cholesterol conversion bile acids when bile synthesis is increased. R]
More research showed that rats fed a diet containing fish protein hydrolysate, rich in taurine and glycine, for 26 days had markedly elevated fasting plasma bile acid levels relative to rats fed soy protein or casein.
‘Concomitantly, the fish protein hydrolysate fed rats had reduced liver lipids and fasting plasma triglyceride levels. Furthermore, visceral adipose tissue mass was reduced and expression of genes involved in fatty acid oxidation and energy expenditure was induced in adipose tissues of rats fed FPH.’R]

Another study demonstrated that the choice of dietary protein source (one rich in taurine) is sufficient to increase plasma bile acid levels in high-fat fed rats.
‘Importantly, the elevated plasma bile acid level was accompanied with attenuated diet-induced obesity and ameliorated characteristics of the metabolic syndrome.’ R]

This study excluded the possibility that taurine may be preventing health dysregulation due to its anti-oxidant powers, since tissue taurine concentrations were unchanged by taurine supplementation.
A bile acid sequestrant, (which removes bile and prevents its signalling), prevented the beneficial effects of the taurine-rich supplement on adiposity, triglycerides and hyperglycaemia.
This strongly indicates that alteration of bile metabolism is the beneficial mechanism behind dietary taurine.

Also supporting the role of taurine in beneficial bile signalling, a study found that when obesity-prone male mice were fed high-fat, high-sucrose diets with protein sources of increasing endogenous taurine content, i.e., chicken, cod, crab and scallop, for 6 weeks. The energy intake was lower in crab and scallop-fed mice than in chicken and cod-fed mice, but only scallop-fed mice gained less body and fat mass.
Triacylglyceride, non-esterified fatty acids and glycerol levels were significantly reduced, whilst the plasma HDL-to-total-cholesterol ratio was higher.
Dietary intake of taurine and glycine correlated negatively with body mass gain and total fat mass, while intake of all other amino acids correlated positively.
In fact, dietary scallop protein completely prevented high-fat, high-sucrose-induced obesity whilst maintaining lean body mass and improving the plasma lipid profile in obesity-prone male mice. R]

Alcohol-Induced Leaky Gut

Fatty liver is a symptom of endotoxemia and intestinal permeability.
Other than a high fat/high carb/high sugar diet; the other well known way to induce fatty liver disease and various other manifestations of inflammatory dysfunction, is via excess alcohol.
A recent study found that the risk of developing metabolic syndrome increases the more a person drinks.
The study found that drinkers in the highest category of intensity have a 60 percent greater risk of developing metabolic syndrome than those in the lowest category.
Researchers found that the effect of drinking patterns is independent of age, race, gender, family history of heart disease and diabetes, smoking, physical activity and other risk factors. R]
Another study showed that binge drinking was associated with increased atherosclerotic progression in an 11-year follow-up of middle-aged men.
The progression of atherosclerosis was increased among men who consumed 6 drinks or more on one occasion.
Drinking large quantities of alcohol more than twice a week increased the risk of stroke mortality in men.

I argue that excessive alcohol consumption causes many of the same metabolic/inflammatory symptoms which manifest during high fat/carb/sugar feeding due to the same mechanism of increased LPS translocation from the intestine to the blood stream.

However, the mechanism which leads to the endotoxemia is different during high-fat-diet feeding compared to alcohol feeding.
During binge drinking of alcohol; there is significantly increased permeability, elevated endotoxin level, alterations of intestinal mucus layer and intestinal antimicrobial defence.
Mice with genetic deletions in the LPS signalling pathway are resistant to alcohol induced liver injury.
Deficiencies in Toll-like receptor 4 (TLR4) (the cellular LPS receptor) CD14 (cellular co-receptor for LPS), or intracellular signalling molecules downstream of the LPS receptor are resistant to alcohol-induced liver injury.
In addition, selective antibiotics reduce plasma endotoxin levels and prevent experimental alcoholic liver disease.

I propose here that alcoholic fatty liver disease is induced by a mechanism which increases hydrophobic bile and it this accumulation of hydrophobic bile in the small intestine which is responsible for alcohol-induced intestinal permeability.

I propose that binge drinking alcohol is particularly effective at increasing endotoxemia and inflammatory disorders since it also increases the abundance of the gram negative, LPS- producing bacteria, by preventing the reabsorption of hydrophobic bile.

The mechanism behind alcoholic fatty liver disease has some similarities to non-alcoholic fatty liver disease, but it isn’t exactly the same.
Both alcoholic fatty liver disease and non-alcoholic fatty liver disease are the result of an increase in hydrophobic bile; however this is where the similarity ends.

In NAFLD, the unconjugated hydrophobic bile is caused by excessive bacterial deconjugation of bile, which occurs in the small intestine.
In AFLD, the increase in hydrophobic unconjugated bile is caused by a failure in the liver.
An excess of alcohol reduces the initial conjugation of bile to taurine in the liver.
It means that the bile which is released from the liver in response to fat is unconjugated before it even reaches the small intestine.
Ethanol alters how bile acids are conjugated in the liver.
In a healthy liver, bile acids are conjugated to taurine or glycine in the liver.
This conjugation makes the bile acids more hydrophilic and less toxic.
Without conjugation to taurine or glycine, the bile acids would be more hydrophobic and toxic to the intestine.

Taurine-conjugated bile acids are more hydrophilic and less toxic than either unconjugated or glycine-conjugated bile acids.

Excess dietary ethanol is ‘characterized by a dramatic decrease in taurine-conjugated bile acids and a marked increase in unconjugated and glycine-conjugated bile acids.’ R]

The conjugation of taurine to bile acids is dependent on the hepatic taurine concentration.
Researchers found that the hepatic bile salt taurine to glycine ratio was 30:1 in control rats but 50:50 in ethanol treated rats.

A recent investigation suggested that the reduction of taurine in the liver in ethanol-treated mice is due to the formation of N-acetyltaurine, a metabolite synthesized from taurine and acetate and excreted in urine.

The idea that a deficiency of taurine conjugation of bile is the primary mechanism behind ethanol induced metabolic endotoxemia and intestinal permeability is supported by the finding that taurine supplementation ameliorates the negative effects of ethanol on NAFLD.

Male rats were administered alcohol for 3 months and split into 2 groups.
The taurine supplemented group had less fatty degeneration and inflammation than that of the control and a taurine depleted group.
These in-vivo findings demonstrated that liver disease caused by chronic alcohol consumption can be prevented and reversed by administration of taurine. R]

Binge Drinking Alcohol Increases Hydrophobic Bile but Causes Leaky Gut via Direct Effects (Rather than via FXR Activation)

HOWEVER, whereas NAFLD appears to be due to excessive activation of FXR by unconjugated hydrophobic bile this does not appear to be part of the mechanism behind hydrophobic bile acid- induced AFLD.

In contrast, alcohol appears to have a direct inhibitory effect on FXR. R]
In the development of AFLD, even though there is an increase in unconjugated hydrophobic bile, similarly to NAFLD; the increase in FXR activation does not occur.
Instead, the hydrophobic bile appears to cause intestinal permeability, endotoxemia and inflammation directly, (rather than via FXR activation) and this appears to be due to its hydrophobic ‘detergent-like’ effects on intestinal cells. R]

Gram negative bacteria (which produce LPS) are believed to be more resistant to bile acids than gram positive bacteria. R]
The fact that binge alcohol drinking increases the accumulation of hydrophobic bile is possibly the reason why gram negative bacteria increase in response.
Bile salts are often used for the ‘selective enrichment’ of gram negative bacteria.
Gram negative bacteria flourish whilst gram positive bacteria perish in the high levels of hydrophobic bile induced by binge alcohol drinking. R]
This creates a perfect storm for metabolic endotoxemia: increased intestinal permeability COMBINED with an increase of gram negative LPS- producing bacteria.

Supporting the argument that alcohol directly inhibits FXR, despite increasing the presence of unconjugated bile in the intestine (which usually activates FXR); is the finding that alcohol increases the ratio of chenodeoxycholic acid. R]

This is what would be expected if FXR were being inhibited by alcohol feeding, since FXR inhibition increases bile synthesis which increases the ratio of chenodeoxycholic acid.

Why Saturated Fat Prevents Alcohol Fatty Liver Disease (But Not Non-Alcoholic Fatty Liver Disease)

The difference in the mechanism behind alcohol- induced endotoxemia/fatty liver and diet-induced fatty liver/endotoxemia explains why saturated fat prevents alcohol-induced fatty liver but may make matters worse in diet-induced fatty liver.

Alcohol-induced endotoxemia is the result of reduced taurine-conjugation of bile acids in the liver.
Whereas diet-induced endotoxemia is the result of deconjugation of bile by bacteria in the small intestine.

Saturated Fat Prevents Alcohol-Induced Leaky Gut, by Increasing the Conjugation of Bile to Taurine in the Liver.

A ‘ dose-dependent improvement of ethanol-induced liver pathology and oxidative stress was observed in rats fed alcohol when dietary saturated fat (beef tallow and MCT oil) was substituted for unsaturated fat (corn oil)’
Substituting saturated fat for unsaturated also prevented intestinal inflammation and the disruption of tight junctions.

Researchers have found that a diet high in saturated fat promoted taurine conjugation of hepatic bile acids.
A study analysing the effects of bile acids in Barrets Oesophagus found that ‘a significant increase in the concentration of taurine-conjugated bile acids, especially taurocholic acid and taurodeoxycholic, was detected in the high cow-fat group compared with animals fed the soybean-oil diet.’ R]

Researchers also found that ‘the exchange of dietary lauric and myristic acids (SFA) for linoleic (USFA) acid was associated with decreased synthesis and excretion of bile acids concurrent with reduced hepatic taurine and taurine-conjugated bile acids.’ R]

Increasing Conjugation of Bile with Taurine (with Saturated Fat During Binge Alcohol Drinking) Increases Endotoxin Detoxifying Enzymes ​

Recall that the taurochenodeoxycholate bile acid greatly increases the activity of the endotoxin detoxifying enzyme; alkaline phosphatase.

Consistent with this, other researchers found that ‘long-chain saturated triglycerides and medium chain triglycerides increased the activity and expression of the LPS detoxifying enzyme; intestinal alkaline phosphatase.’
However, in contrast, the same researchers found that, unsaturated fatty acids reduced alkaline phosphatase activity.
Trans- fatty acids were also found to decrease the activity of intestinal alkaline phosphatase activity. R]

It thus becomes clear why unsaturated fatty acids would be required to induce fatty liver in alcohol-fed mice.
A source of fat is required to induce bile secretion.
It must be unsaturated since saturated fat prevents a build up of unconjugated bile by preventing an alcohol-induced decrease in taurine conjugation of bile in the liver (which maintains intestinal alkaline phosphatase activity).

I.e. saturated fat prevents endotoxemic inflammation and associated disorders during binge-alcohol feeding.

Intestinal alkaline phosphatase is not the only LPS detoxifying enzyme which is increased by saturated fat feeding.

A study of the effects of cocoa butter found that it ‘normalized ethanol-increased hepatic endotoxin level in association with up regulation of an endotoxin detoxifying enzyme, argininosuccinate synthase 1 (ASS1).
Knockdown of this LPS detoxifying enzyme; ASS1 resulted in impaired endotoxin clearance and up- regulated cytokine expression (inflammation) R]

When ethanol fed mice are also fed saturated fatty acids; intestinal bacteria are altered in favour of the firmicutes.
Since firmicutes are selectively destroyed by hydrophobic bile; this is also indicative of saturated fatty acid feeding reducing the hydrophobicity of the bile during ethanol feeding (due to increased taurine conjugation in the liver).

Although saturated fat is preventative of fatty liver in alcohol-fed mice; this doesn’t appear to be the case in diet-induced fatty liver.

In non-alcoholic fatty liver disease, ‘substitution of carbohydrate, coconut oil, or beef tallow for corn oil similarly offers no protection against accumulation of fat in the liver nor on the injury to liver cells that causes increases in liver enzymes.’
In alcoholic fatty liver disease, the addition of saturated fat increases tauro-conjugation of bile in the liver, thereby preventing the accumulation of unconjugated hydrophobic bile.
However, in diet-induced NAFLD, the problem of non- conjugation doesn’t occur in the liver; it occurs in the small intestine.
So the addition of saturated fat is not the answer to the problem of unconjugated bile induced by diet.

The problem of diet-induced unconjugated bile must be addressed in the small intestine, where the deconjugating bacteria lurk.
That would be a job for a low carb diet, intermittent fasting and (to an extent) a low fat, ‘healthy carb’ diet.

Note: Although substituting corn oil for carbs, coconut oil or tallow did not alter the amount of fat in the liver (indicative of ME); It DID dramatically decreases lipid peroxidation and the resulting inflammation. The researchers theorized that ‘corn oil probably promotes inflammation both by increasing vulnerability to lipid peroxidation because of its total PUFA content and by decreasing tissue levels of DHA because of its high omega-6-to-omega-3 ratio.’

Taurine as a Source of Sulphur - May Increase Production of  Lithocholic Acid ( the Super Bile Acid)​

Another mechanism by which increased taurine conjugation may have beneficial effects on health is the fact that taurine is a source of sulphur.

The clostridia and bacteroides bacteria which convert primary bile acids to secondary bile acids require sulphur to grow and they require taurine conjugated bile to provide them with that  sulphur.

This would be particularly beneficial when the primary bile is primarily composed of chenodeoxycholic acid, since clostridia would convert it to lithocholic acid.
Lithocholic acid is an FXR antagonist and the most potent activator of TGR5.
Consistent with  these properties,  lithocholic acid has been found to have potent health and longevity effects, including optimisation of body composition. R]

Conclusion ​

Intestinal Permeability and endotoxemia underlie or exacerbate the pathogenesis of a number of the inflammatory disorders which are characteristic of ‘western’ societies.
Activation of AMPK is the most important regulator of ‘leaky gut’ and endotoxemic inflammation.
Therein lies the utility of macronutrient manipulation for the prevention and reversal of endotoxemic inflammatory disorders.
Protein increases AMPK activation via intestinal gluconeogenesis.
Fat increases AMPK activation via increasing bile signals (when levels of intestinal bacteria are healthy).
Dietary carbohydrates increase AMPK activation (when levels of bacteria are adequately controlled by an optimally functioning innate immune system).
Carbohydrate restriction increases AMPK activation by ‘starving’ the bacteria which ‘damage’ bile (when levels of bacteria are inadequately controlled by the innate immune system).

Which dietary strategy will be most effective or ‘safe’ will depend on the starting point of health: Failing AMPK signals causes failing immune control of problematic bacteria and the need for strategies, such as low carbohydrate or low fat diets, , to compensate for this failure.

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