Low Carb, The Microbiome, Bile and AMPK

The physiological mechanisms which control obesity and diseases of the ‘western’ world are gradually becoming elucidated.
In this post, I attempt to synthesise the latest scientific findings and discoveries, to form a coherent picture of how diet interacts with the body to lead to either health or disease and obesity.
There is some speculation, where studies are lacking and some parts of the theory, no doubt, need refining but I believe that the evidence is robust for a logical conclusion about the main mechanisms involved.
I argue that the strategies which are well known for improving chronic health and obesity: increased protein and fibre, the low- carbohydrate diet, the very low-fat (healthy-type carb) diet and intermittent fasting; exert their beneficial effects primarily via increasing two crucial signals in the intestine: intestinal gluconeogenesis and the hormone, GLP-1.
In terms of dietary modification of carbohydrates and fat, I argue that the pathway which is most critical is the modification of intestinal bacteria and bile.
I argue that that the relevance of bacteria, bile, GLP-1 and intestinal gluconeogenesis is due to their effects to modulate AMPK signalling in the hypothalamus (in the brain), which in turn, controls AMPK signalling throughout the rest of the body.

Low carb (and other corrective diets) improve manifold health symptoms and improve body composition by activating the metabolic 'switch' (AMPK)  in the brain.
The pathway involves dietary effects on intestinal bacteria, bile and intestinal signals to the hypothalamus in the brain. 

AMPK – Master Regulator of Health and Body Composition

Hypothalamic AMPK signalling is the ultimate regulator of body composition.
Hypothalamic AMPK also plays a very powerful role in controlling every health system in the body.
The health of the rest of the body can also be directly affected by factors such as smoking, stress and alcohol.

However, I argue that hypothalamic AMPK is the most powerful  regulator of health, since it can mitigate and  even ameliorate the direct negative effects of other inputs, such as smoking and binge drinking.  

In contrast to many other health symptoms which can be affected by more direct routes than via the hypothalamus; body composition is completely controlled by AMPK in the hypothalamus.

This is because AMPK in the hypothalamus is the ultimate determinant of appetite, which is the ultimate  determinant of how much fat we accumulate on our bodies. R] ( Aside from exercise of course!)

Hypothalamic AMPK has also been found to control the amount of energy-‘burning’ brown fat in rodents. If a similar process occurs in humans; this would also be a mechanism by which hypothalamic AMPK affects levels of body fat.  . R]

I argue that any strategy which corrects obesity works via effects on hypothalamic AMPK.
This post has  more detail about the omnipotence of AMPK for health and body composition.

I will briefly outline here how hypothalamic AMPK controls health here, as it is important to understand the primacy and influence of this signal.

AMPK in the Hypothalamus in the Brain: The Energy Rationing System of the Body

Hypothalamic AMPK is the thermostat of the body.
It is responsible for energy distribution to the rest of the body.
It receives signals about energy supply and storage and uses this to determine how energy should be distributed to the rest of the body.
If the signals to the hypothalamus indicate energy abundance, energy is rationed out abundantly to all systems in the body and the whole body functions optimally, since all systems have plenty of energy to perform functions which ensure robust health and wellness.
If the signals to the hypothalamus indicate energy depletion, the hypothalamus rations out energy more sparingly, favouring the functions which are most basic and essential to survival, whilst functions which are more ‘frivolous’, such as the reproductive system become deprived.

The most important hypothalamic response to signals of energy depletion or energy abundance, in terms of body composition, is the effect to increase or decrease the appetite. R]
This is a vital response, since it causes us to seek out food (energy) when energy supplies are indicated to be depleted and causes us to stop eating or food seeking when energy supplies are indicated to be sufficient.
The hypothalamic AMPK switch is the regulator of appetite.
If we want to gain control of an unruly appetite; hypothalamic AMPK is the switch we want to control.
The manifestation of a hypothalamus chronically in energy–depletion mode is excessive appetite, decreased fat ‘burning’ and the many and varied symptoms of western diseases, including the development of obesity and excess body weight.

The Mechanics of Hypothalamic Energy Management

When the hypothalamus receives signals that the body is in a state of energy sufficiency; AMPK in the hypothalamus becomes inhibited.
AMPK inhibition in the hypothalamus is a signal of energy abundance which decreases the appetite and increases the rations of energy generously to the rest of the body.
The effect of AMPK inhibition to increase energy to the body is mediated via the effect of hypothalamic AMPK inhibition to, in contrast, activate AMPK in the body. R]

The optimal state for general health and body composition is AMPK inhibition in the hypothalamus and AMPK activation in the body.

How does AMPK control the amount of energy which is rationed throughout the body?

AMPK controls energy distribution throughout the body via controlling the distribution, amount and quality of the mitochondria. R]

The mitochondria are the ‘factories’ which produce energy from food and oxygen (or stored fat).
Hypothalamic AMPK determines the activation of AMPK throughout the body and this determines the number of energy-producing mitochondria which are ‘allotted’ to each heath system and this determines the effectiveness of each health system and the manifestation of disease symptoms.

These symptoms of failing AMPK and a lack of functional mitochondria include; metabolic syndrome and the many and varied diseases which have been found to be ‘associated’with metabolic syndrome; such as Alzheimer’s disease, PCOS, kidney disease, gout, anxiety, auto-immune disorders, certain cancers and so on (described in detail in this post).

Note: Title should be 'Diseases and Disorders which are Caused or Exacerbated by Chronic Inappropriate Hypothalamic AMPK Activation

Hypothalamic AMPK Controls Health and Weight Loss

In Chronic Disease and Obesity, the Energy Rationing Switch (AMPK)  Malfunctions 

This AMPK energy- rationing system has been very effective at keeping us alive during our evolution through times of scarcity.
However, we now live in very different times.
Scarcity is not a problem most of us face.
Most of us in the western world, have plenty of food at our finger tips (energy supply)and most have us have more than enough body fat (energy stores).
So why do so many of live with the symptoms of a hypothalamus in energy-conservation, energy-restriction mode, with a body functioning at low energy levels and chronically raised appetite?

Why is the hypothalamus not receiving the signals from the body that energy supply and storage is abundant?

The most important signals of energy status, which inform hypothalamic AMPK; are leptin and insulin.
Leptin is released by fat cells and it tells the hypothalamus that fat cells (energy stores) are plentiful.
Insulin is released by the pancreas when we consume food and it tells the hypothalamus that food has been consumed (that energy supply is plentiful).

Inappropriate Hypothalamic AMPK Activation Induces Hypothalamic Leptin and Insulin Resistance

During the development of obesity and the ‘Western’ disease; leptin and insulin fail to be ‘heard’ by the hypothalamus.
This is called insulin and leptin ‘resistance’ and it plays a vital role in the development and maintenance of obesity and failing health.

In this post, I argue that the most critical cause of faulty AMPK signalling in the hypothalamus is the absence of certain crucial signals from the intestine.
These intestinal signals ‘maintain’ appropriate hypothalamic AMPK signalling.
The absence of these vital intestinal signals causes increased hypothalamic AMPK activation, which in turn causes leptin and insulin resistance via increased endoplasmic reticulum stress.

Hypothalamic Leptin and Insulin resistance  are initiated by this faulty (inappropriately activated) AMPK signal. R]

The increased leptin and insulin resistance exacerbates AMPK activation which further leads to worsening leptin and insulin resistance and thus a vicious cycle of failing AMPK in the hypothalamus manifests.
This is just one of the many vicious cycles which are set in motion, once hypothalamic AMPK begins to malfunction, which compounds the problem and contributes to  the stubborn nature of obesity and failing health.

If we want to find the 'root cause' of obesity and 'western' disease, we need to know what causes the initial inappropriate activation of hypothalamic AMPK, which triggers the leptin and insulin resistance.
I argue, in this article, that the initial trigger of excessive hypothalamic AMPK activation is the absence of certain vital signals from the intestine. 

These signals are required for the proper, healthy function of hypothalamic AMPK.

The inhibitory effect of these intestinal signals on hypothalamic AMPK are required to prevent inappropriate activation, which leads to leptin/insulin resistance and the whole spectrum of 'western disease' and obesity. 

When the critical intestinal signals are down-regulated or absent, failing health and body composition ensues.
When  these signals are upregulated; chronic disease and obesity are reversed and  prevented, even when fed highly obesogenic diets. 

The various strategies which are known to improve metabolic health do indeed upregulate these important intestinal signals.

For example: the gastric bypass is the most effective strategy currently available for reversing failing metabolic health and obesity.
It has been identified that the mechanism which accounts for these profound improvements;  is the enhancement of intestinal signals.
The dramatically corrective effects on health and obesity, observed following the gastric bypass are evidence of the power of these intestinal signals to regulate and correct chronic health disorders and obesity.  

It also suggests that the failure of these intestinal signals is the initial trigger for the vicious cycle of failing health and development of obesity.

I this article; I will attempt to understand how diet induces the dysregulation of these crucial signals from the intestine. 
I will also attempt to describe how various dietary strategies, such as low carb diets, low fat diets and intermittent fasting improve and correct these intestinal signals to lead to the reversal of failing health and obesity. 

GLP-1 and Intestinal Gluconeogenesis – Key Regulators of Hypothalamic AMPK

GLP-1 and Intestinal Gluconeogenesis are intestinal signals which control the metabolically healthy response to the fed and fasted state.
Deficiency of these signals manifests in the poor metabolic response to food, as well as to longer periods between meals.

The Glucagon-Like Peptide 1 Hormone 

Between meals and during fasting, the liver produces glucose to maintain blood glucose levels at a constant in the blood.
When we consume dietary gluose, it is important that the liver stops producing glucose as this would result in too much glucose in the blood: the glucose from the diet, as well as the glucose produced by the liver.
Insulin is released from the pancreas in response to dietary glucose and the job of insulin is to switch off the liver’s own production of glucose in the presence of the addition of dietary glucose to the blood glucose pool.

GLP-1 controls the appropriate insulin response to dietary glucose via the hypothalamus and also via direct action on the pancreas. R]
When GLP- 1 is failing, insulin and pancreatic beta- cell function declines. R]
It has been revealed that the improved insulin response observed with gastric bypass, for example is due to an increase in the activity of GLP-1.
“Human experiments with a GLP-1 receptor antagonist have shown that the improved insulin secretion, which is responsible for part of the anti-diabetic effect of the operation, is reduced and or abolished after GLP-1 receptor blockade. Also the postoperative improvement of glucose tolerance is eliminated and or reduced by the antagonist, pointing to a key role for the exaggerated GLP-1 secretion.” R]
In this study , GLP-1 treatment reduced insulin resistance via activation of central GLP-1 receptors (in the hypothalamus) in mice fed a high-fat diet’
Researchers concluded from another rigorous study that ‘GLP-1R agonists influence body weight by regulating either food intake or energy expenditure by inhibiting hypothalamic AMPK’
R]

Also, ‘GLP-1 treatment decreased liver insulin resistance , which ‘reinforced the inhibitory action of insulin on VLDL-triglyceride production’. And by ‘acting as an energy signal to the hypothalamus, GLP-1 potently inhibits food intake by increasing satiety. R]

By inhibiting AMPK in the hypothalamus and activating it throughout the body; GLP-1 agonists put the whole spectrum of ‘modern’ health disorders in to reverse. R]

Although GLP-1 clearly plays a very important role, there is another intestinal signal which I argue is of equal importance in the maintenance of appropriate hypothalamic AMPK signals.

GLP-1 is the optimal intestinal response to the fed state (glucose influx.)
But of equal importance is the intestinal response to the fasted (or low carb) state, which occurs when dietary glucose influx is absent.

Intestinal Gluconeogenesis

The healthy glucose response to the fasted or low dietary carbohydrate state is an increase in intestinal gluconeogenesis (IGN).
Intestinal gluconeogenesis (IGN) is the endogenous production of glucose by the small intestine.
In a healthy individual, when dietary glucose influx falls, during longer periods between meals, during the overnight fast or during low carbohydrate dieting; blood glucose levels are maintained by endogenous glucose production by the body.
This is called gluconeogenesis (which means the creation of glucose).
I argue that the most important element of gluconeogenesis, in terms of hypothalamic AMPK regulation, is intestinal gluconeogenesis (IGN). R]
Intestinal Gluconeogenesis is the creation of glucose by the small intestine.

Intestinal Gluconeoegenesis Shares  Responsibility  (With the Liver) for Maintaining Glucose Levels in the Absence of Dietary Carbohydrates 

Up to one third of the glucose produced by the body during fasting is produced by the intestine after 72 hours of fasting. R]

Intestinal Gluconeogenesis is an Important Satiety Signal, Which has a Corrective Effect on Metabolic Health ​

In contrast to glucose production by the liver, which contributes to hyperglycaemia and type-2 diabetes; ‘glucose release into the portal vein by the intestine increases glucose uptake and reduces food intake.’ R]
Glucose released in to the portal vein (by the intestine) is a very important satiety signal. R] R]
This is a major element of the satiety mechanism of dietary glucose.

When we consume carbohydrates, glucose is absorbed from the small intestine into the portal vein for transport to the liver.
The glucose in the portal vein causes a signal to be sent to the hypothalamus which potently induces satiety ( a function of AMPK). R]
When the metabolically healthy person is between meals, the drop in dietary glucose influx to the portal vein which would result in a drop in satiety is compensated for by an increase in intestinal gluconeogenesis.
In a healthy individual; during longer periods between meals and in the fasted state; intestinal gluconeogenesis provides the portal vein glucose signal to maintain satiety.
I argue that the provision of glucose into the portal vein by intestinal gluconeogenesis and this satiety mechanism means that we are not craving for more glucose the moment that dietary glucose influx falls.
Without this back up endogenous glucose production by the small intestine, we become dependent on frequent dietary glucose intake to maintain the portal vein glucose satiety signal.
The greater the deficiency in this intestinal gluconeogenesis system, the poorer is the appetite control between meals and the more difficult it will be to last more than an hour or two before we are seeking out more glucose to maintain the feeling of satiety.
And since the intestinal gluconeogenesis satiety signal exerts its satiating effects via energy sufficiency signals to the hypothalamus, the effects of the absence of this hypothalamically replenishing signal are seen throughout the body in the form of failing metabolic health and the many and varied associated disorders.
Mice which lack a necessary enzyme for intestinal gluconeogenesis, exhibit leptin resistance, fasting hyperinsulinemia, glucose intolerance, insulin resistance and a deteriorated pancreatic function, despite normal diet with no change in body weight.

Mice which were unable to undergo IGN were 50% more leptin resistant.
These IGN-deficient mice also became metabolically derailed faster in response to a high fat/high sugar diet.

The researchers concluded that “the IGN signal is mandatory for the hypothalamic function. Furthermore, its deficiency generates proneness to metabolic diseases.” R]

The key role of IGN as a regulator of metabolic health is strongly supported by the fact that increased IGN is essential for the success of the gastric bypass.

Without an increase in IGN, the gastric bypass does not exert its powerful metabolically corrective effects.
The gastric bypass corrects metabolism by increasing the IGN signal. R] R]
To further emphasise that key role of IGN in health and body composition regulation, it has been found that an increase in intestinal gluconeogenesis is the mechanism behind the metabolically corrective and satiating power of protein and fibre.

Intestinal Gluconeogenesis is the Pivotal Mechanism Responsible for the Spectrum of Health Improvements and Reversal of Obesity Observed with Bariatric Surgery 

Protein Induces Satiety and Metabolic Benefits by Increasing Intestinal Gluconeogenesis

Protein intake is known to induce higher satiety in animals and humans and to rapidly improve glucose control in obese diabetic patients.
Protein feeding was shown to induce a strong induction of the expression of enzymes involved in gluconeogenesis in the small intestine.

Following a protein meal, rats actually release glucose from the gut.

When an equivalent quantity of glucose, (as the amount released by the gut following protein intake) was infused into the portal vein of mice not fed protein; they decreased their food intake by the same amount as the protein fed rats.

This strongly suggests that the intestinally produced glucose is responsible for the appetite reduction in response to protein intake.

They showed that the hypothalamus of rats is similarly activated following a high protein meal as it is following a chow meal plus glucose infusions in to the portal vein. R]

Protein increases intestinal gluconeogenesis by antagonising opioid peptides in the portal vein. R] ‘Mu Opioid Receptor-knockout mice do not carry out intestinal gluconeogenesis in response to peptides and are insensitive to the satiety effect induced by protein-enriched diets.’

Short-Chain Fatty Acids and Fibre Induce Satiety and Metabolic Benefits by Increasing Intestinal Gluconeogenesis

Short- chain fatty acids are produced by certain bacteria when they feed on fibre in the colon.
Also, certain dietary approaches, such as low carb, very low-fat diets, high polyphenol or intermittent fasting alter the balance of bacteria throughout the intestine in favour of the short-chain fatty acid (propionate)- producing bacteria such as Akkermansia Muciniphilia.

Propionate and butyrate both activate intestinal gluconeogenesis.

Mice which are genetically altered so that they don’t undergo intestinal gluconeogenesis; do NOT experience the metabolic benefits of body weight improvement and glucose control seen as a result of short-chain fatty acids and dietary fibre intake.

It is clear that IGN and GLP-1 are vitally important intestinal signals which maintain the sensitivity of the hypothalamus, metabolic health and proper body fat regulation.

Intestinal gluconeogenesis and GLP-1 secretion is induced in the intestine by an increase in the important chemical messenger Cyclic AMP (cAMP).R] R]

Since Camp induces both GLP-1 and IGN, it would be logical to say that cAMP signalling would be an important target for improving intestinal signals to the hypothalamus.

If we accept that IGN and GLP-1 are the key regulators of general health and body composition, we now need to know how diet modulates these signals.

I argue here that intermittent fasting, low fat, low carb and low GI diets exert their metabolic benefits via manipulations of bile.
And the relevance of bile is that bile, via activation (or inhibition) of bile receptors, is a potent regulator of intestinal cAMP, GLP-1 secretion and intestinal gluconeogenesis.

Optimal Bile Signalling Increases Intestinal cAMP which Activates IGN and GLP-1 Secretion

Evidence of the power of bile modulation to correct metabolic health and obesity comes from the emerging understanding of how the gastric bypass exerts its powerfully corrective effects.

In contrast to gastric band surgery, which alters the size of the stomach, gastric bypass removes part of the small intestine.
Only gastric bypass patients, and not gastric band patients, exhibit very early metabolic improvements (e.g. decreased hunger and improvements in fasting glucose) disproportionately to weight loss.

Researchers found that two weeks after surgery, gastric bypass mice ‘dramatically reduced food intake and recovered almost normal insulin sensitivity,’ while gastric band and sham-operated mice still exhibited marked insulin resistance.
The Gastric band also has a much higher rate of weight regain.
This indicates that the metabolic and longer-term improvements in appetite observed with gastric bypass, compared to the gastric band, are a result of changes occurring in the small intestine.

Many studies support the theory that it is alterations in intestinal bile signalling which is the mechanism behind the success of the gastric bypass.

In support of this theory; another gastric procedure: bile diversion therapy, which diverts bile to the end of the small intestine, has been shown to be as effective as the gastric bypass in correcting obesity and metabolic health.
Researchers concluded that “only bile diversion to the ileum (the end of the small intestine) results in physiologic changes similar to gastric bypass.”
Both gastric bypass and bile diversion therapy share the feature that bile is delivered directly to the bile receptors which are primarily located at the end of the small intestine.
Both procedures eliminate the long journey of bile along the small intestine.

The question then is: What happens to bile in the small intestine, which reduces optimal activation of the bile receptors located in the ileum?
Are they reabsorbed in the small intestine preventing them from reaching the bile receptors in the ileum or are they damaged in some way in the small intestine in a manner which alters the way in which the receptors are activated?
Before attempting to answer this question, it is necessary to understand the two important bile receptors; TGR5 and FXR.

TGR5 Bile Acid Receptor – Critical Regulator of  Health and Obesity (via AMPK)

The bile acid receptor TGR5 is emerging as a crucial metabolic switch.
The importance of TGR5 derives from its power to activate cAMP, which activates both intestinal gluconeogenesis and GLP-1, depending on the dietary glucose context.

The activation of TGR5 increases cAMP which converts intestinal proglucagon to either GLP-1 or glucagon, depending on the dietary glucose context. R]
“A TGR5 activator effectively promoted GLP-1 release, improved hyperglycaemia and preserved the mass and function of pancreatic β-cells.”
In the presence of dietary glucose, TGR5 activation of cAMP converts proglucagon into GLP-1 to ensure the optimal insulin response.
In the absence of dietary glucose, TGR5 activation of cAMP converts proglucagon into intestinal glucagon to ensure the optimal intestinal production of glucose. R] R]
Recall that IGN and GLP-1 are the vital intestinal signals which maintain the appropriate AMPK signalling and leptin/insulin sensitivity of the hypothalamus.
If TGR5 is failing to effectively induce the conversion of pro-glucagon to either GlP-1 or intestinal glucagon (and thereby adequately activate intestinal gluconeogenesis); the whole spectrum of metabolic health goes in to decline. R] R]

TGR5 is a pivotal lever which controls the effectiveness of glucose control (via controlling intesinal GLP-1 and glucagon production) in the fed and fasted state and this ultimately controls overall metabolic and associated general health.

The crucial role of TGR5 as metabolic regulator is supported by many studies:
TGR5 activation enhances energy expenditure, increases oxygen consumption, prevents obesity, and decreases insulin resistance in a mouse model of obesity. R] R]
In human brown adipocytes (fat cells) and skeletal myocytes, bile acids interact with TGR5 and thereby activate the key enzyme that converts thyroxin (T4) into (T3), a major component involved in cellular basal metabolism.’ R]
Researchers have concluded that TGR5 pathways are ‘extremely important’ in gastric bypass 19] and ‘central to the metabolic improvements observed’ with vertical gastric sleeve.

Vertical gastric sleeve alters both bile acid levels and bile composition in mice, resulting in enhancement of TGR5 signalling in the ileum and brown adipose tissues, concomitant with improved glucose control and increased energy expenditure. ‘

Other researchers concluded that ‘convergent findings point to bile acid–TGR5 interaction as a key regulator endpoint of basal metabolism regulation’ R]
The bile acid, Sodium taurochenodeoxycholate (TCDC) acutely stimulates insulin secretion of b-cells, presumably due to enhancement of GLp-1 secretion. R]

However, TGR5 isn’t the only bile receptor which controls metabolic health and body composition.
There is another bile receptor which has an opposite effect to TGR5.
This is the intestinal FXR receptor.
In contrast to TGR5 activation, intestinal FXR activation leads to metabolic dysregulation and loss of body weight control.
A strategy which optimises metabolic health must not only activate TGR5, it must also inhibit FXR activation.

FXR – The Other Critical Bile Receptor (Which Also Regulates Hypothalamic AMPK)

FXR Activation Negatively Regulates Metabolic Health 

Researchers examining the role of FXR concluded that 'intestinal FXR activation impaired energy expenditure, and further aggravated obesity, and glucose intolerance, while intestinal FXR inhibition exerted metabolic benefits.R]

Whilst increased TGR5 activation protects against diet induced obesity, a reduction in intestinal FXR activation is protective against diet induced obesity and metabolic syndrome.
Mice bred to lack FXR receptors were resistant to diet-induced-obesity, indicating that FXR activation is a vital part of the process of metabolic dysregulation in response to an obesogenic diet.
R]

Bile acid sequestrants are known to improve glucose control and general /metabolic health.
Bile acid sequestrants bind bile and prevents it from activating FXR in the small intestine.

FXR Activation Reduces Intestinal Pro-Glucagon (the  Precursor of GLP-1 and Intestinal Gluconeogenesis)

A mouse study demonstrated that modulation of FXR signalling via a bile acid sequestrants (which would reduce FXR signalling) increased intestinal pro-glucagon gene expression and improved blood glucose levels.

Recall that intestinal pro-glucagon is the precursor for GLP-1 and intestinal glucagon (which induces intestinal gluconeogenesis).
Since, both GLP-1 and IGN are vital regulators of metabolic health; the effect of FXR activation to reduce intestinal pro-glucagon provides an obvious mechanism by which FXR activation contributes to health and body composition dysregulation.
If there is insufficient intestinal proglucagon, there will be insufficient intestinal GLP-1 and intestinal gluconeogenesis, which induces hypothalamic AMPK failure and the decline of systemic health.

FXR signalling in ileum biopsies of humans positively correlates with body mass index. R]
I argue here that the heightened FXR signalling in those with excess body fat is in fact causal of the problem. R]

FXR Activation Increases Bile Reabsorption in the Small Intestine

Another mechanism which is an excellent candidate explanation for the negative effects of  FXR activation  is the fact that FXR activation induces the reabsorption of bile form the intestine.
When bile is removed from the small intestine due to FXR activation; it doesn’t reach the end of the small intestine and the colon, which are the  sites richest in the metabolically corrective TGR5 receptors.
If the bile is of a type which doesn’t activate FXR and doesn’t get taken back up in the small intestine; it will reach the colon and the small intestine for optimal activation of TGR5.
A study found that administration of a bile (taurocholate) enema directly to the colon of healthy men caused a prompt increase of Glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) (both satiety hormones) secretion by the L-cells of the intestine which are most densely located in the colon and rectum and that this was due to TGR5 activation.
This was accompanied by increased fullness, in a dose-dependent manner. R]

FXR Activation Reduces Bile Acid Synthesis 

Also contributing to the dysregulation; is the fact that FXR activation down-regulates bile acid synthesis.
This is because FXR activation is a negative feedback mechanism to reduce bile acid synthesis in the presence of high levels of  hydrophobic unconjugated bile acids.
High levels of unconjugated hydrophobic bile acids activating FXR in the intestine sends a signal to the liver to reduce bile acid synthesis.

The relevance of this is the fact that bile acid synthesis has a pivotal effect on metabolic health.

Mice over-expressing the enzyme which activates bile acid synthesis were protected from diet-induced-obesity, insulin resistance, and atherosclerosis and gall stones. R]
A candidate mechanism for this phenomenon is the effect of increased bile acid synthesis to alter the composition of bile acids which make up the bile.
When bile acid synthesis is up- regulated, the ratio of chenodeoxycholic bile acids increases and the ratio of cholic bile acids decreases. R]

Another explanation may simply be that increased bile synthesis increases the concentration of bile acids in the bile, which increases the potential for TGR5 activation. 

Why the Ratio of Chenodeoxycholic (CDCA) Bile Acids, in Bile,  Matters 

There are several candidate mechanisms which could explain this:

There are far more studies in rodents than humans examining mechanisms but these studies can give us clues.

In rodents the mechanism looks very clear.
In rodents, an increase in bile synthesis causes an increase in the ratio of bile acid muricholic acid.

A study found that ‘mice abundant in muricholic bile acids show resistance to high-fat diet induced steatosis, weight gain, and to impaired glucose metabolism ‘. R]
In rodents, tauromuricholic acid is a potent FXR inhibiting TGR5 activator which optimises metabolic signalling. R]
Muricholic acid is made from the conversion of chendodeoxycholic acid in rodent liver.
This conversion doesn’t happen in humans but chenodeoxycholic does appear to be the analogous metabolically corrective bile acid in humans. R]
‘Oral intake of CDCA increased plasma concentrations of GLP‐1, C‐peptide, glucagon, peptide YY, neurotensin, total bile acids’ R]
‘ Treatment of 12 healthy female subjects with CDCA for 2 days resulted in increased brown adipose tissue activity. Whole-body energy expenditure was also increased upon CDCA treatment.’

Chenodeoxycholic Acid is Converted (in the Colon) to Potent TGR5 Activating Bile Acids: Lithocholic  and Ursodeoxycholic Acid 

Although chenodeoxycholic itself appears to have beneficial metabolic properties, it may be that the main benefit of chenodeoxycholic lies in the type of secondary bile acids to which it is a precursor.
Chenodeoxycholic acid is converted by bacteria to l
ithocholic acid and Ursodeoxycholic acid in the colon.

Lithocholic acid is an FXR antagonist AND the most potent TGR activator.
Taurolithocholic acid is the most potent TGR5 activator of all.
R] R]

Ursodeoxycholic (UDCA) acid is also formed by bacterial dehydroxylation of chenodeoxycholic in the colon and UDCA similarly has FXR antagonistic, TGR5 activating properties.

Following gastric bypass in humans, metabolic improvements were secondary to surges in Ursodeoxycholic acids (UDCA) and its and its glycine and taurine conjugates. R] R] R] R] R]
Consistent with what we know about TGR5 activation; lithocholic acid has been indicated to have potent effects to improve metabolic/general health and increase longevity. R]
When researchers exposed yeast to lithocholic acid, they created exceptionally long-lived yeast mutants that they dubbed "yeast centenarians."
These yeast mutants lived five times longer than their normal counterparts because their mitochondria - the part of the cell responsible for energy production - produced more energy than in normal yeast.
These effects are consistent with AMPK activation (which improves the function of the whole body).

The other benefit of an improved chenodeoxycholic ratio is reduced production of cholic acid’s secondary bile acid, deoxycholic acid (DCA), which is a potent hydrophobic FXR activator and dysregulator of health. R]

Acknowledging the beneficial effects of increased bile acid synthesis ; it is interesting to point out some factors which are known to increase bile acid synthesis.

Other Factors Which Increase  Bile Acid Synthesis

In rats, cholesterol feeding increased synthesis of bile acids by 3- to 4-fold, especially that of chenodeoxycholic acid (mainly À-Muricholic acid in the rat), decreasing the cholic acid/chenodeoxycholic acid (CA/CDCA) ratio in all rats. R]
This mechanism may play a role in the metabolic benefits observed with low-carbohydrate diets, which emphasise cholesterol-rich foods, such as eggs and meat. 
The high cholesterol intake would increase bile acid synthesis, which is strongly indicated to be metabolically beneficial.
Note: it is possible that high cholesterol feeding has a different metabolic effect in a dietary context of high refined-carbohydrates and sugars.

Bile Acid Synthesis is a Major Regulator of  Cholesterol Levels 

Cholesterol intake increases bile acid synthesis and bile acid synthesis reduces levels of cholesterol in the blood.
The understanding that FXR activation controls bile acid synthesis may provide a mechanistic link between cholesterol levels and general/metabolic health.
Cholesterol is the raw material from which bile is made.
When bile acids are synthesised, the hepatic demand for cholesterol is met by increased hepatic cholesterol synthesis and by plasma clearance of lipoproteins from the blood, such as LDL.
This is a ‘major mechanism’ by which blood cholesterol levels are kept within a healthy range.

When FXR is inhibited, bile acid synthesis increases, which 'pulls' cholesterol from the blood to provide the raw materials for bile synthesis.
If blood cholesterol rises high, this may be indicative of reduced bile synthesis, which is indicative of increased FXR activation, which is known to be metabolically disruptive.
This provides a mechanistic link which can (at least partly) explain why high cholesterol and metabolic syndrome/obesity correlate with each other.

Low Carbohydrate Diet Reduces Cholesterol by Improving/Increasing  Bile Synthesis

These phenomena may also offer an explanation for why statins are associated with higher diabetes risk.
Cholesterol-lowering Statin drugs reduce total bile acid production by as much as 30 percent, possibly by interfering with the conversion of cholesterol to bile. R]
Statin- induced down-regulation of bile synthesis would have a negative effect on bile composition which would ultimately reduce TGR5 activation and increase FXR activation with a consequent decline of glucose control and metabolic health.

Glucose and insulin are also major factors which increase bile acid synthesis.
So in a healthy metabolic context, glucose and insulin would have beneficial metabolic effects via increasing bile acid synthesis and altering the bile ratio in favour of the TGR5 activating bile acids.
The problematic nature of glucose occurs in a failing metabolic context, whereby glucose may have detrimental effects on intestinal bacteria which affects bile signalling (as I will argue...)
The fact that glucose and insulin can have this positive effect on bile acid synthesis (in a metabolically corrected/healthy physiological back ground) may be behind the reported beneficial effects of carb cycling, cheat days/meals and also high healthy-type carb/low fat diets.

How Bile. Fibre and Protein Affect Intestinal Proglucagon to Optimise Metabolic Health and Weight Loss

To summarise: we want to increase and accumulate intestinal proglucagon. 
This matters because; if we have adequate proglucagon, we will respond optimally to the fed and fasted state.
When we consume carbohydrates,  we will produce adequate GLP-1 to optimise the insulin response.
When we are on a low-carbohydrate diet, or fasting; intestinal gluconeogenesis will be induced optimally. 
When GLP-1 and intestinal gluconeogenesis are activated optimally, we respond with optimal satiety and health to carbohydrates and also to the low-carbohydrate/fasted state. 
Since a low carbohydrate diet is one of the strategies which is used to improve intestinal proglucagon accumulation; the most relevant part of this picture (for people on a low carb diet) would be the enhancement of intestinal gluconeogenesis. 

Is FXR Inhibition the Mechanism Behind Metformin?

A recent study found that intravenous metformin administration did not reduce hepatic glucose production, although infusion of metformin into the intestine did reduce the liver production of glucose. R]

This indicates that metformin exerts its beneficial effects on glucose metabolism via actions inside the gut.

‘Metformin increases the bile acid pool within the intestine, predominantly through reduced re-absorption in the small intestine.’

Metformin induced AMPK in the intestine which binds directly to FXR and represses its activity.
Metformin is an FXR inhibitor.

This prevents the re-uptake of bile in the intestine, increasing the intestinal bile acid pool available to activate TGR5 and also increases bile acid synthesis, which alters the ratio of bile in favour of chenodeoxycholic acid and its secondary counterparts, the potent TGR5 activators; UDCA and lithocholic acid.

Before I specifically examine different types of diet and how they may be specifically affecting bile and FXR/TGR5 activation, it is necessary to explain the theory of how bacteria in the small intestine interacts with bile to affect bile signalling.

As discussed, gastric bypass and bile diversion therapy surgery both have powerful effects to reverse obesity and failing metabolic health.
What is the event in the small intestine which affects bile and which is prevented by these procedures?
Both procedures prevent the passage of bile along the length of the small intestine.
I argue that the event in the small intestine which is prevented by these procedures is the interaction of bile with the small intestinal microbiome.
The microbiome is known to alter bile and thereby affect its signalling properties.

Although there is a dearth of studies in humans, the mechanism by which the microbiome primarily regulates metabolic health and body composition in rodents has been well elucidated.
We can take major clues from these studies and weigh them up with the rest of the available evidence;  to infer if an analogous process is occurring in humans.

The Small Intestinal Microbiota ‘Damages’ Bile

Researchers have concluded that the intestinal microbiome ‘has a major regulatory effect on the bile acid profile’. R]
Other researchers concluded that ‘through defined enzymatic activities, the gut micro biota can significantly modify the signalling properties of bile acids and therefore can have an impact upon host health’ R] R]

Other studies led researchers to conclude that:

 Microbial modification of bile in favour of bile acids which activate FXR is indeed the mechanism by which the gut microbiota promotes diet-induced-obesity and associated phenotypes. R] R] R]

In rodents, the mechanism by which the intestinal microbiome modulates metabolic health is due to a particular property of certain bacteria to deconjugate bile.

The Intestinal Microbiome Regulates Metabolic Health and Obesity due to its Ability to Deconjugate Bile 

Bile acids are, being acidic; hydrophobic and have toxic effects on cells.
To make them more hydrophilic and less damaging to the cells of the intestine, they are joined to either taurine or glycine in the liver. This is called conjugation.
These taurine/glycine conjugated bile acids are secreted into the intestine.

In a metabolically healthy individual; the conjugated bile inhibits FXR, which increases bile synthesis (via a positive feedback effect)  and this maintains  a large pool of primarily chenodeoxycholic bile acids.
This large pool of chenodeoxycholic acid optimally activates TGR5 and inhibits FXR to maintain good metabolic health and leptin sensitivity.

The problem occurs when there is an excess of certain types of bacteria in the small intestine.
The problematic bacteria in the small intestine are those which are known to deconjugate bile.
This type of bacteria has the ability to remove the taurine and glycine conjugates from the bile acids, transforming them into the unconjugated hydrophobic bile acid.
Since unconjugated bile acids are more damaging to the intestine, they are recycled back to the liver for reconjugation.
This occurs due to the propensity of unconjugated bile acids to activate FXR and it is FXR activation which causes these hydrophobic bile acids to be reabsorbed and recycled to the liver.
As discussed, excessive activation of FXR leads to metabolic dysregulation.
High levels of unconjugated bile acids in the small intestine would therefore lead to increased FXR activation and ultimately, metabolic dysregulation.
Unconjugated bile acids are also more likely to be passively reabsorbed in the small intestine. R]
It is possible that early re-absorption of unconjugated bile may also have an effect to reduce the activation of TGR5 and affect metabolic health in this way.
To compound the problem and create a vicious cycle of worsening metabolic regulation; unconjugated bile, by activating FXR and decreasing bile synthesis increases the ratio of cholic acid.
Unconjugated cholic acid has been shown to further increase the type of bacteria which deconjugates bile (the firmicutes), thereby increasing bacterial deconjugation of bile.
But unconjugated bile, by increasing the proportion of firmicutes in the microbiome, also results in ‘significant expansion’ of the dehydroxylating bacteria which convert the primary cholic acid to the secondary bile acid; deoxycholic acid.

The secondary bile acid, deoxycholic acid is the most hydrophobic, most potent FXR activator of all.

Researchers reported observing that an expansion of the firmicutes results in ‘a 1,000 fold increase in the levels of bile acid 7α-dehydroxylating bacteria (which form the most hydrophobic secondary DCA bile) by feeding mice CA.’ R]

Problematic Bacteria in the Small Intestine Deconjugate Bile due to Increased Bacterial Bile Salt Hydrolase Activity

The ability of small intestinal bacteria to deconjugate bile is due to the action of the enzyme: bacterial bile salt hydrolase.
Bacterial bile salt hydrolase is a bacterial enzyme which deconjugates bile salts. R]
A small intestinal microbiota which is rich in bacteria with bacterial bile salt hydrolase activity will result in bile which has a higher ratio of unconjugated (‘damaged’) bile acids.

Researchers studying this phenomenon, concluded that bacteria modulates FXR signalling in the intestine by ‘altering the composition and concentrations of FXR agonist and antagonist.’ R]

‘FXR agonist enhances while FXR antagonist suppresses obesity, NAFLD and insulin resistance.’

The FXR antagonists and agonists the researchers were referring to, was the ratio of conjugated and unconjugated bile acids, (as controlled by bacterial bile salt hydrolase activity). 

The important role of bacterial bile salt hydrolase to regulate metabolic health via bile modification was supported by a study of mice given CAPE, a bacterial bile salt hydrolase inhibitor. R]

CAPE predictably increased the levels of conjugated bile salts (as it inhibited BBSH activity, which deconjugates bile), particularly increasing the levels of the conjugated bile salt tauro- muricholic acid
Tauro- Muricholic acid is a known FXR antagonist.

The bacterial bile salt hydrolase inhibitor increased the levels of conjugated bile, which also appears to have altered the TYPE of bile salt, in favour of muricholic acid.
This increase in muricholic acid is presumably due to the decreased activation of FXR by unconjugated bile which causes an increase in bile synthesis which alters the composition of bile in favour of muricholic acids (in rodents) or analogously, chenodeoxycholic acid (in humans).

The bacterial bile salt hydrolase inhibitor and the increase in conjugated bile inhibited hepatic glucose production ‘substantially’ as well as having antioxidant, anti-inflammatory, anti-obesity and anti-diabetes effects.

The mechanistic role of bacterial deconjugation of bile is afforded support by other studies which modified levels of intestinal bacteria.

Both germ (bacteria) free and mice treated with certain antibacterial agents had greater accumulations of the conjugated tauro- muricholic acid (due to a reduction in BBSHI activity to deconjugate the bile) which inhibited FXR signalling and improved obesity and metabolic parameters. R] R]

The mice in the studies treated with antibiotics which experienced an increase in conjugated bile salts and improved metabolic parameters had notable reductions in lactobacillus bacteria and enterobacter
Both of these types of bacteria are known to have potent bacterial bile salt hydrolase activity. R]
Consistent with the model, enterobacter has been shown in several studies to be linked to obesity. R]

Conjugated Bile Prevents/Reverses Metabolic Failure and Obesity by Inhibiting the FXR Bile Receptor

Researchers wanted to confirm the mechanistic pathway by which a higher ratio of conjugated bile salts improves metabolic health. R]
Since conjugated bile acids are ‘typically broken down by lactobacillus in the small intestine’, they had to choose a conjugated bile acid which was resistant to bacterial damage.
They chose glycine-β-muricholic acid (Gly-MCA).
This bile salt, which was resistant to deconjugation;  inhibited FXR signalling exclusively in the  intestine, and prevents, or reverses, high-fat diet-induced and genetic obesity, insulin resistance and hepatic steatosis in mice.

Mice which were treated with an FXR agonist, thereby preventing the Gly-MCa antagonism of FXR and mice which were bred to lack FXR in the intestine, were unresponsive to the metabolic benefits of Gly-MCa.

The fact that mice which completely lacked FXR receptors did not experience metabolic benefit, indicates that the absence of FXR activation has a particularly positive effect. 
It is not just the absence of a negative signal; when FXR is not being activated (or being inhibited); FXR signalling becomes positive. 

Conjugated Bile Negatively Regulates FXR Signalling, which Reduces Cholesterol and Free Fatty Acid Absorption. 

A recent study revealed that conjugated bile acid-induced FXR inhibition caused less dietary cholesterol to be absorbed.

Faecal excretion of cholesterol was increased and there was a strong trend for doubled faecal excretion of free fatty acids.R]
This may be the mechanism behind the purported ‘calorie advantage’ of low carbohydrate diets.

The Problematic Bacteria Which Deconjugate Bile

Lactobacillus is known to have strong bacterial bile salt hydrolase activity to deconjugate bile acids. R] R]

A human study found that an obesogenic diet is ‘associated with increased abundance of lactobacillus in peyers patches of the small intestine’ R]

This does not appear to apply to all species of lactobacillus but certain strains of lactobacillus have been found to promote weight gain in animals and humans R]

It is also likely that lactobacillus have different effects in the small intestine than they do in the large intestine.
So studies which find benefit of lactobacillus bacteria may be due to the fact that most studies analyse bacteria in the colon, not the small intestine (which is the site of most relevance for metabolic syndrome).

Methanobacteria Smithii is particularly damaging to tauromuricholic acid: the potent TGR5 activating, FXR antagonising bile acid (in rodents).
M.Smithii is a specific resident of the small intestine.
When rats were inoculated with M.smithii, it was found that all animals had higher M.Smithii in the small intestine than the colon. R]

An obesogenic diet led to higher levels of M.Smithii than those fed normal chow. R] R]
M.Smithii releases methane gas and individuals with methane on breath test have impaired glucose tolerance. R] R]

A human study indicates that the rise in M. Smithii during obesity is at least partly causal of the metabolic dysregulation. R]
When antibiotics were used to eradicate M. Smithii in human subjects; significant improvements in LDL, insulin and glucose levels were seen in pre-diabetic subjects with obesity.’

The eradication of the methanogen bacteria increased insulin sensitivity by 50%!

Methanobrevibactersmithii and Methanospherastadmanae were both shown to encode Bile Salt Hydrolase, capable of deconjugating both taurine- and glycine-conjugates.R]
Lactobacillus are of the genus of bacteria called the firmicutes.
Firmicutes have also been found repeatedly to associate with obesity.
Furthermore, obese people have a significantly higher
level of firmicutes. R]

Before I examine some of the various dietary strategies and argue that their efficacy lies in their ability to modulate intestinal bacteria and bile signalling; it is important to understand the role of the leptin- controlled innate immune system in regulating the microbiome.
This is relevant as it determines the individual tolerances people have for varying food combinations and explains why individuals with varying leptin sensitivity/deficiency have differing strategic dietary requirements.

Leptin Controls Innate Immune Function and the Microbiome, Which  Influences the Tolerance for the Combination of Dietary Fat with Carbohydrates.

Leptin- resistance in the hypothalamus (induced by faulty gut signalling) plays an important role in the pathogenesis and the vicious cycle of progressive obesity.
A further problem to compound this failing leptin system is the fact that when we lose weight (and fat tissue) a physiological state of leptin deficiency manifests.
This is because leptin is released by fat cells, whose job it is to inform the hypothalamus that fat (energy) stores are adequate.
When we lose body fat, during a successful diet attempt, there will be a corresponding reduction in circulating leptin.
The individual who has gained and lost weight is now effectively leptin-deficient.
Any individual who is suffering from metabolic dysregulation or issues with body composition will also be suffering from leptin resistance and leptin deficiency (if they have previously lost weight).

This weight-loss induced leptin deficiency means that the individual has permanently reduced levels of circulating leptin.
Since leptin is a hormone which inhibits AMPK in the hypothalamus;  reduced leptin levels will mean that hypothalamic AMPK will lose an important source of inhibition. 
This means that the leptin-deficient  individual is permanently at a disadvantage with respect to hypothalamic AMPK inhibition. 
I argue that this means that the individual with leptin-deficiency has a reduced 'tolerance' for certain food combinations
An important part of this reduced 'tolerance' is due to hypothalamic AMPK's regulatory effect on the innate immune system.

The innate immune system is a critical mechanism which regulates the intestinal microbiome. 

Importantly, leptin is also an immune hormone, which controls the microbiota. R]

Leptin is a ‘major mechanism by which the gut microbiota is controlled’

This effect is likely due to effects on hypothalamic AMPK and possibly via more direct effects.

The leptin- resistant and leptin-deficient individual will have reduced immune control over the problematic bacteria in the intestine.
The number of bacteria in the intestine, which deconjugate bile in a metabolically unfavourable manner, is higher in the leptin resistant/deficient individual.
Mice which are unable to make leptin ‘eat voraciously and without satiation and become extremely obese.’
Mice which are unable to make leptin, have a 50% increase in firmicutes bacteria R] R].
Lactobacillus, which has particular bacterial bile salt hydrolase potency to deconjugate bile, is a member of the firmicutes family.

A study which highlights the significance of immune signals to affect metabolism via the control of intestinal bacteria reveals that the innate immune receptor toll-like receptor 5, Toll like receptor 5 (TLR5) is vital to the maintenance of metabolic health (at least in mice).
TLR5 mediates the immune response to (and control of) intestinal bacteria.
70]When researchers studied mice which were bred to lack this innate immune receptor; these mice experienced an overgrowth of bacteria in the intestine and this led the mice to develop inflammation, an excessive appetite, insulin resistance, high blood pressure, high cholesterol, high levels of triglycerides, fatty liver and to become 20% heavier than normal mice.
When the researchers transferred the bacteria from these mice to normal mice, they also developed metabolic syndrome and weight gain. Administration of antibiotics to the mice with the overgrown microbes eliminated this inflammation and metabolic syndrome.
The overgrowth of bacteria (in the absence of innate immune control) triggered food cravings and caused obesity and poor metabolic health in these mice.

Other innate immune regulators have also been found to control metabolic health.
Myeloid differentiation primary-response gene 88 (MyD88) is the key signalling adaptor for most innate immune toll-like receptors.
Hepatocyte-specific deletion of the innate immune regulator, MyD88, predisposes to glucose intolerance, inflammation and hepatic insulin resistance, independently of body weight and adiposity. R]

The researchers concluded that the effects of MyD88 deletion were mediated (at least partially) by alterations to the bile acid profile and to changes in the gut micro biota composition.
And that these alterations resembled those observed during ‘diet-induced obesity’.

This study again shows that the innate immune system influences metabolic health and that the pathways involved include regulation of bacteria and bile.

Another study which examined the events which take place in the small intestine during ‘high-fat diet-induced obesity’ and insulin resistance found that there was decreased expression of the inflammatory cytokine interleukin 18 (Il18) in the proximal and middle part of the intestine .
Since Il18 is part of the innate immune system which controls intestinal bacteria, this would support the case that failing immune control of bacteria in the small intestine is involved in the development of obesity and metabolic syndrome.

The importance of the innate immune function (via control of intestinal bacteria) in the development of obesity and metabolic syndrome, was supported by another study, which showed that mice lacking IL18 have markedly increased body weight and are insulin resistant.

Before I present evidence of the leptin resistant/deficient having reduced tolerance for certain food combinations;  it is necessary to understand the theory of how different types of food affect bacteria and bile.
Highly relevant is the issue of how carbohydrates affect intestinal bacteria.

How problematic this is, is highly influenced by the individual state of the leptin-controlled innate immune function, and/or the state of the dietary carbohydrate refinement.

Carbohydrates Feed/Grow the Type of Bacteria Which Deconjugate Bile

The substrate which feeds the problematic small intestinal bacteria is digestible carbohydrates.
Studies have found that ‘simple carbohydrates cause rapid fermentation and growth of bacteria in the small intestine R]
Firmicutes have been identified as a type of bacteria which are usually associated with obesity.
Firmicutes are known to proliferate in response to glucose. R]
Lactobacilli, which are known to have strong bacterial bile salt hydrolase activity, are members of the firmicutes family and are inhabitants of the small intestine.
Any type of carbohydrate which breaks down to simple sugars in the small intestine would provide growth substrates for these bile-‘damaging ' types of bacteria.

The process of refined carbohydrate/sugar - induced flourishing of problematic bacteria in the small intestine as causal in metabolic syndrome likely mirrors the disease process responsible for tooth decay.

It is well-known that fermentation of sugar by bacteria in the mouth leads to tooth decay.
It appears that an analogous process occurs in the small intestine and I argue that similarly, this is the primary process by which high- sugar/refined carbohydrate diets contribute to metabolic syndrome and obesity.
And, as I will argue, in those who have leptin/immune deficits, even whole food carbohydrates may pose a problem. For these people, even the restriction of whole food type carbohydrates appears to be a therapeutic option.
Before I examine the diets which are commonly used to ‘correct’ metabolic health, such as the low carb diet, the low-fat diet and intermittent fasting strategies; I will discuss the diet which is able to induce metabolic dysregulation, even in the metabolically healthy.

A ‘High-Fat Diet’ is Fattening in the Context of Higher Carbohydrates (Especially Refined Carbohydrates and Sugars) Due to Excessive FXR Activation

High Carbohydrate/High Fat Diet Damages Bile Signalling which Activates Hypothalamic AMPK  ( to prevent health and weight loss)

When obesity researchers want to fatten animals for research purposes, they use the most reliably obesogenic diet, which is referred to as a ‘high- fat diet’.
It is called this as it is high in fat. It can be distinguished from the low- carb/ high- fat diet, since it is also high in carbohydrates, preferably refined carbohydrates and sugars.
This is the high refined carb/sugar/fat diet which is basically the rat equivalent of human junk food and appears to be similarly reliably obesogenic in humans. It is the most potently obesogenic food combination.
I will argue that this is due to the ability of this diet to excessively grow the bacteria which deconjugate bile in combination with a large volume of fat- induced bile.
The outcome is a large amount of deconjugated bile in the small intestine which is sufficient to excessively activate FXR and lead to metabolic dysregulation.

Before I discuss the theory of why refined carbohydrates and sugars would be more effective at creating the conditions to excessively deconjugate bile, I will present the evidence which supports the theory that the obesogenic high fat/high carb diet dysregulates metabolism VIA excessive FXR activation.

When the bile is altered by this refined carbohydrate- driven microbiome, there is a threshold amount of dietary fat-induced bile at which FXR is sufficiently activated to cause metabolic dysregulation and the onset of overeating and excess accumulation of body fat.
Researchers examined the micro-events occurring in the small intestine during the intake of a ‘high-fat’ obesogenic diet.
Microarray analyses showed that dietary fat had the most pronounced effect in the middle part of the small intestine and that nuclear receptors, such as Ppars, LXR and FXR play an important role in the regulation of small intestinal metabolism after feeding a high-fat diet.

There was also a strong up-regulation of FXR target gene Shp in the middle part of the small intestine and previous null mice studies showed that mice lacking this FXR target gene are resistant to dietary fat-induced obesity and insulin resistance. R]
This again supports the hypothesis that FXR activation (and bile) is a vital part of the pathway of diet-induced obesity and metabolic syndrome. 
NOTE: This study also found ‘no conclusive evidence for an increased inflammatory status that might contribute to development of dietary fat-induced obesity and insulin resistance.’
This is further supported by the finding that in the absence of FXR, a ‘high- fat diet’ fails to induce metabolic dysregulation or obesity. R]] R]]
Alterations in FXR activation are required for a ‘high- fat diet’ to induce metabolic dysregulation.

CCK - the Receptor which Activates the Release of Bile in to the Intestine is Required for Diet-Induced Obesity

Further evidence that excess ‘faulty’ bile is responsible for the initiation of obesity and metabolic syndrome comes from the fact that mice which are bred to lack CCK receptors are protected from the development of ‘high- fat diet- induced obesity’.
CCK (cholecystokinin) is a hormone which is secreted by cells of the upper small intestine. It is the hormone which responds to protein and fats to activate the release of bile into the intestine.
Cholecystokinin stimulates the gallbladder to contract and release stored bile into the intestine
Without CCK activation, fats and proteins wouldn’t activate bile release.
So, without fat -induced bile release, (via the hormone CCK), a ‘high- fat diet’ fails to initiate obesity and metabolic syndrome, supporting the theory that fat-induced bile release (in an environment of high bacterial deconjugation activity) is the mechanism behind’ high-fat-diet induced obesity’.

Intestinal Bile Uptake (by FXR)  is a Critical Part of the Mechanism of Diet-Induced Obesity and Metabolic Dysregulation

Further evidence to support this theory comes from a recent study which found that ‘high-fat diet’ induced metabolic dysregulation was prevented if bile uptake in the small intestine was blocked. R] (FXR activation is required for bile uptake in the small intestine).
The mice given the drug which blocked intestinal bile uptake had more than ten times less the levels of triglycerides and cholesterol in their livers.
The high-fat/sugar–fed mice which blocked intestinal uptake of bile, had the same levels of triglycerides and cholesterol in their liver as mice fed the low-fat/low-sugar chow diet.
Since FXR activation induces the intestinal uptake of bile, this is further evidence for excessive FXR activation (and intestinal bile uptake) as CAUSAL in the mechanism of ‘high-fat’ diet-induced obesity’

The  Refinement of Carbohydrates/Sugars and Innate Immune Function Determine the Obesogenicity of a High-Fat Diet

This can be explained by the fact that refined carbohydrates are more rapidly broken down into their constituent sugars. The more instant provision of sugars for fermentation to the small intestine would lead to larger flourishes of bacteria which would be less easily controlled by even a healthy innate immune system.
The theory is that a difficult to control small intestinal microbiota, driven by an over-supply of refined carbohydrates and sugars would be more problematic in terms of damage to bile.
Slower digesting carbohydrates would lead to more gradual increases in the carbohydrate-loving, bile-damaging bacteria which could more easily be contained by the innate immune system and would therefore result in less bacterial damage of the bile.
It appears that a diet high in refined carbohydrates/sugars lowers the threshold amount of fat (which induces bile release) required in the diet to induce obesity and metabolic syndrome.
The ‘high-fat’ refined-carbohydrate diet which is used to induce obesity in rodents often has a fat content of about 45%.
And, if the sugar content is high (33%), even 16% fat is sufficient to induce metabolic dysregulation (in this study).

Researchers sought to determine  if the type of carbohydrate affected the obesogenicity of a high-fat diet.
They found that when carbohydrates are given in whole food form, 45% is not enough fat to induce metabolic dysregulation.
In a context of whole food carbohydrates; obesity and metabolic dysregulation was only induced at 74% fat, but not at 48% fat. R]

These results support the theory that the threshold amount of fat (and bile) required to induce obesity is dependent on the state of the microbiome (which is driven by the amount of refined carbohydrates in the diet and/or the individual state of leptin resistance or deficiency).
This can explain the finding of good metabolic health in many healthy cultures who consume diets high in whole food carbohydrates AND fats.
If the carbohydrates are whole and slower to digest, they will release the fermentable simple constituent sugars more slowly.
The simple carbohydrate-induced growth of intestinal bacteria would occur more gradually and be more easily contained by the innate immune system, thereby minimising the damage to bile and preventing the excessive activation of FXR.

The initiating trigger for the onset of metabolic syndrome and obesity requires refined carbohydrates/sugars (to sufficiently dysregulate the small intestinal microbiome) and high levels of fat to induce a sufficient volume of bile (which would be bacterially deconjugated) to sufficiently activate FXR to induce metabolic dysregulation.

An example of this would be the metabolically robust child.
A metabolically healthy child, with a strong innate immune system, would be internally well equipped to control the growth of bacteria in response to carbohydrates.
They would therefore also have a good tolerance for fat (and the bile which it induces) in the diet.
I suggest that the metabolically healthy child would be fine with whole food carbohydrates and moderate amounts of fat.
It is unlikely that the very low-fat diets and low carbohydrate diets, which are required for metabolic correction; would be necessary for those with a robust innate immune system (a healthy leptin system).

Failing Innate Immune Function (as a Result of a Failing Leptin System) Causes Reduced 'Tolerance' for Fat/Carb Combinations Due to Poor Regulation of the Microbiome

So why is it that the metabolically failing do appear to require these more strict dietary approaches to achieve metabolic control?
The answer is the failing innate immune control of bacteria, which is a result of leptin resistance and leptin deficiency.
Diet influences metabolic health and metabolic health in turn influences how we respond to diet. This can be responsible for a vicious cycle of worsening metabolic health and the onset of obesity development.
In the ‘post-dieted’ individual, there is an inadequate control of the intestinal bacteria which deconjugate bile which means that it will take less fat-induced bile to produce enough deconjugated bile to excessively activate FXR and lead to metabolic dysregulation and the onset of obesity.
In the ‘post-dieted’ individual, the threshold amount of fat-induced bile which is required to sufficiently activate FXR is less due to an increase in the bacteria which deconjugate the bile.

This worse tolerance for fat (in the context of dietary carbohydrates) and the crucial role of the microbiome in mediating this reduced dietary tolerance is clearly demonstrated in a recent rodent study.
The study analysed the effects of weight loss (which induces leptin- deficiency) on the microbiome and how this affects the tendency to gain weight and become metabolically dysregulated in response to an obesogenic diet.

Leptin Deficiency-Induced Failing Innate Immune System; the Microbiome and the ‘Yo-Yo Diet’ Effect

The mice in this study exhibited the ‘yo-yo diet’ phenomenon, which is a familiar pattern observed in humans, whereby people who have lost weight (becoming leptin-deficient), have a greatly heightened tendency to gain weight.
The percentage of dieters who manage to maintain all their weight loss is abysmally low and a depressingly high percentage of dieters do indeed regain all the weight they have lost, plus more. (Although I will argue that there are specific strategies which are able to compensate for leptin-deficiency and overcome this ‘yo-yo’ cycle).
Compared to the ‘never-been- fat’, people who are ‘weight- reduced’ have an exaggerated negative response to the high fat/high carb obesogenic diet.
In this study which demonstrates the ‘yo-yo effect’, when mice were fed an obesogenic diet, they predictably gained weight. R]

When the mice were reverted back to a low-fat chow diet, they recovered their metabolic health and healthy body weight.
However, when these mice were then fed the obesogenic rat diet for a second time, the mice gained weight again but this time they gained even more weight and the decline in their metabolism was even greater than on the first exposure to the high-fat diet.
The second exposure to the same obesogenic diet caused an even more rapid and greater decline in metabolic health than the first exposure.
The history of weight -loss and the consequent leptin- deficiency had made the rats more sensitive to and more easily dysregulated by an obesogenic diet.

What caused this greater susceptibility to dysregulation by the obesogenic diet in the post-dieted rats?
The researchers showed that the post-diet altered micro biome mediated this new sensitivity.
When the ‘fattened’ mice were put back on the normal chow, they lost weight and recovered their metabolic health but the microbiome was permanently altered.

Although the symptoms had disappeared, the threshold tolerance for potentially problematic food combinations had lowered.
The researchers transferred this ‘post- dieted’ microbiotas to bacteria -free mice and then gave them an obesogenic ‘high- fat diet’.
The recipients of this ‘post- weight loss’ microbiota gained weight faster than normal mice that had been maintained on chow diet and had not been previously fattened.

Despite not being previously fattened, the ‘post- diet’ microbiome caused them to exhibit the same phenomenon of heightened metabolic dysregulation in response to an obesogenic diet as the mice which had been previously fattened.

This strongly indicates that the post-diet altered microbiome mediated the accelerated weight gain and metabolic dysregulation observed in the mice which had previously been fattened, upon exposure to an obesogenic diet.
What this means is that the altered microbiome in people who have lost weight predisposes them to more rapid weight regain in response to an obesogenic diet, in comparison to the ‘never-been-fat’.

This study supports the model that the ‘weight-reduced’, leptin-deficient individual has a heightened predisposition to metabolic  dysregulation by diet due to a reduced efficiency of the innate immune system to adequately control intestinal bacteria.

The above study identified a worse tolerance for a high fat/high carb (particularly obesogenic) diet; but it appears that the ‘post-dieted’ individual also has a reduced tolerance for ANY type of carbohydrate/fat combination, even when the carbohydrates are non-refined.

This phenomenon has been revealed in several studies, whereby metabolically healthy individuals, without a weight problem, respond differently to carbohydrates than individuals with a weight problem, with notably increased appetite.

Metabolic Vulnerability (Leptin Resistance/Deficiency) Reduces 'Tolerance' for Carbohydrates (with Fats): Causing Appetite Dysregulation

Contrary to expectations, active ghrelin increased in obese girls following a high-carbohydrate breakfast, and the percent increase was higher than in controls’ R]

The obese children reported higher hunger and lower satiety after the high-carbohydrate meal compared to the normal weight subjects, whereas appetite ratings were similar between the groups after the high-protein and high-fat meals.’ R]
Additionally, within the obese group, there was a significantly greater satiety response (PYY hormone), as well as lower AUC hunger, to the high protein meal than the high-carbohydrate and high-fat meals.’

Strict Dietary Strategies are Required to Compensate for  Metabolic Vulnerability and Reduced Tolerance for Carbohydrate/Fat Combinations 

The Very Low-Fat Diet Strategy 

In the rodent ‘yo-yo diet’ study discussed above; the metabolic dysregulation and obesity was prevented by a very low- fat chow diet, despite the ‘post-diet’ altered microbiome.
The consumption of a very low-fat diet was able to compensate for the metabolic vulnerability induced by the overgrowth of bacteria in a context of failing innate immune control.
A very low-fat diet prevents metabolic failure by reducing the amount of bile which is released into the small intestine ( recall that bile release into the intestine is most potently activated by dietary fat).
A low-fat diet thereby prevents excessive FXR activation by 'damaged' bile by controlling the amount of bile in the intestine.

In a context of failing innate immune function (leptin deficiency/resistance) and increased presence of deconjugating bacteria in the small intestine; the very low-fat diet strategy prevents excessive FXR activation by 'damaged' bile by reducing the AMOUNT of bile which is released in to the small intestine. 

The Low-Carbohydrate Diet Strategy ​

Low Carbohydrate Diet Improves Bile Signalling to Improve Health and Weight Loss (via Hypothalamic AMPK)

Besides the very low-fat diet; there is another dietary strategy in town, which has also been proven effective for those who have developed metabolic vulnerability.
This is the popular low carb or ketogenic diet.
How does the low carb diet work to reverse metabolic dysregulation?
I argue that the low carb diet also reverses metabolic syndrome by reducing FXR activation.
However, in contrast to the low-fat diet, which reduces FXR activation by reducing the VOLUME of problematic bile; the low carb diet improves the QUALITY of bile.
I argue that the low-carbohydrate diet achieves this by, alternatively, targeting the dysregulated microbiota (which manifests in a context of leptin/immune failure).

The low carbohydrate diet controls the unruly post-dieted microbiome, by starving it of its substrate: carbohydrates and sugars.
This strategy is able to approximate the microbiome of the metabolically healthy individual (with good leptin function).
By ‘normalising’ the intestinal microbiome, and reducing the presence of the bacteria which 'damage' bile;  the bile will be of altered quality.
Since there would be less bacterial 'damage' of bile; the bile which is released into the intestine, in response to dietary fats; would be the conjugated 'undamaged' type, which does not activate FXR.
In this dietary context of low bacterial 'damage' of bile; fat-induced bile ceases to be problematic and ceases to cause metabolic dysrgeulation.
It is not the fat per SE, which can be problematic; but the bile which is released in response to dietary fats.
And, in the absence of the carb-induced bacteria which 'damage' the bile; the bile is not problematic. 
This would explain the findings of  many studies which have shown that high-fat diets do not cause dysregulation or obesity, in the absence of carbohydrates. 

A Low Carbohydrate Diet Compensates for Poor Immune Control of Bacteria by Starving the Problem Bacteria Instead.

Low Carbohydrate Diets Reduce the Number of the Types of Bacteria which Deconjugate Bile 

It is known that carbohydrates contribute to the growth of the small intestinal microbiota.
If the mechanism behind the success of low-carbohydrate diets is the effects on the microbiome; a ketogenic diet should reduce the number of the type of bacteria which are known to deconjugate bile.
Methane-producing bacteria deconjugate bile and have been found to increase metabolic dysregulation.
A study in pigs (whose metabolism is even more similar to humans than rodents) found that a ketogenic diet ‘significantly depressed’ the production of methane. R]

Carbohydrate Digestion Inhibitors Restore Glucose Tolerance Via Modulation of Bile Signals

Voglibose is a diabetic drug which inhibits the carbohydrate digestive enzymes and thus the hydrolysis of carbohydrates in the small intestine into glucose and other monosaccharides.
It would reduce the presence of the simple sugars upon which bacteria in the small intestine thrive.
Rats treated with this carbohydrate digestion inhibitor exhibited improved metabolic profiles and reduced weight gain in response to a high fat diet. R]
This mimics observations in humans who take Voglibose.
The 12-week Voglibose administration decreased the ratio of Firmicutes to Bacteroidetes found in faeces, which is consistent with the theoretical role of firmicutes in the pathogenesis of metabolic syndrome.
It was recently shown that at least part of the mechanism by which Voglibose (carbohydrate digestion inhibitor) has an ‘ameliorative effect on glucose tolerance is via alterations in bile acids and the up-regulation of genes which are induced by bile acids.
This study shows that carbohydrate digestion alters bile metabolism and that this modification of bile is the very mechanism by which  carbohydrate digestion affects glucose tolerance.
This supports the theory that carbohydrate restricted diets work via modifying bile signals.

Voglibose is a diabetic drug which inhibits the carbohydrate digestive enzymes and thus the hydrolysis of carbohydrates in the small intestine into glucose and other monosaccharides.
It would reduce the presence of the simple sugars upon which bacteria in the small intestine thrive.
Rats treated with this carbohydrate digestion inhibitor exhibited improved metabolic profiles and reduced weight gain in response to a high fat diet. R]
This mimics observations in humans who take Voglibose.
The 12-week Voglibose administration decreased the ratio of Firmicutes to Bacteroidetes found in faeces, which is consistent with the theoretical role of firmicutes in the pathogenesis of metabolic syndrome.
It was recently shown that at least part of the mechanism by which Voglibose (carbohydrate digestion inhibitor) has an ‘ameliorative effect on glucose tolerance is via alterations in bile acids and the up-regulation of genes which are induced by bile acids.
This study shows that carbohydrate digestion alters bile metabolism and that this modification of bile is the very mechanism by which  carbohydrate digestion affects glucose tolerance.
This supports the theory that carbohydrate restricted diets work via modifying bile signals.

These findings indicate a new mechanism for carbohydrates and their relevance for metabolic health, alternative to the circulating idea that carbohydrates affect metabolic health and obesity primarily via postprandial insulin and glucose effects.

Alterations to FXR Signalling are Essential to the Effectiveness of Low-Carbohydrate/Ketogenic Diets 

If the theory that a low-carbohydrate diet works mainly via starving bacteria and improving bile signalling is correct; there should be evidence that alterations in FXR activation are required for these types of diet to be effective.
This is what we do find, in the limited studies which have examined this.

Alterations in FXR bile signalling are required for the metabolic benefits of a ketogenic diet to manifest. R]
Deletion of FXR in mice suppressed the ability of an HF-LC ketogenic diet to manifest the metabolic benefits. R]
Alterations in FXR bile signalling are required for the induction of ketogenesis and fasted gluconeogenesis. R]

What this means is that the induction of ketosis and metabolic benefits on a low carbohydrate diet, is controlled by bile.
It adds support to the model presented here; which is that the mechanism behind the metabolic benefits of the low carbohydrate diets is the modification of bile signals. 

Fasting (which also 'Starves' Bacteria) Increases Intestinal Gluconeogenesis (at Least in  Part by Increasing TGR5 Bile Receptor Signalling).

As already discussed, TGR5 activation sends corrective signals to the hypothalamus via the induction of intestinal gluconeogenesis.
It is known that fasting (which is also an absence of carbohydrates) does increase this powerfully corrective IGN signal.
An increase in intestinal gluconeogenesis is, in fact, essential to maintaining normal blood glucose levels during fasting. R]

It is certain that enhanced bile signalling is required for the induction of intestinal gluconeogenesis, during fasting (as described above).
Optimal TGR5 signalling is essential to the induction of intestinal gluconeogenesis ( as it increases intestinal proglucagon levels).
It is possible that the reduction of carbohydrate-'loving' bacteria which occurs during fasting; improves the 'quality' of bile by reducing bacterial 'damage'.
This fasting-induced improvement of bile 'quality' enhances TGR5 activation, intestinal proglucagon and intestinal gluconeogenesis. 
Fasting and low carbohydrate diets may therefore share the same mechanism: an enhancement of bile signals, which increases intestinal gluconeogenesis. 

More evidence that low-carbohydrate diets do work by the same mechanism as other interventions which exert metabolically protective effects via intestinal modifications is that all of these: germ-free mice,  antibiotic-treated mice, the gastric bypass and ileal bile diversion therapy; similarly increase bile acid synthesis and the bile acid pool size (which implicates FXR inhibition by conjugated bile and the consequent reduction of uptake of bile in the small intestine). R] R] R] R]

Dietary Fats, in the Context of a Controlled Intestinal Microbiome, are Non-Problematic, Potentially Beneficial?

As mentioned previously, low carbohydrate diets, which reduce the abundance of the bacteria which deconjugate bile in the small intestine; increase the tolerance for dietary fat.

Germ (bacteria) free mice are ‘completely protected’ from the development of ‘high-fat-diet induced obesity’. (As long as it’s not palm oil ... another story...)

In an intestinal environment in which the problematic bacteria are minimised, high- fat diets lose their power to dysregulate.
This is also observed in rodents treated with certain antibiotics.
This phenomenon appears to be mirrored by the high-fat low -carbohydrate diet, in which higher fat intakes do not cause dysregulation  and can even be part of a therapeutic strategy.
I argue that in all these cases: the germ-free rodent, the antibiotic-treated rodent, gastric bypass and the low-carbohydrate/ high-fat diet;  the key uniting factor is the absence of the bile –deconjugating small intestinal microbiome.
In all these contexts, the bile which is induced by a high- fat diet does not lead to metabolic dysregulation due to the absence of bile-'damaging' bacteria. 
Again, it is not the dietary fat itself which is causing the problem; it is the TYPE of bile which is released in response to the dietary fat.
And the type of bile is determined by the small intestinal microbiome; which in turn is determined by the presence of refined carbohydrates and sugars in the diet and also the individual state of innate immune control (as determined by leptin resistance and leptin deficiency).
Fats in a low- carbohydrate context are clearly far better tolerated.
The question is; are fats in this context, in fact, beneficial for metabolic health and obesity?

A theoretical basis for dietary fats being beneficial in a low-carbohydrate context, may be that in contrast to deconjugated bile, conjugated ‘good’ bile may, in fact, be metabolically beneficial, due to its power to activate the metabolically rejuvenating TGR5.

CCK-Induced Bile (which is Activated by Fat and Protein) Improves Metabolic Health and Obesity (Until Bile Becomes 'Damaged' by Poor Diet and Leptin Deficiency)

More evidence that a high fat-diet can have positive metabolic effects (if the fat-induced bile is better quality) comes from the fact that CCK- induced bile release has been found to have a glucose lowering effect.
CCK is the hormone which responds to fats and proteins in the diet to activate the release of bile from the gall-bladder into the small intestine.
Researchers reporting in the journal Cell Metabolism, reported: ‘ We show for the first time that CCK from the gut activates receptors to regulate glucose levels,” It does so via a gut-brain-liver neuronal axis.”
‘A primary increase of CCK, in the upper intestine lowers glucose production independently of any change to circulating insulin levels...However, the positive effects of the hormone begin to fail early in the onset of high-fat diet-induced insulin resistance, they report.’ R]
This is consistent with the model:
In a context in which the bile is of good quality (conjugated); CCK-induced bile has a beneficial effect on metabolism.
However, when bile becomes increasingly deconjugated, during the progression of metabolic syndrome: CCK-induced bile release instead starts to contribute to the problem, rather than prevent it.  

​A Study in Which a Fat-Modified Fast was More Effective than Fasting 

A study which indicates the metabolic benefit of fat, as distinguished from the metabolic benefit of carbohydrate restriction, in a high-fat, low-carbohydrate diet, compared fasting with a ketogenic diet.

Fasting is low in carbohydrates, but a ketogenic diet is low in carbohydrates but also high in fats.

In this study, a low- carbohydrate diet with intermittent fats created a more favourable metabolic milieu than pure fasting.
In contrast to the fast, which minimises both carbohydrates and fats;  the ketogenic diet, which restricted only carbohydrates, preferentially burned fat rather than muscle.
This is indicative of improved whole-body AMPK activation, which is at the root of good metabolic health.
The intermittent addition of fat to a 10 day fasting regime increased the amount of fat which was ‘burnt’ despite a higher intake of calories, (1000 more calories per day). R]
On the pure fasting plan, 64.6% of the weight loss was loss of lean body mass, whilst 35.4% of the weight loss was due to fat loss.
On the fat-modified- fast, only 3% of the weight loss was due to lean tissue loss, whilst 97% of the weight loss was due to fat loss.
Despite consuming 1000 more calories per day, the fat fast group lost 6.4kg of fat, compared to the pure fasting group, who lost 3.4kg.
The addition of 1000 calories of fat to a fasting regime created a metabolic environment which favoured fat burning and preserved lean muscle.

Not only this , but consistent with the theory that fat-induced bile has metabolically favourable effects , in the absence of carb-driven microbiome which ‘damages’ bile, the ‘fat- modified fast’ lead to weight loss without attendant food cravings, weakness, lethargy and other negative symptoms.

It can be logically deduced that the improved metabolic environment on a low-carbohydrate, high-fat/protein diet compared to fasting, is due to higher TGR5 activation due to fat and protein- induced bile release.

Comparing the Low-Fat Diet to the Low-Carbohydrate Diet: Which is Superior for Enhancement of Bile Signals and Metabolic Correction?

If the amount  of bile matters to the activation of TGR5; this might support the notion that a low-carbohydrate diet, high in fat or protein is superior for metabolic correction than a low-fat diet.
Low- fat diets cause a reduction of bile release, which reduces FXR activation. This would, no doubt, have benefit, by increasing bile synthesis and improving the composition of bile, in favour of chenodeoxycholic acid. 
However, since a very low- fat diet would also mean a dramatic reduction in the amount of bile which is released into the intestine; it is questionable if there would be enough bile to optimally activate TGR5.

Although both low carb and low-fat diets exert beneficial effects via the reduction of FXR activation; it may be that the low-carb diet has the metabolic edge,  due to greater activation of TGR bile receptor.

Low- carbohydrate diets do fairly consistently outperform low- fat diets, in terms of metabolic benefit, in the short- term studies which have compared the two.
The very limited number of  longer term studies have showed less difference, but long term studies are plagued with issues of compliance.
There is an abundance  of anecdotal evidence of people who have corrected obesity and metabolic health using a low-carbohydrate diet,  in the long term, when adherence is high.

There is also anecdotal evidence of people losing weight and correcting health long term on low-fat vegan type diets; although it appears that these are fewer in number.

These could be to do with a totaly separate thing- protein deficeincy. 

The idea that a strict low-carbohydrate diet may be superior for metabolic correction to a strict low- fat diet is supported by the finding that high fat ketogenic mice tend to be leaner with superior metabolic profiles than low- fat chow fed mice. R]

The benefits of intermittent fasting could be well explained by this paradigm.
Intermittent periods of fasting would ‘starve the problem bacteria’ as well as provide relief of FXR activation by the intermittent abstinence from carbs, fats AND proteins.
The intermittent relief of FXR activation would enhance leptin sensitivity and therefore immune control of bacteria and this combined with the intermittent ‘starvation’ of bacteria would mean that when food is eaten in the eating window, it would have less power to dysregulate.
The better leptin sensitivity and immune control and lower abundance of problem bacteria would mean food of all kinds would be better tolerated.
Dietary carbohydrates would lead to reduced proliferations of problem bacteria, fat would be less likely to be deconjugated.
This would be a good explanation for the oft reported capacity of intermittent fasters to be able to eat whatever they like, as long as it is in a restricted ‘feeding window’.

Further Questions:

As weight loss, which  decreases leptin levels (and innate immunity), continues; is the immune regulation of intestinal bacteria sufficient to allow the same liberal servings of fat which may have been experienced earlier in the weight loss journey?
Does a high fat, low carb diet need to give way to a lower fat version of a low carb diet, to maintain the same level of metabolic control and weight loss success?
Do high carbohydrate /low fat diets stimulate enough bile secretion for optimal TGR5 activation and optimal metabolic correction?
It is possible that similar to the intermittent fasting strategy; high carb/low fat/low protein diets would benefit from an eating window of protein and fats to optimise TGR5 signalling.
These are questions which warrant further investigation in the quest for optimised,  individualised dietary strategies. 

Conclusion

The seeming intractability of obesity and failing health, once it has manifested, is driven by leptin resistance and leptin deficiency- induced microbial dysregulation, which causes faulty bile signalling. 

The various dietary strategies which are known to improve  health and reverse obesity, compensate for dysregulated bacteria/bile interactions by either reducing the amount of bile secreted into the small intestine or by improving the quality of bile, by 'starving' out the bacteria which 'damage' the bile. 

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