How a Low- Carbohydrate Diet Mimics the Gastric Bypass: the Bacteria/Bile/Intestinal Gluconeogenesis Story.
How a Low- Carbohydrate Diet Mimics the Gastric Bypass: the Bacteria/Bile/Intestinal Gluconeogenesis Story.
The following is a theory of how diet initiates metabolic dysregulation and obesity via modulating bile signalling and how low-carbohydrate, intermittent fasting strategies (and also low-fat strategies to an extent) correct that faulty bile signalling to reverse the progression of metabolic dysregulation.
I argue that this theory of mechanism makes good sense of the available evidence.
I welcome critique, to eliminate inaccuracies and advance the quest for truth finding J
1.) Bile is emerging as a crucially important regulator of metabolic health and body weight.
2.) Bile regulates metabolic health and body weight via two important bile acid receptors; the FXR receptor and the TGR5 receptor.
3.) Activation of the FXR receptor has a negative effect on metabolic health
4.) Activation of the TGR5 receptor has a positive effect on metabolic health.
5.) High fat diet induced obesity is due to the fat induced release of an excess of faulty bile which excessively activates FXR leading to metabolic dysregulation.
6.) An excess of certain bacteria in the small intestine ‘damages’ the bile making it more prone to FXR activation.
7.) A low carbohydrate diet corrects failing metabolic health by ‘starving’ the carbohydrate-loving problem bacteria in the small intestine.
8.) By reducing bacterial damage of bile, the bile induced by saturated fats and proteins in a low carbohydrate diet cease to activate FXR problematically.
9.) Instead the bile induced by saturated fats in a low carbohydrate diet is in fact metabolically corrective due to its potency to activate TGR5 preferentially (rather than FXR).
10.) In summary; the low-carbohydrate diet corrects failing metabolic health by ‘starving’ problematic bacteria which flourish in a poor metabolic environment.
The low carbohydrate diet therefore alters the quality and quantity of bile to most thoroughly prevent FXR activation and maximally enhance TGR5 activation to optimise metabolic health and body weight regulation.
Glucose Control at the Heart of Body Weight Regulation and Metabolic Syndrome
A defining characteristic of the metabolic syndrome is declining glucose control.
The manifestation of this is a poor response to the influx of dietary glucose which results in blood glucose levels rising to damagingly high levels.
The other aspect of poor glucose control which is less well-known is the glucose response to the fasted state.
This state refers to longer periods between meals when the dietary glucose influx falls.
The healthy glucose response to the fasted state is an increase in intestinal gluconeogenesis (IGN), the endogenous production of glucose by the small intestine.
Intestinal Gluconeogenesis releases glucose into the portal vein which increases satiety between meals.
Without these described healthy glucose responses; glucose raises dangerously high following meals and a lack of intestinal gluconeogenesis between meals results in poor inter-meal satiety.
Poor satiety between meals leads to overeating and the loss of body weight control.
The satiety signals which are induced by intestinal gluconeogenesis also have an overall corrective effect on the hypothalamus in the brain.
Since the hypothalamus is the metabolic control centre which regulates the energy rations of the entire body; the loss of this hypothalamically corrective IGN signal has profound implications for not only satiety, but the energy level and therefore, function of the whole bodily system.
I argue here that a failing intestinal gluconeogenesis back up glucose system is at the root of metabolic syndrome, since the absence of this signal causes hypothalamic decline which leads to the many and multitude symptoms associated with metabolic syndrome.
I will argue that alterations in intestinal gluconeogenesis are the mechanism behind almost all of the strategies which are known to have a corrective effect on metabolic health.
In this post, I will pay special attention to the role of bacteria and bile in modulating the intestinal gluconeogenesis signal, as I will argue that, alterations to bile and bacteria are the mechanism behind the different metabolic effects of varying macronutrients, such as using a high fat diet to induce obesity or using a low carbohydrate or low fat diet to help put metabolic syndrome into reverse.
The Body’s Glucose Response to Dietary Glucose Intake
When we eat carbohydrates, they are processed by the liver and glucose is released into the blood.
When we consume carbohydrates (dietary glucose), insulin is released to stop the endogenous production of glucose.
If insulin didn’t stop the endogenous production of glucose during dietary influx, glucose levels would rise dangerously high.
If the insulin doesn’t work properly to stop endogenous glucose production when there is also a supply of exogenous dietary glucose, there will be too much glucose in the blood.
The sufficient insulin response to dietary glucose is controlled by the hormone GLP-1.
When GLP- 1 is failing, insulin and pancreatic beta- cell function declines. 1]
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.”
The sufficient insulin response to glucose is controlled by the hormone GLP-1.
The important question then is there any strategies which we can use to improve GLp-1 and thereby improve insulin response to glucose?
I will argue that there are and that this strategy also improves the fasting glucose response.
Fasting Glucose Response
In a healthy individual, when dietary glucose influx falls and after a certain amount of stored glucose is used up (glycogen), during longer periods between meals and during the overnight fast, glucose levels are maintained by endogenous glucose production by the body.
This is called gluconeogenesis (which means the creation of glucose)
An important element of endogenous glucose production is the glucose which is produced by the small intestine; Intestinal Gluconeogenesis (IGN).
The glucose which is released by the small intestine enters the portal vein.
Glucose in the portal vein is a very important satiety signal. 2] 3]
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 reduces the appetite.
When we are between meals, in the metabolically healthy person, the drop in dietary glucose influx to the portal vein induced satiety is compensated for by a rise in glucagon which increases the endogenous production of glucose by the small intestine.
Between meals and in the fasted state, intestinal gluconeogenesis provides the portal vein glucose signal to maintain satiety.
The provision of glucose into the portal vein by intestinal gluconeogenesis and this satiety mechanism means that we are not craving for another meal, 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 since the intestinal gluconeogenesis satiety signal exerts its effects via modulating the hypothalamus, the effects of the absence of this hypothalamically replenishing signal are seen throughout the body in the form of failing metabolic health, the permutations of which are endless.
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.”
The crucial role of IGN as a regulator of metabolic health is given strong support 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 effects.
The gastric bypass corrects metabolism by increasing the IGN signal, the release of glucose by the small intestine into the portal vein.
To further emphasise the important role of IGN, it has been revealed that an increase in IGN is the mechanism behind the metabolically corrective and satiating power of protein and fibre.
Protein antagonises opioid peptides in the portal vein and this induces intestinal gluconeogenesis.
Similarly, short-chain fatty acids produced from soluble fibre exert their anti-obesity and anti-diabetic effects via increasing intestinal gluconeogenesis. 4] 5] 6] 7] 8] 9]
So, we know that intestinal gluconeogenesis is the crucial metabolic pivot which is manipulated by gastric bypass, protein and short-chain-fatty-acids to improve metabolic health and body weight regulation.
Is intestinal gluconeogenesis also the mechanistic switch which is behind the benefits of the well-known diet strategies which are used to improve metabolic health and body weight control; intermittent fasting, the high-fat, low-carb diet and also the high-carb, low-fat diet?
I argue here that IGN is also the switch which is up-regulated by these diet strategies and is responsible for their metabolically corrective effects.
I will argue that alterations to bile (which modulates IGN), is the mechanism behind macronutrient induced effects on metabolic health.
This mimics what is observed in the gastric bypass procedure, whereby it is via alterations in bile that intestinal gluconeogenesis is up-regulated to improve metabolic health.
Gastric Bypass Up-Regulates Intestinal Gluconeogenesis via Modifying Bile Signalling.
In contrast to gastric band surgery, which alters the size of the stomach, gastric bypass removes 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, with poor long-term success for fat loss maintenance.
This indicates that the metabolic improvements and long-term appetite control observed with gastric bypass, compared to the gastric band, are a result of changes occurring in the small intestine.
When mice were engineered to lack bile acid receptors, they gained all the weight back, following gastric bypass.
This strongly indicates that bile acid receptor activation is a crucial part of the mechanism behind the corrective effects of 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 bile based events which take place in the small intestine.
What happens to bile in the small intestine which induces metabolic damage and which is prevented by bile diversion and gastric bypass?
First, we need to understand the two relevant bile receptors which regulate metabolic health and body fat.
TGR5 Bile Acid Receptor – Crucial Regulator of Metabolic Health and Obesity
The bile acid receptor TGR5 is emerging as a crucial metabolic switch.
Its importance derives from the fact that TGR5 activation controls the glucose response to the fed and fasted state.
As already described; in the fed state, it is important that the glucose influx induces insulin to stop the endogenous release of glucose, otherwise glucose levels would raise too high.
In the fasted state, it is important that the absence of dietary glucose influx induces intestinal gluconeogenesis, to supply the portal vein with a steady supply of glucose to maintain satiety.
TGR5 controls this process as it controls the efficiency of conversion of pro-glucagon, which exists in the pancreas of the L cells, into either GLp1 (to induce insulin secretion in the fed state, or glucagon, to induce intestinal gluconeogenesis, in the fasted state. 12]
“A TGR5 activator effectively promoted GLP-1 release, improved hyperglycemia and preserved the mass and function of pancreatic β-cells.”
The conversion of pro-glucagon into either GLp1 or glucagon is controlled by pro-hormone convertase.
PC1 converts pro-glucagon to GLp1
PC2 converts pro-glucagon to glucagon.
Which one is activated depends on the glucose levels.
So if glucose levels are high PC1 is activated to increase GLp1
TGR5 regulates the efficiency of the PHC to convert pro-glucagon to the necessary GLp1 or glucagon.
If TGR5 is failing to effectively induce the conversion of pro-glucagon to either Glp1 or glucagon (and thereby IGN); glucose tolerance, appetite regulation and metabolic health decline. 15]16]
TGR5 is the pivotal lever which controls the effectiveness of glucose control (GLP-1 and glucagon) in the fed and fasted state and this ultimately controls overall metabolic and general health.
The crucial role of TGR5 as metabolic regulator is supported by several studies:
In human brown adipocytes and skeletal myocytes, bile acids interact with TGR5 and thereby activate the key enzyme that converts thyroxine (T4) into (T3), a major component involved in cellular basal metabolism.
TGR5 activation has been identified as a vital part of the mechanism which is responsible for the manifestation of the metabolic improvements of gastric bypass.
Researchers have concluded that TGR5 pathways are ‘extremely important’ in gastric bypass 19] and ‘central to the metabolic improvements observed’ with vertical gastric sleeve. 20]
Vertical gastric sleeve alters both bile acid levels and 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’ 21]
However TGR5 isn’t the only bile receptor which plays a role in metabolic regulation.
There is a bile receptor which works in opposition to TGR5.
This is the intestinal FXR receptor.
In contrast to TGR5 activation, 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 Bile Acid Receptor – Crucial Metabolic Regulator
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.’ 22]
Whilst increased TGR5 activation protects against diet induced obesity, a reduction in intestinal FXR 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.
FXR signalling in ileum biopsies of humans positively correlates with body mass index. 24]
Researchers have concluded that the inhibition of FXR activation by bile acids interferes with intestinal production of pro-glucagon and GLp-1.
As already described; pro-glucagon is the precursor of glucagon and GLP1.
A reduction in pro-glucagon would mean a reduction in the formation of both glucagon and GLp-1.
Since both glucagon and GlP1 are responsible for the appropriate glucose response to the fed and fasted state and overall metabolic health, it is evident that this would be one mechanism by which FXR activation controls metabolic health.
Bile acid sequestrants are known to improve glucose control and general /metabolic health.
Bile acid sequestrants bind bile and prevent them from activating FXR in the small intestine.
When FXR is activated, it sends a signal to the liver to reduce bile acid synthesis.
This is important because bile acid synthesis is an important metabolic switch. Mice over-expressing the enzyme which activates bile acid synthesis were protected from diet-induced-obesity and insulin resistance. 27]
Increasing bile acid synthesis is protective of diet –induced-obesity because increased bile acid synthesis alters the ratio of bile acids (which compose the bile) in favour of the type of bile acids which activate TGR5 and inhibit FXR.
When BA synthesis is increased, the ratio of cholic acids to chenodeoxycholic acids improves.
Cholic acid and its derivatives are potent TGR5 agonists.
Bile acid sequestrants, by inhibiting FXR activation, increased cholic acid concentration by more than twofold. 28]
The inhibition of FXR increases bile acid synthesis, which increase the ratio of bile in favour of TGR5 activation and further prevents FXR activation, thereby creating a positive cycle.
FXR Activation – Powerful Modulator of Cholesterol Levels
The understanding that FXR and TGR5 activation control 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 draws cholesterol from the blood to provide the raw materials for bile synthesis.
If blood cholesterol rises high, this is indicative of reduced bile synthesis, which is indicative of increased FXR activation and reduced TGR5 activation, both of which are 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
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. 31]
Statin- induced down-regulation of bile synthesis would have a negative effect on bile composition which would ultimately reduce TGR5 activation, with the consequent decline of glucose control and metabolic health.
Clearly the metabolically desirable mechanistic events are activation of TGR5 and inhibition of FXR.
Gastric bypass and bile diversion therapy alter the intestinal environment in a manner that optimally enhances TGR5 activation and optimally inhibits FXR activation.
Both procedures do this by eliminating the passage of bile along the small intestine.
What happens in the small intestine which is so detrimental to bile signalling and which is prevented by gastric bypass and bile diversion?
The candidate mechanism, I will argue, is that gastric bypass and bile diversion therapy prevent the ‘damage’ of bile by bacteria in the small intestine by eliminating the site where this would usually occur; the small intestine which is the habitat for millions of microbes.
The ‘damage’ I am referring to is the deconjugation of bile by bacteria.
Conjugated Bile Acids Vs Unconjugated Bile Acids for Metabolic Regulation
Bile acids are conjugated (joined) to glycine or taurine in the liver.
This makes them less hydrophobic and less damaging to the intestine.
Conjugated bile acids preferentially activate TGR5 and inhibit FXR.
In contrast, deconjugated bile acids preferentially activate FXR.
Clearly a higher abundance of conjugated bile and a lower abundance of unconjugated bile is the metabolically desirable state.
I argue that in the metabolically unhealthy, events along the small intestine alter the ratio of conjugated to unconjugated bile acids in favour of FXR activation and a reduction of TGR5 activation.
I argue that these ‘events’ are the small intestinal microbiota unconjugating the bile as it passes along it.
The Small Intestinal Microbiota ‘Damages’ Bile
The intestinal microbiome ‘has a major regulatory effect on the bile acid profile’. 32]
Other researchers concluded that ‘through defined enzymatic activities, the gut microbiota can significantly modify the signalling properties of bile acids and therefore can have an impact upon host health’ 33] 34]
And further studies led researchers to state 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. 35] 36]37]
The small intestinal microbiota alters the ratio of unconjugated to conjugated bile acids in the bile, thereby altering the power of bile to either preferentially activate TGR5 or FXR.
This property of small intestinal bacteria to modify bile negatively in this way is due to bacterial bile salt hydrolase activity.
Bacterial bile salt hydrolase is a bacterial enzyme which deconjugates bile salts. 38]
A small intestinal microbiota which is rich in bacteria with bacterial bile salt hydrolase activity will have bile which is richer in unconjugated (‘damaged’) bile acids.
Researchers studying this phenomenon, confirmed that bacteria modulates FXR signalling in the intestine by ‘altering the composition and concentrations of FXR agonist and antagonist.’ 39]
‘FXR agonist enhances while FXR antagonist suppresses obesity, NAFLD and insulin resistance.’
The antagonists and agonists the researchers were referring to was the ratio of conjugated and unconjugated bile acids.
The role of bacterial bile salt hydrolase to regulate metabolism via bile modification, was supported by a study of mice given CAPE, a bacterial bile salt inhibitor. 40]
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 inhibited hepatic glucose production ‘substantially’ as well as having antioxidant, anti-inflammatory, anti-obesity and anti-diabetes effects.
The mechanistic role of bacteria and deconjugated bile is afforded support by other studies which modified levels of 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 unconjugate the bile) which inhibited FXR signalling and improved obesity and metabolic parameters. 41] 42]
The mice treated with antibiotics had notable reductions in lactobacillus bacteria and
Both of these types of bacteria are known to have potent bacterial bile salt hydrolase activity. 43]
Consistent with the model, enterobacter has been shown in several studies to be linked to obesity. 44]
Researchers wanted to confirm the mechanistic pathway by which conjugated bile salts improve metabolic health. 45]
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 conjugated bile acid inhibits FXR signalling exclusively in 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.
This study provides strong evidence that the bacteria – bile- deconjugation- FXR pathway is the metabolically relevant one.
It underlines that the inhibition of FXR by conjugated bile is CRUCIAL to the metabolic benefits of bile.
A further mechanism by which an accumulation of conjugated bile may prevent diet-induced-obesity may be revealed by the discovery that conjugated bile acid induced FXR inhibition also meant that less dietary cholesterol was actually absorbed.
‘Fecal excretion of cholesterol was increased and there was a strong trend for doubled fecal excretion of free fatty acids.’ 46]
this may be the mechanism behind the purported ‘calorie advantage’ of certain diets.
There is even indication that Lactobacillus acidophilus reduces the release of leptin from fat cells, which could be part of the initiating mechanism of obesity. A reduction of leptin release from fat cells would be dysregulating to appetite and metabolism. 49]
A human study found that an obesogenic diet is ‘associated with increased abundance of lactobacillus in peyers patches of the small intestine’ 50]
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 51]
Methanobacteria Smithii is particularly damaging to tauro- muricholic acid, the most potent TGR5 activating, FXR inhibiting, bile acid (in rodents).
M.smithii is a particular 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. 52]
This attributes more relevance to M.Smithii compared to certain other types of intestinal bacteria since it is events in the small intestine which have the greatest power to modulate metabolism.
An obesogenic diet led to higher levels of M.Smithii than those fed normal chow. 53] 54]
M.Smithii releases methane gas and individuals with methane on breath test have impaired glucose tolerance. 55]
A human study indicates that the rise in m. smithii during obesity is at least partly causal of the metabolic dysregulation. 56]
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%!
I am confident that these studies have elucidated the mechanisms involved in the microbial/bile/FXR pathway of metabolic modification in rodents.
Another study found that ‘mice abundant in muricholic bile acids show resistance to high-fat diet induced steatosis, weight gain, and to impaired glucose metabolism ‘. 57]
However, humans do not produce MCA and therefore they lack tauro-β-MCA, which is a known farnesoid X receptor antagonist in rodents that modulates obesity, insulin resistance, and hepatosteatosis. 58]
Unfortunately we don’t have the abundance of studies in humans that we have in rodents but the evidence is strong that very similar processes regulate metabolism in humans as they do in rodents.
Humans exhibit almost identical responses to gastric procedures and very similar responses to dietary strategies as rodents, so it seems most likely that very similar mechanisms are involved.
Gastric bypass increases the ratio of conjugated bile acids in humans and in animals similarly.
Gastric bypass increases the size of the bile pool and increases the cholic acid /chenodeoxycholic acid ratio ‘in both humans and rodents. 59]
If similar processes regulate metabolism rodents and humans, is there a candidate conjugated bile salt FXR inhibitor which would be analogous to the conjugated tauromuricholic acid FXR inhibitor observed in rodents?
An excellent candidate for this would be ursodeoxycholic acid and its glycine and taurine conjugates. Following gastric bypass in humans, metabolic improvements were secondary to surges in these bile acids.
In rodents, the inhibition of FXR alters the bile ratio in favour of muricholic acid, which is a potent TGR5 activator.
In humans, it appears that the inhibition of FXR enhances the bile ratio in favour of ursodeoxycholic acid which is similarly powerfully TGr5 activating and FXR inhibiting, thereby contributing to a positive cycle of improving metabolic health. 63]
Is the Mechanism of Metformin FXR Inhibition?
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. 64]
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 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 the TGR5 activating cholic acids (muricholic or ursodeoxycholic acids).
This model makes sense of the observations of metabolic alteration with diets of varying macronutrient ratio.
Why a ‘High-Fat Diet’ is Fattening in the Context of Higher Carbohydrates (Especially Refined Carbohydrates and Sugars).
When obesity researchers want to fatten animals for research purposes, they use an 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- carbohydrate high- fat diet, diet which has been used successfully by many to correct metabolic health and lose body fat, since it is also high in carbohydrates, preferably refined carbohydrates and sugars.
It appears that in the context of carbohydrates, there is a threshold of dietary fat beyond which metabolic dysregulation ensues.
And this threshold is reached more quickly in the context of sugar in the diet and rapidly digested carbohydrates than it is in the context of slower digesting carbohydrates.
The addition of refined carbohydrates and sugars makes the diet more readily dysregaulting.
This is why foods which combine high fat with high sugar are the most notorious for being fattening and bad for metabolic health and it is why the obesogenic ‘high fat diet’ used by researchers to fatten rodents usually includes sugar.
I argue that events in the small intestine can explain these phenomena and particularly the effects of a high fat diet on FXR activation.
As I will argue in the next section, carbohydrates in the diet drive a type of microbiome which alters bile which alters the metabolic effects of high- fat diets.
When the bile is sufficiently altered by a certain carbohydrate driven microbiome, at a certain threshold, enough of this type of bile will detrimentally activate FXR leading to metabolic dysregaultion.
A carbohydrate driven microbiome alters bile such that a high- fat diet driven large volume of bile release excessively activates FXR, leading to metabolic dysregulation.
Evidence That ‘High-Fat-Diet’ Induced Obesity is Caused by Excessive Bile FXR Activation
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 .
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 an argument against the hypothesis that bacteria induced inflammation is behind metabolic dysregulation.
Rather, it supports the theory that small intestinal bacteria alter metabolic status via bile modulation.
The theory that excessive activation of FXR by bile is the mechanism behind ‘high- fat diet induced obesity’ is supported by the finding that in the absence of FXR, a high fat diet fails to induce metabolic dysregulation or obesity. 85]86]
Alterations in FXR activation are REQUIRED for a high fat diet to induce metabolic dysregulation.
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 the introduction of amino acids, or fatty acids to the stomach or duodenum, 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 is the mechanism behind’ high-fat-diet induced obesity’.
Carbohydrates and Particularly Sugar, Feed Carbohydrate- Loving Bacteria (Which Damage Bile).
Before I start this section I want to point out that carbohydrate- loving bacteria appear to be fine in the intestine in the absence of very high levels of dietary fat (and bile).
Hence why there are many healthy populations consuming high-carbohydrate, low-moderate fat diets, such as the Okinawans (for example!)
The background metabolic healthiness of the individual also influences how problematic the carbohydrate induced microbiome is.
So a metabolically healthy individual, such as an Okinawan, with good immune control of intestinal bacteria and low/moderate levels of fat in the diet would not have the internal conditions of excessive activation of FXR by high- fat induced highly damaged bile which would be sufficient to initiate metabolic dysregulation.
However, a diet high in refined carbohydrates, sugars, AND high in fats does appear to be sufficient to initiate metabolic dysregulation, as evidenced by the poor metabolic health observed in western societies.
The tolerance for carbohydrates is reduced even further once metabolic dysregulation has ‘set in’, due to the weakening of innate immune control over bacteria in the intestine.
The substrate which feeds the problem small intestinal bacteria is digestible carbohydrates.
If we imagine any fermentation process, what do we add to cause the bacteria to proliferate? We add carbohydrates.
Grapes to make wine, potatoes to make vodka, sugar to make Kombucha, milk to make yogurt.
Bacteria use carbohydrates to grow and flourish.
The process of carbohydrate 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 diets lead to metabolic syndrome and obesity.
Studies have found that ‘Simple carbohydrates cause rapid fermentation and growth of bacteria in the small intestine’ 65.]
Firmicutes have been identified as a type of bacteria which are usually associated with obesity.
Firmicutes are known to proliferate in response to glucose ‘The members of this order are known for their sugar metabolism ’66.]
Lactobacilli which are known to have strong bacterial bile salt hydrolase activity are members of the firmicutes family.
Any type of carbohydrate which breaks down to simple sugars in the small intestine would provide growth substrates for these problematic types of bacteria.
Leptin Resistance, Weight- Loss -Induced Leptin Deficiency, the Microbiome and Reduced Tolerance for Various Food Combinations.
One of the symptoms of metabolic dysregulation is leptin resistance.
Anyone who is suffering from other symptoms of metabolic dysfunction will also be in a state of leptin resistance.
A further problem to compound this failing leptin system is the fact that when we lose weight, and fat cells, a physiological state of leptin deficiency manifests.
The individual who has gained and lost weight is now effectively leptin deficient.
Since leptin is also an immune hormone, which controls the microbiota; leptin resistance and deficiency results in a more ‘unruly’ microbiome.67]
Leptin is a ‘major mechanism by which the gut microbiota is controlled’
The leptin resistant and/or the leptin-deficient (anyone with a weight problem or poor metabolic health) have reduced immune control over the problematic bacteria.
The load of bacteria in the intestine which alters bile in a metabolically unfavourable manner is higher in the leptin resistant/deficient individual.
As discussed, the problematic bacteria are those which have a high level of bacterial bile salt hydrolase activity to unconjugate (damage) bile
Lactobacillus, which has particular bacterial bile salt hydrolase potency, is a member of the firmicutes family
A study which highlights the significance of immune signals like leptin to affect metabolism via the control of intestinal bacteria reveals that the innate immune receptor TLR5 is vital to the maintenance of metabolic health
TLR5 mediates the immune response to (and control of) intestinal bacteria.
When researchers studied mice which were bred to lack this innate immune receptor 70]
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 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 shown to be regulators of metabolic health, again indicating a role for the innate immune system (via intestinal bacteria) in the regulation of metabolic health.
Myeloid differentiation primary-response gene 88 (MyD88) is the key signalling adaptor for most innate immune TLRs.
Hepatocyte-specific deletion of MyD88 predisposes to glucose intolerance, inflammation and hepatic insulin resistance, independently of body weight and adiposity. 71]
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 microbiota composition.
And that these alterations resembled those observed during diet-induced obesity.
This study shows that the innate immune system plays an important role in the regulation of metabolic health and that the pathways involved include regulation of bile and bacteria.
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 poor immune control of bacteria in the small intestine is involved in the progression of obesity and metabolic syndrome.
The causative role of reduced il18 innate immune response 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 resistance.
The relevance of leptin resistance/ deficiency induced dysregulated microbiome to the propensity to weight regain and the decline in tolerance to various food combinations is supported by a recent rodent study.
This 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 a high fat diet.
Weight- Loss-Induced Leptin Deficiency, the Microbiome and the Yo-Yo Diet Effect
The mice in this study exhibited the yo-yo diet phenomena which is a familiar pattern observed in humans, whereby people who have lost weight and become leptin deficient, have a greatly heightened tendency to gain weight.
This is reflected in the abysmally low percentage of dieters who manage to maintain their weight loss and the fact that a depressingly high percentage of dieters do indeed regain all the weight they lost, plus more. (Although I will argue that a specific low- carbohydrate strategy is able to compensate for leptin deficiency and overcome this yo-yo effect.)
Compared to the ‘never-been- fat’, weight reduced people have an exaggerated negative response to an obesogenic diet which causes increased food cravings and appetite which drives over eating and rapid weight regain.
In this study which demonstrates the ‘yo- yo effect’, when mice were fed a high-fat diet, they predictably gained weight. 72]
As discussed, the excellent candidate explanation for this would be the high fat diet- induced large increase of bile secretion which would lead to excessive FXR activation.
In the context of carbohydrates and sugars in the diet (and the increase in microbes which feed on them) there is a threshold at which a high-fat diet starts to dysregulate via FXR.
When the mice were reverted back to a low-fat chow diet, they recovered their metabolic health and healthy body weight.
This would be well explained by the fact that high-fat diet-induced bile secretion would be reduced which would eliminate the excessive activation of FXR.
HOWEVER when these mice were then fed a high fat 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 high fat diet caused an even more rapid and greater decline in metabolic health than the first exposure.
The history of weight gain and loss and the consequent leptin deficiency had made the rats MORE sensitive and more easily dysregulated by a high-fat diet.
What caused this greater susceptibility to dysregulation by the high-fat diet in the post-dieted rats?
The researchers showed that the post diet altered microbiome 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 heightened sensitivity to problematic foods remained.
The researchers transferred this post dieting microbiota to bacteria -free mice and then gave them a 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 phenomena 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 a high-fat diet.
What this means is that the altered microbiome in people who have lost weight predisposes them to rapid weight regain in response to a high fat diet. They don’t have the same tolerance for an obesogenic that the ‘never- been- fat’ have.
How would this post-diet altered microbiome increase the susceptibility to dysregulation in response to a high-fat diet?
The post-diet rodents would be leptin deficient and therefore have a more unruly microbiome rich in bacteria with bacterial bile salt hydrolase activity to ‘damage the bile which would be increased by the high fat obesogenic diet used in the study.
The greater damage to the bile by the increased bile damaging enzymes would mean that this bile would be more excessively FXR activating and more rapidly dysregulating.
This study highlightsthe microbiome as pivotal in the altered tolerance for potentially problematic food which is observed in those with poor metabolic health and a weight problem.
The post weight loss failing microbiome is the REASON that obesity and poor metabolic health is such an intractable problem for so many.
It explains why these people have to follow either a low- fat or a low carbohydrate diet if they are to have any hope of keeping the weight off.
Low fat reduces the quantity of bile (in an intestinal environment which damages bile).
A low carbohydrate diet improves the quality of bile (by compensating for the poor immune control of bacteria).
It reveals that the microbiome is a target that may be manipulated to correct this propensity to regain the fat which is lost when we diet.
We may be able to stop the vicious cycle of weight loss, weight regain which is accompanied by increasingly worse leptin deficiency.
The question is then; is there a strategy available to us that we can use to correct the weight-loss-induced problematic microbiome and thereby prevent this vicious cycle?
I argue here that there is.
A Low-Carbohydrate Diet Compensates for Poor Immune Control of Bacteria by Starving the Problem Bacteria Instead.
A low- carbohydrate diet would starve the bacteria of its growth substrate and thereby compensate for the lack of leptin control in the leptin resistant/deficient individual.
In the absence of strong leptin control, starving the bacteria of its ‘food’ is a strategy to approximate the microbiome of the metabolically healthy.
As discussed, methane producing bacteria appear to have a causal role in metabolic syndrome.
If the theory that low carbohydrate diets improve metabolism by reducing the population of problematic bacteria is correct; a ketogenic diet should also lead to a reduction of the methanogen bacteria.
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. 73]
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 monosaccharide’s.
It would reduce the formation 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. 74]
This mimics observation 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 and metabolic syndrome.
It was recently shown that at least part of the mechanism by which Voglibose 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.’
Circulating levels of tauro- cholic and cholic acid were significantly higher in the Voglibose group.
This ratio of bile acids is indicative of reduced FXR activation, increased bile synthesis and reduced bile deconjugation.
This study shows that carbohydrate digestion alters bile and that this is the mechanism by which carbohydrates have an effect on metabolic health.
This indicates a new link between carbohydrates and metabolic health, alternative to the traditional idea that carbohydrates affect metabolic health via postprandial insulin and glucose effects.
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 signalling are required for the metabolic benefits of a ketogenic diet to manifest. 75]
Deletion of FXR in mice suppressed the ability of an HF-LC ketogenic diet to manifest the metabolic benefits. 76]
Alterations in FXR signalling are required for the induction of ketogenesis and fasted gluconeogenesis. 77]
As already discussed, it appears that 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 signal and the increase in intestinal gluconeogenesis is in fact essential to maintaining normal blood glucose levels during fasting. 78]
More evidence for a shared mechanism behind the metabolic optimisation of gastric surgery procedures, antibiotic treated, germ-free rodents and low-carbohydrate diets is the fact that all these procedures similarly increase the bile acid pool size due to inhibition of FXR and reduced reuptake of bile in the small intestine which increases bile acid synthesis. 79] 80] 81] 82.]
Why Refined Carbohydrates and Sugars Can Be Even More Metabolically Damaging, Especially Combined With a High- Fat Diet.
As I have already discussed, if the bile is sufficiently deconjugated by bacteria; at a certain threshold, there will be enough bile to sufficiently activate FXR to lead to metabolic dysregulation and fat gain.
In the presence of sugar, the threshold appears to be about a 45% fat diet.
In the presence of healthier carbohydrates, the threshold appears to be higher; as much as 70% fat. REF
This can be explained by the fact that sugar more readily feeds bacteria and would lead to more rapid, less easily controlled flourishes of bacteria.
Slower digesting carbohydrates would lead to more gradual rises in bacteria which could be more easily contained by the immune system.
Sugar then would create a more unruly microbiome more capable of creating more damage to the bile. It would then require less fat- induced bile to activate FXR as a greater proportion of the bile would be ‘damaged’ (deconjugated).
Slower digesting carbohydrates would create a less bile damaging bacterial environment. It would therefore take more fat- induced bile to supply enough of the problematic damaged bile acids to activate FXR and initiate metabolic dysregulation.
At the extreme of this spectrum is the low carbohydrate diet, almost completely starved of the problematic bile damaging bacteria, in which case even a 100% fat diet is not enough to initiate metabolic dysregulation since the fat-induced bile is completely lacking in damaging bile acids.
Dietary Fats in the Context of a Healthy Intestinal Milieu are Metabolically Beneficial!
Germ (bacteria) free mice are ‘completely protected’ from the development of ‘high-fat-diet induced obesity’
In an intestinal environment in which the problematic bacteria are minimised, high fat diets lose their power to dysregulate.
This phenomenon appears to be mimicked by the high-fat low -carbohydrate diet, whereby a high fat appears to lose its power to dysregaulte. (Volek and Phinney studies, for example).
I argue that in both contexts, the key factor is the absence of a dysregaulting small intestinal microbiome.
In both contexts, the bile which is induced by a high fat diet fails to lead to dysregulation due to an absence of bile damaging small intestinal microbes.
the large amount of bile which is released by a high fat diet in a low carbohydrate context does not excessively activate FXR and therefore does not lead to metabolic failure and obesity.
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?
I argue that they are.
In the absence of bile damaging carbohydrate driven bacteria, a high fat diet induces a greater amount of bile release.
This non-damaged conjugated bile inhibits FXR and activates TGR5.
In a small intestinal environment low in certain bacterial activity, a high- fat diet induced increase in bile release increases the activation of metabolically beneficial TGR5.
CCK induced bile release has been found to have a glucose lowering effect
Researchers reporting in the Cell Metabolism, stated that ‘ 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.’87]
This is consistent with the model: a certain amount of healthy bile has a beneficial metabolic effect (presumably by activating TGR5).
However, at a certain amount of fat-induced bile release, the CCK- induced bile starts to have the opposite effect by excessively activating FXR.
The usefulness of fat-induced bile is determined by its power to activate either FXR or TGR5, and this is determined by both the amount and the quality of the bile (which is influenced by the fat, protein and carbohydrate content of the diet). 88]
Low-carbohydrate diets plus fats and proteins have been compared with low carbohydrate diet without fats and proteins in studies. The latter is fasting.
In the following study a low carbohydrate diet with intermittent fats created a more favourable metabolic milieu than pure fasting.
The fast which was modified with fats created a metabolic environment which preferentially burned fat rather than muscle.
This is indicative of 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 oxidised despite a higher intake of calories. (1000 more calories per day) 89]
On the pure fasting regime, 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 of higher AMPK activation on a low carbohydrate, high fat diet compared to total fasting, a low carbohydrate, high fat diet leads to fat loss without attendant food cravings, weakness, lethargy and other negative symptoms.
The higher AMPK activation on a LCHF diet compared to fasting can be attributed to the higher TGR5 activation due to fat and protein- induced bile release. (TGR5 sends signals to the hypothalamus which send downstream signals to activate AMPK in the body, with all the positive health outcomes which that entail).
If bile activation of TGR5 matters, this might support the notion that a low carbohydrate diet is superior for metabolic correction than a low-fat diet.
Low- fat diets lead to a reduction of bile release.
In contrast to a low carbohydrate diet, the low fat diet reduces activation of FXR by reducing the amount of bile flowing into the intestine.
By restricting the dietary intake of fats, bile release will be reduced.
This will prevent excessive activation of FXR, regardless of the actual quality of the bile.
However, by reducing the quantity of bile it may be that TGR5 activation is not optimised.
In contrast to fasting and low-fat diets, the low carbohydrate diet with ample fats and protein induces metabolic correction by altering the quality of bile rather than the quantity, thereby maximising the activation of TGR5, the receptor which is responsible for the profound metabolic improvements observed with gastric bypass.
This may explain why low- carbohydrate diets consistently outperform low- fat diets in terms of metabolic benefit in the short term studies which have compared the two.
Longer studies show less of a difference in benefit, but this is likely an adherence issue rather than reflecting the inherent value of the approach.
I suspect practical strategies to enhance adherence would lead to a similar gulf in results as those recorded in the shorter-term studies.
The idea that a low- carbohydrate diet may be metabolically superior to a low- fat diet is supported by the finding that high fat ketogenic mice are leaner with superior metabolic profiles than low- fat chow- fed mice. 90]
The candidate explanation is that although low –fat fed mice have low FXR activation, they lack the extra TGR5 activation by high-fat diet induced bile activation of TGR5, which would optimise metabolic health in the ketogenic mice.
Another observation which might indicate that a low- carbohydrate strategy is superior to the low-fat strategy for the correction of metabolic health is the observation that very low- fat diets are associated with gall stones due to the lack of fat-stimulated bile secretion.
In my next post, I will examine whether the type of fat, saturated or unsaturated, consumed on a low- carbohydrate diet makes a difference to the metabolic and body- fat regulation effects and attempt to understand why via the lens of events in the small intestine.
Antibacterial Foods Enhance Metabolic Health
Several rodent studies have shown that antibiotics were able to reverse the effects of a ‘high-fat diet’90]
to disturb the gut-brain signals and cause brain inflammation in rodents. 91]
As a result, antibiotic-treated animals are less and gained less weight.
Researchers wanted to test if foods known to have anti-bacterial properties could also reverse the negative effect of a high fat diet, similarly to the antibiotic treatment.
Animals which were fed a high fat diet supplemented with blueberries, a fruit rich in anthocyanins, and a natural anti-microbial ingredient had a completely different microbiota profile, less inflammation, and more stable blood sugar levels.
Is it a coincidence that many of the plant foods which are known for their wide spectrum of health corrective properties are also foods which have potent anti-microbial properties, e.g. mushrooms, garlic, vinegar, berries, coffee, herbs and spices, green tea etc..?
Nutritional Regulation of Bile Acids
When mice were fed two different types of protein; casein and salmon protein hydrolysate; the sph mice had far better metabolic markers and were in fact completely resistant to diet induced obesity. 92]
The study found that blood bile acid concentration in rats was increased by exchanging the dietary protein source from casein to salmon protein hydrolysate (SPH).
The researchers tested whether bile acids were playing a role in the protective effects of SPH by removing the bile acids with cholstyramine.
The removal of bile acids ‘completely abolished’ the beneficial effects of the salmon protein hydrolysate to prevent and improve the features of metabolic syndrome.
The researchers concluded that ‘our data provide evidence that bile acid metabolism can be modulated by diet and that such modulation may prevent/ameliorate the characteristic features of the metabolic syndrome.’
The metabolically dysregulated are either leptin resistant or, following weight loss; leptin deficient.
There isn’t a lot we can do about the weight- loss- induced leptin deficiency which drives people who have lost weight to regain most of the lost weight (via powerfully increased food cravings).
But we can compensate for the lower leptin levels by targeting the downstream pathways.
Since the small intestinal microbiota mediates the leptin deficiency induced heightened tendency to regain weight, this offers a target to correct the metabolic vulnerability.
By ‘starving’ the small intestinal microbiota we can compensate for the leptin deficiency induced reduction in innate immune control.
With dietary manipulation we can approximate, even surpass, the intestinal environment of the metabolically healthy, whereby bile is prevented from bacterial damage and we are able to benefit from the powerfully enhancing metabolic signals provided by a high fat diet induced increased flow of TGR5 activating bile.
By optimally enhancing both the quality and quantity of bile acids activating TGR5, metabolic health is powerfully reversed, appetite normalized, inappropriate cravings vanish and calorie intake spontaneously drops to allow stored body fat to be burned for energy.
In this manner, the low carbohydrate diet mimics the gastric bypass, which is similarly known to be profoundly corrective of metabolic health and body fat.
By optimally activating the key TGR5 receptor to correct the hypothalamic function in the brain, the low- carbohydrate, high- fat diet mimics the metabolic pathways which are responsible for the metabolic benefits of the gastric bypass and thereby offers a less invasive solution to a problem which requires a very targeted strategy.