Fructose Promotes Leaky Gut, Endotoxemia, And Liver Fibrosis

[Mito]

It would be good to know what they fed the rats and mice including exactly how much fructose they ingested.


Abstract
Fructose intake is known to induce obesity, insulin resistance, metabolic syndrome, and nonalcoholic fatty liver disease (NAFLD). We aimed to evaluate the effects of fructose drinking on gut leakiness, endotoxemia, and NAFLD and study the underlying mechanisms in rats, mice, and T84 colon cells. Levels of ileum junctional proteins, oxidative stress markers, and apoptosis‐related proteins in rodents, T84 colonic cells, and human ileums were determined by immunoblotting, immunoprecipitation, and immunofluorescence analyses. Fructose drinking caused microbiome change, leaky gut, and hepatic inflammation/fibrosis with increased levels of nitroxidative stress marker proteins cytochrome P450‐2E1 (CYP2E1), inducible nitric oxide synthase, and nitrated proteins in small intestine and liver of rodents. Fructose drinking significantly elevated plasma bacterial endotoxin levels, likely resulting from decreased levels of intestinal tight junction (TJ) proteins (zonula occludens 1, occludin, claudin‐1, and claudin‐4), adherent junction (AJ) proteins (β‐catenin and E‐cadherin), and desmosome plakoglobin, along with α‐tubulin, in wild‐type rodents, but not in fructose‐exposed Cyp2e1‐null mice. Consistently, decreased intestinal TJ/AJ proteins and increased hepatic inflammation with fibrosis were observed in autopsied obese people compared to lean individuals. Furthermore, histological and biochemical analyses showed markedly elevated hepatic fibrosis marker proteins in fructose‐exposed rats compared to controls. Immunoprecipitation followed by immunoblot analyses revealed that intestinal TJ proteins were nitrated and ubiquitinated, leading to their decreased levels in fructose‐exposed rats.

Conclusion: These results showed that fructose intake causes protein nitration of intestinal TJ and AJ proteins, resulting in increased gut leakiness, endotoxemia, and steatohepatitis with liver fibrosis, at least partly, through a CYP2E1‐dependent manner.

https://aasldpubs.onlinelibrary.wiley.com/doi/abs/10.1002/hep.30652

 

[Kartoffel]

I think the most likely explanation for their results is fructose malabsorption. The rats had increased Bacteroidetes, and more importantly, significantly higher concentrations of Proteobacteria, which produces lots of toxic stuff and damage the intestinal wall.

 

[Kartoffel]

Look at how much ethanol the rats had in their blood. They were literally getting drunk from all the fermentation in their gut.

 

[Mito]

I think the most likely explanation for their results is fructose malabsorption. The rats had increased Bacteroidetes, and more importantly, significantly higher concentrations of Proteobacteria, which produces lots of toxic stuff and damage the intestinal wall.




View attachment 13445

Why the malabsorption?

 

[Richiebogie]

Page 9 shows that the rats on water ate about 12g of chow per day, while the rats on fructose ate about 8g of chow per day.

Standard rat chow is cheap and nasty. It contains soy flour. It is 3% fat by weight but this fat is 62% PUFA. So that is about 2g PUFA per 100g of food.

We recommend humans eat less than 4g of PUFA per day which is less than 4g per kg of dried food! Otherwise high PUFA interferes with sugar metabolism. Rat chow has at least 5 times this amount of PUFA.

Also, fructose is not the same as sucrose and less like Orange Juice or fruit, which comes with potassium and vitamin C and other nutrients.

It might be better to see how humans fare on a fish and beef diet with and without bananas!

 

[CLASH]

@Mito
In order to be absorbed by the body fructose must be accompanied by glucose. In its absence fructose is left in the intestinal lumen and bacteria are able to ferment it. If the fructose is not accompanied by glucose and the other nutrients that come with fruit as well as the phytochemicals that are semi anti-microbial its basically free range in the gut for the bacteria to explode. This is the general problem with refined foods, even starches and glucose. Fructose happens to be the worst tho because it wont be absorbed at all or at the very least very minimally, meanwhile the starches and glucose can be easily absorbed.

This study would be more relevant if they had another group that ate sucrose, another group that ate glucose, another group that ate starch and anothe group that got fruit juice. The article is redundant at best. Free fructose is not even close to comparable to the fructose found in the synergy that is fruit, especially fruit that has a 1:1 fructose to glucose ratio and is lower in fodmaps.

 

[Rafael Lao Wai]

The scientists really try hard to paint fructose in a bad light and make unrelated things seem related. If they feed just fructose to the rats, obviously there will be malabsorption. It's almost like they designed to study for it to provide the results they wanted. And don't even get me started on the statements they used: "Fructose intake is known to induce obesity, insulin resistance, metabolic syndrome, and nonalcoholic fatty liver disease (NAFLD)." Just LOL. Known by whom? Under what circumstances? During nutrient deficiencies?

 

[Rafael Lao Wai]

They should at least try to be more impartial and use food sources of fructose such as apple juice or pear juice before making these absurd claims.

 

[CLASH]

@Rafael Lao Wai
Gotta convince the population that grains, beans, soy and vegetable oils are the way to go. Profits are depending on this

I think apple and pear juice might still cause some issues because depeding on the amount taken, they have a high fructose content in relation to glucose, i know this may be why your reccomended it tho.

 

[Mito]

@Mito
In order to be absorbed by the body fructose must be accompanied by glucose. In its absence fructose is left in the intestinal lumen and bacteria are able to ferment it. If the fructose is not accompanied by glucose and the other nutrients that come with fruit as well as the phytochemicals that are semi anti-microbial its basically free range in the gut for the bacteria to explode. This is the general problem with refined foods, even starches and glucose. Fructose happens to be the worst tho because it wont be absorbed at all or at the very least very minimally, meanwhile the starches and glucose can be easily absorbed.

This study would be more relevant if they had another group that ate sucrose, another group that ate glucose, another group that ate starch and anothe group that got fruit juice. The article is redundant at best. Free fructose is not even close to comparable to the fructose found in the synergy that is fruit, especially fruit that has a 1:1 fructose to glucose ratio and is lower in fodmaps.

Fructose can be absorbed by the small intestine as discussed in this study The Small Intestine Converts Dietary Fructose Into Glucose And Organic Acids, but in can be overwhelmed by too much.

 

[CLASH]

@Mito
The studies I have seen in humans, i’ll try to see if i can find it, show that people cant absorb more than 5-25g of excess fructose in absence of glucose. I think the microbial products are the biggest issue. I think even sucrose can cause mirobial issues in its free form.

 

[Luming Zhou]

There is a theory that the bad effects of simple sugars (like LPS and fatty liver) originate from bacterial fermentation. This makes sense because studies have shown that honey do not have the same effect probably because honey has anti-microbial agents. From an evolutionary standpoint, it makes sense that honey is naturally anti-microbial.

Differential Effect of Sucrose and Fructose in Combination with a High Fat Diet on Intestinal Microbiota and Kidney Oxidative Stress

There is controversial information about the adverse effect of sucrose (S) or fructose (F) in the development of obesity. Thus, the purpose of the study was to evaluate the effect of S or F in a high fat diet (HF) on gut microbiota and renal oxidative stress. Rats were fed for four months with either high-fat + sucrose (HFS) or high-fat + fructose (HFF) or a control diet (C). Half of the HFS or HFF groups were maintained with the same diet and the other half were switched to the consumption of C. HFS and HFF groups increased 51% and 19% body weight, respectively, compared with the C group. Body fat mass, metabolic inflexibility, glucose intolerance, lipopolysaccharide (LPS), insulin, renal reactive oxygen species (ROS), malondialdehyde (MDA), Nadphox, and Srebp-1 were significantly higher and antioxidant enzymes and lean body mass were significantly lower in the HFS group with respect to the HF-F group. Change in the consumption of HFS or HFF to a C diet ameliorated the insulin and glucose intolerance. The type of carbohydrate differentially modified the microbiota composition, however, both groups significantly decreased C. eutactus with respect to the C group. Thus, metabolic alterations with the HFS diet had a more detrimental effect than HFF.​

There is also a study comparing free glucose and free fructose and free glucose also had a negative effect.

High-Glucose or -Fructose Diet Cause Changes of the Gut Microbiota and Metabolic Disorders in Mice without Body Weight Change.

High fat diet-induced changes in gut microbiota have been linked to intestinal permeability and metabolic endotoxemia, which is related to metabolic disorders. However, the influence of a high-glucose (HGD) or high-fructose (HFrD) diet on gut microbiota is largely unknown. We performed changes of gut microbiota in HGD- or HFrD-fed C57BL/6J mice by 16S rRNA analysis. Gut microbiota-derived endotoxin-induced metabolic disorders were evaluated by glucose and insulin tolerance test, gut permeability, Western blot and histological analysis. We found that the HGD and HFrD groups had comparatively higher blood glucose and endotoxin levels, fat mass, dyslipidemia, and glucose intolerance without changes in bodyweight. The HGD- and HFrD-fed mice lost gut microbial diversity, characterized by a lower proportion of Bacteroidetes and a markedly increased proportion of Proteobacteria. Moreover, the HGD and HFrD groups had increased gut permeability due to alterations to the tight junction proteins caused by gut inflammation. Hepatic inflammation and lipid accumulation were also markedly increased in the HGD and HFrD groups. High levels of glucose or fructose in the diet regulate the gut microbiota and increase intestinal permeability, which precedes the development of metabolic endotoxemia, inflammation, and lipid accumulation, ultimately leading to hepatic steatosis and normal-weight obesity.
​

A lot of Peatists have trouble with sucrose. Perhaps because it feeds bacteria? Would eating sucrose along with antimicrobial agents like coconut oil and vinegar ease their symptoms?

 

[Rafael Lao Wai]

There is a theory that the bad effects of simple sugars (like LPS and fatty liver) originate from bacterial fermentation. This makes sense because studies have shown that honey do not have the same effect probably because honey has anti-microbial agents. From an evolutionary standpoint, it makes sense that honey is naturally anti-microbial.

Differential Effect of Sucrose and Fructose in Combination with a High Fat Diet on Intestinal Microbiota and Kidney Oxidative Stress

There is controversial information about the adverse effect of sucrose (S) or fructose (F) in the development of obesity. Thus, the purpose of the study was to evaluate the effect of S or F in a high fat diet (HF) on gut microbiota and renal oxidative stress. Rats were fed for four months with either high-fat + sucrose (HFS) or high-fat + fructose (HFF) or a control diet (C). Half of the HFS or HFF groups were maintained with the same diet and the other half were switched to the consumption of C. HFS and HFF groups increased 51% and 19% body weight, respectively, compared with the C group. Body fat mass, metabolic inflexibility, glucose intolerance, lipopolysaccharide (LPS), insulin, renal reactive oxygen species (ROS), malondialdehyde (MDA), Nadphox, and Srebp-1 were significantly higher and antioxidant enzymes and lean body mass were significantly lower in the HFS group with respect to the HF-F group. Change in the consumption of HFS or HFF to a C diet ameliorated the insulin and glucose intolerance. The type of carbohydrate differentially modified the microbiota composition, however, both groups significantly decreased C. eutactus with respect to the C group. Thus, metabolic alterations with the HFS diet had a more detrimental effect than HFF.​

View attachment 13470
There is also a study comparing free glucose and free fructose and free glucose also had a negative effect.

High-Glucose or -Fructose Diet Cause Changes of the Gut Microbiota and Metabolic Disorders in Mice without Body Weight Change.

High fat diet-induced changes in gut microbiota have been linked to intestinal permeability and metabolic endotoxemia, which is related to metabolic disorders. However, the influence of a high-glucose (HGD) or high-fructose (HFrD) diet on gut microbiota is largely unknown. We performed changes of gut microbiota in HGD- or HFrD-fed C57BL/6J mice by 16S rRNA analysis. Gut microbiota-derived endotoxin-induced metabolic disorders were evaluated by glucose and insulin tolerance test, gut permeability, Western blot and histological analysis. We found that the HGD and HFrD groups had comparatively higher blood glucose and endotoxin levels, fat mass, dyslipidemia, and glucose intolerance without changes in bodyweight. The HGD- and HFrD-fed mice lost gut microbial diversity, characterized by a lower proportion of Bacteroidetes and a markedly increased proportion of Proteobacteria. Moreover, the HGD and HFrD groups had increased gut permeability due to alterations to the tight junction proteins caused by gut inflammation. Hepatic inflammation and lipid accumulation were also markedly increased in the HGD and HFrD groups. High levels of glucose or fructose in the diet regulate the gut microbiota and increase intestinal permeability, which precedes the development of metabolic endotoxemia, inflammation, and lipid accumulation, ultimately leading to hepatic steatosis and normal-weight obesity.
​

A lot of Peatists have trouble with sucrose. Perhaps because it feeds bacteria? Would eating sucrose along with antimicrobial agents like coconut oil and vinegar ease their symptoms?

They don't mention the composition of the rats's diet, and considering that malondialdehyde levels were higher in the rats that ate high fat diets, I think it's very safe to assume that they were eating a high PUFA diet, so the lowered glucose tolerance, weight gain and higher blood glucose can be ascribed to the PUFA and not the sugars. Fructose seems to have benefited the rats with regards to glucose levels, oxidative stress, and endotoxins, in spite of the high PUFA diet.

And I agree that bacteria in the gut can do a lot of bad things, and lowering their amount can solve problems, such as gas, bloating, endotoxins, etc. Antimicrobial things can certainly help( in some cases stronger antimicrobial measures are required).. People that do low-carb/ paleo/primal diet think that sugar is bad because they have too much bacteria in their gut( and also because their blood sugar control sucks due to years of low-carb and PUFA loading), but instead of trying to see sugar as essential, they just resign to thinking that "yup, sugar is bad and I'm done with it". And they even recommend supplementing with probiotics, wtf!.

 

[yerrag]

They don't mention the composition of the rats's diet, and considering that malondialdehyde livels were higher in the rats that ate high fat diets, I think it's very safe to assume that they were eating a high PUFA diet, so the lowered glucose tolerance, weight gain and higher blood glucose can be ascribed to the PUFA and not the sugars. Fructose seems to have benefited the rats with regards to glucose levels, oxidative stress, and endotoxins, in spite of the high PUFA diet.

And I agree that bacteria in the gut can do a lot of bad things, and lowering their amount can solve problems, such as gas, bloating, endotoxins, etc. Antimicrobial things can certainly help( in some cases stronger antimicrobial measures are required).. People that do low-carb/ paleo/primal diet think that sugar is bad because they have too much bacteria in their gut( and also because their blood sugar control sucks due to years of low-carb and PUFA loading), but instead of trying to see sugar as essential, they just resign to thinking that "yup, sugar is bad and I'm done with it". And they even recommend supplementing with probiotics, wtf!.

It seems to me the study was designed with deception in mind. I wonder why they would use high fat as a condition in studying the effects of sucrose and fructose consumption. But it seems that by being vague about the type of fat used they are trying to make a conclusion of sugars that would suit a predetermined conclusion that their sponsors would like them to come up with.

They act oblivious to the fact that the type of fat used would have a large impact on their conclusions. They're not stupid, just deceptive.

 

[rei]

If i read that correctly they only mention the control diet. If so, the study is invalid and should not have been published as it contains too little information for replication.

 

[Kartoffel]

There is a theory that the bad effects of simple sugars (like LPS and fatty liver) originate from bacterial fermentation. This makes sense because studies have shown that honey do not have the same effect probably because honey has anti-microbial agents. From an evolutionary standpoint, it makes sense that honey is naturally anti-microbial.

I think the initital study of this thread strongly supports that theory. Also, honey has been shown to strongly downregulate lactate dehydrogenase, which shows that it promotesd the oxidative pathway over glycolysis.

A lot of Peatists have trouble with sucrose. Perhaps because it feeds bacteria? Would eating sucrose along with antimicrobial agents like coconut oil and vinegar ease their symptoms?

Do they? The people that have problems with sucrose usually eat large amounts of it because they think they have to, and then complain about weight gain, etc. Studies show that sucrose is not malabsorbed even in large quantities.

They study you posted is one of these useless pieces where they fed rats a high fat diet plus sucrose and fructose but had no high-fat control group. So, there is no way to distinguish the effetcs of sucrose and fructose from those of the high-fat diets. If the high-fat diets had the same fat as the control diet (AIN-93) then the fat was soy-oil. A high fat soy oil diet is probably sufficient on its' own to induce all of the complications.

 

[Rafael Lao Wai]

It seems to me the study was designed with deception in mind. I wonder why they would use high fat as a condition in studying the effects of sucrose and fructose consumption. But it seems that by being vague about the type of fat used they are trying to make a conclusion of sugars that would suit a predetermined conclusion that their sponsors would like them to come up with.

They act oblivious to the fact that the type of fat used would have a large impact on their conclusions. They're not stupid, just deceptive.

I think so too.

 

[Rafael Lao Wai]

@Rafael Lao Wai
Gotta convince the population that grains, beans, soy and vegetable oils are the way to go. Profits are depending on this

I think apple and pear juice might still cause some issues because depeding on the amount taken, they have a high fructose content in relation to glucose, i know this may be why your reccomended it tho.

Indeed, massive propaganda from an early age is the only way to numb people's intuition to the point of them tolerating ingesting foul-smelling oils and fart-producing beans and rejecting animal protein and fruits.

Yes, I mentioned those juices because they naturally have more fructose than glucose( although they still don't have just fructose, since, as far as I know, that doesn't exist in nature). If a person doesn't do well with free sugars, then apple juice wouldn't be a good choice and would probably cause bacterial issues.

 

[RWilly]

I don't have access to the full study, but I would be curious how much fructose was used. I've seen several studies on rats where the water supply was 70% fructose with no glucose ... so not exactly a normal condition.

 

[Kelj]

For what it's worth, Ray says,

"People have told me that when they looked for articles on fructose in PubMed they couldn't find anything except articles about its bad effects. There are two reasons for that. PubMed, like the earlier Index Medicus, represents the material in the National Library of Medicine, and is a medical, rather than a scientific, database, and there is a large amount of important research that it ignores. And because of the authoritarian and conformist nature of the medical profession, when a researcher observes something that is contrary to majority opinion, the title of the publication is unlikely to focus on that. In too many articles in medical journals, the title and conclusions positively misrepresent the data reported in the article."

Also, about these kinds of studies:

"In 1963 and 1964, experiments (Carroll, 1964) showed that the effects of glucose and fructose were radically affected by the type of fat in the diet. Although 0.6% of calories as polyunsaturated fat prevents the appearance of the Mead acid (which is considered to indicate a deficiency of essential fats) the "high fructose" diets consistently add 10% or more corn oil or other highly unsaturated fat to the diet. These large quantities of PUFA aren't necessary to prevent a deficiency, but they are needed to obscure the beneficial effects of fructose."
Glucose and sucrose for diabetes.

Maybe this, too, is a factor to consider:

Relationships Between Nutrition, Alcohol Use, and Liver Disease
"Malnutrition, regardless of its causes, can lead to liver damage and impaired liver function.....severe malnutrition also could lead to liver injury in adults...those who consume a substantial portion of their daily calories in the form of alcohol, often show evidence of malnutrition such as deficits in amino acids, proteins, and certain vitamins. These deficits can derive from an inadequate diet as well as from alcohol’s effects on these nutrients and their metabolism.....vitamin A deficits and excessive vitamin A levels can lead to liver damage, including fibrosis."

As mentioned by others in this thread, what were the rats eating previous to the fructose feeding and was the alcohol formation the problem?

In the 9/11 KMUD interview : Sugar, Cholesterol, Obesity and Heart Disease, Ray says fructose is protective even against liver damage from alcohol.

Liver fibrosis is the scarring from the body's attempts to heal liver damage. It seems plausible to me, that ill-fed rats suddenly exposed to fructose will start to heal, with some counterintuitive effects as described by those very familiar with eating disorder recovery, like here:

Time and Scope: Recovery Is Tough

"Food is nourishing and energizing so how on earth can it generate so much physical discomfort? Swelling, aching, exhaustion, palpitations, shortness of breath, pain, numbness, tingling, sweating, chills, hair loss, soreness, nausea, bloating…all because you are providing your body with the energy it has been denied for months or years?....
the process of rectifying an imminent disaster by re-feeding: hypoglycemia, pre-diabetes, high cholesterol, hypothyroidism and Hashimoto’s, osteopenia and osteoporosis, acid reflux, dental enamel erosion, infertility, reproductive hormone inadequacies, depression, memory and retention degeneration, gastroparesis, Barrett’s esophagus, non-alcoholic fatty liver disease, liver enzyme anomalies, kidney function anomalies, anemia, leukopenia…

Many long term eating disorder patients can be horrified by how chaotic their lab results appear once they enter a real recovery effort, when for years things have been stable and perhaps only marginally out of tolerance or just plain ‘normal’."

Notice the liver symptoms? These are all effects which eventually resolve with with persistent refeeding after restriction. They appear after you start to eat enough calories. The nutrient, fructose, is definitely a factor in the body's ability to reestablish a normally functioning body. The road there, however, can appear scary.

There is a need for us to realize that a symptom that appears in the context of finally eating enough, is a symptom of regeneration, not degeneration, and the body that finally has enough calories and nutrients will gradually work through it's own repair in a rational manner. The liver anomalies are a phase.
I can personally attest to that as I continue to enjoy my fruit juice, and yes, even my Pepsi with high fructose corn syrup, which is close to the same 50/50 glucose to fructose ratio as sucrose.