Sugar, Leaky gut and liver disease

Let’s do some lumberjacking!

By Dr. Bayne French, MD DC

Tell me something I care about:

·       This article will detail how sugar disrupts intestinal flora, damages the gut lining, and leads to liver disease.

·       There are many things that make your gut flora unhappy. Sugar is at the top of the list.

·       Consuming sugar in extremely low amounts, eating a healthy diet and supplementing with probiotics is a solid game plan for happy flora. And happy flora contributes to a healthy metabolism.

Timber!

A Mr. Burt Macklin provided some feedback about my writing recently:

Dear Bayne, Your claims suck and you should stop blogging forever… Maybe you should spend more time researching modern science instead of pretending to be a lumberjack in your backyard… Maybe start trying to find a job in another field. Not journalism, though.

There was much more I omitted, to spare you. The sheer quantity of explanation points rivaled only by a note I received from Blair Polywog in the 9th grade when she learned I was actually not ill, but went camping instead of to the prom with her.

Mr. Macklin also claimed to be a previous patient of mine. Something I had no recollection of, although the troll-type don’t stay long with me. Later I realized that Burt Macklin is the alter-ego of character Andy Dwyer in the hilarious sitcom Parks and Recreation. If triggered by my writing, why drag in my avocation of choice…lumberjacking? Yes, I do that, and many other things, in my backyard.

How about we fire up our chainsaws together and put in a solid day’s work learning about the biochemical damage sugar causes to our intestinal environment? I promise to dumb it down, so Burt can follow along.

Definitions:

·       Sugar. A molecule containing one part glucose and one part fructose.

·       Gut-liver axis. The bidirectional communication and interaction between the gastrointestinal tract (gut) and the liver. This involves many direct chemical messengers, both from our diet and those derived from our gut flora. Some researchers consider immune system, hormonal, and neurological messengers a part of this axis.

·       GI. Gastrointestinal, our stomach and intestine.

·       Intestinal lumen. The hollow space inside the intestine where digestion takes place.

·       Enterocyte. A single cell of the intestinal lining that is the interface between the intestinal lumen and the blood stream that heads directly to the liver.

·       Microbiota. Refers to our entire microbial community. Flora is a similarly used term. There are four main phyla of bacteria: Firmicutes (64%), Bacteroidetes (23%), Proteobacteria (8%), and Actinobacteria (8%). Within each phylum are numerous families, genera, and species of bacteria.

·       Gut Microbiome. Refers to a group of microorganisms living in a symbiotic way in our gastrointestinal tract. More precisely the genome of these bacteria. Our microbiome is so complex some researchers consider it a distinct organ in our body.

·       Dysbiosis. This is an imbalance in our different types of intestinal bacteria.

·       SCFAs. Short chain fatty acids acetate, propionate and butyrate are made by our gut flora. A healthy gut flora produces them in appropriate ratios and they provide numerous benefits to gut health and metabolism in general. A dysbiotic gut flora produces SCFAs abnormally, directly damaging the intestinal barrier.

·       NAFLD. Non-alcoholic fatty liver disease. This represents a spectrum of diseases not caused by alcohol. It includes steatosis (fatty liver) and non-alcoholic steatohepatitis (NASH).

·       NASH. Non-alcoholic steatohepatitis. This is the more serious form of NAFLD, with liver inflammation, injury and scar formation which can lead to cirrhosis.

·       Endotoxin. Toxins produced by our gut flora primarily via dysbiosis.

·       Probiotic. Live bacteria that confer health benefits.

Our intestinal lining:

Our intestinal lining is an individual immunological site. The direct interaction of bacteria with the host (us) takes place here. And this is where “cross talk” occurs between our gut flora via chemical messengers with our immune system and blood stream.

The details of this “conversation” have tremendous importance in our health. If the talk is a bit sassy then weight gain, insulin resistance, and a leaky barrier ensue leading to a sick liver and metabolism. If the talk is civil, collegial, and caring, the risk of these disease processes is much lower (Mazzotti et al. Dig. Dis. 2016).

Koh et al. (Cell. 2016) showed that if proper gut flora interaction with the host is disturbed, even cancer risk is heightened. I’m hoping my flora talks sweetly to my intestinal wall. I think my bacteria are kind and sweet, like the rest of me.

Sugar’s journey:

After consuming sugar, the enzyme sucrase breaks it apart into glucose and fructose.

Glucose is absorbed into the intestinal wall, specifically into the enterocyte, by the transporters SLGT1 and GLUT2. Fructose is absorbed by a different transporter, GLUT5.

The number of GLUT5 transporter molecules is influenced by dietary fructose…eat and drink more sugary crap, get more GLUT5 transport ability. This is the primary goal of gut training that metabolically clueless researchers and lecturers advocate under the guise of enhanced athletic performance. And to sell more sugary crap.

Once fructose is within the enterocyte, the enzyme ketohexokinase (KHK) alters it so it cannot leak back into the intestine. If I was an enzyme, I’d want to be KHK. I think the other enzymes would fear me. I’d probably go rogue, exploring other parts of the body with my axe.

Anyway, once fructose is chemically altered by KHK, it can then move from the enterocyte into the blood stream and head directly to the liver. This is what is supposed to happen. With high sugar/fructose consumption, KHK is not able to act on all the fructose that enters the enterocyte, and some fructose enters the blood stream unaltered.

Once reaching the liver, most of the fructose enters the liver cells. This is in contrast to glucose. Most glucose bypasses the liver and reaches the systemic circulation where all cells can use it as fuel. Elevated blood glucose is not at all metabolically favorable however, and drives disease over time via numerous pathways.

Back to fructose. When it enters liver cells it is acted on by numerous other wimpy enzymes that fear me. Eventually fatty acid synthase (FASN) converts it to fat. Which is exactly what most of America wants to avoid.

More on fructose’s story:

This simple sugar molecule naturally occurs in fruit, honey, and in smaller amounts in vegetables. We partook of hand-to-hand combat with baboons, and each other, to get fructose. We risked life and limb for it because it drives fat formation and those who could make fat the best had a higher chance of survival. Survival of the fattest. An example of what was good for our fore-people when old age was 31, isn’t favorable for us now.

Decades ago, fructose was felt to be favorable for the management of diabetes because it does not need insulin to be metabolized, and it does not spike blood sugar. Sounds favorable right?

In 1960 high fructose corn syrup was introduced into our food industry as a sugar substitute and wow did we get healthier. Burt, that’s sarcasm. Today, the view on fructose (from those that understand basic human biochemistry, the genesis of disease, and are not dogmatic morally-stunted purveyors of toxic slurries) has changed dramatically. Its regular consumption is now widely known as a risk factor for the development of obesity and several metabolic diseases.

“Fructose in the form of added sugar is particularly implicated in metabolic syndrome, hypertension, insulin resistance, lipogenesis, diabetes and associated retinopathy, kidney disease and inflammation” (Garcia et al. Diabetology. 2022).

Numerous authors including Melchior et al. (Unit. Eur. Gastro. J. 2014) have studied fructose as a cause of Irritable Bowel Syndrome (IBS). IBS is more of a descriptive term than a diagnosis. I prefer Sucky Gut Syndrome of Pain, Cramp, Diarrhea, Bloat and Toots. There are many things that can cause Sucky Gut Syndrome, but regular fructose consumption is one of the most common in my experience…understanding that empiric observation of 10’s of thousands of patients over 25 years isn’t exactly scientific in Burt’s book. Timber!

Gut microbiome and gut dybiosis:

Our gut flora, when healthy, modulates our intestinal immune system. They protect us from harmful germs, and they act as gatekeepers for our intestinal barrier function. They are fit, capable, and have sharp saws.

Our gut flora communicates with our immune system via chemical messengers. Lambert et al. (Front Immunol. 2017) termed “crosstalk” and through this communication inflammation, insulin resistance, and gut lining permeability are affected. In that wonderful article, mechanisms were outlined of “fructose-induced alterations of the tight junction proteins affecting the gut permeability, leading to the translocation of bacteria and bacterial endotoxin into the blood circulation”. This article fascinated me as I read it in my backyard, throwing a machete at tree stumps.

Our GI flora is highly influenced by our dietary choices. Sen et al. (Physiol. Behav. 2017) showed that a high sugar diet distorted our gut diversity in 1 week. Turnbaugh et al. (Sci. Transl. Med. 2009) showed that transitioning from a healthy Mediterranean diet to a standard American diet high in sugar altered gut flora within ONE day. Healthy food, particularly dietary fiber is fermented in the colon (large intestine) by healthy bacteria. Numerous compounds are produced through this process including SCFA’s (see below), trimethylamine, ammonia, and hydrogen sulfide. These chemicals maintain the integrity of our intestinal lining and optimizing its function as a formidable barrier.

deSouza Rodriques et al. (Brain Behav. Immun. 2017) studied the standard American diet high in sugar and found an increased vulnerability to numerous metabolic diseases including NAFLD and cardiovascular disease. Zelber-Sagi et al. (Liver Int. 2017) found that a diet high in olive oil, fish, nuts, vegetables and fruits negatively correlated with the development of NAFLD. These foods nurture our gut flora.

According to Kang et al. (iScience. 2022), a high fructose diet has “profound effects on the gut microbiota linked to adverse outcomes on GI tract physiology”. And “Notwithstanding the complex mechanisms driving these disease processes, it’s plausible that gut dysbiosis, in most part, is a major contributor to the myriad diet-induced metabolic dysfunctions.”

When the gut flora is distorted (dysbiosis), inflammatory chemicals called cytokines are released. These directly damage the tight junctions between enterocytes leading to numerous chemicals entering the blood stream right to the liver. These chemicals are supposed to remain in the intestinal lumen.

It is well known that sugar consumption plays a key role in the development of dental cavities, diabetes, cardiovascular disease, high blood pressure, hyperactivity, obesity, abnormal cholesterol, fatty liver disease and cancers (Monteiro-Alfredo et al. Nutrients. 2021; Paglia et al. Eur. J. Paediatr.). What’s fascinating to me is that numerous researchers, including Fan et al. (Digestion. 2021) found that patients with the above diseases displayed gut dysbiosis. This means that individuals with numerous different metabolic diseases all displayed a distorted gut flora.

Our gut flora also has an important role in our body weight. Many researchers have reported on a decrease in Bacteroidetes group of flora, and an increase in Firmicutes with a high sugar, crappy diet. Furthermore, numerous studies have shown that Firmicutes bacteria in our gut promote the accumulation of fat (Turnbaugh et al. Cell Host Microbe. 2008; Khan et al. J Obes. 2016).

Sugar drives the obesity pandemic by:

·       Spiking blood glucose levels with a resultant insulin dump and eventual insulin resistance, leading to diabetes, cancer, and cardiovascular disease.

·       Directly driving fat formation in the liver.

·       Driving Firmacute overpopulation of our gut flora.

In a broad stroke, high dietary sugar causes major changes in the diversity of our gut flora, and altered bacterial metabolism. These changes create inflammation that detrimentally affects the barrier function of our intestinal lining.

To state this in a way Burt would understand…sugar hurt gut bacteria. Intestine lining get leaky. Bad stuff go into blood. Liver get hurt. Dat “sucks”.

Sugar-addicted, dogmatic rats:

I’m not talking about Mr. Macklin here. I mean literal rats.

Do et al. (Nutrients. 2028) studied rats fed both a high glucose and high fructose diet. The tight junctions between the enterocytes were damaged in these rodents and became more permeable.

Wang et al. (Mediat. Inflamm. 2020) also studied rats. Burt applied for that trial and was nearly accepted I’m told. The rat cohort was divided into 3 groups in relation to how much fructose they were given: low, moderate, and high. These unfortunate reptiles drank sugary crap for 20 weeks. All three groups showed elevated inflammatory compounds and a decrease in anti-inflammatory compounds. The highest sugar eating rats had the most distorted gut flora.

Sun et al. (J. Nutr. Biochem. 2021) also looked at sugar-addicted rats for a month. They exhibited much worse cholesterol profiles and higher fat in their blood. Not surprisingly their gut flora “sucked”.

SCFAs:

Let’s discuss short chain fatty acids (SCFAs) in more detail. They are compounds directly made by our gut flora. They consist of 3 main compounds: acetate, propionate, and butyrate in approximately a 60:20:20 ratio.

Our digestive tract lacks enzymes to effectively digest fibers and highly non-digestible carbohydrates like inulin, pectic, and cellulose. When these healthy nutrients reach the intestine, they stimulate the growth and activity of bacteria capable of fermenting these nutrients. During fermentation, SCFAs are formed. These 3 compounds are critical for gut health directly, but also act as signaling molecules to tissues remote from the intestine.

Per Kasubachi et al. (Nutrients. 2015), SCFA’s “acting as signal transduction molecules with epigenetic impact”. Let’s think about his for a moment. Not you Burt, I mean those capable of thought. A healthy, low sugar diet leads to bacteria that efficiently produce SCFAs. These compounds then exert numerous healthful actions, including interacting with our DNA!

The benefits of SCFAs don’t end here. According to den Beslen et al. (Lipid Res. 2013), SCFA’s provide almost 10% of the human energy requirement per day. This means they are energetically dense, and causes yet another hole in the very porous notion that high sugar consumption results in more energy production. High sugar consumption results in a much lower concentration of SCFA formation.

Summary of SCFA benefits:

·       Provides energy for the body.

·       Butyrate in particular nurtures the colon lining providing enterocytes themselves energy and protecting against colorectal cancer and inflammation (Gonvalvesa et al. Porto Biomed. 2016).

·       Cause satiety (feeling full), improved blood sugar metabolism, and insulin sensitivity (Canfora et al. Nat. Rev. Endocrinol. 2015).

·       Higher intestinal production of SCFAs (like in those people that don’t consume much sugar) is associated with having a lean body weight, reduced inflammation, and feeling less hungry (Boulange et al. Genome Med. 2016).

·       SCFAs influence eating habits and host metabolism acting to prevent excessive food intake and a lower incidence of obesity (Dahiya et al. Front. Microbiol. 2017).

·       Propionate in particular decreases glucose production from the liver, thereby reducing elevated blood sugar levels and resultant insulin resistance and obesity (den Besten et al. J. Lipid Res. 2013).

·       Acetate affects the brain, resulting in a lower appetite (Frost et al. Nat. Commun. 2014).

·       All 3 SCFAs decrease gut permeability by bolstering the tight junctions between enterocytes. This protects the gut barrier function (Miyoshi et al. Nutrition. 2008).

·       SCFAs influence nerve function of the gut itself. This improves motility, secretion, inflammation and lowers tumorgenesis (formation of tumors) (Soret et al. Gastroenterology. 2010).

·       SCFAs lower the pH of the gut, creating a more acidic environment. This further nurtures a favorable gut flora.

·       Sugar, and especially fructose alters SCFA formation indirectly by causing gut flora dysbiosis (see the next session).

How fructose causes liver disease:

Let’s gas up our saws, tighten our suspenders, and find out how sugar, especially fructose damages our liver.

More than small amounts of fructose (usually from sugar or high fructose corn syrup) directly alter the diversity of gut flora. Certain microbial groups predominate, and others are suppressed. This is dysbiosis discussed above and is directly driven by excessive sugar consumption.

“Multiple studies (mouse, rat, monkey, and human) reported fructose as a critical factor contributing to NAFLD progression by modulating intestinal microbiota” (Lambertz et al. Front. Immunol. 2017). A human study looked at adolescents who had already developed NAFLD (Yes, high sugar consuming kids get liver disease). These kids, whose health care you’ll be paying for, were fed high-fructose beverages. After only 24 hours, endotoxin levels were elevated (Jin et al. Int. J. Hepatol. 2014). Recall that endotoxin are bacterial produced toxic substances.

An unhealthy, dysbiotic gut flora produces high levels of endotoxin lipopolysaccharides (LPS). LPS are damaging in many ways. They contribute to gut lining inflammation and a leaky barrier, thus creating their own entry into the blood stream. The liver is the next target.

Not surprisingly, patients with diagnosed NAFLD and NASH were found to consume much more carbohydrate, particularly fructose (Spruss et al. J. Nutr. Biochem. 2009).

Numerous researchers have found associations between the consumption of fructose and the amount of endotoxin in the blood stream (Bergheim et al. J Hepatol. 2008; Kavanagh et al. Am J Clin Nutr. 2013; Jin et al. Int J Hepatol. 2014).

But how? How is fructose in sugar and high-fructose corn syrup causing GI toxins to enter our blood stream and damage our liver (and many other organs)? Our enterocytes are tightly connected by tight junctions called desmosomes and adherens junctions which protect our blood stream from toxic gut substances. A diet high in fructose changes the diversity of our gut flora, favoring pro-inflammatory bacteria that secrete endotoxin, like LPS discussed above.

LPS is directly toxic to our enterocytes and tight junctions. These endotoxins also activate our immune system resulting in the release of further damaging chemicals. The result being damage to our desmosomes and adherens junctions, higher permeability of our gut barrier, and a flooding of toxin that reaches our liver.

To summarize, Lambertz et al. felt that numerous studies taken in concert support fructose’s ability to damage the liver in two main ways:

1. Fructose from the gut is taken up by liver cells and potently drives lipogenesis, fat formation. A fatty liver is a diseased liver.
2. Fructose damages the diversity and symbiosis of our gut flora, leading to dysbiosis. Endotoxins like LPS are formed in much higher concentrations which damages the gut lining barrier, creates leaking, then exerts toxicity directly on the liver.

Let’s not forget uric acid:

I have written about the metabolic harms of uric acid many times. Irresponsible and metabolically clueless individuals recommend the high consumption of sugar for athletic reasons. It’s important to understand that if you abide by this crappy advice, fructose will flood your liver. This potently drives the formation of uric acid which is directly toxic to hepatocytes (liver cells). Fructose in the liver is further acted on by enzymes to form triosephosphate, which is then converted to fat.

So, uric acid formation, potently driven by sugar consumption, directly damages the liver, and drives the formation of fat. This fat is stored in the liver, creating NAFLD, but also stored EVERYWHERE, contributing to unwanted weight gain. If you’re an endurance athlete, this hampers your power-to-weight ratio, making you less efficient and incapable of reaching your potential.

The fructose in sugar has a two-pronged effect on uric acid. Not only does it drive the formation of uric acid, it also acts on the kidney to suppress their ability to remove uric acid from the body (Nakagawa et al. Am J Physiol Renal Physiol. 2006. Thus, fructose can make more uric acid and keep it in the body longer.

Conclusion:

I jump around a fair bit. Not just in my backyard with sharp things, but I mean in this article. There are just so many direct and indirect, interconnected, toxicities of sugar on our digestive tract that they’re hard to outline in a logical sequence.

Aside from consuming sugar in very low and occasional amounts, reserved for celebratory events, how can we bolster our gut flora and intestinal lining? Is there any validity to probiotic supplementation?

Xue et al. (Sci Rep. 2017) studied a lot of rats. I supplied Dr. Xue with several of them that I had trapped in my back yard. This study made several observations. Rats that were fed a crappy diet produced much less endotoxin when they also were fed probiotic. Specifically, levels of LPS were lower, despite a terrible diet, when these reptiles consumed probiotic.

The livers of the probiotic-supplementing rats also showed less swelling, inflammation, and fat formation. Furthermore, their cholesterol profiles were better and they exhibited less fat in their blood. They probably would’ve lived forever like in the movie Green Mile, had they not been killed and their livers examined.

Dr. Xue was not done however. Probiotic-supplementing rats showed improvement in gut flora and an actual improvement in tight junction protein function between the intestinal lining enterocytes. This is favorable, and is the opposite of leaky gut.

Burt Macklin likely drinks a lot of sugary crap. Unwise. He likely also feels that through regular exercise he is somehow immune to the metabolic cauldron that follows this sugary crap consumption. Not just unwise, but deluded, and breaks all laws of biochemistry and rational thought.

How about we take a sugary trip through Burt Macklin’s bowels?

·       Sugar in Burts Bowel is broken down by sucrase, liberating glucose and fructose.

·       Fructose and glucose are absorbed, passing through Burts enterocytes by their own respective transporters, and enter the blood stream headed directly to Burts sick liver.

·       Most glucose bypasses said liver and instead spikes blood sugar, elevating insulin, and driving diseases that most of America will die of. But not Burt, because he exercises (sarcastic face emoji).

·       Most absorbed fructose enters the liver and drives lipogenesis, the formation of fat. This is why Burt has gained weight, especially around the mid-section. This frustrates him.

·       Fructose also drives the formation of uric acid which is directly toxic to liver cells, and further intensifies fat formation and the insidious storage of fat in Burt’s liver and entire torso. Which frustrates him.

·       Back to Burts Bowels…sugar disrupts his gut flora, causing dysbiosis. The phylum Firmicutes predominate, and produce numerous toxins like LPS. Burt reeks of endotoxin.

·       LPS directly damages the tight junctions between his enterocytes and creates leak. The LPS and other toxic substances in Burts Bowel also trigger an immune response in his gut lining, further damaging his enterocytes and tight junctions between them.

·       Now that Burts gut is leaky, all kinds of horrible substances are entering his circulation. This damages his liver, and likely affects his judgement, causing him to criticize the noble pursuit of lumberjacking.