As I covered in an earlier blog, the pentose phosphate pathway plays a fairly large role in adrenal function through the creation of NADPH. While we are not done with NADPH and will be covering more on it later in this blog, our first order of business is to address how thiamine status affects gut health. This includes another function of the pentose phosphate pathway: creation of ribose 5 phosphate, a major building block for nucleic acids.
Nucleic acids such as DNA and RNA are the building blocks of life. DNA is essentially the blueprint for life while RNA simply carries out the instructions dictated by the DNA. Ribose-5-phosphate(R5P) created via the pentose phosphate pathway is required in the process of building DNA and RNA. Cell types that experience frequent turnover, such as intestinal epithelial cells, have higher rates of flux through the pentose phosphate pathway in order to create the nucleic acids that these cells need to replicate. This process is regulated, in part, by the thiamine dependent enzyme transketolase. Transketolase also happens to be the same enzyme that helps create higher levels of NADPH through the pentose phosphate pathway.
The 2 phases of the pentose phosphate pathway create products that suit different needs. The first phase, known as the oxidative phase, creates NADPH while the second phase, the non-oxidative phase, essentially shifts carbons around to form different sugars. For optimal function of the pentose phosphate pathway, thiamine is needed to allow cellular needs to be met. In tissues where R5P is needed to keep pace with cellular turnover, the oxidative phase of the pentose phosphate pathway can be skipped and intermediates from glycolysis can enter the non-oxidative phase of the pentose phosphate pathway provided there is adequate transketolase activity, which is dependent on thiamine. No thiamine and this process stops dead in its tracks. Even worse, the alternative pathways form advanced glycation endproducts.
A lack of R5P leads to reduced cellular replication, and there is evidence that a thiamine deficiency can cause what we would expect to see in cells with a high turnover rate that are experiencing a reduced replication rate. In a study looking at thiamine deficiency in rats, a diet deficient in thiamine led to a 45% reduction of the ratio of intestinal weight to intestinal length which was at least partially attributed to thinning of the microvilli as well as general thinning of the intestinal wall(1). This could potentially be due to reduced R5P availability for cellular replication. In addition, activity of several brush border enzymes such as sucrase, lactase, maltase, alkaline phosphatase, and leucine aminopeptidase were dramatically reduced when compared to pair-fed controls. Decreased brush border enzyme activity is a significant risk factor for small intestinal bacterial overgrowth(SIBO)(2) as undigested sugars and proteins are made available to resident bacteria because they aren't broken down and absorbed from the GI tract. The current thought process is that SIBO reduces brush border enzyme activity by damaging the GI tract, but it is equally as likely that decreased brush order enzyme activity could precede SIBO and provide an environment conducive to bacterial overgrowth.
Another area worth exploring in GI health is the effect acetylcholine has on digestion. Both the vagus nerve and enteric nerves primarily use acetylcholine and require glucose to make it. Enteric nerves form the enteric nervous system, a part of the autonomic nervous system that regulates digestive function. The vagus nerve as well as the nerves of the enteric nervous system cause the secretion of gastric acid and pepsinogen in the stomach, as well as pancreatic enzymes, via the action of acetylcholine on secretory cells(2). In addition to its role in gastric secretion, acetylcholine is necessary for the inflammatory reflex, a dampening of the inflammatory immune response by stimulation of the vagus nerve(3). This was discussed, in detial, in my previous blog. Acetylcholine is also synthesized and secreted by non-neuronal cells including epithelial cells in the GI tract as well as immune cells and many other cells throughout the body. Science has moved past the thinking of acetylcholine being simply a neurotransmitter.
Recall from my previous blogs that thiamine is necessary for converting pyruvate in to acetyl CoA which, coupled with choline, forms acetylcholine. Thus, synthesizing acetylcholine in neurons of the vagus and enteric nerves is dependent on thiamine. A study looking at the effect of a high fat diet on enteric nervous system function found increased neuronal loss and a decrease in acetylcholine levels that was reversed by Alpha lipoic acid(ALA)(4). ALA is another cofactor in both the pyruvate dehydrogenase complex as well as the alpha-ketoglutarate dehydrogenase complex, two thiamine dependent enzyme complexes. In fact, most of the thiamine dependent enzymes also rely on ALA, and it's separate function as an antioxidant can prevent it from performing its cofactor function when free radical levels are high. When ALA donates an electron to a free radical, it cannot be used as an enzymatic cofactor until it receives an electron from glutathione or another antioxidant. If you haven't figured it out by now, ALA is another important nutrient to pay attention to for adrenal fatigue and we will discuss it at a later time.
Thiamine and the immune systemThe final role we will discuss involving thiamine and GI health will bring us back to NADPH and links gut health, immune system function, and thyroid function together. Cells of the immune system that engulf invaders, called phagocytes, use an NADPH oxidase system to kill invaders.
When bacteria or other invaders become engulfed by a phagocyte, NADPH oxidase transfers electrons from NADPH to oxygen to form superoxide, which is used to kill the engulfed bacteria. Without sufficient levels of NADPH, this process cannot occur because there is no substrate to donate electrons. The end result, a compromised immune system, opens up the host to parasitic GI infections as the immune system is unable to keep invaders in check. This would also open up the host to recurrent upper respiratory infections, another common symptom in adrenal fatigue.
NADPH oxidase and thyroid functionAn interesting aspect of the NADPH oxidase system is that it plays a major role in thyroid function. Thyroid hormone synthesis is dependent on NADPH in both the thyroid and the liver. In the thyroid, two separate NADPH oxidase systems are used to generate free radicals, particularly hydrogen peroxide(H2O2), that are used to build the thyroid hormones T4 and T3(5, 6). In the liver, the less active T4 is converted in to T3 by an NADPH-dependent enzyme, 5'-deiodinase(7, 8) that utilizes reduced glutathione to make this conversion. Again, the solution to problems like this are much more complex than just throwing thiamine at them. T4 and T3 help regulate the conversion of riboflavin to FAD(9, 10, 11) which participates in many of the thiamine dependent enzymes as a cofactor and both FAD and selenium are needed for the glutathione cycle to work properly.
ConclusionGiven the critical roles that thiamine plays in adrenal function as well as other important physiological functions such as gut health, immunity, and thyroid function, achieving and maintaining adequate thiamine status should be a primary goal for anyone with suboptimal adrenal function. One could look at the symptomology that accompanies adrenal fatigue and see how the systems involved interplay with one another. One thought is that once one of these systems gets thrown out of whack, the others follow. This appears to be the prevailing thought process on how adrenal fatigue manifests itself and why a prolonged recovery is necessary. The current protocol for dealing with adrenal fatigue involves taking digestive enzymes in the hopes that the digestive system will improve in a way that allows the individual to begin absorbing nutrients better while at the same time killing off bacterial overgrowth by making the digestive tract inhospitable to bacterial/parasitic overgrowth. In time this could lead to resolution of symptoms, but is this the best way?
The theory that I have put forth in this blog series is that this may not necessarily be the proper way to solve the problem. Perhaps the multi-system dysfunction seen in adrenal fatigue is the physical manifestation of a deficiency of a nutrient or group of nutrients that all of these systems require for proper function. Thiamine and its cofactors fit the bill nicely as they are critical for a number of processes involved in optimal function of the systems that are affected in adrenal fatigue and are also likely to be affected by a low carbohydrate diet and overemphasis on exercise that relies on glycolytic energy pathways. However, going back to the analogy of the home heating system, just fixing the failed ignitor won't fix the problem if you don't fix the thermostat and fuel supply. Providing the proper nutrients fixes the ignitor, but you also have to change your lifestyle to fix the thermostat and increase carbohydrate intake to fix the fuel supply.
In people with Type 2 diabetes the problem, and therefore, the solution, is different. Their lifestyle is nearly polar opposite to a person undertaking a low carbohydrate version of the Paleo diet and hammering away at Crossfit 7 days a week. High carbohydrate consumption and low physical activity affects insulin sensitivity in a way that causes thiamine status to be low through poorer absorption and higher excretion rates. With these people, job #1 is to improve thiamine status by re-establishing proper insulin sensitivity through an increase in physical activity, a decrease in carbohydrate consumption(particularly processed carbohydrate) and improving intestinal barrier integrity.