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Thiamine Deficiency - A Potential Cause of SIBO and other Gut Dysfunction?



Thiamine deficiency - A consequence or cause of SIBO?

In the previous article, I explained how SIBO and gut dysbiosis could increase the risk of thiamine deficiency. Thiamine's uptake from the gut may be disrupted in cases of malabsorption, which is a common feature of SIBO. The composition of the microbiota resident in the gut also appears to be important, since certain bacteria can rapidly degrade thiamine. Additionally, sulfite (an intermediate in hydrogen sulfide metabolism) destroys thiamine, and elevated sulfide may also increase the requirement for thiamine in the brain. This means that people who produce more hydrogen sulfide gas in the gut might be more susceptible to thiamine deficiency. Although this is not an area which has received much attention in gut-health circles, thiamine deficiency might also be considered a primary cause of SIBO and other functional gut disorders.


I have speculated in the past that dysbiotic gut flora may play beneficial roles for host health, and that killing-strategies are likely not the most appropriate solution for everyone. In this article I will explain how SIBO can be a symptom of underlying systemic bioenergetic deficit which results in autonomic nervous system dysfunction, and can be driven by chronic thiamine deficiency.


Quick takeaway points:

  • Thiamine is a key component in the metabolism of glucose, both for energy production and in the pentose phosphate pathway. A lack of thiamine means that glucose cannot be metabolized through the oxidative pathway and instead is fermented into lactate.

  • Thiamine is essential for the nervous system function - it facilitates the nerve transmission and is required for production of neurotransmitters GABA, glutamate, aspartate, and acetylcholine.

  • Thiamine deficiency can be induced by excessive consumption of refined carbohydrates and "empty calories".

  • Gut motility, stomach acid and digestive enzyme secretion, and regulation of the intestinal barrier are governed by the vagus nerve, which is a component of the autonomic nervous system.

  • The lower parts of the brain responsible for autonomic nervous system coordination are highly sensitive to thiamine deficiency.

  • Thiamine deficiency can lead to autonomic nervous system dysfunction, abnormal vagal tone, and lower acetylcholine synthesis.

  • Autonomic dysfunction can induce all of the symptoms associated with SIBO and should be considered in cases where traditional therapies are ineffective.

Essential roles


To understand how a lack of thiamine might be relevant to gut issues, we must first examine some of thiamine's primary biological roles.

The Role of Thiamine Deficiency in Alcoholic Brain Disease. (2003). Alcohol Research & Health.

Thiamine is a key component of oxidative glucose metabolism, sitting at the entry point of the TCA cycle as a cofactor for the pyruvate dehydrogenase complex (PDH). PDH is responsible for converting pyruvate into acetyl CoA. Acetyl CoA is subsequently fed through the TCA cycle to produce hydrogen-carrying molecules NADH and FADH2, which are destined to reach the electron transport chain for ATP synthesis.


Thiamine deficiency reduces the activity of pyruvate dehydrogenase and re-routes glucose towards non-oxidative glycolytic metabolism, yielding high levels of lactate. For this reason, elevated urinary pyruvate and/or lactate on an organic acids test may be an indicator of low thiamine.


It serves as a cofactor for another midway component of the TCA cycle, called the alpha ketoglutarate dehydrogenase complex (KDH). This means that thiamine is also needed for the break down of fatty acids for energy. In addition to energy metabolism, KDH's dual purpose is to synthesize neurotransmitters such as glutamate, GABA and aspartate.


Although the glycolytic pathway is the primary route for glucose oxidation, another alternative route exists which is called the pentose phosphate pathway. This alternative pathway can be used to form the precursors for nucleic acid synthesis, and in the reduction of NADP+ to NADPH. NADPH is different kind of energy-carrying molecule involved in a variety of processes including:

  • Regeneration of oxidized glutathione

  • Oxidative burst in immune cells

  • Cholesterol and fatty acid synthesis

The Role of Thiamine Deficiency in Alcoholic Brain Disease. (2003). Alcohol Research & Health.

Transketolase is a thiamine-dependent enzyme which functions as a 'bridge' between the glycolytic pathway and the pentose phosphate pathway by facilitating the inter-conversion of intermediate-sugars for the production ATP or other anabolic reactions. This enzyme provides cell metabolism with flexibility and the ability to adapt to environmental conditions depending on the individual needs of the cell.


Cells with a high turnover-rate, such as those in the intestinal epithelial tissue, are heavily dependent upon the pentose phosphate pathway. The products of this pathway are in high demand during cell proliferation, and this requirement is expected to increase to facilitate repair following damage to the intestinal lining.


Thiamine's vital role in glucose metabolism renders certain parts of the brain uniquely sensitive to thiamine deficiency. The brain utilizes a large portion of the total pool of body glucose for its metabolic requirements, both in the synthesis of ATP and also as substrate for the formation of various neurotransmitters, including acetylcholine.


Thiamine is needed for glutamate dehydrogenase, an enzyme which breaks down the excitatory neurotransmitter glutamate. Thiamine deficiency has been shown to reduce acetylcholine synthesis in the brain and induce excessive glutamate release, effectively paving the way for neuronal excitotoxicity and dysfunction.


Thiamine also appears to be required for the activation of other vitamins. The activation of vitamin B6 to Pyridoxal-5-Phosphate is achieved by the enzyme pyridoxal kinase, and this enzyme may be downregulated in thiamine deficiency. Low levels of activated B6 disrupt the enzymatic breakdown of tryptophan in the brain and may contribute to accumulation of neurotoxic compounds such as quinollinic acid, further contributing to the brain burden. Thiamine is also likely involved in nerve conduction, although the mechanisms are not well elucidated at this point.

The essential roles played by thiamine in the brain and nervous system mean that insufficient amounts can have drastic consequences for practically every other system in the body. The autonomic nervous system is a branch of the central nervous system responsible for maintaining homeostatic control and coordinating involuntary physiological processes such as heart rate, body temperature, and digestion (among many other processes). Through shifting the balance between sympathetic and parasympathetic activation, this system allows the body to adapt to varied environmental stimuli and effectively stay alive.

Brain regions most sensitive to thiamine deficiency. The Role of Thiamine Deficiency in Alcoholic Brain Disease. (2003). Alcohol Research & Health.

The control centers for autonomic regulation are located within lower regions of the brain, the brain stem and the limbic system. These areas are particularly sensitive to thiamine deficiency because of their high rate of oxygen consumption. Defective energy metabolism in these regions can result in autonomic dysfunction, or "dysautonomia", characterized by sympathetic or parasympathetic dominance and faulty homeostatic control. The early stages of thiamine deficiency can produce dysautonomic symptoms. Dysautonomias can manifest in a variety of ways, with symptoms ranging from resting tachycardia, cardiac arrhythmias, bowel dysmotility, irregular sweating, gastroparesis, and orthostatic hypotension. Postural Orthostatic Tachycardia Syndrome, a prime example of dysautonomia, can be caused by thiamine deficiency.

How can thiamine deficiency cause gut dysfunction?


The gastrointestinal tract possesses its own individual enteric nervous system (ENS), often referred to as the "second brain". The ENS is technically a third branch of the autonomic system, responsible for modulating the activity of the gut and transferring information to and from the central nervous system (CNS). The bi-directional flow of information between the ENS and the CNS occurs through both sympathetic and parasympathetic nerves.

Source: https://socratic.org/questions/does-the-vagus-nerve-belong-to-the-sensory-somatic-or-autonomic-system

Although the ENS can perform its job somewhat autonomously, inputs from the CNS via the autonomic branches serve to modulate gastrointestinal functions. As a general rule, sympathetic nervous stimulation of the GI tract exerts an inhibitory effect on digestive activities such as secretion and motility, whereas parasympathetic stimulation promotes them. Parasympathetic input into the upper gut is predominantly through the vagus nerve, which plays a central role in maintaining healthy digestive capacity.

The vagus nerve originates at the dorsal motor nucleus of the medulla located in the brainstem, one of the brain regions susceptible to thiamine deficiency. Inefficient metabolism in the medulla due to a lack of thiamine can result in abnormal activity of the vagus nerve and autonomic dysfunction, which have numerous downstream effects on the gastrointestinal system. Interestingly, decreased vagal tone reflective of dysautonomia has been reported in both inflammatory bowel diseases and irritable bowel syndrome, and vagal nerve stimulation is being investigated as a possible treatment for SIBO and other gut-related problems.

Now recall that thiamine in needed to synthesis the neurotransmitter acetylcholine. Both the vagus nerve and the enteric neurons utilize acetylcholine to stimulate intestinal contractions of the smooth muscles to facilitate motility. This means that to have healthy gut motility, the autonomic nervous system and vagal tone must be in "good shape". Notably, one of the primary factors characterising SIBO is abnormal or impaired intestinal motility.


Vagal and enteric release of acetylcholine is also responsible for digestive enzyme secretion, hepatic bile release , and grastic acid secretion in the stomach. To produce these substances, the body must have a properly-working autonomic nervous system (which depends on adequate supply of acetylcholine/ thiamine). It is important to note here that poor bile flow and low stomach acid are both considered to be clinical risk factors for developing SIBO.


Brush border enzymes are essential for carbohydrate breakdown, and undigested carbohydrates in the upper gut are also considered to be a risk factor for SIBO. Thiamine deficiency reduces brush border enzymes in the gut, whilst also reducing intestinal weight. According to one author, thiamine deficiency has been reported in cases of SIBO. Thiamine deficiency also reduces enzyme activity in the liver, kidney, and heart.

Leaky gut


Increased intestinal permeability appears to play a significant role in so many different health conditions and can lead to detrimental consequences when present for long periods of time. Therefore, improving the integrity of the intestinal epithelial barrier should be one of the primary aims in any in "gut healing" protocol. However, simply throwing in gut-healing supplements such as L-glutamine may not be addressing the root problem.

In fact, leaky gut is not even something that needs to be fixed. The permeability of the intestine is modulated by higher control centers, and the intestine simply adapts to the signals it receives from the local and systemic environment. For example, chronic and acute immune activation acts as a signal for the gut to become leaky. Unless the root cause underlying the immune activation is addressed, supplements designed to "heal the gut" may only be beneficial temporarily, if at all.

Bonaz, Bruno et al. “The Vagus Nerve at the Interface of the Microbiota-Gut-Brain Axis” Frontiers in neuroscience vol. 12 49. 7 Feb. 2018, doi:10.3389/fnins.2018.00049

A key controller of intestinal permeability is actually the vagus nerve. Although the mechanisms are not well understood, the vagus nerve serves to maintain the intestinal barrier by increasing the expression of occludin tight junction proteins. Vagal nerve stimulation has even been shown to protect the gut barrier against LPS-induce permeability, and also prevents burn induced intestinal permeability.


According to the authors of one paper:

Vagal activity provides a protective function to the intestinal epithelial barrier and a low vagal activity makes intestinal epithelium more permeable thus promoting systemic inflammation and chronic disease. [emphasis added]

Poor vagal tone and abnormal vagal activity is present is present in dysautonomia, a cluster of conditions can be caused by system bioenergetic deficits that are not localized to the gut.


In addition, reduction of peripheral inflammation is a task also undertaken by vagal transmission through the "anti-inflammatory cholinergic pathway". This is accomplished through the release of acetylcholine which goes on to bind with alpha-7-nicotinic receptors of resident immune cells (macrophages) in the gut. The effect is to inhibit the release of pro-inflammatory mediators such as TNFα.

Matteoli G, Boeckxstaens GE The vagal innervation of the gut and immune homeostasis Gut 2013;62:1214-1222

This is important because inflammation in the intestine may actually induce dysbiotic changes in the gut bacteria. Altered immune homeostasis in these cells has been shown to induce a "metabolic reprogramming", driving shifts in colonocyte metabolism to yield abnormal quantities of certain metabolic byproducts. These include increased concentrations of molecular oxygen and nitrate, which are theorized to facilitates the growth of facultative anaerobic bacteria in the gut.

Elevated intestinal permeability and intestinal inflammation can lead to system inflammation, and since the vagus nerve is involved in the control of both of these processes, maintaining healthy vagal tone should be a top priority. The central role played by the vagus nerve, and by extension, the autonomic nervous system as a whole, thereby implicates autonomic nervous system dysfunction in the manifestation of gut problems. And because the autonomic nervous system needs thiamine, a deficiency in this key nutrient must therefore be taken into consideration when approaching SIBO and other functional gut-based conditions.

Connecting the dots


The reader should now have an appreciation for the importance that autonomic balance has on maintaining proper gut function.


The autonomic nervous system is involved in:

  • Secretion of stomach acid, pancreatic enzymes, and brush border enzymes

  • Release of bile from the liver

  • Maintaining regular intestinal peristalsis (motility)

  • Reducing intestinal permeability (leaky gut)

  • Reducing inflammation

Thiamine's key role in energy metabolism of the brain regions responsible for controlling autonomic balance, coupled with its role in acetylcholine synthesis, indicate that a deficiency could easily cause the symptoms which we associate with SIBO.


In fact, characteristic features of SIBO such as bloating, gas, infrequent bowel movements, and abdominal pain are also common in Postural Orthostatic Tachycardia Syndrome (POTS), a prime example of dysautonomia. The authors of one study concluded that

"the same autonomic impairment that leads to postural tachycadia may also affect the enteric nervous system, leading to gastroparesis, abnormal gut motility, and eosophageal reflux."

In other words, autonomic nervous system dysfunction can produce symptoms which are practically identical to SIBO. Thiamine is therefore crucial for maintaining gut health, and thiamine status should be considered in every case of chronic gut dysfunction that is unresponsive to other therapies.

A deficiency of epic proportions in today's sugar-laden world


The shift away from traditional diets toward processed foods has lead to a high dietary intake of "empty calories", characterized by excesses of macronutrients and deficits of micronutrients. Chronic over-consumption of sugars and refined carbohydrates effectively paves the way for thiamine deficiency because the metabolism of glucose "uses up" thiamine. Thiamine is water soluble, which means that it needs to be continuously topped up to meet the demands of daily metabolic activities.


Ordinarily, whole foods would also provide adequate thiamine. However, after a food/food-product has been refined or heavily processed, its thiamine content is reduced significantly. Chronic consumption of these refined products gradually depletes internal stores of thiamine to produce subclinical/chronic deficiencies.


The body may attempt to adapt to the lack of thiamine in a variety of ways which include down-regulating thiamine transporters on cell membranes, down-regulating the production of thiamine-dependent enzymes, and adjusting features of metabolism in maladaptive ways in an attempt to maintain homeostasis.

World-leading authority on the subject, Dr Derrick Lonsdale, has written extensively about the biochemistry of thiamine, the physiological features of deficiency, and the clinical application of thiamine for a variety of health conditions. Dr Lonsdale recently published a book (2017) on the topic, co-authored by Chandler Marrs PhD, called Thiamine Deficiency Disease, Dysautonomia, and High Calorie Malnutrition.


Although the book is quite complex in some sections, I would highly recommend readers to purchase and read through it if you have an interest in thiamine metabolism and the clinical uses of this nutrient. The book also includes numerous case studies, documenting the wide array of benefits achieved through high-dose thiamine supplementation.


Dr Lonsdale's many years working as a physician and testing patients demonstrated that thiamine deficiency was extremely common - especially in cases of autonomic - and these conditions could be greatly improved via thiamine repletion therapy. However, thiamine was often needed in very high doses and for long periods in conjunction with other specific nutrients such as magnesium and the other B vitamins to have any lasting effect. Dr Lonsdale postulates that long-term, chronic deficiency states foster a downregulated expression of the machinery required to process thiamine, and that a sustained high-dose was needed to 'kick-start' the production of new enzymes and transport proteins involved in thiamine metabolism. This approach makes sense, and since thiamine is water-soluble, it is extraordinarily safe to do and poses very little risk of toxicity. In my own clinical experience, I have been using thiamine in some of my clients with digestive issues, and some have found substantial benefit from high-dose thiamine supplementation.


Conclusion


The common treatment for SIBO typically focuses on modulating gut microbiota via exogenous means involving the use of antibiotics, antimicrobials, and pre/probiotics. The problem is that this approach often results in a relapse of symptoms after treatment has been completed.


The information presented here suggests that SIBO and other gut dysfunction may be one symptom of an underlying issue with systemic metabolism, rather than something that can be fixed by targeting it directly.


With this in mind, I believe that focusing on improving energy metabolism systemically, especially within the higher control centers (the autonomic nervous system), may prove to be a more effective strategy in resolving the underlying cause. Although this article has honed in on thiamine, metabolic inefficiencies can be caused by a deficiency in any of the micronutrients, which can also be induced or exacerbated by chemical, metal, or environmental toxicities of various kinds.

Recommended resources


- Thiamine Deficiency Disease, Dysautonomia, and High-Calorie Malnutrition

- A Review of the Biochemistry, Metabolism and Clinical Benefits of Thiamin(e) and Its Derivatives

- Hormones Matter website

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