Insufficient thiamine intake creates a state of cell level hypoxia. Although it is called pseudo-hypoxia, because no obstruction is evident, deficiency-induced hypoxia elicits all of the same molecular changes one might expect with obstructive hypoxia. Most notably, the lack of thiamine stabilizes something called hypoxia-inducible factors or HIFs. There are multiple isoforms of this protein that perform slightly different functions in different regions of the body, but overall their job is to re-regulate the genes responsible for maintaining oxygen homeostasis in the face of low oxygen. To that end, HIFs control the transcription of hundreds of genes. Some of the functions managed by HIFs include erythropoiesis – the production of more red blood cells, angiogenesis to bring more blood and hence more oxygen to the region, and the switch to anaerobic metabolism so that energy production may be maintained, at least partially. Anaerobic metabolism is much less efficient than aerobic metabolism.
Where this gets interesting is once HIFs are stabilized, they turn around and block thiamine uptake. A recently published study found that in the epithelial cells that line the colon, and I would suspect elsewhere as well, HIF stabilization inhibits thiamine uptake by downregulating thiamine transporters. So the same proteins that are upregulated with insufficient thiamine, also downregulate the very nutrient required to resolve the hypoxia. In other words, low thiamine creates cell level hypoxia that stabilizes – turns on – the HIF cascades to bring more oxygen to the region. Simultaneously, stabilized HIF proteins limit thiamine uptake, causing a greater deficiency and larger hypoxic state. If extra thiamine is not consumed, which it rarely is, this would lead to a very destructive cycle.
In the intestines, this process alters, and ultimately limits, microbial synthesis, and uptake of thiamine. It also disrupts the microbial ecosystem itself, favoring more pathogenic organisms better equipped to maintain some semblance of thiamine sufficiency via what are called thiamine salvage pathways. The net result of these changes, is the downward spiral of gastrointestinal dysbiosis and dysmotility. Research like this points to gut dysfunction as one of the leading indicators of poor thiamine management.
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When you refer to the hypoxic brain, I think of this as a possible cause (or at least corelated with..) for many health-related issues. The one that “ju mps” out at me is Restless Leg Syndrome, which I deal with as adjunct to Parkinson’s. When it hits, I have always thought of it as brain suffocation.as it sends out pulse after pulse of “get me some air in here NOW!” Then again, it just a thought.. that needs oxygen to finish(!).
The Healing Project
“Blocking thiamine uptake” under the circumstances described makes no sense to me. Could the authors be wrong? It has occurred before.
They were looking specifically into the epithelial cells of the colon and the transporters there. From the article: “We showed that hypoxia causes significant inhibition in TPP and free thiamin uptake by colonic NCM460 cells and colonoid monolayers; it also caused a significant reduction in the expression of TPP (SLC44A4) and free thiamin (SLC19A2 and SLC19A3) transporters and in activity of their gene promoters.” I extrapolated that the same process may occur elsewhere in the body. I think the missing piece though, is that thiamine deficiency initiates the upregulation and stabilization of HIFs in the first place. It may be that deficiency itself is causing the downregulating of the transporter proteins and the association with HIFs is not direct, but rather, indirect. Of course, a long list of variables increase HIF stabilization, but all of which come back to thiamine by one path or another. So it is a bit of of a chicken and egg dilemma. I will note one more thing, with microbiota produced thiamine, which represents ~2% of total thiamine systemically, but most of the colonic thiamine locally, shifts in microbial populations towards the more pathogenic ones, tend to limit systemic thiamine uptake and apparently starve the more benign microbes, so I could see transporters proteins downregulating there after a time in response.
Thank you for such an insightful article linking thiamine deficiency and gut dysbiosis.
Can initial high dosage thiamine therapy (am on 1000mg)cause the gut symptoms to get worse as a paradoxical reaction? How long would it take to see positive effects and healing?