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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