how I think that vitamin A metabolism issues result in SIBO or SIFO. I hope to have some diagrams at some point, but here is my general idea of what is happening. I think the development of SIBO/SIFO is multifactorial, but I will explain it from a vitamin A point of view.
In general vitamin A is needed at ***physiological levels*** in the gut to fight both candida and also bacteria. Zoey had high serum A which the GI doctor, me (dietitian), and the GI dietitian assumed was an accumulation of toxic amounts of vitamin A from some unknown alteration in enzyme activity perhaps. She is very unique. So, the solution that we all agreed on was ZERO vitamin A including no eggs (I didn’t know that Dr. Smith or Grant G existed at that time, so this was all on my own initiative).
When she went low vitamin A, but had high serum A, all parties assumed that she would have plenty of vitamin A to use in her GI tract. What we didn’t account for is that although vitamin A bound to RBP4 can get back to the GI tract, it still has to be taken up and stored in cellular retinol binding protein. Also, it has to become retinoic acid in those immune cells that take it up.
****The reasons why I think dietary vitamin A has helped her is because the enterocyte can metabolize vitamin A into retinoic acid using ALDH1A1. This retinoic acid can then transfuse into the blood and gut associated lymphoid tissue to be used by the immune cells. It bypasses the need for retention of retinol inside of cells of the immune system****
Zoey was struggling with both activities it seems. First, she struggles with calcium dysregulation. Zoey struggles with a mild form of renal tubular acidosis due to a down regulated mRNA expression for a bicarbonate transporter, but also, she has an underlying issue with sleep apnea which induces a pathway called hypoxia inducible factor 1 alpha (HIF-1alpha). This pathway causes lactic acidosis. The acidosis causes loss of magnesium in the urine. Magnesium is crucial for controlling calcium levels in cells by being part of the EF hand of a calcium binding molecule calmodulin that regulates cellular dynamics. Calmodulin controls the STRA6 pore that decides on whether vitamin A stays in the cell or leaves the cell. When cellular calcium is high, vitamin A is preferentially effluxed back into the blood onto RPB4 leaving the cell void of retinol. This includes immune cells as macrophages, B-cell, and mature dendritic cells all contain STRA6.
In macrophages, just binding of RPB4 to TLR4 induces an inflammatory response. The increase in NF-KB that happens when RPB4 docs with macrophages upregulates HIF-1alpha gene transcription. (LPS can also induce the NF-KB pathway in macrophages leading to HIF-1alph activation.) This should help increase the ability of immune cells to fight fungal infections. However, because of calcium dysregulation, retinol doesn’t stay in the cells to be able to make retinoic acid which upregulates dectin-1 receptor production. Neutrophils and dendritic cells also respond to retinoic acid by increasing the dectin-1 receptor.
So, you may have an increase in HIF-1alpha pathway (which by the way causes lactic acidosis which worsens magnesium losses and increases ionized calcium as well as increases calcium uptake into cells), but a decreased recognition of candida. Candida is recognized by the immune system specifically through the fact that it has beta-glucan on its cell wall. The immune system recognizes beta-glucan using the dectin-1 receptor. If dectin-1 expression is low, this can result in decreased ability to fight fungus despite having HIF-1alpha turned on. I don’t think the fight is completely stopped though. It’s just less efficient. Retinoic acid upregulates dectin-1 receptor. It isn’t necessarily absent when retinoic acid is low. However, in B-lymphocytes, lack of retinoic means decreased secretory IgA for binding to LPS. Less retinoic acid also means poor conversion of monocytes to macrophages and failure to recruit more white blood cells from the blood to the sight of infection in the gut due to less cytokine production. When LPS increase, it also triggers macrophages to make NF-KB which can increase HIF-1alpha transcription and lead to the HIF-1alpha pathway. The only gut bug that can dampen this response is enterohemorrhagic E. coli. And that is NOT a good thing. Either having EHEC or having poor retinoic acid production will cause candida to flair badly. This is what leads to SIFO I believe.
Lack of sulfate causing damage to immune cells in the gut because of anhydroretinol toxicity?
Another factor for Zoey that I see happening in many people is the lack of sulfate for back up alcohol metabolism in the gut. Specifically, b-lymphocytes have been shown to produce anhydroretinol (alcohol + acetic acid at human pH = anhydroretinol). Excess alcohol in the gut can result in death of B-lymphocytes which means less secretory IgA and more risk for LPS entering the body.
This lack of sulfate was coming from two issues. 1: oxalate (uses same transporter as sulfate) 2. Molybdenum deficiency (needed for SUOX enzyme to turn sulfite into sulfate). The oxalate issue was because a well meaning dietitian’s handout (kidney dietitian .org) has plantain as low oxalate when it is not. The molybdenum deficiency was caused by high amounts of vitamin A return to the liver I think and when vitamin A is high, the body using AOX for metabolism. Also, though, due to chronic hypoxia, Zoey had been stuck in the HIF-1alpha pathway that is the same pathway used to fight candida. In this pathway the enzyme CDO is upregulated which increases the need for SUOX activity. However, on top of that sleep apnea increase xanthine oxidase activity which also needs molybdenum. And then to add to that mess, Zoey has upregulated mocosulfurase mRNA expression which means she preferentially makes AOX and XO over SUOX. Phew. So in general she became very slow at SUOX, but needed more SUOX due to HIF-1alpha upregulation of CDO. (Jenny Jones, PhD and I have done significant work on this Moco Steal pathway. I will share more about it soon.)
Here is where SIBO comes in…
One of the things that HIF-1alpha does when fighting candida is increase the gene transcription for heme oxygenase 2 (HO-2). HO increases carbon monoxide levels which leads to a down regulation of CBS enzyme activity. This means LESS hydrogen sulfide. So, to compensate, the body might allow H2S producing bacteria to grow to help the body out with the lack of H2S available due to high RBP4 or LPS triggering NF-KB which increase HIf-1alpha. (Something to think about is that high serum A is a sign of high RBP4, but low serum A is NOT a sign of low RBP4 as RBP4 doesn’t have to be carrying vitamin A. It can carry palmitate and also anhydroretinol. Vitamin A can be low on tests and there still be an issue with RBP4).
This theory of growing sulfur metabolizing bacteria is actually a Greg Nigh theory of SIBO, but the process of what is causing us to not make enough at times is something I think goes along with vitamin A dysregulation. I love Greg’s theory, and it fits with what Zoey experienced with vitamin A dysregulation. It fits 100% with her developing SIBO when going very low vitamin A.
Other inducers of HIF-1alph besides hypoxia and candida include probably spike protein, nicotine, and beta-glucan.
Can HIF-1alpha pathway cause Vitamin A dysregulation and high serum vitamin A levels? Yes. I think it can.
Now back to that upregulated HO-2 enzyme from the HIF-1alpha pathway. As CO levels increase, O2 levels in the tissue drop. This eventually causes slowing of HO-2, and so then CBS turns back on because there is less carbon monoxide. When this surge of H2S happens, potassium leaving the cell is blocked. This causes an uptake of calcium and high intracellular calcium levels if the PMCA pump is not working well (calmodulin dependent and also needs magnesium on the EF hand). This is when I think there is even more vitamin A dysregulation as vitamin A effluxes back out of cells and worsens the whole situation especially for immune cells in the gut that require retinoic acid to make secretory IgA.
So there are many places in this path to think “what comes first, the chicken or the egg”. Is it high serum A that causes all the dysfunction? Is it the poor production of retinoic acid in the gut? Is it hypoxia alone inducing the HIF-1alpha pathway? Is it sneaky anhydroretinol? Maybe using a cod liver oil brand with a bunch of anhydroretinol?
What has helped for Zoey?
- Electrolyte balance. This is difficult to translate to all people. I suggest tracking your intakes in Cronometer and making sure you get at least 2400 mg sodium (need the Na-Ca exchange transporter working). Goal for potassium is what your RDA is when you put in your stats. Then on magnesium, if you are in acidosis, making sure to get twice the RDA perhaps. I don’t go higher because too much magnesium can act like a beta blocker and slow down the gut more. I typically don’t push electrolytes in doses. I add them to 2 liters of water and give over the course of one day. I use a combination of citrate, gluconate, and bicarbonate. I sort of just have found what works with her. I keep the bicarbonate at no more than 250 mg of potassium bicarbonate per day because going higher seems to make candida grow. Plus, huge shifts in bicarbs sends her reeling because even though she has RTA most of her acidosis seems to be lactic acidosis or glycolate poisoning from hypoxia.
- Zoey also gets 250 to 500 mcg of B12 per day added to the 2 liters of water. She gets 250 to 350 mg betaine as well. Both of these help with the iNOS causing high nitric oxide and a functional B6 deficiency
- She gets 15 mg of nicotinamide riboside at each meal that has 25% of the daily value of vitamin A (usually 1 to 2 meals per day – goal is 50% daily value). We don’t use nicotinic acid because it causes calcium dysregulation to worsen. We don’t do high dose because it puts burden on AOX which means more of MoCo steal and worsening sulfite issues. I don’t recommend any niacinamide, nicotinic acid, or nicotinamide riboside to anyone who is a carrier of enterohemorrhagic E. coli as it has been shown to encourage the adherence of this E. coli to the gut. I am thinking about switching to NMN, actually.
- She gets 100 mg ginger extract at each meal with vitamin A to increase the ALDH1A1 enzyme activity in the gut, so she makes retinoic acid. She is thankful to have a g-tube for this reason! Haha (yes, she does eat orally, but gets liquids through a stomach tube)
- We use Orthomolecular Motility Pro as a prokinetic agent. It works well. I give it only once a day on an empty stomach.
- We keep fat intake to 10-15 grams per meal maximum to lower LPS entrance in chylomicrons. This also helps to decrease TMAO production by bacteria in the gut. The higher the fat, the more TMAO. That leads to lower bile acid pools and worsening constipation. Constipation is not good for SIBO and SIFO.
Phew! Think that’s about it. Love to you all.