Is your vitamin B12 abnormal due to your genetics and microbes?  Check out out audio transcript to learn more.

Vitamin B12: A Nutrient Shaped by Genetics and Microbes

Dawn (00:00):

Hello and welcome to the Gastric Health Show. My name is Dawn Boxell, a Registered Dietitian, and this week’s topic is vitamin B-12, a nutrient shaped by genetics and microbiome. So we are going to dig in a little bit deeper, well, I guess I would say a lot deeper into vitamin B-12 and what influences the actual level that you see on your blood work. And this is where I would say can really get complicated and really make someone really have to have a good understanding of their body to truly make informed decisions. So if you are struggling with a B-12 deficiency or having high levels of vitamin B-12, these can give us insights into truly maybe some other underlying drivers like your genetics or your gut microbiome playing a factor in that outcome. So we did talk about a couple weeks ago we talked about why is vitamin B-12 so important after bariatric surgery?

What is vitamin B12, and why do we need it?

(01:19):

We’re going to, this is kind of an extension to that, but if you want to go back to that one first, you’ll really kind of understand the intricacies of just vitamin B-12 and how it’s absorbed, what impacts it, what labs that you check, and not relying just on one serum vitamin B-12 level as your way to make a decision. So let’s dig into the genetics and the gut microbiome connection so that you can fully make informed decisions. So what is vitamin B-12 and why do we need it? We know that the human body does not produce vitamin B-12, so we have to get it extrinsically. We have to get it from outside sources. And this is where animal products are so important for this to occur because you cannot get vitamin B-12 from plants. So this is where having a balanced diet, and I would say in my experience to keep life simple, it is better to add in animal protein in some way, shape or form.

You will need to supplement with some additional vitamin B-12

(02:37):

And that may mean that yes, you’re a vegetarian, but maybe you include some dairy products or maybe you include some eggs, whatever you feel comfortable with. Vegans, I would say the job is hard and you have to supplement. It’s unlikely going to work out well. I would guess you could think about the genetics and the gut microbiome really influencing that. But in most, I would say the majority of cases, if you are following a vegan diet, you will need to supplement with some additional vitamin B-12. Otherwise a vegetarian may or may not. Someone who actually consumes animal products regularly may or may not after bariatric surgery. It is typically for most people a must to take some vitamin B-12 supplementation. I do find occasionally that there are gaps in this, but I would say for the most part, most all of my bariatric patients truly do need a vitamin B-12 supplementation, and I’ll get into that in a minute.

What is vitamin B12, and why do we need it?

(03:58):

So we know that your body cannot produce vitamin B-12. It has to come from exogenous sources from your diet, and some people may require more or less vitamin B-12 depending on their age, their health status, lifestyle, genetic makeup, medications. There’s a variety of things that can really influence how well you absorb, utilize and transport vitamin B-12. So vitamin B-12 plays a significant role in a lot of biochemical reactions. One important one which impacts your cardiometabolic health is homocysteine and it influences homocysteine metabolism, and homocysteine is just an amino acid, but when this level is elevated, it can damage your blood vessels if it is left at high levels for periods of time. Now vitamin B-12 helps convert homocysteine to methionine. It’s a component of protein synthesis and cellular function. It also plays a role in red blood cell production, D N a synthesis and nerve function.

How do genetic variations affect vitamin B12 levels?

(05:15):

All of that is dependent upon your vitamin B-12 level. So that is super important and really can impact your health positively or negatively. How do genetic variations affect vitamin B-12 levels? Let’s dig into these genes and there are six genes that I’m going to talk about and they all play a role in how your body transports utilizes metabolizes vitamin B-12. So if you have any of these genetic variations or a combination of these. So it could be that you have multiple. You could have all six of these genetic variations. You could have half of them. So the weighting of the impact is dependent on that. So if you have a very high impact gene of one of these genetic SNPs, then the likelihood of you struggling with your vitamin B-12 level regardless of your diet, including animal protein, and regardless of taking vitamin B-12 supplementation, all of that can play a significant role in your actual B-12 level.

FUT2: 

(06:38):

So the first one is the FUT2, F-U-T-two FUT2 encodes an enzyme that adds sugar molecules to intestinal cells. And this sugar molecule acts as a receptor for intrinsic factor which binds vitamin B-12 and facilitates its absorption in the small intestines. And we talked about that last week. Intrinsic factor is a protein in the lower portion of your stomach that gets stapled off or removed with bariatric surgery. So it gets stapled off with the roid gastric bypass and it gets removed with the gastric sleeve. So either one of those is going to cause problems with intrinsic factor. That’s why for one bariatric surgery truly does influence the whole picture of B-12 and this is part of that picture. So now you throw on not only maybe does a patient have bariatric surgery that they also have this genetic SNP, this influences intrinsic factor which then impacts their vitamin B-12 level.

Variant FUT2

(07:55):

So those with the variant FUT2 are called non-secretors as their intestinal cells don’t secrete sugar molecules and non-secretors have lower intrinsic factor and vitamin B-12 absorption levels than actual secrets. Non-secretors have lower intrinsic factor and vitamin B-12 absorption levels than secretors who have normal enzyme activity. And a study found that non-secretors had 25% lower serum vitamin B-12 than the secretor. Now the second one is TCN2, and this is the transcobalamin II. And we did lightly talk about this a couple weeks ago when we were digging into vitamin B-12 after bariatric surgery and this protein transports vitamin B-12 from the intestine into the bloodstream and delivers it to the cells. So this piece is pretty important and people who have variants in this TCN2 that reduce the amount or function of the transcobalamin II have lower levels of circulating vitamin B-12.

TCN2: 

(09:13):

Then people with normal TCN2 in one study, people with the TCN2 variant had 31% lower serum vitamin B-12 levels. So having this genetic SNP sets you up for lower vitamin B-12 levels regardless of bariatric surgery. But it would be interesting to see a study with bariatric patients who have this genetic SNP to see if that percentage rises. The next one is MTHFR, and this one is very well known and a lot of people have this genetic ssn. So this gene encodes an enzyme which converts folate to its active form and the active form converts homocysteine to methionine, which requires vitamin B-12 as a co-factor. A person with the variant of the MTHFR will have a higher level of homocysteine and a lower level of the active form. And this can impair the methylation cycle and affect the availability of vitamin B-12 for other metabolic pathways.

MTHFR:

(10:25):

And if you recall, if you’ve listened to any of my other podcasts, I talk about methylation being the safety. So your genes load the gun methylation is the safety that gets released, and then your diet and lifestyle or your epigenetics are what pull the trigger. According to one study, people with the MTHFR variant had 16% lower serum vitamin B-12 levels than those without the variant. The next one is MTR this gene encodes an enzyme known as methionine synthase, MTR, which converts homocysteine to methionine by using the active form of the 5-MTF and vitamin B-12. So those with this MTR variant that reduce the enzyme activity have higher homocysteine levels and lower methionine levels than those with normal MTR. And this can also affect the methylation cycle in the demand for vitamin B-12. So that means your needs of vitamin B-12 may go up.

MTR

(11:40):

One study found that people with MTR variant had 14% lower serum vitamin B-12 levels than people without the variant. However, in another study, the MTR variant was not associated with serum levels of vitamin B-12. So there’s a lot to still learn about how MTR variants affect vitamin B-12 levels. The next one is MTRR, and this gene encodes methionine syntase reductase MTRR. An enzyme responsible for restoring vitamin B-12’s active form in MTR. And a person with a variant of that reduces enzyme activity has lower levels of MTR activity and higher levels of homocysteine than the individual with a normal MTRR. As a result, vitamin B-12 may become more necessary as the methylation cycle is impaired. So one study found that people with an MTRR variant had 18% lower serum vitamin B-12 levels than people without the variant. And then the last one is NBPF3, and this gene encodes neuroblastoma breakpoint family member three. And it is a DNA repair and chromatin remodeling component.

NBPF3

(13:10):

And a person with the NBPF3 variant that increases the gene’s expression has higher levels of the DNA damage and lower levels of vitamin B-12. Than someone who doesn’t have this genetic snp. And as a result, the genome stability and integrity of the cell’s functionality may be affected. So it’s important to understand that it’s not just take a vitamin B-12 supplement because if you have some of these genetic SNPs or a combination of these, your ability to utilize what’s available is impacted. And it doesn’t mean that all forms are going to work equally, we do find that the individuals that have these genetic SNPs typically do need more of the methylated forms of vitamin B-12 or of the B vitamins. So it even includes like B-6 and folate. So it’s not just B-12, you need the methyl forms of these.

How does the gut microbiome affect vitamin B12 levels?

(14:30):

And when it comes to B-12 in general, there are different forms of vitamin B-12, most over the counter vitamin B twelves that you purchase, whether it be a sublingual or liquid or a tablet or even the pills, which I don’t recommend for bariatric patients because you’re not going to absorb those well at all. Whereas the sublingual forms where you put it underneath your tongue, whether it’s a dissolvable tablet or if it’s a liquid dropper that you just put a few drops under and it dissolves underneath your tongue and gets right into the bloodstream, those are great ways as well. You’re kind of bypassing the gut and I’m not opposed to those, but some people need the methylated forms, so they need to find instead of the cyanocobalamin, you need the methylcobalamin. There’s also adenalsylcobalamine and hydroxycobalamin. So there’s different forms and having these genetic SNPs can really influence which type of B-12 or cobalamin that you actually will absorb better.

Tri Cobalamin

(15:44):

And sometimes I use a blend, it’s called Tricobalamin that I utilize their product and it is just a mix of all of those methylated forms and we find that some people that have different other genetic SNPs, they maybe need, they over methylate and they have high levels. So we need to address that as well and look at the whole picture on how your body is functioning. So that’s why it’s important to really, if you are struggling with your energy, you’re having some anemia issues and you haven’t felt well for a while, this could be part of the puzzle. And really understanding this, having those genetics to really dig into can really make a difference in utilizing the right product and the right timing and the delivery, whether you do a sublingual, whether you do an injection, whether we work on your gut, all of that stuff matters for the outcome.

How does the gut microbiome affect vitamin B12 levels?

(17:04):

Now let’s talk about how does the gut microbiome affect vitamin B-12 levels and several microorganisms can actually produce vitamin B-12 which your body or the bacteria in your body will absorb. So dependent on lots of factors is dependent on what is happening with that. However, there are differences in the amount of vitamin B-12 produced by different gut bacteria. So certain gut bacteria can produce more than others as well as they can produce different forms of vitamin B-12, such as pseudo B-12, which is not biologically active in humans. Now approximately 20% of gut bacteria can produce vitamin B-12 and more than 80% of gut bacteria require vitamin B-12 for metabolic reactions. So you can see how important it is to include vitamin B-12 rich foods in your diet because your gut bacteria need them for jobs that they do.

Factors Affecting Gut Microbiome: Shaping the B12 Landscape

(18:21):

Competition between the gut microbes and your body and the microbes to microbes, so microbes to your body and then microbes to microbes create the risk of vitamin shortage and the intestines if you don’t consume enough by diet, if your diet is lacking in vitamin B-12 rich food, then your gut bacteria are going to utilize whatever they can get from your diet and then potentially leaving you with less available for your body. Now, small intestinal bacteria overgrowth also cause megaloblastic anemia, which results from vitamin B-12 deficiency and binding of vitamin B-12 to bacteria in the upper small intestines can prevent absorption of the vitamin in the ileum. So when you have typically kind of a look on labs, so when you’re trying to figure out if someone has small intestinal bacteria overgrowth, a very common lab look is they’ll have a high RBC folate and a low vitamin B-12. serum vitamin B-12.

A low B-12 is not conclusive of SIBO

(19:39):

Now I would of course be checking the methylmalonic acid, I’d be checking at homocysteine, I would be looking at that full picture because I would want to I guess have more evidence kind of build the case that hey, we might have small intestinal bacterial overgrowth or SIBO present and we might need to do some gut work. So I will say that although it’s not conclusive, having a high RBC folate and a low B-12 is not conclusive of SIBO. A breath test is really your only guaranteed way of knowing. Some of the stool tests can give you insights. The blood tests can give you insights, symptoms can give you insight, food tolerance and intolerance. Certain foods can give you insights and it really depends on the practitioner as to how they approach SIBO. And I’ve worked with multiple GI docs and some of them just don’t have a lot of faith in the breath tests and they will end up treating empirically. I’ve worked with several bariatric surgeons and they kind of approach it the same way.

How vitamin B-12 looks for you in the human body

(21:05):

There are some questions when it comes to the breath test for bariatric patients in the accuracy because transit time is different and you’re looking at time, you’re looking at time on this breath test and it matters to a certain minute level. And once you get past that, then we assume you’re in the colon and we don’t want that information, we just want the information from your small intestines. So you want to interpret it correctly. And so you have to look at the timing. Well, bariatric surgery transit through your small intestines is different than a normal anatomy person. You can’t always derive the same information, but you have to look at it through the lens of, hey, this, you should be getting into your colon faster with this breath test because of bariatric surgery. So those alterations specifically. Especially a Roux-en-y gastric bypass is really one that. You would have to look at the big picture of timing and just really looking at the detail of, hey, is this truly accurate when it comes to the interpretation? So factors affecting your gut microbiome which end up shaping the B-12 landscape. So we know that your gut microbes fuel off of this. We know that certain gut microbes produce vitamin B-12. So what influences how vitamin B-12 looks for you in the human body, your diet, antibiotic probiotics and infections diseases? Of course your genetics can influence your gut microbiome and its composition and these factors can affect how much and what type of vitamin B-12 the gut microbes produce and how available it is for the host.

You might have more constipation

(23:15):

So in my eyes, this is where it’s important to have a healthy gut and making sure that you are addressing any gut imbalances and gut dysbiosis, small intestinal bacteria overgrowth and really truly resolving this to move this out as a problem because ignoring this or just living with the symptoms, although not pleasant, you can still live with them. So you might have more constipation, you might have constipation, diarrhea, you might have a lot of bloating and discomfort after food. Again, the livable things, but it’s what it’s doing on the backside. When I start seeing all of these levels being impacted and how it’s truly impacting your overall health, what is it contributing to on the flip side, what is it doing on the other side that it’s prohibiting you from getting resolution to some of those comorbidities because we’re not dealing with these basic things that are truly driving it.

How does your vegan diet look?

(24:26):

That gut microbiome is really for a lot of people at the root of a lot of their disease and we can’t get resolution until we kind of repair, rebalance and repopulate and just really recondition that whole gut and get it to a better place. So you have to think about vegan diets that exclude animal products can reduce vitamin B-12 intake from outside sources. So being a vegan is something that we really have to pay attention to and how it’s not just impacting your overall B-12 level per se, but it’s also impacting your gut health, your gut microbiome, the positive. I would say one of the positives, if you’re doing a vegan diet correctly, again, how does your vegan diet look? Is it full of quinoa and amaranth and tofu and lots of cruciferous vegetables and lots of fruits and just tons of plants and really getting in a diversity of plant foods, whole new ballgame.

Why it’s important to work with a Registered Dietitian

(25:48):

But if you’re relying on tortilla chips with guacamole and box mac and cheese and vegan chicken nuggets or meatless beyond meat, all of those things, whole different outcome to what’s happening in your body. So that’s why it’s important to work with a Registered Dietitian when it comes to a vegan diet after bariatric surgery because it is complicated and it is something that you have to truly, you have to kind of track and know what you’re doing to see if you’re even hitting your protein goals and to make sure that you are getting all the vitamins and minerals that your body needs. Now another big one is antibiotics, which is not a surprise that antibiotics would kill or inhibit beneficial and harmful bacteria in the gut. So I would say with the exception of xifaxin… Xifaxan is an antibiotic, but it is very unique. It is not a systemic antibiotic where it kills the good and the bad throughout your whole body.

Don’t lose all of the good guys to keep your immune system active and vibrant

(27:06):

It is literally localized to your small intestines. So it’s very unique. So when I talk about antibiotics, I’m talking about the ones that are systemic and they do kill the good and the bad in the gut. And at times sometimes you just have to have antibiotics and that’s just okay and the best thing you can do is just really support your body during that treatment. With taking good probiotics, I like to do a blend where like our ultimate gut restore with our sacchromyces boulardii that has beneficial yeast plus 50 billion CFUs and a good mix of different lactobacillus and bifidobacterium strains and species that can truly help support. So you don’t lose all of the good guys to keep your immune system active and vibrant. And then not only do you think about just taking probiotics, then you’ve really got to fuel it with the prebiotics. And I really like to use food in this case, and you could even just blend some up in a smoothie and really taking those prebiotic foods to a new level.

Could you take a probiotic to help increase your vitamin B-12?

(28:22):

Of course you can buy powdered prebiotics, but again, food first one, it’s going to be way cheaper. And two, it is providing you with nutrients that that isolated nutrient of a prebiotic is not. So that’s the difference. That’s why it’s food first is really going to provide you the best outcome, but I’m also real and realize that sometimes it’s overwhelming and it’s just too much and sometimes you just need a prebiotic powder to throw in your protein shake and you don’t have to think about it and there’s nothing wrong with that. I just try to encourage you and teach you how to do it with food so that you get the best outcomes and you feel the best when it’s over. Now you may be thinking, could you take a probiotic to help increase your vitamin B-12? So one study found that a daily probiotic treatment of lactobacillus performed a beneficial effect on both bacterial overgrowth and vitamin B-12 absorption, suggesting that the probiotic treatment might improve the vitamin B-12 deficiency via inhibiting the vitamin B-12 consuming bacteria overgrowth.

Bacteria that is overgrown in your small intestines are consumers of vitamin B-12.

(29:48):

So what that is saying is the bacteria that is overgrown in your small intestines are consumers of vitamin B-12. They gobble up all of the B-12 so that your body does not have any to utilize creating a vitamin B-12 deficiency. And what they’re saying is taking a probiotic that has lactobacillus species in it can help prevent an overgrowth of bacteria in your small intestines. So you’re stopping it before it occurs is really what it’s coming down to. And in all of the studies that I shouldn’t say all of the studies, but in a lot of studies that I reviewed on bariatric surgery and bacterial overgrowth a lot found that taking a probiotic can prohibit this from occurring. So taking probiotics can help prevent SIBO from becoming a problem. So I think to me, I would say that is one thing that I really encourage people to be consistent with.

Probiotic beginning on day one of preop their pre-op consultation.

(31:07):

Taking a probiotic, we would always have our patients take a probiotic beginning on day one of preop their pre-op consultation. So they come in for the very first time and meet the surgeon, meet the staff, get introduced to everyone, and as well as get to hear and talk to the surgeon and learn more about the different surgeries and what that surgeon does. And at that first visit is when we send them home with, okay, it’s time to start taking vitamins and probiotics was one of them and we wanted them during those beginning phases because some insurance companies required three months or six months worth of dietitian, doctor visits, and sometimes you do psych evals and they need some additional time or they have some additional work to do. We want them working on their gut and we want to optimize all those vitamin levels prior to them going into bariatric surgery.

Short chain fatty acid production and it’s a positive that taking cobalamine

(32:13):

So we set them up for success. So if you have not had bariatric surgery yet. I would strongly encourage you to start taking a probiotic. So that you can prohibit that overgrowth of bacteria in your small intestines. Which is not where the bacteria should be growing. Another study suggested that an addition of the or B-12 increases the generation of short chain fatty acids. Especially butyrate and proprionic acid. And I talk about short chain fatty acids all the time. How it’s truly beneficial to the integrity of your gut lining helps build that mucus layer which is your protection. And helping prevent intestinal permeability issues. Autoimmunity. So there’s a lot of benefit for having a short chain fatty acid production and. It’s a positive that taking cobalamine, especially in food form is a great way to optimize your gut health. Now I also want to just throw in here a few other factors that can influence your vitamin B-12 levels we talked about even last week or two weeks ago, I should say age, the amount of stomach acid and intrinsic factor decreases with age.

Age: 

(33:44):

And this is necessary for your body to break down the food and cleve off the vitamin B-12 from the food. And when that doesn’t occur because there isn’t enough stomach acid, then you’re missing that. So you’re putting in the effort and you’re not getting the benefit from it. Age also plays a role in that intrinsic factor production and the transcobalamin II. Which is what transports it to your cells through your bloodstream and into your organs and all that. It’s the transporter. And then also you got to think about medications, chronic disease, all of those may influence it as well. Then sunlight exposure, skin synthesizes vitamin D. And so we get sunshine on our skin and our body synthesizes vitamin D. Which is additionally important for your bone and immune health. But vitamin D also regulates the expression of genes related to vitamin B-12.

Sunlight exposure

(34:54):

Metabolism. Such as the TCN2 and the MTHFR low vitamin D levels may impair these genes function. And affect vitamin B-12 status. So it’s kind of all of these vitamins and minerals work synergistically and. They work off of each other and they impact the total outcome of the whole picture of what you’re experiencing. So they’ve even done some studies on osteoporosis and the connection with vitamin B-12. They have yet to have a full understanding if the B vitamin family really plays a role in developing osteoporosis. But they do show that it can influence it in small ways. So making sure that you understand your genetics. But do the basics, get some sun, 15 minutes, no sunscreen at noon is your optimal time for getting vitamin D and. You have to expose your arms and your preferably your arms and your legs, your face, all of that.

Smoking

(36:15):

Personally, I’m going to wear sunscreen on my face and neck and I’m going to expose my arms and legs. So guess what? Winter months I’m not really getting vitamin D from the sun. Yes, I’m a snow skier and yes. I am out and about, but I am wearing sunscreen. So I’m not getting a great amount when I’m skiing. I do take a vitamin D supplement vitamin D three, and that is important to consider. If that influences your ability to maintain a stable B-12. I would make sure that you check your vitamin D level as well so that you know for sure if you are optimal on your level. The next one is smoking. So smoking increases oxidative stress and inflammation damaging the cells and tissues that regulate vitamin B-12. It also reduces vitamin B-12 absorption from food and increases it excretion in urine.

Physical activity

(37:18):

Studies have shown smokers may require more vitamin B-12 than non-smokers and maintain just to maintain adequate levels. And then physical activity can influence vitamin B-12 levels by influencing homocysteine clearance. And a high level of homocysteine can cause cardiovascular problems like we’ve discussed. But vitamin B-12 is necessary to convert homocysteine into methionine, which is essential for cellular function and protein synthesis. Moderate physical exercise increases blood flow and oxygen delivery to the tissues which can lower your homocysteine level. However, excessive physical activity can increase homocysteine through muscle breakdown and tissue damage. So people who exercise regularly must balance their vitamin B-12 intake with their physical activity level. And again, it’s just really paying attention. Attention to your lab work and making sure that all of these things are in check. So that homocysteine level, although again. Your bariatric team may not love checking that asking your primary care provider. Or whoever you see for normal blood work on an annual basis. Asking them to check this homocysteine level is a really good thing.

Are you using weights a lot?

(38:51):

And that again, it’s just giving you insight. Your bariatric team should already be checking your serum B-12 and a methylmalonic acid or the MMA. And that will give them the full picture of. Hey, is my B-12 actually normal? And that will help you make decisions paired with your movement and understanding. Are you training for things? you doing a marathon or a bunch of five Ks? Are you using weights a lot? What is occurring and what is driving that homocysteine level up out inappropriate ranges? So let’s wrap this up. So vitamin B-12, as you can see, really is complicated. And it has a complex deepness to it when it comes to genetics. And your gut microbiome that can truly influence the outcome of what you see on your blood work. So is it your gut that’s driving it? Are the gut microbes causing this elevation?

Vitamin B-12 pill and check your serum B-12.

(40:02):

Are the gut microbes causing a deficiency? Is it you have a genetic SNP that is really influencing your ability to utilize the B-12 that you get? All of that matters. So it’s more than just take a vitamin B-12 pill and check your serum B-12. It is more than that because it truly does impact other vitamins and minerals and. Truly does impact disease state your cardiovascular health, your immune health methylation that turns genes on and turns genes off. All of that determines your health outcomes. So I hope this has made a little dent in your understanding of the importance of vitamin B-12. And getting it from your food, taking a supplement in most cases, but then considering. Hey, let me work on improving my gut. Let’s recondition your gut, let’s get it healthier so that you can utilize. You’re already doing the things you need to do to optimize and have a good level. It’s just your gut isn’t capable of taking that

Conclusion

(41:33):

And turning it into adequate B-12 for your body. So hopefully this has given you that insight and maybe some additional questions to have with your primary care team. Or your bariatric team so that you really can get the outcomes that you desire. Because we know that vitamin B-12 truly does impact how well you feel physically and mentally. So don’t discount something so simple as vitamin B-12. You guys have a great week and we will see you next time. Bye-bye.

Listen, Learn, Enjoy…

1. 1. Surendran, S., Adaikalakoteswari, A., Saravanan, P., Shatwaan, I. A., Lovegrove, J. A., & Vimaleswaran, K. S. (2018). An update on vitamin B12-related gene polymorphisms and B12 status. Genes & nutrition, 13(1), 1-35.
   2. Zhang, T. P., Li, R., Wang, L. J., Tang, F., & Li, H. M. (2022). Clinical relevance of vitamin B12 level and vitamin B12 metabolic gene variation in pulmonary tuberculosis. Frontiers in Immunology, 13, 947897.
   3. Weisberg, I. S., Jacques, P. F., Selhub, J., Bostom, A. G., Chen, Z., Ellison, R. C., … & Rozen, R. (2001). The 1298A→ C polymorphism in methylenetetrahydrofolate reductase (MTHFR): in vitro expression and association with homocysteine. Atherosclerosis, 156(2), 409-415.
   4. Raigani, M., Lakpour, N., Soleimani, M., Johari, B., & Sadeghi, M. R. (2021). Association of MTHFR C677T and MTRR A66G gene polymorphisms with Iranian male infertility and its effect on seminal folate and vitamin B12. International Journal of Fertility & Sterility, 15(1), 20.
   5. Tungtrongchitr, R., Pongpaew, P., Soonthornruengyot, M., Viroonudomphol, D., Vudhivai, N., Tungtrongchitr, A., … & Schelp, F. P. (2003). Relationship of tobacco smoking with serum vitamin B12, folic acid and haematological indices in healthy adults. Public health nutrition, 6(7), 675-681.
   6. https://www.nature.com/articles/s41467-018-07412-6#:~:text=Abstract,de%20novo%20aerobic%20biosynthetic%20pathway.
   7. https://journals.asm.org/doi/10.1128/msystems.00313-21#:~:text=In%20humans%2C%20there%20are%20several,Bacteroides%20is%20associated%20with%20the
   8. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9792504/#:~:text=For%20instance%2C%20daily%20probiotic%20treatment,overgrowth%20(207%2C%20208).
   9. https://www.funmeddev.com/img/fichier_55aa91310382c1d1aaccd11e7cb18c14.pdf
   10. https://www.frontiersin.org/articles/10.3389/fnut.2020.00083/full
   11. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5282855/#:~:text=Large%20scale%20industrial%20production%20of,or%20Sinorhizobium%20meliloti%20%5B7%5D.
   12. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9227236/
   13. https://microbiomejournal.biomedcentral.com/articles/10.1186/s40168-023-01461-w
   14. https://journals.iupui.edu/index.php/IMPRS/article/view/22706