Smart Supplementation Series

Cobalamin (Vitamin B12)

Gut Microbiome – Human Health Connectivity

 

What is Cobalamin (Vitamin B12)

Vitamin B12, also known as “Cobalamin,” is the largest and structurally the most complex water soluble vitamin that is essential for human health.  Although it is required in smaller quantities compared to other vitamins, it play a critical role in several major biological processes to maintain optimal health.

 

What are the sources of Cobalamin (Vitamin B12)

Cobalamin is unique in that it cannot be synthesized by plants or animals.  It is exclusively produced by certain micro-organisms.  It is one of the eight B-vitamins that we obtain from dietary sources; mainly animal derived foods (meat, fish, seafood, dairy products, eggs and/or fortified food); hence potential for deficiency in individuals who follow vegetarian or vegan diets.

The gut microbiome is a critical source of Vitmain B12. Importantly, the bacteria in the human gut, i.e. the microbiome express complete set of genes required for making sufficient amounts of vitamin b12 for their own use, the excess is available for use by the human body.  In fact, the cobalamin riboswitch (that binds to vitamin b12 to switch genes on or off), is the 2nd most common abundant gene-switch found in the gut bacterial genome influencing gene expression and functions to maintain gut microbiome health.  However, the amount of vitamin b12 produced by the gut microbiome is not sufficient to meet the body daily needs, hence sourcing from food and/or supplements is essential to maintain normal body functions.

 

Function of Vitamin B12 (Cobalamin) in Human Health

The human body needs Vitamin B12 for the following functions:

  • Red blood cell production: Vitamin B12 works along with Vitamin B9 (folate, will be covered in separate blog) to form health new red blood cells.

  • Nervous System: Vitamin B12 contributes to the production of myelin, a sheath or cover that forms a coat around the nerves.  Without B12, there is potential for nerve damage, numbness, tingling and even decline in cognition.

  • DNA Synthesis & Cell Division: Vitamin B12 is critical for DNA synthesis and cell division – processes that are involved in growth, development and tissue repair.

  • Energy Production: Vitamin B12 help convert food into glucose, which eventually gets converted to energy (vitamin b12 deficiency is observed in individuals often experiencing fatigue and/or low energy).

  • Methylation Reactions: Methylation is a process, where a chemical (methyl) group is added to other molecules to influence their function.  For example, addition of methyl group to homocysteine converts it into methionine, an amino acid required for protein synthesis.  However, vitamin b12 deficiency can increase the blood levels of homocysteine, which is a risk factor for heart disease.

Function of Vitamin B12 (Cobalamin) in Gut Microbiome

Most of the vitamin b12 synthesis in the human gut occurs in anaerobic (in the absence of oxygen) bacteria.  Key producers of vitamin b12 in the human gut include Bacteroides, Lactobacillus and Bifidobacterium.  Some of the vitamin b12 produced in the gut is absorbed into the systemic circulation and used by the cells for various purposes (described in the previous section).  A few microbes compete for or modify the available cobalamin for other purposes.

Interestingly, mRNA segments with the ability to sense, recognize and bind to cobalamin constitute the 2nd most abundant riboswitches in the gut bacteria.  As described previously, riboswitches functions as “on/off” switches influencing bacterial gene expression.  Cobalamin riboswitches are located in bacterial genes, act as molecular sensors and provide rapid and precise genetic regulation in bacteria without the need for additional protein machinery.  Cobalamin riboswitches regulate genes involved in Vitamin B12 synthesis, transport and metabolic adaptation.  Given the presence of cobalamin riboswitches across the microbial genome, the ability of Vitamin B12 influencing broad gene expression in bacteria to influence gut health is an area of active investigation.

 

Research supporting Vitamin B12 in Human Health

  • Neurological Function and Cognition

  • Myelin synthesis and protection of the nerve

  • Studies have linked low Vitamin B12 to neurodegenerative diseases including Alzheimer’s Disease and Parkinson’s Disease.

  • The VITACOG trial found that high-dose of B-vitamin supplementation (B12, B6 and folate) reduced brain atrophy rates in individuals with mild cognitive impairments.

    Hematological Health (Red blood cell production & prevention of anemia)

  • Vitamin B12 Is essential for normal red blood formation and function.

  • Clinical research has shown that cobalamin supplementation helps improve hemoglobin levels and corrected anemia in B12 deficient patients.

  • High doses of Vitamin B12  has been shown to be effective in correcting pernicious anemia.

    Cardiovascular Health

  • Higher blood levels of homocysteine is an independent risk factor for cardiovascular disease.

  • Vitamin B12 supplementation is associated with reduced homocysteine levels.

  • Lowering homocysteine levels through Vitamin B12 supplementation reduced stroke risk, specifically in populations with low folate intake.

  • Bone health

  • Low blood levels of Vitamin B12 correlated with higher hip fracture incidences in older adults.

  • Vitamin B12 deficiency associated with reduced bone mineral density and risk of osteoporosis.

 

Vitamin B12 Deficiency (At Risk Population)

  1. Vegetarians and Vegans: Since B12 is naturally found in animal products, those who follow plant-based diets must ensure they obtain B12 from fortified foods or supplements.

  2. Older Adults: Decreased stomach acid production and age-related absorption issues make older adults more susceptible to deficiency.

  3. People with Gastrointestinal Disorders: Conditions like Crohn’s disease, celiac disease, and those who have had gastrointestinal surgeries are at increased risk.

  4. Patients with Type 2 diabetes taking metformin are at increased risk.

  5. Pregnant and Breastfeeding Women: Pregnant and breastfeeding women, especially those on vegetarian or vegan diets, may have increased B12 needs.

 

Vitamin B12 Supplementation

The recommended daily intake of Vitamin B12 depends on age, life stage, and individual health needs. Below are general guidelines:

  • Adults (18 years and older): 2.4 micrograms (mcg) per day

  • Pregnant women: 2.6 mcg per day

  • Breastfeeding women: 2.8 mcg per day

  • Children (1-3 years): 0.9 mcg per day

  • Children (4-8 years): 1.2 mcg per day

  • Children (9-13 years): 1.8 mcg per day

  • Teens (14-18 years): 2.4 mcg per day

For individuals at risk of deficiency (e.g., vegans, older adults, or people with digestive issues), higher doses through supplements may be recommended:

  • For B12 deficiency treatment: Supplements or injections ranging from 500 to 2,000 mcg daily are common, depending on the severity of deficiency.

Since B12 is water-soluble, excess amounts are usually excreted in urine, making high doses in supplements generally safe for most people. However, it's best to consult with a healthcare provider before starting a high-dose supplement, especially if you suspect a deficiency.

Summary

Cobalamin is a vital nutrient for maintaining overall health, particularly in terms of red blood cell formation, nervous system function, DNA synthesis, and energy production. Deficiency in Vitamin B12 can lead to severe and potentially irreversible health consequences. Therefore, it is essential to ensure adequate intake through diet, fortified foods, or supplements, especially for those at risk of deficiency. Regular monitoring and early intervention can prevent complications and support long-term health.

Cobalamin represents a remarkable example of how a single micronutrient can profoundly impact human health. The story of cobalamin reveals a complex molecular narrative involving intricate interactions between microorganisms, genetic regulatory mechanisms, and host physiology. Riboswitches and the microbiome demonstrate nature's elegant solution to metabolic regulation. Its wide-ranging functions underscore the importance of maintaining adequate vitamin B12 levels through diet, supplementation, and regular health monitoring. By understanding cobalamin's critical role, individuals can make informed choices to support their overall health and well-being.

References

1. Neurological Function and Cognitive Health

  1. Smith AD, Refsum H. Homocysteine, B Vitamins, and Cognitive Impairment. Annu Rev Nutr. 2016;36:211-239. [DOI: 10.1146/annurev-nutr-071715-050746]

  2. Morris MS. The role of B vitamins in preventing and treating cognitive impairment and decline. Adv Nutr. 2012;3(6):801-812. [DOI: 10.3945/an.112.002535]

  3. Douaud G, Refsum H, de Jager CA, et al. Preventing Alzheimer’s disease-related gray matter atrophy by B-vitamin treatment. Proc Natl Acad Sci USA. 2013;110(23):9523-9528. [DOI: 10.1073/pnas.1301816110]

  4. Clarke R, Bennett DA, Parish S, et al. Homocysteine and dementia: an international meta-analysis. Am J Clin Nutr. 2015;103(4):1042-1054. [DOI: 10.3945/ajcn.115.110940]

  5. Tucker KL, Qiao N, Scott TM, Rosenberg I. High homocysteine and low B vitamins predict cognitive decline in aging men: the Veterans Affairs Normative Aging Study. Am J Clin Nutr. 2005;82(3):627-635. [DOI: 10.1093/ajcn/82.3.627]

  6. Syed EU, Wasay M, Awan S. Vitamin B12 supplementation in treating major depressive disorder: a randomized controlled trial. J Psychiatr Res. 2013;47(3):299-302. [DOI: 10.1016/j.jpsychires.2012.10.013]

2. Hematological Health (Anemia Prevention and Treatment)

  1. Stabler SP. Vitamin B12 deficiency. N Engl J Med. 2013;368(2):149-160. [DOI: 10.1056/NEJMcp1113996]

  2. Devalia V, Hamilton MS, Molloy AM. Guidelines for the diagnosis and treatment of cobalamin and folate disorders. Br J Haematol. 2014;166(4):496-513. [DOI: 10.1111/bjh.12959]

  3. Wang Y, Sun J, Zhang S, et al. Oral versus intramuscular vitamin B12 for vitamin B12 deficiency: a systematic review and meta-analysis of randomized controlled trials. Cochrane Database Syst Rev. 2018;(3):CD004655. [DOI: 10.1002/14651858.CD004655.pub3]

  4. Dharmarajan TS, Adiga GU, Norkus EP. Vitamin B12 deficiency: recognizing subtle symptoms in older adults. Geriatrics. 2003;58(3):30-34.

3. Cardiovascular Health and Homocysteine Regulation

  1. Homocysteine Studies Collaboration. Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis. JAMA. 2002;288(16):2015-2022. [DOI: 10.1001/jama.288.16.2015]

  2. Martí-Carvajal AJ, Solà I, Lathyris D, Salanti G. Homocysteine-lowering interventions for preventing cardiovascular events. Cochrane Database Syst Rev. 2017;(8):CD006612. [DOI: 10.1002/14651858.CD006612.pub5]

  3. Qin X, Huo Y, Langman CB, et al. Folic acid therapy reduces the first stroke risk associated with hyperhomocysteinemia in hypertensive patients. Lancet. 2015;385(9974):372-382. [DOI: 10.1016/S0140-6736(14)62038-8]

  4. Lonn E, Yusuf S, Arnold MJ, et al. Homocysteine lowering with folic acid and B vitamins in vascular disease. N Engl J Med. 2006;354(15):1567-1577. [DOI: 10.1056/NEJMoa060900]

  5. Bakker SJ, Gansevoort RT, de Zeeuw D, et al. Lowering homocysteine with B vitamins and cardiovascular function: a randomized controlled trial. Circulation. 2006;113(10):1435-1443. [DOI: 10.1161/CIRCULATIONAHA.105.580936]

4. Mitochondrial Function and Energy Metabolism

  1. Regland B, Engqvist B, Andersson M, et al. Increased concentrations of homocysteine in the cerebrospinal fluid in patients with fibromyalgia and chronic fatigue syndrome. Pain Med. 2015;16(3):454-458. [DOI: 10.1111/pme.12579]

  2. Obeid R, Herrmann W. Mechanisms of homocysteine neurotoxicity in neurodegenerative diseases with special reference to dementia. FEBS Lett. 2006;580(13):2994-3005. [DOI: 10.1016/j.febslet.2006.03.087]

  3. Coelho D, Kim JC, Miousse IR, et al. Mutations in ABCD4 cause a new inborn error of vitamin B12 metabolism. Nat Genet. 2012;44(10):1152-1155. [DOI: 10.1038/ng.2379]

5. Bone Health and Osteoporosis Risk

  1. Tucker KL, Hannan MT, Qiao N, et al. Low plasma vitamin B12 is associated with lower BMD: the Framingham Osteoporosis Study. J Bone Miner Res. 2005;20(1):152-158. [DOI: 10.1359/JBMR.041018]

  2. Vaes BL, Lute C, Blom HJ, et al. Vitamin B12 in relation to bone health and osteoporosis. Eur J Clin Nutr. 2013;67(10):1080-1085. [DOI: 10.1038/ejcn.2013.137]

6. Gastrointestinal Health and Microbiome Interactions

  1. Degnan PH, Barry NA, Mok KC, et al. Human gut bacteria use multiple vitamin B12 acquisition strategies. Curr Biol. 2014;24(12):1407-1415. [DOI: 10.1016/j.cub.2014.05.045]

  2. Dashti SG, Hazewinkel MH, Stubbs RS, et al. Altered gut microbiota in patients with vitamin B12 deficiency. Nat Rev Gastroenterol Hepatol. 2022;19(4):245-256. [DOI: 10.1038/s41575-021-00544-1]

  3. Kasper DL, Fauci AS, Hauser SL, Longo DL, Jameson JL, Loscalzo J. Harrison’s Principles of Internal Medicine. 20th ed. McGraw-Hill; 2018. (Chapter on vitamin B12 metabolism and absorption).